tbuckley/cabot-search huggingface dataset:
CRISPR/Cas9-Mediated Gene Correction in Newborn Rabbits with Hereditary Tyrosinemia Type I
Authors: Nan Li, Shixue Gou, Jiaowei Wang, Quanjun Zhang, Xingyun Huang, Jingke Xie, Li Li, Qin Jin, Zhen Ouyang, Fangbing Chen, Weikai Ge, Hui Shi, Yanhui Liang, Zhenpeng Zhuang, Xiaozhu Zhao, Meng Lian, Yinghua Ye, Longquan Quan, Han Wu, Liangxue Lai, Kepin Wang
Journal: Molecular Therapy (2020)

Patients with hereditary tyrosinemia type I (HT1) present acute and irreversible liver and kidney damage during infancy. CRISPR-Cas9-mediated gene correction during infancy may provide a promising approach to treat patients with HT1. However, all previous studies were performed on adult HT1 rodent models, which cannot authentically recapitulate some symptoms of human patients. The efficacy and safety should be verified in large animals to translate precise gene therapy to clinical practice. Here, we delivered CRISPR-Cas9 and donor templates via adeno-associated virus to newborn HT1 rabbits. The lethal phenotypes could be rescued, and notably, these HT1 rabbits reached adulthood normally without 2-(2-nitro-4-trifluoromethylbenzyol)-1,3 cyclohexanedione administration and even gave birth to offspring. Adeno-associated virus (AAV)-treated HT1 rabbits displayed normal liver and kidney structures and functions. Homology-directed repair-mediated precise gene corrections and non-homologous end joining-mediated out-of-frame to in-frame corrections in the livers were observed with efficiencies of 0.90%–3.71% and 2.39%–6.35%, respectively, which appeared to be sufficient to recover liver function and decrease liver and kidney damage. This study provides useful large-animal preclinical data for rescuing hepatocyte-related monogenetic metabolic disorders with precise gene therapy. Patients with hereditary tyrosinemia type I (HT1) present acute and irreversible liver and kidney damage during infancy. CRISPR-Cas9-mediated gene correction during infancy may provide a promising approach to treat patients with HT1. However, all previous studies were performed on adult HT1 rodent models, which cannot authentically recapitulate some symptoms of human patients. The efficacy and safety should be verified in large animals to translate precise gene therapy to clinical practice. Here, we delivered CRISPR-Cas9 and donor templates via adeno-associated virus to newborn HT1 rabbits. The lethal phenotypes could be rescued, and notably, these HT1 rabbits reached adulthood normally without 2-(2-nitro-4-trifluoromethylbenzyol)-1,3 cyclohexanedione administration and even gave birth to offspring. Adeno-associated virus (AAV)-treated HT1 rabbits displayed normal liver and kidney structures and functions. Homology-directed repair-mediated precise gene corrections and non-homologous end joining-mediated out-of-frame to in-frame corrections in the livers were observed with efficiencies of 0.90%–3.71% and 2.39%–6.35%, respectively, which appeared to be sufficient to recover liver function and decrease liver and kidney damage. This study provides useful large-animal preclinical data for rescuing hepatocyte-related monogenetic metabolic disorders with precise gene therapy.
Abstract 14242: Temporal Trends and Clinical Course of Deep Vein Thrombosis in Evacuees Post2016 Kumamoto Earthquakes
Authors: Kenji Sakamoto, Koji Sato, Yoichiro Hashimoto, Kazuhiko Hanzawa, Sunao Kojima, Daisuke Sueta, Koichiro Fujisue, Takeshi Ogo, Hisao Ogawa, Kenichi Tsujita, Seiji Hokimoto
Journal: Circulation (2019)

Introduction: Kumamoto prefecture in Japan was struck by a series of earthquakes, including a maximum magnitude (Mw) 7.3 on April 16, 2016. After the earthquakes, more than 180,000 people evacuated...
The Enemy Within
Authors: Chonyang L. Albert, Andres E. Carmona-Rubio, Aaron J. Weiss, Gary G. Procop, Randall C. Starling, E. Rene Rodriguez
Journal: Circulation (2020)

Information about a real patient is presented in stages (boldface type) to expert clinicians (Drs Albert, Weiss, Starling, Rodriguez, and Procop), who respond to the information and share their reasoning with the reader (regular type)
Optimizing clinical research procedures in public health emergencies
Authors: Ainhoa Madariaga, Lawrence Kasherman, Katherine Karakasis, Pamela Degendorfer, Ann M. Heesters, Wei Xu, Shahid Husain, Amit M. Oza
Journal: Medicinal Research Reviews (2020)

Abstract Public Health Emergencies of International Concern, such as the coronavirus disease 2019 pandemic, have a devastating impact on an individual and societal level, and there is an urgent need to learn, understand and bridge the therapeutic gap at a time of extreme stress on the patient, health care systems and staff. Well‐designed, controlled clinical trials play a crucial role in the discovery of novel diagnostic and management strategies; however, these catastrophic circumstances pose unique challenges in initiating research studies at institutional, national, and international levels, highlighting the importance of a coordinated, collaborative approach. This review discusses key elements necessary to consider for developing clinical trials within a Public Health Emergency setting.
Abstract 15085: Association Between Bone Mineral Density and Incident Heart Failure in a Biracial Cohort of Older Adults: The Health, Aging, and Body Composition Study
Authors: Hans Gao, Raymond B Fohtung, Sheena Patel, Shuo Xu, Peggy M Cawthon, Anne B Newman, Jane A Cauley, Laura Carbone, Phyllis K STEIN, Roberto Civitelli, Jorge R Kizer
Journal: Circulation (2020)

Background: Osteoporosis and heart failure (HF) are age-related disorders that share some pathogenetic features and may influence each other. Previous studies have suggested an association between bone mineral density (BMD) and HF risk, which may be race-dependent. We sought to further investigate race- and sex-specific associations of BMD with HF in a longitudinal study of older adults. Methods: We evaluated the relationship between BMD and HF in the Health, Aging, and Body Composition study, a sample of community-dwelling adults aged 70-79. BMD was measured by dual-energy X-ray absorptiometry (DXA) of the total hip and femoral neck, and in half the cohort by computed tomography of the spine. Analyses were stratified a priori by sex and race, and Cox models were used to estimate risk after adjustment for potential confounders. Results: Of 2835 participants, 572 (49% women, 42% black) developed HF during a median follow up of 12.2 years. Lower BMD of the total hip by DXA was associated with higher risk of HF in black women (adj. HR 1.84 [95% CI, 1.43 - 2.37] per SD decrement), with suggestion of lower risk in black men that was not significant (adj. HR 0.81 [0.64 - 1.02]). Corresponding analyses failed to reveal significant associations in white women (adj. HR 0.86 [0.71-1.04]) or white men (adj. HR 1.10 [0.93 - 1.30]). There were a significant interaction of total hip BMD by sex among blacks (p=0.002), but not whites (p=0.363), as well as by race among women (p=0.026) and men (p=0.049). Relationships of BMD of the femoral neck were similar in all groups. Likewise, lower volumetric BMD of the spine was associated with higher risk in black women (adj. HR 1.34 [1.02 - 1.77] per SD decrement), but there were no significant associations in black men (adj. HR 0.91 [0.78 - 1.18]), white women (adj. HR 0.83 [0.64 - 1.08]), or white men (adj. HR 1.17 [0.95 - 1.44]). Conclusions: Among a biracial cohort of older adults, lower BMD was associated with higher risk of HF in black women, with no clear evidence of an association in white women or in men of either race. Further research is needed to understand the factors that may account for the particular association in black women, and whether these can be leveraged for therapeutic intervention.
CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity
Authors: April C. Watt, Paloma Cejas, Molly J. DeCristo, Otto Metzger-Filho, Enid Y. N. Lam, Xintao Qiu, Haley BrinJones, Nikolas Kesten, Rhiannon Coulson, Alba Font-Tello, Klothilda Lim, Raga Vadhi, Veerle W. Daniels, Joan Montero, Len Taing, Clifford A. Meyer, Omer Gilan, Charles C. Bell, Keegan D. Korthauer, Claudia Giambartolomei, Bogdan Pasaniuc, Ji-Heui Seo, Matthew L. Freedman, Cynthia Ma, Matthew J. Ellis, Ian Krop, Eric Winer, Anthony Letai, Myles Brown, Mark A. Dawson, Henry W. Long, Jean J. Zhao, Shom Goel
Journal: Nature Cancer (2020)
Heterozygous, Polyploid, Giant Bacterium,<i>Achromatium</i>, Possesses an Identical Functional Inventory Worldwide across Drastically Different Ecosystems
Authors: Danny Ionescu, Luca Zoccarato, Artur Zaduryan, Sina Schorn, Mina Bizic, Solvig Pinnow, Heribert Cypionka, Hans-Peter Grossart
Journal: Molecular Biology and Evolution (2020)

Abstract Achromatium is large, hyperpolyploid and the only known heterozygous bacterium. Single cells contain approximately 300 different chromosomes with allelic diversity far exceeding that typically harbored by single bacteria genera. Surveying all publicly available sediment sequence archives, we show that Achromatium is common worldwide, spanning temperature, salinity, pH, and depth ranges normally resulting in bacterial speciation. Although saline and freshwater Achromatium spp. appear phylogenetically separated, the genus Achromatium contains a globally identical, complete functional inventory regardless of habitat. Achromatium spp. cells from differing ecosystems (e.g., from freshwater to saline) are, unexpectedly, equally functionally equipped but differ in gene expression patterns by transcribing only relevant genes. We suggest that environmental adaptation occurs by increasing the copy number of relevant genes across the cell’s hundreds of chromosomes, without losing irrelevant ones, thus maintaining the ability to survive in any ecosystem type. The functional versatility of Achromatium and its genomic features reveal alternative genetic and evolutionary mechanisms, expanding our understanding of the role and evolution of polyploidy in bacteria while challenging the bacterial species concept and drivers of bacterial speciation.
S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling
Authors: Pingping Luo, Ming Zheng, Rui Zhang, Hong Zhang, Yingxia Liu, Wei Li, Xiaoming Sun, Qian Yu, George L. Tipoe, Jia Xiao
Journal: Acta Pharmaceutica Sinica B (2020)

Alcoholic liver disease (ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine (SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model (the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC (300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis, insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor (INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3β signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC (250 μmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC's beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model. Long-term (90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3β pathway.
COVID-19 IMPACT ON HEPATITIS B PREVENTION PROGRAMS IN CLINICS SERVING AT-RISK POPULATIONS
Authors: L. Martin-Braswell, J. Deerin, M. Weng, A. Harris
Journal: Hepatology (2020)

Background: Prevention of hepatitis B virus (HBV) infection includes vaccination of susceptible individuals, testing and linkage to care of persons at risk for chronic hepatitis B (CHB) There are about 1 million persons living with CHB in the United States, and 32 states reported increased incidence of acute HBV infection in 2017 In July 2019, to address the public health burden of HBV infection, the Department of Health and Human Services Office of Minority Health (OMH) funded six grantees (health department, federally qualified health center, academic institutions, and non-profit organizations) to develop comprehensive hepatitis B prevention programs, targeting at-risk populations who are disproportionately impacted by hepatitis B The objective of this analysis was to evaluate the impact of COVID-19 on the OMH grantees' delivery of hepatitis B services to at-risk populations Methods: The six OMH grantees collected data from electronic health records during a 3-week period in June 2020 for two defined timeperiods;pre-pandemic from 12/1/2019 - 2/29/2020 and early-pandemic from 3/1/2020 - 5/31/2020 All patient visits to the clinics during pre-pandemic and early-pandemic were included Data was organized into the number of people tested for hepatitis B, number of hepatitis B vaccine doses given, number of telemedicine visits, and number of in-person clinic visits Data from all grantees were combined for this analysis Descriptive statistics were performed to evaluate the impact of the COVID-19 pandemic on the delivery of hepatitis B services Results: Following the pre-pandemic period, there was a decrease in the number of in-person visits from 35,095 to 17,054 (63 5% decrease) and an increase in the number of telemedicine visits from 12 to 29,686 (211,566 7% increase) (Table 1) The overall number of patient visits increased from 35,107 to 46,740 (33 1% increase) The number of people tested for HBV decreased from 5,145 to 1,988 (70 5% decrease), and the number of HBV vaccine doses administered decreased from 2,432 to 999 (69 6% decrease) Conclusion: Prior to the COVID-19 pandemic, the six OMH grantees made progress on establishing hepatitis B prevention programs Grantees are utilizing telemedicine to provide healthcare during the COVID-19 pandemic, yet, hepatitis B services provided have been reduced substantially Innovative approaches to delivering hepatitis B vaccinations and testing are needed in the era of COVID-19(Table Presented)
Decitabine Induces Gene Derepression on Monosomic Chromosomes: <i>In Vitro</i> and <i>In Vivo</i> Effects in Adverse-Risk Cytogenetics AML
Authors: Gabriele Greve, Julia Schüler, Björn A. Grüning, Bettina Berberich, Julia Stomper, Dennis Zimmer, Lea Gutenkunst, Ulrike Bönisch, Ruth Meier, Nadja Blagitko-Dorfs, Olga Grishina, Dietmar Pfeifer, Dieter Weichenhan, Christoph Plass, Michael Lübbert
Journal: Cancer Research (2020)

Abstract Hypomethylating agents (HMA) have become the backbone of nonintensive acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) treatment, also by virtue of their activity in patients with adverse genetics, for example, monosomal karyotypes, often with losses on chromosome 7, 5, or 17. No comparable activity is observed with cytarabine, a cytidine analogue without DNA-hypomethylating properties. As evidence exists for compounding hypermethylation and gene silencing of hemizygous tumor suppressor genes (TSG), we thus hypothesized that this effect may preferentially be reversed by the HMAs decitabine and azacitidine. An unbiased RNA-sequencing approach was developed to interrogate decitabine-induced transcriptome changes in AML cell lines with or without a deletion of chromosomes 7q, 5q or 17p. HMA treatment preferentially upregulated several hemizygous TSG in this genomic region, significantly derepressing endogenous retrovirus (ERV)3–1, with promoter demethylation, enhanced chromatin accessibility, and increased H3K4me3 levels. Decitabine globally reactivated multiple transposable elements, with activation of the dsRNA sensor RIG-I and interferon regulatory factor (IRF)7. Induction of ERV3–1 and RIG-I mRNA was also observed during decitabine treatment in vivo in serially sorted peripheral blood AML blasts. In patient-derived monosomal karyotype AML murine xenografts, decitabine treatment resulted in superior survival rates compared with cytarabine. Collectively, these data demonstrate preferential gene derepression and ERV reactivation in AML with chromosomal deletions, providing a mechanistic explanation that supports the clinical observation of superiority of HMA over cytarabine in this difficult-to-treat patient group. Significance: These findings unravel the molecular mechanism underlying the intriguing clinical activity of HMAs in AML/MDS patients with chromosome 7 deletions and other monosomal karyotypes. See related commentary by O'Hagan et al., p. 813
Abstract 14036: Enhanced External Counterpulsation Reduces Blood Pressure in Patients With Chronic Stable Angina: A Meta-Analysis
Authors: Bradley Williams, Mehak Aggarwal, Cole Kiser, Krishnaswami Vijayaraghavan, Sachin A Shah
Journal: Circulation (2020)

Background: Hypertension is a modifiable risk factor for ASCVD. Enhanced External Counterpulsation (EECP ® ) is an FDA-approved, non-invasive treatment modality for patients with angina and symptoms of ischemic heart failure. Various studies have demonstrated hemodynamic changes with EECP ® therapy, but the true magnitude of benefit remains unknown. We conducted a meta-analysis to assess the change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) post- EECP ® therapy. Methods: A literature search across multiple databases was conducted from its inception to March 2020. Studies evaluating the impact of EECP ® in chronic stable angina patients that reported systolic and diastolic blood pressures were extracted. Human studies published in English, where patients completed 35 hours of EECP ® (administered as 1-hour sessions) were included for analysis. Studies that reported data in multiple arms were treated as individual studies. The weighted mean difference from baseline for SBP and DBP was calculated using the DerSimonian-Laird random-effects model. Statistical heterogeneity was assessed by the I 2 statistic with publication bias evaluated using the Egger bias statistic. Subgroup analyses were performed to assess for clinical heterogeneity. Results: We identified 272 articles, of which 15 unique studies (n=659) reporting data on systolic and diastolic blood pressure were included. Post- EECP ® treatment, SBP decreased by 8.9 mmHg (95% CI 4.0 to 13.7 mmHg, I 2 =87.3%) and DBP reduced by 3.6 mmHg (95% CI 2.1 to 5.0 mmHg, I 2 =38.9%). Patients with a baseline SBP 130 mmHg appear to derive greater benefit (SBP reduced by 13.0 mmHg, 95% CI 8.3 to 17.6, I 2 =70.4%) compared to patients with a baseline SBP&lt;130 (SBP reduced by 3.2 mmHg, 95% CI 0.4 to 6.0, I 2 =25.2). The Egger bias statistic showed no publication bias for the primary endpoints (both p-values&gt;0.33). Conclusion: EECP ® treatment reduced SBP and DBP by over 8 and 3 mmHg respectively. The pleiotropic benefits from EECP ® provide additional hypertension control in patients with chronic stable angina.
Long‐Term Continuous Glucose Monitoring Using a Fluorescence‐Based Biocompatible Hydrogel Glucose Sensor
Authors: Jun Sawayama, Shoji Takeuchi
Journal: Advanced Healthcare Materials (2020)

Abstract Fluorescence‐based hydrogel glucose sensors with boronic acid‐based glucose recognition are promising regarding their potential to improve continuous glucose monitoring by facilitating long‐lasting accuracy. However, these sensors typically become encapsulated after implantation, and the dynamic range decreases following long‐term implantation and use. Herein, a four‐arm polyethylene glycol (PEG) hydrogel is developed with an immobilized glucose‐responsive fluorescence dye (GF‐PEG‐gel); this hydrogel is effective in mitigating foreign body reactions (FBRs) that hinder stable glucose responses in vivo. The GF‐PEG‐gel attached to an implantable device successfully traces blood glucose concentrations in diabetic model rats for 45 days. A pig experiment shows that the device measures the glucose concentration with an equivalent accuracy to that required for clinically available settings.
Abstract 14540: Gender Differences in the Association of Metabolic Syndrome and LDL Cholesterol With Incident Cerebro-Cardiovascular Disease Among Koreans Without Diabetes Mellitus: A National Population-Based Study
Authors: Sung Gyun Ahn, So-Young Kim, Tae-Hwa Go, Dae-Ryong Kang, Jang Young Kim
Journal: Circulation (2019)

Introduction: Combination of LDL-C and metabolic syndrome (MetS) may have a detrimental synergistic effect on cerebro-cardiovascular disease (CCVD). We aimed to investigate sex differences in the a...
Abstract 17112: Acute Myocardial Infarction in a Young Man in the COVID-19 Era: A Case Report
Authors: Eman Rashed, Matthew Cagliostro, Mazullah Kamran
Journal: Circulation (2020)

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through ACE2 receptors, leading to coronavirus disease (COVID-19)-related pneumonia, as well as significant cardiovascular complications, such as acute myocardial infarction (AMI). There is controversy on the mechanism and management of AMI during the COVID-19 era. We describe a case of a 22 year old patient with no past medical history who presents with an acute myocardial infarction, who was found to be COVID-19 positive. Investigations: Patient’s vitals were: temperature 99.3F, blood pressure 136/99 mmHg, heart rate 80 bpm, respiratory rate 16 breaths/minute, SpO2 96% on room air. There were no abnormalities on pulmonary or cardiovascular exam. Initial laboratory testing showed elevated inflammatory markers such as ferritin, IL-6, C-reactive protein, lactate dehydrogenase, and an elevated white blood cell count with a neutrophilic predominance. LDL was normal. There was also an initial elevated troponin T. A chest radiograph was without abnormalities. EKG was notable for ST elevations in leads II, III, aVF, with depressions in leads V1, V2, V4, V5 accompanied by hyperacute T waves. Echocardiogram was notable for inferior and infero-lateral wall hypokinesis. COVID-19 PCR resulted positive. Management: Coronary angiography revealed one hundred percent stenosis of proximal left circumflex artery. The lesion was a total thrombotic occlusion with an organized thrombus. Aspiration thrombectomy was performed, and an Onyx 2.5x26 stent was placed and TIMI III flow achieved. Discussion: This is a very unique case of COVID-19 in a young patient with no co-morbidities who presented with an acute myocardial infarction. Plaque instability and rupture due to cytokine release in patients with existing atherosclerosis is a common hypothesis. It is also postulated that direct endothelial injury can occur via entry of the SARS-CoV-2 virus, with activation of the renin-angiotensin-aldosterone system causing widespread endothelial dysfunction and multiple organ injuries. This issue warrants further study, as well as discussion regarding post- intervention care in this population who are at significant thrombotic risk.