StemCell Therapy

Molecular geneticists look at genes and ways to manipulate them for use in areas including medicine or industry. They may discover a treatment for a genetic disease. If molecular genetics sounds appealing to you, read on to learn more.

The primary focus of molecular genetics is the molecular-level study of the function and structure of genes. Molecular geneticists study the evolution and inheritance of genes. They are curious about how genes control the development and function of organisms. Molecular genetics has lead to mapping the human genome to identify disease-related genetic abnormalities, analyzing genetic changes in tumors and developing new procedures and tests. Genes are the focus, but molecular genetics also involves developmental, cellular and molecular biology.

The educational background needed to work in molecular genetics includes coursework in math, physics, chemistry and biology. Students may earn a bachelor's, master's or doctoral degree in molecular genetics. Courses may include developmental and cell biology, molecular genetics, genetic analysis, DNA transactions, human genetics and biochemistry. Dual degree programs combine molecular genetics with other sciences, such as microbiology. A Ph.D. in Molecular Genetics involves students conducting original research and writing a dissertation for faculty review. The following Study.com pages contain more information on programs, courses and degrees.

Nowadays, science courses are widely available online. View these Study.com pages for more information about online and hybrid programs for aspiring molecular geneticists.

There are many career options for students pursuing a degree in molecular genetics. The list below contains only a few examples, so be sure to visit other Study.com pages for more information.

Molecular genetics offers varied career opportunities with excellent potential for growth and salaries. The U.S. Bureau of Labor Statistics (BLS) expected job prospects for medical scientists in the decade 2012-2022 to grow by 13% (www.bls.gov). Employment for laboratory technicians was expected to grow by 30% in the same period. The BLS reported that, as of May 2012, the median annual wage for medical and clinical laboratory technicians was $37,240; biological science professors, $74,180; and medical scientists, $76,980. Payscale.com reported in March 2014 that most geneticists made a salary of between $30,000 and $132,839 annually.

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Molecular Genetics - Study.com

2007228 5-Fluorouracil (5-FU) Toxicity and Chemotherapeutic Response, 5 Mutations 5-Fluorouracil Sensitivity 5-FU, 5-Fluorouracil Toxicity and Chemotherapeutic Response Panel, Pharmacogenetics (PGx), Colorectal Cancer 2012166 Dihydropyrimidine Dehydrogenase (DPYD) Genotyping, 3 Mutations 5-Fluorouracil Sensitivity DYPD 5-Fluorouracil toxicity5-FU toxicity5-FU toxicity5FU toxicityAdrucil (DPYD) Genotyping, 3 MutationsXeloda (capecitabine) (DPYD) Genotyping, 3 Mutations DPDUftoral (tegafur/uracil) (DPYD) Genotyping, 3 Mutations 0051266 Achondroplasia (FGFR3) 2 Mutations Achondroplasia AD PCR, Skeletal Dysplasias, Neuroblastoma 0051265 Achondroplasia Mutation, Fetal Achondroplasia AD PCR FE, Skeletal Dysplasias 2011708 Alpha Globin (HBA1 and HBA2) Sequencing and Deletion/Duplication Alpha Thalassemia AG FGA, 2011622 Alpha Globin (HBA1 and HBA2) Deletion/Duplication Alpha Thalassemia HBA DD, Alpha thalassemia, alpha globin mutations, alpha globin gene analysis, A globin 0051495 Alpha Thalassemia (HBA1 & HBA2) 7 Deletions Alpha Thalassemia ALPHA THAL, Hemoglobinopathies 2002398 Alport Syndrome, X-linked (COL4A5) Sequencing and Deletion/Duplication Alport Syndrome ALPORT FGARenal disease, chronic kidney disease, hematuria 0051786 Alport Syndrome, X-linked (COL4A5) Sequencing Alport Syndrome ALPORT FGSRenal disease, chronic kidney disease, hematuria 2013341 Apolipoprotein E (APOE) Genotyping, Alzheimer Disease Risk Alzheimer's Disease APOE AZ 2005077 Angelman Syndrome and Prader-Willi Syndrome by Methylation Angelman Syndrome AS PWS, Angelman, Prader-Willi, Neurocognitive Impairments 2005564 Angelman Syndrome (UBE3A) Sequencing Angelman Syndrome UBE3A FGS 2012232 Angelman Syndrome and Prader-Willi Syndrome by Methylation, Fetal Angelman Syndrome AS PWS FE Prader-Labhart-Willi Syndrome, AS, PWS 2006540 Aortopathy Panel, Sequencing and Deletion/Duplication, 21 Genes Aortopathies AORT PANEL, Thoracic aortic aneurysms, dissections, familial thoracic TAAD AAT, ACTA2 (AAT6), FBN1, MYH11 (AAT4), MYLK (AAT7), SMAD3, TGFBR1 (AAT5), TGFBR2 (AAT3), SLC2A10, FBN2, COL3A1ACTA2, CBS, COL3A1, COL5A1, COL5A2, FBN1, FBN2, MYH11, MYLK, PLOD1, SKI, SLC2A10, SMAD3, SMAD4, TGFB2, TGFBR1, TGFBR2 2005584 Marfan Syndrome (FBN1) Sequencing and Deletion/Duplication Aortopathies FBN1 FGA 2005589 Marfan Syndrome (FBN1) Sequencing Aortopathies FBN1 FGS 2002705 TGFBR1 & TGFBR2 Sequencing Aortopathies LDS FGS, Loeys-Dietz, aortic aneurysm see Loeys-Dietz Syndrome Aortopathies see Marfan Syndrome and FBN1-Related Disorders Aortopathies 0055654 Apolipoprotein B Mutation Detection (G9775A, C9774T) Apolipoprotein B (APOB) APO B, Risk Markers - CVD (Non-traditional) 2013341 Apolipoprotein E (APOE) Genotyping, Alzheimer Disease Risk Apolipoprotein E (APOE) APOE AZ 2013337 Apolipoprotein E (APOE) Genotyping, Cardiovascular Risk Apolipoprotein E (APOE) APOE CR 0051415 Ashkenazi Jewish Diseases, 16 Genes Ashkenazi Jewish Panel (16 disorders) AJP, Jewish Genetic, Fanconi's, Fanconis,ABCC8, TMEM216, NEB, G6PC, DLD, BCKDHB, CLRN1, PCDH15 2013725 ABCC8-Related Hyperinsulinism, 3 Variants Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 2013745 NEB-Related Nemaline Myopathy, 1 Variant Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 0051433 Bloom Syndrome (BLM),1 Variant Ashkenazi Jewish Panel (16 disorders) BLM, Jewish Genetic 0051453 Canavan Disease (ASPA), 4 Variants Ashkenazi Jewish Panel (16 disorders) ASPA, Jewish Genetic 0051463 Dysautonomia, Familial (IKBKAP), 2 Variants Ashkenazi Jewish Panel (16 disorders) IKBKAP, Jewish Genetic Disease 0051468 Fanconi Anemia Group C, (FANCC), 2 Variants Ashkenazi Jewish Panel (16 disorders) FANCC, Jewish, Ashkenazi, Fanconi's, Fanconis, carrier testing, DNA 0051438 Gaucher Disease (GBA), 8 Variants Ashkenazi Jewish Panel (16 disorders) GBA, Jewish Genetic, Glucocerebrosidase, Glucosylceramidase 2013740 Glycogen Storage Disease, Type 1A (G6PC), 9 Variants Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 2013909 Joubert Syndrome Type 2 (TMEM216), 1 Variant Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 2013735 Lipoamide Dehydrogenase Deficiency (DLD), 2 Variants Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 2013730 Maple Syrup Urine Disease, Type 1B (BCKDHB), 3 Variants Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 0051448 Mucolipidosis Type IV (MCOLN1), 2 Variants Ashkenazi Jewish Panel (16 disorders) MCOLN1, Jewish Genetic, lysosomal 0051458 Niemann-Pick, Type A (SMPD1), 4 Variants Ashkenazi Jewish Panel (16 disorders) SMPD1, Jewish Genetic, acid sphingomyelinase, ASM, NP-A, lysosomal storage, L302P, 1bp del fsP330, R496L, R608del 0051428 Tay-Sachs Disease (HEXA), 7 Variants Ashkenazi Jewish Panel (16 disorders) HEXA, Jewish Genetic, Hex A, GM2 gangliosidosis, hexosaminidase, lysosomal storage, delta 7.6kb, IVS9(+1)G>A, 1278insTATC, IVS12(+1)G>C, G269S, R247W, R249W 2013750 Usher Syndrome, Types 1F and 3 (PCDH15 and CLRN1), 2 Variants Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 2014314 Autism and Intellectual Disability Comprehensive Panel Autism Creatine, epilepsy, amino acids, organic acids, mucopolysaccharidoses (MPS), MPS, acylcarnitine, mental retardation, Fragile X, microarray 0051614 Rett Syndrome (MECP2), Full Gene Analysis Autism RETT FGA, MECP2-related, Rett, atypical Rett, neonatal encephalopathy, PPM-X, neurocognitive impairments 2002470 PTEN-Related Disorders Sequencing and Deletion/Duplication Autism PTEN FGA, PTEN hamartoma tumor, PHTS, Cowden, CS, Bannayan-Riley-Ruvalcaba, BRRS, Proteus, PS, Proteus-like, PSL, macrocephaly, autism 2004935 CDKL5-Related Disorders (CDKL5) Sequencing and Deletion/Duplication Autism CDKL5 FGA, X-linked infantile spasm 2005077 Angelman Syndrome and Prader-Willi Syndrome by Methylation Autism AS PWS, Angelman, Prader-Willi, Neurocognitive Impairments 2005564 Angelman Syndrome (UBE3A) Sequencing Autism UBE3A FGS 2010117 Beta Globin (HBB) Sequencing and Deletion/Duplication Beta Globin BG FGA, Beta thalassemia, beta globin, HBB 0050388 Beta Globin (HBB) Sequencing, Fetal Beta Globin BG SEQ FE 0051422 Beta Globin (HBB) HbS, HbC, and HbE Mutations, Fetal Beta Globin HB SCE FE 0051700 Biotinidase Deficiency (BTD), 5 Mutations Biotinidase Deficiency BTD MUT, Multiple carboxylase 0051730 Biotinidase Deficiency (BTD) Sequencing Additional Technical Information Biotinidase Deficiency BTD FGS, Multiple carboxylase 0051368 Rh Genotyping D Antigen (RhD positive/negative and RhD copy number) Blood Genotyping RHD, Hemolytic Disease of the Newborn, fetal erythroblastosis, isoimmunization, alloimmune hemolytic 0050421 RhCc Antigen (RHCE) Genotyping Blood Genotyping RH C, Hemolytic Disease of the Newborn, fetal rhesus type, alloimmunization, alloantibodies, maternal-fetal Rh incompatibility 0050423 RhEe Antigen (RHCE) Genotyping Blood Genotyping RH E, Hemolytic Disease of the Newborn, fetal rhesus type, alloimmunization, alloantibodies, maternal-fetal Rh incompatibility 0051644 Kell K/k Antigen (KEL) Genotyping Blood Genotyping KEL, Hemolytic Disease of the Newborn, K/k, Kell/Cellano 0051433 Bloom Syndrome (BLM),1 Variant Bloom Syndrome BLM, Jewish Genetic 2012026 Breast and Ovarian Hereditary Cancer Panel, Sequencing and Deletion/Duplication, 20 Genes Breast Cancer BOCAPAN, Breast Cancer, Tumor Markers, FISH, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MEN1, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PTEN, RAD51C, RAD51D, STK11, TP53 2011949 Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and BRCA2) Sequencing and Deletion/Duplication Breast Cancer BRCA FGA, BRACA, HBOC 2011954 Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and BRCA2) Sequencing Breast Cancer BRCA FGS, BRACA, HBOC 2002722 PTEN-Related Disorders Sequencing Breast Cancer PTEN FGS, PTEN hamartoma tumor, PHTS, Cowden, CS, Bannayan-Riley-Ruvalcaba, BRRS, Proteus, PS, Proteus-like, PSL, macrocephaly, autism 2002470 PTEN-Related Disorders Sequencing and Deletion/Duplication Breast Cancer PTEN FGA, PTEN hamartoma tumor, PHTS, Cowden, CS, Bannayan-Riley-Ruvalcaba, BRRS, Proteus, PS, Proteus-like, PSL, macrocephaly, autism 2009313 Li-Fraumeni (TP53) Sequencing and Deletion/Duplication Breast Cancer TP53 FGA, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2009302 Li-Fraumeni (TP53) Sequencing Breast Cancer TP53 FGS, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2008398 Peutz-Jeghers Syndrome (STK11) Sequencing and Deletion/Duplication Breast Cancer STK11, STK11 FGA, hamartomatous polyps, mucocutaneous hypergigmentation 2008394 Peutz-Jeghers Syndrome (STK11) Sequencing Breast Cancer STK11, STK11 FGS, hamartomatous polyps, mucocutaneous hypergigmentation 0051453 Canavan Disease (ASPA), 4 Variants Canavan Disease ASPA, Jewish Genetic 2012032 Cancer Panel, Hereditary, Sequencing and Deletion/Duplication, 47 Genes Cancer, Hereditary CANCERPAN, Lynch syndrome, breast cancer, multiple endocrine neoplasia, melanoma, retinoblastoma, paraganglioma, Li-Fraumeni, familial adenomatous polyposis, Peutz-Jegher, HNPCC, inherited cancer, renal cancer, GI cancer, colorectal cancer, NGS cancer panel 2010183 Cardiomyopathy and Arrhythmia Panel, Sequencing (85 Genes) and Deletion/Duplication (83 Genes) Cardiomyopathy CARDIACPAN, Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM), Arrhythmogenic right vernticular cardiomyopathy (ARVC), Left ventricular noncompaction (LVNC), catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome (BrS), Long QT syndrome (LQTS), Romano-Ward, Short QT syndrome (SQTS), ABCC9, ACTC1, ACTN2, AKAP9, ANK2, ANKRD1, CACNA1C, CACNB2, CASQ2, CAV3, CORIN, COX15, CSRP3, CTF1, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, EYA4, FKRP, FKTN, FXN, GAA, GLA, GPD1L, ILK, JPH2, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNQ1, KLHL3, LAMA4, LAMP2, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYH10, MYL2, MYL3, MYLK2, MYOT, MYOZ2, MYPN, NEXN, OBSCN, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SCO2, SGCA, SGCB, SGCD, SGCG, SLC25A4, SNTA1, SYNE1, TAZ, TCAP, TGFB3, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRPM4, TTN, TTR, VCLABCC9, ACTC1, ACTN2, AKAP9, ANK2, ANKRD1, CACNA1C, CACNB2, CASQ2, CAV3, CORIN, COX15, CSRP3, CTF1, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, EYA4, FKRP, FKTN, FXN, GAA, GLA, GPD1L, ILK, JPH2, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNQ1, KLHL3, LAMA4, LAMP2, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYH10, MYL2, MYL3, MYLK2, MYOT, MYOZ2, MYPN, NEXN, OBSCN, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SCO2, SGCA, SGCB, SGCD, SGCG, SLC25A4, SNTA1, SYNE1, TAZ, TCAP, TGFB3, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRPM4, TTN, TTR, VCL, arrhythmogenic right ventricular cardiomyopathy (ARVC), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), left ventricular noncompaction (LVNC), long QT syndrome (LQTS), Romano-Ward, short QT syndrome (SQTS) 2004203 Carnitine Deficiency, Primary (SLC22A5) Sequencing and Deletion/Duplication Carnitine Deficiency PCD FGA, OCTN2, carnitine uptake 0051682 Carnitine Deficiency, Primary (SLC22A5) Sequencing Carnitine Deficiency PCD FGS, OCTN2, carnitine uptake 0051415 Ashkenazi Jewish Diseases, 16 Genes Carrier Screening Panels AJP, Jewish Genetic, Fanconi's, Fanconis,ABCC8, TMEM216, NEB, G6PC, DLD, BCKDHB, CLRN1, PCDH15 2014674 Expanded Carrier Screen Genotyping Carrier Screening Panels ECS GENO 2014671 Expanded Carrier Screen Genotyping with Fragile X Carrier Screening Panels ECS GEN FX 2014680 Expanded Carrier Screen by Next Generation Sequencing Carrier Screening Panels ECS SEQ 2014677 Expanded Carrier Screen by Next Generation Sequencing with Fragile X Carrier Screening Panels ECS SEQ FX 2004931 CDKL5-Related Disorders (CDKL5) Sequencing Additional Technical Information CDKL5-Related Disorders CDKL5 FGS, X-linked infantile spasm 2004935 CDKL5-Related Disorders (CDKL5) Sequencing and Deletion/Duplication CDKL5-Related Disorders CDKL5 FGA, X-linked infantile spasm 2005018 Celiac Disease (HLA-DQA1*05, HLA-DQB1*02, and HLA-DQB1*03:02) Genotyping Do not use in the initial evaluation for celiac disease. Useful in ruling out celiac disease (CD) (high negative predictive value) in selective clinical situations such as: Equivocal small-bowel histologic finding (Marsh I-II) in seronegative individuals Evaluation of individuals on a gluten-free diet (GFD) in whom no testing for CD was done before GFD Celiac Disease HLA CELIAC 2002965 Von Hippel-Lindau (VHL) Sequencing and Deletion/Duplication Central Nervous System Cancer VHL FGA, Brain Tumors, Pheochromocytoma 2002970 Von Hippel-Lindau (VHL) Sequencing Central Nervous System Cancer VHL FGS, Congenital polycythemia 2012032 Cancer Panel, Hereditary, Sequencing and Deletion/Duplication, 47 Genes Central Nervous System Cancer CANCERPAN, Lynch syndrome, breast cancer, multiple endocrine neoplasia, melanoma, retinoblastoma, paraganglioma, Li-Fraumeni, familial adenomatous polyposis, Peutz-Jegher, HNPCC, inherited cancer, renal cancer, GI cancer, colorectal cancer, NGS cancer panel 2009313 Li-Fraumeni (TP53) Sequencing and Deletion/Duplication Central Nervous System Cancer TP53 FGA, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2009302 Li-Fraumeni (TP53) Sequencing Central Nervous System Cancer TP53 FGS, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2012160 Charcot-Marie-Tooth Type 1A (CMT1A)/Hereditary Neuropathy with Liability to Pressure Palsies (HNPP), PMP22 Deletion/Duplication Charcot-Marie-Tooth Disease CMT DD, AARS, AIFM1, ARHGEF10, ATL1, ATP7A, BAG3, BICD2, BSCL2, CCT5, DCTN1, DHTKD1, DNAJB2, DNM2,DNMT1, DYNC1H1, EGR2, FAM134B, FBLN5, FGD4, FIG4, GAN, GARS, GDAP1, GJB1, GNB4, HARS, HEXA, HINT1, HK1, HOXD10,HSPB1, HSPB3, HSPB8, IGHMBP2, IKBKAP, INF2, KARS, KIF1A, KIF1B, KIF5A, LAS1L, LITAF, LMNA, LRSAM1, MARS, MED25, MFN2,MPZ, MTMR2, MYH14, NDRG1, NEFL, NGF, NTRK1, PDK3, PLEKHG5, PMP22, PRNP, PRPS1, PRX, RAB7A, REEP1, SBF1, SBF2, SCN9A,SETX, SH3TC2, SLC12A6, SLC5A7, SOX10, SPTLC1, SPTLC2, TDP1, TFG, TRIM2, TRPV4, WNK1, YARS 2012155 Charcot-Marie-Tooth (CMT) and Related Hereditary Neuropathies, PMP22 Deletion/Duplication with Reflex to Sequencing Panel Charcot-Marie-Tooth Disease CMT REFLEX,AARS, AIFM1, ARHGEF10, ATL1, ATP7A, BAG3, BICD2, BSCL2, CCT5, DCTN1, DHTKD1, DNAJB2, DNM2,DNMT1, DYNC1H1, EGR2, FAM134B, FBLN5, FGD4, FIG4, GAN, GARS, GDAP1, GJB1, GNB4, HARS, HEXA, HINT1, HK1, HOXD10,HSPB1, HSPB3, HSPB8, IGHMBP2, IKBKAP, INF2, KARS, KIF1A, KIF1B, KIF5A, LAS1L, LITAF, LMNA, LRSAM1, MARS, MED25, MFN2,MPZ, MTMR2, MYH14, NDRG1, NEFL, NGF, NTRK1, PDK3, PLEKHG5, PMP22, PRNP, PRPS1, PRX, RAB7A, REEP1, SBF1, SBF2, SCN9A,SETX, SH3TC2, SLC12A6, SLC5A7, SOX10, SPTLC1, SPTLC2, TDP1, TFG, TRIM2, TRPV4, WNK1, YARS 2012151 Charcot-Marie-Tooth (CMT) and Related Hereditary Neuropathies Panel Sequencing Charcot-Marie-Tooth Disease CMT SEQ, AARS, AIFM1, ARHGEF10, ATL1, ATP7A, BAG3, BICD2, BSCL2, CCT5, DCTN1, DHTKD1, DNAJB2, DNM2,DNMT1, DYNC1H1, EGR2, FAM134B, FBLN5, FGD4, FIG4, GAN, GARS, GDAP1, GJB1, GNB4, HARS, HEXA, HINT1, HK1, HOXD10,HSPB1, HSPB3, HSPB8, IGHMBP2, IKBKAP, INF2, KARS, KIF1A, KIF1B, KIF5A, LAS1L, LITAF, LMNA, LRSAM1, MARS, MED25, MFN2,MPZ, MTMR2, MYH14, NDRG1, NEFL, NGF, NTRK1, PDK3, PLEKHG5, PMP22, PRNP, PRPS1, PRX, RAB7A, REEP1, SBF1, SBF2, SCN9A,SETX, SH3TC2, SLC12A6, SLC5A7, SOX10, SPTLC1, SPTLC2, TDP1, TFG, TRIM2, TRPV4, WNK1, YARS 2012609 CHARGE Syndrome, CHD7 Sequencing CHARGE Syndrome 2012717 CHARGE Syndrome (CHD7) Sequencing, Fetal CHARGE Syndrome 2002065 Chimerism, Recipient Pre-Transplant Chimerism STR-PRE 2002067 Chimerism, Donor Chimerism STR-DONOR 2002064 Chimerism, Post-Transplant, Sorted Cells Chimerism STR-POSTSC 2002066 Chimerism, Post-Transplant Chimerism STR-POST 2006356 Chronic Granulomatous Disease (CYBB Gene Scanning and NCF1 Exon 2 GT Deletion) with Reflex to CYBB Sequencing Chronic Granulomatous Disease CGD PANEL, Cytochrome b-Positive, Type I, NCF1 Deficiency, Niemann-Pick Disease Type A, p47-PHOX, Soluble Oxidase Component II 2006361 Chronic Granulomatous Disease, X-linked (CYBB) Gene Scanning with Reflex to Sequencing Chronic Granulomatous Disease CYBB, Cytochrome b-Positive, Type I, NCF1 Deficiency, Niemann-Pick Disease Type A, p47-PHOX, Soluble Oxidase Component II 2006366 Chronic Granulomatous Disease (NCF1) Exon 2 GT Deletion Chronic Granulomatous Disease NCF1, Cytochrome b-Positive, Type I, NCF1 Deficiency, Niemann-Pick Disease Type A, p47-PHOX, Soluble Oxidase Component II 2006261 Citrin Deficiency (SLC25A13) Sequencing Citrin Deficiency CITRIN FGSCitrin DeficiencyCitrullinemia Type II Failure to Thrive and Dyslipidemia Caused by Citrin Deficiency Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency 2007069 Citrullinemia, Type I (ASS1) Sequencing Citrullinemia, Type I 2011157 Cobalamin/Propionate/Homocysteine Metabolism Related Disorders Panel, Sequencing (25 Genes) and Deletion/Duplication (24 Genes) Cobalamin/Propionate/Homocysteine Metabolism Related Disorders VB12 PANEL, "ABCD4, ACSF3, AMN, CBS, CD320, CUBN, GIF, HCFC1, LMBRD1, MAT1A, MCEE, MMAA, MMAB, MMACHC, MMADHC, MTHFR, MTR, MTRR, MUT, PCCA, PCCB, SUCLA2, SUCLG1, TCN1, TCN2Methylmalonic aciduria and homocystinuria, cblJ typeCombined malonic and methylmalonic aciduriaMegaloblastic anemia-1, Norwegian typeHomocystinuria due to cystathionine beta-synthase deficiencyMethylmalonic aciduria due to transcobalamin receptor defectMegaloblastic anemia-1, Finnish typeIntrinsic factor deficiencyMethylmalonic acidemia and homocysteinemia, cblX type Methylmalonic aciduria and homocystinuria, cblF typeMethionine adenosyltransferase deficiencyMethylmalonyl-CoA epimerase deficiencyMethylmalonic aciduria, cblA typeMethylmalonic aciduria, cblB typeMethylmalonic aciduria and homocystinuria, cblC typeMethylmalonic aciduria and homocystinuria, cblD typeHomocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase activityHomocystinuria-megaloblastic anemia, cblG typeHomocystinuria-megaloblastic anemia, cbl E typeMethylmalonic aciduria due to methylmalonyl-CoA mutase deficiencyPropionic acidemiaMitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria)Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria)Transcobalamin I deficiencyTranscobalamin II deficiency 2013386 Congenital Adrenal Hyperplasia (CAH) (21-Hydroxylase Deficiency) Common Mutations Congenital Adrenal Hyperplasia (CAH) 2006220 Congenital Amegakaryocytic Thrombocytopenia (CAMT) Sequencing Congenital Amegakaryocytic Thrombocytopenia CAMT FGS, GeneDx 2008610 Creatine Transporter Deficiency (SLC6A8) Sequencing and Deletion/Duplication Creatine SLC6A8 FGA, SLC6A8-Related Creatine Transporter Deficiency, SLC6A8 Deficiency 2008615 Creatine Transporter Deficiency (SLC6A8) Sequencing Additional Technical Information Creatine SLC6A8 FGS, SLC6A8-Related Creatine Transporter Deficiency, SLC6A8 Deficiency 0051110 Cystic Fibrosis (CFTR) Sequencing Cystic Fibrosis CF-CFTR, Diagnostic, CF 0051640 Cystic Fibrosis (CFTR) Sequencing with Reflex to Deletion/Duplication Cystic Fibrosis CFTR FGA, Diagnostic, CF 2013661 Cystic Fibrosis (CFTR), 165 Pathogenic Variants Cystic Fibrosis CF VAR 2013662 Cystic Fibrosis (CFTR), 165 Pathogenic Variants, Fetal Cystic Fibrosis CF VAR FE 2013663 Cystic Fibrosis (CFTR), 165 Variants with Reflex to Sequencing Cystic Fibrosis CF VAR SEQ 2013664 Cystic Fibrosis (CFTR), 165 Variants with Reflex to Sequencing and Reflex to Deletion/Duplication Cystic Fibrosis CFVAR COMP 2014547 Cytochrome P450 2D6 (CYP2D6) 15 Variants and Gene Duplication Cytochrome P450 CYP 2D6, Tamoxifen, Pharmacogenetics (PGx), Schizophrenia, Breast Cancer, breast biomarkers 2012769 Cytochrome P450 2C19, CYP2C19 - 9 Variants Cytochrome P450 CYP2C19, Pharmacogenetics (PGx), Schizophrenia, Breast Cancer, breast biomarkers 2012766 Cytochrome P450 2C9, CYP2C9 - 2 Variants Additional Technical Information Cytochrome P450 CYP2C9, Warfarin Sensitivity, Pharmacogenetics (PGx) 2012740 Cytochrome P450 3A5 Genotyping, CYP3A5, 2 Variants Cytochrome P450 2013098 Cytochrome P450 Genotype Panel Cytochrome P450 CYP PAN 2006234 Diamond-Blackfan Anemia (RPL5) Sequencing Diamond-Blackfan Anemia RPL5 FGS, GeneDx 2006236 Diamond-Blackfan Anemia (RPL11) Sequencing Diamond-Blackfan Anemia RPL11 FGS 2006238 Diamond-Blackfan Anemia (RPS19) Sequencing Diamond-Blackfan Anemia RPS19 FGS 2011241 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication with Reflex to Sequencing Duchenne/Becker Muscular Dystrophy DMD REFLEX, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011235 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication Duchenne/Becker Muscular Dystrophy DMD DD, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011153 Duchenne/Becker Muscular Dystrophy (DMD) Sequencing Duchenne/Becker Muscular Dystrophy DMD SEQ, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011231 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication, Fetal Duchenne/Becker Muscular Dystrophy DMD DD FE, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2006244 Dyskeratosis Congenita, Autosomal (TERC) Sequencing Dyskeratosis Congenita TERC FGS, GeneDx 2006228 Dyskeratosis Congenita, X-linked (DKC1) Sequencing Dyskeratosis Congenita DKC1 FGS 2011241 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication with Reflex to Sequencing Dystrophinopathies DMD REFLEX, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011235 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication Dystrophinopathies DMD DD, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011153 Duchenne/Becker Muscular Dystrophy (DMD) Sequencing Dystrophinopathies DMD SEQ, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011231 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication, Fetal Dystrophinopathies DMD DD FE, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 0080351 Ehlers-Danlos Syndrome Type VI Screen, Urine Ehlers-Danlos Syndrome Type VI (Kyphoscoliotic Form) EDS6Ehlers-Danlos Syndrome, Kyphoscoliotic FormEDS Kyphoscoliotic FormEDS Type VIEDS VIEhlers-Danlos Syndrome Type VILysyl-Hydroxylase DeficiencyEhlers-Danlos Syndrome Type VIANevo SyndromePLOD1Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1EDSVIEDS6EDS 6 2005559 Ehlers-Danlos Syndrome Kyphoscoliotic Form, Type VI (PLOD1) Sequencing and Deletion/Duplication Ehlers-Danlos Syndrome Type VI (Kyphoscoliotic Form) EDS-VI FGA 2005360 Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing and Deletion/Duplication Endocrine Cancer MEN1 FGA, Multiple endocrine adenomatosis, Wermer syndrome, Multiple Endocrine Neoplasias (MEN) 2005359 Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing Endocrine Cancer MEN1 FGS, Multiple endocrine adenomatosis, Wermer syndrome, Multiple Endocrine Neoplasias (MEN) 0051390 Multiple Endocrine Neoplasia Type 2 (MEN2), RET Gene Mutations by Sequencing Endocrine Cancer MEN2 SEQ, Thyroid Cancer, Pheochromocytoma, Multiple Endocrine Neoplasias (MEN), MEN 2A, MEN 2B, familial medullary thyroid carcinoma, FMTC, RET proto-oncogene 2002965 Von Hippel-Lindau (VHL) Sequencing and Deletion/Duplication Endocrine Cancer VHL FGA, Brain Tumors, Pheochromocytoma 2002970 Von Hippel-Lindau (VHL) Sequencing Endocrine Cancer VHL FGS, Congenital polycythemia 2007167 Hereditary Paraganglioma-Pheochromocytoma (SDHB, SDHC, and SDHD) Sequencing and Deletion/Duplication Panel Endocrine Cancer 2012032 Cancer Panel, Hereditary, Sequencing and Deletion/Duplication, 47 Genes Endocrine Cancer CANCERPAN, Lynch syndrome, breast cancer, multiple endocrine neoplasia, melanoma, retinoblastoma, paraganglioma, Li-Fraumeni, familial adenomatous polyposis, Peutz-Jegher, HNPCC, inherited cancer, renal cancer, GI cancer, colorectal cancer, NGS cancer panel 2006948 SDHB with Interpretation by Immunohistochemistry Endocrine Cancer 2007108 Hereditary Paraganglioma-Pheochromocytoma (SDHB) Sequencing and Deletion/Duplication Additional Technical Information Endocrine Cancer 2007117 Hereditary Paraganglioma-Pheochromocytoma (SDHC) Sequencing and Deletion/Duplication Additional Technical Information Endocrine Cancer 2002722 PTEN-Related Disorders Sequencing Endocrine Cancer PTEN FGS, PTEN hamartoma tumor, PHTS, Cowden, CS, Bannayan-Riley-Ruvalcaba, BRRS, Proteus, PS, Proteus-like, PSL, macrocephaly, autism 2007122 Hereditary Paraganglioma-Pheochromocytoma (SDHD) Sequencing and Deletion/Duplication Additional Technical Information Endocrine Cancer 2002470 PTEN-Related Disorders Sequencing and Deletion/Duplication Endocrine Cancer PTEN FGA, PTEN hamartoma tumor, PHTS, Cowden, CS, Bannayan-Riley-Ruvalcaba, BRRS, Proteus, PS, Proteus-like, PSL, macrocephaly, autism 2009313 Li-Fraumeni (TP53) Sequencing and Deletion/Duplication Endocrine Cancer TP53 FGA, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2009302 Li-Fraumeni (TP53) Sequencing Endocrine Cancer TP53 FGS, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2007533 Progressive Myoclonic Epilepsy (PME) Panel, Sequence Analysis and Exon-Level Deletion/Duplication Additional Technical Information Epilepsy PROG EPIL, seizures, PME, myoclonus, Lafora, Unverricht-Lundborg, neuronal ceroid lipofuscinoses, NCL, PRICKLE1, EPM2A, EPM2B, NHLRC1, CSTB, PPT1, CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN8, CLN10, TPP1, MFSD8, CTSD, GeneDx 2006069 Febrile Seizures Panel Epilepsy FEBRIL PAN 2007545 Childhood-Onset Epilepsy Panel, Sequencing and Deletion/Duplication Additional Technical Information Epilepsy CHILD EPIL, Early-onset epileptic encephalopathy, SCN1A, Sodium channel protein type 1 alpha, PCDH19, Protocadherin-19, SLC2A1, Solute carrier family 2, facilitated glucose transporter member 1, POLG, DNA polymerase subunit gamma-1, SCN2A, Sodium channel protein type 2 alpha, Generalized epilepsy with febrile seizures plus, GEFS+, SCN1A, Sodium channel protein type 1 alpha, SCN1B, Sodium channel subunit beta-1, GABRG2, Gamma-aminobutyric acid receptor subunit gamma-2, SCN2A, Sodium channel protein type 2 alpha, Juvenile Myoclonic Epilepsy, JME, EFHC1, EF-hand domain-containing protein 1, CACNB4, Voltage-dependent L-type calcium channel subunit beta-4, GABRA1, Gamma-aminobutyric acid receptor subunit alpha-1, Progressive Myoclonic Epilepsy, EPM2A, Laforin, NHLRC1, EPM2B, NHL repeat-containing protein 1, malin, CSTB, Cystatin-B, PRICKLE1, Prickle-like protein 1, Autosomal Dominant Focal Epilepsies, CHRNA4, Neuronal acetylcholine receptor alpha-4, CHRNB2, Neuronal acetylcholine receptor beta-2, CHRNA2, Neuronal acetylcholine receptor alpha-2, LGI1, Leucine-rich glioma-inactivated protein 1, atypical Rett syndromes, MECP2, Methyl CpG binding protein 2, CDKL5, Cyclin-dependent kinase-like 5, FOXG1, Forkhead box protein G1, Angelman, Angelman-like, Pitt-Hopkins, UBE3A, Ubiquitin protein ligase E3A, SLC9A6, Sodium/hydrogen exchanger 6, TCF4, Transcription factor 4, NRXN1, Neurexin-1, CNTNAP2, Contactin-associated protein-like 2, Mowat-Wilson, ZEB2, Zinc finger E-box-binding, homeobox 2, Creatine deficiency, GAMT, Guanidinoacetate N-methyltransferase, GATM, Glycine amidinotransferase, mitochondrial, Neuronal Ceroid Lipofuscinoses, NCL, PPT1, CLN1, Palmitoyl-protein thioesterase 1, TPP1, CLN2,Tripeptidyl-peptidase 1, CLN3, Battenin, CLN5, Ceroid-lipofuscinosis neuronal protein 5, CLN6, Ceroid-lipofuscinosis neuronal protein 6, MFSD8, CLN7, Major facilitator superfamily domain-containing protein 8, CLN8, Ceroid-lipofuscinosis neuronal protein 8, CTSD, CLN10, Cathepsin D, Adenosuccinate lyase deficiency, ADSL, Adenylosuccinate lyase, SYN1, Synapsin-1, Microcephaly with early-onset intractable seizures and developmental delay, MCSZ, PNK, Bifunctional polynucleotide, phosphatase/kinase, seizures, GeneDx 2007535 Infantile-Onset Epilepsy Panel, Sequencing and Deletion/Duplication Additional Technical Information Epilepsy INFANT EPIL; SCN1A; PCDH19; SLC2A1; POLG; SCN2A; SCN1A; SCN1B; GABRG2; EFHC1; CACNB4; GABRA1; EPM2A; NHLRC1; EPM2B; CSTB; PRICKLE1; CHRNA4; CHRNB2; CHRNA2; LGI1; MECP2; CDKL5; FOXG1; UBE3A; SLC9A6; TCF4; NRXN1; CNTNAP2; ZEB2; GAMT; GATM; PPT1; CLN1; TPP1; CLN2; CLN3; CLN5; CLN6; MFSD8; CLN7; CLN8; CTSD; CLN10; ADSL; SYN1; PNKP; benign familial neonatal seizures; generalized epilepsy with febrile seizures; juvenile myoclonic epilepsy; progressive myoclonic epilepsy; autosomal dominant focal epilepsies; Rett/atypical Rett syndromes; Angelman/Angelman-like/Pitt-Hopkins syndromes; Mowat-Wilson syndrome; creatine deficiency syndromes; neuronal ceroid lipofuscinoses; adenosuccinate lyase deficiency; epilepsy with variable learning and behavioral disorders; microcephaly with early onset intractable seizures and developmental delay", GeneDx 2006332 Exome Sequencing with Symptom-Guided Analysis Exome EXOME SEQ 2006336 Exome Sequencing Symptom-Guided Analysis, Patient Only Exome EXOSEQ PRO 0030192 APC Resistance Profile with Reflex to Factor V Leiden Factor V Leiden APC R, Venous thrombosis, Thromboembolism, Thrombophilia, clotting 0097720 Factor V Leiden (F5) R506Q Mutation Factor V Leiden FACV, Venous thrombosis, Thromboembolism, Thrombophilia, clotting 2001549 Factor V, R2 Mutation Factor V Leiden F5 R2, Venous thrombosis, Thromboembolism, Thrombophilia, clotting, A4070G 2003220 Factor XIII (F13A1) V34L Variant (assess thrombotic risk in Caucasians) Factor XIII (F13A1) V34L Variant FAC 13 MUT, Venous thrombosis, Thromboembolism, Thrombophilia, clotting 2004915 Familial Adenomatous Polyposis Panel: APC Sequencing, APC Deletion/Duplication, and MYH 2 Mutations Familial Adenomatous Polyposis FAP Panel, Familial Adenomatious Polyposis familial cancer, Colorectal Cancer, colon cancer, CRC, polyps, FAP, familial cancer 2004863 Familial Adenomatous Polyposis (APC) Sequencing Familial Adenomatous Polyposis APC FGS, Colorectal Cancer, colon cancer, CRC, polyps, Familial Adenomatious Polyposis FAP, familial cancer 2004911 MUTYH-Associated Polyposis (MUTYH) 2 Mutations Familial Adenomatous Polyposis MYH SEQ, Hereditary Colorectal Cancer, MAP, MUTH Associated Polyposis 2006191 MUTYH-Associated Polyposis (MUTYH) Sequencing Familial Adenomatous Polyposis MUTYH, FGS, MYH 2006307 MUTYH-Associated Polyposis (MUTYH) 2 Mutations with Reflex to Sequencing Familial Adenomatous Polyposis MUTYH RFLX MYH 0051463 Dysautonomia, Familial (IKBKAP), 2 Variants Familial Dysautonomia IKBKAP, Jewish Genetic Disease 2002658 Familial Mediterranean Fever (MEFV) Sequencing Familial Mediterranean Fever (MEFV) FMF FGS, DNA 2001961 Familial Mutation, Targeted Sequencing

The following genes are available:ACADVL, ACADM, ACVRL1, APC, ASS1, ATP7A, BMPR1A, BMPR2, BTD, CCM1, CCM2, CCM3, CDKL5, CFTR, COL4A5, CYP1B1, ENG, F8, F9, FBN1, G6PD, GALT, GJB2; HBA1, HBA2, HBB, INSR, LMNA, MECP2,MEFV, MEN1, MLH1, MSH2; MSH6, MUTYH, MYH3, NF1, OTC, PLOD1, PMS2; PRSS1, PTEN, PTPN11, RASA1, RET, SDHB, SDHC, SDHD, SLC22A5, SLC25A13, SMAD4, SPRED1, SPINK1, SOS1, STK11, TACI, TGFBR1, TGFBR2, UBE3A, VHL, VWF

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Molecular Genetics | ARUP Laboratories

The Department of Microbiology, Immunology & Molecular Genetics is part of theLong School of Medicineat theUniversity of Texas Health Science Center at San Antonio. Our faculty conducts research on the immune system, infectious agents and cancer. Accordingly, the department is the nucleus for research and education in immunological and microbiological topics for the five schools at theUniversity of Texas Health Science Center at San Antonio, and provides a dynamic environment for scientific discovery and training.

Our mission is to further research in molecular immunology, microbial pathogenesis, tumor immunology,autoimmunity, immunodeficienciesand development of the immune system, in order to build the knowledge necessary for vaccines and therapies of the future. We use molecular genetics and epigenetics approaches in conjunction with next-generation sequencing tools to dissect mechanisms for generations of antibodies and lymphocytes that protect against viruses, bacteria, fungi, as well as tumor cells. We also strive to understand molecular mechanisms of tumorigenesis, with particular emphasis on B lymphocyte neoplastic transformation in the context of the developing immune system. To this end, basic and translational research are of equal importance, to foster discovery of biological truths and translate those discoveries into new therapeutics.

We are committed to developing the next generation of scientists in biomedical research with an emphasis on molecular immunology, and to this end, we offer a spectrum of training opportunities. We house anUndergraduate Research Program,in addition to aMaster of Science Program in Immunology and Infection. Our faculty also teach and mentor PhD students through theInfection, Inflammation and Immunity Discipline of the Integrated Biomedical Science Program in the Graduate School of Biomedical Sciences, in addition to providing the teaching in immunology and infection to our medical students. Finally, in addition to undergraduate and graduate trainees,Postdoctoral Fellowsare important in our overall research effort. Postdoctoral fellowships are available in most laboratories of the Department of Microbiology, Immunology & Molecular Genetics.

The Department of Microbiology, Immunology & Molecular Genetics supports a variety of learning and training opportunities in seminars, lectures and events, including:

Contact the Program Coordinators at: immunity@uthscsa.edu

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Microbiology, Immunology & Molecular Genetics - Microbiology

The basis of human longevity and healthy aging, and how to achieve these desirable phenotypes, remain among the principal challenges of biology and medicine. While an understanding of lifestyle and environmental factors will maximize our ability to prevent disease and maximize health in the general population, studying the genetic basis of longevity and healthy aging in exceptional individuals is providing important biological insights. In model organisms it has been possible to demonstrate effects of mutations in genes that can extend lifespan nearly tenfold (Ayyadevara et al. 2008). Studies of inbred lab strains and of natural genetic variants in model organisms including yeast and worms (Tissenbaum and Guarente 2002), flies (Paaby and Schmidt 2009) and mice (Yuan et al. 2011) have clearly implicated many specific genes in the lifespan of these organisms. Our understanding of human lifespan stands in contrast to this, with only one consistently replicable genetic association, APOE, observed to date in several genome-wide association scans (GWAS) of longevity-related traits. This may be because healthy aging and longevity are particularly complex traits, involving not only maintenance of long-term function but also absence or reduction of disease and other morbidities. It has been proposed that human lifespan is influenced not only by longevity assurance mechanisms and disease susceptibility loci but also by the environment, geneenvironment interactions, and chance (Cournil and Kirkwood 2001). It will be important to understand the effects of environment (lifestyle) and of genetics, as well as how they interact to affect health and lifespan.

The importance of age and aging is underscored by the recognition that all common complex diseases increase with age. Questions remain about whether aging is the cause or effect of such diseases (Hekimi 2006). The study of desirable phenotypes like longevity and healthy aging has been referred to as positive biology (Farrelly 2012). Its premise is that understanding the basis for such desirable traits may allow us to design interventions to improve human health.

This review was intended to summarize our current understanding of genetic factors affecting the phenotypes of longevity and healthy aging in humans, including the definition and heritability of these traits, and linkage, association, and sequencing studies. The surprising and novel findings that centenarians do not appear to have a relative lack of common complex disease risk alleles, and that some genetic variants appear to buffer or protect against specific risk alleles, are discussed in detail. Shorter summaries of the findings related to somatic mosaicism and the promising study of epigenetics of aging are included for completeness.

The phenotypes used in studies of the genetics of human aging are usually lifespan (age at death), longevity (long life, usually defined as being a specific advanced age or older at the time of study), exceptional longevity (defined as attaining or exceeding a specific exceptional age), or healthy aging (a combination of old age and health, often defined as freedom from specific disorders or desirable performance levels on functional tests). Longevity studies focus on long-lived individuals (LLI), often centenarians aged 100 or more years. One advantage of such studies is the simplicity of phenotype definition. Healthy aging can be defined in various ways, usually with regard to reaching an at least moderately old age in the absence of certain diseases or disabilities, and/or in the presence of desirable traits such as intact cognition or mobility. Both types of studies should be differentiated from the study of the fundamental biological processes of aging (for example, cellular senescence).

A major difference between longevity and healthy aging studies is that the former focuses on lifespan, whereas the latter is focused on healthspan. Lifespan and healthspan are intimately related, however, and individuals who live exceptionally long also tend to be healthy for much of their lives. A landmark study of the health of supercentenarians (aged 110119), semisupercentenarians (aged 105109), centenarians (in this context aged 100104), nonagenarians, and younger controls found that the older the age group, the greater the delay in onset of major disease (Andersen et al. 2012). Remarkably, for every category of increasing age, the hazard ratio for each of six disorders (cancer, cardiovascular disease (CVD), dementia, hypertension, osteoporosis, and stroke) was <1.0 relative to the next oldest group. This delay in disease development and postponement of cognitive and physical decline in the oldest group amounted to a compression of morbidity (Fries 1980). Based on these findings, Andersen et al. (2012) suggest that a realistic and practical limit of human lifespan is 110115years, close to that of the oldest documented person in the world to date, who lived to 122 (Robine and Allard 1998).

Women have a lower mortality rate than men at every age, and women live longer than men in most human populations. Any given exceptional age, therefore, is more exceptional for men than for women. As noted by Sebastiani and Perls (2012) 1% of US women (but only 0.1% of men) born circa the turn of the last century lived to be 100. Potential explanations for this difference include hormonal and immune differences, hemizygosity of the X-chromosome in men (which may allow manifestation of unfavorable sex-linked variants), and unrecognized confounders [reviewed in Newman and Murabito (2013)].

Age at death in adulthood has a heritability of approximately 25% (summarized in Murabito et al. 2012). A population-based study of 2,872 Danish twin pairs born between 1870 and 1900 found that the heritability of adult lifespan was 0.26 in men and 0.23 in women (Herskind et al. 1996). This cohort was not only population-based but nearly non-censored and, with follow-up for 94years, encompassed essentially the entire human lifespan. Importantly, the heritability of longevity increases with greater age. The heritability of living to at least 100 has been estimated at 0.33 in women and 0.48 in men (Sebastiani and Perls 2012). Male and female siblings of US centenarians were 17-fold and eightfold more likely (compared with US Social Security data) to reach the age of 100, respectively (Perls et al. 2002). The increase in heritability of longevity at greater age is consistent between several studies. In over 20,000 Scandanavian twins, heritability of longevity was negligible from age 660, but increased with age thereafter (Hjelmborg et al. 2006). Long life was heritable in Icelanders aged over 70years (Gudmundsson et al. 2000). The siblings of Okinawan centenarians show increased adult survival probability that starts at age 55 and increases with age (Willcox et al. 2006); the authors speculate based in part on absence of many age-related diseases from Okinawan (Bernstein et al. 2004) and other centenarians (Evert et al. 2003), that these individuals have genetic factors that confer resistance to such diseases and increase the likelihood of reaching exceptional old age. The estimation of heritability also depends on how it is studied; Murabito et al. (2012) note that the Framingham heart study cohorts give much greater estimates of heritability when longevity is studied as a dichotomous trait (36% heritability for survival to 65 and 40% for survival to 85), compared with 16% heritability when age at death is treated as a continuous trait.

Clustering of longevity and healthy aging is observed in families. Parents of centenarians born in approximately 1870 were sevenfold more likely than their contemporaries to have lived to age 9099; offspring of centenarian parents showed lower prevalence of age-related disease than age-matched control groups (Atzmon et al. 2004). Exceptional familial clusters of extreme longevity have also been reported (Perls et al. 2000). Healthy aging is also heritable. Reed and Dick (2003) defined wellness in male twins as achieving the age of 70 free of heart attack, coronary surgery, stroke, diabetes or prostate cancer, and showed that this trait had a heritability exceeding 50%.

Environment and lifestyle likely constitute much of the remaining influence on human lifespan and healthspan. These factors have varied greatly over time and may not reflect the extrinsic factors that will affect the lifespan of babies born today. Many members of the elderly and centenarian cohorts under study today lived through times of caloric restriction (e.g., the Great Depression) and grew up before the use of antibiotics and vaccines became commonplace. The selective pressures that influenced their mortality are not identical to those experienced by later generations, and this is an important consideration for study design.

Phenotype definition is particularly important in genetic studies; it affects the interpretation and meaning of results, and the ability to compare to the results of other studies. Studies of longevity can include extreme longevity (defined as living beyond a specific extreme age) or age at death. Studies of healthy aging may use age to disease onset, successful aging or wellness (which can also have a variety of definitions), or other phenotypes (Manolio 2007). Linkage or family-based association study designs, longitudinal cohort studies, or case/control designs have been used. Family-based designs have the advantage of being robust to population stratification. Longitudinal cohorts have the advantage of limiting sampling bias, but take time and due to practical limits of size may not contain many individuals of extreme age. Sample size is a consideration for all these study designs. To date, the largest studies of LLI are in the low thousands of subjects; this is much smaller than the largest studies of common complex diseases (which now include over 100,000 subjects), despite the likely similar modest size of many of the genetic factors being sought.

Choice of a comparison group to contrast with exceptionally long-lived or exceptionally healthy elderly individuals is also critical. Health data for LLI can be compared with archived data for deceased individuals of the same birth cohort, but DNA samples from an ideal comparison group (such as their birth cohort) are not available. Case/control molecular genetic studies of long-lived or healthy aged individuals often compare elderly cases to younger controls. Potential pitfalls of such studies include inadequate detection and control for population stratification, particularly for populations that have experienced immigration of different ethnicities over time (Nebel and Schreiber 2005). The use of principal components analysis (Price et al. 2006) or genomic controls (Devlin and Roeder 1999) can mitigate this problem, as can the conduct of studies within specific ethnic groups (Barzilai et al. 2001). In the case/control design, the control group is also expected to contain individuals who will go on to become equivalent to cases; their presence in the control group reduces power. Environmental factors must be acknowledged in such studies as potential confounders; inevitably, the cases and controls have lived in different times and experienced different lifestyles. A way to mitigate some of these problems; however, is to choose controls that are no older than 50 (Halaschek-Wiener et al. 2008) because in modern day developed countries, mortality before age 50 is minimal. Choosing a comparison group <50years of age makes the control group essentially an unselected group with regard to mortality from age-related diseases. Choosing a control group in their 70 or 80, however, would exacerbate this issue, as the control group would fail to include individuals who died in their 50s or 60s.

Several studies, such as the Longevity Gene Study (Barzilai et al. 2001), the Leiden Longevity Study (LLS) (Mooijaart et al. 2011), the New England Centenarian Study (NECS) (Terry et al. 2004), and the Long Life Family Study (LLFS) (Newman et al. 2011) include comparisons of the offspring of LLI (who are assumed to have inherited some longevity factors) to contemporary age-matched controls. They have observed that the offspring of LLI have more favorable blood lipid profiles (Barzilai et al. 2001; Newman et al. 2011) and lower prevalence of hypertension and metabolic and cardiovascular disease (Atzmon et al. 2004; Westendorp et al. 2009; Newman et al. 2011) and all-cause mortality (Terry et al. 2004) than age-matched controls. Comparison of the offspring of LLI with their contemporaries controls for cohort effects such as variation in BMI in human populations over time; it has the limitation, however, of under-estimating the difference in phenotypes and genotypes that would presumably be observed if the LLI could be compared with their largely long-deceased birth cohort.

Linkage studies of long-lived sibships or extended pedigrees with exceptionally long-lived individuals have identified several putative and one replicated longevity linkage. In 2001, the NECS (Puca et al. 2001) reported a 10-cM sib-pair based linkage scan of 308 individuals in 137 sibships with exceptional longevity (defined as having a proband of at least 98 and a 91-year-old male or 95-year-old female sib). They found significant evidence for linkage of longevity to a region around D4S1564. Suggestive support for this region was obtained through analysis of 95 concordant pairs of fraternal male twins with a wellness phenotype (age at least 70 with no overt CVD or prostate cancer) (Reed et al. 2004). Initial convergence of two linkage studies with very different phenotypes led to excitement about this region and its suspected role in longevity and health. Subsequent study of the region focused in part on a regional biological candidate gene, microsomal triglyceride transfer protein (MTP), identified through haplotype analysis (Geesaman et al. 2003).

In 2010 a larger and higher density linkage study (Boyden and Kunkel 2010) expanded on the initial NECS resource, with a genome-wide linkage study of 279 families with multiple long-lived sibs 90years and older, including 129/137 of those previously described (Puca et al. 2001). A limitation of this study was the use of expected life span (estimated from age- and gender-specific life expectancies) for the 70% of subjects who were still living. This analysis of 9,751 SNPs found just-significant LOD scores at 3p22-24 and 9q31-34, as well as modest evidence for linkage at the original site, 4q22-25 and possibly at 12q. A larger study (Kerber et al. 2012) replicated the linkage of 3p22-24 to extreme longevity and identified possible additional loci. Working with 732 subjects from the Utah population database and database and population controls, including 433 Caucasian individuals aged 86109 who showed a phenotype including both excess individual longevity (the difference between observed and expected lifespan) and excess familial longevity (a weighted average of excess longevity for all family members), they used a linkage screen with 1,100 microsatellite markers to identify a strongly suggestive peak at 3p at the same position as Boyden and Kunkel. Meta-analysis of linkage in the Utah and New England data sets supported linkage at the chromosome 3 locus. Other linkage peaks were observed in the Utah data at 18q23-24, 8q23, and 17q21; meta-analysis provided additional support but not outright replication for 8q, 9q, and 17q. The new data; however, did not support linkage to chromosome 4 or chromosome 12. Larger sample sets and denser and more informative linkage analyses were pointing away from the original chromosome 4 linkage observation, and converging instead most strongly at 3q24-22.

Two linkage studies of successful aging in Amish individuals over 80years of age within a single 13-generation pedigree showed linkage to chromosomes 6, 7, and 14, different regions than those found in the longevity linkage studies. Successful aging was defined as cognitively intact and without depression, high functioning, and satisfied with life. These studies (Edwards et al. 2011; Edwards 2012) analyzed 263 cognitively intact Amish over 80years old (74 successfully aged and 189 normally aged) within 12 sub-pedigrees using 630,309 autosomal SNPs. Linkage was found at 6q25-27, as well as association of a SNP, rs205990, in the interval linked to the successfully aged phenotype. The chromosome 6 linkage identified in the Amish is different from those identified in the Utah and New England studies; this may reflect the different phenotype, or may be due to genetic factors specific to the Amish founder population.

The largest linkage study to date was done in the multi-site European Genetics of Healthy Aging (GEHA) Study, which looked at 2118 European full sib-pairs over 90years old (Beekman et al. 2013). GEHA found linkage at 4 regions: 14q11.2, 17q12-q22, 19p13.3-p13.11, and 19q13.11-q13.32. The chromosome 14 linkage is at a different site from that observed in the Amish study; the large chromosome 17 region overlaps the 17q21 locus observed by Kerber et al. Fine mapping of these linkage regions using GWAS data in a subset of 1228 unrelated nonagenarians and 1907 controls identified a SNP near APOE at the 19q locus as significantly associated with longevity. Apolipoprotein E (apoE) isoforms are known risk factors for cardiovascular disease (CVD) and Alzheimer disease (AD), likely due to their involvement in inflammation, elevated lipid levels, and oxidative stress (Huebbe et al. 2011). ApoE has three main isoforms: apoE2, apoE3 and apoE4. Combined modeling in the GEHA study showed that APOE4 (p=0.02) and APOE2 (p=1.0105) account for the linkage at 19q. The APOE linkage was characterized by absence of APOE4, but enrichment for APOE2 among the nonagenarians. In this study the APOE2 allele is the stronger association, and the authors refer to APOE as a longevity gene.

The multiple linkage signals observed in these studies likely indicate genetic heterogeneity of longevity and healthy aging in human populations. Interestingly, the GEHA study observed heterogeneity among its multiple geographic regions; Northern European subjects contribute most to some of the linkage peaks they observe, including the APOE locus. Gender-specific effects were also observed, with a male-specific linkage peak at 8p and female-specific ones at 15q and the 19q APOE locus (Beekman et al. 2013). While the lack of association at the other linkage regions in the GEHA study may be due to power limitations, it could also imply that multiple rare or private variants contribute to linkage but not association at these loci.

Candidate genes examined for association with longevity or healthy aging or related phenotypes fall into several categories. They include genes nominated based on observations of lifespan extension in model organisms; and genes involved in lipid metabolism, immune response and inflammation, stress response, and others. Candidate genes tested for association with longevity and related phenotypes have been the subject of several excellent reviews (Christensen et al. 2006; Wheeler and Kim 2011; Ferrario et al. 2012; Newman and Murabito 2013); an exhaustive listing is beyond the scope of this review.

Of the candidate genes assessed for association with longevity, variants in APOE and FOXO3A have been most consistently replicated, though some candidate genes have been associated with longevity phenotypes in more than one population but not in all populations tested; many more have been associated in a single study but failed to replicate in others (reviewed by (Christensen et al. 2006)). In a study of 1,344 healthy Italians aged 2290, APOE4 was found at lower frequency and APOE2 at higher frequency in elderly and centenarians than in younger individuals (e.g., Seripa et al. 2006); APOE2 is a putative protective factor in this context and APOE4 can be considered a frailty allele (Gerdes et al. 2000). FOXO3A is a homologue of the C. elegans Daf-16 gene that is important in control of lifespan in the worm (Hsin and Kenyon 1999); it is part of the insulin/IGF1 signaling pathway. FOXO3A variants have been associated with longevity in many populations (reviewed in Wheeler and Kim 2011).

Additional genes show promise of great relevance to healthy aging. A variant at CETP, for example, though inconsistently associated with longevity in different populations (reviewed by (Christensen et al. 2006)), in 213 Ashkenazi Jewish individuals of average age 98 is associated not only with longevity but also with additional aging-related phenotypes including a desirable lipid profile (Barzilai et al. 2003) and preservation of cognitive function (Barzilai et al. 2006). Other recent studies with extensive replication data are also encouraging. Association of a SNP in a heat shock factor gene, HSF2 with all-cause mortality was seen in the longitudinal Rotterdam Study (5,974 participants and 3,174 deaths), with replication in eight population-based cohorts (Broer 2012).

Other candidate genes have been associated with longevity or healthy aging phenotypes in some but not all studies. MTP, identified as a regional candidate at the 4q25 locus, failed to show replication of association with longevity in larger studies of approximately 1500 LLI each (Beekman et al. 2006; Bathum et al. 2005; Nebel et al. 2005). Progeria genes have shown association with longevity in some studies. A haplotype of SNPs at LMNA, the gene that is mutated in Hutchinson-Gilford progeria, was associated with long life (age >95years) in 873 LLI and 443 controls, and remained significant upon meta-analysis of 3,619 subjects from four independent samples (Conneely et al. 2012). Polymorphisms at WRN have shown inconsistent associations with age (Castro et al. 2000; Kuningas et al. 2006). Sirtuins mediate the effects of caloric restriction, a non-genetic factor known to increase life span in many organisms. The effect of polymorphisms in sirtuin genes (SIRT1-7) on longevity and age-related diseases was reviewed by Polito et al. (2010). There is evidence that variants in SIRT3 (Rose et al. 2003) are associated with longevity. A functional promoter variant at DNA repair gene EXO1 was associated with longevity in female centenarians (Nebel et al. 2009), but tagSNPs in the gene showed no association with longevity in men (Morris 2013).

Given the multifactorial nature and likely genetic heterogeneity of healthy aging and longevity, as well as environmental influences on these complex traits, it may not be reasonable to expect that replication of candidate gene studies would be uniform between populations. Reasons for lack of replication include limitations of sample size, rarity (low minor allele frequency) of actual variants, and small true effect sizes. Poorly designed or under-powered studies will result in false positives that legitimately fail to replicate. For studies of longevity and healthy aging, in particular, differences in phenotype or type of study will also result in findings that are non-uniform between studies. While larger case/control studies are frequently suggested as a solution to the limitations of present-day association studies, combining data from populations with different lifestyles and genetic backgrounds, even if well-matched for ethnicity, may obscure true association signals.

To date, SNPs in or near APOE are the only ones to achieve genome-wide significance (GWS, generally p5108) in genome-wide association studies (GWAS) of lifespan-related traits. In three GWAS of long-lived individuals vs. younger controls, APOE was significantly associated with longevity at the genome-wide level. The first of these included 763 long lived (94110years) and 1,085 control (4577years) from German biobanks and replication in an independent set of German samples (754 cases aged 95108, 860 controls aged 6075) (Nebel et al. 2011). Only rs4420638 near APOC1 and in linkage disequilibrium (LD) with APOE achieved GWS. GWAS of 403 unrelated nonagenarians (average age 94) from longevity families in the LLS vs. 1,670 controls (average age 58) showed similar results (Deelen et al. 2011a). Only one of 62 SNPs carried forward to meta-analysis with 4,149 nonagenarian cases and 7,582 younger controls from the Rotterdam study, the Leiden 85+ study and the Danish 1905 Cohort reached GWS, rs2075650 at TOMM40 near APOE. Meta-analysis of the APOE2 and APOE4 SNPs showed significant associations of both SNPs with longevity, with E2 being protective of long life (OR 1.31, CI 1.171.46, p=1.35106), and E4 being deleterious (OR 0.62, CI 0.560.68, p=1.331023). A third longevity GWAS (Sebastiani et al. 2012) included three phases: a discovery phase with 801 New England centenarians (aged 95119, many with a family history of extreme longevity) vs. 914 controls genetically matched by means of principal components analysis; a first replication in 253 centenarians (89114) vs. 341 genetically matched controls; and a second replication with 60 additional centenarians (100114) and unmatched controls. Of 243,980 SNPs analyzed only one, TOMM40 SNP rs2075650 near APOE, reached GWS. Inverse association of APOE4 with longevity (p=5.3103) was also detectable in the Southern Italian centenarians study (SICS) of 440 LLIs aged 90109 and 553 young controls aged 1845 (Malovini et al. 2011), despite the known lower frequency of the E4 allele in Southern, as compared with Northern, Europe (Haddy 2002).

Other GWAS of lifespan-related phenotypes revealed no associations that were significant at the genome-wide level. A GWAS of the Framingham health study (Lunetta et al. 2007) (258 Original Cohort and 1,087 Offspring individuals, members of the 330 largest families in the study) revealed no GWS SNPs for any of five aging-related phenotypes. Newman et al. (Newman et al. 2010) meta-analyzed four cohort studies in the cohorts for heart and aging research in genomic epidemiology (CHARGE) Consortium for survival to at least 90years of age. Cases were 1,836 people who achieved survival to at least 90; controls were 1,955 participants who died aged 5580. SNPs were genotyped and imputed in subjects of European ancestry, with systematic elimination of outliers and correction for population stratification. Replication was carried out in the LLS (950 long-lived probands and 744 partners of their offspring and 680 blood bank donors) and the Danish 1905 Cohort Survey (2,262 long-lived participants and 2007 Danish twin study controls aged 4668). No SNPs reached genome-wide significance.

Walter et al. (2011) conducted a meta-analysis of GWAS of nine longitudinal cohort studies in the CHARGE Consortium, including 25,000 unselected people of European ancestry. They analyzed two continuous traits, all-cause mortality, and event-free survival (where event was defined as myocardial infarction, heart failure, stroke, dementia, hip fracture, or cancer). No SNPs reached GWS for either phenotype. SNPs near APOE reached only nominal significance in the CHARGE study (Walter et al. 2011), in contrast to the results of GWAS of centenarians, in which APOE has been a significant and replicable finding. The CHARGE meta-analysis contained few extremely old individuals, and so in comparison with centenarian studies or those targeting long-lived healthy individuals, has examined earlier mortality and events, a different phenotype. The Framingham Study GWAS (Lunetta et al. 2007), which also showed no GWS SNPs also represents a much younger group, on average, than studies of oldest old or centenarians. This may mean that different genes and variants may come into play in different phases of aging, with APOE being most relevant at older ages. Earlier mortality is often related to lifestyle as well, and the heritability of aging is lower at younger ages, as described above.

A genome-wide association study of copy number variants (CNVs) in the Rotterdam study RS1 cohort, with replication in the RS2 cohort and the FHS, found that large common deletions are associated with mortality (vs. survival) at old age (Kuningas et al. 2011a). They tested 312 common CNV regions and measures of CNV burden for association with mortality during follow-up. A higher burden of CNVs of 500kb or more in size was associated with mortality. Two specific regions were also associated with mortality, 11p15.5 and 14q21.3. The 11p15.5 association, which would survive Bonferroni correction for 312 tests, includes insertions and deletions which were analyzed together relative to non-carriers; it contains 41 genes including some related to longevity or complex diseases. The 14q21.3 region contains no genes and is characterized only by deletions. Runs of homozygosity, which can indicate presence of recessive loci, were not associated with survival to old age in this cohort (Kuningas et al. 2011b).

Analyses of phenotypes that may influence long-term good health have also been undertaken. Personality traits are associated with healthy aging and longevity (Terracciano et al. 2008). In the LLFS, a GWAS of five personality factors in 583 families with 4,595 individuals and replication in 1,279 other subjects identified a locus associated with agreeableness, and identified several significant ageSNP interactions that may affect longevity through effects on personality (Bae et al. 2013).

In contrast to the results of longevity GWAS, GWAS of common complex diseases have revealed hundreds of SNPs associated with cancers, CVD, diabetes and other age-related diseases, albeit with increasing numbers of associations found with increasing GWAS size. One explanation for this may be that the phenotypes of healthy aging and longevity may be much more complex than those of these complex diseases, in part because they often (depending on phenotype definition) involve absence of specific complex diseases. If GWAS studies of survival to elderly ages are even more confounded by environmental (E) factors than GWAS of diseases, combining studies from different populations in pooled or meta-analyses may complicate the E effects even more. In studies of older individuals, it is particularly hard to control for E factors experienced over many decades of life.

SNPs at only one locus, APOE, have achieved Bonferroni-corrected levels of GWS in GWAS of longevity. By current standards these GWAS, which involved fewer than 1,000 centenarians, or a few 1,000 nonagenarians, are modest in size. Larger GWAS may in theory allow additional SNPs to achieve this threshold. There are other indications, however, that support the idea that SNPs that do not reach this threshold of GWS may be biologically important, either individually or through their joint effects. Several studies used a variety of techniques to analyze collections of nominally longevity-associated SNPs to determine if they act in concert to affect lifespan.

In the Framingham study GWAS of 5 aging-related phenotypes (Lunetta et al. 2007) observed that SNPs in some candidate genes, including SNPs near the Werner syndrome gene WRN and FOXO1A, as well as GAPDH, KL, LEPR, PON1, PSEN1, and SOD2 were associated with age at death. Kulminski and Culminskaya (2011) used Framingham Affymetrix 50K SNP data to perform GWAS of four endophenotypes (CVD, cancer, systolic blood pressure, and total cholesterol) to identify 63 SNPs that were associated at p<106 with at least one endophenotype. 76 genes at or near these SNPs were enriched in terms of Gene Ontology annotations related to aging-relevant processes. Yashin et al. (2010) hypothesized that lifespan depends on the number of small-effect longevity alleles present in individual genomes. They re-analyzed Framingham 550K SNP data and identified 169 SNPs associated at p<106. The number of these SNPs carried by an individual correlated with lifespan and explained 21% of its variance; in contrast, randomly chosen SNPs did not correlate with lifespan.

Gene set analysis of GWAS data from the LLS and Rotterdam studies was used to show that genes in the insulin/IGF-1 signaling (IIS) and telomere maintenance TM pathways are associated with longevity (Deelen 2011b). 1021 and 88 GWAS SNPs were identified within 10kb of 68 IIS and 13 TM genes, respectively. Both pathways were associated with longevity. Nine IIS genes (AKT1, AKT3, FOXO4, IGF2, INS, PIK3CA, SGK, SGK2, and YWHAG) and one TM gene (POT1) were the main determinants of the association.

Sebastiani et al. (2012) constructed a model in which 281 SNPs showed 89% sensitivity and 89% specificity to predict longevity in their GWAS Discovery set, and 5861% specificity and 5885% sensitivity in independent sets. They call this a genetic signature of exceptional longevity. These SNPs explain nearly 20% of the heritability of extreme longevity. They find that the TOMM40 SNP near APOE alone has poor predictive value; removing it from the model reduces specificity and sensitivity by only 1%. The 281 SNPs include 137 in 130 genes, including LMNA, WRN, SOD2, CDKN2A, SORCS1 and SORCS2, and GIP. This set of 130 genes is highly and significantly enriched for those related to Alzheimer disease (38 genes), 42 related to dementia, 38 to tauopathies, 24 to CAD, and several to neoplasms.

GWAS of the SICS Study of 410 LLI and 553 younger controls identified 67 SNPs that reached a permutation-defined level of genome-wide significance of p<104 (Malovini et al. 2011). Among them was rs10491334 at the calcium/calmodulin-dependent protein kinase IV (CAMKIV) that replicated in 116 additional LLI and 160 controls. Malovini et al. demonstrate that CAMK4 phosphorylates and activates survival proteins FOXO3A, AKT, and SIRT1. Homozygous carriers of the minor allele had lower CAMKIV protein expression and were under-represented among LLIs, consistent with a deleterious effect of this allele on longevity.

The biological relevance of other SNPs besides those at APOE is also strongly supported by similarities between the results of human GWAS and mouse lifespan studies. Eight of the ten top CHARGE SNPs detected by GWAS, but which did not achieve GWS, correspond to mouse lifespan quantitative trait loci (QTL) (Murabito et al. 2012). These studies connect GWAS findings that do not reach GWS with many genes that are relevant to aging or age-related diseases. In several cases, this convergence with genes of biological interest is statistically unlikely to be due to chance and is likely to reflect the presence of true association signals that are not consistent enough to be replicated predictably as candidate genes or achieve GWS, or have effects that are too subtle to be detected individually. Such potential true signals may be more affected by E factors than those that have been replicated, i.e., APOE and FOXO3A. As pointed out by Yashin et al., the same sets of variants would not be expected to work in all populations because of differences in environment (Yashin et al. 2010).

Several recent studies have shown that centenarians do not carry smaller numbers of risk alleles for common complex diseases than average people. In an important paper in 2010, Beekman et al. (2010) studied two case/control collections: (1) 723 nonagenarian siblings (mean age 94) from the LLS vs. 721 unrelated younger controls (mean age 52), and (2) 979 long-lived individuals over 85 (mean age 87) from the pop-based Leiden 85+ study vs. 1,167 younger controls (mean age 41) from the Netherlands Twin Register. They looked at 30 SNPs known to be associated with CVD, cancer or type 2 diabetes (T2D). The cases and controls each carried an average of 27 disease risk alleles. The distribution of risk alleles was the same in elderly and young subjects. Beekman et al. note that GWAS-identified disease risk alleles do not compromise human longevity and suggest that a lack of rare disease factors, or the presence of protective factors, is at work in the long-lived individuals. It is important to note, however, that CVD, cancer, and T2D are diseases that have very clear lifestyle components and that part of the effect could be due to lifestyle differences.

Mooijaart et al. (2011) extended this observation the following year, showing that SNPs associated with T2D and identified by GWAS are not major determinants of the beneficial glucose tolerance that characterizes familial longevity. They compared the offspring of the LLS long-lived individuals with the offsprings spouses and other controls. The LLS offspring had a better metabolic profile and better glucose tolerance than same-age controls, although the frequency of 15 known T2D SNPs did not differ between the two groups. When individuals were compared within each group, however, glucose levels did correlate with the number of T2D SNPs. They speculate that the LLS offspring may have protective factors that improve their metabolic profile and glucose tolerance in spite of the presence of T2D GWAS SNPs. This comparison, using same-age groups of individuals, clearly points to protective genetic factors contributing to preservation of a healthy phenotype, rather than lifestyle and environmental factors that should be very similar (at least in adulthood) between the offspring and their spouses.

Sebastiani et al. (2012) also noted that there was not a substantial difference in the numbers of 1,214 known disease-associated SNPs in centenarians and controls. A similar observation was made in their whole genome sequence data from one male and one female supercentenarian (Sebastiani et al. 2011).

These important and perhaps surprising results show that extreme longevity, and the long-term good health that often accompanies it, is not incompatible with the presence of many disease risk alleles. At least for the common SNPs associated with common complex diseases, it is not the absence of bad alleles, but more likely the presence of good alleles that influences longevity, though effects of good environmental factors may also contribute. Protective factors of some kind may allow these risk variants to not be manifest. These results also have implications beyond the study of longevityin an age when substantial effort is being invested in personalized disease risk prediction, the presence of many disease alleles that are non-penetrant in some individuals potentially complicates predictions of disease.

One mechanism for a lack of effect by an undesirable allele is the buffering mechanism explored by Barzilai et al. They propose that some individuals who show exceptional longevity may do so despite the presence of unfavorable alleles because those alleles are buffered by favorable alleles in other genes (Bergman et al. 2007). They suggest that buffering gene variants (longevity variants) will show a monotonic increase in frequency from early old age (65) to later ages; examples of buffering genotypes are CETP VV, APOC3 CC, and a +2019 deletion in ADIPOQ. Buffered alleles, in contrast, should show a U-shaped frequency curve, higher at younger ages, dipping low in early old age, and then increasing in the exceptionally old (who have the buffering protective genotype that allows disease-related variants to accumulate); examples of buffered genotypes are heterozygotes for deleterious alleles of KLOTHO and LPA. Importantly, Bergman et al. use a cross-sectional study design, with 1,200 subjects in their 611th decades of life to show experimental support for the buffering hypothesis; their data support the idea that CETP VV genotype buffers the deleterious effects of an LPA genotype. They show a genetic interaction between CETP genotype and LPA; LPA heterozygotes with the CETP IV/II genotypes monotonically decrease in frequency with age, but those in CETP VV individuals increase from age 70 onward. They argue that case/control analyses are insufficient to reveal this effect because it does not reveal the shape of the allele frequency age curve.

Earlier observations are also explained by a buffering mechanism. De Benedictis et al. (1998) described an age-related convex trajectory of a 3APOB-VNTR genotype that they interpret as consistent with crossing mortality curves relevant to subgroups of individuals with different genotypes. A X-sectional study of 800 healthy aging subjects from 18 to 109years free of clinically apparent disease genotyped variants in APOA1, APOC3, and APOA4 (Garasto et al. 2003). They noted that an allele of APOA1 that correlated with higher serum LDL-C was paradoxically increased in frequency in the oldest old. The authors called it another genetic paradox of centenarians. While this observation could reflect population stratification in the different age groups, it may also be due to the U-shaped curve of a buffered gene.

The buffering mechanism may also explain some of the inconsistency in the findings for MTP. Huffman et al. (2012) find that MTP CC is a deleterious genotype that is buffered by any of three longevity genotypes of CETP, APOC3, or ADIPOQ. MTP CC shows a U-shaped curve, declining ages 5585, and then dramatically increasing in those who live 90 or more years. If this MTP genotype is observed at high frequency in centenarians, but only in the presence of specific protective variants, this may in part explain why the linkage at chromosome 4 was not observed consistently between studies.

Buffering has been described in model organisms. The heat-shock protein Hsp90 is known to buffer genetic variation in Drosophila, allowing it to accumulate under neutral conditions (Rutherford and Lindquist 1998). Such a gene is known as a phenotypic capacitor, and it masks the presence of phenotypic variation. It is interesting to speculate that protective genetic variants carried by centenarians may be capacitors for the disease risk variants we now know they carry at, on average, the same frequency as other people. Identification of buffering/capacitor genes and study of their function will be necessary to understand the longevity phenotype. It will also be important to determine if such capacitors operate in healthy aging as well as extreme longevity. Because such variants are likely rare, intensive study of rare individuals at the upper ends of the human lifespan and healthspan, perhaps by whole genome sequencing and examination of unusual variants they carry, is paramount.

The interaction between buffering and buffered genes and genotypes also has implications for study design. The exquisite studies carried out by Barzilais group are done in a single well-defined ethnicity, Ashkenazi Jewish individuals. Since a buffered gene will only show a distinctive U-shaped curve in the presence of its buffer, and a buffer may only be advantageous in the presence of a deleterious gene that it buffers, this underscores the importance of avoiding population stratification in such studies. If some of the associations detected to date in case/control studies of healthy aging and longevity are actually underlain by genotypes with U-shaped curves, the choice of ages for the cases and controls will greatly affect whether an association is detected, and may explain some failures of associations to replicate. Finally, the concept of buffering genes has implications for the use of centenarians, or exceptionally healthy elderly individuals as super-controls for disease studies; if the exceptional elderly are healthy because of a protective factor rather than lack of a disease allele, their use as an extreme comparison group may not necessarily be helpful.

Given that lifestyle is expected to have a greater impact than genetics on healthy aging, it seems unlikely that differences in lifestyle are not confounding association studies of longevity and healthy aging. It is challenging to quantify lifestyle in an optimal comparison group for, for example, centenarians. Younger control groups inevitably have different lifestyles than the elderly had at their age. For example, the CHARGE consortium (Newman et al. 2010), which compared individuals who survived to at least 90 to those who died aged 5580, found that the younger controls had higher rates of smoking.

The Longevity Gene Study overcame the birth cohort limitation using pre-existing lifestyle data from 3,164 NHANES controls of the same birth cohort as 477 Ashkenazi Jewish individuals aged 96109 (Rajpathak et al. 2011). They found no obvious differences in lifestyle and suggested that the long-lived individuals may interact with lifestyle factors differently than others. This study, however, did note subtle differences between the long-lived and comparison groups. They saw significantly fewer obese men, more overweight women, and fewer obese women in the long-lived group; in addition, more control men smoked. These differences, combined with recall limitations of the long-lived group, imply that this analysis may have missed many small lifestyle differences that could add up to substantial health differences. It will likely be difficult to take into account all but the largest lifestyle factors when planning GxE studies of longevity and healthy aging. Biomarkers of exposures may vary not only with exposure but also over time, complicating the use of such methods for these phenotypes.

Mitochondria are thought to be important to aging due to their key roles in oxidative phosphorylation, cell metabolism, and apoptosis. A relationship of variation in the mitochondrial genome with health and/or longevity is implied by the observation that age at death correlates more closely with the age at death of a persons mother more so than that of the father (Brand et al. 1992). Associations of mitochondrial genome sequence variants or haplogroups (combinations of specific variants that correlate with specific populations) with healthy aging or longevity have been noted in many populations including, for example, Italian (De Benedictis et al. 1999), Japanese (Tanaka et al. 1998), Amish (Courtenay et al. 2012), Chinese Uygur (Ren et al. 2008), Costa Rican (Castri et al. 2009), Ashkenazi Jewish (Iwata et al. 2007), Irish (Ross et al. 2001), and Finnish individuals (Niemi et al. 2003). The associations observed are inconsistent between populations and do not involve the same variant or haplogroup. This lack of consistency may be due in part to the relatively small size of many of these studies. Three common problems have been noted about such studies: inadequate matching of cases and controls, inadequate correction for multiple tests, and undetected population stratification (Shlush et al. 2008).

Interestingly, when the frequencies of different mitochondrial haplogroups are plotted for Italian individuals aged 20 to over 100, the curve shapes observed include monotonic increase for haplogroup J, and a U-shaped curve for haplotype H (de Benedictis et al. 2000), reminiscent of the longevity and buffered variants described earlier. A variant at the origin of replication of the mitochondrial heavy strand, C150T, has been observed at higher frequencies in centenarians, both through inheritance and through somatic increase in frequency, with some individuals achieving homoplasmy for this variant in their lymphocytes and monocytes, but not in granulocytes; a selective advantage of achieving high frequency of this variant in at least some cell types has been suggested (Zhang et al. 2003). Interactions between nuclear genome variants and both inherited and somatic mitochondrial variants have also been suggested to play a role in aging and longevity (Santoro et al. 2006; Tranah 2011).

Sebastiani et al. (2011) recently reported the whole genome sequencing of one male and one female supercentenarian of European ancestry from the NECS. The genomes of these exceptionally long-lived individuals were similar, in terms of the rate of nonsynonymous SNPs and number of indels, to other genomes sequenced to date. They have a similar number of known disease-associated variants to other genomes showing that their exceptional lifespan does not seem to be due to lack of known disease-associated variants. It is possible, though, that they failed to inherit a combination of variants that would have acted together to cause disease. Both supercentenarians lacked APOE4 alleles. They do not carry most of the longevity variants reported previously in the literature, implying that these known variants are not necessary for longevity. It is possible that they carry as yet undiscovered protective variants. One per cent of the variants observed were novel. Interestingly, an excess of coding region variants was seen in genes closest to GWAS-identified longevity variants, an observation that supports the idea that rare variants of these genes may contribute to the longevity phenotype.

Telomeres are indisputably important to aging. Telomeres shorten with age and are considered to be a biomarker of age. The role of telomere biology in healthy aging and disease was recently reviewed (Zhu et al. 2011). Leukocyte telomere length (LTL) has been correlated with measures of health and ability in elderly individuals. In a community-based cohort of 70- to 79-year-olds, LTL was associated with more years of healthy life; LTL was suggested to be a biomarker of healthy aging (Njajou et al. 2009). Louisiana Healthy Aging Study results concurred with this observation; LTL was correlated with measures of healthy aging in an age-dependent way (Kim et al. 2012). LTL was also found to correlate positively with physical ability (but not cognitive function) in Danish twins aged at least 77years (Bendix et al. 2011) and inversely with disability in American seniors (Risques et al. 2010). Ashkenazi centenarians and their offspring also showed longer telomeres, for their age, than controls; longer telomeres correlated with less disease (Atzmon et al. 2010). In contrast, in a study of Canadian Super-Seniors (individuals aged at least 85 and never diagnosed with cancer, cardiovascular disease, Alzheimer disease, major pulmonary disease or diabetes) the healthy oldest-old did not have exceptional telomere length for their age, but showed less variability in telomere length than mid-life controls, implying that they may be selected for optimal rather than extreme telomere length (Halaschek-Wiener et al. 2008).

Variation in genes involved in telomere maintenance has also been associated with longevity. One SNP at SIRT1 (Kim et al. 2012) and one in TERC (Soerensen et al. 2012) are associated with both LTL and longevity. Detailed analysis of TERT and TERC in Ashkenazi centenarians showed an excess of genetic variation in both genes in the centenarians and identified a TERT haplotype associated with extreme longevity (Atzmon et al. 2010). Gene set analysis of GWAS data also supported the relevance of telomere maintenance (Deelen et al. 2013). Overall, the relationship between telomeres, aging, healthy aging, and longevity is multi-layered. Telomere maintenance is an important process in aging, and also a biomarker of it. LTL is a biomarker of aging and of healthy aging. Variation in telomere maintenance genes appears to affect both telomere length, and life span and health span in humans.

Two recent large-scale analyses of data from GWAS studies have established that mosaicism for large genomic alterations increases with age (Laurie et al. 2012; Jacobs et al. 2012). In one study, data for 50,222 subjects found that <0.5% of people aged <50, and 23% of elderly (2.7% in subjects >80years), have detectable mosaicism in peripheral blood. Age was a significant predictor of mosaic status, but sex, ancestry, and smoking status were not. The second study used data from 31,717 cancer cases and 26,136 controls from 13 GWAS studies and found detectable clonal mosaicism in 0.87% of individuals. In the cancer-free controls, they found mosaicism in 0.23% of those <50years old and in 1.91% of those aged 7579, a significant difference (p=4.8108). Somatic mosaicism (heteroplasmy) of the mitochondrial genome also increases over the lifespan (Sondheimer et al. 2011). Of course, telomere shortening is another somatic genomic change that occurs over the human lifespan. Such somatic changes are both a genetic aspect of aging and an aging-related phenotype.

Epigenetics, at the interface between the genome and the environment, is emerging as an important factor in longevity, and has been the subject of recent excellent reviews (Gravina and Vijg 2010; Ben-Avraham et al. 2012). Methylation patterns change with age, and discordance in methylation between MZ twins also increases with age (Talens et al. 2012), an observation consistent with the effect of environment and lifestyle on the epigenome. Studies of DNA methylation support the idea that aging is associated with a relaxation of epigenetic control and that this epigenetic drift may affect the development of aging-related diseases (Gravina and Vijg 2010). An epigenome-wide association scan (EWAS) identified age-related differentially methylated regions as well as differentially methylated regions associated with age-related phenotypes (Bell et al. 2012). Whole genome bisulfite sequencing of DNA from CD4+ T cells of a centenarian and a newborn identified differentially methylated regions that were usually hypomethylated and less correlated with methylation of adjacent CpG dinucleotides in the centenarian (Heyn et al. 2012). These results support the idea that small cumulative DNA methylation changes accumulate over a lifetime. Age-related temporal changes in DNA methylation also show significant familial clustering, indicating that methylation maintenance is a familial trait (Bjornsson et al. 2008). A study of DNA methylation in centenarians and their offspring compared with the offspring of non-long-lived individuals and young individuals showed that the offspring of the centenarians delay age-related methylation changes (Gentilini 2012). A landmark paper by Hannum et al. (2013) offers an explanation for this familiality. They used methylome analysis to compare human aging rates in individuals of age 19101 and identify methylation QTLs (meQTLs) (including one at methyl-CpG binding domain protein 4) that affect it. Indeed, trans-generational epigenetic inheritance of extended lifespan has been demonstrated in C. elegans (Greer et al. 2011).

It is likely that the effects of epigenetic changes manifest in part by effects on gene expression. Longevity-selected lines of Drosophila show gene expression profiles that are similar to younger control flies (Sarup et al. 2011). This type of observation is more difficult to make in humans, however. Several human studies have compared gene expression between LLI and younger individuals. Blood miRNA expression differences between LLI and younger controls identified genes known to be differentially expressed in age-related diseases (ElSharawy et al. 2012). This study design, however, does not allow discrimination between genes that are differentially expressed because they are involved in longevity, related to chronological age, or affected by environmental differences between the old and young groups. A cross-sectional analysis of individuals aged 5090, and centenarians, was used to identify a miRNA, miR-363*, whose expression declined with age but was preserved at youthful levels in the centenarians (Gombar et al. 2012). The Leiden Longevity Study, however, used LLI and their offspring to show that RPTOR in the mTOR pathway is differentially expressed between the offspring of the LLI and their spouses (Passtoors et al. 2013). The study design issues that are important to avoid confounding by lifestyle factors in studies of inherited factors will be even more important in gene expression studies. It seems likely that as yet unidentified genetic factors and lifestyle practices that help us maintain a favorable epigenetic profile and optimal gene expression will be important in longevity and healthy aging.

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Overview

The type and severity of the side effects from high-dose chemotherapy and allogeneic stem cell transplant are influenced by the degree of HLA matching between donor and recipient; the condition and age of the patient; the specific high-dose chemotherapy treatment regimen; and the degree of suppression of the immune system. The safety of allogeneic transplant has improved a great deal because of advancements in supportive care to manage the many potential side effects. While high doses of chemotherapy and radiation therapy can potentially affect any of the bodys normal cells or organs, the more common side effects are well described and include the following:

Bone Marrow Suppression

High-dose chemotherapy directly destroys the bone marrows ability to produce white blood cells, red blood cells and platelets. Patients experience side effects from low numbers of white blood cells (neutropenia), red blood cells (anemia) and platelets (thrombocytopenia). Patients usually need blood and platelet transfusions to treat anemia and thrombocytopenia until the new graft beings producing blood cells. The duration of bone marrow suppression can be shortened by infusing an optimal number of stem cells and growth factors that hasten the recovery of blood cell production.

Infections

During the 2-3 weeks it takes the new bone marrow to grow and produce white blood cells, patients are susceptible to infection and require the administration of antibiotics to prevent bacterial and fungal infections. Bacterial infections are the most common during this initial period of neutropenia. Stem cells collected from peripheral blood tend to engraft faster than bone marrow and may reduce the risk of infection by shortening the period of neutropenia. The growth factor Neupogen also increases the rate of white blood cell recovery and has been approved by the Food and Drug Administration for use during allogeneic stem cell transplant.

The immune system takes even longer to recover than white blood cell production, with a resultant susceptibility to some bacterial, fungal and viral infections for weeks to months. Patients are often required to take antibiotics to prevent infections from occurring for weeks to months after initial recovery from allogeneic stem cell transplant. Prophylactic antibiotic administration can prevent Pneumocystis carinii pneumonia and some bacterial and fungal infections. Prophylactic antibiotics can also decrease the incidence of herpes zoster infection, which commonly occurs after high-dose chemotherapy and allogeneic stem cell transplant.

Mucositis

Mucositis is an inflammation of the lining of the mouth or gastrointestinal (GI) tract. This condition is also commonly referred to as mouth sores. Mucositis is one of the most common side effects of the intensive therapy that precedes stem cell transplantation. The majority of patients treated with a stem cell transplant will develop mucositis. In fact, patients undergoing stem cell transplantation have complained that mucositis is the single most debilitating side effect from treatment.[1]

Chemotherapy and radiation therapy are effective at killing rapidly dividing cells, a hallmark characteristic of some cancers. Unfortunately, many normal cells in the body are also rapidly dividing and can sustain damage from chemotherapy as well. The entire GI tract, including the mouth and the throat, is made up of cells that divide rapidly. For this reason, the GI tract is particularly susceptible to damage by chemotherapy and radiation treatment, which results in mucositis.

Until recently, the only approaches to managing oral mucositis included good oral care; mouthwashes; cryotherapy (sucking on ice chips) to minimize the damage from chemotherapy drugs; Salagen, a drug that stimulates salivary flow; and other investigational treatments.

A promising new approach to the prevention and treatment of mouth sores is the use of growth factors. Growth factors are natural substances produced by the body to stimulate cell growth. The body produces many different types of growth factors. Kepivance (palifermin)is a type of growth factor that is made through laboratory processes to mimic the natural compound made in the body. Kepivance has properties that stimulate the cells that line the mouth and GI tract (called epithelial cells) to grow and develop, which may help to reduce mucositis.

Kepivance is the first FDA-approved drug for the prevention and treatment of oral mucositis. In clinical trials, Kepivance has demonstrated the ability to protect the epithelial cells from the damaging effects of radiation, and chemotherapy in patients undergoing autologous stem cell transplants[2],[3],[4],[5] and is being further evaluated to determine whether it may benefit patients undergoing allogeneic stem cell transplantation.

Veno-Occlusive Disease of the Liver (VOD)

High-dose chemotherapy can result in damage to the liver, which can be serious and even fatal. This complication is increased in patients who have had a lot of previous chemotherapy and/or radiation therapy, a history of liver damage or hepatitis. Veno-occlusive disease of the liver typically occurs in the first 2 weeks after high-dose chemotherapy treatment. Patients typically experience symptoms of abdominal fullness or swelling, liver tenderness and weight gain from fluid retention. Development of strategies to prevent or treat veno-occlusive disease is an active area of clinical investigation.

Interstitial Pneumonia Syndrome (IPS)

High-dose chemotherapy can cause damage directly to the cells of the lungs. This may be more frequent in patients treated with certain types of chemotherapy and/or radiation therapy given prior to the transplant. This complication of transplant may occur anytime from a few days after high-dose chemotherapy to several months after treatment. This often occurs after a patient has returned home from a transplant center and is being seen by a local oncologist.

Patients typically experience a dry non-productive cough or shortness of breath. Both patients and their doctors often misinterpret these early symptoms. Patients experiencing shortness of breath or a new cough after allogeneic transplant should bring this to the immediate attention of their doctor since this can be a serious and even fatal complication.

Graft-versus-Host Disease (GVHD)

Graft-versus-host disease is a common complication of allogeneic stem cell transplant. Lymphocytes contained in donated marrow or blood stem cells cause a reaction called graft-versus-host disease. In this reaction, lymphocytes from the donor attack cells in the body of the recipient especially in the skin, gastrointestinal tract and liver. The common symptoms of acute graft-versus-host disease are skin rashes, jaundice, liver disease and diarrhea. Graft-versus-host disease also increases a patients susceptibility to infection. Graft-versus-host disease can develop within days or as long as 3 years after transplantation. Generally, graft-versus-host disease that develops within 3 months following transplantation is called acute graft-versus-host disease, whereas graft-versus-host disease that develops later is called chronic graft-versus-host disease.

Removal of T-lymphocytes from the stem cell collection and immunosuppressive drugs such as methotrexate, cyclosporine, prednisone and other new agents administered after bone marrow or blood stem cell infusion are used to prevent or ameliorate graft-versus-host disease. Graft-versus-host disease can also have an anti-cancer effect because donor lymphocytes can kill cancer cells as well as normal cells. When donor lymphocytes kill cancer cells, doctors refer to this as agraft-versus-cancer effect. There are ongoing studies attempting to control this graft-versus-cancer reaction for therapeutic purposes.

Graft Failure

Graft failure occurs when bone marrow function does not return. The graft may fail to grow or be rejected in the patient resulting in bone marrow failure with the absence of red blood cell, white blood cell and platelet production. This results in infection, anemia and bleeding. Insufficient immune system suppression is the main cause of graft rejection. Graft failure may also occur in patients with extensive marrow fibrosis before transplantation, a viral illness or from the use of some drugs (such as methotrexate). In leukemia patients, graft failure often is associated with a recurrence of cancer; the leukemic cells may inhibit the growth of the transplanted cells. In some cases, the reasons for graft failure are not known.

Long-Term Side Effects of Allogeneic Stem Cell Transplant

There are several long-term or late side effects that result from the chemotherapy and radiation therapy used with allogeneic stem cell transplant. The frequency and severity of these problems depends on the radiation or chemotherapy that was used to treat the patient. It is important to have the doctors providing your care explain the specific long-term side effects that can occur for the actual treatment they propose. Some examples of complications you should be aware of include the following:

Cataracts:Cataracts occur in the overwhelming majority of patients who receive total body irradiation in their treatment regimen. In patients who receive chemotherapy without total body irradiation, cataracts are much less frequent. The onset of cataracts typically begins 18-24 months following treatment. Patients who have received large doses of steroids will have an increased frequency and earlier onset of cataracts. Patients are advised to have slit lamp eye evaluations annually and early correction with artificial lenses.

Infertility:The overwhelming majority of women who receive total body irradiation will be sterile. However, some prepubertal and adolescent females do recover ovulation and menstruation. In patients who receive chemotherapy only preparative regimens, the incidence of sterility is more variable and more age related, i.e., the older the woman is at the time of treatment the more likely chemotherapy will produce anovulation. These are important considerations because of the need for hormone replacement. All females should have frequent gynecologic follow-up.

The overwhelming majority of men who receive total body irradiation will become sterile. Sterility is much more variable after chemotherapy only regimens. Men should have sperm counts done to determine whether or not sperm are present and should be examined over time, as recovery can occur.

New cancers:Treatment with chemotherapy and radiation therapy is known to increase the risk of developing a new cancer. These are called secondary cancers and may occur as a late complication of high-dose chemotherapy. Patients treated with high-dose chemotherapy and allogeneic stem cell transplantation appear to have an increased risk of developing a secondary cancer. In a report evaluating almost 20,000 patients treated with allogeneic stem cell transplantation, 80 patients developed a new cancer. This represents an approximate 2.5% greater risk compared to normal individuals

The longer patients survived after high-dose chemotherapy and allogeneic stem cell transplantation, the greater the risk of developing a secondary cancer. Patients treated with total body irradiation appear to be more likely to develop new cancer than those treated with lower radiation doses or high-dose chemotherapy. High-dose chemotherapy and allogeneic stem cell transplant is increasingly used to treat certain cancers because it improves cure rates. Patients should be aware of the risk of secondary cancer following high-dose chemotherapy treatment and discuss the benefits and risks of high-dose chemotherapy with their primary cancer physician.

References

1. Bellm LA, Epstein JB, Rose-Ped A, et al. Patient Reports of Complications of Bone Marrow Transplantation. Support Care Cancer. 2000;8:33-39.

2. Spielberger R, Emmanouilides C, Stiff P. Use of recombinant human keratinocyte growth factor (rHuKGF) can reduce severe oral mucositis in patients (pts) with hematologic malignancies undergoing autologous peripheral blood progenitor cell transplantation (auto-PBPCT) after radiation-based conditioning results of a phase 3 trial. Proceedings of the 39th meeting of the American Society of Oncology 2003;22: Abstract #3642.

3. Emmanouilides C, Spielberger R, Stiff P, Rong A, et al. Palifermin Treatment of Mucositis in Transplant Patients Reduces Health Resource Use: Phase 3 Results. Proc Am Soc Hem. Blood. 2003;102(11):251a, Abstract #883.

4. Syrjala KL, Hays RD, Kallich JD, Farivar SS, et al. Impact of Oral Mucositis and Its Sequelae on Quality of Life. Proc Am Soc Hem. Blood. 2003;102(11):751a, Abstract #2771.

5. Stiff P, Bensinger W, Emmanouilides C, Gentil T, et al. Treatment of Mucositis with Palifermin Improves Patient Function and Results in a Clinically Meaningful Reduction in Mouth and Throat Soreness (MTS): Phase 3 Results. Proc Am Soc Hem. Blood 2003;102(11):194a, Abstract #676.

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Complications or Side Effects of Allogeneic Stem Cell ...

Recognition.The antigen or cell is recognized as nonself. To differentiate self from nonself, unique molecules on the plasma membrane of cells called themajor histocompatibility complex (MHC)are used as a means of identification.

Lymphocyte selection.The primary defending cells of the immune system are certain white blood cells called lymphocytes. The immune system potentially possesses billions of lymphocytes, each equipped to target a different antigen. When an antigen, or nonself cell, binds to a lymphocyte, the lymphocyte proliferates, producing numerous daughter cells, all identical copies of the parent cell. This process is calledclonal selectionbecause the lymphocyte to which the antigen effectively binds is selected and subsequently reproduces to make clones, or identical copies, of itself.

Lymphocyte activation.The binding of an antigen or foreign cell to a lymphocyte may activate the lymphocyte and initiate proliferation. In most cases, however, a costimulator is required before proliferation begins. Costimulators may be chemicals or other cells.

Destruction of the foreign substance.Lymphocytes and antibodies destroy or immobilize the foreign substance. Nonspecific defense mechanisms (phagocytes, NK cells) help eliminate the invader.

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Specific Defense (The Immune System) - Written by Teachers

What is the Immune System?

Just like the human immune system, the animal immune system is an amazingly intricate and complex system that keeps animals healthy and protects them against all sorts of invaders including viruses, bacteria, microbes, parasites and toxins. The subject of immunity and the immune system is one that regularly crops up in conversation, in the newspaper and in magazines not to mention the vast number of adverts promoting products aimed at working with this system.

If the immune system is weakened, every body system in the animal body is at risk. In order to understand the true importance of the immune system, we firstly need to understand a little bit about how the immune system works.

How does the animal Immune System Work?

The animal immune system has many different components both inside and outside the animal body. If we start from the outside we will see that an animals body has many different barriers that form part of his or her immune system.

While an animals skin is obviously a physical barrier to many germs and toxins, it also contains special immune cells that act as warning bells to alert the immune system to any foreign material, while also regulating the immune response to this material this is evident in the skin of an animal reacting to fleas or certain plants.

The skin also secretes antibacterial substances that hinder the growth of excess bacteria on the skin. An animals eyes, nose and mouth are all possible ports of entry for invading germs but an animals tears, nasal secretions and saliva all contain enzymes or cells of the immune system to keep the invaders at bay.

The mucous membrane linings of the respiratory, gastrointestinal, and genitourinary tracts also provide the one of the first lines of defense against invasion by microbes or parasites. Internal defense mechanisms for an animal include the Lymphatic system, Thymus gland, bone marrow, spleen, white blood cells and antibodies.

The immune system is amazingly resilient and powerful system, protecting an animal daily from a wealth of viruses, bacteria, foreign cells and an animals own body cells that have "gone bad" such as cancer cells. However, like with most amazing systems, sometimes things go wrong.

Many animals suffer from allergies that are caused by a hypersensitivity reaction of the immune system to certain allergens in the environment. When these antigens enter the body system, the immune system tends to over react and antibodies quickly cause the release of histamine which results in an allergic reaction.

These reactions differ in severity and may include itchiness, lesions, blocked sinus, Asthma, Eczema and Contact dermatitis. When cells of the immune system are over-produced, they become out of control and the result is cancer or auto immune diseases, for example in humans when the body over produces white blood cells, the result is leukemia.

Antibiotics are created for the purpose of treating bacterial infections when an animals immune system cannot mount an adequate response. So does it not stand to reason that if an animals immune system were strong enough it would not need the antibiotics? Antibiotics are specific chemicals aimed at killing off the targeted bacteria.

They are not effective against viruses and should not be given to a pet for a viral infection. Unfortunately antibiotics have been excessively and improperly used -The more you give your animals antibiotics, the more you depress their immune systems - and the more depressed their immune systems are, the more likely they are to get another infection and if they get another infection they are given another antibiotic and so the vicious cycle continues!

There is a lot that can be done naturally to help boost your pets immune system. A strong, healthy immune system is the best armor you can give your animal. Here are some of the lifestyle factors that you can employ with your pets to keep their immune systems in peak condition and able to ward off recurrent infections:

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Immune System - PetAlive

HIV, AIDS and the Immune SystemAIDS, HIV and The Immune SystemIntroductionThe virus responsible for the condition known as AIDS (Acquired Immunodeficiency Syndrome), is named HIV (Human Immunodeficiency Virus). AIDS is the condition whereby the body's specific defense system against all infectious agents no longer functions properly. There is a focused loss over time of immune cell function which allows intrusion by several different infectious agents, the result of which is loss of the ability of the body to fight infection and the subsequent acquisition of diseases such as pneumonia. We will examine the virus itself, the immune system, the specific effect(s) of HIV on the immune system, the research efforts presently being made to investigate this disease, and finally, how one can try to prevent acquiring HIV.The VirusHIV is one member of the group of viruses known as retroviruses. The term "retrovirus" stems from the fact that these kinds of viruses are capable of copying RNA into DNA. No other organism so far discovered on earth is capable of this ability. The virus has two exact copies of single-stranded RNA as its basic genetic material (genome) in the very center of the organism. The genome is surrounded by a spherical core made of various proteins in tightly-packed association with one another. The core is itself surrounded by a membrane (called an "envelope", made of fat [lipids] and various membrane-bound proteins). One of the membrane-boundproteins can bind to a particular protein on the surface of certain immune cells, called T-cells (we'll talk about these in a minute) which results in the virus becoming physically attached. Upon binding, the virus is brought inside of the T-cell (cells do this kind of thing all of the time), and the envelope is removed by enzymes normally present inside the cell. The internal core is thus exposed, and it too is broken-down. This last phase results in exposure of the virus's RNA genetic material. An enzyme attached to the RNA, known as "reverse transcriptase", begins to make a complimentary base-pair single-strand copy of the RNA into DNA (please see What the Heck is PCR? ). The single strand of DNA is also copied by the same enzyme to form double-stranded DNA. This DNA inserts somewhere into one of the 46 chromosomes within our cells, and there it is used as a template for production of all of the things necessary to form new virus particles ( replication of the virus). These new virus particles can be subsequently released from the infected cell, and can infect adjacent cells.The Immune SystemThe immune system is a system within all vertebrates (animals with a backbone) which in general terms, is comprised of two important cell types: the B-cell and the T-cell. The B-cell is responsible for the production of antibodies (proteins which can bind to specific molecular shapes), and the T-cell (two types) is responsible either for helping the B-cell to make antibodies, or for the killing of damaged or "different" cells (all foreign cells except bacteria) within the body. The two main types of T-cells are the "helper"T-cell and the cytotoxic T-cell. The T-helper population is further divided into those which help B-cells (Th2) and those which help cytotoxic T-cells (Th1). Therefore, in order for a B-cell to do its job requires the biochemical help of Th2 helper T-cells; and, for a cytotoxic T-cell to be able to eliminate a damaged cell (say, a virally-infected cell), requires the biochemical help of a Th1 helper T-cell.

Whenever any foreign substance or agent enters our body, the immune system is activated. Both B- and T-cell members respond to the threat, which eventually results in the elimination of the substance or agent from our bodies. If the agent which gains entry is the kind which remains outside of our cells all of the time (extracellular pathogen), or much of the time (virus often released) the "best" response is the production by B-cells of antibodies which circulate all around the body in the bloodstream, and eventually bind to the agent. There are mechanisms available which are very good at destroying anything which has an antibody bound to it. On the other hand, if the agent is one which goes inside one of our cells and remains there most of the time (intracellular pathogens like viruses or certain bacteria which require the inside of one of our cells in order to live), the "best" response is the activation of cytotoxic T-cells (circulate in the bloodstream and lymph), which eliminate the agent through killing of the cell which contains the agent (agent is otherwise "hidden"). Both of these kinds of responses (B-cell or cytotoxic T-cell) of course require specific helper T-cell biochemical information as described above. Usually, both B-cell and cytotoxic T-cell responses occur against intracellular agents which provides a two-pronged attack. Normally, these actions are wonderfully protective of us. The effect of HIV on the immune system is the result of a gradual(usually) elimination of the Th1 and Th2 helper T-cell sub-populations.

The fight between the virus and the immune system for supremacy is continuous. Our body responds to this onslaught through production of more T-cells, some of which mature to become helper T-cells. The virus eventually infects these targets and eliminates them, too. More T-cells are produced; these too become infected, and are killed by the virus. This fight may continue for up to ten years before the body eventually succumbs, apparently because of the inability to any-longer produce T-cells. This loss of helper T-cells finally results in the complete inability of our body to ward-off even the weakest of organisms (all kinds of bacteria and viruses other than HIV) which are normally not ever a problem to us. This acquired condition of immunodeficiency is called, AIDS.

Our immune system's ability to recognize any foreign substance or agent, depends entirely upon how the substance or agent "looks" with respect to the molecular shapes displayed - just as your elbow looks different than someone else's elbow - even though each are clearly elbows. Therefore, while an individual may become infected with a single strain of HIV, over several years of many, many viral generations, an individual may have 10 different strains of HIV present. Further, to date no two people have been identified to have been infected with the same strain of HIV. Consequently, against which strain should a population be immunized? In such cases, one tries to identify molecular shapes which are common to all known strains - in this way, all strains would theoretically be recognizable by our immune system. Sadly, this research has failed to provide an effective vaccine. This virus is subtle, and can do some very covert things using biochemical mechanisms we do not yet understand. Because of recent basic research in the field of immunology (the discipline which develops an understanding of the intricate workings of the immune system), based upon years of previous basic research in this and other fields however, some light is beginning to emerge which may help us.

It is becoming clear that the two helper T-cell types identified only a few years ago may be significantly more important than first assumed. Remember, the Th1 helper-cell helps generate a cytotoxic T-cell response, and the Th2 helper-cell helps generate an antibody response. As it turns out, certain intracellular pathogens primarily elicit a Th2 response in certain in-bred strains of mice, while in a different in-bred mouse strain, the same pathogen primarily elicits a Th1 response. In this example, all mice which respond primarily with antibody (B-cell; Th2 help), die; and, all mice which primarily respond with a cytotoxic T-cell response (Th1 help), live! Such is not the case for every intracellular pathogen - some responses are very balanced with respect to B-cell and cytotoxic T-cell contributions, and others are imbalanced in one or the other direction. The balance in contribution of these two paths to an immune response, appears to not only depend upon the particular infectious organism, but also upon the particular genetic background of the infected animal. Thus, one can imagine that one may be able to find a way to tip the balance towards the most effective response path against a given organism, e.g., either antibody production by B-cells, or development of cytotoxic T-cells. This research is one of the prime areas under investigation with regard to HIV. There are very limited data to date; but, those individuals who have had HIV for a really long time, but have not yet acquired AIDS (there are indeed now a number of such individuals), appear to have their immune response shifted towards the cytotoxic side (Th1 help). This limited information on HIV, in combination with basic research information on several different diseases using animal models (mice), has generated a quick response within the research community. Consequently, there are efforts currently underway to identify the biochemical substances which are involved in directing a response along the Th1 path, and efforts to determine how the immune system might be manipulated to direct a response along a given path. Such experimentation is long and difficult, and requires money, skill, unflinching commitment, and an abiding faith that this problem can be solved.

Under normal circumstances, the design of the immune system's various tissues and connections, allows the agent to be focused within a regional lymph node, which greatly improves the probability of an effective defensive response. In the case of HIV, however, this ability either brings the target cells to the virus, or brings the virus to the target cells. Consequently, the only way to prevent exposure to the virus, is to avoid situations which allow the potential for entry of the virus. Such situations are overwhelmingly associated with sexual intercourse, intravenous drug use, and exposure of a cut in one's skin to the bodily fluids (secretions, blood) of an HIV-infected individual. Such situations do not include hugging, touching, or other nonfluid-exchange expressions of caring for someone infected with HIV.

Oral, vaginal, and anal intercourse can lead to tiny abrasions of the mucosal tissue in these areas; and, within the tissues of the mouth (gums in particular) there will almost always be tiny abrasions present under any circumstances. These openings provide access by the virus to the blood and lymphatic streams, as well as to cells within the tissue. If a person is infected with HIV, there will be virus within the secretions of the person (particularly the seminal fluid of males), and in the blood of the person.Consequently, the direct exposure to bodily fluids (secretions, blood) can potentially occur between both partners (female/female, male/male, female/male) during any kind of sexual intercourse, whether or not ejaculation by a male partner occurs. While the body may be able to ward-off a small amount of virus, repeated exposure to such amounts places a person, particularly women having vaginal intercourse, and men and women having anal intercourse with an HIV-infected partner, at significant risk of HIV infection. Under any circumstance, there is a risk of HIV infection through only one sexual intercourse encounter. The use of a condom for the male partner, in combination with chemical substances which kill viruses, is recommended. Multiple sexual partners, unprotected sexual intercourse, anal sexual intercourse, the presence of other sexually-transmitted disease, and intravenous drug usage significantly increase the risk of HIV infection.

One can be tested for the presence of HIV through an appointment with one's local Health Department (state-supported). Health department test results are completely confidential and inaccesible to anyone but the patient and testing physician at the public-health clinic. While a personal physician's records are also confidential, these records are however, subject to examination at any time by the health insurer(s) of the physician.No matter where one chooses to be examined, one will be required to undergo a pre-test and post-test psychological counseling session.

Recent Statistics (January, 1995): The CDC report showed 401,749 cases of AIDS in the U.S. through the middle of 1994, while approximately one-million within the U.S. are infected with HIV. Twenty percent of all AIDS cases within the U.S. are within the 20s age-group - (apparently contracted HIV while teenagers).

The CDC AIDS Hotlines are:English: 800-342-2437 (800-342-AIDS)Spanish: 800-344-7432 (800-344-SIDA)Deaf: 800-243-7889.Your local Health Department is also a good source of information. Become informed.

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AIDS, HIV and The Immune System - Single Sign-On | The ...

The U.S. Department of Agriculture's Food Safety and Inspection Service (FSIS) announced that H-E-B Meat Plant, a San Antonio, Tex. establishment, is recalling approximately 1,150 pounds of diced chicken thighs due to misbranding and undeclared allergens. There have been no confirmed reports of adverse reactions due to consumption of these products.

Sid Wainer & Son of New Bedford, MA announced the recall of Jansal Valley brand Dried Chili De Arbol Peppers due to presence of allergen, peanuts. No illnesses have been reported to date in connection with this problem. During repacking, the peanut contamination was discovered in the sealed bulk containers of the product.

TAI FOONG USA of Seattle, WA announced the recall of Royal Asia Shrimp Wonton Noodle Soup due to undeclared egg. One allergic reaction complaint has been confirmed to date, due to consumption of the recalled product.

Prestage Foods, Inc., a St. Pauls, N.C. establishment, is recalling approximately 38,475 pounds of ground turkey that may be contaminated with extraneous materials. The fresh ground turkey was produced on September 25 and 26, 2017. There have been no confirmed reports of adverse reactions due to consumption of these products.

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Overview of PBSCT

Peripheral blood stem cell transplants, or PBSCT's, are procedures that restore stem cells that have been destroyed by high doses of chemotherapy. Stem cells are cells that give rise to the blood cells -- red blood cells that carry oxygen, white blood cells that help the body to fight infections, and platelets that help make the blood clot.

It used to be that stem cell transplants came from donated bone marrow.

Though most of the stem cells are present in bone marrow, some are out circulating -- in the peripheral blood stream. These can be collected and then transfused in patients to restore their stem cell reserve. Most stem cell transplants (but not all for a number of reasons) are now PBSCT's. Prior to donating stem cells, donors are given a medication which increases the number of stem cells in the blood. Peripheral blood stem cells work very well when compared with bone marrow transplants, and in fact, in some cases may result in platelets and a type of white blood cells known as neutrophils "taking" even better, when the donor is not related to the recipient.

In order to really understand how stem cell transplants work, it can help to talk a little more about what stem cells really are. As noted above, stem cells -- also known as hematopoietic stem cells - give rise to all the different types of blood cells in the body.

By transplanting stem cells which can subsequently differentiate and evolve into the different types of blood cells - a process called hematopoiesis - a transplant can replace a deficiency in all of the type of blood cells.

In contrast, medical treatments to replace all of these cells are intensive and carry many complications.

For example, you can give platelet transfusions, red blood cell transfusions, and give medications to stimulate both the formation of red blood cells and white blood cells, but this is very intensive, difficult, and has many side effects and complications.

Chemotherapy delivered in high doses destroys cancers better, but also destroys stem cells present in the bone marrow. Stem cell transplants help restore the bone marrow so that the patient can tolerate the high doses of chemotherapy.

There are three types of stem cell transplant:

PBSC donation involves taking circulating blood stem cells, rather than cells from the bone marrow, so theres no pain from accessing the bone marrow. But in PBSC, the medication given to boost the number of stem cells in the donors circulation can be associated with body aches, muscle aches, headaches, and flu-like symptoms.

These side effects generally stop a few days after the last dose of the stem-cell-boosting medication.

There are many possible complications of PBSCT's. The high dose chemotherapy prior to the transplant poses a serious risk of infection due to a lack of white blood cells (immunosuppression) as well as problems related to a lack of red blood cells (anemia) and low platelets (thrombocytopenia.)

A common risk after transplant is that of graft versus host disease (GvH), which happens to some degree in almost all stem cell transplants. In GvH disease the transplanted cells (from the donor) recognize the host (the recipient of the transplant) as foreign, and attack.

For this reason people are given immunosuppresive drugs following a stem cell transplant.

Yet the immunosuppressive drugs also pose risks. The decrease in immune response due to these drugs increases the risk of serious infections, and also increases the risk of developing other cancers.

Undergoing a PBSCT is a major procedure. Not only is it preceded by very aggressive chemotherapy, but the symptoms of graft versus host disease, and complications of immunosuppressive drugs make it a procedure that is usually reserved for younger, and in general very healthy, people.

One option that may be considered for patients who are older or in compromised health is a non-myeloablative stem cell transplant. In this procedure, instead of ablating (essentially destroying) the bone marrow with very high dose chemotherapy, a lower dose of chemotherapy is used. The secret behind these forms of transplants actually lies in a type of graft versus host disease. Yet, instead of the graft - the transplanted stem cells - attacking "good" cells in the recipients body, the transplanted stem cells attack the cancerous cells in the recipients body. This behavior is termed "graft versus tumor."

Also Known As:

PBSCT, Peripheral Blood Stem Cell Transplantation

Related Terms:

HSCT = hematopoietic stem cell transplantation

HCT = hematopoietic cell transplantation

SCT = stem cell transplant

G-CSF = Granulocyte-colony stimulating factor -- a growth factor, a stem cell boosting medication, sometimes given to donors to mobilize hematopoietic stem cells from the bone marrow into the peripheral blood.

Sources:

National Cancer Institute. Stem Cell Transplant. Updated 04/19/15. http://www.cancer.gov/about-cancer/treatment/types/stem-cell-transplant

Singh, V., Kumar, N., Kalsan, M., Saini, A., and R. Chandra. Mechanism of Induction: Induced Pluripotent Stem Cells (iPSCs). Journal of Stem Cells. 2015. 10(1):43-62.

Wu, S., Zhang, C., Zhang, X., Xu, Y., and T. Deng. Is peripheral blood or bone marrow a better source of stem cells for transplantation in cases of HLA-matched unrelated donors? A meta-analysis. Critical Reviews in Oncology and Hematology. 2015. 96(1):20-33.

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Peripheral Blood Stem Cell Transplant (PBSCT) - Verywell

Even with the success of the Human Genome Project, there still isn't a genetic test for every disease. A disease may run in a family and clearly be inherited, but the gene responsible may not be identified yet. Our team will see if there is a genetic test available for the condition running in your family.

If a test exists, we will find the best laboratory to use. Some laboratories offer clinical testing and must follow federal quality control standards. Clinical laboratories typically quote a fixed price and a standard return time for results.

Other laboratories offer research testing and are usually linked to academic centers and universities. They do testing at no cost in most cases. Often research laboratories do not provide results. If they do, it may take months or years to deliver results. Research test results should be confirmed in a clinical laboratory if medical management is based on the result.

Testing costs and turnaround times vary. Genetic test results are usually ready in three to four weeks. Though genetic testing costs are often paid for by insurance carriers, patients may be required to pay some or all of the cost when the test is ordered. When indicated we can write a letter of medical necessity explaining the benefits genetic testing might have for you. This can often increase the likelihood that your insurance company will pay for the testing.

Not everyone who has a genetic disease will have a mutation or a biochemical abnormality that shows up in testing. Because of this limitation, in a family it makes sense to first test someone who has had the disease in question.

If a genetic risk factor is found, ways of managing or preventing the disease due to that genetic risk can be discussed. Additionally, at-risk relatives can check their own status by testing for that specific risk factor. If that specific genetic risk factor is not found in an at-risk relative (i.e., they have a normal test result), he or she can be reassured. If the at-risk relative has a positive genetic test result, he or she has a greater chance of getting the condition. Relatives whose risk has been confirmed can start screening and prevention practices targeted for their genetic risk.

Sometimes testing a family member who has the disease isn't possible. (The person may be dead, unavailable or unwilling to be tested.) Then, an unaffected person can take the test. Finding a genetic risk factor will certainly give useful information. But a normal test result doesn't always mean there's no risk. Many genes responsible for an inherited susceptibility are not yet known. In other words, a normal test result can exclude the genetic risk factors that have been tested but not the possibility of an inherited susceptibility. It may be valuable to test other family members.

If you were to have genetic testing it would be important to interpret your test results in light of your personal and family medical history. We will also identify family members who might benefit from genetic consultation and genetic testing. If necessary, we can provide referrals for relatives outside the Denver area.

If you test positive for a genetic condition, you can better understand how this condition arose in you and your relatives. If you do not yet have symptoms, you can start to plan for the future, such as planning for a family, career, and retirement. You might want to start seeing specialists to help manage the condition. Preventive actions may be useful as well. Drugs, diet and lifestyle changes may help prevent the disease improve treatment.

Close relatives might value having this information. They can go through testing themselves to determine their disease risks and the best treatment approach.

If you test negative for a genetic risk factor that is known to run in your family you may be relieved that a major risk factor has been excluded.

Diagnosing a genetic condition does not tell us how or when the disease will develop. Although DNA-based genetic testing is very accurate, there is a chance that an inherited mutation will be missed. If a mutation is not found, the test results cannot exclude the possibility of an inherited risk since there may be a mutation in another gene for which testing was not done. If you still have symptoms of a genetic condition, a normal test result might not get you 'off the hook'. An inherited disease risk can only be excluded if a known mutation in the family has been excluded.

Family relationships may be affected by this information. If you have a genetic condition, other family members might benefit by also knowing. In the process of sharing your genetic risk information, family members may learn things about you that you do not want known. In addition, you may learn things about relatives that you did not want to know. For example, it may be revealed that a family member is adopted.

Some people find it hard to learn that they carry a gene that makes their risk of developing a disease greater. They may feel many emotions, including anger, fear about the future, anxiety about their health or guilt about passing a mutation on to their children. They may be shocked by the news. They may go through denial or a change in their self-esteem.

Knowing that you have a higher risk of getting a particular disease (when you don't currently show symptoms) may affect your ability to be insured (health, life and disability). Several state and federal laws prohibit use of genetic information by health insurance companies. In general, health insurers cannot use this information as a pre-existing condition that could disqualify you when applying for new insurance. Genetic information cannot be used to raise premium payments or to deny coverage. However, these laws are not fully comprehensive and may not entirely prevent discrimination. You may want to contact your insurance company to see what effect, if any, genetic testing may have on your coverage.

Sometimes genetic test results are uninformative or ambiguous, making it difficult or impossible to say if a person has a higher risk. These ambiguous results can be the most difficult as they don't provide a clear-cut answer.

For people with normal test results, where the genetic risk in the family has been excluded, a variety of emotions might occur. Most people feel tremendous relief. Others may feel survivor guilt, wondering why they were spared the risk. This can sometimes lead to changes in relationships between family members.

In some cases, an inherited risk for disease seems likely but the gene responsible has not yet been identified. The Adult Medical Genetics Program can help link families with researchers studying that disease. We can contact researchers for you and help you become part of the gene discovery studies. Although being part of research studies doesn't always give you answers, it does allow you to contribute to science.

Continued here:
Information about Genetic Testing | School of Medicine ...

At the Center for Personalized Medicine we specialize in customized treatment plans for each patient. We are dedicated to help you achieve your wellness objectives.

We understand the importance of your wellness. To achieve your wellness objectives, you have come to expect the highest levels of service and patient care. As a result, we continuously commit ourselves to meeting and exceeding your expectations. To us, providing a total healthcare experience means dedicated and friendly staff, flexible and convenient hours, and the highest quality care available.

Services Offered

At the Center for Personalized Medicine we specialize in prescription natural hormone replacement for both women and men. We can also customize a vitamin program for you. Your nutritional needs are as unique to you as your fingerprint.

At the Center for Personalized Medicine we can also help your memory stay sharp, help your skin stay more youthful, and show you safe and simple ways to increase your growth hormone level. We also have nurses and nutritionists who will meet with you to develop your own individualized weight management program to help you achieve maximum weight loss and keep the weight off.

Have our doctors show you how to lower cholesterol without a prescription. We help cancer patients with nutritional support. If you have diabetes, let us show you new treatment options. In short, at the Center for Personalized Medicine we will take a functional medicine approach to your health care needs.

Whether you want to maintain your current good health, or if you have a disease, we will look at how your body works and design a treatment plan for you and you only. We do not mask your symptoms with medications, we instead try to fix the cause of the problem and use medications only when necessary.

Read more from the original source:
Center for Personalized Medicine | Founder & Director ...

Integrative medicine pairs traditional medicine with other treatments to care for your mind, body, and spirit. For example, your doctor may suggest chemotherapy to fight cancer as well as acupuncture to help manage its side effects.

It isnt just medicine. Your care team may also design a plan to help you build healthy behaviors and skills -- like smart eating habits and stress-busting activities. These things can keep you healthy for the long term.

Integrative medicine uses complementary treatments, but they have to be backed by good science. Always tell your doctor before you try a nontraditional treatment. That way, youll know if its safe and likely to work.

There are a lot of new terms to learn when you go outside regular medical care:

Conventional medicine. This is what you get from medical doctors, nurses, physical therapists, psychologists, and similar health care professionals. You might hear it called:

Alternative medicine. True to its definition, this type of care is used instead of (an alternative to) standard medical care. For example, you might go on a special diet that claims to cure cancer instead of taking drugs your doctor prescribes. This isnt common, but it does happen. Talk to your doctor before you decide to skip traditional treatment.

Complementary medicine. Its often used along with traditional medicine. It can help you manage the side effects of cancer treatment.

Integrative medicine. This approach takes the most effective treatments from different disciplines, including standard medicine and complementary approaches. The result is a personalized health plan for your unique physical and emotional needs.

Its a medical specialty. That means you can find a doctor who is board-certified in integrative medicine and trust that your treatments will be safe and proven to work. What you can expect from this kind of medical care?

You might hear it called integrative oncology. No matter what the name, the idea is the same: Treat the whole patient, not just the disease. For cancer patients especially, that includes ways to ease stress and worry and boost your sense of well-being. You might try:

Evidence is what makes the big difference between the complementary treatments that are considered part of integrative medicine and all the other complementary and alternative treatments out there (you may hear your doctor lump them together into one term: CAM). With integrative medicine, you get science-backed therapies that your doctor has chosen to treat your condition. If you try CAM on your own, you may not know whether a product or treatment is safe.

For example, the label all natural doesnt mean a product is safe. Some natural ingredients can be toxic. Others might keep your cancer treatments from working like they should.

What might CAM treatments do for you?

Acupuncture:

Hypnotherapy (hypnosis):

Massage therapy:

Meditation:

Physical activity:

Nutrition counseling:

Excerpt from:
Can Integrative Medicine Help Fight Cancer? - webmd.com

Overview

Arthritis is inflammation of one or more of your joints. The main symptoms of arthritis are joint pain and stiffness, which typically worsen with age. The most common types of arthritis are osteoarthritis and rheumatoid arthritis.

Osteoarthritis causes cartilage the hard, slippery tissue that covers the ends of bones where they form a joint to break down. Rheumatoid arthritis is an autoimmune disorder that first targets the lining of joints (synovium).

Uric acid crystals, infections or underlying disease, such as psoriasis or lupus, can cause other types of arthritis.

Treatments vary depending on the type of arthritis. The main goals of arthritis treatments are to reduce symptoms and improve quality of life.

The most common signs and symptoms of arthritis involve the joints. Depending on the type of arthritis you have, your signs and symptoms may include:

The two main types of arthritis osteoarthritis and rheumatoid arthritis damage joints in different ways.

The most common type of arthritis, osteoarthritis involves wear-and-tear damage to your joint's cartilage the hard, slick coating on the ends of bones. Enough damage can result in bone grinding directly on bone, which causes pain and restricted movement. This wear and tear can occur over many years, or it can be hastened by a joint injury or infection.

In rheumatoid arthritis, the body's immune system attacks the lining of the joint capsule, a tough membrane that encloses all the joint parts. This lining, known as the synovial membrane, becomes inflamed and swollen. The disease process can eventually destroy cartilage and bone within the joint.

Risk factors for arthritis include:

Severe arthritis, particularly if it affects your hands or arms, can make it difficult for you to do daily tasks. Arthritis of weight-bearing joints can keep you from walking comfortably or sitting up straight. In some cases, joints may become twisted and deformed.

Aug. 08, 2017

See the rest here:
Arthritis - Symptoms and causes - Mayo Clinic

A panel of experts has recommended that the Food and Drug Administration approve a treatment developed by Spark Therapeutics for a rare form of blindness. Spark Therapeutics hide caption

A panel of experts has recommended that the Food and Drug Administration approve a treatment developed by Spark Therapeutics for a rare form of blindness.

Gene therapy, which has had a roller-coaster history of high hopes and devastating disappointments, took an important step forward Thursday.

A Food and Drug Administration advisory committee endorsed the first gene therapy for an inherited disorder a rare condition that causes a progressive form of blindness that usually starts in childhood.

The recommendation came in a unanimous 16-0 vote after a daylong hearing that included emotional testimonials by doctors, parents of children blinded by the disease and from children and young adults helped by the treatment.

"Before surgery, my vision was dark. It was like sunglasses over my eyes while looking through a little tunnel," 18-year-old Misty Lovelace of Kentucky told the committee. "I can honestly say my biggest dream came true when I got my sight. I would never give it up for anything. It was truly a miracle."

Several young people described being able to ride bicycles, play baseball, see their parents' faces, read, write and venture out of their homes alone at night for the first time.

"I've been able to see things that I've never seen before, like stars, fireworks, and even the moon," Christian Guardino, 17, of Long Island, N.Y., told the committee. "I will forever be grateful for receiving gene therapy."

The FDA isn't obligated to follow the recommendations of its advisory committees, but it usually does.

If the treatment is approved, one concern is cost. Some analysts have speculated it could cost hundreds of thousands of dollars to treat each eye, meaning the cost for each patient could approach $1 million.

Spark Therapeutics of Philadelphia, which developed the treatment, hasn't said how much the company would charge. But the company has said it would help patients get access to the treatment.

Despite the likely steep price tag, the panel's endorsement was welcomed by scientists working in the field.

"It's one of the most exciting things for our field in recent memory," says Paul Yang, an assistant professor of ophthalmology at the Oregon Health and Science University who wasn't involved in developing or testing the treatment.

"This would be the first approved treatment of any sort for this condition and the first approved gene therapy treatment for the eye, in general," Yang says. "So, on multiple fronts, it's a first and ushers in a new era of gene therapy."

Ever since scientists began to unravel the genetic causes of diseases, doctors have dreamed of treating them by fixing defective genes or giving patients new, healthy genes. But those hopes dimmed when early attempts failed and sometimes even resulted in the deaths of volunteers in early studies.

But the field may have finally reached a turning point. The FDA recently approved the first so-called gene therapy product, which uses genetically modified cells from the immune system to treat a form of leukemia. And last week, scientists reported using gene therapy to successfully treat patients suffering from cerebral adrenoleukodystrophy, or ALD, a rare, fatal brain disease portrayed in the film Lorenzo's Oil. Researchers are also testing gene therapy for other causes of blindness and blood disorders such as sickle cell disease.

The gene therapy endorsed by the committee Thursday was developed for RPE65-mutation associated retinal dystrophy, which is caused by a defective gene that damages cells in the retina. About 6,000 people have the disease worldwide, including 1,000 to 2,000 people in the United States.

The treatment, which is called voretigene neparvovec, involves a genetically modified version of a harmless virus. The virus is modified to carry a healthy version of the gene into the retina. Doctors inject billions of modified viruses into both of a patient's eyes.

In a study involving 29 patients, ages 4 to 44, the treatment appeared to be safe and effective. More than 90 percent of the treated patients showed at least some improvement in their vision when tested in a specially designed obstacle course. The improvement often began within days of the treatment.

"Many went from being legally blind to not being legally blind," said Albert Maguire, a professor of ophthalmology who led the study at the University of Pennsylvania, in an interview before the hearing.

The improvement varied from patient to patient, and none of the patients regained normal vision. But some had a significant increase in their ability to see, especially at night or in dim light, which is a major problem for patients with this condition.

"What I saw in the clinic was remarkable," Maguire told the committee. "Most patients became sure of themselves and pushed aside their guides. Rarely did I see a cane after treatment."

That was the case of Allison Corona, who's now 25 and lives in Glen Head, N.Y. She underwent the treatment five years ago as part of the study.

"My light perception has improved tremendously," Corona said during an interview before the hearing. "It's been life-changing. I am able to see so much better. I am so much more independent than what I was. It is so much better."

The patients have been followed for more than three years, and the effects appear to be lasting. "We have yet to see deterioration," Maguire says. "So far the improvement is sustained."

The injections themselves did cause complications in a few patients, such as a serious infection that resulted in permanent damage, and a dangerous increase in pressure in the eye. But there were no adverse reactions or any signs of problems associated with the gene therapy itself, the researchers reported.

While this disease is rare, the same approach could work for similar forms of genetic eye disease, Maguire says."There are a lot of retinal diseases like this, and if you added them together it's a big thing because they are all incurable."

If approved, the treatment would be marketed under the name Luxturna.

View original post here:
First Gene Therapy For An Inherited Disorder Gets Expert ...

How can you tell if you have diabetes? Most early symptoms are from higher-than-normal levels of glucose, a kind of sugar, in your blood.

The warning signs can be so mild that you don't notice them. That's especially true of type 2 diabetes. Some people don't find out they have it until they get problems from long-term damage caused by the disease.

With type 1 diabetes, the symptoms usually happen quickly, in a matter of days or a few weeks. They're much more severe, too.

Both types of diabetes have some of the same telltale warning signs.

Hunger and fatigue. Your body converts the food you eat into glucose that your cells use for energy. But your cells need insulin to bring the glucose in.

If your body doesn't make enough or any insulin, or if your cells resist the insulin your body makes, the glucose can't get into them and you have no energy. This can make you more hungry and tired than usual.

Peeing more often and being thirstier. The average person usually has to pee between four and seven times in 24 hours, but people with diabetes may go a lot more.

Why? Normally your body reabsorbs glucose as it passes through your kidneys. But when diabetes pushes yourblood sugarup, your kidneys may not be able to bring it all back in. This causes the body to make more urine, and that takes fluids.

You'll have to go more often. You might pee out more, too. Because you're peeing so much, you can get very thirsty. When you drink more, you'll also pee more.

Dry mouth and itchy skin. Because your body is using fluids to make pee, there's less moisture for other things. You could get dehydrated, and your mouth may feel dry. Dry skin can make you itchy.

Blurred vision. Changing fluid levels in your body could make the lenses in your eyes swell up. They change shape and lose their ability to focus.

These tend to show up after your glucose has been high for a long time.

Yeast infections. Both men and women with diabetes can get these. Yeast feeds on glucose, so having plenty around makes it thrive. Infections can grow in any warm, moist fold of skin, including:

Slow-healing sores or cuts. Over time, high blood sugar can affect your blood flow and cause nerve damage that makes it hard for your body to heal wounds.

Pain or numbness in your feet or legs. This is another result of nerve damage.

Unplanned weight loss. If your body can't get energy from your food, it will start burning muscle and fat for energy instead. You may lose weight even though you haven't changed how you eat.

Nausea and vomiting. When your body resorts to burning fat, it makes ketones. These can build up in your blood to dangerous levels, a possibly life-threatening condition called diabetic ketoacidosis. Ketones can make you feel sick to your stomach.

If you're older than 45 or have other risks for diabetes, it's important to get tested. When you spot the condition early, you can avoid nerve damage, heart trouble, and other complications.

As a general rule, call your doctor if you:

SOURCES:

Cleveland Clinic: "Diabetes: Frequently Asked Questions" and "What Is Diabetes?"

University of Michigan Health System: "Type 1 Diabetes."

National Diabetes Information Clearinghouse: "Am I at Risk for Type 2 Diabetes? Taking Steps to Lower Your Risk of Getting Diabetes."

Baylor Scott & White Healthcare: "Urinary Frequency" and "Diabetes and Diabetic Neuropathy Hard-to-Heal Wounds."

Sutter Health: "Question & Answer: Is Sudden Weight Loss a Sign of Diabetes? If So, Why?"

Neithercott, T. Diabetes Forecast, August 2013.

University of Rochester Medical Center: "Diabetic Skin Troubles."

Joslin Diabetes Center: "Diseases of the Eye" and "Diabetic Neuropathy: What You Need to Know."

The Nemours Foundation: "When Blood Sugar Is Too High."

Virginia Mason Medical Center: "Complications."

Carolinas Health System: "Diabetes: Yeast Infections and Diabetes: What You Should Know."

Continue reading here:
Diabetes Symptoms - webmd.com

Resource page

For the purposes of the information provided on this page we have adopted the definition of the term regenerative medicine that was used in the House of Lords Regenerative Medicine Report (see below). This was:

regenerative medicine is used to refer to methods to replace or regenerate human cells, tissues or organs in order to restore or establish normal function. This includes cell therapies, tissue engineering, gene therapy and biomedical engineering techniques, as well as more traditional treatments involving pharmaceuticals, biologics and devices.

Each regulator has a clear remit and regulates distinct areas of the regenerative medicine process. However, we work closely together to provide effective advice and guidance to support establishments through the regulatory requirements. Each regulator has a core set of standards that apply depending on where you are in the process, from cell derivation to treatment. We are all focused on ensuring that the standards that are applied at one stage of the process do not act as a barrier at another.

The role of each of the regulators in regenerative medicine is set out below:

Health Research Authority (HRA) has a remit to provide an ethics opinion on clinical trials. Those involving gene therapy regenerative medicines are reviewed through the Gene Therapy Advisory Committee (GTAC). Other regenerative medicine studies may be reviewed by other appropriately flagged RECs. It also provides the Integrated Research Application System (IRAS) through which applications and approvals from GTAC/RECs and MHRA for clinical trials involving regenerative medicines can be made.

Human Fertilisation and Embryology Authority (HFEA)[external link] regulates the use of human embryos or human admixed (human-animal) embryos to derive stem cells for use in the treatment of patients.

Human Tissue Authority (HTA) [external link] remit includes regulation of organisations that remove, store and use of human tissue or cells; this includes where they are used as starting materials for Advanced Therapy Medicinal Products (ATMPs). Under the European Union Tissues and Cells Directives (EUTCD), it licenses establishments that remove, test, process, store, and distribute tissues or cells that will (or may) be used to treat patients.

Medicines and Healthcare products Regulatory Agency (MHRA)[external link] remit includes responsibility for granting the appropriate authorisation for the manufacturing site of ATMPs, which are prepared and used under the hospital exemption, and for ATMPs made and supplied under the specials scheme under the relevant provisions in medicines legislation. In the area of clinical trials, the MHRAs remit includes assessment of applications for clinical trial authorisation and the associated manufacturers licence for investigational ATMPs. The National Institute for Biological Standards and Control (NIBSC) [external link], which houses the UK National Stem Cell bank, is part of the MHRA.

Please refer to the Research Community area of the website for information about the approvals for research studies and how to apply to individual review bodies. Further information about GTAC is also provided on this site. Additionally the Stem Cell Toolkit [external link] provides regulatory routemaps that are specific to individual stem cell projects.

Department for the Environment Food and Rural Affairs (DEFRA) [external link] has an Advisory Committee on Releases to the Environment (ACRE) [external link], which advises government on requests for permission to release genetically modified organisms (GMO) into the environment. In 2013, this committee published advice on gene therapy clinical trial for heart disease.

Health and Safety Executive (HSE) [external link] has the Scientific Advisory Committee on Genetically Modified Organisms (Contained Use) SACGM (CU) [external link]. This committee provides technical and scientific advice to the UK Competent Authorities on all aspects of the human and environmental risks, and is responsible for maintaining guidance on the contained use of GMOs.

From 13 October 2014, the MHRAs Innovation Office is the portal for all regulatory queries concerning regenerative medicines. A one stop shop service provides a single point of access from the four regulators in the field, the Human Tissue Authority (HTA), the Human Fertilisation and Embryology Authority (HFEA), Health Research Authority (HRA) and the Medicines and Healthcare products Regulatory Agency (MHRA), who will provide a co-ordinated single response service for free regulatory advice.

Any query relating to the regulation of regenerative medicines, including Advanced Therapeutic Medicinal Products (ATMPs) can be submitted to the MHRAs Innovation Office and will be answered by the relevant experts from the four regulatory bodies.

Individuals or companies who have regulatory questions concerning regenerative medicines and who are unsure which agency to direct their inquiry to, or have a query that impacts several regulators, should use the Innovation Office advice form.

The HRA and others work closely together and will continue to engage with those involved in regenerative medicine, including researchers, the British Society for Gene and Stem Cell Therapy [external link], and the Cell Therapy Catapult [external link] to help clarify the regulatory requirements that apply.

The HRA recently held a regenerative medicine event hosted by the Cell Therapy Catapult to look at changes and discuss issues with the sector, regulators and representative bodies. Additionally in 2012, the MHRA hosted an event on the regulation of regenerative medicine [external link].

As set out in the Government Response to the House of Lords Inquiry [external link] a Regenerative Medicine Expert Group (RMEG) is being established to develop an NHS regenerative medicine delivery readiness strategy and action plan. This group will build on existing initiatives so that the NHS is fully prepared to deliver these innovative treatments. The group will be supported by the Department of Health; members will be drawn from a number of groups and organisations, including the HRA. The remit of the Regenerative Medicine Expert Group will include a role to monitor the effect of regulation on the development of regenerative medicines in the UK.

More generally, the HRA is working in partnership with a range of organisations to improve the environment for research in the UK. Please refer to our projects and plans pages for more information.

During 2012-13, the House of Lords Science and Technology Committee held an inquiry into regenerative medicine in the UK. For more information about the inquiry, the resulting report and the HRAs responses please use the links below:

UK Stem Cell Toolkit [external link]This toolkit is intended to be a reference tool for those who wish to develop a programme of human stem cell research and manufacture, including clinical applications. It applies only to the regulation of human stem cells and their use in the laboratory and clinical settings. The toolkit provides regulatory routemaps that are specific to individual stem cell projects. It does this by using your responses to questions when you start using the toolkit.

Clinical Trials Toolkit [external link]This toolkit provides practical advice to researchers in designing and conducting publicly funded clinical trials in the UK. It provides information on best practice and outlines the current legal and practical requirements for conducting clinical trials. The toolkit is primarily focused on Clinical Trials of Investigational Medicinal Products (CTIMPs) and the regulatory environment and requirements associated with these. However researchers and R&D staff working on trials in other areas will also find useful information and guidance of relevance to the wider trials environment.

Cell Therapy Catapult [external link]The Cell Therapy Catapult was established in 2012 to grow the UK cell therapy industry. It was set up to help businesses take innovative ideas through to commercialisation. The website has specific regulatory resource pages, which include an overview of the relevant regulations for cell therapy.

MHRA Innovation Office [external link]The MHRA Innovation Office helps organisations that are developing innovative medicines, medical devices or using novel manufacturing processes to navigate the regulatory processes in order to be able to progress their products or technologies. Examples of innovative products include Advanced Therapy Medicinal Products (ATMPs), nanotechnology, stratified medicines, novel drug/device combinations, and advanced manufacturing.

UK Regenerative Medicine Platform (UKRMP) [external link]The Medical Research Council (MRC), Biotechnology and Biological Sciences Research Council (BBSRC) and the Engineering and Physical Science Research Council (EPSRC) have established the UKRMP to address the challenges associated with translating scientific discoveries towards clinical impact.

UK Stem Cell Bank [external link]The UK Stem Cell Bank was established to provide a repository of human embryonic, foetal and adult stem cell lines as part of the UK governance for the use of human embryos for research. Its role is to provide quality controlled stocks of these cells that researchers worldwide can rely on to facilitate high quality and standardised research. It also prepares stocks of EUTCD-Grade cell lines for use as starting materials for the development of cellular therapies. The UK Stem Cell Bank is hosted by NIBSC [external link], which is part of the MHRA.

UK Trade & Investment (UKTI) Life Science Investment Organisation (LSIO) [external link]This dedicated unit within UKTI is intended to support overseas companies to invest and expand in the UK from the earliest research and development collaborations through to clinical trials, commercial operations and partnerships.

Knowledge Transfer Network (KTN) Regenerative Medicine Priority Area [external link]This is an official group within the Healthtechnologies and Medicine Knowledge Transfer Network (KTN). Knowledge Transfer Networks have been set up by the Technology Strategy Board (TSB) to facilitate collaboration and stimulate innovation by bringing together people from a range of organisations with a variety of expertise.

DEFRA Advisory Committee on Releases to the Environment (ACRE) [external link]

HSE Scientific Advisory Committee on Genetically Modified Organisms (Contained Use) (SACGM (CU) [external link].

MHRAs Clinical Trials, Biologicals and Vaccines Expert Advisory Group[external link]

Regenerative Medicine Expert Group [external link]

Read more from the original source:
Regenerative Medicine - Health Research Authority

By Dr. Mercola

Kristin Comella,1 named No. 1 on the Academy of Regenerative Practices list of Top 10 stem cell innovators, has been a stem cell researcher for nearly two decades. In this interview, she discusses the enormous regenerative potential of stem cell therapy.

Comella, who holds degrees in chemical and biomedical engineering, began working with stem cells in graduate school, using a technique called magnetic cell sorting, which involves tagging nanoparticle magnets onto cells and then separating the cells based on the proteins they express.

"What we've learned over the years is that stem cells express different proteins than other kinds of cells in your body," she explains. "That began my career in the field of stem cells."

Over the years, she's worked for several different companies. At a start-up in Maryland, she used stem cells from bone marrow (culture-expanded mesenchymal stem cells) for meniscus regeneration. By placing these cells directly into the knee joint, you can repair or even grow back a damaged meniscus.

For a time, she also headed up the Good Manufacturing Practices (GMP) facility at Tulane University, which is a U.S. Food and Drug Administration (FDA) facility located at the Tulane Center for Gene Therapy. There, her work revolved around using bone marrow mesenchymal stem cells for spinal cord regeneration.

For the past 13 years, she's worked for U.S. Stem Cell, a company founded in 1999. The company began bringing stem cells for cardiac care to the public. Muscle-derived stem cells can be used to repair heart damage associated with heart attacks. "Our company treated our first patient in 2001. Since that time, we've treated over 7,000 patients. We began looking at other indications about a decade ago. We also began looking at stem cells from a variety of different sources," she says.

The primary purpose of stem cells is to maintain, heal and regenerate tissues wherever they reside in your body. This is a continuous process that occurs inside your body throughout your life. If you didn't have stem cells, your lifespan would be about an hour, because there would be nothing to replace exhausted cells or damaged tissue. In addition, any time your body is exposed to any sort of toxin, the inflammatory process causes stem cells to swarm the area to repair the damage.

"As an example, you might have gone to the gym this morning [and] done some squats. As a result of that, you would get tiny tears inside the muscle. The stem cells that reside beneath the muscle would come out and repair all those tears.

The reason that, if you continuously go to the gym, you would start to build new muscle, is because those stem cells, hard at work underneath your muscle, are helping to repair and build that new muscle. This would apply to all of the tissues inside your body," Comella explains.

While it's easy to think of stem cell therapy as a magic bullet, it would be wise to implement strategies that nourish and thereby help optimize the stem cells you already have in your body. As noted by Comella:

"You have to create an appropriate environment for these cells to function in. If you are putting garbage into your body and you're constantly burdening your body with toxins, your stem cells are getting too distracted trying to fight off those toxins. By creating an appropriate environment, optimizing your diet and reducing exposure to toxins, that will allow the stem cells that we're putting in to really home in and focus on the true issue that we're trying to treat.

The other thing we've discovered over the years is that [stem cell therapy] is not the type of thing where you take one dose and you're cured forever. Your tissues are constantly getting damaged You're going to have to repeat-dose and use those stem cells to your advantage.

When you think about a lizard that loses its tail, it takes two years to grow back the tail. Why would we put unrealistic expectations on the stem cells that we're trying to apply to repair or replace damaged tissue? This is a very slow process. This is something that will occur over months and may require repeat dosing."

Historically, stem cells were isolated from bone marrow, and have been used for bone marrow transplants for cancer patients since the 1930s. However, you can get stem cells from just about any tissue in your body, as every tissue contains stem cells.

Your bone marrow actually has very low amounts of mesenchymal stem cells, which are now believed to be the most important, from a therapeutic perspective. Mesenchymal stem cells help trigger an immunomodulatory response or a paracrine effect, which means they send signals out to the rest of your body, calling cells to the area to help promote healing.

"What we've discovered in more recent years is that a more plentiful source of stem cells is actually your fat tissue. [Body] fat can contain up to 500 times more cells than your bone marrow, as far as these mesenchymal type stem cells go.

One thing that's also critically important when you're talking about isolating the cells is the number of other cells that are going to be part of that population. When you're isolating a bone marrow sample, this actually is very high in white blood cells, which are pro-inflammatory."

White blood cells are part of your immune response. When an injury occurs, or a foreign body enters your system, white blood cells will attack. Unfortunately, white blood cells do not discriminate, and can create quite a bit of damage as they clean the area out.

Stem cells, in particular your mesenchymal cells, quiet down the white blood cells and then start the regeneration phase, which leads to new tissue. Bone marrow tends to be very high in white blood cells and low in the mesenchymal cells. Isolating stem cells from fat tissue is preferred not only because it's easier on the patient, but fat also contains a higher population of mesenchymal cells and fewer white blood cells.

"The benefit also of isolating [stem cells from] fat is that it's a relatively simple procedure. There's typically no shortage of fat tissue, especially in Americans," Comella says. "[Also], as you age, your bone marrow declines with regards to the number of cells in it, whereas the fat tissue maintains a pretty high number of stem cells, even in older individuals.

We can successfully harvest fat off of just about anyone, regardless of their age or how thin they are. The procedure is done under local [anesthesia], meaning that the patient stays awake. They don't have to go under general anesthesia. We can harvest as few as 15 cubic centimeters of fat, which is a very small amount of fat, and still get a very high number of stem cells."

A stem cell procedure can cost anywhere from $5,000 to $15,000, depending on what you're having done, and rarely if ever will insurance cover it. Still, when you compare it to the cost of long-term medications or the out-of-pocket cost of getting a knee replacement, stem cell therapy may still be a less expensive alternative. Also, a single extraction will typically yield enough stem cells for 20 to 25 future treatments, should you decide to store your stem cells for future need.

"I think it's accessible for patients," Comella says. "It's an out-patient procedure. You plan to be in clinic for about two hours; no real limitations afterwards, just no submerging in water, no alcohol, no smoking for a week. But other than that, patients can resume their normal activities and go about their regular daily lives."

Interestingly, Comella notes that patients who eat a very healthy diet, focusing on organic and grass fed foods, have body fat that is very hearty and almost sticky, yielding high amounts of very healthy stem cells.

"We can grow much better and faster stem cells from that fat than [the fat from] somebody who eats a grain-based diet or is exposed to a lot of toxins in their diet," she says. "Their fat tends to be very fluffy, buttery yellow. The cells that come out of that are not necessarily as good a quality. It's just been very interesting. And of note, patients that are cigarette smokers, their fat is actually gray-tinged in color. The stem cells do not grow well at all."

What's been described above is what's called an autologous donation, meaning you're getting the stem cells from yourself. A number of companies provide non-autologous donations using cells harvested from other people, typically women, like amniotic or embryonic mesenchymal cells. This is an important distinction.

"There are now just a couple of studies that have been published comparing an autologous source, meaning cells from you own body, to an allogeneic source, meaning cells from someone else.

So far, what has been discovered is that the autologous cells, meaning your own cells, will outperform somebody else's cells inside your body. Now, this is not fully understood at this point. It may be that the environment that your cells function in, they're used to that environment. They recognize it. It's the same DNA and they can function well.

However, once you culture expand and get a pure population of these mesenchymal cells not necessarily the sample that's coming right off of the liposuction, but a sample that has been taken to the lab and grown those cells will not elicit an immune response if you use them in someone else. You could scientifically and medically use those in an unmatched person. However, there are some regulatory aspects of that with regards to the FDA."

In the U.S., there are a variety of new stem cell products available, referred to as amniotic, cord blood products or placenta products, which are prepared at a tissue bank. Such facilities must be registered with the FDA, and the products must undergo additional processing.

For example, they must be morselized, or snap frozen or blended in some way. Such processing typically breaks the membrane, releasing growth factors, and the resulting products are called acellular, meaning there are no living cells remaining in the sample.

The amniotic products available in the U.S. are not so much stem cell products as they are growth factor products. According to Comella, they can be useful in creating an immunomodulatory response, which can help to promote healing, but that still differs from the living stem cell procedures that can be done by either isolating cells from your fat or bone marrow. As a general rule, you don't achieve the clinical benefits when using an amniotic product, primarily because they don't contain living stem cells.

"I want to contrast that to what are called embryonic stem cells," Comella adds. "The products obtained from cord blood, from women who are having babies, are not embryonic stem cells. Embryonic stem cells are when you are first bringing the egg and sperm together. Three days after that, you can isolate what is called an inner cell mass. This inner cell mass can be used to then grow cells in culture, or that inner cell mass could eventually lead to the formation of a baby.

Those are embryonic stem cells, and those are pluripotential, meaning that they have the ability to form an entire being, versus adult stem cells or stem cells that are present in amniotic tissue, [which] are multipotential, which only have the ability to form subsets of tissue.

When you're dealing with different diseases or damaged tissue or inflammation, mostly you want to repair tissue. If somebody has damage in their knee, they don't necessarily need embryonic cells because they don't need a baby in their knee. They need new cartilage in their knee."

A common question is whether stem cells can cause overgrowth, leading to cancer or tumor formation. As noted by Comella, this is a problem associated with embryonic stem cells, which tend to grow very rapidly and can form a teratoma because of the rapid cell growth. Adult stem cells the cells obtained from your own body have growth inhibitions and will not form teratomas.

"The theoretical concern that has been addressed in animal models or in petri dishes is that if you take cancer cells that are growing in a dish and apply stem cells, it may make those cancer cells grow more rapidly. But this does not translate in-vivo to humans.

If there was truly an issue with applying stem cells to a patient who has cancer, we would know about it by now, because we've been dosing cancer patients with stem cells since the '30s. The safety profile is strong and there are tens of thousands of patients documented with these treatments," Comella says.

Another useful therapy is platelet-rich plasma (PRP). Your peripheral blood contains platelets, which act as first responders when there's an injury. They come in and start the clotting mechanism, thereby preventing you from bleeding to death. They also give marching orders to other cells. For example, platelets can command stem cells to multiply and grow, or to differentiate and form new tissue.

These platelets also have many different growth factors associated with them, which can help to promote healing and stop inflammation. PRP involves taking a blood sample and then spinning the blood in a centrifuge to isolate the platelets. The platelet-rich plasma is then injected back into the area that is inflamed.

"One of the most common uses of platelet-rich plasma or PRP is in a joint. Now, platelets are going to be most successful in something that is rich in stem cells [such as] an acute or a very recent injury.

If you just hurt your knee, the first thing you should do is get PRP, because it's going to help promote healing, and those platelets will attach to the surface receptors of the stem cells that are already going to the area to promote healing. It would be like putting fertilizer on your seed, which are the stem cells.

If you have something more chronic, this tends to be a stem cell-poor environment. In other words, you have osteoarthritis or you've got knee pain that's 5 years old and it's been there for a long time; just putting PRP in it would be like putting fertilizer on dirt without planting a seed first."

The beauty of stem cell therapy is that it mimics a process that is ongoing in your body all the time. Your stem cells are continuously promoting healing, and they do not have to be manipulated in any way. The stem cells naturally know how to home in on areas of inflammation and how to repair damaged tissue.

"All we're doing is harnessing the cells from one location where they're sitting dormant and relocating them to exactly where we want them and we need them to work," Comella says. "Basically, anything inside your body that is inflamed, that is damaged in some way, that is lacking blood supply, the [stem] cells can successfully treat.

That means orthopedics, knee injections, shoulder injections, osteoarthritis, acute injuries, anterior cruciate ligament tears in your back back pain associated with degenerative disc disease or damaged tendons or ligaments, herniated and bulging discs. You can also use it in systemic issues, everything from diabetes, to cardiac, to lungs any tissue organ inside your body that's been damaged.

Autoimmune diseases [can also be treated]. The stem cells are naturally immunosuppressant, meaning they can help quiet down an over reactive immune system and help the immune system function in a more normal way. Neurological diseases, traumatic brain injury, amyotrophic lateral sclerosis, Parkinson's. All of these have to do with tissue that's not functioning properly. The cells can be used to address that."

It's quite impressive, the list of different diseases that could benefit from this intervention. That said, I want to reemphasize that this is not a magic bullet. However, you can dramatically improve the benefits of this intervention by combining it with other healthy lifestyle factors that optimize mitochondrial function, such as eating a healthy whole food diet, exercising, sleeping well, avoiding toxins and detoxifying from toxic influences.

Stem cells can also be used as part of an antiaging program. Comella has used stem cells on herself for several years, and report feeling better now than she did a decade ago.

"The ability to reduce inflammation inside your body is basically making yourself live longer. Inflammation is what kills us all. It's what makes our telomeres shrink. It's what causes us pain and discomfort. It's what makes the tissues start to die. The ability to dose yourself with stem cells and bring down your inflammation, which is most likely caused by any sort of toxin that you've been exposed to breathing air is exposure to toxins this is going to lengthen your lifespan.

I typically will do a dose every six to 12 months, regardless of what's going on. If I have anything that's bothering me, if I tweak my knee at the gym, then I absolutely will come in and do an injection in my knee. I want to keep my tissue healthy for as long as possible.

I want to stay strong. I don't want to wait until something is wrong with me. I think that this is the future of medicine. This is what we're going to start to see. People will begin to get their regular doses of [their own] stem cells and it'll just be common practice."

Keep in mind there's a gradual and progressive decline in the quality and the number of stem cells as you age, so if you're considering this approach, it would be to your advantage to extract and bank your stem cells as early on as possible. U.S. Stem Cell provides a stem cell bank service, so you can store them until a later date when you might need them.

"Your stem cells are never as young as they are right now. Every minute that you live, your telomeres are shrinking. The ability to lock in the youth of your cells today can be very beneficial for you going forward, and for your health going forward. God forbid something happens. What if you have a heart attack? You're not going to get clearance to get a mini-lipo aspirate procedure.

If you have your cells waiting in the bank, ready for you, it becomes very easy to pull a dose and do an IV delivery of cells. It's almost criminal that we're not doing this for every single one of our cardiac patients. This should be standard practice. We should be having every single patient bank their stem cells at a young age and have them waiting, ready and available. The technology is there. We have it. I'm not sure why this technology is not being made available to everyone," she says.

"I think stem cell therapy is very different than traditional medicine. Stem cell therapy may actually make it so that you don't have to be dependent on pharmaceutical medications. You can actually repair the tissue and that's it. This is a very different way of viewing medicine."

If you're interested in having this procedure done, contact the U.S. Stem Cell Clinic on USStemCellClinic.com. You could either have the procedure done at their facility, or if there's a physician in your area providing the service, you can go there. U.S. Stem Cell can help you locate a qualified doctor.

Oftentimes, practitioners will specialize in specific procedures, such as spinal procedures, or knee procedures. There's also a veterinary division, called Vet Biologics, which offers treatment to small pets like cats and dogs, as well as horses.

"One of the things that we've been treating recently is traumatic brain injuries," Comella says. "We had a woman who fell two stories and hit her head. She spent months in a coma and was not able to talk or walk or do any activities. By the time she came to us, it was two years after her injury. The best hospitals in the world told her this was her life 'You're never going to be able to talk or walk or take care of your young children again.' That was just not good enough.

She came to us and we began applying stem cells in a way to allow the cells to cross the blood-brain barrier and to get to her brain. After her first treatment, when she walked into the clinic on her own and began telling me, in full sentences, about the day she had the head injury, tears came down my face. This is the kind of thing that traditional medicine would say is impossible.

We've had patients who were wheelchair-bound, whether it's from multiple sclerosis or Parkinson's, up and out of their chair, literally jogging around cones. This is life-changing Patients who were told they weren't going to return to sports for years are back on the field and playing. There's just many ways that you can heal your tissue to change the course of an injury or a disease."

See more here:
How Stem Cell Therapy Can Help Repair and Regenerate Your Body

Bryan Christie

Injected anti-VEGF agents can help reverse eye damage and stabilize vision.

Wet macular degeneration occurs when abnormal blood vessels grow under the retina, often leaking fluid or blood into the macula and damaging central vision. Although far less common than the dry form, in which deposits destroy the macula, wet AMD is much more destructive, leading to more rapid and profound vision loss. Fortunately, a new class of drugs called anti-VEGF agents, now widely available, can halt and sometimes even reverse the damage. Injected into the eye, the medications block VEGF proteins, which normally help blood vessels form. "Before anti-VEGF agents, we had nothing to stop wet macular degeneration," says Jeffrey Heier, M.D., chair of research and therapeutics for the American Society of Retina Specialists and director of the Vitreoretinal Service at Ophthalmic Consultants of Boston. "Now, in a majority of patients, we can stabilize vision and, in some patients, even restore some vision."

The shots have one big drawback: They have to be administered as often as monthly. To eliminate repeated injections, researchers are developing innovative ways to deliver medication to the eye. One approach under investigation is to implant a small reservoir that steadily releases medication over time, says Heier. Another, more dramatic possibility: using gene therapy to reprogram cells in the eye to produce their own anti-VEGF agents.

The holy grail of research to treat macular degeneration, though, is finding ways to regenerate healthy cells to replace those damaged by disease. That may not be far off. In 2014, a team at the Jules Stein Eye Institute at the University of California, Los Angeles, reported early success growing retinal cells in the lab and injecting them into the eyes of patients with several different forms of AMD. The scientists began with pluripotent stem cells, which have the ability to become any cell. "Over a period of months, the cells are coaxed into becoming retinal pigment epithelial cells, which support the photoreceptor cells in the retina," explains Eddy Anglade, M.D., chief medical officer for Ocata Therapeutics, the Massachusetts-based company that is developing the procedure. Early results show significant improvements in vision in some patients, and clinical trials are under way to refine the procedure.

The rest is here:
Treating Blindness and Vision Loss - Restoring Eyesight

Article

First Online: 24 June 2008

Transplantation of bone marrow or peripheral blood stem cells is increasingly being used to treat a variety of oncologic disorders. These procedures are associated with a large spectrum of neurologic complications that significantly contribute to patient morbidity and mortality. These complications may arise at any time during and after the transplantation process and are particularly common in patients requiring chronic immunosuppression. The most frequent complications are infections and cerebrovascular or metabolic events, and toxicity from radiation or chemotherapy. Because of the unique circumstances and treatments involved in each step of the transplantation process, there is a higher incidence of some neurologic complications during discrete time periods, and an awareness of the temporal relationship of the neurologic disorder to the transplantation process facilitates diagnosis. With the exception of post-transplant lymphoproliferative disorder, in which reduced immunosuppression may be an effective therapeutic strategy, therapies are often the same as in the nontransplant patient. Complications of therapy can arise because of the presence of multiple comorbidities and medication interactions. Anticipation of common opportunistic infections and appropriate use of prophylactic medications can significantly reduce the incidence of infectious complications.

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1.

Bleggi-Torres LF, de Medeiros BC, Werner B, et al.:

.

2000,

301307.

2.

Snider S, Bashir R, Bierman P:

.

1994,

681684.

3.

de Brabander C, Cornelissen J, Smitt PA, et al.:

.

2000,

3640.

4.

Graus F, Saiz A, Sierra J, et al.:

.

1996,

10041009.

5.

Sostak P, Padovan CS, Yousry TA, et al.:

.

2003,

842848.

6.

Faraci M, Lanino E, Dini G, et al.:

.

2002,

18951904.

7.

Uckan D, Cetin M, Yigitkanli I, et al.:

.

2005,

7176.

8.

Burt RK, Fassas A, Snowden J, et al.:

.

2001,

112.

9.

Openshaw H, Stuve O, Antel JP, et al.:

.

2000,

21472150.

10.

De La Camara R, Tomas JF, Figuera A, et al.:

.

1991,

363364.

11.

Pelgrims J, De Vos F, Van den B J, et al.:

.

2000,

291294.

12.

Kassim AA, Chinratanalab W, Ferrara JL, Mineishi S:

.

2005,

565574.

13.

Lee HJ, Oran B, Saliba RM, et al.:

.

2006,

299303.

14.

Batchelor TT, Taylor LP, Thaler HT, et al.:

.

1997,

12341238.

15.

Freise CE, Rowley H, Lake J, et al.:

.

1991,

31733174.

16.

Erer B, Polchi P, Lucarelli G, et al.:

.

1996,

157162.

17.

Gaggero R, Haupt R, Paola FM, et al.:

.

2006,

861866.

18.

Hinchey J, Chaves C, Appignani B, et al.:

.

1996,

494500.

19.

Pranzatelli MR, Mott SH, Pavlakis SG, et al.:

.

1994,

131140.

20.

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Neurologic complications of bone marrow and stem-cell ...