Category Archives: Transhuman News

Scientists have long contemplated a future where genome editing could alter the building blocks of our world to help humans live longer, healthier lives.

That dream is no longer a possibility, but a reality, thanks largely to the discovery of CRISPR and its ability to edit DNA. In 2020, Emmanuelle Charpentier and Jennifer A. Doudna won the Nobel Prize in Chemistry for the discovery, the first pair of women to do so.

In late June, scientists took a leap forward in proving CRISPRs power as a medical tool. Study results published in The New England Journal of Medicine showed that a one-time injection of the gene-editing system was extremely effective at treating patients with a rare genetic disease.

CRISPR is also being widely used in agriculture. Scientists are building genetically modifiedcrops that are better suited to the changing climate.

However, the hopes of CRISPR also bring significant, ethical hurdles that the international scientific community will have to face.

Genome editing is a powerful, scientific technology that can reshape medical treatments and peoples lives, but it can also harmfully reduce human diversity and increase social inequality by editing out the kinds of people that medical science, and the society it has shaped, categorize as diseased or genetically contaminatedpeoplewho are understood as having bad genes.

What promise does CRISPR hold in the coming years? And how do we manage its possible perils?

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The Hopes And Hurdles Of CRISPR And Gene Editing - New Hampshire Public Radio

DALLAS July 6, 2021 Using artificial intelligence, UT Southwestern scientists have identified thousands of genetic mutations likely to affect the immune system in mice. The work is part of one Nobel laureates quest to find virtually all such variations in mammals.

Bruce Beutler, M.D., director of the Center for the Genetics of Host Defense (CGHD)

This study identifies 101 novel gene candidates with greater than 95% chance of being required for immunity, says Bruce Beutler, M.D., director of the Center for the Genetics of Host Defense (CGHD) and corresponding author of the study published this week in the Proceedings of the National Academy of Sciences. Many of these candidates we have already verified by re-creating the mutations or knocking out the genes. Lead author Darui Xu, a computational biologist at CGHD, wrote the software.

Weve developed software called Candidate Explorer (CE) that uses a machine-learning algorithm to identify chemically induced mutations likely to cause traits related to immunity. The software determines the probability that any mutation weve induced will be verified as causative after further testing, Beutler says. His discovery of an important family of receptors that allow mammals to quickly sense infection and trigger an inflammatory response led to the 2011 Nobel Prize in Physiology or Medicine.

The purpose of CE is to help researchers predict whether a mutation associated with a phenotype (trait or function) is a truly causative mutation. CE has already helped us to identify hundreds of genes with novel functions in immunity. This will improve our understanding of the immune system so that we can find new ways to keep it robust, and also know the reason it sometimes falters, says Beutler, Regental Professor, and professor of immunology and internal medicine at UT Southwestern.

CE provides a score that tells us the likelihood that a particular mutation-phenotype association will be verified for cause and effect if we re-create the mutation or knock out the gene, he says.

CE examines 67 features of the primary genetic mapping data to arrive at an estimate of the likelihood of causation. For some mutations, causation is very clear; for others, less so. Over time, the program learns from experiments in which researchers re-create the mutation in a fresh pedigree and verify or exclude the hypothesis of causation. All mutations are made available to the scientific community through a public repository, and the data supporting causation are viewable within the Candidate Explorer program on the CGHD website, Mutagenetix.

The team used CE to evaluate about 87,000 mutation/trait associations that passed the initial statistical threshold for candidacy. The traits examined were flow cytometry data collected on circulating immune cells of third-generation mutant mice. In this screen, Candidate Explorer ranked a total of 2,336 mutations in 1,279 genes as good or excellent candidates for causation of traits, the team reports.

Beutler adds that this work is part of a research program he set out on nearly a decade ago to identify every mutation that may affect the mouse immune system.

Weve now worked through about 60% of the genome and have identified thousands of genes hundreds of them novel that participate in immunity in the mouse, he says.The vast majority of these also contribute to human immunity.

Beutler adds that the mouse and human genome are very similar in size and content of genes. Almost all mouse genes have a human counterpart, and vice versa, he says.

The current study focused on changes in cells known to be tied to immunity such as B cells, T cells, macrophages, and natural killer cells.

UTSW co-authors include: Stephen Lyon, Chun Hui Bu, Sara Hildebrand, Jin Huk Choi, Xue Zhong, Aijie Liu, Emre E. Turer, Zhao Zhang, Jamie Russell, Sara Ludwig, Elena Mahrt, Evan Nair-Gill, Hexin Shi, Ying Wang, Duanwu Zhang, Tao Yue, Kuan-wen Wang, Jeffrey A. SoRelle, Lijing Su, Takuma Misawa, William McAlpine, Lei Sun, Jianhui Wang, Xiaoming Zhan, Mihwa Choi, Roxana Farokhnia, Andrew Sakla, Sara Schneider, Hannah Coco, Gabrielle Coolbaugh, Braden Hayse, Sara Mazal, Dawson Medler, Brandon Nguyen, Edward Rodriguez, Andrew Wadley, Miao Tang, Xiaohong Li, Priscilla Anderton, Katie Keller, Amanda Press, Lindsay Scott, Jiexia Quan, Sydney Cooper, Tiffany Collie, Baifang Qin, Jennifer Cardin, Rochelle Simpson, Meron Tadesse, Qihua Sun, Carol A. Wise, Jonathan J. Rios, and Eva Marie Y. Moresco. Researchers in Japan and China also contributed to the study.

The work received support from the National Institutes of Health (grants R01 AI125581 and U19 AI100627).

Beutler holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr.

About UTSouthwestern Medical Center

UTSouthwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in about 80 specialties to more than 117,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 3 million outpatient visits a year.

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UT Southwestern scientists closing in on map of the mammalian immune system - UT Southwestern

Researchers at OHSU have devised a method that delivers a 10-fold improvement in the amount of DNA that can be recovered from a single cell to be sequenced and interpreted. The finding, published in the journal Nature Biotechnology, is a big leap forward in the effort to understand cancer development, brain function and immunity. (Getty Images)

Researchers have devised a way to multiply by more than ten-fold the accessible details of gene activity in individual cells. Its a big leap in the effort to understand cancer development, brain function, immunity and other biological processes driven by the complex interactions of multitudes of different cell types.

Organs and tissues are made up of cells that may look the same, but individual cells can actually differ dramatically. Single-cell analysis allows the study of this cell-to-cell variation within an organ, tissue or cancerous tumor. But the research has been hampered by limits on the depth of information that can be gleaned at the single-cell level when working with large numbers of cells.

Andrew Adey, PH.D.

The downside has been the low-quality of single-cell profiles. Our method allows us to get a much more complete profile of any given single cell, said Andrew Adey, Ph.D., senior author of a paper in Nature Biotechnology describing the innovation. Adey is an associate professor of molecular and medical genetics in the OHSU School of Medicine.

He said the new method delivers about a ten-fold improvement in the amount of DNA that can be recovered from a single cell to be sequenced and interpreted. The genetic code is written in DNA in a sequence of units, called bases, that are like letters of an alphabet. Sequencing DNA reveals the order of the bases, and it is the first step to understanding the genetic makeup of a cell and whether particular genes are active or silent.

Single-cell studies are particularly important in understanding cancer. The cells of a tumor can be strikingly diverse. Different cells pick up different DNA mutations as the tumor grows, and some of the mutations and changes in gene activity give rise to sub-populations of tumor cells with new qualities, such as the ability to spread to other body parts or resist anti-cancer drugs.

Adey and colleagues showed that their method can be used to reveal DNA alterations that have emerged in a subset of cells in tumor samples taken from patients with pancreatic cancer. Thats important because it can help researchers understand how populations of tumor cells evolve and become deadly.

For example, you can potentially identify rare cell subtypes within a tumor that are resistant to therapy, Adey said. His team has already begun working with OHSU Knight Cancer Institute researchers testing the single-cell method as a way find out if some of the cells in a patients tumor have evolved resistance to a particular chemo drug or targeted therapy. That knowledge could be used to develop individualized treatment plans for patients.

If you are working with something like a cancer biopsy from a patient, a very small piece of tissue, you really want to make every cell count, you really have to get a lot of info from each single cell, Adey said.

The new method builds on a technique called single-cell combinatorial indexed sequencing, which Adey and colleagues developed earlier. Its a way to generate DNA libraries collections of DNA fragments that can be used to analyze genes and mutations for thousands of single cells at the same time. The process uses an enzymatic reaction to attach primers to the ends of the DNA fragments. They are kind of like handles the sequencer uses to start reading, Adey says.

While the technique greatly increases the number of single cells that can be analyzed in one experiment, it comes with the tradeoff of sparse coverage of readable DNA sequences per cell. To be readable, a primer must be attached at both ends of the DNA fragment, which the reaction accomplishes only half of the time.

The new method results in all library fragments having primers on both ends, while also improving efficiency in other ways. The researchers said the efficiency has the added benefit of reducing sequencing costs by about one third.

The adapters are designed such that standard sequencing recipes can be used instead of the custom workflows and primers that are required for competing methods. That makes the method compatible with many different tests commonly used to explore the state of single cells.

This chemistry can just slot into many other assays, Adey said. People can just start using it.

This research was supported by the National Institutes of Health (grants R01DA047237, R35GM124704, and R01MH113926).

In our interest of ensuring the integrity of our research and as part of our commitment to public transparency, OHSU actively regulates, tracks and manages relationships that our researchers may hold with entities outside of OHSU. In regards to this research, Andrew Adey and OHSU colleague Ryan M. Mulqueen are authors on licensed patents that cover components of the technologies described here. Review details of OHSU's conflict of interest program to find out more about how we manage these business relationships.

Excerpt from:
Innovation massively expands view into workings of single cells - OHSU News

Introduction

Coronary arteriosclerosis heart disease (CAD) is induced by many factors, and its morbidity and fatality are increasing worldwide, with a particularly high rate of increase in young people. Morbidity and fatality of myocardial infarction (MI) in patients with heart and cerebrovascular diseases are both high, and the impact of MI on human health is clear.1 One of the causes of CAD is oxidative damage caused by lipid peroxidation. The most representative of the aldehydes produced in this reaction is 4-hydroxynonenal (4-HNE), which is very stable and can easily spread to other cells, where it causes further tissue damage.2 The Glu504Lys polymorphism is a very important single-nucleotide polymorphism of mitochondrial acetaldehyde dehydrogenase 2 (ALDH2), and it is a genetic risk marker for acute coronary syndrome.3 ALDH2 has a higher affinity for acetaldehyde than other ALDH isozymes do, and it is the main enzyme for scavenging 4-HNE. ALDH2 can effectively reduce the cytotoxic effect of aldehydes produced in oxidative stress and protect the myocardium.4,5 The ALDH2 homozygous genotype AA is associated with susceptibility to CAD, as demonstrated by the results of a whole genome association study carried out in Japan in 2012.6 The allele frequency distribution of the ALDH2 Glu504Lys polymorphism is significantly different across different races, nationalities and regions7. The purpose of this study is to explore the association of ALDH2 polymorphism with the occurrence of MI in Qingyuan, Guangdong Province, in order to better understand the genetic susceptibility factors for MI and guide the prevention and delay of MI.

The MI group in this study comprised 468 patients diagnosed with myocardial infarction for the first time who were treated in the Department of Cardiovascular Medicine of the Sixth Hospital affiliated to the Guangzhou Medical University (Qingyuan City Peoples Hospital) from 2017 to 2019. The male to female ratio of the MI group was 337:131 and the age range was 2596 years. Of the 468 patients in the MI group, 347 were diagnosed with acute nonST-segment elevation cardiac infarction and 121 were diagnosed with acute ST-segment elevation cardiac infarction. The study also included a control group comprising 132 medical examiners who were present at the hospital during the same time period, with a male to female ratio of 27:17 and an age range of 1995 years. The exclusion criteria for the control group were: (1) hepatic and renal insufficiency and gastrointestinal disease, (2) no ALDH2 gene test, and (3) a definite previous history of MI. Clinical baseline information (sex, age, and personal history) was collected for all study subjects. Three generations of the subjects ancestors were determined to be Han Chinese who were born or lived in Qingyuan and the surrounding areas. This study was conducted in accordance with the declaration of Helsinki and approved by the Ethics Committee of the Sixth Affiliated Hospital of Guangzhou Medical University. Written informed consent was obtained from all participants.

The study used the ALDH2 (Glu504Lys) gene detection kit from Shanghai BaiO Technology Co., Ltd. (Shanghai, China) and the DP318 blood genomic deoxyribonucleic acid (DNA) extraction kit from Tiangen Biotech Co., Ltd. (Beijing, China). The main instruments included the Lab-Aid 824 nucleic acid extraction system (Zeesan Biotech Co., Ltd., Fujian, China), the NanoDrop2000 UV-Vis spectrophotometer (Thermo Fisher Scientific Inc., Waltham, MA, USA), and Life Express nucleic acid amplifiers. Other equipment included the BaiO BR-526-24 fully automated hybridizer, the BaiO BE-2.0 biochip reader, and the BaiO Array Doctor Version 2.0 gene chip image analysis software (Shanghai BaiO Technology Co., Ltd., Shanghai, China).

Myocardial infarction: Coronary angiography examination revealed at least one organic coronary stenosis of more than 50% of the main coronary artery or its main branches. Clinical presentation and electrocardiographic changes met the diagnostic criteria of the fourth universal definition of myocardial infarction.

Samples of 12 mL of venous blood from each subject were collected in anticoagulated tubes containing ethylenediaminetetraacetic acid and stored at 4C for up to one week. The genomic DNA was extracted from the whole blood using the DP318 blood genomic DNA extraction kit, and a 1 L DNA sample was analyzed for concentration and purity by UV-Vis spectrophotometer. A DNA sample met the detection criteria if the DNA concentration was 1060 ng/L, a significant absorption peak was exhibited at OD260, and the ratio of OD260/OD280 was 1.52.0. A TE buffer solution of pH 7.6 was used as a diluent for samples with a higher DNA concentration. DNA samples were stored at 4C for one week or 20C for one month, and they were not reused after three repeated freezethaw cycles.

After the PCR amplification solution had been prepared and the ALDH2 amplification reagent thawed at room temperature, the two were centrifuged at low speed. After centrifugation and mixing at low speed, the PCR amplification reaction system had a volume of 25 L. The reaction conditions were set for the nucleic acid amplifiers and the product was removed after amplification and stored at 4C. The immunochromogenic reagent was removed to prepare the antibody solution (stored at 20C), and the amplification product was added to the hybridization buffer to make the hybridization solution (stored at 4C). The hybridization program was set up following the instructions for the automatic hybridization instrument, and the gene chip was removed and labeled. Together with the pre-installed washing solution, the hybridization solution, antibody solution, and chromogenic reagent were placed in their corresponding positions in an octuple hybridization test tube. The hybridization test tube and gene chip were placed in the automatic hybridization instrument. The amplification product and the ALDH2 gene detection probe initiated the biotin-labeled hybridization. Because the enzyme chromatography reaction produced different hybridization signals, gene chip image analysis software was used to scan the chip, analyze the data, and return the results of the genotype test.8

Sample analysis calculation was performed using SPSS software (IBM, Armonk, NY, USA). Where counting data were presented as percentages, measurement data that conformed to a normal distribution are presented as mean standard deviation; otherwise, data are presented as medians and quartiles [M (Q1, Q3)]. The MI group and the control group were compared using the independent sample t-test or the MannWhitney non-parametric test. The distributions of ALDH2 genotypes and allele frequencies were tested by the row-list and the association analysis was performed by multifactorial logistic regression. The chi-square test was used to verify whether the ALDH2 genotype distribution in the population complied with the HardyWeinberg law. A difference of P < 0.05 was considered statistically significant.

Based on the analysis of the collected ALDH2 genotypes of the Han population in Qingyuan, the actual frequencies of GG, GA, and AA in the MI group were 203, 215, and 50, respectively, while the frequencies of GG, GA, and AA in the control group were 70, 48, and 14, respectively. The actual frequency in each group was compared with the theoretical frequency using the HardyWeinberg equilibrium (HWE) test. The analysis of the MI group found 2 = 0.194 and P = 0.907, and the analysis of the control group found 2 = 0.779 and P = 0.678. The actual and theoretical frequencies of the two groups ALDH2 genotypes matched well, and the genotypic distributions were in accordance with HWE (P > 0.05), indicating that the subjects in both groups were regionally representative. (Table 1).

Table 1 Equilibrium Test of ALDH2 Genotype Polymorphisms

The distribution of the ALDH2 genotypes and the allele frequencies in the MI group and the control group were analyzed by DNA microarray; the results are shown in Table 2. The proportions of GG, GA and AA genotypes were 43.4%, 45.9%, and 10.7%, respectively, in the MI group, and they were 53.0%, 36.4%, and 10.6%, respectively, in the control group. The G and A allele frequencies were 66.3% and 33.7%, respectively, in the MI group, and 71.2% and 28.8%, respectively, in the control group. The A allele was mainly expressed as the GA genotype of the ALDH2 gene in both the MI and control groups, which suggests that the A allele is mainly present in the GA heterozygous type in the Qingyuan population. Because the chi-square test showed no significant difference between GA and AA genotypes (2 = 0.4400, P = 0.5071), the ALDH2 genotypes were divided into GG and GA/AA genotypes. When the MI and control groups were compared, there was found to be a statistically significant difference in the distribution of the GG and GA/AA genotypes of ALDH2 (2 = 3.8699, P = 0.0492).

Table 2 Distribution of ALDH2 Genotype and Allele Frequencies

According to the results of the analysis, the MI group and the control group differed significantly (P < 0.05) in terms of their gender and age distributions, rates of hypertension and diabetes, levels of tobacco and alcohol use, and serum levels of glucose; myocardial injury markers (cardiac troponin I and myoglobin); myocardial enzymes (lactate dehydrogenase, creatine kinase, and creatine kinase-MB); and blood lipids (total cholesterol), triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol). All of the risk factorsthe percentage of men; rates of hypertension and diabetes; levels of tobacco and alcohol use; and levels of myocardial damage indicators, myocardial enzymes, TC, LDL-C, and glucosewere significantly higher in the MI group than in the control group (P < 0.05), while the age distribution was significantly lower in the MI group than in the control group (P < 0.01) There was no statistically significant difference in the TG and HDL-C levels of the MI and control groups (P > 0.05). (Table 3).

Table 3 Comparison of Clinical Baseline Data in MI and Control Groups

All subjects were classified into the mutant group (GA and AA type) or the GG group based on the presence of the A allele. Subgroup analysis was then used to analyze the relevant risk factors, which included male gender, age, hypertension, diabetes, tobacco use, alcohol use, serum levels of myocardial injury markers and glucose, and dyslipidemia index. The subgroup analysis found that the distribution of ALDH2 genotype was statistically significant (P < 0.05) among subjects who drank alcohol, had evidence of myocardial injury (Mb >140 g/L), or had low levels of HDL-cholesterol (HDL-C 1.74 mmol/L); in these groups, the incidence of MI was significantly different between those with ALDH2 genotype GA+AA and those with GG, suggesting that alcohol consumption, elevated Mb levels and reduced HDL-C levels can cause an increased risk of MI; this may indicate that alcohol consumption, high Mb levels, and low HDL-C levels can increase the risk of MI. There was no statistical significance in the ALDH2 genotype distribution among the subjects when grouped by the other factors (P > 0.05). (Table 4).

Table 4 Subgroup Analysis of ALDH2 Genotypes in Two Groups [n (%)]

According to the study of Bellia et al, metabolic syndrome is related to cardiovascular disease, and blood glucose, blood pressure and blood lipids are important influencing factors of metabolic syndrome. Therefore, history of hypertension, history of diabetes, TC, TG, HDL-C, LDL-C and GLU and other common risk factors were included in Logistic regression analysis.9 Independent risk factors were screened using multifactorial logistic regression analysis with MI as the dependent variable and the conventional risk factors and ALDH2 genotype as the dependent variables. The results are shown in Table 5. Male gender, age, hypertension, diabetes, tobacco use, and alcohol use were strongly associated with the occurrence of MI. Among subjects with these risk factors, carriers of the A allele of the ALDH2 gene had a higher risk of MI compared to carriers of the GG genotype; this suggests that the GA/AA genotype of ALDH2 is an independent risk factor for MI (P < 0.05, OR = 1.479, 95% CI = 1.0032.179).

Table 5 Logistic Regression Analysis on Risk Factors of MI

The ALDH2 gene is located on chromosome 12, and it has a major single-nucleotide polymorphism site rs671 on exon 12 that can affect enzyme activity. As a result, when the codon that encodes amino acid 504 undergoes the base substitution GA, the changes in the codon cause an amino acid change, namely the conversion of glutamate (Glu) into lysine (Lys). The result is the Glu504Lys polymorphism of the ALDH2 gene. Based on genetic laws, the ALDH2 genotype can be divided into the GG type, the GA type, and the AA type; among these, GA and AA are mutant types. The dehydrogenase activity of the mutant types is significantly reduced, where the GA type has only 6% of the dehydrogenase activity of the GG type, and dehydrogenase activity is essentially absent in the AA type.10 Less than 2% of the Chinese Han population has the AA genotype ALDH2, which means that the majority of A alleles in the Chinese Han population are found in the GA genotype.11 As previously reported, there was no statistically significant difference between the GA and AA genotypes, so they were combined in the statistical analyses of the distribution of ALDH2 genotypes.

The study enrolled 468 patients with MI and 132 healthy people from the Qingyuan area. The analysis found the proportion of the ALDH2 genotype GA/AA to be significantly higher (P = 0.0492) in the MI group than it was in the control group. This suggests that the Glu504Lys polymorphism of the ALDH2 gene is closely related to the occurrence of MI in the Qingyuan population.

As mentioned in the previous section, the results of the HWE test confirmed that the genotype distribution was well-represented in both the MI and control groups. The proportion of the AA genotype of ALDH2 was 10.7% in the MI group and 10.6% in the control group respectively, which is higher than the proportion of the wider Chinese Han population previously reported (less than 2%).11 There was a significant difference in the distribution of ALDH2 genotypes between the MI and control groups (P < 0.05). Subgroup analysis of the ALDH2 genotypes found alcohol use, high levels of Mb, and low levels of HDL-C to be associated with the occurrence of MI. After adjusting for gender, age, hypertension, diabetes, tobacco use, alcohol use, and other factors, logistic regression showed the GA/AA genotype of ALDH2 to be also associated with MI occurrence, where the risk of MI was 1.479 times higher for individuals with the GA/AA genotype than for individuals with the GG genotype. This suggests that the GA/AA genotype of ALDH2 is an independent risk factor for MI.

Preliminary studies conducted in Japan investigated the relationship between ALDH2 gene polymorphism and coronary heart disease, but they did not reach a unified conclusion. One study identified the AA genotype of ALDH2 as a risk factor for the development of MI, suggesting that it may increase the risk of MI by decreasing the concentration of HDL-C,12 a conclusion which is consistent with the findings of this study. A second study proposed that the AA genotype of ALDH2 has an anti-atherosclerotic effect.13 The study suggested that ALDH2 gene polymorphism regulates the level of HDL-C, a protective factor for MI, by moderating alcohol consumption,14 but the exact mechanism of this regulation process has not yet been determined. More recent studies have found that the ALDH2 gene may affect the occurrence and development of cardiovascular diseases caused by oxidative stress, lifestyle factors, and other mechanisms. The results of one study indicate that adrenal phaeochromocytoma (PC12) cells can increase sensitivity to 4-HNE by transfecting the deficient ALDH2 complementary DNA, thereby reducing the incidence of coronary heart disease.15 Another study observed for rats that the accelerated metabolism of aldehydes can alleviate lung ischemia-reperfusion injury, and the protective effects of accelerated aldehyde metabolism were found to be closely related to high levels of ALDH2 activity.16 But while the results of these studies suggest that ALDH2 gene polymorphism influences the risk of MI due to genetic, environmental, and metabolic interactions, the key mechanism of this influence is still unknown. More effort should be made in future studies to understand the relationship between the ALDH2 gene and other diseases.

In fact, many potential biomarkers of heart disease and vascular disease at the small molecular level have been found long before the study of genetic associations with heart disease. In the early stage of Acute Myocardial Infarction (AMI), Anello et al showed that H-FABP had a higher positive detection rate than high-sensitivity troponin (hs-TNL),17 they also proposed that the detection of high-sensitivity troponin (HSTNL) using Single Molecule Counting technique is a candidate strategy for the identification and management of acute coronary syndromes, which can effectively stratify the risk of suspected patients18 Bivona et al reviewed the limited value of heart-type fatty acid binding protein (HFAPB) in the early diagnosis of acute coronary syndromes and the prediction of mortality after diagnosis.19 Zinellu et al found that the molecule ADMA in plasma can act as a biomarker and play an important role in suggesting restenosis after endarterectomy.20 Galectin-3 (Gal-3) serves as an independent predictor of poor prognosis and mortality from heart failure in patients with progression from cardiovascular disease to heart failure.21 Through in-depth studies at all levels of protein-gene, small molecular biomarkers have increasingly been found to play a crucial role in the diagnosis, treatment and prognosis evaluation of vascular diseases.

Researchers have recently begun to study the distribution of ALDH2 gene polymorphism in the Han populations of different regions of China. Epidemiological studies have shown that the frequency of the rs671 polymorphism in the ALDH2 gene differs according to race and region. It is most common in Asian populations, where 30% to 50% of the population has this polymorphism: the mutation rate is 2030% in the Chinese Han population, 30% in India, and up to 34.1% in Japan. By contrast, this polymorphism is relatively rare in the White and Black populations of Europe and America.22,23 Within the Asian countries of India, China, Japan, and Korea, the distribution of ALDH2 gene polymorphism also differs along ethnic and regional lines.24,25 The frequency of the Glu504Lys polymorphism differs between the southern and northern regions of China and between different ethnic groups.2629 Mi et al30 found that the A allele frequency of the ALDH2 gene was 19.7% in the Shanghai Han population compared to 14.7% in the Han population of Shandong province. Zhang31 determined that the frequency of the AA genotype in the Han population of the city of Luoyang was lower than in Shanghai or Taiwan but significantly higher than in Japan or China. Li32 also found that the Beijing Han population had a lower frequency of mutated genes than the Luoyang Han population. The A allele of ALDH2 was identified by Wu as a risk factor for the development of coronary stenosis in the population of Hainan.33 Hou suggests that the AA genotype may be a susceptible allele for AMI occurrence.8 To summarize, while ALDH2 gene polymorphism is common among different groups, the rs671 polymorphism is generally more frequent in northern Han populations than in southern Han populations.

This study has proposed that the Glu504Lys polymorphism in the ALDH2 gene influences the onset of MI in the Qingyuan population and that the GA/AA genotype of the ALDH2 gene may be an independent risk factor for MI. The failure of this study to obtain the same results as previous studies should be considered in light of the following: (1) ALDH2 gene mutations are very common in China. While the study subjects were all from Qingyuan and neighboring regions, our limited information about their geographic origins and genetic background meant that we could not guarantee that they were originally from Qingyuan or of Han ethnicity. (2) There was no uniform standard for the collection of baseline data between the MI group and the control group, such as whether medication was used or an operation performed prior to testing; different times of detection and different frequencies of tests can lead to biased results. (3) The conclusions about the association between the ALDH2 gene and MI are inconsistent and need further exploration. (4) As the main settlement area for ethnic minorities in Guangdong province, Qingyuan has a large ethnic minority population: A study that only considers Han subjects cannot represent the wider Qingyuan population. To better understand ALDH2 gene polymorphism and prevent and treat MI and related diseases, there should be more comprehensive analysis and comparison of the gene polymorphism exhibited by different ethnic groups in Qingyuan. Follow-up studies with large samples are also necessary to provide theoretical support for MI susceptibility screening and individualized control in the Qingyuan region.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

This work was supported by Qingyuan Industrial Technology Research and Development Special Funds (No.2017A021); Natural Science Foundation of Guangdong Province (No.2018A030307065); Qingyuan Science and Technology Program Funding in Disease Prevention and treatment (No.2019A035).

The authors report no conflicts of interest in this work.

1. Pan C. Research progress of acetaldehyde dehydrogenase 2 and cardiovascular and cerebrovascular diseases. Chin J Cardiol. 2016;2(44):6367.

2. Chen J, Ran PX. Role of 4-hydroxynonenal in pathophysiological process. Int J Respir. 2006;(11):821824.

3. Feng X. Role of aldehyde dehydrogenase 2 Glu504lys polymorphism in acute coronary syndrome. J Cel Mol Med. 2011;9(15):19551962.

4. Xu DL, Sun AJ, Wang SJ, et al. Aldehyde dehydrogenase 2 prevents rat cardiomyocytes from apoptosis induced by hypoxia. Chin J Pathophysiol. 2006;(04):683686.

5. Sun AJ, Xu DL, Wang SJ, et al. The mechanism study of aldehyde dehydrogenase 2 transgene in preventing rat cardiomyocytes from apoptosis induced by hypoxia. Chin J Circ Res. 2006;1(1):3134.

6. Fumihiko T. Genome-wide association study of coronary artery disease in the Japanese. Eur J Hum Genet. 2012;3(20):333340.

7. Mizuno Y, Hokimoto S, Harada E, et al. Variant aldehyde dehydrogenase 2 (ALDH2*2) in east Asians interactively exacerbates tobacco smoking risk for coronary spasm- possible role of reactive aldehydes. Circ J. 2016;81(1):96102. doi:10.1253/circj.CJ-16-0969

8. Hou JY, Xie YQ, Zhao PS, et al. Association between acetaldehyde dehydrogenase 2 gene polymorphism and acute myocardial infarction in a southern Chinese Hakka population. J Mol Diag Ther. 2019;11(03):170175.

9. Bellia C, Bivona G, Scazzone C, Ciaccio M. Association between homocysteinemia and metabolic syndrome in patients with cardiovascular disease. Ther Clin Risk Manag. 2007;3(6):9991001.

10. Crabb DW, Edenberg HJ, Bosron WF, et al. Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant. J Clin Invest. 1989;83(1):314316. doi:10.1172/JCI113875

11. Cao XR, Wu DS. Compare of distributions of gene polymorphisms about alcohol metabolizing-related enzymes in five Chinese nationalities. J Hyg Res. 2002;31(3):156159.

12. Takagi S, Iwai N, Yamauchi R. Aldehyde dehydrogenase 2 gene is a risk factor for myocardial infarction in Japanese men. Hypertens Res. 2002;5(25):677681. doi:10.1291/hypres.25.677

13. Masako N. Effects of aldehyde dehydrogenase genotypes on carotid atherosclerosis. Ultrasound Med Biol. 2003;10(29):14151419.

14. Bian Y, Chen YG, Xu F, et al. Correlation between polymorphism of acetaldehyde dehydrogenase 2 gene and acute myocardial infarction in Shandong Han population. Chin J Gerontology. 2010;30(16):22632265.

15. Yan Z. Glu504Lys Single nucleotide polymorphism of aldehyde dehydrogenase 2 gene and the risk of human diseases. Biomed Res Int. 2015;2015:174050.

16. Zhang YJ, Lin TT, Xia FF, et al. Attenuation of lung ischemia-reperfusion injury by Alda-1 via activating mitochondrial acetaldehyde dehydrogenase in rats [J]. J Wenzhou Med Univ. 2019;49(10):744747.

17. Agnello L, Bivona G, Novo G, et al. Heart-type fatty acid binding protein is a sensitive biomarker for early AMI detection in troponin negative patients: a pilot study. Scand J Clin Lab Invest. 2017;77(6):428432. doi:10.1080/00365513.2017.1335880

18. Agnello L, Bellia C, Scazzone C, et al. Establishing the 99th percentile for high sensitivity cardiac troponin I in healthy blood donors from Southern Italy. Biochem Med (Zagreb). 2019;29(2):020901. doi:10.11613/BM.2019.020901

19. Bivona G, Agnello L, Bellia C, Lo Sasso B, Ciaccio M. Diagnostic and prognostic value of H-FABP in acute coronary syndrome: still evidence to bring. Clin Biochem. 2018;58:14. doi:10.1016/j.clinbiochem.2018.04.021

20. Zinellu A, Sotgia S, Porcu P, et al. Carotid restenosis is associated with plasma ADMA concentrations in carotid endarterectomy patients. Clin Chem Lab Med. 2011;49(5):897901. [PMID: 21288172]. doi:10.1515/CCLM.2011.121

21. Agnello L, Bellia C, Lo Sasso B, et al. Establishing the upper reference limit of Galectin-3 in healthy blood donors. Biochem Med (Zagreb). 2017;27(3):030709. doi:10.11613/BM.2017.030709

22. Yokoyama A, Muramatsu T, Omori T, et al. Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in Japanese alcoholics. Carcinogenesis. 2001;22(3):433439. doi:10.1093/carcin/22.3.433

23. Mansoori AA, Jain SK. ADH1B, ALDH2, GSTM1 and GSTT1 gene polymorphic frequencies among alcoholics and controls in the Arcadian population of central India. Asian Pac J Cancer Prev. 2018;19(3):725731. doi:10.22034/APJCP.2018.19.3.725

24. Hui L. Refined geographic distribution of the oriental ALDH2*504Lys (nee 487Lys) variant. Ann Hum Genet. 2009;3(73):335345.

25. Dong JL, Lin YK, Wei H, et al. Genetic polymorphism of ALDH2 among the Han population in Wuhan. Central South Pharm. 2019;17(01):112116.

26. Wang H. Study of aldehyde dehydrogenase 2 gene Glu504Lys polymorphism among the Han population in Guangdong. Lab Med Clin. 2018;21(15).

27. An JF, Wan Y, Wan CY, et al. Gene polymorphism of alcohol metabolism key enzyme ALDH2 in Ningxia Hui and Han ethnic. Basic Clin Med. 2019;39(02):222224.

28. Liu Y, Wang CC, Liang J, et al. Study on relationship between ALDH2 gene polymorphism and the Tibetan and Han patients with alcoholic liver disease [J]. J Qinghai Med Col. 2014;35(2):9294.

29. Xie YZ, Iwai N, Yamauchi R, et al. Study on the distribution of ALDH2 gene polymorphisms in Han Chinese population in Jiangsu, Shanxi and Hunan provinces. Sci Tech Inform Gansu. 2018;47(10):7173.

30. Mi SL, Fan F, Li J,et al. Distributed dfference of adehyde dhydrogenase 2 (ALDH2) plymorphism in Shanghai and Shandong Han ppulation. Chin J Clin Med. 2011;18(06):735737.

31. Zhang ZM. Studies of genetic polymorphisms of ADH2 and ALDH2 among the Han population in Luoyang China. Hereditas. 2002;5(24):532536.

32. Li ZX, Xie GL. Detection of the twelfth extron(G/A) polymorphism of ALDH2 in Beijin Han people. Chin J Mod Med. 2005;(03):457458.

33. Wu HD. Characteristics of ALDH2 gene polymorphism and its effect on coronary artery stenosis in elderly coronary heart disease patients with type 2 diabetes mellitus in Hainan. Shandong Medl J. 2019;5(59):1720.

The rest is here:
Association of ALDH2 with Myocardial Infarction. | JIR - Dove Medical Press

In this time of transition, were back with our annual list of health, medicine, and science books to check out this summer and this time weve thrown podcasts in the mix, too.

Read on for recommendations from the likes of Anthony Fauci, Rochelle Walensky, and Chelsea Clinton. Plus, STAT readers from New York to Sweden share their picks, in addition to our staff. Enjoy!

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The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human RaceBy Walter IssacsonI recommend it because this captivating book provided clear and accessible explanations of the scientific discovery of CRISPR-Cas9 and its remarkable power as a gene editing tool, interwoven with the complex human stories of Jennifer Doudna and her relationships with the many other accomplished scientists who brought it all together. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases

The Other Wes Moore: One Name, Two FatesBy Wes MooreThe Other Wes Mooreis a disquieting read.For those who are looking to understand social determinants of health, look toThe Other Wes Mooreto understand the challenges of emerging in the absence of role models and resources, and the importance of basic life securities, education, and opportunity. And then, read it through the lens of what a difference just one person can make to positively alter the life of another. Rochelle Walensky, director of the Centers for Disease Control and Prevention

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EPIDEMIC podcastHosted by Dr. Cline GounderDuring the past year, Ive been listening to a lot of podcasts on public health and in my opinion, Dr. Cline Gounders EPIDEMIC is one of the best. As someone who reads and listens to as much as I can, I still always learn something new through her thoughtful insights, terrific interviews, and expert guests. She has done a particularly good job shining a light on an issue I care about deeply the serious risks that the anti-vaccine movement poses to widespread Covid vaccine adoption, which we know is the surest way out of this pandemic. Chelsea Clinton, DPhil, MPH, vice chair of the Clinton Foundation and host of In Fact

What Can a Body Do? How We Meet the Built WorldBy Sarah HendrenWho doesnt love a book that alters how you see the world and forces you to rethink your prevailing mental models?What Can A Body Do?by Sarah Hendren, an artist, design researcher, writer, and professor at the Olin College of Engineering, wrote one of those mind-changing books. Hendren takes on the challenge of bodies that dont always match the built world. She widens the focus from the body to the social world around it, the tools and furniture and classrooms and sidewalks that make it possible or impossible for the body, however configured, to do its tasks, and larger structures of institutions and economies that make human flourishing possible. Jay Baruch, professor of emergency medicineand director of the Medical Humanities and Bioethics Scholarly Concentration, Alpert Medical School of Brown University

The Political Determinants of HealthBy Daniel E. DawesThe experience of the past year made crystal clear how important social factors are as drivers of health. But these social drivers have their origins in policies and politics. This book draws the connections and offers a useful framework for assessing and addressing these political determinants, and was a particularly compelling read during the pandemic. Kirsten Bibbins-Domingo, professor and chair, department of epidemiology and biostatistics, UCSF, and and vice dean for population health and health equity, UCSF School of Medicine

The Memory Thief: And the Secrets Behind How We RememberBy Lauren AguirreTheres something about a good medical detective story the initial puzzle of a single inexplicable illness, the gradual realization of more than one, the way the cases start to link that is both fascinating and compulsively readable. And Lauren Aguirres book, The Memory Thief, is an excellent, dont-put-this-down, detective story about an unexpected group of scientists struggling to decipher a series of drug-induced memory failures. Theres neuroscience history here, theres a modern understanding of what we do and dont know about memory in a bigger-picture sense. But my favorite thing about the book is its vivid, sometimes quirky, always human picture of science at its working best. Deborah Blum, author of The Poison Squad: One Chemists Single-Minded Crusade for Food Safety at the Turn of the Twentieth Century, and director of the Knight Science Journalism Program at MIT

White Rage: The Unspoken Truth of Our Racial DivideBy Carol AndersonThere is this pesky and pervasive notion that white opposition to Black citizenship read: land ownership, public education, right to vote, or rights in general for that matter is predominantly manifest through the fragility of individualized defensiveness and microaggressions. In a scathing and honest look at U.S. history, Carol Anderson eviscerates that notion. As she presents, the problem of whiteness is not fragility, as manifest in interpersonal slights, it is rage, as manifest in bald and persistent attempts made by those who believe themselves to be white, to enshrine white supremacy in the very fabric of this nation from our laws to our social morals. And so the history she tells is one of violence, to be sure, but not simply the type of brutality that bleeds, but also the type that bends this nation away from its purported values and ultimately forecloses the fullness of what this nation could be for any of its citizenry. From the strategic closure of state public schools to evade the racial integration mandated and promised by Brown v. Board to the relentless fights against Black citizens right to vote (or to have their votes deemed worthy of selecting political leaders) Carol Anderson tells a story that too many are willing to, wrongly, believe only includes bad apples and backward ideas. It is a must-read for anyone attempting to understand racism in the U.S. and its devastating tolls. Rhea Boyd, pediatrician, health advocate, and scholar who studies the interaction between structural racism and health and who co-developed THE CONVERSATION: Between Us, About Us, a national campaign to bring information about the Covid vaccines directly to Black communities

Deep Medicine: How Artificial Intelligence Can Make Healthcare Human AgainBy Eric TopolWith all the rapid change in health tech accelerated by the Covid-19 p andemic, its well worth your time to revisit this classic treatise on the coming technological revolution in health care, authored by Dr. Eric Topol (it went live in 2019 and its already a classic!). A physician-scientist and cardiologist by training, Topol provides several concrete examples of the ways in which innovative diagnostics and wearables were already impacting clinical delivery pre-pandemic. Understanding whats possible in the years ahead requires a grounding in whats already been successfully achieved, and Deep Medicine will get you there. Vin Gupta, Amazon chief medical officer of pandemic response

Everyday ZenBy Charlotte Joko BeckI havent had much time to read during Covid-19. But this is a book that I can always pick up and read again. I like it because it describes a warm, compassionate look at Zen, which can be sometimes very austere. It talks about using meditation to help you deal with everyday life situations, remaining calm and balanced. What I have called the Eye of the Hurricane. Rachel Levine, assistant secretary for health at the Department of Health and Human Services

The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human RaceBy Walter IssacsonWalter Isaacsons book dives into to the timely and riveting story of Jennifer Doudna, an American biochemist and Nobel Prize winner responsible for pioneering critical innovation in CRISPR gene editing. In the book, Isaacson walks readers through Doudnas passion for science and discovery from a young age, through her studies, and then her profound work as an adult to forever alter the way scientists will treat viruses and diseases. Doudna recently spoke at our BIO Digital event and this book builds on many of the topics she discussed. It is an inspiring, must read for anyone passionate about how science can transform the lives of people around the globe. Michelle McMurry-Heath, CEO of the Biotechnology Innovation Organization

The Doctors Blackwell: How TwoPioneering Sisters Brought Medicine toWomenand Women to MedicineBy Janice P. NimuraElizabeth Blackwell, the first woman in America to earn a medical degree, is an icon. But for most of us in medicine, she is only that. Few people today know much about what she actually did, and fewer are even aware of her younger sister Emily, by far the more accomplished clinician. Janice P. Nimura aims to give both doctors their proper due. She brings new life to the story of two extraordinary and idiosyncratic physicians who forever changed the medical profession. Danielle Ofri, primary care physician at Bellevue Hospital, clinical professor of medicine at New York University School of Medicine, editor-in-chief of theBellevue Literary Review, and author of When We Do Harm: A Doctor Confronts Medical Error

Endure: Mind, Body, and the Curiously Elastic Limits of Human PerformanceBy Alex HutchinsonSometimes Im out running and just cant go on. I used to take comfort in what I learned in medical school: lactic acid builds up and theres nothing anyone can do about it. This book made me feel much less good about myself. Via a rigorous exploration of which physiological limits are real, and which arent, this book makes a persuasive case that psychology is the binding constraint, not physiology. It taught me a lot about myself, both when Im running and when Im not. Ziad Obermeyer, Blue Cross of California Distinguished Associate Professor of Health Policy and Management, University of California, Berkeley, School of Public Health

The Premonition: A Pandemic StoryBy Michael LewisLewis opens a unique window into pre-pandemic U.S. unreadiness and failure of the CDC. Theres no shortage of substrate for his master storytelling. From Dr. Charity Dean, the fireball public health official, to Laura Glass, the 13-year-old who came up with the model to fight Covid spread, to the Wolverines group of seven redneck epidemiologists. We learn why the CDC is really CDOR Center for Disease Observation and Reporting (not capable of any action) and my favorite metaphor in the book, watering the plastic flowers (which really happened but has deep meaning). Eric Topol, director and founder of the Scripps Research Translational Institute

The Beauty in BreakingBy Michele HarperYou learn firsthand what it takes to be an ER doctor: courage, calm, and compassion. There are lessons in ethics, in patience (from patients), in how the practice of medicine works along with personal healing through yoga, love, and self-confidence. Heide Aungst, Cincinnati, Ohio

The Nocturnists podcastHosted by Emily Silverman, M.D.Great collection of medical storytelling. They have an archive of healthcare workers experiences working during the pandemic but from an emotional and personal point of view. Very eye-opening and relatable. Sarah Bedell, Florida

The Lost Family: How DNA Testing is Upending Who We AreBy Libby CopelandA great mix of storytelling woven with medical, historical and scientific information. We are all curious about these tests, but there are some whose lives have changed because of it. Beth Glicker, Vienna, Va.

Kill Shot: A Shadow Industry, a Deadly DiseaseBy Jason DearenThis heart-pounding medical mystery traces a deadly fungus that claimed the lives of more than 100 Americans in 2012, and the loopholes in federal drug laws that let allowed the tragedy to unfold. Dearen has written a page-turner that reads like fiction but, for better or worse, is pure fact. Rachel E. Gross, Brooklyn, N.Y.

Flip the Script podcastHosted by Max TiakoI am a double-lung transplant recipient. By definition I will have a lifetime of frequent encounters with a plethora of physcians and other medical professionals. As an African American, this podcast is a reliable resource for my self-education. It gives me trusted insights into areas that I may encounter during my transplant journey. Jennifer Loud, Washington

This Podcast Will Kill YouHosted by Erin Welsh and Erin Allmann UpdykeThis podcast is about diseases and human illnesses of all types, made by two women who work in health. They also cover the ongoing pandemic in special episodes, with interviews with topical experts. They present topics such as how parasites work or the definition of a serovar in an accessible manner. Laina S. Miller, Silver Spring, Md.

Gravity podcast, episode five: On Cancer and Metaphor with Shekinah Elmore & Elena SeminoHosted by Lucy KalanithiCancer touches everyones life, but I hadnt given much thought to how we talk about it, and how that shapes how patients face their diagnosis, and doctors treat disease. This podcast is hosted by Dr. Lucy Kalanithi, whose husband died of cancer, bringing a deep sensitivity to both the medical and human side of the disease. I found the interview with multiple cancer survivor and oncologist Dr. Shekinah Elmore inspiring for her sensitivity to meet patients where they are, and the menu of cancer metaphors by linguist Dr. Elena Semino extremely helpful to talk with a friend currently undergoing breast cancer treatment, where bending with the wind or following a journey feel much closer to the truth than a battle. Kimberly Nicholas, Lund, Sweden

If Our Bodies Could Talk: A Guide to Operating and Maintaining a Human BodyBy James HamblinI met Dr. Hamblin for this books signing and found him hilarious, inquisitive, and amusing just like the book! If Our Bodies Could Talk provides superb explanations to sometimes absurd health questions and phenomena. In todays day and age of misinformation, Hamblin successfully debunks and informs the inner workings of our bodies through humor, fascination, and a quite readable fashion. Zach Olah, Brooklyn, N.Y.

The Death Panel podcastHosted by Beatrice Adler-Bolton, Artie Vierkant, and Phil RoccoThis podcast is by far the best resource for a sober analysis of the American healthcare system and how working people interact with it. Additionally, theyre a force for progress with regard to trans health care, disability rights, long-term care, and effective public health policy. Callie C. Orange, Massachusetts

PhDivas PodcastHosted by Dr. Liz Wayne and Dr. Christine Xine YaoThe hosts, Drs. Liz Wayne and Christine Xine Yao, are amazing scientists. They also are amazing storytellers who speak honestly about what its like to be a woman and a minority in the world of scientific academia. If my daughter decides to become a scientist one day, I will have her listen to these podcasts. Adam Silverstein, New York

I Contain Multitudes: The Microbes Within Us and a Grander View of LifeBy Ed YongThis book is one of the most transformative I have ever read, in terms of forcing me to change how I think and interact with the world. A complete perspective shift and one all of us should read. Ron Stokes-Walters, New York

Pleased to Meet Me: Genes, Germs, and the Curious Forces That Make Us Who We AreBy Bill SullivanThis book is one of the best written books for the lay (non-scientist/non-academic) person. Bill uses humor and pop culture to explain microbiology and epigenetics. Such a fantastic read and one you can share with younger students, family, friends. Melissa Trevio, Indianapolis

Tradeoffs podcastHosted by Dan GorensteinA great podcast that gives different perspectives on some of the different challenges facing the U.S. healthcare system. Tradeoffs features great guest experts to explain some complicated topics. The podcast has become my go-to for health policy topics. Megidelawit Yirefu, Baltimore

Shuggie BainBy Douglas StuartWhen a friend of mine recommended this novel to me, he warned me that it was so emotionally intense he had to take breaks. I did, too: Stuarts depiction of growing up queer in late 80s Glasgow is an unvarnished story of addiction and its effects, observed in meticulous, devastating detail. But I kept coming back, drawn in by the vividness and empathy of Stuarts scenes: Shuggie playing among the slag heaps, practicing a new gait thatll allow him to fit in. His mother shimmying open the electric meter to reuse the coins. Shuggie discerning whether his mother has been drinking, just from the way she scrapes her key in the lock. Again and again, Stuart brings alive the people trapped by illness and circumstance, making you feel as if they were your own family. Eric Boodman, general assignment reporter

Cant Just Stop: An Investigation of CompulsionsBy Sharon BegleyConfession time: Im still reading this book, written by my friend and colleague, Sharon Begley, who died earlier this year. The Covid-19 pandemic hasnt allowed me much time for recreational reading for the last 18 months, but as its grasp on the United States eases, I am enjoying Sharons exploration of compulsions and how, though some may seem bizarre and pathological at first glance, they can be adaptive responses that help those afflicted cope with deep anxiety. Sharons wise and compassionate voice comes through in her lovely prose.Helen Branswell, senior writer, infectious disease

The Great BelieversBy Rebecca MakkaiA book about identity, love, and socioeconomic power, The Great Believers is a powerful interrogation of concepts like family and art whose narrative unfolds within the underground gay communities of Chicago in the 1980s. Through the voices of fictionalized gay artists in the Reagan era, get a glimpse of what life was like as the HIV/AIDS epidemic hit one of the countrys cosmopolitan hubs. As the president was downplaying and stigmatizing the illness, it was devastating entire communities, killing friends, lovers, and families who only had access to limited, subpar treatments. Be prepared for an emotional roller coaster this part-suspense, part-drama had me laughing, crying, and sitting at the edge of my seat. This book provides a rare window into the immutable link between equity and health. Read it with tissues nearby. Erin Brodwin, health tech correspondent

Hidden Valley Road: Inside the Mind of an American FamilyBy Robert KolkerOne of the many things I lost the ability to do during the pandemic was read for an extended time. Hidden Valley Road helped break that. The story is about the Colorado-based Galvin family and how six of the 12 Galvin siblings were diagnosed with schizophrenia. Long-standing research and therapeutic gaps meant the sick Galvins were shuffled around in a health system that routinely failed them. Interwoven with the Galvins story is discussion of the state of schizophrenia research, and how, with half of the siblings diagnosed, the family is a perfect case study for studying schizophrenias genetic underpinnings. It can be a difficult read as Kolker constructs vivid scenes of the erratic and sometimes violent behavior of the Galvins who were sick, the parents who seemed all but helpless against and sometimes complicit in the trauma experienced by the other siblings. Beyond the compelling narrative and informational content, the book is also a master class in science writing, for any fellow writers out there. Shraddha Chakradhar, reporter, Morning Rounds writer, and intern coordinator

Empire of Pain: The Secret History of the Sackler DynastyBy Patrick Radden KeefeI got some odd looks when I mentioned I was bringing a book about the corporate dynasty behind the opioid epidemic on vacation, but Patrick Radden Keefe masterfully makes the complicated history of the Sackler clan a gripping read. Its at its core a story about family about love, betrayal, mistrust, pride, and legacy. Personal dynamics are expertly woven with a detailed indictment of what the Sacklers knew about the powerful, addictive drugs they sold, and what decisions they made with that information. Even in dissecting a world of wealth and power, Keefe never loses sight of the people in the Sacklers orbit who suffered the devastating consequences of their actions. Rachel Cohrs, Washington correspondent

The Undocumented AmericansBy Karla Cornejo VillavicencioKarla Cornejo Villavicencio turned down the suggestion to sell a memoir about her undocumented youth for years before writing The Undocumented Americans. The book circumvents stereotypes and introduces readers to real, complicated people living in undocumented America, where the lack of papers can erode ones health day by day, for a lifetime. There are undocumented Americans who responded to 9/11 and Hurricane Sandy, forever recovering; others who wear down their bodies as day laborers for decades; many who find health care in herbs and potions, with no safe access to hospitals. Maybe you wont like it, Villavicencio says in the introduction. I didnt write it for you to like it.The stories are reported, but drift both into memoir and magical realism, all in Villavicencios sharp, unforgettable voice. Theresa Gaffney, multimedia producer

Station ElevenBy Emily St. John MandelReading a novel about a global pandemic during a global pandemic isnt for everyone. But I found it strangely soothing to see some of the fears and unknowns that we experienced at the beginning of Covid-19 depicted in fiction. The virus in Mandels Station Eleven is even worse than the one were dealing with though, rest assured, would likely peter out too quickly to wreak such contagious devastation in reality. As the world adjusts to the many changes enforced by Covid-19, I loved reading about how Mandels society starts to remake itself, and the cultural institutions that somehow survive. Olivia Goldhill, investigative reporter

Crying in H MartBy Michelle ZaunerThis is a memoir that centers on Zauners mothers diagnosis of and eventual death from cancer. Its moving, funny, and heartbreaking, while providing an honest and intimate look at what dying from cancer can actually look like, and what it means when peoples lives are upended and they become caregivers. (Its also an absolutely terrific book about food and what the food we share and gravitate to means.) And while the book is not about the pandemic, I couldnt help but think about this deep and individual story of loss and grief in the context of Covid-19, when so many people around the world are simultaneously experiencing the deaths of loved ones and are reflecting on those relationships that were cut too short. Andrew Joseph, general assignment reporter

The Great Influenza: The Story of the Deadliest Pandemic in HistoryBy John M. BarryIf you havent yet read The Great Influenza by historian John M. Barry, its time. This book about the 1918 pandemic is highly relevant to our current pandemic: It shows few of the hard-learned lessons from a century ago were retained, and analyzes the historical fallout of the earlier pandemic, including, possibly, the rise of Nazism as a response to the Treaty of Versailles. (Barry argues that President Woodrow Wilson, weak, disoriented, and feverish from the flu, did not forcefully negotiate a treaty that may have led to a different post-war Europe.) I read the book earlier this year to learn how we emerged from the 1918 pandemic and to look for clues about how we might emerge from this one. I remain haunted by Barrys observation that few of the great writers of the 1920s Ernest Hemingway and F. Scott Fitzgerald among them tackled the pandemic in their works, as if they and the world just wanted to move on and forget, and worry we will do the same. Usha Lee McFarling, national science correspondent

Dr. Fauci: How a Boy from Brooklyn Became Americas DoctorBy Kate Messner, illustrated by Alexandra ByeAll last year, your kids watched him on TV. But how much do they really know about Dr. Anthony Fauci? Did they know that before he became Americas Doctor, he was once a curious kid like them who pondered the cosmos and the mysteries of the deep sea? Or that he played stickball with his friends in his neighborhood streets and was captain of his schools basketball team, despite being on the short side? In this childrens book aimed at kids aged 4 to 8, Messner tells of Faucis youth growing up in Brooklyn and attending medical school to becoming a doctor combating the AIDS epidemic to eventually becoming the man the nation would turn to during the Covid-19 pandemic. Through telling Faucis tale, Messner helps show kids that maybe one day they too could be a hero when the world needs them the most. Nicholas St. Fleur, general assignment reporter and associate editorial director of events

Correction: A previous version of this article misspelled the name of Kirsten Bibbins-Domingo.

Read the original post:
36 books and podcasts on health and science to check out this summer - STAT

DetailsCategory: DNA RNA and CellsPublished on Tuesday, 06 July 2021 15:58Hits: 290

PASADENA, CA, USA I July 6, 2021 I Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) today announced positive interim results from the first two cohorts of AROHIF21001, a Phase 1b dose-finding clinical study of ARO-HIF2, the companys investigational RNA interference (RNAi) therapeutic being developed as a treatment for patients with clear cell renal cell carcinoma (ccRCC). ARO-HIF2 is the first tumor-targeted investigational medicine to utilize Arrowheads proprietary Targeted RNAi Molecule (TRiM) platform in a clinical trial. Arrowhead is currently enrolling the third planned patient cohort of AROHIF21001 and the company intends to present additional data at an appropriate medical congress.

James Hamilton, M.D., MBA, senior vice president of discovery and translational medicine at Arrowhead, said: The AROHIF21001 Phase 1b study is designed to evaluate safety as well as preliminary pharmacodynamics and efficacy in an advanced ccRCC patient population. We believe that in the first two dose cohorts investigational ARO-HIF2 is showing clear signs of meaningful target engagement and some potentially early signs of efficacy in at least one patient. This is an encouraging start for the study. Specifically, in seventeen patients treated with investigational ARO-HIF2, nine had tumor biopsy material that could be evaluated. Seven of these nine tumor samples demonstrated reductions in HIF2 protein, as measured by immunohistochemistry H-score. The mean of these reductions was -48% with a range from -9% to -82%. In addition, one patient achieved a partial response with tumor shrinkage of approximately 65% and four additional patients in cohort 2 remain on study drug with stable disease. Tumors typically have a high level of heterogeneity and the patients in AROHIF21001 have advanced ccRCC and have failed multiple lines of treatment including checkpoint inhibitors and anti-VEGF regimens, so these early results in a heavily pre-treated population are encouraging for investigational ARO-HIF2 and our tumor-targeted platform broadly. ARO-HIF2 has been generally well-tolerated and we look forward to continued dose escalation.

Key Results from AROHIF21001

AROHIF21001 (NCT04169711) is a Phase 1b dose-finding clinical study in patients with advanced ccRCC to evaluate the safety of ARO-HIF2 and to determine the recommended Phase 2 dose. Secondary objectives include the assessment of pharmacokinetics and preliminary efficacy, based on Response Evaluation Criteria in Solid Tumors (RECIST). Exploratory objectives for AROHIF21001 are post-dose tumoral expression of HIF genes in response to treatment with ARO-HIF2, change in Karnofsky Performance Status (KPS), correlation of tumor response based on RECIST with tumor HIF2 gene expression and tumor integrin expression, correlation of integrin expression with changes in HIF gene expression, evaluation of serum biomarkers of ARO-HIF2 activity, correlation of RCC-related gene expression to ARO-HIF2 activity, and evaluation of plasma and urine metabolites.

About Arrowhead Pharmaceuticals

Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowheads RNAi-based therapeutics leverage this natural pathway of gene silencing.

For more information, please visit http://www.arrowheadpharma.com, or follow us on Twitter @ArrowheadPharma. To be added to the Company's email list and receive news directly, please visit http://ir.arrowheadpharma.com/email-alerts.

SOURCE: Arrowhead Pharmaceuticals

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Arrowhead Announces Positive Interim Results from Phase 1b Study of ARO-HIF2 for Treatment of Clear Cell Renal Cell Carcinoma | DNA RNA and Cells |...

Collaboration combines Apellis expertise in complement, a complex biological system, with Beams proprietary base editing platform

Companies will collaborate on six research programs directed to tissues modulated by the complement system, including the eye, liver, and brain

WALTHAM, Mass. and CAMBRIDGE, Mass., June 30, 2021 (GLOBE NEWSWIRE) -- Apellis Pharmaceuticals, Inc. (Nasdaq: APLS) and Beam Therapeutics Inc. (Nasdaq: BEAM) today announced an exclusive five-year research collaboration focused on the use of Beams proprietary base editing technology to discover new treatments for complement-driven diseases. The companies will collaborate on six research programs focused on C3 and other complement targets in the eye, liver, and brain.

Beam has pioneered base editing, which holds significant promise as a best-in-class technology for precision gene editing. This collaboration builds on our deep scientific expertise in complement and, together with our growing pipeline, positions Apellis for long-term leadership in the complement field, said Cedric Francois, M.D., Ph.D., co-founder and chief executive officer, Apellis. Apellis and Beam share a vision for advancing transformative medicines for patients, which is critically important as we embark on a highly innovative effort to modulate complement and discover new treatments across a wide range of debilitating diseases.

Base editing represents a potential new class of precision genetic medicine that uses a chemical reaction designed to create precise, predictable, and efficient single base changes at targeted genomic sequences without making double-stranded breaks in the DNA. Editing key elements of the complement pathway in target organs has the potential to alter the complement cascade and durably address diseases driven by abnormal complement activity.

Apellis has established itself as a leader in complement with the advancement of compelling targeted C3 therapies, said John Evans, chief executive officer, Beam. This collaboration allows us to combine our proprietary technologies and capabilities in base editing with Apellis expertise in targeting the complement pathway to develop new medicines for diseases driven by complement biology. This also represents an important strategic initiative to explore opportunities that expand the application of base editing to address more biologically complex diseases for patients in need of new treatment options.

Under the terms of the collaboration agreement, Beam will apply its base editing technology and conduct preclinical research on up to six base editing programs that target specific genes within the complement system in various organs, including the eye, liver, and brain. Apellis will have exclusive rights to license each of the six programs and will assume responsibility for subsequent development. Beam may elect to enter a 50-50 U.S. co-development and co-commercialization agreement with Apellis with respect to one program licensed under the collaboration.

As part of the collaboration, Beam will receive a total of $75 million in upfront and near-term milestones from Apellis $50 million upon signing and an additional $25 million payment on the one-year anniversary of the contract execution date. After exercise of the opt-in license rights for each of the up to six programs, Beam will be eligible to receive development, regulatory, and sales milestones from Apellis, as well as royalty payments on sales. The collaboration has an initial term of five years and may be extended up to two years on a per year and program-by-program basis.

About ApellisApellis Pharmaceuticals, Inc. is a global biopharmaceutical company that is committed to leveraging courageous science, creativity, and compassion to deliver life-changing therapies. Leaders in targeted C3 therapies, we aim to develop transformative therapies for a broad range of debilitating diseases that are driven by excessive activation of the complement cascade, including those within hematology, ophthalmology, nephrology, and neurology. For more information, pleasevisit https://www.apellis.com.

About Beam TherapeuticsBeam Therapeutics (Nasdaq: BEAM) is a biotechnology company committed to establishing the leading, fully integrated platform for precision genetic medicines. To achieve this vision, Beam has assembled a platform that includes a suite of gene editing and delivery technologies and is in the process of building internal manufacturing capabilities. Beams suite of gene editing technologies is anchored by base editing, a proprietary technology that enables precise, predictable and efficient single base changes, at targeted genomic sequences, without making double-stranded breaks in the DNA. This enables a wide range of potential therapeutic editing strategies that Beam is using to advance a diversified portfolio of base editing programs. Beam is a values-driven organization committed to its people, cutting-edge science, and a vision of providing life-long cures to patients suffering from serious diseases.

Apellis Forward-Looking StatementStatements in this press release about future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, statements in respect of the expected closing of the exchanges. The words anticipate, believe, continue, could, estimate, expect, intend, may, plan, potential, predict, project, should, target, will, would and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: whether the research collaboration will result in programs that are licensed by Apellis; whether any product candidates that arise from these programs or are otherwise developed by Apellis will advance into clinical trials or through the clinical trial process on a timely basis or at all; whether the results of clinical trials of the companys product candidates will warrant submissions for regulatory approval or regulatory approval; whether any products that receive regulatory approval will be successfully distributed and marketed; and other factors discussed in the Risk Factors section of Apellis Quarterly Report on Form 10-Q with the Securities and Exchange Commission on April 28, 2021 and the risks described in other filings that Apellis may make with the Securities and Exchange Commission. Any forward-looking statements contained in this press release speak only as of the date hereof, and Apellis specifically disclaims any obligation to update any forward-looking statement, whether as a result of new information, future events or otherwise.

Beam Forward-Looking StatementThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Investors are cautioned not to place undue reliance on these forward-looking statements, including, but not limited to, statements related to: the therapeutic applications and potential of our technology, including our ability to develop life-long, curative, precision genetic medicines for patients through base editing. Each forward-looking statement is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statement, including, without limitation, risks and uncertainties related to: our ability to raise additional funding, which may not be available; our ability to obtain, maintain and enforce patent and other intellectual property protection for our platform technology; the potential impact of the COVID-19 pandemic; risks related to competitive products; and the other risks and uncertainties identified under the heading Risk Factors in our Annual Report on Form 10-K for the year ended December 31, 2020, our Quarterly Report on Form 10-Q for the quarter ended March 31, 2021, and in any subsequent filings with the Securities and Exchange Commission. These forward-looking statements (except as otherwise noted) speak only as of the date of this press release. Factors or events that could cause our actual results to differ may emerge from time to time, and it is not possible for us to predict all of them. We undertake no obligation to update any forward-looking statement, whether as a result of new information, future developments or otherwise, except as may be required by applicable law.

Contacts:

Apellis:

Media:Lissa Pavlukmedia@apellis.com617.977.6764

Investors:Argot Partnersapellis@argotpartners.com212.600.1902

Beam Therapeutics:

Media:Dan Budwick1ABdan@1abmedia.com

Investors:Chelcie ListerTHRUST Strategic Communicationschelcie@thrustsc.com

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GlobeNewswire Apellis and Beam Therapeutics Enter Exclusive Research Collaboration to Apply Base Editing to Discover Novel - GlobeNewswire

The bacteria, archaebacteria, viruses, and fungi that live in the human gut collectively known as the gut microbiota have a profound effect on both physical and mental well-being.

Research suggests that by feeding the beneficial members of this community, dietary plant fibers can help stave off chronic health conditions, such as cardiovascular disease, type 2 diabetes, and obesity.

However, Western-style diets are often high in fat and deficient in these plant fibers.

The idea of supplementing otherwise unhealthy snacks, such as cookies and chips, with fiber might seem straightforward, but the relationship between diet, the microbiota, and individual health is highly complex.

Scientists at the Center for Gut Microbiome and Nutrition Research at Washington University School of Medicine in St Louis, MO, are investigating this relationship with a view to developing prebiotic snack products.

In previous work, they identified sources of fiber that are not only cheap and readily available such as typically discarded peels, rinds, and husks but also boost the gut microbes that adults with obesity tend to lack.

In their new research, which appears in Nature, they tested how snacks supplemented with some of these fibers affected the gut microbiota of mice and humans, looking at their possible physiological effects.

Since snacks are a popular part of Western diets, we are working to help develop a new generation of snack food formulations that people will like to eat and that will support a healthy gut microbiome that affects many aspects of wellness, says senior author Prof. Jeffrey I. Gordon, M.D., who directs the Edison Family Center for Genome Sciences & Systems Biology at Washington University School of Medicine.

The snack food manufacturer Mondelz International, which owns brands such as belVita, Cadbury, and Oreo, partly funded the work.

In the first phase of their research, the scientists used gnotobiotic mice, which are raised in sterile conditions so that they lack any gut microbes of their own.

They colonized the guts of these mice with microbes from people with obesity, then fed the animals the type of high fat, low fiber diet that is associated with overweight and obesity.

Next, they consecutively introduced snacks to the mices diet that were supplemented with pea fiber, orange fiber, or barley bran. Between each type of snack were washout periods during which the mice only ate the high fat, low fiber diet.

This approach allowed the researchers to track the effects of each fiber type on the gene pool of the animals gut microbiota, which they did through analyses of microbial DNA in fecal samples.

They discovered that each snack led to an increased abundance of the genes necessary to make enzymes for digesting that particular fiber. Presumably, this was because the fiber gave bacteria with the right genes a competitive edge over the others.

In the second phase of the research, the researchers carried out similar experiments involving 12 human volunteers who were overweight or had obesity.

To avoid any changes arising from differences in their diets, the volunteers ate a strictly controlled diet that was high in saturated fat and low in fiber.

The researchers then monitored genetic changes in their microbiota before, during, and after a 2-week period, during which they also ate snack bars supplemented with pea fiber.

The team observed similar changes in the volunteers gut microbiota to those that they had seen in the mice, with an increased abundance of the genes needed to digest this fiber.

Finally, the scientists investigated whether eating snacks containing several different types of fiber would lead to more significant changes in the microbiota than eating pea fiber alone.

A group of 14 volunteers first ate a snack containing a combination of two fibers: pea fiber and inulin, which occurs naturally in onions, bananas, asparagus, artichokes, and chicory root. Later, after a washout period, they ate a snack containing four fibers: inulin, pea fiber, orange fiber, and barley bran.

This part of the study showed that the more types of fiber in the diet, the greater the abundance of bacterial genes that play a role in fiber metabolism.

These genetic changes were closely correlated with changes in the levels of proteins in the blood that contribute to a wide range of key physiological processes.

For example, there were significant changes in the levels of proteins involved in glucose metabolism, immunity, blood coagulation, blood vessel function, and the biology of bone and nerve cells.

Overall, the experiments reveal how responsive the gut microbiota is to changes in dietary fiber, even in individuals who are accustomed to eating a low fiber diet.

In principle, the fibers can be incorporated into a variety of snack formats familiar to consumers chips, bars, biscuits, etc., Prof. Gordon told Medical News Today.

One of the limitations of the study was that the volunteers ate a tightly controlled diet in addition to the fiber-supplemented snacks. In the real world, diets are much more complicated.

However, the researchers are already exploring whether their preliminary findings hold up when people can eat what they like.

Follow-on studies involve administering the snack food prototypes to participants who are consuming their normal diets, said Prof. Gordon.

This approach can provide insights about the robustness of the effects, and dose dependency, of fiber snack formulations on the gut microbiome and host physiology under more realistic consumer settings, he added.

The study identified protein biomarkers of possible physiological changes in participants blood. However, it is currently unknown whether such changes would reflect genuine health benefits.

Only clinical trials can reveal whether such snacks might help prevent type 2 diabetes or obesity, for example.

In an accompanying article, Avner Leshem and Eran Elinav from the Weizmann Institute of Science in Rehovot, Israel, conclude:

[These] findings provide valuable mechanistic insights into the microbial contributions to human dietary responses. This will probably lead to long-term, randomized clinical trials that assess causal links between distinct food ingredients, microbiome modulation, and downstream health-related outcomes for humans.

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Could adding prebiotics to snacks improve gut health? - Medical News Today

Newswise University of Maryland School of Medicine (UMSOM) Professor of Diagnostic Radiology & Nuclear Medicine, Linda Chang, MD, MS, received the National Institute on Drug Abuse (NIDA) 2021 Avant Garde Award (DP1) for HIV/AIDS and Substance Use Disorder Research a National Institutes of Health (NIH) Directors Pioneer Award. This prestigious award supports researchers with exceptional creativity, who propose high-impact research with the potential to be transformative to the field. Her proposed project will involve a team of experts in brain imaging, infectious diseases, addiction, animal research, and gene-editing technology with the goal to essentially eradicate all traces of HIV from the body, and treat commonly co-existing substance use disorders. 2021 Avant Garde Awardees are expected to receive more than $5 million over five years.

I am extremely pleased, and feel very fortunate to have received this award, says Dr. Chang, who has a secondary appointment in the Department of Neurology at UMSOM. This project takes my work in a new direction. I believe my track record of being able to work across multiple disciplines with various researchers to initiate new areas of research and getting good results, along with the outstanding collaborators and resources at UMB, gave the proposal reviewers confidence that my team and I can significantly advance this new project.

About 38 million people around the world live with HIV, according to the Centers for Disease Control and Prevention. Although antiretroviral therapies can treat HIV to the point of undetectable viral levels and lead to long, healthy lifespans, these medications must be taken for life to prevent a resurgence, as HIV can hide from these drugs by integrating copies of itself into a persons genome. Once the drugs are stopped, the virus can reemerge.

From start to finish, Dr. Changs plan is to remove HIV from the genome, even in tough to reach spots like the brain, get more of the antiretroviral therapies into the brain, and stimulate the reward system in the brain to reduce drug cravings. The work will start out in mice before it can be tested in people.

Dr. Chang plans to use the gene-editing technology known as CRISPR to cut out copies of the hidden HIV genes in the genomes of mice, so they can be eradicated by antiretroviral drugs.

However, getting the CRISPR therapy into the brain can be difficult because of the blood-brain barrier, which protects the brain from infectious bacteria and foreign substances. The blood-brain barrier also prevents antiretroviral drugs from reaching high enough concentrations in the brain and central nervous system to effectively destroy HIV.

To seek out HIV in the brain, Dr. Chang and her team will temporarily disrupt the blood-brain barrier to allow more of the antiretroviral drugs or the CRISPR compounds to cross over the blood-brain barrier using an unique resource at the University of Marylandthe MRI-guided focused ultrasound system. This technique uses the MRI scan to help guide 2,000 pinpointed beams of high energy sound waves, along with microscopic bubbles, to non-invasively and temporarily open an area of the brain with the goal of eliminating the hidden reservoirs of virus in the brains immune cells.

About half of the people with HIV use substances, like drugs or alcohol, or have substance use disorders. Even tobacco or cannabis use in people with HIV is at 2-3 times that of the general population. Together with Victor Frenkel, PhD, an Associate Professor in the Department of Radiology and the Director of Translational Focused Ultrasound, and Donna Calu, PhD, Assistant Professor in the Department of Anatomy and Neurobiology, Dr. Chang will use low energy MR-guided focused ultrasound to suppress brain activity in the reward center of the brain, the nucleus accumbens. They hope this approach will suppress drug cravings in people with HIV who have substance use disorders.

The different components of this project will first be tested in mouse or rat models before moving onto clinical studies. As HIV does not normally infect mice, researchers use humanized mice that have weak immune systems, which are replaced with human blood stem cells that become human immune cells that can be infected with HIV. Although these humanized mice make lots of T cells a main cell for HIV infectionthey dont make the immune cells that HIV uses to hide in the brain, known as microglia. Recently, Dr. Changs collaborator Howard E. Gendelman, MD, Margaret R. Larson Professor of Internal Medicine and Infectious Diseases Chair at University of Nebraska Medical Center, and his lab created a modified humanized mouse that has an extra human gene that allows the human blood stem cells to now make microglia.

These new mice mean that these experiments can be done in a fraction of the time and cost and without the other hurdles that come along with using non-human primates, which are the only other animal that a special strain of HIV can infect, says collaborator Alonso Heredia, PhD, Associate Professor of Medicine and scientist at UMSOMs Institute of Human Virology.

He adds, There have been many attempts to eradicate HIV in the body, and it is thought they have not been successful, in part because we cannot get to the HIV reservoirs in the brain. If this works, we will be much closer to a practical cure for HIV. Dr. Heredia will be collaborating with Dr. Chang on this project using HIV-infected humanized mice that he has developed for his other ongoing projects.

For the addiction studies, Dr. Changs team will use the expertise and rodent models of addiction developed and optimized by Mary Kay Lobo, PhD, Professor of Anatomy and Neurobiology, and Dr. Calu. The mice will self-administer fentanyl, a powerful, synthetic opioid.

Dr. Frenkel and Dheeraj Gandhi, MBBS, Professor of Diagnostic Radiology and Nuclear Medicine and Clinical Director of Center of Metabolic Imaging and Therapeutics at UMSOM, are the teams MRI-guided focused ultrasound and clinical research experts.

My hearty congratulations to Dr. Chang and her colleagues and collaborators. If anything is called cutting edge this work surely qualifies for that praise. We wish this group all the success possible, said Robert C. Gallo, MD, The Homer & Martha Gudelsky Distinguished Professor in Medicine, Co-Founder and Director, Institute of Human Virology (IHV), University of Maryland School of Medicine, a Global Virus Network (GVN) Center of Excellence, and GVN Co-Founder and International Scientific Advisor.

Dr. Chang is an expert in using brain imaging to study how HIV or drug use affect the brain in adults and during adolescence, and how exposure to drugs in the womb affects childhood development. She has also conducted clinical trials for treating HIV-associated cognitive disorders and substance use disorders.

Dr. Chang joined UMSOM in 2017 through the Deans initiative Special Trans-Disciplinary Recruitment Award Program (STRAP). The STRAP Initiative was part of UMSOM's multi-year research strategy ACCEL-Med (Accelerating Innovation and Discovery in Medicine) to increase the quality and reputation of clinical and basic science research bringing UMSOM among other top-tier medical research schools.

Dr. Changs arrival to UMSOM spurred the exact kind of collaborative efforts we had hoped to foster through our recruitment program in order to accelerate discoveries, treatments and cures for the worlds most pressing diseases, says E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, UMSOM.I look forward to following her teams progress on this ambitious project in the hope that one day we can eradicate HIV.

Dr. Chang served on the National Advisory Council on Drug Abuse for NIDA and is a current member on the Council of Councils at the NIH.

Now in its third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as one of the fastest-growing, top-tier biomedical research enterprises in the world -- with 45 academic departments, centers, institutes, and programs; and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished two-time winner of the Albert E. Lasker Award in Medical Research.

With an operating budget of more than $1.2 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic and clinically-based care for nearly 2 million patients each year. The School of Medicine has more than $563 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding. As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 student trainees, residents, and fellows.

The combined School of Medicine and Medical System (University of Maryland Medicine) has an annual budget of nearly $6 billion and an economic impact of more than $15 billion on the state and local community. The School of Medicine, which ranks as the 8th highest among public medical schools in research productivity, is an innovator in translational medicine, with 600 active patents and 24 start-up companies. The School of Medicine works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visitmedschool.umaryland.edu

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UM School Of Medicine Researchers Receive NIH Avant Garde Award For Out-Of-Box, Innovative Concept To Cure HIV And Treat Co-Existing Addiction -...