StemCell Therapy

Introduction

The arrival and prevalence of drug-resistant tuberculosis has become a major problem in global tuberculosis (TB) control. In 2019, it was estimated that there were 500,000 cases of rifampicin-resistant TB (RR-TB) worldwide, of which 78% were multidrug-resistant TB (MDR-TB), resistant to both isoniazid (INH) and rifampicin (RIF). China has a high burden of TB and RR/MDR-TB and accounts for 14% of global RR/MDR-TB cases.1 INH and RIF are the core first-line drugs in the treatment of TB, but treatment of RR/MDR-TB with these first-line regimens will have poor effect. It is important to quickly identify the results of drug susceptibility tests (DST) in patients, especially tests relating to INH and RIF, to enable appropriate drugs to be chosen based on DST profiles.

Detection of drug-resistant target gene mutation can help to detect drug resistance earlier than phenotypic DST. Molecular DST in MTB has been widely used in clinical work to evaluate resistance to INH and RIF. KatG and inhA gene mutations are the main mechanism of INH resistance in MTB.2 Gene inhA (including promoter and coding areas) is one of important molecular markers of INH resistance, and inhA is also the molecular basis of cross resistance to ethionamide (ETH) prothionamide (PTH),24 a group C drug recommended by the WHO for the treatment of MDR-TB.5 ETH/PTH and INH are activated by monooxygenase EthA and catalase-peroxidase KatG. The activated forms of the two drugs act on a common targetthe NADH-dependent enoyl-ACP reductase inhA (Rv1484) bindingwith a bactericidal effect that affects cell wall synthesis.2 ETH/PTH has obvious adverse reactions such as nausea and drug-induced liver injury,6 and care is needed when choosing this drug. However, due to the convenience and ease of oral administration, ETH/PTH is still recommended in MDR-TB treatment in China.6 Based on the correlation between ETH/PTH resistance and inhA, clinicians may refer to inhA gene detection to guide the use of ETH/PTH.3,4,7

A variety of reports suggest that mutations in the inhA gene in TB strains can predict ETH/PTH resistance, although some studies have also shown that clinical strains with inhA mutations are sensitive to ETH.3,4,7 MeltPro TB assay utilizes the real-time polymerase chain reaction (PCR) probe-based melting curve analysis technique8 to detect the common drug-resistant mutation sites of katG, inhA and rpoB genes in MTB and rapidly diagnose INH and RIF resistance. This technique is widely used in clinical work.9,10 In this study, we analyze the correlation between inhA mutation test results and phenotypic ETH susceptibility through MeltPro TB assay and evaluate whether the inhA test can be used to guide the clinical application of ETH where phenotypic DST results are unavailable.

In this retrospective study, patients undergoing treatment at Beijing Chest Hospital, Capital Medical University with positive MeltPro TB assay results for inhA and katG genes (mutated or not mutated) were screened from February 2015 to February 2016. Samples were tested for katG and inhA genes with culture and phenotypic DST and the dissociation curve method. Patients who met the following conditions were subsequently included in the analysis: cultured clinical specimens were positive for MTB; DST results were available for INH, RIF, Levofloxacin (Lfx), Amikacin (Am), Capreomycin (Cm), and ETH; and test results were positive for katG and inhA mutations. If two or more samples from the same patient were positive, the first sample was recorded. The basic information collected for each patient included their age, gender, disease diagnosis, initial treatment, and subsequent treatment.

The study was conducted in accordance with the Declaration of Helsinki (revised 2013). The study was approved by Beijing Chest Hospital, Capital Medical University (No.201986) and informed consent was obtained from all the patients.

Sample processing, culture, and drug susceptibility detection were conducted in accordance with the Laboratory Inspection Procedure of Tuberculosis Diagnosis.11 The clinical samples were treated and cultured on a modified LowensteinJensen culture medium (Zhuhai intkr Co. Ltd., China). Positive colonies were cultured for DST and strain identification using the LowensteinJensen proportion method. The critical concentration references were as follows: low-concentration INH 0.2 g/mL, high-concentration INH 1.0 g/mL, RIF 40 g/mL, Levofloxacin2 g/mL, Amikacin 30g/mL, Capreomycin 40 g/mL, and ETH 40g/mL. Growth (cultivation) at this concentration was defined as indicating drug resistance.3

An automatic DNA extraction machine (Zeesan Biotech, Xiamen, China) and a paramagnetic particle method were used to extract crude DNA (1 mL) from the decontaminated samples according to the MeltPro TB assay instructions. The amplification program was used to analyze the melting. The fluorescence signal intensity was collected on the LightCycler 480 System (Indianapolis Roche Group) in the FAM and TET channels, and the melting temperature TM value was obtained by identifying the peak of the melting.7,12 The detection sites of INH resistance included inhA94, inhA promoter region 17 ~ 8 mutation, and katG315 codon mutation. The katG and inhA mutation results were recorded.

Data collection was carried out using Excel 2007 and the statistical analysis employed SPSS 17.0 software. The count data were represented by rate (%), 2 TEST and Fishers exact test to compare the differences between the groups. The parameters of the continuous measurements were expressed as mean standard deviation and compared using a t-test. P < 0.05 indicated that a result was statistically significant.

A total of 704 clinical specimens were tested using the dissociation curve method and found to be positive for inhA and katG genes. Specimens of MeltPro TB assay detect negative, specimens without phenotypic DST results and repeated samples were removed. Following this, 382 patients were enrolled in the study. These patients included 283 (74.1%) cases of sputum, 58 (15.2%) cases of bronchial lavage fluid, 1(0.3%) case of cerebrospinal fluid, and 40 (10.5%) cases of sanious; 292 were initial treatment patients and 90 were re-treatment patients. And 28 (7.3%) cases were resistant to ETH. The proportion of re-treatment patients with resistance to ETH was higher than the proportion of initial treatment patients (P < 0.001; Table 1). In addition, 11.0% (42/382) were MDR-TB, 10.2% (39/382) were pre-extensively drug resistant tuberculosis (pre-XDR-TB); 4.2% (16/382) were extensively drug resistant tuberculosis (XDR-TB).

Table 1 Demographic and Clinical Characteristics of Patients

Of the 382 bacterial strains, 118 strains (30.9%) were resistant to INH. Among these INH resistant strains, 22.9% (27/118) were also resistant to ETH, and all of these strains were MDR-TB. Of the 118 INH-resistant strains, katG mutation accounted for 52.5% (62/118), inhA mutation accounted for 20.3% (24/118), and inhA+katG mutation accounted for 4.2% (5/118); strains with no mutation accounted for 22.9% (27/118). Of the 28 phenotypic ETH-resistant strains, 27 (96.4%) resistant to INH resistance. Of the same 28 strains, inhA mutation accounted for 42.9% (12/28). Of the 34 inhA mutant strains, 85.3% (29/34) had an inhA mutation without a katG mutation; among this group, 34.5% (10/29) showed low resistance to INH, 48.3% (14/29) showed high resistance to INH, and 13.8% (5/29) were sensitive to INH. The rates of ETH-resistance in low- and high-level INH-resistant strains showed no statistical differences (2 = 2.264; P = 0.132; Fishers test). The rate of single inhA mutations (without katG mutation) in strains with low INH-resistance was higher than the rate in strains with high INH-resistance (2 = 13.076; P < 0.001; Fishers test). All of 21 INH-resistant but non-MDR-TB strains were sensitive to ETH; four of these were inhA mutant strains. In addition, eight strains (four INH-resistant and four INH-sensitive) with single inhA mutation (without katG and rpoB mutations) were sensitive to ETH, and the patients carrying those eight strains were not initially treated with anti-TB drugs (Figure 1 and Table 2).

Table 2 Frequency of Ethionamide Resistance in Low-and High-Level Isoniazid Resistant and Isoniazid Susceptible Mycobacterium tuberculosis Isolates

Figure 1 Phenotypic DST results of ETH in MTB with inhA gene mutation enrolled in this study.

China has a high burden of TB and one of the highest incidences of MDR-TB in the world.13 Particularly in recent years, the incidence of DR-TB has been on the rise in China. Rifampicin (RIF) and isoniazid (INH) are the leading first-line anti-TB drugs, playing an important role in the treatment of TB. MDR-TB is widely regarded as an important factor in the failure of chemotherapy in treating TB. The resistance of genes to INH is more complicated, and is mainly caused by mutations in genes such as katG and inhA. Each mutation site has a certain correlation with drug resistance. ETH/PTH is a second-line drug treatment for TB, used mostly in MDR-TB and XDR-TB. According to data from domestic and overseas research, the majority of ETH/PTH-resistant strains also show INH resistance.10,14,15 In the present study, almost all ETH-resistant strains were also found to be resistant to both INH and RIF (96.4%), and the ETH-resistance rate in MDR-TB was 27.8%, which is consistent with our previous studies and similar data (20%24.8%) from TB treatment institutions in China.1619

The main molecular mechanisms underlying INH resistance are inhA and katG mutations, reported to account for 8%43% and 50%95% of drug-resistant strains, respectively.20 Tests for these two genetic mutations are used to diagnose the majority of instances of MTB resistance to INH. Mutations in the inhA gene are the molecular basis of cross resistance to ETH/PTH and INH. Therefore, the inhA gene can also aid in diagnosing ETH resistance. This study analyzed inhA and katG mutations and phenotypic INH and ETH susceptibility in clinical strains. Of the 118 INH-resistant strains analyzed, 56.7% (67/118) were katG mutations, and 24.5% (29/118) were inhA mutations. Of the 28 phenotypically ETH-resistant strains, inhA mutations accounted for 42.9%, which is consistent with previous reports.10,20 However, in this study, only 35.3% of the 34 inhA mutant strains were resistant to ETH, and only 42.9% of ETH-resistant strains had inhA mutations. A recent study in South Korea found that only 23 (67%) of 34 PTH-resistant strains had an inhA mutation, while data from a study in Guangzhou, China indicates that, of 46 PTH-resistant strains, 43.2% had an inhA promoter (12 strains were c-15t and 4 strains t-8c), and 6.2% had a coding gene mutation (all were S94A).10,21 The results of the present study show an inhA mutation rate in ETH-resistant strains (42.9%) similar to that in the study in China referenced above.

The question of whether inhA mutations can indicate phenotypic ETH resistance remains. Most previous research has focused on inhA mutations in INH- or ETH/PTH-resistant strains (mainly MDR-TB), while inhA mutations in sensitive strains have rarely been studied. There is a moderate level of evidence for an association between c-15t inhA promoter mutations and low-to-moderate INH resistance.22 This study shows that only 35.3% of 34 inhA mutant strains were resistant to ETH. The possible reasons for the inconsistency between inhA mutation and the ETH-resistant phenotype include the dissociation curve detection of mutant codons on inhA94 from 17 to 8 in the inhA promoter region. In addition, some positive mutations may be synonymous mutations and will not cause protein changes or ETH resistance.15,17,23 The ETH-resistant phenotype may have other regulatory mechanisms that cause strains with inhA mutations not to generate ETH resistance. This study also found that all strains with single inhA mutations (without katG or rpoB mutations) were sensitive to ETH. Taking the results of the present study in combination with those of other domestic studies, it can be argued that inhA mutations are not a reliable indicator of ETH resistance in China;17,24 the detection of inhA mutations is not necessarily a sign of resistance to ETH, and genotypic and phenotypic drug susceptibility must be detected simultaneously to guide clinical use of ETH.

Although inhA mutations have been shown to be associated with low INH resistance, this study shows that, of 29 inhA mutant strains, 48.3% (14/29), mainly INH- and RIF-resistant strains, had high INH resistance.2 InhA mutations were not a good indicator of low INH resistance. Other studies have also shown that inhA mutant (non-katG mutation) strains are highly resistant to INH, as are some strains combined with furA, oxyr-ahpc, or inhA double (c-15t combined with S94A or I194T) mutations.25 The data in this study were derived from clinical data, and no particular type of inhA mutation was specified. In addition, apart from inhA and katG315, no other INH-resistant genes were examined. Hence, the specific mechanism underlying the high drug resistance of nearly half of inhA remains unclear. Nonetheless, we found that the single inhA mutant strain (without katG and rpoB mutation) showed low-level resistance and susceptibility to INH, and these strains were sensitive to ETH. Hence, ETH and high-dose INH treatment may be effective for the majority of single inhA mutated INH-resistant strains.

However, this study has certain limitations. First, the present study is a summary of clinical data. Laboratory tests only reported whether or not the isolates had katG and inhA mutations; they did not provide detailed descriptions including the mutation sites. In addition, we did not discuss the mechanism of drug resistance in isolates where the inhA genotype and ETH-resistant phenotype were inconsistent. This will be the focus of further study, and we will evaluate the feasibility of using the targets identified by the melting curve analysis in the Chinese population. Third, the sample size was small, and all included patients came from the hospital where the author worked. The research findings may therefore contain some bias; however, they are still encouraging.

Although inhA mutations are associated with mechanisms of joint INH and ETH resistance, they may not be a reliable indicator of ETH resistance. In particular, TB strains with single inhA mutations (without katG or rpoB mutations) may remain sensitive to ETH. This is a preliminary study,future work is required to explore the mechanism of ETH resistance, to look for the reasons of inconsistency of phenotype and gene mutation.

We are particularly grateful to all the people who have given us help on our article.

There is no funding to report.

The authors declare that they have no competing interests.

1. World Health Organization. Global tuberculosis report. 2020.

2. Vilchze C, Jacobs JR. WR. Resistance to isoniazid and ethionamide in Mycobacterium tuberculosis: genes, mutations, and causalities. Microbiol Spectr. 2014;2(4):MGM22013. doi:10.1128/microbiolspec.MGM2-0014-2013

3. Vadwai V, Ajbani K, Jose M, et al. Can inhA mutation predict ethionamide resistance? Int J Tuberc Lung Dis. 2013;17(1):129130. doi:10.5588/ijtld.12.0511

4. Niehaus AJ, Mlisana K, Gandhi NR, Mathema B, Brust JC. High prevalence of inhA promoter mutations among patients with drug-resistant tuberculosis in KwaZulu-Natal, South Africa. PLoS One. 2015;10(9):e0135003. doi:10.1371/journal.pone.0135003

5. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment. 2020. Availble from: https://www.who.int/tb/publications/global_report/TB20_Exec_Sum_20201014.pdf. Accessed December 23, 2020.

6. Tuberculosis society of Chinese Medical Association. Chinese expert consensus on multidrug-resistant tuberculosis and Rifampicin-resistant tuberculosis treatment. Chin J Tuberc Respir. 2019;42(10):733749.

7. Lee JH, Jo KW, Shim TS. Correlation between genoType MTBDRplus assay and phenotypic susceptibility test for prothionamide in patients with genotypic isoniazid resistance. Tuberc Respir Dis (Seoul). 2019;82(2):143150. doi:10.4046/trd.2018.0027

8. Pang Y, Dong H, Tan Y, et al. Rapid diagnosis of MDR and XDR tuberculosis with the MeltPro TB assay in China. Sci Rep. 2016;6:25330. doi:10.1038/srep25330

9. Haeili M, Fooladi AI, Bostanabad SZ, Sarokhalil DD, Siavoshi F, Feizabadi MM. Rapid screening of rpoB and katG mutations in Mycobacterium tuberculosis isolates by high-resolution melting curve analysis. Indian J Med Microbiol. 2014;32(4):398403. doi:10.4103/0255-0857.142245

10. Darban-Sarokhalil D, Nasiri MJ, Fooladi AA, Heidarieh P, Feizabadi MM. Rapid detection of rifampicin- and isoniazid-resistant Mycobacterium tuberculosis using TaqMan allelic discrimination. Osong Public Health Res Perspect. 2016;7(2):127130. doi:10.1016/j.phrp.2016.01.003

11. Basic Professional Committee of China National Defense Tuberculosis Association. TB diagnostic laboratory test procedures. Beijing: China Education Press; 2006.

12. Wang G, Dong W, Lan T, et al. Diagnostic accuracy evaluation of the conventional and molecular tests for Spinal Tuberculosis in a cohort, head-to-head study. Emerg Microbes Infect. 2018;7(1):109. doi:10.1038/s41426-018-0114-1

13. Jou R, Lee WT, Kulagina EV, et al. Redefining MDR-TB: comparison of Mycobacterium tuberculosis clinical isolates from Russia and Taiwan. Infect Genet Evol. 2019;72:141146. doi:10.1016/j.meegid.2018.12.031

14. Morlock GP, Metchock B, Sikes D, Crawford JT, Cooksey RC. ethA, inhA, and katG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother. 2003;47(12):37993805. doi:10.1128/AAC.47.12.3799-3805.2003

15. Rueda J, Realpe T, Mejia GI, et al. Genotypic analysis of genes associated with independent resistance and cross-resistance to isoniazid and ethionamide in Mycobacterium tuberculosis clinical isolates. Antimicrob Agents Chemother. 2015;59(12):78057810. doi:10.1128/AAC.01028-15

16. Song YH, Wang GR, Huo FM, et al. Correlation analysis of inhA gene mutation in MTB and propioniazid resistance. Chin J Def Consumpt. 2018;40(8):821824.

17. Liu YP, Wang J, Zhang JX, et al. Detection of clinical isolates of Mycobacterium tuberculosis resistant to isoniazid and propioniazid and study on related gene mutation. Chin J Def Consumpt. 2016;38(9):718721.

18. Chen HF, Huang QS, Gao AX, et al. Observation on the sensitivity of mDR-MYCObacterium tuberculosis to second-line anti-tuberculosis drugs. J Nanjing Med Univ. 2014;34(1):6971.

19. Li XD. Analysis of resistance of 174 mDR-Mycobacterium tuberculosis strains to second-line anti-tuberculosis drugs. Int J Lab Med. 2014;13:17321733,1748.

20. Zhang Y, Yew WW. Mechanisms of drug resistance in Mycobacterium tuberculosis: update 2015. Int J Tuberc Lung Dis. 2015;19(11):12761289. doi:10.5588/ijtld.15.0389

21. Tan Y, Su B, Zheng H, Song Y, Wang Y, Pang Y. Molecular characterization of prothionamide-resistant mycobacterium tuberculosis isolates in Southern China. Front Microbiol. 2017;8:2358. doi:10.3389/fmicb.2017.02358

22. Organization W.H. The use of next-generation sequencing technologies for the detection of mutations associated with drug resistance in Mycobacterium tuberculosis complex: technical guide. 2018.

23. Malinga L, Brand J, Jansen van Rensburg C, Cassell G, van der Walt M. Investigation of isoniazid and ethionamide cross-resistance by whole genome sequencing and association with poor treatment outcomes of multidrug-resistant tuberculosis patients in South Africa. Int J Mycobacteriol. 2016;5(Suppl 1):S36S37. doi:10.1016/j.ijmyco.2016.11.020

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25. Machado D, Perdigo J, Ramos J, et al. High-level resistance to isoniazid and ethionamide in multidrug-resistant Mycobacterium tuberculosis of the Lisboa family is associated with inhA double mutations. J Antimicrob Chemother. 2013;68(8):17281732. doi:10.1093/jac/dkt090

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[Full text] The Value of the inhA Mutation Detection in Predicting Ethionamide Res | IDR - Dove Medical Press

A research report on Regenerative Medicine Market features a succinct analysis on the latest market trends. The report also includes detailed abstracts about statistics, revenue forecasts and market valuation, which additionally highlights its status in the competitive landscape and growth trends accepted by major industry players.

Regenerative Medicine Market: Increased in bone and joint surgeries and increased prevalence of neurodegenerative, orthopedic, oncology, and genetic diseases are the key drivers for Global Regenerative Medicine Market.

Regenerative Medicine Market is valued at around USD 16148.16 Million in 2017 and expected to reach USD 74831.35 Million by 2024 with the CAGR of 22.27% over the forecast period.

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Regenerative medicines are those medicines which are used to repair, regenerate, and replace the tissues or organs damaged due to disease, injury or natural aging. Regenerative medicines are used in the treatment of various disorders such as orthopedic, neurodegenerative, oncology and others. These medicines help in the restoration of natural functioning of the organs and tissues. Regenerative medicines can also be used for the treatment of various chronic and genetic disorders, it also helps in the treatment of organ transplant which has reduced the rejection cases to a major extent.

There are various factors driving the growth of the regenerative medicine market, one of the major driving the growth of the market are increased prevalence of various chronic and genetic diseases over the period of time. Moreover, increase in technological advancement has also help in the development of effective and better therapies for the treatment of chronic disorders. Furthermore, the increased burden of these diseases has increased the demand of various effective medications which led to the increase in the regenerative medicine market. Increased research on stem cells has given a new direction to the regenerative medicines an expected to create various opportunities over the forecast period. However, high cost of treatment and stringent government regulations are expected to inhibit the growth of regenerative medicines over the forecast period.

Global regenerative medicines market report covers prominent players like Stryker Corporation, Cook Biotech Inc., Vericel Corporation, DePuy Synthes, Inc. Medtronic, Inc., Organogenesis Inc., Osiris Therapeutics, Inc., NuVasive, Inc., Acelity (KCI Concepts), Zimmer Holdings, Inc., Integra LifeSciences, C.R. Bard and others.

Regenerative Medicine Market Segmentation

By Product Type Cell-based products, Acellular products

By Application Orthopedic & Musculoskeletal Disorders, Cardiology, Dermatology, Diabetes, Central Nervous System Disorders, Others

By Therapy Cell therapy, Gene therapy, Tissue engineering, Immunotherapy

By Region

North America, US, Mexico, Chily, Canada, Europe, UK, France, Germany, Italy, Asia Pacific, China, South Korea, Japan, India, Southeast Asia, Latin America, Brazil, The Middle East and Africa, GCC, Africa, Rest of Middle East and Africa

Regenerative Medicine MarketKey Players

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January 29, 2021 I COVID-19 may become seasonal, severe infection associated with myeloid immune cells, potential Achilles heel of coronaviruses identified, melatonin synthesized in lungs could have protective effect, and plitidepsin outperforms remdesivir in preclinical trials. Plus: NSAID use during COVID-19 is time-dependent on its harm or benefit and NAU to test Allarity drug against Coronavirus Variant B117.

Research News

COVID-19 may be seasonal, like the flu, suggests a new paper published in Evolutionary Bioinformatics. Authors of the paper show that COVID-19 cases and mortality rates, among other epidemiological metrics, are significantly correlated with temperature and latitude across 221 countries. They also explain that our own immune systems could be partially responsible for the pattern of seasonality. For example, our immune response to the flu can be influenced by temperature and nutritional status, including vitamin D, a critical nutrient to our immune defenses. The researchers add that it is, however, too soon to say how seasonality and our immune systems interact in the case of COVID-19. DOI:10.1177/1176934321989695

SARS-CoV-2 independently entered Russia at least 67 times, primarily at the end of February and beginning of March 2020, according to a new study published in Nature Communications. Researchers of the study used 211 virus genomes, which were sequenced at Smorodintsev Research Institute of Influenza, and all genomes had been obtained from patients from 25 Russian regions during mid-March to April 2020. They determined that the vast majority of introductions came from European countries, and no cases of introduction from China were registered, which they attribute to the timely closure of borders with the country. Currently, nine local virus lineages are circulating in Russia, which are not present elsewhere in the world. DOI:10.1038/s41467-020-20880-z

Research led at Vanderbilt University Medical Center has discovered a proofreading exoribonuclease, called nsp14-ExoN, which can correct errors in the RNA sequence that occur during replication, when copies of a virus are generated. They believe that this may be the Achilles heel of the coronavirus, a finding that could help close the door on COVID-19 and possibly head off future pandemics. Using cutting-edge technologies and novel bioinformatics approaches, the researchers discovered that this ExoN also regulates the rate of recombination, which is the ability of the coronavirus to shuffle parts of its genome and even pull genetic material from other viral strains while it replicates in order to gain evolutionary advantage. These patterns of recombination are conserved across multiple coronaviruses, including SARS-CoV-2. They believe that the coronavirus ExoN is therefore a conserved, important target for inhibition and attenuation in the ongoing pandemic. This research is published in PLOS Pathogens. DOI:10.1371/journal.ppat.1009226

Also at Vanderbilt University Medical Center (VUMC), researchers have identified genetic factors that increase the risk for developing pneumonia to help identify patients with COVID-19 at greatest risk for this life-threatening complication. The researchers conducted genome-wide association studies (GWAS) of more than 85,000 patients whose genetic information is stored in VUMCs BioVU biobank. They identified nearly 9,000 cases of pneumonia in patients of European ancestry and 1,710 cases in patients of African ancestry. After further analysis, the research team linked the gene that causes cystic fibrosis (CF) and European ancestry and the mutation that causes sickle cell disease (SCD) in patients of African ancestry as the strongest pneumonia associations. After removing patients with CF and SCD, they then pinpointed a pneumonia-associated variation in a gene called R3HCC1L in patients of European ancestry, and one near a gene called UQCRFS1 in patients of African ancestry. They believe these findings could be applied to identifying patients with high risk of severe pneumonia to enable early interventions. They have published this work in the American Journal of Human Genetics. DOI:10.1016/j.ajhg.2020.12.010

Melatonin produced in the lungs acts as a barrier against SARS-CoV-2, blocking the expression of genes that encode proteins in cells serving as viral entry points, finds researchers at the University of So Paulo (USP). The hormone, therefore, prevents infection of these cells by the virus and inhibits the immune response so that the virus remains in the respiratory tract for a few days and then leaves the host, say the researchers. They used RNA sequencing data to quantify the level of expression of 212 COVID-19 signature genes in 288 samples from healthy human lungs. The researchers correlated these gene expression levels with a gene index that estimated the capacity of the lungs to synthesize melatonin (MEL-index). They then were able to determine that when the MEL-index was high, the entry points for the virus in the lungs were closed, and vice-versa. The research team suggests the potential for nasal administration of melatonin to prevent disease from developing in pre-symptomatic COVID-19 patients. This study is published in Melatonin Research. DOI:10.32794/mr11250090

In a new study, published in Cell Reports Medicine, La Jolla Institute for Immunology (LJI) researchers suggest that T cells can mount attacks against many SARS-CoV-2 targets, beyond the key sites on the viruss spike protein. They believe that by attacking the virus from many angles, the body is equipped to potentially recognize different SARS-CoV-2 variants. The researchers examined T cells from 100 people who had recovered from COVID-19 to take a closer look at the genetic sequence of the virus to separate the potential epitopes from the epitopes that these T cells would recognize. Their analysis revealed that not all parts of the virus induce the same strong immune response in everyone, and T cells can recognize dozens of epitopes on SARS-CoV-2 that vary from person to person. They determined that each study participant had the ability to recognize about 17 CD8+ T cell epitopes and 19 CD4+ T cell epitopes. DOI:10.1016/j.xcrm/2021/100202

John Hopkins Medicine researchers, in collaboration with Immunoscape, have published a complete profile of the response of T cells in people who have recovered from SARS-CoV-2 infection. The paper, published in The Journal of Clinical Investigation, better defines which T cells interact with which specific portion of the SARS-CoV-2 virus and how those interactions can provide long-lasting immunity against COVID-19. The researchers collected blood samples from 30 convalescent patients who had recovered from mild cases of COVID-19 and the Immunoscape team, a U.S.-Singapore biotechnology company, used its highly sensitive human leukocyte antigen (HLA)-SARS-CoV-2 tetramers to tag and identify the types of virus-recognizing CD8+ T cells. The researchers found that as levels of neutralizing antibodies increased in the convalescent plasma, so did the number of memory CD8+ T cells that recognized SARS-CoV-2 epitopes. They believe this means lasting protection against reinfection, and this knowledge will guide COVID-19 vaccine design to produce a strong immune response that could provide years of protection. DOI:10.1172/JCI145476

Severe COVID-19 patients have significantly elevated levels of a certain type of immune cell in their blood, call monocytic myeloid-derived suppressor cells (M-MDSC), according to a new study published in the Journal of Clinical Investigation. Karolinska Institutet researchers studied 147 patients with mild to fatal COVID-19 who were sampled repeatedly from blood and respiratory tract. These samples were then compared with patients who had influenza and healthy individuals. They found that the patients with severe COVID-19 had significantly higher levels of M-MDSCs in their blood when compared to milder cases and healthy participants. COVID-19 patients also had fewer T cells in their blood than healthy individuals that showed signs of impaired function. Additionally, their analysis revealed that the levels of M-MDSCs early in the course of infection seemed to reflect subsequent disease severity. DOI:10.1172/JCI44734

Researchers have engineered an antibody that effectively neutralizes SARS-CoV-2 and that also acts against multiple SARS-like viruses. Their antibody, ADG-2, was studied in mice. To engineer this broadly neutralizing antibody (bnAb), the researchers started with antibodies from the memory B cells of a 2003 SARS survivor that cross-neutralized multiple SARS-related viruses with modest potency. They then selectively engineered the binding affinities of several of these bnAbs, creating improvements in their abilities to bind the virus. The researchers then studied the engineered antibodies for SARS-CoV-2 neutralizing activity in mouse cell lines. ADG-2 was particularly effective. It showed broad binding activity to more than a dozen SARS-related coronaviruses. This research is published in Science. DOI:10.1126/science.abf4830

Plitidepsin has shown a potent efficacy against SARS-CoV-2 in preclinical trials, outperforming the antiviral remdesivir. These results, published in Science, show that in studies in human cells, plitidepsin demonstrated potent anti-SARS-CoV-2 activity: 27.5-fold more so than remdesivir as tested in the same cell line. In a model of human lung cells, plitidepsin greatly reduced viral replication. In further experiments involving both plitidepsin and remdesivir in vitro, the researchers suggest that plitidepsin has an additive effect with the approved drug and would be a potential candidate for a combined therapy. Authors of the research article believe that this promising treatment, which has limited clinical approval for the treatment of multiple myeloma, should be strongly considered for expanded clinical trials for the treatment of COVID-19. DOI:10.1126/science.abf4058

Oregon Health & Science University (OHSU) researchers have demonstrated that antibodies generated by the SARS-CoV-2 virus react to other strains of coronavirus and vice-versa. They determined, however, that antibodies generated by the 2003 SARS outbreak had only limited effectiveness in neutralizing SARS-CoV-2. The researchers believe that these findings have implications on both vaccine effectiveness and diagnosis of COVID-19. They believe that more work needs to be done to determine the lasting effectiveness of COVID-19 vaccine, given the speed of mutations. The team believes their study also suggests that efforts to accurately discern a previous COVID-19 infection, by analyzing antibodies in the blood, may be complicated by the presence of antibodies reacting to other strains of coronavirus including the common cold. This study is published in Cell Reports. DOI:10.1016/j.celrep.2021.108737

A new method to mapping viral mutations that escape leading clinical antibodies against COVID-19 has revealed mutations in the SARS-CoV-2 virus that allow it to evade treatments, including a single amino-acid mutation that fully escapes Regenerons antibody cocktail. University of Washington researchers and colleagues developed this scanning method to map how mutations to the receptor-binding domain (RBD) affect its recognition by antibodies. Their maps identified mutations that escape antibody binding, including a single mutation that escapes both antibodies in the Regeneron antibody cocktail. To further investigate, the team examined deep sequencing data from a persistently infected patient who was treated with the antibody cocktail at day 145 after diagnosis with COVID-19, and their analysis identified resistance mutations that arose in the patient. Furthermore, after they examined all human-derived SARS-CoV-2 sequences available as of mid-January 2021, the researchers report a substantial number of RBD mutations that escaped one or more of the antibodies that are in circulation. This paper is published in Science. DOI:10.1126/science.abf9302

Monash University researchers have discovered two new molecules that provide profound protection in experimental models of asthma, as well as protection from acute respiratory distress syndrome (ARDS) that is seen in some patients with severe COVID-19. In their study, originally designed to investigate how the immune system impacts gut bacteria, the researchers found that p-cresol sulfate (PCS), a gut bacteria by-product, led to a striking protection against asthma. They then determined that PCS was produced by enhanced bacterial metabolism of L-tyrosine, a well-known amino acid found in dietary supplements. The researchers saw significant protection against lung inflammation in mice given either L-tyrosine or PCS, as well as protection from ARDS. The researchers now aim to test one of the molecules in a clinical trial in asthmatics this year. These new findings are published in Nature Immunology. DOI:10.1038/s41590-020-00856-3

Non-steroidal anti-inflammatory drugs (NSAIDs) reduced both antibody and inflammatory responses to SARS-CoV-2 infection in mice, a new study finds that is published in the Journal of Virology. The authors of the study highlight that the timing of NSAID use during COVID-19 is important. They explain that NSAIDs anti-inflammatory activity could be detrimental early in SARS-CoV-2 infection because inflammation is usually helpful during this stage. This changes at later stages of COVID-19, particularly if the patient experiences intense inflammation known as cytokine storm. The researchers also note that a reduction in neutralizing antibodies caused by NSAIDs could be benign, or it might hinder the immune systems ability to fight the infection in its early stages. It could also reduce the magnitude or duration of protection from either natural infection or vaccination. DOI:10.1128/JVI.00014-21

Rhesus macaque monkeys infected with SARS-CoV-2 developed protective immune responses that could be reproduced with a vaccine, according to University of California, Davis (UC Davis) researchers. The team infected eight rhesus macaques at the California National Primate Research Center (CNPRC) with SARS-CoV-2 virus isolated from the first human patient treated at UC Davis, and they followed the immune responses in the monkeys over two weeks. The animals showed signs of lasting immunity and, most importantly, structures called germinal centers developed in the lymph nodes near the lungs. These germinal centers contained cells call T follicular helper (Tfh) cells. Germinal centers and Tfh cells are associated with generating plasma cells that remain in the body for many years to produce antibodies against pathogens the immune system has seen before, the researchers explain. They believe these results suggest that vaccines that induce this response will support immunity against COVID-19. This study is published in Nature Communications. DOI:10.1038/s41467-020-20642-x

Patients who have recovered from severe COVID-19 infection could be left with more protective T cells needed to fight reinfection, finds a team of researchers led at La Jolla Institute for Immunology (LJI). For their study, published in Science Immunology, the team analyzed CD8+ T cells from 39 COVID-19 patients and 10 individuals who had never been exposed to the virus. Of the COVID-19 patients, 17 had a mild case that did not require hospitalization, 13 had been hospitalized, and nine needed intensive care support. Surprisingly, the researchers saw weaker CD8+ T cell responses in patients with milder COVID-19 cases and saw the strongest CD8+ T cell responses in the patients who required hospitalization or intensive care. The team now hopes to study how T cells in tissues hit hardest by SARS-CoV-2, such as the lungs, react to the virus. They explain the importance of this as the memory T cells that provide long-term immunity need to live in the tissues. DOI:10.11260/sciimmunol.abe4782

In a new study published in Science Signaling, scientists discovered that SARS-CoV-2 may enter and replicate in human cells by exploiting newly identified sequences within cell receptors. They also suggest that these sequences could potentially serve as targets for new therapies against COVID-19. After analyzing the Eukaryotic Linear Motif database, the team of scientists discovered that ACE2 and various receptors contained several short linear motifs (SLiMs), or small amino acid sequences, that they predict plays a role in endocytosis and autophagy, or the entering of human cells and cellular housekeeping. The team determined that two SLiMs in ACE2 bound to endocytosis-related proteins, and one SLiM in the integrin beta-3 (3) bound to two proteins involved in autophagy. They believe that their prediction models could help identify similar SLiMs that assist with the replication of not only SARS-CoV-2, but other viruses that cause disease. DOI:10.1126/scisignal.abd0334

Ohio University researchers have published the first structural biology analysis of a section of the COVID-19 viral RNA called the stem-loop II motif, which they believe could be a potential target for anti-viral drugs to combat the virus. The research team identified this non-coding section of the RNA that is likely key to SARS-CoV-2 replication. Interestingly, they determined that the structural flexibility of this noncoding RNA motif differs by only a single nucleotide when compared to that in the early 2000s SARS-CoV outbreak, and the team also identified FDA-approved drugs that bind to the RNA motif and alter its flexibility. Since the structure and flexibility of noncoding RNA affects its function, the researchers suggest that it may be possible to develop antiviral drugs that specifically target this RNA motif to battle the virus. This research is published in Biochemical and Biophysical Research Communications. DOI:10.1016/j.bbrc.2021.01.013

Innate immunity may play a larger role in controlling SARS-CoV-2 viral load than adaptive immunity, according to a new study published in ACS Pharmacology & Translational Science. Researchers of the study developed a mathematical model that predicts viral load over time in organs that express the ACE2 receptor, which allows SARS-CoV-2 entry into human cells. They then used this model to simulate different conditions to determine this key role for innate immunity in controlling viral load. The researchers suggest the importance of starting antiviral or interferon therapy as soon as possible after the onset of COVID-19 symptoms. DOI:10.1021/acsptsci.0c00183

Industry News

Allarity Therapeutics in Denmark plans to further test the antiviral activity of stenoparib, its Poly ADP-Ribose Polymerase (PARP) inhibitor, against the B.1.1.7 variant of SARS-CoV-2. Stenoparib is a small molecule, targeting inhibitor of PARP, a key DNA damage repair enzyme active in tumors, which was originally developed by the pharmaceutical company Eisai. Results of previous pre-clinical studies for SARS-CoV-2 demonstrated that stenoparib inhibits SARS-CoV-2 as a single agent, and stenoparib in combination with remdesivir was active in inhibiting coronavirus in vitro. Allarity will now work with scientists at Northern Arizona Universitys Pathogen and Microbiome Institute (PMI) to test the similar ability of stenoparib to block the infection and replication of Coronavirus Variant B117. Press Release

Clear Labs announced the availability of the Clear Dx Whole Genome Sequencing (WGS), the first automated WGS solution that determines the complete RNA sequence of the SARS-CoV-2 genome in less than 24-hours with only minutes of hands-on time. The Clear Dx platform is powered by next generation sequencing (NGS), robotics and cloud-based analytics, and as a result, their WGS can more easily determine the nature of virus transmission by differentiating virus strains and monitoring mutations that lead to variants. In addition to WGS, the platform also features the Clear Dx SARS-CoV-2 Diagnostic Assay, which has received EUA, that allows labs to perform diagnostic screening and genomic surveillance simultaneously. Press Release

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Profile of T Cells, Broadly Neutralizing Antibodies, Anti-Viral Targets: COVID-19 Updates - Bio-IT World

BOSTON--(BUSINESS WIRE)--Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that the U.S. Food and Drug Administration (FDA) has accepted its supplemental New Drug Application (sNDA) to expand the use of TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor) to include children ages 6 through 11 years old who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or a mutation in the CFTR gene that is responsive based on in vitro data. The FDA has granted Priority Review of the sNDA and assigned a Prescription Drug User Fee Act (PDUFA) target action date of June 8, 2021. The submission was supported by data from a global Phase 3 study of TRIKAFTA in children ages 6 through 11 years old with cystic fibrosis (CF) who have either two copies of the F508del mutation or one copy of the F508del mutation and one minimal function mutation.

If approved for this expanded use, we will have the opportunity to treat the underlying cause of the disease earlier in life with TRIKAFTA and potentially benefit approximately 1,500 additional children with CF, said Carmen Bozic, M.D., Executive Vice President and Chief Medical Officer at Vertex. Since our initial approval of TRIKAFTA in 2019, we have continued to work tirelessly to bring this medicine to those waiting as quickly as possible. We look forward to working with the Agency as they review the application over the course of the coming months.

Vertex plans to submit a Marketing Authorization Application (MAA) variation for the triple combination in the European Union in the first half of 2021 for children ages 6 through 11. Global regulatory filings in additional markets, including Canada and Australia, are planned in the coming months for this age group.

About Cystic Fibrosis

Cystic Fibrosis (CF) is a rare, life-shortening genetic disease affecting more than 80,000 people globally. CF is a progressive, multi-system disease that affects the lungs, liver, GI tract, sinuses, sweat glands, pancreas and reproductive tract. CF is caused by a defective and/or missing CFTR protein resulting from certain mutations in the CFTR gene. Children must inherit two defective CFTR genes one from each parent to have CF. While there are many different types of CFTR mutations that can cause the disease, the vast majority of all people with CF have at least one F508del mutation. These mutations, which can be determined by a genetic test, or genotyping test, lead to CF by creating non-working and/or too few CFTR proteins at the cell surface. The defective function and/or absence of CFTR protein results in poor flow of salt and water into and out of the cells in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death. The median age of death is in the early 30s.

INDICATION AND IMPORTANT SAFETY INFORMATION FOR TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor)

What is TRIKAFTA?

TRIKAFTA is a prescription medicine used for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who have at least one copy of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or another mutation that is responsive to treatment with TRIKAFTA. Patients should talk to their doctor to learn if they have an indicated CF gene mutation. It is not known if TRIKAFTA is safe and effective in children under 12 years of age.

Patients should not take TRIKAFTA if they take certain medicines or herbal supplements, such as: the antibiotics rifampin or rifabutin; seizure medications such as phenobarbital, carbamazepine, or phenytoin; or St. Johns wort.

Before taking TRIKAFTA, patients should tell their doctor about all of their medical conditions, including if they: have kidney problems; have or have had liver problems; are pregnant or plan to become pregnant because it is not known if TRIKAFTA will harm an unborn baby; or are breastfeeding or planning to breastfeed because it is not known if TRIKAFTA passes into breast milk.

TRIKAFTA may affect the way other medicines work, and other medicines may affect how TRIKAFTA works. Therefore, the dose of TRIKAFTA may need to be adjusted when taken with certain medications. Patients should especially tell their doctor if they take antifungal medications such as ketoconazole, itraconazole, posaconazole, voriconazole, or fluconazole; or antibiotics such as telithromycin, clarithromycin, or erythromycin.

TRIKAFTA can cause dizziness in some people who take it. Patients should not drive a car, operate machinery, or do anything that needs them to be alert until they know how TRIKAFTA affects them.

Patients should avoid food or drink that contains grapefruit while they are taking TRIKAFTA.

TRIKAFTA can cause serious side effects, including:

High liver enzymes in the blood, which is a common side effect in people treated with TRIKAFTA. The patient's doctor will do blood tests to check their liver before they start TRIKAFTA, every 3 months during the first year of taking TRIKAFTA, and every year while taking TRIKAFTA. Patients should call their doctor right away if they have any of the following symptoms of liver problems: pain or discomfort in the upper right stomach (abdominal) area; yellowing of the skin or the white part of the eyes; loss of appetite; nausea or vomiting; dark, amber-colored urine.

Abnormality of the eye lens (cataract) in some children and adolescents treated with TRIKAFTA. If the patient is a child or adolescent, their doctor should perform eye examinations before and during treatment with TRIKAFTA to look for cataracts.

The most common side effects of TRIKAFTA include headache, diarrhea, upper respiratory tract infection (common cold) including stuffy and runny nose, stomach (abdominal) pain, inflamed sinuses, increase in liver enzymes, increase in a certain blood enzyme called creatine phosphokinase, rash, flu (influenza), and increase in blood bilirubin.

These are not all the possible side effects of TRIKAFTA. Please click the product link to see the full Prescribing Information for TRIKAFTA.

About Vertex

Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has multiple approved medicines that treat the underlying cause of cystic fibrosis (CF) a rare, life-threatening genetic disease and has several ongoing clinical and research programs in CF. Beyond CF, Vertex has a robust pipeline of investigational small molecule medicines in other serious diseases where it has deep insight into causal human biology, including pain, alpha-1 antitrypsin deficiency and APOL1-mediated kidney diseases. In addition, Vertex has a rapidly expanding pipeline of genetic and cell therapies for diseases such as sickle cell disease, beta thalassemia, Duchenne muscular dystrophy and type 1 diabetes mellitus.

Founded in 1989 in Cambridge, Mass., Vertex's global headquarters is now located in Boston's Innovation District and its international headquarters is in London. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia and Latin America. Vertex is consistently recognized as one of the industry's top places to work, including 11 consecutive years on Science magazine's Top Employers list and a best place to work for LGBTQ equality by the Human Rights Campaign. For company updates and to learn more about Vertex's history of innovation, visit http://www.vrtx.com or follow us on Facebook, Twitter, LinkedIn, YouTube and Instagram.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, statements made by Dr. Carmen Bozic in this press release, statements regarding our plans to submit an MAA in the EU and other global regulatory filings in additional markets, our expectations regarding the number of patients newly eligible for TRIKAFTA, and statements regarding the potential benefits of TRIKAFTA. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that the sNDA to expand the use of TRIKAFTA to include children ages 6 through 11 could not be approved on a timely basis, or at all, that data from the company's development programs may not support registration or further development of its compounds due to safety, efficacy or other reasons, and other risks listed under the heading Risk Factors in Vertex's most recent annual report and subsequent quarterly reports filed with the Securities and Exchange Commission (SEC) and available through the company's website at http://www.vrtx.com and on the SECs website at http://www.sec.gov. You should not place undue reliance on these statements. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX-GEN)

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Vertex Announces U.S. FDA Acceptance of Supplemental New Drug Application for TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor) in Children...

When the French Emmanuelle Charpentier and the American Jennifer Doudna, won the Nobel Prize in Chemistry 2020, the award fell short compared to the importance of their contribution to the gene editing. These girls, yeah they discovered the black thread with their scissors CRISPR to alter and repair DNA, contributing to the health of living beings. A revolutionary technique, thanks to which mice with damage to the spinal cord They have walked again, hoping that one day it could be applied to humans.

Although it seems inspired by the Lucy movie, gene editing also known as biohacking, it is nothing other than correct and repair the cells of the DNA Or, insert the missing cells, which cause genetic diseases as simple as myopia to the diabetes. In addition, they have been shown to have an important benefit in other types of patients such as HIV. Being a new miracle in medicine.

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In a simple explanation, one of the theories of CRISPR, is that genetic diseases are due to damage or absence in the genomic sequence. What the experts do is all engineering work, repairing or inserting the genetic sequence. For example, some genetic diseases such as sclerosis, diabetes or muscular dystrophy are believed to be due toin the absence or damage de a gene X, while biohackers take care of repair it. It is truly fascinating.

However, gene editing therapies in humans are illegal in many countries, in addition to being a potentially controversial issue because it questions the objective of prolonging life and practically playing god. In fact, a group of UNESCO scientists requested the prohibition of any edition of the human germ line since they could lead to actions of baby design .

Twitter: @N_Neandertalien

However, a study of the Ruhr University, in Germany, revives the debate on the future of genetic medicine, by getting a group of hamsters with spinal cord damage to walk again dfter two to three weeks of receiving a new gene therapy, while there is a huge chance that this new treatment will have the same success in humans.

The scientists worked with mice with spinal damage and consequently lost all mobility on both legs. They first began by stimulating the nervous system to identify the damaged gene, after a series of studies, they developed the gene hyperinterleukin-6genetically modified and injected it into the sensory motor cortex and did what they could at the time: wait.

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Being an unpublished study, the consequences could have been diverse, but once the hyper-interleukin-6, achieved adapt to the genetic sequence, for the production of the protein within the cells. Lto protein, or hyperinterleukin-6 (hIL-6), acts assuming a key characteristic Disabling spinal cord injuries, which is damage to nerve fibers known as axons. What is special about our study is that the protein is not only used to stimulate nerve cellss that produce it themselves, but also takes it further (through the brain) , Gave DailyMail, Dr. Dietmar Fischer, who led the study.

Nature

There is no miracle, everything is thanks to science and like all treatment, genetic editing would take time to show the first results. But, after a couple of weeks, the CRISPR worked its magic. All mice managed to recobrar movement body and not only that, Little time they all walked again.

Now the scientists will have to wait to analyze if the mice do not suffer from serious side effects, if so, they will take the next step to study if this gene-editing therapy can be applied in humans, which could save more than five million people in the world who suffer from partial or total paralysis.

It sounds spectacular, we know. But please dont try to play scientist. Gene editing may have grave consequences in humans, if it is practiced in a way experimental. While modified genes are not found in nature, they are designed specifically for genetic engineers with all the knowledge and within a laboratory. Better, if you are interested in the subject and you would like to enter the world of CRISPR, we recommend the Netflix documentary entitled Unnatural Selection

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The story of the hamster that walked again thanks to genetic editing - Explica

Introduction

Elizabethkingia anophelis (E. anophelis) is an aerobic, immotile, oxidase-positive, indole-positive, Gram-negative, non-fermenting bacillus, belonging to the genus Elizabethkingia and the family Flavobacteriaceae, which was first isolated from the midgut of the mosquito Anopheles gambiae in 2011.1 The first clinically significant E. anophelis infection was associated with a case of neonatal meningitis in Bangui, Central African Republic in 2011.2

Thereafter, within the genus Elizabethkingia, E. anophelis has emerged as a major nosocomial pathogen, which can cause severe pneumonia, meningitis, infections of the bloodstream, osteomyelitis, endocarditis, endophthalmitis, skin and soft tissue infection, urinary tract infection and abdominal infection.310,14,15 Whole genome sequencing (WGS) has recently uncovered a wide range of virulence factors contributing to the pathogenesis of E. anophelis, including products of the capsule, lipopolysaccharides, endopeptidases, lipid biosynthesis and metabolism, magnesium transport proteins, macrophage infectivity, heat shock proteins, catalase, peroxidases, superoxide dismutase, two-component regulatory system, and more.5,1820

Extensive research has shown that E. anophelis isolates are resistant to most -lactams, carbapenems and aminoglycosides.4,5,1417 The emergence of multidrug-resistant (MDR) bacterial pathogens is considered a potential public health hazard, they are widely detected in the environment and their transmission to humans is either by the food chain or via infected animals, poultry, and fish.2629 Furthermore, MDR bacterial pathogens often pose a therapeutic dilemma for clinicians and are therefore associated with a high mortality rate and poor prognosis.

Recently, the incidence of infections caused by the genus Elizabethkingia has increased continuously worldwide, especially those caused by E. anophelis species. A single-hospital study from South Korea reported that there was an increase in the prevalence of Elizabethkingia genus infections among hospitalized patients from 0.02 in 2009 to 0.88 in 2017.9 The first recorded outbreak of E. anophelis infection was from Singapore in 2012, in which three out of five patients died of septicemia.3 Furthermore, during 20142016, several outbreaks have occurred in the Midwestern United States, including Wisconsin, Illinois, and Michigan, in which the patient fatality rate related to E. anophelis infections ranged from 30.8% to 70%.58 Therefore, E. anophelis infection is regarded as profoundly serious and important and should be taken seriously by clinicians.

A recent study indicated that E. anophelis has been continuously misidentified as Elizabethkingia meningoseptica (E. meningoseptica) using conventional methods (API/ID32, Phoenix 100 ID/AST, Vitek 2 and Vitek MS).13 Therefore, most of the previously reported data regarding clinical characteristics, antimicrobial susceptibility patterns and carbapenem resistance mechanisms of E. anopheles, may be incorrect. To date, however, the susceptibility patterns of E. anophelis isolates have not been reported in Mainland China, especially with data collated using the more robust broth dilution method. Genome-wide analysis has revealed that this multidrug-resistant pathogen carries a class A serine--lactamase, CME, 2 metallo--lactamases, GOB and BlaB, in addition to numerous genes encoding for putative efflux pumps.5,1820 However, no studies have focused on the function of these putative efflux pumps in E. anophelis isolates. In addition, data reporting on risk factors associated with infection and mortality in E. anophelis infected patients may potentially help clinicians identify high-risk patients and help guide future therapeutic strategies.

The present study was therefore initiated to: (i) identify the risk factors associated with E. anophelis infection and in-hospital mortality, (ii) investigate the antimicrobial susceptibility patterns and carbapenem resistance mechanisms of E. anophelis isolates and (iii) characterize the function of -lactamases and putative efflux pumps expressed in E. anophelis isolates.

This study used the clinical microbiology database from a 3200-bed university-affiliated medical center (Chongqing, China) to retrospectively collect those strains that were identified as the genus Elizabethkingia between January 2015 and December 2019. Sampling and isolation of bacterial strains were a part of the routine hospital laboratory procedures and microbial identification was performed in the microbiology laboratory using the VITEK2 compact (bioMrieux, Inc., NC, USA) and the VITEK MS (bioMrieux, MO, USA) systems. All strains from the genus Elizabethkingia were stored at 80C in 15% glycerol until use. Complete 16S rRNA gene sequencing was used to reconfirm the identity of all isolates. The primers used for amplification and sequencing of the 16S rRNA gene are listed in Table S1 in Additional file 1. The sequences were assembled using SeqMan (DNAStar) and compared with publicly available sequences in the NCBI (http://www.ncbi.nlm.nih.gov) using the BLAST algorithm. Strains were considered to be accurately identified when a strain shared >99.0% 16S rRNA sequence with a type of strain in GenBank. The sequences of 16S rRNA were performed using ClustalW, and the phylogenetic trees were constructed in MEGA7 software using the Neighbor-Joining method.

Electronic medical records of the patients were collected retrospectively and we excluded subjects with the following characteristics: patients with polymicrobial infection and patients admitted for <48 hours. Only the first episode was considered for patients with more than one positive E. anophelis culture. To evaluate the risk factors associated with E. anophelis infection, controls were defined as randomly selected patients with non-E. anophelis infections during the same time (at a 3:1 ratio to the case group). Selected epidemiological, demographic, clinical, laboratory, treatment and outcome data were obtained from the electronic medical records. Empirically administering agents to isolates that were not susceptible was defined as inappropriate empirical antimicrobial therapy. Shock was defined as the coexistence of a systolic pressure of <90 mm Hg and organ dysfunction of the respiratory system, liver, or kidneys. Serum total protein content of <60 g/L or albumin content <25 g/L was the criteria used to define hypoproteinemia. Hypokalemia was diagnosed for a serum potassium level <3.5 mmol/L. Systemic steroid use was defined as oral or intravenous administration of at least 20 mg/day of a steroid (prednisone, hydrocortisone, methylprednisolone, or dexamethasone) within 1 month of infection. We defined anemia as a hemoglobin level of <130 g/L in men and <120 g/L in women according to the World Health Organization (WHO) guidelines. The primary clinical outcome was in-hospital mortality.

The reference broth microdilution method was used to evaluate the minimum inhibitory concentrations (MICs) of all antibiotics in E. anophelis and recombinant strains according to the Clinical and Laboratory Standards Institute (CLSI) M07-Ed11 (2019). The criterion suggested by the CLSI for other non-Enterobacteriaceae was used to determine the susceptibility of isolates to antibiotics except for ceftazidime/avibactam, aztreonam/avibactam, vancomycin, tigecycline, rifampicin, colistin and fosfomycin. The US Food and Drug Administration (FDA) Enterobacteriaceae criteria were used to interpret isolate susceptibility to tigecycline (resistant MIC 8 g/mL, susceptible MIC 2 g/mL and intermediate MIC = 4 g/mL). The MIC breakpoint applied to vancomycin and rifampicin was adapted from the CLSI criteria for Staphylococcus spp. A MIC of 16/4 g/mL was considered resistant for the combination of ceftazidime/avibactam and aztreonam/avibactam. MICs for colistin were interpreted at susceptible breakpoints of 2 g/mL and resistant breakpoints of >2g/mL according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) Enterobacteriaceae criteria. Likewise, for fosfomycin, we elected to use the susceptible breakpoint of 32 g/mL and resistant breakpoint of >32 g/mL based on EUCAST Enterobacteriaceae criteria. The reference strains Escherichia coli (ATCC 25922) and Pseudomonas aeruginosa (ATCC 27853) were used as negative controls and quality controls for antibiotic susceptibility testing.

The presence of the carbapenemase genes (blaKPC, blaIMP, blaVIM, blaNDM, blaBlaB, blaGOB and blaOXA-48-like) and extended-spectrum beta-lactamase (ESBL) genes (blaTEM, blaSHV, blaCME and blaCTX-M) were confirmed by touch-down PCR assays and sequencing. Touch-down PCR amplification was performed using a thermal cycler (Applied Biosystems VeritiPro PCR, CA, USA) under the following cycling conditions: Initial step of 95C for 3 min, followed by 8 cycles of 92C for 20 sec, with annealing temperatures starting at 68C for 20 sec (decreasing 2C/cycle), and with a final extension at 72C for 30 sec; this step was followed by 21 cycles of 92C for 20 sec, 55C for 20 sec, 72C for 30 sec, and finally, 72Cfor 5 min. DNA sequencing was performed using an Applied Biosystems 3730 DNA Analyzer.

We amplified the full-length coding sequences (CDSs) of the genes using specific primers flanked by restriction sites (EcoRI, XhoI or BamHI). These included genes encoding for blaCME, blaBlaB, blaGOB, CzcABC family efflux RND transporter, Efflux ABC transporter (ATP-binding protein), the MATE family of MDR efflux pumps, small multidrug resistance family (SMR) proteins and MFS-type transporter. Amplified PCR fragments were purified and cloned into the corresponding sites within the pET-28a plasmid and then electroporated into BL21 competent E. coli. Positive clones were verified by PCR and sequencing. The sets of primers used for amplification and sequencing of target genes are provided in Table S1 in Additional file 1.

The data were evaluated using SPSS statistical software (version 22.0, IBM). Data are presented as counts (proportions) for categorical variables. Direct comparisons between two groups were determined using the 2 test or Fishers exact test. Means ( standard deviation) were used to express normally distributed continuous variables and the median ( inter-quartile range) was calculated for non-normally distributed variables. Comparisons between two groups were conducted using Students t-test for normally distributed variables or a MannWhitney U-test for non-normally distributed variables. To evaluate independent risk factors for the infection and in-hospital mortality of E. anophelis isolates, we examined all plausible variables using a univariate analysis. Risk factors with a P value <0.1 as detected by the univariate analysis were included in a multivariate logistic-regression model with the enter method. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined for each risk factor of infection and in-hospital mortality. A two-tailed P value <0.05 was considered statistically significant.

The Institutional Review Board and Ethics Committee of Chongqing Medical University approved this study (approval number: 2020703). The study was conducted in accordance with the Declaration of Helsinki. The collection of culture isolates and collation of anonymous clinical data was in accordance with the approved clinical practice guidelines. The need to give informed consent for this study was waived by the Institutional Review Board due to the nature of the retrospective analysis with no individual patient identifiers.

A total of 59 non duplicated Elizabethkingia isolates were collected from the clinical microbiology laboratory for microbial trait investigation. Full 16S rRNA gene sequencing was performed on 59 Elizabethkingia clinical strains. After comparison with available sequences in the NCBI using BLAST, 16S rRNA sequencing showed that 39 (69.6%) isolates were identified as Elizabethkingia anophelis R26. The phylogenetic tree based on 16S rRNA showed the genetic relationship among Elizabethkingia anophelis (Figure 1).

Figure 1 Phylogenetic tree showing the relationship of the 39 E. anophelis isolates using 16S rRNA gene sequence. Bootstrap support value above branches, the scale bar indicates the number of substitutions per site.

Of the E. anophelis isolates with a documented site of infection, 18 (46.2%) were from the respiratory tract, eight (20.5%) were from the urinary tract, six (15.4%) from blood, three (7.7%) from cerebrospinal fluid, and four were from peritoneal fluid, amniotic fluid, conjunctival sac, and the cornea (Table 5). From January 2015 to December 2019, 39 E. anophelis samples were isolated from 39 consecutive patients who were enrolled in the study. These patients consisted of 21 males (53.8%) and 18 females (46.2%) with a median age of 61.

Notably, chronic obstructive pulmonary disease was the most frequent comorbidity (76.9%), followed by anemia (66.7%). The empirical antibiotics used in the 39 patients included carbapenems (38.5%), -lactam/lactamase inhibitors (33.3%), -lactams (30.8%), teicoplanin (25.6%), levofloxacin (17.9%), aminoglycosides (17.9%), minocycline (12.8%) and antibiotics administered either alone or in combination (Table 5), and 84.6% of these empirical antibiotic therapies were deemed as inappropriate antibiotic use. Overall, the in-hospital mortality rate of patients with E. anophelis infection was 51.3%. Furthermore, -lactam/lactamase inhibitor antibiotics were used significantly more in patients who did not survive (P = 0.041).

Compared to the non-E. anophelis infection controls, the potential risk factors for the acquisition of E. anophelis infections are shown in Tables 1 and 2. Univariate analysis indicated that hypertension, cerebrovascular diseases, chronic obstructive pulmonary disease, renal diseases, surgery in the past 6 months, anemia, hypoproteinemia, and hypokalemia were significantly more frequent in patients with E. anophelis infections (P < 0.05). There was also a positive correlation between patient age and their likelihood of acquiring an E. anophelis infection (P < 0.05). In the multivariate analysis, coronary artery diseases (OR 5.81, 95% CI: 1.0930.93, P = 0.039), chronic obstructive pulmonary disease (OR 6.71, 95% CI: 1.5528.99, P = 0.011), surgery in the past 6 months (OR 18.04, 95% CI: 3.2998.87, P = 0.001), anemia (OR 6.72, 95% CI: 1.1240.42, P = 0.038) and systemic steroid use (OR 9.87, 95% CI: 1.3074.94, P = 0.027) were independent risk factors for the acquisition of an E. anophelis infection.

Table 1 Univariate Analysis of Clinical Features of Patients Infected with E. anophelis Isolates

Table 2 Multivariate Analysis of Clinical Features of Patients Infected with E. anophelis Isolates

Univariate and multivariate logistic-regression analysis results for the factors associated with in-hospital mortality are shown in Table 3. Univariate analysis showed that cerebrovascular disease (P = 0.035), chronic obstructive pulmonary disease (P = 0.020), nasogastric tube insertion (P = 0.008) and anemia (P = 0.002) were associated with a higher mortality rate. Using further multivariate analysis, anemia (OR 86.38, 95% CI: 1.425251.29; P = 0.033) was identified as the only independent risk factor for in-hospital mortality in patients with E. anophelis infections.

Table 3 Risk Factors Associated with In-Hospital Mortality

The susceptibility of the 39 E. anophelis isolates to the antimicrobial agents tested in this study is shown in Table 4. The isolates showed high in-vitro susceptibility towards minocycline (100%), and piperacillin/tazobactam (71.8%) but with lower in-vitro susceptibility towards levofloxacin (38.5%), ciprofloxacin (30.8%), rifampicin (20.5%), piperacillin (17.9%) and tigecycline (10.3%). The MIC50, MIC90 and MIC range for minocycline on the isolates were 0.5, 1, and 0.251 g/mL, respectively, whereas the MIC50, MIC90 and MIC range for piperacillin/tazobactam were 16, 32, and 464 g/mL, respectively. All isolates displayed resistance to vancomycin, ceftazidime, cefepime, aztreonam, ceftazidime/clavulanic acid, cefepime/clavulanic acid, colistin and fosfomycin according to the breakpoints used. It is worth noting that while all isolates produced the MBLs BlaB and GOB, aztreonam/avibactam could not further inhibit growth.

Table 4 Antimicrobial Susceptibilities of E. Anophelis Isolates Determined by the Broth Microdilution Method

PCR experiments were used to detect the presence of blaGOB and blaBlaB in 37 isolates, and blaCME -lactamase genes in 36 isolates from the original 39 E. anophelis isolates (Table 5 and Figure 2). Sequence alignments showed that E. anophelis strains harbored two types of the blaCME gene, blaCME-1 (n = 34) and blaCME-2 (n = 2), eight types of the blaBlaB gene, including blaBlaB-29 (17), blaBlaB-2 (7), blaBlaB-1 (5), blaBlaB-17 (3), blaBlaB-3 (1), blaBlaB-9 (1), blaBlaB-33 (1) and blaBlaB-34 (1), and eight types of the blaGOB gene, including blaGOB-38 (19), blaGOB-20 (8), blaGOB-32 (3), blaGOB-50 (3), blaGOB-39 (1), blaGOB-4 (1), blaGOB-40 (1) and blaGOB-45 (1). The most detected combination of -lactamases was CME-1 + BlaB-29 + GOB-38 (n = 17).

Table 5 Empirical Antimicrobial Therapy in Patients Infected with E. anophelis Isolates

Figure 2 (A) Electrophoretic pattern of BlaB gene (759 bp); M: 1002000 bp DNA ladder; Lanes 1, 2, 3, 5, 6, 7, 8, 9: positive E. anophelis strains; Lanes 4: negative E. anophelis strain. (B) Electrophoretic pattern of CME gene (912 bp); M: 1002000 bp DNA ladder; Lanes 1, 2, 3, 4, 6, 7, 8: positive E. anophelis strains; Lanes 5, 9: negative E. anophelis strains. (C) Electrophoretic pattern of GOB gene (885 bp); M: 1002000 bp DNA ladder; Lanes 1, 2, 4, 5, 7, 8, 9: positive E. anophelis strains; Lanes 3, 6: negative E. anophelis strains.

We also investigated the presence of other -lactamase genes, however, none of the 39 E. anophelis isolates harbored carbapenemase genes (blaKPC, blaIMP, blaVIM, blaNDM and blaOXA-48-like) or ESBL genes (blaTEM, blaSHV and blaCTX-M).

To further evaluate the function of -lactamases, the most prevalent forms of blaCME, blaBlaB and blaGOB genes from E. anophelis isolates were cloned into a pET28a(+) plasmid vector. We also amplified and cloned genes encoding putative efflux pump proteins including the CzcABC family efflux RND transporter, Efflux ABC transporter (ATP-binding protein), MATE family members of the MDR efflux pump, small multidrug resistance family (SMR) proteins and MFS-type transporter. These plasmids were transformed into BL21 (DE3) E.coli and the MICs of the common antibiotics were tested in the resultant strains. The strain transformed with pET-CME displayed an increased MIC for ampicillin, piperacillin, cefazolin, cefuroxime, ceftazidime, ceftriaxone and aztreonam when compared to the pET28a(+) vector construct. This suggests that the extended-spectrum serine--lactamase CME is functionally involved in cephalosporin and monobactam resistance (Table 6). The MIC for imipenem increased 32-fold (from 0.125 to 4 g/mL) in the presence of the pET-BlaB construct and 16-fold (from 0.125 to 2 g/mL) in the presence of the pET-GOB construct. This suggests that the MBLs BlaB and GOB, are responsible for increased imipenem resistance (Table 6). Along with the increase in imipenem resistance, the pET-BlaB and pET-GOB constructs also conferred an increased MIC for ampicillin, piperacillin, cefazolin, cefuroxime, and ceftazidime. This indicates that the MBLs BlaB and GOB can also degrade ampicillin, piperacillin, cefazolin, cefuroxime, and ceftazidime (Table 6). All the efflux pump transformants tested, including pET-ABC, pET-MFS, pET-MATE, pET-SMR and pET-RND did not result in increased MICs for any of the antibiotics tested (Table 6).

Table 6 The Antibiotic Susceptibilities of BL21 (DE3) E. coli Expressing CME, BlaB, GOB, Putative Efflux Proteins or the pET28a(+) Vector

Infection with E. anophelis in humans is increasing in many countries and there have been several reports of E. anophelis outbreaks in the community and nosocomial environment in Singapore and the Midwestern United States, including Wisconsin, Illinois, and Michigan.310 However, as suggested previously, E. anophelis is commonly misidentified as E. meningoseptica when using biochemical identification methodologies or automated identification systems in clinical settings. Therefore, data regarding the clinical features, clinical prognosis, and the antimicrobial susceptibility profiles of E. anophelis could be skewed. For these reasons, we have, for the first time identified the risk factors associated with the acquisition of E. anophelis and we have found that anemia is an independent risk factor for in-hospital mortality in patients with E. anophelis infections. Moreover, we demonstrate for the first time that various putative efflux pumps found in E. anophelis do not alter antimicrobial resistance and therefore, do not possess a drug efflux function. -Lactamases were commonly found in E. anophelis isolates and the MBLs BlaB and GOB, are responsible for carbapenem resistance, whereas the ESBL, CME is functionally involved in resistance to cephalosporins and monobactams.

In the present study, we initially explored risk factors associated with E. anophelis infection and using multivariate analysis, we found that coronary artery diseases, chronic obstructive pulmonary disease, surgery in the past 6 months, anemia and systemic steroid use were independently associated with E. anophelis infection. Previous studies have suggested that patients with E. anophelis infection could have greater underlying comorbidities and this study is the first to provide a statistical analysis to support this hypothesis.310 Moreover, surgery in the past 6 months, anemia and systemic steroid use are known to compromise the immune status of the patients. Therefore, these patients are more vulnerable to the acquisition of E. anophelis infection in the same hospital environment.

In previous reports, the case fatality rate of patients with E. anophelis infection ranged from 24% to 60% in different countries.414 In line with this, our study showed that the in-hospital mortality rate of patients with an E. anophelis infection was 51.3%. We, therefore, went on to explored the factors influencing this mortality. When compared with the only previous study investigating risk factors for mortality,10 our study demonstrated that anemia was the only independent predictor of mortality in patients infected with E. anophelis, a factor which has not been reported previously and these patients may present as anemic because of the hemolytic activity of E. anophelis. Several studies have reported that this bacterium can lyse erythrocytes to access essential nutrients (such as amino acids) using hemolysins and heme-degrading proteins.2022 This process may alter the host's physiological status and compromise the immune system, thereby worsening the patient prognosis with E. anophelis. Therefore, anemic patients with a confirmed E. anophelis infection should be considered as higher risk and should be given greater scrutiny and special care. Unexpectedly, inadequate antibiotic therapy was not associated with mortality, this is probably because of the small sample size of infected patients in our study.

Published information concerning the antimicrobial susceptibility patterns of E. anophelis, identified using reliable methods is limited. Studies from Singapore and Taiwan have demonstrated that E. anophelis was resistant to carbapenems, -lactams, -lactam/-lactam inhibitor and aminoglycosides.1416 However, previous research showed that the susceptibility of E. anophelis to fluoroquinolones, tigecycline, piperacillin, piperacillin-tazobactam and trimethoprim-sulfamethoxazole was variable.46,10,17 Using a disk diffusion or agar dilution test, studies from Hong Kong, South Korea and the USA reported the following susceptibilities of E. anophelis to ciprofloxacin (22%100%), levofloxacin (29%96%), piperacillin (41.1%100%), piperacillin-tazobactam (92%), vancomycin (0%100%) and trimethoprim-sulfamethoxazole (22%70.6%).4,5,17 However, when using the broth microdilution test, researchers from Taiwan and Singapore showed the following susceptibilities of E. anophelis to ciprofloxacin (1%21.5%), levofloxacin (16%78.5%), piperacillin (19.4%), piperacillin-tazobactam (30.6%92.4%), vancomycin (0%), tigecycline (5.1%26.4%), minocycline (97.5%100%) and trimethoprim-sulfamethoxazole (4%92.4%).1416 As shown above, there are huge discrepancies in the susceptibility levels of E. anophelis to ciprofloxacin, levofloxacin, piperacillin, and vancomycin when comparing the disk diffusion or agar dilution tests and the broth microdilution test. This suggests that the susceptibility of E. anophelis seen using the disk diffusion test or agar dilution test may be unreliable and inaccurate, as the broth microdilution test represents the gold-standard method for antimicrobial susceptibility testing.

There are also obvious differences in the susceptibility of E. anophelis to antibacterial agents when the standard broth microdilution test is used. A possible explanation for this inconsistency is that natural geographical differences cause variation in the susceptibility patterns observed in previous studies. It is therefore necessary to investigate the antimicrobial susceptibility of E. anophelis in local areas as a guide to antibiotic selection. Our study showed the following susceptibility of E. anophelis to various treatments: minocycline (100%), piperacillin-tazobactam (71.8%), levofloxacin (38.5%), ciprofloxacin (30.8%), piperacillin (17.9%), rifampicin (20.5%) and tigecycline (10.3%). All isolates displayed resistance to ceftazidime, cefepime, aztreonam, ceftazidime/clavulanic acid, cefepime/clavulanic acid, colistin and fosfomycin, according to the breakpoints used. Most of the antimicrobial susceptibility results in this study are consistent with those of previous studies performed using the broth microdilution test. These results suggest that antimicrobial therapy for E. anophelis should prioritize minocycline or piperacillin-tazobactam. However, in our study, patients in the non-survival group were treated with significantly more -lactam/lactamase inhibitor antibiotics as compared to the survival group (P = 0.041). This observation indicates that piperacillin-tazobactam is not an effective treatment for E. anophelis infections. This study was limited by the fact that antimicrobial susceptibility in-vitro does not equate to in-vivo clinical efficacy. Therefore, large prospective clinical trials are urgently needed to validate therapeutic recommendations.

In this study, we screened for the presence of carbapenemase genes (blaKPC, blaIMP, blaVIM, blaNDM, blaBlaB, blaGOB and blaOXA-48-like) and ESBL genes (blaTEM, blaSHV, blaCME and blaCTX-M) in all 39 E. anophelis isolates. No carbapenemase genes (blaKPC, blaIMP, blaVIM, blaNDM and blaOXA-48-like) or ESBL genes (blaTEM, blaSHV and blaCTX-M) were detected in any isolates. However, we identified 35 (89.7%) isolates co-harboring blaGOB, blaBlaB and blaCME -lactamase genes. The most detected combination of -lactamases was CME-1, BlaB-29, and GOB-38 (n = 17).

To further evaluate the function of -lactamases, recombinant strains harboring either blaCME, blaBlaB or blaGOB were constructed. The transformed strain expressing CMEs displayed an increased MIC for ampicillin, piperacillin, cefazolin, cefuroxime, ceftazidime, ceftriaxone and aztreonam as compared to the pET28a(+) vector construct. This suggests that the ESBL CME is functionally involved in resistance to cephalosporins and monobactams. The MIC for imipenem increased 32-fold (from 0.125 to 4 g/mL) in the presence of the BlaB-expressing construct and 16-fold (from 0.125 to 2 g/mL) in the presence of the GOB-expressing construct. This suggests that the metallo--lactamases BlaB and GOB are responsible for the observed carbapenem resistance.

Aztreonam/avibactam is a novel class of combinational -lactamase-inhibitor, designed to treat serious infections of metallo--lactamase (MBL)-producing Gram-negative bacteria, which is currently in Phase I clinical trials (NCT01689207). Aztreonam is relatively stable against MBL hydrolysis, however, it is easily inactivated by class A (eg, KPC), class C (eg, AmpC) and certain class D (eg, OXA-48) serine--lactamase enzymes.23 Avibactam potently inhibits class A, class C and certain class D serine--lactamase enzymes and displays a broader -lactamase inhibition profile than other -lactamase inhibitors.23 When in combination, aztreonam/avibactam is effective against isolates co-producing ESBLs and MBLs with porin loss/deficiency.24 However, it was quite unexpected that E. anophelis is resistant to aztreonam/avibactam according to our experimental results.

Genomic annotation of all Elizabethkingia spp. reveals that besides -lactamases, there are also numerous putative efflux pump proteins including CzcABC family efflux RND transporter, Efflux ABC transporter (ATP-binding protein), MATE family of MDR efflux pumps, small multidrug resistance family (SMR) proteins and MFS-type transporter. Interestingly, however, none of these transporters have been phenotypically characterized.5,1820 It was, therefore, critical to investigate the function of these putative efflux pumps. Our data showed that all recombinant efflux pump strains including pET-ABC, pET-MFS, pET-MATE, pET-SMR and pET-RND did not result in increased MICs for -lactam and non--lactam antibiotics. These results suggest that the putative efflux pump genes from E. anophelis are not responsible for antimicrobial drug resistance. Similarly, Schindler et al cloned and expressed 21 putative efflux pump genes in Staphylococcus aureus which had no effect on any of the antibiotics tested.25 In summary, we demonstrate for the first time that the various putative efflux pumps found in E. anophelis do not possess antimicrobial drug efflux function.

There were some limitations to our study; however, firstly, the small sample size from the single-center study prevented its translation to the wider population. However, the identification of both a carbapenem resistance mechanism and the susceptibility profile of the drug-resistant E. anophelis are of great clinical importance and warrant an urgent, wider, in-depth study. Secondly, no further investigation into the clonality of these isolates was performed, so that the possibility of infection outbreaks cannot be ruled out.

In conclusion, this study provided a detailed report of risk factors, antimicrobial susceptibility patterns and carbapenem resistance mechanisms in E. anophelis clinical isolates from one medical center in Southwest China. Our data showed that patients with anemia, coronary artery diseases, chronic obstructive pulmonary disease or patients who have received systemic steroids or surgery in the past 6 months are more likely to acquire an E. anophelis infection. Furthermore, patients with anemia have a worse prognosis and therefore require more attention and special care from clinicians. The collected clinical isolates exhibited remarkable multidrug resistance to colistin, fosfomycin, aztreonam/avibactam and tigecycline, which are all regarded as last-resort treatments for carbapenem-resistant Enterobacteriaceae, while minocycline is the most effective antibiotic against E. anophelis in-vitro. Mechanistic analysis revealed that carbapenem resistance is associated with the hydrolytic activity of the MBLs BlaB and GOB and is not associated with various putative efflux pumps expressed in E. anophelis. Future in-vivo and prospective clinical trials are urgently needed to determine optimal antimicrobial agent efficacies based on in-vitro drug susceptibility testing results and resistance mechanisms.

This study was supported by the Natural Science Foundation of Chongqing (No.cstc2019jcyj-msxmX0253). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

The authors report no conflicts of interest in this work.

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[Full text] MBLs, Rather Than Efflux Pumps, Led to Carbapenem Resistance in Fosfom | IDR - Dove Medical Press

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Discovery could aid early screening, shed light on how Chiari malformation arises

The lowest part of a child's brain is visible below the bottom of the skull in this MRI scan and shows evidence of a Chiari 1 malformation. Researchers at Washington University School of Medicine in St. Louis have shown that Chiari 1 malformation can be caused by variations in two genes linked to brain development, and that children with large heads are at increased risk of developing the condition.

About one in 100 children has a common brain disorder called Chiari 1 malformation, but most of the time such children grow up normally and no one suspects a problem. But in about one in 10 of those children, the condition causes headaches, neck pain, hearing, vision and balance disturbances, or other neurological symptoms.

In some cases, the disorder may run in families, but scientists have understood little about the genetic alterations that contribute to the condition. In new research, scientists at Washington University School of Medicine in St. Louis have shown that Chiari 1 malformation can be caused by variations in two genes involved in brain development.

The condition occurs when the lowest parts of the brain are found below the base of the skull. The study also revealed that children with unusually large heads are four times more likely to be diagnosed with Chiari 1 malformation than their peers with normal head circumference.

The findings, published Dec. 21 in the American Journal of Human Genetics, could lead to new ways to identify people at risk of developing Chiari 1 malformation before the most serious symptoms arise. It also sheds light on the development of the common but poorly understood condition.

A lot of times people have recurrent headaches, but they dont realize a Chiari malformation is the cause of their headaches, said senior author Gabriel Haller, PhD, an assistant professor of neurosurgery, of neurology and of genetics. And even if they do, not everyone is willing to have brain surgery to fix it. We need better treatments, and the first step to better treatments is a better understanding of the underlying causes.

If people start experiencing severe symptoms like chronic headaches, pain, abnormal sensations or loss of sensation, or weakness, the malformation is treated with surgery to decompress the Chiari malformation.

Theres an increased risk for Chiari malformations within families, which suggests a genetic underpinning, but nobody had really identified a causal gene, Haller said. We were able to identify two causal genes, and we also discovered that people with Chiari have larger head circumference than expected. Its a significant factor, and easy to measure. If you have a child with an enlarged head, it might be worth checking with your pediatrician.

To identify genes that cause Chiari 1 malformation, Haller and colleagues sequenced all the genes of 668 people with the condition, as well as 232 of their relatives. Of these relatives, 76 also had Chiari 1 malformation and 156 were unaffected. The research team included first author Brooke Sadler, PhD, an instructor in pediatrics, and co-authors David D. Limbrick, Jr., MD, PhD, a professor of neurosurgery and director of the Division of Pediatric Neurosurgery, and Christina Gurnett, MD, PhD, a professor of neurologyand director of the Division of Pediatric and Developmental Neurology, among others.

Sequencing revealed that people with Chiari 1 malformation were significantly more likely to carry mutations in a family of genes known as chromodomain genes. Several of the mutations were de novo, meaning the mutation had occurred in the affected person during fetal development and was not present in his or her relatives. In particular, the chromodomain genes CHD3 and CHD8 included numerous variants associated with the malformation.

Further experiments in tiny, transparent zebrafish showed that the gene CHD8 is involved in regulating brain size. When the researchers inactivated one copy of the fishs chd8 gene, the animals developed unusually large brains, with no change in their overall body size.

Chromodomain genes help control access to long stretches of DNA, thereby regulating expression of whole sets of genes. Since appropriate gene expression is crucial for normal brain development, variations in chromodomain genes have been linked to neurodevelopmental conditions such as autism spectrum disorders, developmental delays, and unusually large or small heads.

Its not well known how chromodomain genes function since they have such a wide scope of activity and they are affecting so many things at once, Haller said. But they are very intriguing candidates for molecular studies, to understand how specific mutations lead to autism or developmental delay or, as in many of our Chiari patients, just to increased brain size without cognitive or intellectual symptoms. Wed like to figure out the effects of each of these mutations so that in the future, if we know a child has a specific mutation, well be able to predict whether that variant is going to have a harmful effect and what kind.

The association between chromodomain genes and head size inspired Haller and colleagues to measure the heads of children with Chiari malformations, comparing them to age-matched controls and to population averages provided by the Centers for Disease Control and Prevention. Children with Chiari tended to have larger than average heads. Those children with the largest heads bigger than 95% of children of the same age were four times more likely to be diagnosed with the malformation.

The findings suggest that children with larger heads or people with other neurodevelopmental disorders linked to chromodomain genes may benefit from screening for Chiari malformation.

A lot of kids that have autism or developmental disorders associated with chromodomain genes may have undiscovered Chiari malformations, Haller said. The only treatment right now is surgery. Discovering the condition early would allow us to watch, knowing the potential for serious symptoms is there, and perform that surgery as soon as its necessary.

Sadler B, Wilborn J, Antunes L, Kuensting T, Hale AT, Gannon SR, McCall K, Cruchaga C, Harms M, Voisin N, Reymond A, Cappuccio G, Burnetti-Pierri N, Tartaglia M, Niceta M, Leoni C, Zampino G, Ashley-Koch A, Urbizu A, Garrett ME, Soldano K, Macaya A, Conrad D, Strahle J, Dobbs MB, Turner TN, Shannon CN, Brockmeyer D, Limbrick DD, Gurnett CA, Haller G. Rare and de novo coding variants in chromodomain genes in Chiari I malformation. American Journal of Human Genetics. Dec. 21, 2020. DOI: 10.1016/j.ajhg.2020.12.001

This study was funded by Sam and Betsy Reeves and the Park-Reeves Syringomyelia Research Consortium; the University of Missouri Spinal Cord Injury Research Program; the Childrens Discovery Institute of St. Louis Childrens Hospital and Washington University; the Washington University Institute of Clinical and Translational Sciences, grant number UL1TR000448 from the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH); the Eunice Kennedy Shriver National Institute of Child Health & Human Development, award number U54HD087011 to the Intellectual and Developmental Disabilities Research Center at Washington University; the Swiss National Science Foundation, grant number 31003A_182632; and the Jrme Lejeune Foundation.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Common brain malformation traced to its genetic roots - Washington University School of Medicine in St. Louis

Dawn Wells, the actress who radiated all-American wholesomeness, Midwestern practicality and a youthful nave charm as the character Mary Ann on the hit 1960s sitcom Gilligans Island, died on Wednesday at a nursing home in Los Angeles. She was 82.

Her publicist, Harlan Boll, said the cause was related to Covid-19.

Debuting on CBS in 1964, Gilligans Island followed an unlikely septet of day trippers (on a three-hour tour, as the theme song explained) who ended up stranded on a desert island.

There, shipwrecked alongside a movie star (who spent most of her time in evening gowns), a science professor, a pompous, older rich couple, and two wacky crew members was Mary Ann Summers (Ms. Wells), a farm girl from Kansas who had won the trip in a local radio contest.

The character had a relatively scant back story it was said that she worked at the hardware store back home and had a boyfriend but Mary Anns persona alone made her memorable. Gingham blouses, short shorts, double ponytails and perky hair bows were all parts of her signature look.

The first version of the shows theme song mentioned five of the characters and the rest, but the lyrics were soon changed to name the professor (Russell Johnson) and Mary Ann as well. The others in the cast were Bob Denver (Gilligan), Alan Hale Jr. (the Skipper), Jim Backus and Natalie Schafer (as the couple Thurston Howell III and Lovey Howell), and Tina Louise (as the actress, Ginger). Ms. Louise is the last surviving member of the original cast.

That the premise of Gilligans Island was pretty much implausible and its humor simplistic made no difference to the shows millions of fans or its producers, who would discover in the years to come that they had spawned a cultural phenomenon.

Though Gilligans Island lasted only three seasons, canceled in 1967, it hardly slipped from the horizon. Endless reruns ensued, and the cast members had a series of encore performances. Ms. Wells, for one, reprised her role as Mary Ann in three reunion TV movies: Rescue From Gilligans Island (1978), The Castaways on Gilligans Island (1979) and The Harlem Globetrotters on Gilligans Island (1981).

In 1982, she did the voices of both her character and Ms. Louises movie star for Gilligans Planet, an animated spinoff series. And she went on to play Mary Ann in episodes of at least four other (unrelated) shows: Alf (1986), Baywatch (1989), Hermans Head (1991) and Meego (1997). Gilligans-themed episodes had a certain camp value.

Even her career as an author related directly to the series. Mary Anns Gilligans Island Cookbook, which included Skippers Coconut Pie, was published in 1993. What Would Mary Ann Do? A Guide to Life, a memoir she wrote with Steve Stinson, appeared in 2014.

Jan. 2, 2021, 5:13 p.m. ET

Mary Anns advice in the book included this thought: Failure builds character. What matters is what you do after you fail. The San Francisco Book Review called the book a worthwhile mix of classic values and sincerity.

Asked decades later about her favorite Gilligans Island episodes, Ms. Wells mentioned And Then There Were None, which included a dream sequence in which she got to do a Cockney accent. She also cited Up at Bat, an episode in which Gilligan imagined that he had turned into Dracula.

I loved being the old hag, she said.

Dawn Elberta Wells was born in Reno, Nev., on Oct. 18, 1938, the only child of Joe Wesley Wells, a real estate developer, and Evelyn (Steinbrenner) Wells. Dawn majored in chemistry at Stephens College in Columbia, Mo., then became interested in drama and went to the University of Washington in Seattle. She graduated in 1960 with a degree in theater arts and design, having taken some time off to win a state beauty title and compete in the 1960 Miss America pageant.

Big deal, she said in a 2016 interview with Forbes, making light of her Miss Nevada win. There were only 10 women in the whole state at the time.

For the Miss America pageant in Atlantic City, her talent performance was a dramatic reading from Sophocles Antigone.

A 1961 episode of the drama The Roaring Twenties was her screen debut. When she was cast on Gilligans Island, she had appeared onscreen only about two dozen times, mostly in prime-time series, including 77 Sunset Strip (multiple episodes), Surfside Six, Hawaiian Eye, Bonanza and Maverick.

After her television career cooled down, Ms. Wells returned to her first love: theater, doing at least 100 productions nationwide. Her last television role was in 2019, as the voice of a supernatural dentist on the animated Netflix series The Epic Tales of Captain Underpants.

Her last onscreen appearance was in a 2018 episode of Kaplans Korner, about actors running an employment agency. Her only soap opera appearance was in a 2016 episode of The Bold and the Beautiful, in which she played a fashion buyer from a wealthy family.

Ms. Wellss marriage in 1962 to Larry Rosen, a talent agent, ended in divorce in 1967, the same year Gilligans Island went off the air. She is survived by a stepsister, Weslee Wells.

Ms. Wells went on to operate charity-oriented businesses. She was a prominent supporter of the Elephant Sanctuary in Tennessee, the nations largest natural habitat refuge developed for African and Asian elephants.

She also taught acting, creating the nonprofit Idaho Film and Television Institute while living at her ranch in the Teton Valley. But a screen career was never her childhood dream.

I wanted to be a ballerina, then a chemist, she recalled in the Forbes interview. If I had to do it all over again, Id go into genetic medicine.

Alex Traub contributed reporting.

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Dawn Wells, Mary Ann on Gilligans Island, Dies at 82 - The New York Times

Judith Lightfoot was managing her illness herself, until she couldnt.

It felt like a bad flu. She was sick to her stomach. She couldnt eat.

I was passing out all over the house said Lightfoot, who is the interim chairperson for Rowan Universitys department of internal medicine, chief of infectious disease and department director for internal medicine.

This was early March and Lightfoot, who was well aware of the COVID-19 virus sweeping across the world, spent two months battling back from it. Her expertise in the medical field and as a survivor of the coronavirus has made her a valued source for NJ Advance Media and other news outlets.

Lightfoot, 57, is a doctor of osteopathic medicine, which differs from a medical doctor in philosophy. Doctors of osteopathic medicine treat their patients holistically and believe that the body can heal itself.

She was on an international jazz cruise in January with her husband when she heard a BBC news report about the virus overtaking Wuhan, China. Her alarm level increased when she saw what happened at the nursing home in Washington State.

I was criticized for saying we should wear masks early on, she said.

By late February, she was angering more people at the university when she vocally opposed letting students travel abroad, she said.

I felt people were trying to discount what I was saying, they just didnt know and they didnt want to think it was going to be this serious, Lightfoot said.

She attended a gala at the Borgata on March 7 and remembers telling her husband that she had a headache and wanted to leave after the awards. Within days she couldnt eat, couldnt drive and lost a clothing-size worth of weight.

Im an avid spinner and I could barely walk around the block, she said. I couldnt lift 5 pounds. I had lost so much weight and muscle mass.

Lightfoot is a former ballerina. Growing up in the Washington, D.C. area she wanted to be a professional dancer, but her father told her she needed to find a job that would allow her to support herself. She was drawn to science and inspired by a teacher who told stories about her husbands work for NASA.

There was also a push to increase the number of female engineers. Mechanical and electrical engineering didnt interest her, but genetic engineering did. That led her to osteopathic medicine. Shes been at Rowan University for almost three years.

Lightfoot had developed pneumonia from the coronavirus by the time she went to the hospital on March 18. I didnt want to go to the hospital because COVID was there, she said.

It took until July for her to regain her full strength. Ive seen every bit of this, Lightfoot said. How it robs you.

You have to rest. The breathing was the hardest -- and trying to survive, she said

Now, that the second wave is here, Lightfoot wants people to know that the cases are just as serious as the first round -- and people are still dying.

Not everyone understands the science, she said. Some people think youre not talking about them when it comes to wearing the mask.

One of her patients rented out a movie theater for 20 of his friends and family. Seven of those who went now have COVID-19.

People are under this perception that their circle is safe. We know who weve been around, Lightfoot said. No one is safe.

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Allison Pries may be reached at apries@njadvancemedia.com.

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This doctor survived COVID-19 during the first wave. Shes one of the experts we turn to for advice. - NJ.com

2020 was the year of the pandemic. But the arrival of Covid-19 in January not only threw an Earth-sized wrench into our lives, it also dictated the course of scientific discovery. Never before have so much attention, investment, and passion been devoted to one scientific problem. Never before have pre-print servers exploded in popularity, allowing scientists to share discoveries at lightning speed. And never before have we managed to build an arsenal to beat back a life form entirely novel to us, massively accelerating vaccine development by months, if not yearsa true paradigm shift not just in vaccinology, but also in how science is done and communicated under fire.

Yet I dont want to focus solely on Covid-19. Were now in the end game. Last week, the FDA and its Canadian and British equivalents approved the Pfizer-BioNTech mRNA vaccine for emergency use. Modernas mRNA vaccine is hot on its heels, also boasting a success rate of over 90 percent. Front-line workers are receiving the jab all over the country. And dozens of other vaccines are still in the rat race.

Theres no escaping Covid-19 in an end-year retrospective. But theres good reason to look aheadthe biotech and camaraderie that created an entirely new type of vaccine in record pace isnt confined to the pandemic, vaccine research, or infectious diseases. They have the power to completely overhaul medicine.

You might have heard that mRNA vaccines have never previously been approved by the FDA. Yet the science behind them is decades long, courtesy of a young Hungarian-born biologist behind a key mRNA discoveryone so novel and groundbreaking it precipitated the death of her career.

Nearly all lifeforms are built by and run on proteins. But the instructions for building proteins are saved in our genetic material. Think of DNA as a library, and the cells protein-building factory as a far-off facility speaking a different language. mRNA, short for messenger RNA, is the translator that literally moves between our cells DNA library and the protein factory.

In other words, our bodies listen to mRNA to decide which proteins to build. If we could design and synthesize artificial mRNA and deliver them into cells, its possible in theory to hijack our cells own protein-building system to make any protein we wanteven those that are foreign, such as viral proteins.

Thats the reasoning behind both Pfizer-BioNTech and Modernas vaccines. By delivering the mRNA of a viral part into our cells, our bodies will make these proteins. Because these proteins are basically alien invaders, our immune system learns to recognize them and creates a memory of those foes. When it encounters a real infection, the entire immune military of trained antibodies and killer cells can then rapidly spur to life, nixing the invader before they have a chance to spread or reproduce.

Theres a reason mRNA vaccines are so desirable. Compared to traditional protein-based ones, such as those involving dead viruses that need to be grown in chicken embryos (not kidding), mRNA is incredibly easy to scale in production with low costs. This also makes it possible to screen through candidates at super-sonic speedand in a pandemic, speed is everything.

At least, thats the theory on paper. Thanks to recent advances in biotech and Covid-19 lighting sciences behind on fire, mRNA drugs have finally become a widely successful reality.

Broadly speaking, three main technologies have propelled mRNA vaccines to success in the Covid-19 race: whole-genome reading, mRNA design and packaging, and mRNA synthesis.

The first step to combating any viral foe is to know thy enemy. By January 11, Chinese scientists had deposited parts of the viruss genetic blueprint onto GenBank, a highly popular online database for genetic information. Whole-genome sequences soon followed, digitizing the virus and allowing comparisons between its genetic blueprint and other known viruses. Within a month, we knew that the virus belonged to the coronavirus family, allowing scientists to draw upon previous experience with similar virusesSARS, MERSto hone in on the newcomers surface spike proteins, named after their jagged shapes, as a potential vaccine target.

Genetic sequencing soon took the reins. As an offshoot of synthetic biology, a field that reshuffles the building blocks of life, the cost of making artificial genetic sequences has dropped dramaticallyso much so that its now simple to order these molecules through commercial companies at dollars a pop.

Its also made it possible to recreate an entire genome from scratch halfway across the world. A Swiss group, for example, used Chinas data to synthesize SARS-CoV-2s entire genome in the lab, essentially instantly teleporting it into their hands without having to wait for physical samples. Other teams reproduced only the spike protein to analyze for portions that are especially incendiary towards our immune system, which could spark a larger immune response. In early February, long before the world realized wed be in the midst of a pandemic, scientists had already nailed down the sequence and shape of the protein that eventually spurred the development of our newfangled mRNA vaccines.

The next step was finding a weapon against the virusand getting it inside a cell. Thanks to computational alignment tools, figuring out the genetic code for the spike protein was a piece of cake. The harder part was designing mRNA candidates, the instructions, to encode for the spike protein. One frustrating reason why mRNA vaccines have previously failed is because these molecules are extremely fragile. The body, with its relatively high heat and multitudes of molecular-digesting proteins, is a hostile place.

The hostility also goes the other way. Synthetic mRNAs are very foreign to our bodies. Without care, they can trigger the immune system to go into overdrivea dangerous condition that could result in serious problems.

Heres where new tech stood on the shoulders of age-old research. With hopes of making mRNA drugs a reality, scientists have long worked to change their basic componentsletters very similar to DNAs familiar quad squad of A, T, C, and Gwith slightly chemically-improved ones to increase their stability. Other swaps fine-tune the mRNAs efficacy so that it triggers a Goldilocks-like immune responsenot too much, not too little.

Finally, naked mRNA needs to get inside a cell to work. But once it does, its almost instantaneously chopped up. Without mRNA sticking around, our bodies cant make the viral spike protein, hence no immunity. To deliver it into cells, scientists relied on fatty bubblesalso known as lipid nanoparticlesto form a vessel around the mRNA strands. These cellular spaceships are also a gift from the past: back in 2018, the FDA approved their use for delivering another type of RNA molecules. Pfizer-BioNTech and Modernas results provide some of the strongest evidence that they also work well with mRNAs.

The success is indisputable: Moderna went from analyzing the viruss genetic sequence to an experimental jab in the arm in just 63 days. Pfizer-BioNTech broke lightspeed with its vaccine for emergency use in less than a year.

The biotechnologies that made Covid-19 mRNA vaccines are here to stay. So are the fountains of knowledge weve gained from this terrifying trial by fire. From the ins and outs of immune responses to what makes mRNA more stable, less toxic, and easier to deliver, to advances in synthetic biology and seamless global collaboration, the battle against Covid-19 highlights how a decade-long scientific dream just blossomed to fruition.

Covid-19 is only one foe. A similar strategy could now be used, with far more confidence, on our long-battled enemies such as HIV. Even novel vaccines are just a small slice of whats possible. mRNA is the bodys guidebook for building proteinany protein. A synthetic mRNA strand that recognizes certain types of cancer could lead to highly-specific cancer vaccines. BioNTech, for example, reported in 2017 that a vaccine against melanoma, tailor-made to each of its 13 participants unique cancer genetic profile, had higher immunity against their tumors and reduced the chance of spread. Synthetic mRNA could artificially produce missing or defective proteins in the body, such as those critical for normal eyesight or nerve function.

The dream of mRNA therapeutics has been alive since the 90s. One just came true. Keep your eyes peeled for others in 2021.

Image Credit: Felipe Esquivel Reed/Wikimedia Commons

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Fighting Covid-19 Brought These Lasting Breakthroughs to Science and Medicine - Singularity Hub

Dec. 28, 2020 13:04 UTC

BOSTON--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced its New Drug Submission for TRIKAFTA, Vertexs investigational triple combination medicine, has been accepted for Priority Review by Health Canada for the treatment of cystic fibrosis (CF) in people ages 12 years and older.

We are pleased this submission has been accepted for Priority Review by Health Canada, and we anticipate this accelerated review process will enable access for patients as early as possible, said Carmen Bozic, M.D., Executive Vice President, Global Medicines Development and Medical Affairs, and Chief Medical Officer at Vertex.

With Priority Review, the conventional review timeline of 300 days is reduced to 180 days. The expected approval target by Health Canada is in the first half of 2021.

About Cystic Fibrosis

Cystic fibrosis (CF) is a rare, life-shortening genetic disease affecting approximately 75,000 people worldwide. CF is a progressive, multi-system disease that affects the lungs, liver, GI tract, sinuses, sweat glands, pancreas and reproductive tract. CF is caused by a defective and/or missing CFTR protein resulting from certain mutations in the CFTR gene. Children must inherit two defective CFTR genes one from each parent to have CF. While there are many different types of CFTR mutations that can cause the disease, the vast majority of all people with CF have at least one F508del mutation. These mutations, which can be determined by a genetic test, or genotyping test, lead to CF by creating non-working and/or too few CFTR proteins at the cell surface. The defective function and/or absence of CFTR protein results in poor flow of salt and water into and out of the cells in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death. The median age of death is in the early 30s.

About Vertex

Vertex is a global biotechnology company that invests in scientific innovation to create medicines for people with serious diseases. The company has multiple approved medicines that treat cystic fibrosis (CF) a rare, life- threatening genetic disease and has several ongoing clinical and research programs in CF. Beyond CF, Vertex has a robust pipeline of investigational small molecule medicines in other serious diseases where it has deep insight into causal human biology, including pain, alpha-1 antitrypsin deficiency and APOL1-mediated kidney diseases. In addition, Vertex has a rapidly expanding pipeline of genetic and cell therapies for diseases such as sickle cell disease, beta thalassemia, Duchenne muscular dystrophy and type 1 diabetes mellitus.

Founded in 1989 in Cambridge, Mass., Vertex's global headquarters is now located in Boston's Innovation District and its international headquarters is in London. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia and Latin America. Vertex is consistently recognized as one of the industry's top places to work, including 11 consecutive years on Science magazine's Top Employers list and a best place to work for LGBTQ equality by the Human Rights Campaign. For company updates and to learn more about Vertexs history of innovation, visit http://www.vrtx.com or follow us on Facebook, Twitter, LinkedIn, YouTube and Instagram.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, statements made by Carmen Bozic in this press release, including expectations for patient access to our medicine, and statements regarding the anticipated timing of the expected approval target by Health Canada. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that the New Drug Submission to Health Canada may not be approved in the expected timeline, or at all, that data from the company's development programs may not support registration or further development of its compounds due to safety, efficacy or other reasons, and other risks listed under the heading Risk Factors in Vertex's most recent annual report and subsequent quarterly reports filed with the Securities and Exchange Commission at http://www.sec.gov and available through the company's website at http://www.vrtx.com. You should not place undue reliance on these statements. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX-GEN)

View source version on businesswire.com: https://www.businesswire.com/news/home/20201228005171/en/

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Vertex Announces New Drug Submission for Investigational Triple Combination Medicine for the Treatment of Cystic Fibrosis Has Been Accepted for...

In August 2020, the FDA approved the first diagnostic test that combines next-generation sequencing and liquid biopsy. The test is intended to help guide treatment decisions for patients with specific types of mutations of the epidermal growth factor receptor (EGFR) gene in metastatic nonsmall cell lung cancer (NSCLC), which is particularly deadly. The FDA called it a new era for mutation testing. The approval was granted to Guardant360CDx to provide information on multiple solid tumor biomarkers and to help identify EGFR mutations in patients who will benefit from treatment with osimertinib (Tagrisso), which is approved for a form of metastatic NSCLC.

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4. Dr Andre Goy Discusses What Weve Learned About CAR T Therapies and Cytokine Responses

In a video interview, Andre Goy, MD,chairman, director, and chief of the Division of Lymphoma at John Theurer Cancer Center in Hackensack, NJ,discussed what has been learned from existing chimeric antigen receptor T (CAR T)-cell therapies in managing cytokine responses.

Watch the interview here.

3. OneOncology, Foundation Medicine Create Partnership to Deliver Targeted Care

Also in August 2020, OneOncology, a network of nearly 170 community oncology care sites, and cancer genomic profiling firm Foundation Medicine announced a partnership to give patients and physicians access to genomic profiling tools as well as expanded research opportunities. In addition, OneOncology will help Foundation Medicine to create new assays for community oncology practices.

Read the full article here.

2. Broad Testing for Multiple Genes Benefits Patients With Cancer, Relatives

A study published in JAMA Oncology described how universalmultigene panel testingwas linked with increased detection of actionable, heritable variants beyond what one would expect to find using targeted genetic testing based on current cancer guidelines. The multicenter cohort study found that 1 in 8 patients had a pathogenic germline variant, half of which would not have been found if using guidelines alone. In addition, for the nearly 30% of patients with a high-penetrance variant, the findings led to a change in treatment.

Read the full article here.

1. How DNA Medicines Could Transform Treatment of Glioblastoma Multiforme

In an article appearing in the August 2020 edition of Evidence-Based Oncology, Jeffrey Skolnick, MD, the vice president of clinical development at biotech firm Inovio, discusses the companys proprietary technology that uses a computer algorithm to build DNA medicines that can target almost any antigen that can be presented to the human immune system through the major histocompatibility class I system. DNA medicines are built in the form of circular strands of synthetic DNA called plasmids, which can neither propagate nor integrate into the human genome. He also discusses their use in a potential application for glioblastoma, which is incurable.

Read the full article here.

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The Top 5 Most-Read Precision Oncology Articles of 2020 - AJMC.com Managed Markets Network

In an in-depth study of how COVID-19 affects a patients brain, National Institutes of Health researchers consistently spotted hallmarks of damage caused by thinning and leaky brain blood vessels in tissue samples from patients who died shortly after contracting the disease. In addition, they saw no signs of SARS-CoV-2 in the tissue samples, suggesting the damage was not caused by a direct viral attack on the brain. The results were published as a correspondence in the New England Journal of Medicine.

We found that the brains of patients who contract infection from SARS-CoV-2 may be susceptible to microvascular blood vessel damage. Our results suggest that this may be caused by the bodys inflammatory response to the virus, said Avindra Nath, M.D., clinical director at the NIHs National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study. We hope these results will help doctors understand the full spectrum of problems patients may suffer so that we can come up with better treatments.

Although COVID-19 is primarily a respiratory disease, patients often experience neurological problems including headaches, delirium, cognitive dysfunction, dizziness, fatigue, and loss of the sense of smell. The disease may also cause patients to suffer strokes and other neuropathologies.

Several studies have shown that the disease can cause inflammation and blood vessel damage. In one of these studies, the researchers found evidence of small amounts of SARS-CoV-2 in some patients brains. Nevertheless, scientists are still trying to understand how the disease affects the brain.

In this study, the researchers conducted an in-depth examination of brain tissue samples from 19 patients who had died after experiencing COVID-19 between March and July 2020. Samples from 16 of the patients were provided by the Office of the Chief Medical Examiner in New York City while the other 3 cases were provided by the department of pathology at the University of Iowa College of Medicine, Iowa City. The patients died at a wide range of ages, from 5 to 73 years old. They died within a few hours to two months after reporting symptoms. Many patients had one or more risk factors, including diabetes, obesity, and cardiovascular disease. Eight of the patients were found dead at home or in public settings. Another three patients collapsed and died suddenly.

Initially, the researchers used a special, high-powered magnetic resonance imaging (MRI) scanner that is 4 to 10 times more sensitive than most MRI scanners, to examine samples of the olfactory bulbs and brainstems from each patient. These regions are thought to be highly susceptible to COVID-19. Olfactory bulbs control our sense of smell while the brainstem controls our breathing and heart rate. The scans revealed that both regions had an abundance of bright spots, called hyperintensities, that often indicate inflammation, and dark spots, called hypointensities, that represent bleeding.

The researchers then used the scans as a guide to examine the spots more closely under a microscope. They found that the bright spots contained blood vessels that were thinner than normal and sometimes leaking blood proteins, like fibrinogen, into the brain. This appeared to trigger an immune reaction. The spots were surrounded by T cells from the blood and the brains own immune cells called microglia. In contrast, the dark spots contained both clotted and leaky blood vessels but no immune response.

We were completely surprised. Originally, we expected to see damage that is caused by a lack of oxygen. Instead, we saw multifocal areas of damage that is usually associated with strokes and neuroinflammatory diseases, said Dr. Nath.

Finally, the researchers saw no signs of infection in the brain tissue samples even though they used several methods for detecting genetic material or proteins from SARS-CoV-2.

So far, our results suggest that the damage we saw may not have been not caused by the SARS-CoV-2 virus directly infecting the brain, said Dr. Nath. In the future, we plan to study how COVID-19 harms the brains blood vessels and whether that produces some of the short- and long-term symptoms we see in patients.

This study was supported by NIH Intramural Research Program at the National Institute of Neurological Disorders and Stroke (NS003130) and an NIH grant (NS109284).

Reference: Lee, MH, et al. Microvascular Injury in the Brains of Patients with COVID-19. N Engl J Med. 2020. ePub 30 Dec. doi: 10.1056/NEJMc2033369.

About National Institute of Neurological Diseases and Stroke (NINDS): NINDS is the nations leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institute on Aging (NIA): NIA leads the U.S. federal government effort to conduct and support research on aging and the health and well-being of older people. Learn more about age-related cognitive change and neurodegenerative diseases via NIAs Alzheimer's and related Dementias Education and Referral (ADEAR) Center website. For information about a broad range of aging topics, visit the main NIA website and stay connected.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

NIH...Turning Discovery Into Health

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NIH study uncovers blood vessel damage and inflammation in COVID-19 patients' brains but no infection - National Institute on Aging

In 1987, when researchers first used the word genomics to describe the newly developing discipline of mapping DNA, Eric Green had just finished medical school. A few years later, he found himself working on the front lines of the young fields marquee moon shot: the Human Genome Project. To lead the nations participation in the global effort, Congress established the National Human Genomics Research Institute, or NHGRI, in 1989.

Sequencing the entire human genome began the following year, and it took 13 years to complete. Not long after, in 2009, Green took the helm of the research institute. By then, NHGRIs mission had evolved to include expanding the field of genomics into medicine. That meant funding and coordinating projects aimed at pinpointing the mutations responsible for genetic disorders, then developing tests to diagnose them and therapies to treat them. And even more broadly, it meant generating evidence that DNA data could effectively improve outcomes, even for people who dont suffer from rare diseases.

To help chart that course, one of Greens tasks is to periodically put together a strategic vision for the field. Aimed at celebrating progress, identifying technological gaps, and inspiring scientists to pursue the most impactful areas of research, his team published its latest projection in October. For the first time, Green and his colleagues outlined a set of 10 bold predictions about what might be realized in human genomics by the year 2030. Among them: High schoolers will show off genetic analyses at the science fair, and genomic testing at the doctors office will become as routine as basic blood work.

Three decades after that sequencing race began, weve perhaps reached the end of the early genomics era, a period of explosive technological growth that led to breakthroughs like the sequencing of the first dog, chicken, and cancer cells and the advent of cheap home DNA tests. The field has matured to the point that genomics is nearly ubiquitous in all of biologyfrom fighting invasive giant hornets to brewing better-tasting beer. Genomic medicine is no longer theoretical. But its also not widespread. Although scientists have mapped the human genome, they do not yet completely understand it. Green spoke to WIRED about what the next decade, and the next era in genomics, may have in store. This interview has been edited for length and clarity.

WIRED: October marked the 30th anniversary of the Human Genome Project. When you look around at where we are today, how does it live up to the expectations you had for the impacts the project would make in medicine?

Eric Green: I was inside the Human Genome Project from day one, and I cant stress enough how back then we didnt know what we were doing. We had this big audacious goal of reading out the 3 billion letters of the human instruction book, but we didnt have the technology to do it. We didnt have the methods. We didnt even have a functional internet. There was no playbook. So, as someone who got into this as a young physician, I could sort of imagine that one day genomics might be part of clinical care. But I truly did not think it would happen in my lifetime.

If we go back just 10 years, nobody was really using genomics in health care. We fantasized then about the idea of having a patient in front of us, where we did not know what was wrong with them, and being able to sequence their genome and figure it out. That was a hypothetical in 2011. Now it's routine. At least for people suspected of having a rare genetic disease.

Thats amazing. But also, its still a far cry from some of the hype around what the Human Genome Project was going to accomplish. In his remarks at the White House in 2000, then-NHGRI director Francis Collins said it would likely take 15 or 20 years to see a complete transformation in therapeutic medicine, promising personalized treatments for everything from cancer to mental illness. Obviously, that hasnt exactly come to pass. Why not?

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30 Years Since the Human Genome Project Began, Whats Next? - WIRED

rBIO launched last week with technology that can reduce the cost of insulin by 30 percent, making U.S. manufacturing cost-effective for insulin and several other drugs.

This new method is an enhancement of the recombinant DNA (rDNA) processes that have been used since the 1980s to produce insulin.

Forty years later, were taking it to the next level, Cameron Owen, rBIO co-founder and CEO, told BioSpace. It is akin to expediting billions of years of evolution.

The company genetically modified E. coli to cause it to hyper-produce peptide hormones initially, insulin thereby creating more product from the same quantity of material. Those bacteria will then manufacture the product at scale using standard vat fermentation processes.

The idea emerged when Owen was a graduate student at Johns Hopkins Universitys Carey Business School.

I had started another biotech company (Aevus Precision Diagnostics) that looked at the pharmacogenomics of diabetes medications, so I got to know the diabetes space really well, he said.

As he learned, Insulin is too expensive for many people who depend on it, and its supply chain is vulnerable because like most drugs used in the U.S. a large percentage of insulin is manufactured offshore. With 30 million diabetics in the U.S. now, and an expected 60 million by 2030, keeping up with demand is a significant challenge.

In 2016, the J. Craig Venter Institute determined the minimum number of genes bacteria needed to survive.

If you can take those minimal genes and add to them, youve eliminated a lot of processing waste, Owen said.

Therefore, rBIO is rewriting E.colis genetic code, eliminating the unnecessary genes and coding the genome so the bacteria hyper-expresses the maximum quantities of insulin but does not produce the products needed for the bacterias normal metabolic function.

rBIOs goal is to increase production to the cells theoretical limits. In this case, thats 100 molecules of insulin.

We havent achieved 100% theoretical maximum yield, he said, but production rates are approximately double that of todays generally accepted insulin production methods.

Whats different about this approach, beyond its high yield, is how the genetic code as devised. Were now at the point in genetics where the genetic code can be not only manipulated, but written, Owen said.

Rather than cut and paste genes in or out of organisms, rBIO actually designs the DNA, he said.

Were writing the DNA code from scratch, the way a computer programmer would, and translate it to biology, he said. Rather than use ones and zeros, we use ACGT the bases found in DNA molecules. We can manipulate those letters to write anything you want.

The rBIO team doesnt start entirely from scratch, of course. There are set sequences that we know work, so we are using those sequences, and designing others, Owen said. We wrote three different genetic codes for the bacteria during the past several months and put them into a lab setting to determine if they first and foremost grew and divided, and secondly whether they produced the product we wanted.

Two of the three bacteria strains were successful, and optimization is continuing.

Once rBIO determines the genetic code it wants, it outsources the actual gene assembly. rBIO has produced several milligrams of insulin this way in the lab.

The next stage, Owen said, is to scale up the company. That means bringing in management with the skills to take the organization to the next level and to help shape its direction.

This early in its existence, all the options are open.

My goal is to become a manufacturer, Owen said, but, realistically, this is more of an out-licensing opportunity to a company with the existing infrastructure for mass manufacturing already in place.

rBIO is still developing a platform technology, Owen pointed out. The company is focused on insulin, but also is considering eight other drugs for its pipeline, including erythropoietin and epinephrine. They each have a projected compound annual growth rate (CAGR) of 12 percent for the next decade, he said, so represent significant opportunities for the company.

Owen said the companys technology also has the potential to make reshoring attractive for several drugs that currently are produced offshore.

The COVID-19 pandemic put the spotlight on the risks of off-shoring pharmaceutical products. According to the FDA, only 21% of the drugs on the World Health Organizations Essential Medicines List are manufactured in the U.S.

Medicine security shouldnt be allowed to be affected by the fluctuations of international trade policies, he said. Having the manufacture of life-saving medicines offshore is a major national security issue. Imagine what would happen if 30 million American diabetics couldnt access insulin. Wed be in a world of hurt.

Whether or not such drastic trade wars happen, rBIOs hyperproduction technology may offer significant benefits to therapeutic manufacturers and customers alike. He isnt overly concerned about competition. Instead, he sees potential allies.

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rBIO Launches with Technology to Hyper-Produce Insulin Cost-Effectively, at Scale - BioSpace

Peer victimization is recognized as a pressing public health issue, affecting 1 in 5 youth. Although extensive research demonstrates the negative effects of peer victimization on youth mental health, considerably less is known about if and how peer victimization adversely impacts physical health. Focusing on studies published in the past 5 years, this state-of-the-art review synthesizes recent research examining the relationship between peer victimization and physical health outcomes among children and adolescents. In addition to reviewing evidence for associations between peer victimization and global subjective health indices (eg, somatic symptoms), I highlight several biological sequelae of victimization (eg, cortisol dysregulation, inflammation) that may increase long-term risk for illness and disease. I conclude by considering strengths and limitations of existing work and suggesting several key directions for future research. I also discuss implications for practitioners and the role primary care providers can play in promoting health among peer victimized youth.

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Effects of Peer Victimization on Child and Adolescent Physical Health - American Academy of Pediatrics

AstraZeneca and MSDs Lynparza (olaparib) has been approved in Japan for the treatment of advanced ovarian, prostate and pancreatic cancers.

The three approvals authorise Lynparza for: maintenance treatment after 1st-line chemotherapy containing bevacizumab (genetical recombination) for patients with homologous recombination repair deficient (HRD) ovarian cancer; the treatment of patients with BRCA gene-mutated (BRCAm) castrate-resistant prostate cancer with distant metastasis (mCRPC); and as maintenance treatment after platinum-based chemotherapy for patients with BRCAm curatively unresectable pancreas cancer.

The concurrent approvals by the Japanese Ministry of Health, Labour, and Welfare are based on positive results from the PAOLA-1, PROfound and POLO Phase III trials, which each were published in The New England Journal of Medicine.

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: These three approvals allow patients in Japan to be treated with Lynparza, a targeted treatment personalised to their specific biomarkers. They further underline the critical importance of biomarker testing at diagnosis, which helps physicians determine a course of treatment tailored to individual patients to substantially delay disease progression.

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: For patients in Japan diagnosed with each of these types of cancer there are very few treatment options. Approvals for treatments such as Lynparza, the first PARP inhibitor to be approved in these specific types of metastatic castration-resistant prostate cancer and metastatic pancreatic cancer in Japan, enable us to advance this evolving era of personalised medicine and change how these cancers are treated.

Lynparza in ovarian cancerThe approval as 1st-line maintenance treatment with bevacizumab for patients with HRD-positive advanced ovarian cancer is based on a biomarker subgroup analysis of the PAOLA-1 Phase III trial which showed Lynparza, in combination with bevacizumab maintenance treatment, demonstrated a substantial progression-free survival (PFS) improvement versus bevacizumab alone, for patients with HRD-positive advanced ovarian cancer.

In 2020, nearly 11,000 women in Japan were diagnosed with ovarian cancer, with more than 5,000 women dying of the disease.1 One in two women with advanced ovarian cancer has an HRD-positive tumour.2,3

Lynparza in prostate cancerThe approval for the treatment of BRCAm mCRPC is based on a subgroup analysis of the PROfound Phase III trial which showed Lynparza demonstrated a substantial improvement in radiographic progression-free survival (rPFS) and overall survival (OS) versus enzalutamide or abiraterone in men with BRCA1/2 mutations. Lynparza is the first and only PARP inhibitor approved in Japan in advanced prostate cancer.

Prostate cancer is the third most common type of cancer in Japan and in 2020, accounted for over 100,000 new cases.1 With limited treatment options, the average survival for men with mCRPC is only 9-13 months.8 Approximately 12% of men with mCRPC have a BRCA mutation,5 a subgroup of patients with a particularly poor prognosis.

Lynparza in pancreatic cancerThe approval for BRCAm metastatic pancreatic cancer is based on the results of the POLO Phase III trial which showed Lynparza demonstrated a statistically significant and clinically meaningful improvement in PFS versus placebo in patients with germline BRCAm metastatic pancreatic cancer. Lynparza is the first and only PARP inhibitor approved in this disease.

Pancreatic cancer has one of the lowest survival rates of the most common cancers and in Japan was responsible for almost 40,000 deaths in 2020 the fourth most common cause of cancer death.1,5 Japan has the third-highest rate of pancreatic cancer in the world with 44,000 new cases diagnosed in 2020.1,6 Approximately 5-7% of patients with metastatic pancreatic cancer have a germline BRCA mutation.7

AstraZeneca and MSD are exploring additional trials in advanced prostate cancer including the ongoing PROpel Phase III trial testing Lynparza as a 1st-line treatment for patients with mCRPC in combination with abiraterone versus abiraterone alone. Data are anticipated in the second half of 2021. AstraZeneca is exploring additional trials in advanced ovarian cancer, including the DUO-O Phase III trial testing Imfinzi (durvalumab) in combination with chemotherapy and bevacizumab, followed by maintenance treatment with Imfinzi, bevacizumab, and Lynparza in newly diagnosed advanced ovarian cancer patients.

PAOLA-1PAOLA-1 is a double-blinded Phase III trial testing the efficacy and safety ofLynparzaadded to standard-of-care bevacizumab versus bevacizumab alone, as a 1st-line maintenance treatment for newly diagnosed advanced FIGO Stage III-IV high-grade serous or endometroid ovarian, fallopian tube, or peritoneal cancer patients who had a complete or partial response to 1st-line treatment with platinum-based chemotherapy and bevacizumab. AstraZeneca and MSD announced in August 2019 that the trial met its primary endpoint of PFS in the overall trial population.

The PAOLA-1 Phase III trial showed that Lynparza, in combination with bevacizumab maintenance treatment, reduced the risk of disease progression or death by 67% (based on a hazard ratio [HR] of 0.33, 95% confidence interval [CI] 0.25-0.45). The addition of Lynparza improved PFS to a median of 37.2 months versus 17.7 with bevacizumab alone in patients with HRD-positive advanced ovarian cancer.

PROfoundPROfound is a prospective, multicentre, randomised, open-label, Phase III trial testing the efficacy and safety of Lynparza versus enzalutamide or abiraterone in patients with mCRPC who have progressed on prior treatment that included new hormonal agents (abiraterone or enzalutamide) and have a qualifying tumour mutation in BRCA1/2, ATM or one of 12 other genes involved in the homologous recombination repair (HRR) pathway.

The trial was designed to analyse patients with HRR gene mutations in two cohorts: the primary endpoint was rPFS in those with mutations in BRCA1/2 or ATM genes and then, if Lynparza showed clinical benefit, a formal analysis was performed of the overall trial population of patients with HRR gene mutations (BRCA1/2, ATM, CDK12 and 11 other HRR gene mutations). AstraZeneca and MSD announced in August 2019 that the trial met its primary endpoint of rPFS.

The subgroup analysis from the PROfound Phase III trial showed Lynparza reduced the risk of disease progression or death by 78% (based on a HR of 0.22, 95% CI, 0.15-0.32; nominal p<0.0001) and improved rPFS to a median of 9.8 months versus 3.0 with enzalutamide or abiraterone in men with mCRPC with BRCA1/2 mutations. Lynparza reduced the risk of death by 37% (based on a HR of 0.63, 95% CI 0.42-0.95) with median OS of 20.1 months versus 14.4 with enzalutamide or abiraterone.

POLOPOLO is a randomised, double-blinded, placebo-controlled, multi-centre Phase III trial of Lynparza tablets (300mg twice daily) as maintenance monotherapy versus placebo. The trial randomised 154 patients with germline BRCAm metastatic pancreatic cancer whose disease had not progressed on 1st-line platinum-based chemotherapy. Patients were randomised (3:2) to receive Lynparza or placebo until disease progression. The primary endpoint was PFS and key secondary endpoints included OS, time to second disease progression, overall response rate and health-related quality of life.

Data from the Phase III POLO trial showed Lynparza nearly doubled the time patients with germline BRCAm metastatic pancreatic cancer lived without disease progression or death to a median of 7.4 months versus 3.8 on placebo and reduced the risk of disease progression or death by 47% (based on a HR of 0.53, 95% CI 0.35-0.82; p=0.004).

BRCABRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role in maintaining the genetic stability of cells. When either of these genes are mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer and confer sensitivity to PARP inhibitors including Lynparza.8-11

HRDHRD, which defines a subgroup of ovarian cancer, encompasses a wide range of genetic abnormalities, including BRCA mutations and beyond. As with BRCA gene mutations, HRD interferes with normal cell DNA repair mechanisms and confers sensitivity to PARP inhibitors including Lynparza.12

LynparzaLynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in HRR, such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.

Lynparza is currently approved in a number of countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer. It is approved in the US, the EU, Japan, China, and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in the US and EU as a 1st-line maintenance treatment with bevacizumab for patients with HRD-positive advanced ovarian cancer (BRCAm and/or genomic instability). Lynparza is approved in the US, Japan, and a number of other countries for germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer. It is also approved in the US, the EU and several other countries for the treatment of germline BRCAm metastatic pancreatic cancer. Lynparza is approved in the US for HRR gene-mutated metastatic castration-resistant prostate cancer (BRCAm and other HRR gene mutations) and in the EU for BRCAm metastatic castration-resistant prostate cancer. Regulatory reviews are underway in several countries for ovarian, breast, pancreatic and prostate cancers.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 40,000 patients worldwide. Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZenecas industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

The AstraZeneca and MSD strategic oncology collaborationIn July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the worlds first PARP inhibitor, and Koselugo (selumetinib), a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.

AstraZeneca in oncologyAstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients lives and the Companys future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of six scientific platforms Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics, and Cell Therapies and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

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Lynparza approved in Japan for the treatment of advanced ovarian, prostate and pancreatic cancers - India Education Diary

A well attended online Campus course staged by the SIG Reproductive Genetics heard that the expansion of sequencing analysis is poised to push forward the development of cost-effective preconception tests able to identify several underlying genetic causes of infertility

The everyday implications of preconceptional medicine have so far been largely evident in lifestyle advice conducive to successful pregnancy, but a well attended online Campus meeting staged in December suggests that genomic medicine has an increasingly important role to play. Sessions at the meeting not only covered the much debated subject of genetic risk assessment by expanded carrier screening, but explored the application of genome-wide sequencing in recurrent miscarriage, in predicting ART outcomes from parental genome analysis, and even in explaining the different responses to ovarian stimulation with gonadotrophins. Such subjects, especially expanded carrier screening, are not without their ethical problems, notably in the disclosure (or not) of secondary findings, so it was also appropriate at this meeting to hear a preview of ESHREs forthcoming recommendations on expanded carrier screening in ART.

In his opening lecture Stphane Viville, a former coordinator of ESHREs SIG Reproductive Genetics, said that known genetic and chromosomal factors account for around 20% of all infertility cases, with three additional (and relatively unknown) phenotypes now moving into active research: POI, oocyte maturation defect, and preimplantation embryonic lethality, all of which were covered at this meeting. Viville added that so far at least 21 genes have been implicated in POI and advised that genetics is now getting more and more into IVF labs and no longer confined to chromosomal aberrations or microdeletions on the Y chromosome.

Much of the content of this Campus course has been explored in detail in a recent Human Reproduction Update review, whose first author, Antonio Capalbo, is deputy of ESHREs SIG Reproductive Genetics and an organiser of this course.(1) In the review, as was repeatedly implied at this meeting, Capalbo et al note that the expansion of sequencing analysis may enable the development of cost-effective preconception tests capable of identifying underlying genetic causes of infertility, which until now have largely been defined as idiopathic.

One such step in this move towards a more positive and personalised approach to preconceptional medicine is in genetic risk assessment by expanded carrier screening, which occupied a large section of this meeting. James Goldberg, prominent in the development of ECS, said its availability now steps beyond the disparities and restrictions of ethnicity-specific screening and aims to inform couples about their risk of having children with autosomal recessive and X-linked recessive disorders and thereby to support informed decision making. Nevertheless, two of the current guidance statements on ECS cited by Goldberg both from the USA are largely based on ethnicity screening with an emphasis on cystic fibrosis and spinal muscular dystrophy. ECS, said Goldberg, represents a more equitable approach to identifying risk. Such risk assessment in both the general population and IVF couples - will allow identification of those who carry recessive mutations, and thereby provide increased reproductive autonomy to couples deemed at risk and where PGT is available for embryo selection.

However, when a publicly provided ECS programme was set up in Amsterdam offering a test panel of 50 genes (at a cost of 650 euro per test) and following the guidance of the European Society of Human Genetics, there was a relatively quiet response (20%) from the general risk population, and higher (80%) from the high risk population.(2) Nevertheless, assessment of the programme, began in 2016, appeared to raise more questions than answers, and no clear resolution of how such a programme might be best provided. Capalbo and his fellow Update reviewers concluded that ECS represents one of the most effective and advanced applications of preconception genomic medicine worldwide today and is expected to grow in application in coming years.

The preview of recommendations from ESHREs Ethics Committee was specifically about ECS ahead of ART (and not just involving gamete donors). Thus, asked Dutch bioethicist Guido de Wert, would the offer of ECS to all such applicants be proportionate, and if so, for what kinds of disorders and under what conditions? Applying the three ethicists principles of proportionality, respect for autonomy and justice, De Wert firstly noted that any possible benefits should clearly outweigh any possible harms, that ECS should still be embedded in a research framework, and that a couples access to ECS should only be on condition that they take preventive measures and apply for PGT, donor gametes, or, maybe, prenatal diagnosis.

Even the outcome of fertility treatments may well be affected by genetic mutations, and such extreme outcomes as oocyte maturation failure and embryonic developmental arrest are now investigated as a genetic cause of infertility. Indeed, Semra Kahraman from theIstanbul Memorial Hospital reported that variants in more than 2000 genes are now predicted to be involved in various infertility pathways. She described her own study in which 22 IVF patients whose repeated failure was attributed to oocyte maturation failure and embryo development arrest and who were investigated using whole exome sequencing panels. Family history analysis had also identified infertility and early menopause in the family of nine of the subjects. The analysis identified genomic variants in eight of the 22 subjects, including four genes known to be lethal at the embryonic stage.

With ovarian ageing identified as one of todays most frequent causes of infertility, John Berry, an MRC investigator from Cambridge, reported in a keynote lecture that ten years ago population studies had identified four common genetic variants associated with menopause. Today, he added, there are now more than 300 loci identified, which explain around 10% of the heritable component. Too few to be clinically useful? he asked. Again, there appeared more questions than answers, notably if POI can be explained solely by monogenic alleles and if menopausal age can indeed be predicted by genetics.

The conclusions from this meeting, as well as the increasing number of genes and variants identified, suggest that genomic assessment ahead of conception may have real clinical benefits at both the individual (in identifying genetic risks in the male and female partner) and the couple level (in allowing a specific reproductive prognosis). Information at this early stage may thus lay the basis for personalised interventions, and certainly make at-risk couples better informed of their reproductive choices.

1. Capalbo A, Poli M, Riera-Escamilla A, et al. Preconception genome medicine: current state and future perspectives to improve infertility diagnosis and reproductive and health outcomes based on individual genomic data, Hum Reprod Update 2020; doi:10.1093/humupd/dmaa044

2. Henneman L, Borry P, Chokoshvili D, et al. Responsible implementation of expanded carrier screening. Eur J Hum Genet 2016; 24: e1-e12. doi:10.1038/ejhg.2015.27

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The expanding role of genomics in preconceptional 'personalised' medicine - ESHRE

This clinical pilot will evaluate the effectiveness of Digbi Health's obesity management digital program personalized to each bariatric surgery patient, one-year post sleeve gastrectomy, based on their lifestyle, genetic and gut microbiome risks, in further reducing weight and maintaining weight loss. Obesity is a complex metabolic disease and an ongoing epidemic, with associated inflammatory, digestive, musculoskeletal, skin morbidities, as well as a risk factor for diabetes, cardiovascular disease, COVID-19, and reduced life expectancy, which currently affects 42 percent of the adult population in the United States. Bariatric surgery is the most effective long term intervention for morbid obesity, and successful bariatric surgery outcomes depend on lifelong changes in eating patterns and social support.

Research indicates individuals' genetic and gut microbiome makeups are intrinsically linked to their metabolism and following personalized nutrition recommendations and meal plans curated to an individual's genetic and gut microbiome markers may assist with further weight loss and ongoing weight maintenance post sleeve gastrectomy.

"WVU Bariatrics is excited to partner with Digbi Health to better understand how genomic, gut microbiome and metabolomic factors can contribute to successful weight loss following bariatric surgery," said Nova Szoka MD, FACS, FASMBS, Assistant Professor at J.W. Ruby Memorial Hospital, WVU Bariatrics Surgical Weight-Loss Center and principal investigator of the study.

"Digbi Health is the first company to operationalize a genetic and gut microbiome-based prescription-grade platform for doctors and payers to deliver weight loss, digestive health, and diabetes care programs at scale," said Ranjan Sinha, CEO, and founder of Digbi Health.

"Digbi is committed to empowering people suffering from obesity and chronic inflammatory lifestyle illnesses, struggling with ineffective one-size-fits-all diets, with personalized nutrition and lifestyle support that works for them. Through this collaboration with WVU Medical, we aim to deeper explore the critical importance of personalized nutrition and its direct impact on people suffering from obesity and associated illnesses," said Sinha.

More information about J.W. Ruby Memorial Hospital, WVU Medical, and Surgical Weight-Loss Center can be found here.

About Digbi HealthDigbi Healthis a first-of-its-kind precision digital therapeutics company that offers a prescription-grade digitally enabled personalized obesity and obesity-related gut, skin disorders, hypertension, and other cardiometabolic health management programs based on an individual's gut biome, genetic risks, blood markers, and lifestyle factors. Digbi Health and members of its physician network are committed to empowering people to take control of their own health and wellness. Digbi Health is prescribed by doctors, healthcare providers, and insurance companies.

SOURCE Digbi Health

digbihealth.com

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Digbi Health partners with West Virginia University Medicine and WVU Bariatrics Surgical Weight-Loss Program to improve postoperative weight loss...

Dec. 24, 2020 23:30 UTC

SAN FRANCISCO--(BUSINESS WIRE)-- Audentes Therapeutics, an Astellas genetic medicines company, today announced that the U.S. Food and Drug Administration (FDA) has lifted the clinical hold for the ASPIRO clinical trial evaluating AT132 in patients with X-linked myotubular myopathy (XLMTM). XLMTM is a serious, life-threatening neuromuscular disease characterized by extreme muscle weakness, respiratory failure, and early death.

We are grateful for the efforts of our team and investigators who have worked tirelessly to answer the FDAs questions and we now look forward to resuming this study, said Natalie Holles, President and Chief Executive Officer of Audentes. We want to again extend our deepest sympathies to patients families impacted by the events earlier this year. We are deeply committed to the continued safe development of AT132 for the families and patients living with XLMTM, a disease with no existing treatments.

The company is now working to complete all clinical and regulatory activities necessary to resume dosing and plans to have discussions at a future date with the regulators on the path forward toward global registration filings for AT132.

About X-linked Myotubular Myopathy XLMTM is a serious, life-threatening, rare neuromuscular disease that is characterized by extreme muscle weakness, respiratory failure and early death. Mortality rates are estimated to be 50 percent in the first 18 months of life. For those patients who survive past infancy, there is an estimated additional 25 percent mortality by the age of 10. XLMTM is caused by mutations in the MTM1 gene that lead to a lack or dysfunction of myotubularin, a protein that is needed for normal development, maturation and function of skeletal muscle cells. The disease affects approximately 1 in 40,000 to 50,000 newborn males.

XLMTM places a substantial burden of care on patients, families and the healthcare system, including high rates of healthcare utilization, hospitalization and surgical intervention. More than 80 percent of XLMTM patients require ventilator support, and the majority of patients require a gastrostomy tube for nutritional support. In most patients, normal developmental motor milestones are delayed or never achieved. Currently, only supportive treatment options, such as ventilator use or a feeding tube, are available.

About the ASPIRO Study ASPIRO is a two-part, multinational, randomized, open-label ascending dose trial to evaluate the safety and preliminary efficacy of AT132 in XLMTM patients less than five years of age. Primary endpoints include safety (adverse events and certain laboratory measures) and efficacy (assessments of neuromuscular and respiratory function). Secondary endpoints include the burden of disease and health-related quality-of-life, and muscle tissue histology and biomarkers.

About AT132 for the treatment of X-linked Myotubular Myopathy Audentes is developing AT132, an AAV8 vector containing a functional copy of the MTM1 gene, for the treatment of XLMTM. AT132 may provide patients with significantly improved outcomes based on the ability of AAV8 to target skeletal muscle and increase myotubularin expression in targeted tissues following a single intravenous administration. The preclinical development of AT132 was conducted in collaboration with Genethon (www.genethon.fr).

AT132 has been granted Regenerative Medicine and Advanced Therapy (RMAT), Rare Pediatric Disease, Fast Track, and Orphan Drug designations by the U.S. Food and Drug Administration (FDA), and Priority Medicines (PRIME) and Orphan Drug designations by the European Medicines Agency (EMA).

About Audentes Therapeutics, Inc. Audentes Therapeutics, an Astellas company, is developing genetic medicines with the potential to deliver transformative value for patients. Based on our innovative scientific approach and industry leading internal manufacturing capability and expertise, we have become the Astellas Center of Excellence for the newly created Genetic Regulation Focus Area. We are currently exploring three gene therapy modalities: gene replacement, exon skipping gene therapy, and vectorized RNA knockdown, with plans to expand our focus and geographic reach under Astellas. We are based in San Francisco, with manufacturing and laboratory facilities in South San Francisco and Sanford, North Carolina.

About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+ healthcare solutions combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at https://www.astellas.com/en

Cautionary Notes In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on managements current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas intellectual property rights by third parties.

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Audentes Therapeutics Announces FDA Lifts Hold on ASPIRO Clinical Trial of AT132 for Treatment of X-Linked Myotubular Myopathy (XLMTM) - BioSpace