tbuckley/cabot-search huggingface dataset:
Aquaporin 9 induction in human iPSC‐derived hepatocytes facilitates modeling of ornithine transcarbamylase deficiency
Authors: Alexander Laemmle, Martin Poms, Bernadette Hsu, Mariia Borsuk, Véronique Rüfenacht, Joshua Robinson, Martin C. Sadowski, Jean‐Marc Nuoffer, Johannes Häberle, Holger Willenbring
Journal: Hepatology (2021)

Patient-derived human-induced pluripotent stem cells (hiPSCs) differentiated into hepatocytes (hiPSC-Heps) have facilitated the study of rare genetic liver diseases. Here, we aimed to establish an in vitro liver disease model of the urea cycle disorder ornithine transcarbamylase deficiency (OTCD) using patient-derived hiPSC-Heps.Before modeling OTCD, we addressed the question of why hiPSC-Heps generally secrete less urea than adult primary human hepatocytes (PHHs). Because hiPSC-Heps are not completely differentiated and maintain some characteristics of fetal PHHs, we compared gene-expression levels in human fetal and adult liver tissue to identify genes responsible for reduced urea secretion in hiPSC-Heps. We found lack of aquaporin 9 (AQP9) expression in fetal liver tissue as well as in hiPSC-Heps, and showed that forced expression of AQP9 in hiPSC-Heps restores urea secretion and normalizes the response to ammonia challenge by increasing ureagenesis. Furthermore, we proved functional ureagenesis by challenging AQP9-expressing hiPSC-Heps with ammonium chloride labeled with the stable isotope [15 N] (15 NH4 Cl) and by assessing enrichment of [15 N]-labeled urea. Finally, using hiPSC-Heps derived from patients with OTCD, we generated a liver disease model that recapitulates the hepatic manifestation of the human disease. Restoring OTC expression-together with AQP9-was effective in fully correcting OTC activity and normalizing ureagenesis as assessed by 15 NH4 Cl stable-isotope challenge.Our results identify a critical role for AQP9 in functional urea metabolism and establish the feasibility of in vitro modeling of OTCD with hiPSC-Heps. By facilitating studies of OTCD genotype/phenotype correlation and drug screens, our model has potential for improving the therapy of OTCD.
Lifetime burden of disease due to incident tuberculosis: a global reappraisal including post-tuberculosis sequelae
Authors: Nicolas A Menzies, Matthew Quaife, Brian W Allwood, Anthony L Byrne, Anna K Coussens, Anthony D Harries, Florian M Marx, Jamilah Meghji, Debora Pedrazzoli, Joshua A Salomon, Sedona Sweeney, Sanne C van Kampen, Robert S Wallis, Rein M G J Houben, Ted Cohen
Journal: The Lancet Global Health (2021)

Many individuals who survive tuberculosis disease face ongoing disability and elevated mortality risks. However, the impact of post-tuberculosis sequelae is generally omitted from policy analyses and disease burden estimates. We therefore estimated the global burden of tuberculosis, inclusive of post-tuberculosis morbidity and mortality.We constructed a hypothetical cohort of individuals developing tuberculosis in 2019, including pulmonary and extrapulmonary disease. We simulated lifetime health outcomes for this cohort, stratified by country, age, sex, HIV status, and treatment status. We used disability-adjusted life-years (DALYs) to summarise fatal and non-fatal health losses attributable to tuberculosis, during the disease episode and afterwards. We estimated post-tuberculosis mortality and morbidity based on the decreased lung function caused by pulmonary tuberculosis disease.Globally, we estimated 122 (95% uncertainty interval [UI] 98-151) million DALYs due to incident tuberculosis disease in 2019, with 58 (38-83) million DALYs attributed to post-tuberculosis sequelae, representing 47% (95% UI 37-57) of the total burden estimate. The increase in burden from post-tuberculosis varied substantially across countries and regions, driven largely by differences in estimated case fatality for the disease episode. We estimated 12·1 DALYs (95% UI 10·0-14·9) per incident tuberculosis case, of which 6·3 DALYs (5·6-7·0) were from the disease episode and 5·8 DALYs (3·8-8·3) were from post-tuberculosis. Per-case post-tuberculosis burden estimates were greater for younger individuals, and in countries with high incidence rates. The burden of post-tuberculosis was spread over the remaining lifetime of tuberculosis survivors, with almost a third of total DALYs (28%, 95% UI 23-34) accruing 15 or more years after incident tuberculosis.Post-tuberculosis sequelae add substantially to the overall disease burden caused by tuberculosis. This hitherto unquantified burden has been omitted from most previous policy analyses. Future policy analyses and burden estimates should take better account of post-tuberculosis, to avoid the potential misallocation of funding, political attention, and research effort resulting from continued neglect of this issue.National Institutes of Health.
Development and Testing of a Lymphoma Clinical Trials Specific Frailty Index: A Secondary Analysis of the LY.12 Clinical Trial
Authors: Abi Vijenthira, Xinzhi Li, Michael Crump, Annette E. Hay, Lois E. Shepherd, Ralph Meyer, Marina S. Djurfeldt, Bingshu E. Chen, Anca Prica
Journal: Blood (2021)
Expanding the Repertoire of Electrospinning: New and Emerging Biopolymers, Techniques, and Applications
Authors: Liszt Y. C. Madruga, Matt J. Kipper
Journal: Advanced Healthcare Materials (2021)

Abstract Electrospinning has emerged as a versatile and accessible technology for fabricating polymer fibers, particularly for biological applications. Natural polymers or biopolymers (including synthetically derivatized natural polymers) represent a promising alternative to synthetic polymers, as materials for electrospinning. Many biopolymers are obtained from abundant renewable sources, are biodegradable, and possess inherent biological functions. This review surveys recent literature reporting new fibers produced from emerging biopolymers, highlighting recent developments in the use of sulfated polymers (including carrageenans and glycosaminoglycans), tannin derivatives (condensed and hydrolyzed tannins, tannic acid), modified collagen, and extracellular matrix extracts. The proposed advantages of these biopolymer‐based fibers, focusing on their biomedical applications, are also discussed to highlight the use of new and emerging biopolymers (or new modifications to well‐established ones) to enhance or achieve new properties for electrospun fiber materials.
Exercise in Octogenarians: How Much Is Too Little?
Authors: Graeme Carrick-Ranson, Erin J. Howden, Benjamin D. Levine
Journal: Annual Review of Medicine (2021)

The global population is rapidly aging, with predictions of many more people living beyond 85 years. Age-related physiological adaptations predispose to decrements in physical function and functional capacity, the rate of which can be accelerated by chronic disease and prolonged physical inactivity. Decrements in physical function exacerbate the risk of chronic disease, disability, dependency, and frailty with advancing age. Regular exercise positively influences health status, physical function, and disease risk in adults of all ages. Herein, we review the role of structured exercise training in the oldest old on cardiorespiratory fitness and muscular strength and power, attributes critical for physical function, mobility, and independent living.
High Bacterial Abundances of <i>Dorea</i> and <i>Pediococcus</i> in the Gut Microbiome Linked to Expansion, Immune Checkpoint Expression and Efficacy of CD19-Directed CAR T-Cells in Patients with r/r DLBCL
Authors: Viktoria Blumenberg, Galina Busch, Stephan Baumann, Sabine Schmidt, Hanna Schuhmacher, Michael Winkelmann, Friederike Hildebrandt, Kai Rejeski, Franziska J Vettermann, MD, Wolfgang G. Kunz, Michael von Bergwelt, Veit Buecklein, Christoph Stein-Thöringer, Marion Subklewe
Journal: Blood (2021)
Sustained safety and efficacy of ligelizumab in patients with chronic spontaneous urticaria: A one‐year extension study
Authors: Marcus Maurer, Ana Giménez‐Arnau, Jonathan A. Bernstein, Chia‐Yu Chu, Inna Danilycheva, Michihiro Hide, Michael Makris, Martin Metz, Sinisa Savic, Karl Sitz, Weily Soong, Petra Staubach, Gordon Sussman, Avantika Barve, Alis Burciu, Eva Hua, Reinhold Janocha, Thomas Severin
Journal: Allergy (2021)

Ligelizumab, a next-generation, humanized anti-immunoglobulin E (IgE) monoclonal antibody is in development as a treatment for patients with chronic spontaneous urticaria, whose symptoms are inadequately controlled with standard-of-care therapy.To evaluate the long-term safety and re-treatment efficacy of ligelizumab 240 mg in patients who completed the core study and extension study.This open-label, single-arm, long-term Phase 2b extension study was designed to assess patients who were previously administered various doses of ligelizumab, omalizumab or placebo in the Phase 2b, dose-finding core study and who presented with active disease after Week 32. In the extension study, patients received ligelizumab 240 mg subcutaneously every 4 weeks, for 52 weeks and were monitored post-treatment for 48 weeks.Overall, ligelizumab was well-tolerated with no newly identified safety signals. A total of 95.4% (226/237) screened patients received ligelizumab 240 mg in the extension study; 84.1% (190/226) of patients experienced at least one treatment-emergent adverse event. Most reported events were mild (41.6%) or moderate (35.8%) and mostly unrelated to the study treatment. At Week 12, 46.5% of patients had a complete response increasing to 53.1% after 52 weeks. Following 52 weeks of extension study treatment, 75.8% (95% confidence interval, 69.9, 81.3) of patients had cumulative complete responses. The median time to relapse in complete responders was 38 weeks.The long-term safety profile of ligelizumab 240 mg in patients with chronic spontaneous urticaria was consistent with the core study and re-treatment efficacy was shown.ClinicalTrials.gov Identifier: NCT02477332 and NCT02649218.
Abstract 9464: Left Ventricular Ejection Fraction Trajectory Predicts Outcomes in Patients With Heart Failure and Mildly Reduced Ejection Fraction
Authors: Robert J Miller, Majid Nabipoor, Erik Youngson, Gynter Kotrri, Nowell Fine, Jonathan G Howlett, Ian Paterson, Justin Ezekowitz, McAlister Finlay
Journal: Circulation (2021)

Introduction: Heart failure and mildly reduced ejection fraction (HFmrEF) is associated with a favourable prognosis compared heart failure with reduced EF. However, HFmrEF may be a transitory state and serial imaging might clarify if these patients demonstrate an increasing, decreasing or stable EF. Hypothesis: LVEF trajectory can identify sub-groups of patients with HFmrEF with different prognosis. Materials and Methods: Patients with a diagnosis of HF and at least two echocardiograms performed ≥6 months apart were included if the LVEF measured 40-49% on the second study. They were classified based on change from their first echocardiogram as: a) HFmrEF-Incr if LVEF had increased ≥ 10% (n=450), b) HFmrEF-Dec if LVEF had decreased ≥10% (n=512), or c) HFmrEF-stable if they did not meet the other criteria (n=389). The primary outcome was a composite of all-cause mortality or cardiovascular hospitalization (ACM/CVH). Associations with time to first event were assessed with multivariable Cox analyses adjusted for age, medical history, and medications. Results: In total, 1351 patients with HFmrEF were included (median age 74, 35.8% women). During a median follow-up of 15.3 months, ACM/CVH occurred in 811 patients (324 ACM, 487 CVH). HFmrEF-Incr was associated with a lower incidence of ACM/CVH compared to patients with HFmrEF-Stable (adjusted HR 0.72, 95% CI 0.59 - 0.87, p&lt;0.001). Patients with HFmrEF-Dec were more likely to experience the composite outcome in unadjusted analyses (unadjusted HR 1.19, p=0.040) but not adjusted analyses (adjusted HR 1.13, 95% CI 0.96 - 1.34, p=0.140). Conclusions: Patients with HFmrEF and positive trajectory of LVEF were less likely to experience adverse outcomes, while those with a negative LVEF trajectory demonstrated a trend to higher risk. Categories based on LVEF trajectory provide clinically meaningful information and may help physicians make decisions regarding the need to pursue more aggressive medical therapy and surveillance.
Histone H3K27 Methylation Perturbs Transcriptional Robustness and Underpins Dispensability of Highly Conserved Genes in Fungi
Authors: Sabina Moser Tralamazza, Leen Nanchira Abraham, Claudia Sarai Reyes-Avila, Benedito Corrêa, Daniel Croll
Journal: Molecular Biology and Evolution (2021)

Epigenetic modifications are key regulators of gene expression and underpin genome integrity. Yet, how epigenetic changes affect the evolution and transcriptional robustness of genes remains largely unknown. Here, we show how the repressive histone mark H3K27me3 underpins the trajectory of highly conserved genes in fungi. We first performed transcriptomic profiling on closely related species of the plant pathogen Fusarium graminearum species complex. We determined transcriptional responsiveness of genes across environmental conditions to determine expression robustness. To infer evolutionary conservation, we used a framework of 23 species across the Fusarium genus including three species covered with histone methylation data. Gene expression variation is negatively correlated with gene conservation confirming that highly conserved genes show higher expression robustness. In contrast, genes marked by H3K27me3 do not show such associations. Furthermore, highly conserved genes marked by H3K27me3 encode smaller proteins, exhibit weaker codon usage bias, higher levels of hydrophobicity, show lower intrinsically disordered regions, and are enriched for functions related to regulation and membrane transport. The evolutionary age of conserved genes with H3K27me3 histone marks falls typically within the origins of the Fusarium genus. We show that highly conserved genes marked by H3K27me3 are more likely to be dispensable for survival during host infection. Lastly, we show that conserved genes exposed to repressive H3K27me3 marks across distantly related Fusarium fungi are associated with transcriptional perturbation at the microevolutionary scale. In conclusion, we show how repressive histone marks are entangled in the evolutionary fate of highly conserved genes across evolutionary timescales.
Abstract 14064: Echocardiographic Parameters Predicting Left Ventricular Ejection Fraction Improvement Following Transcatheter Aortic Valve Replacement
Authors: Muhammad R Uqaily, Pratik Agrawal, Matthew Shotwell, Yasmin Hamirani, Ramesh Daggubati, IRFAN ZEB
Journal: Circulation (2021)

Introduction: There is limited data available in terms of identifying echocardiographic parameters predicting improvement in left ventricular ejection fraction (LVEF) following a transcatheter aortic valve replacement (TAVR). Additionally, association of baseline cardiac disease burden with normal post-TAVR LVEF is poorly understood. Hypothesis: Higher baseline cardiac disease burden is associated with lower rates of normal post-TAVR LVEF. Methods: We retrospectively studied 352 consecutive patients who underwent TAVR at our institute, and who had 30-day follow-up data available. The patients were divided into two groups: pre-TAVR LVEF &lt; 50% and ≥ 50%. We defined improvement in LVEF as a binary variable by studying for absolute improvement of +5% in LVEF on the 30-day post-TAVR echocardiogram. Furthermore, baseline cardiac disease burden was defined as a composite ordinal score of LVEF, severity of mitral regurgitation, mitral stenosis, coronary artery disease, tricuspid regurgitation, and pulmonary hypertension. Results: There was a significant difference in improvement of LVEF between the two pre-TAVR LVEF groups &lt; 50% versus ≥ 50% (67% vs. 31%, p &lt; 0.0001). On multivariate logistic regression analysis of pre-TAVR echocardiographic parameters, clinical variables and TAVR valve-related variables, only aortic valve (AV) area index (r = 3.86, p = 0.004), LV end-diastolic dimension (r = -0.74, p = 0.005), aortic regurgitation severity (r = 1.10, p = 0.010) and 29-mm valve size (r = -1.09, p = 0.021) were significant in predicting improvement in LVEF post-TAVR. LVEF was a weak predictor on multivariate logistic regression model (r = -0.11, p &lt; 0.0001). Furthermore, patients with a higher baseline cardiac disease burden (defined as ≥ median composite score of 7) were significantly associated with lower rates of post-TAVR LVEF ≥ 50% (OR = 5.22 [2.49 - 10.96]; p &lt; 0.0001). Conclusions: Higher baseline cardiac disease burden is significantly associated with lower rates of post-TAVR LVEF ≥ 50%. Additionally, specific echocardiographic parameters can predict improvement in LVEF following TAVR.
Enhancing cancer chemo-immunotherapy by biomimetic nanogel with tumor targeting capacity and rapid drug-releasing in tumor microenvironment
Authors: Lihuan Shang, Xue Jiang, Ting Yang, Hongbo Xu, Qi Xie, Mei Hu, Conglian Yang, Li Kong, Zhiping Zhang
Journal: Acta Pharmaceutica Sinica B (2021)

In the development of chemo-immunotherapy, many efforts have been focusing on designing suitable carriers to realize the co-delivery of chemotherapeutic and immunotherapeutic with different physicochemical properties and mechanisms of action. Besides, rapid drug release at the tumor site with minimal drug degradation is also essential to facilitate the antitumor effect in a short time. Here, we reported a cancer cell membrane-coated pH-responsive nanogel (NG@M) to co-deliver chemotherapeutic paclitaxel (PTX) and immunotherapeutic agent interleukin-2 (IL-2) under mild conditions for combinational treatment of triple-negative breast cancer. In the designed nanogels, the synthetic copolymer PDEA-co-HP-β-cyclodextrin-co-Pluronic F127 and charge reversible polymer dimethylmaleic anhydride-modified polyethyleneimine endowed nanogels with excellent drug-loading capacity and rapid responsive drug-releasing behavior under acidic tumor microenvironment. Benefited from tumor homologous targeting capacity, NG@M exhibited 4.59-fold higher accumulation at the homologous tumor site than heterologous cancer cell membrane-coated NG. Rapidly released PTX and IL-2 enhanced the maturation of dendritic cells and quickly activated the antitumor immune response in situ, followed by prompted infiltration of immune effector cells. By the combined chemo-immunotherapy, enhanced antitumor effect and efficient pulmonary metastasis inhibition were achieved with a prolonged median survival rate (39 days).
Correction to: Randomized phase 2 trial of pevonedistat plus azacitidine versus azacitidine for higher-risk MDS/CMML or low-blast AML
Authors: Mikkael A. Sekeres, Justin Watts, Atanas Radinoff, Montserrat Arnan Sangerman, Marco Cerrano, Patricia Font Lopez, Joshua F. Zeidner, Maria Diez Campelo, Carlos Graux, Jane Liesveld, Dominik Selleslag, Nikolay Tzvetkov, Robert J. Fram, Dan Zhao, Jill Bell, Sharon Friedlander, Douglas V. Faller, Lionel Adès
Journal: Leukemia (2021)
Incidence and Risk Factors Associated with Fatal Graft Vs Host Disease after Solid Organ Transplantation in United Network of Organ Transplant Database
Authors: Pavan Tenneti, Jiaxian He, Peter Lalli, Pranav Tenneti, Michael R. Grunwald, Edward A. Copelan, Belinda Avalos, Srinivasa Reddy R. Sanikommu
Journal: Blood (2021)
Pillar[5]arene‐Based Acid‐Triggered Supramolecular Porphyrin Photosensitizer for Combating Bacterial Infections and Biofilm Dispersion
Authors: Lei Xia, Jia Tian, Tao Yue, Hongliang Cao, Ju Chu, Haibo Cai, Weian Zhang
Journal: Advanced Healthcare Materials (2021)

Abstract The treatment of pathogenic bacterial infection has long been the most serious threat to human life and attracted widespread attention. Herein, a supramolecular photosensitizer platform based on carboxylatopillar[5]arene ( CP5 ) and tetrafluorophenyl porphyrin functionalized with a quaternary ammonium group ( TFPP‐QA ) for combating bacteria and dispersing biofilm via photodynamic treatment is constructed. By introducing the host macrocycle CP5 and host–guest interaction, the supramolecular photosensitizer has great biocompatibility and acid responsiveness. On the one hand, the acid‐triggered dissociation of TFPP‐QA/CP5 could induce the porphyrin photosensitizer to target bacterial cells and disrupt the charge balance of bacterial membranes, enhance the permeability of the bacterial membrane. On the other hand, the TFPP‐QA/CP5 antibacterial platform possesses superb reactive oxygen species (ROS) generation capability under light irradiation, leading to enhanced photodynamic antibacterial efficacy. The in vitro and in vivo studies show that the supramolecular photosensitizers exhibit high antibacterial efficiency and biofilm dissipation effect under 660 nm light irradiation. Therefore, it is anticipated that the rational design and integration of photosensitizers and quaternary ammonium compounds through the supramolecular strategy would provide a promising prospect for clinical photodynamic antimicrobial therapy.
Abstract 9175: Clinical Significance of Resting Heart Rate on Exercise Capacity and Prognosis: Comparison Among Heart Failure Patients with Reduced, Preserved and Mid-Range Ejection Fraction
Authors: Takamasa Sato, Akiomi Yoshihisa, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2021)

Introduction: Resting heart rate (rHR) has a big influence on clinical outcomes and exercise capacity in patients with chronic heart failure (CHF). However, the association of rHR with exercise capacity and prognosis has not been fully elucidated in patients with heart failure with reduced, preserved and mid-range ejection fraction (HFrEF, HFpEF and HFmrEF). Aims: We aimed to determine the differences in the association of rHR with exercise capacity and prognosis in patients with HFrEF, HFpEF and HFmrEF. Methods: 877 CHF patients with sinus rhythm (SR) were divided into four groups according to rHR (G1: rHR &lt; 60 /min, G2: 60&lt;rHR &lt; 70 /min, G3: 70&lt;rHR &lt; 80 /min and G4: rHR&lt;80 /min) in HFrEF, HFpEF and HFmrEF, respectively. We compared the parameters of cardiopulmonary exercise testing and adverse cardiac event rates (cardiac death and re-hospitalizations for worsening heart failure) among HFrEF, HFpEF and HFmrEF. Results: Of 877 CHF patients, 388 were in HFrEF, 360 in HFpEF and 179 in HFmrEF. Patients with HFrEF were the youngest among three groups. Patients with HFrEF had the highest plasma BNP level and the lowest estimated glomerular filtration rate, followed by those with HFmrEF and HFpEF. Patients with HFrEF had the lowest peak oxygen consumption (PVO 2 ) , heart rate reserve (HRR: [peak HR-rHR] / [predicted max HR-rHR]) and oxygen uptake efficiency slope (OUES) , and the highest minute ventilation and carbon dioxide production (VE/VCO 2 ) slope, followed by those with HFmrEF and HFpEF. In HFrEF, patients with rHR from 70 to 80 /min had the highest PVO 2 and HRR and the lowest VE/VCO 2 slope. On the other hands, as rHR increased, adverse cardiac event rates increased. In HFpEF, patients with rHR less than 60 had the lowest PVO 2 , HRR and OUES, and the highest VE/VCO 2 slope and adverse cardiac event rates. In HFmrEF, patients with rHR less than 60 had the lowest PVO 2 , HRR and OUES and the highest VE/VCO 2 slope. In contrast, adverse cardiac event rate was not significant different in relation to rHR. Conclusions: rHR was associated with exercise capacity and clinical outcomes in patients with CHF and SR. However, influence of rHR on exercise capacity and adverse clinical outcomes were different among HFrEF, HFpEF and HFmrEF.
Single Cell Analysis Elucidates the Maturation of Human Stem and Progenitor Cell Function from Fetal through Adult Hematopoiesis
Authors: Hojun Li, Jideofor Ezike, Anton Afanassiev, Laura Greenstreet, Stephen Zhang, Jennifer S. Whangbo, Vincent Butty, Enrico Moiso, Guinevere Connelly, Vivian Morris, Dahai Wang, George Q. Daley, Salil Garg, Stella T. Chou, Aviv Regev, Edroaldo Lummertz da Rocha, Geoffrey Schiebinger, R. Grant Rowe
Journal: Blood (2021)