tbuckley/cabot-search huggingface dataset:
Diagnostic Accuracy of Monitoring Tests of Fellow Eyes in Patients with Unilateral Neovascular Age-Related Macular Degeneration
Authors: Sobha Sivaprasad, Katie Banister, Augusto Azuro-Blanco, Beatriz Goulao, Jonathan A. Cook, Ruth Hogg, Graham Scotland, Heinrich Heimann, Andrew Lotery, Faruque Ghanchi, Richard Gale, Geeta Menon, Louise Downey, Nicola Hopkins, Peter Scanlon, Ben Burton, Craig Ramsay, Usha Chakravarthy
Journal: Ophthalmology (2021)

To evaluate the diagnostic accuracy of routinely used tests of visual function and retinal morphology compared with fundus fluorescein angiography (FFA) to detect onset of active macular neovascularization in unaffected fellow eyes of patients with unilateral neovascular age-related macular degeneration (nAMD). Prospective diagnostic accuracy cohort study conducted in 24 eye clinics in the United Kingdom over 3 years. Older adults (>50 years) with recently diagnosed unilateral nAMD with a fellow (study) eye free of nAMD. Self-reported vision, Amsler, clinic-measured visual acuity (VA), fundus assessment, and spectral domain OCT. The reference standard is FFA. Sensitivity and specificity of the 5 index tests. Of 552 participants monitored for up to 3 years, 145 (26.3%) developed active nAMD in the study eye, of whom 120 had an FFA at detection and constituted the primary analysis cohort. Index test positives at nAMD detection in those confirmed by FFA were self-reported vision much worse (5), distortion on Amsler (33), 10-letter decrease in acuity from baseline (36), fundus examination (64), and OCT (110). Percentage index test sensitivities were: self-reported vision 4.2 (95% confidence interval [CI], 1.6-9.8); Amsler 33.7 (95% CI, 25.1-43.5); VA 30.0 (95% CI, 22.5-38.7); fundus examination 53.8 (95% CI, 44.8-62.5); and OCT 91.7 (95% CI, 85.2-95.6). All 5 index test specificities were high at 97.0 (95% CI, 94.6-98.5), 81.4 (95% CI, 76.4-85.5), 66.3 (95% CI, 61.0-71.1), 97.6 (95% CI, 95.3-98.9), and 87.8 (95% CI, 83.8-90.9), respectively. The combination of OCT with one other index test that was a secondary outcome measure increased sensitivity marginally and decreased specificity for all combinations except fundus examination. Tests of self-reported change in vision, unmasking of new distortion, measurements of acuity, and fundus checks to diagnose active nAMD performed poorly in contrast to OCT. Our findings support a change to guidelines in clinical practice to monitor for onset of nAMD.
International differences in lung cancer survival by sex, histological type and stage at diagnosis: an ICBP SURVMARK-2 Study
Authors: Marzieh Araghi, Miranda Fidler-Benaoudia, Melina Arnold, Mark Rutherford, Aude Bardot, Jacques Ferlay, Oliver Bucher, Prithwish De, Gerda Engholm, Anna Gavin, Serena Kozie, Alana Little, Bjørn Møller, Nathalie St Jacques, Hanna Tervonen, Paul Walsh, Ryan Woods, Dianne L O'Connell, David Baldwin, Mark Elwood, Sabine Siesling, Freddie Bray, Isabelle Soerjomataram
Journal: Thorax (2021)

Introduction Lung cancer has a poor prognosis that varies internationally when assessed by the two major histological subgroups (non-small cell (NSCLC) and small cell (SCLC)). Method 236 114 NSCLC and 43 167 SCLC cases diagnosed during 2010–2014 in Australia, Canada, Denmark, Ireland, New Zealand, Norway and the UK were included in the analyses. One-year and 3-year age-standardised net survival (NS) was estimated by sex, histological type, stage and country. Results One-year and 3-year NS was consistently higher for Canada and Norway, and lower for the UK, New Zealand and Ireland, irrespective of stage at diagnosis. Three-year NS for NSCLC ranged from 19.7% for the UK to 27.1% for Canada for men and was consistently higher for women (25.3% in the UK; 35.0% in Canada) partly because men were diagnosed at more advanced stages. International differences in survival for NSCLC were largest for regional stage and smallest at the advanced stage. For SCLC, 3-year NS also showed a clear female advantage with the highest being for Canada (13.8% for women; 9.1% for men) and Norway (12.8% for women; 9.7% for men). Conclusion Distribution of stage at diagnosis among lung cancer cases differed by sex, histological subtype and country, which may partly explain observed survival differences. Yet, survival differences were also observed within stages, suggesting that quality of treatment, healthcare system factors and prevalence of comorbid conditions may also influence survival. Other possible explanations include differences in data collection practice, as well as differences in histological verification, staging and coding across jurisdictions.
Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins
Authors: Jiayi Lin, Jinmei Jin, Yiwen Shen, Lijun Zhang, Gang Gong, Huiting Bian, Hongzhuan Chen, Dale G. Nagle, Ye Wu, Weidong Zhang, Xin Luan
Journal: Theranostics (2021)

Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence protein functions.The emerging targeted protein degradation (TPD) strategies exemplified by PROteolysis TArgeting Chimeras (PROTACs) are revolutionizing conventional drug discovery modality to target proteins of interest (POIs) that were categorized as "undruggable" before, however, these strategies are limited within intracellular POIs.The novel new degrader technologies such as LYsosome-TArgeting Chimaeras (LYTACs) and Antibody-based PROTACs (AbTACs) have been successfully developed to expand the scope of TPD to extracellular and membrane proteins, fulfilling huge unmet medical needs.Here, we systematically review the currently viable protein degradation strategies, emphasize that LYTACs and AbTACs turn a new avenue for the development of TPD, and highlight the potential challenges and directions in this vibrant field.
MicroRNA-185-5p inhibits hepatic gluconeogenesis and reduces fasting blood glucose levels by suppressing G6Pase
Authors: Hui Zheng, Jian Wan, Yi Shan, Xi Song, Jie Jin, Qing Su, Song Chen, Xinyuan Lu, Jialin Yang, Quanmin Li, Yuping Song, Bo Li
Journal: Theranostics (2021)

Aims/hypothesis: MicroRNAs (miRNAs) are known to contribute to many metabolic diseases, including type 2 diabetes. This study aimed to investigate the roles and molecular mechanisms of miR-185-5p in the regulation of hepatic gluconeogenesis. Methods: MicroRNA high-throughput sequencing was performed to identify differentially expressed miRNAs. High-fat diet-induced obese C57BL/6 mice and db/db mice, a genetic mouse model for diabetes, were used for examining the regulation of hepatic gluconeogenesis. Quantitative reverse transcriptase PCR and Western blotting were performed to measure the expression levels of various genes and proteins. Luciferase reporter assays were used to determine the regulatory roles of miR-185-5p on G6Pase expression. Results: Hepatic miR-185-5p expression was significantly decreased during fasting or insulin resistance. Locked nucleic acid (LNA)-mediated suppression of miR-185-5p increased blood glucose and hepatic gluconeogenesis in healthy mice. In contrast, overexpression of miR-185-5p in db/db mice alleviated blood hyperglycemia and decreased gluconeogenesis. At the molecular level, miR-185-5p directly inhibited G6Pase expression by targeting its 3'-untranslated regions. Furthermore, metformin, an anti-diabetic drug, could upregulate miR-185-5p expression to suppress G6Pase, leading to hepatic gluconeogenesis inhibition. Conclusions/interpretation: Our findings provided a novel insight into the role of miR-185-5p that suppressed hepatic gluconeogenesis and alleviated hyperglycemia by targeting G6Pase. We further identified that the /G6Pase axis mediated the inhibitory effect of metformin on hepatic gluconeogenesis. Thus, miR-185-5p might be a therapeutic target for hepatic glucose overproduction and fasting hyperglycemia.
Differential Pathophysiological Mechanisms in Heart Failure With a Reduced or Preserved Ejection Fraction in Diabetes
Authors: Milton Packer
Journal: JACC Heart Failure (2021)

Diabetes promotes the development of both heart failure with a reduced ejection fraction and heart failure with a preserved ejection fraction through diverse mechanisms, which are likely mediated through hyperinsulinemia rather than hyperglycemia. Diabetes promotes nutrient surplus signaling (through Akt and mammalian target of rapamycin complex 1) and inhibits nutrient deprivation signaling (through sirtuin-1 and its downstream effectors); this suppresses autophagy and promotes endoplasmic reticulum and oxidative stress and mitochondrial dysfunction, thereby undermining the health of diabetic cardiomyocytes. The hyperinsulinemia of diabetes may also activate sodium-hydrogen exchangers in cardiomyocytes (leading to injury and loss) and in the proximal renal tubules (leading to sodium retention). Diabetes may cause epicardial adipose tissue expansion, and the resulting secretion of proinflammatory adipocytokines onto the adjoining myocardium can lead to coronary microcirculatory dysfunction and myocardial inflammation and fibrosis. Interestingly, sodium-glucose cotransporter 2 (SGLT2) inhibitors-the only class of antidiabetic medication that reduces serious heart failure events-may act to mitigate each of these mechanisms. SGLT2 inhibitors up-regulate sirtuin-1 and its downstream effectors and autophagic flux, thus explaining the actions of these drugs to reduce oxidative stress, normalize mitochondrial structure and function, and mute proinflammatory pathways in the stressed myocardium. Inhibition of SGLT2 may also lead to a reduction in the activity of sodium-hydrogen exchangers in the kidney (leading to diuresis) and in the heart (attenuating the development of cardiac hypertrophy and systolic dysfunction). Finally, SGLT2 inhibitors reduce the mass and mute the adverse biology of epicardial adipose tissue (and reduce the secretion of leptin), thus explaining the capacity of these drugs to mitigate myocardial inflammation, microcirculatory dysfunction, and fibrosis, and improve ventricular filling dynamics. The pathophysiological mechanisms by which SGLT2 inhibitors may benefit heart failure likely differ depending on ejection fraction, but each represents interference with distinct pathways by which hyperinsulinemia may adversely affect cardiac structure and function.
The Impact of COVID-19 Pandemic on Patients with Chronic Liver Disease (CLD): Data from the Global Registry
Authors: Zobair Younossi, Yusuf Yilmaz, Mohammed El-Kassas, Ajay Duseja, Saeed Hamid, Gamal Esmat, Nahum Mendez-Sanchez, Wah-Kheong Chan, Ashwani Singal, Brian Lam, Sean Felix, Elena Younossi, Manisha Verma, Jillian Price, Fatema Nader, Issah Younossi, Andrei Racila, Maria Stepanova
Journal: Journal of Hepatology (2021)
Phase 1 Trial of ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Patients with Solid Tumors and Lymphomas Bearing Wild-type <i>TP53</i>
Authors: Mansoor N. Saleh, Manish R. Patel, Todd M. Bauer, Sanjay Goel, Gerald S. Falchook, Geoffrey I. Shapiro, Ki Y. Chung, Jeffrey R. Infante, Robert M. Conry, Guilherme Rabinowits, David S. Hong, Judy S. Wang, Ulrich Steidl, Gurudatta Naik, Vincent Guerlavais, Vojislav Vukovic, D. Allen Annis, Manuel Aivado, Funda Meric-Bernstam
Journal: Clinical Cancer Research (2021)

We describe the first-in-human dose-escalation trial for ALRN-6924, a stabilized, cell-permeating peptide that disrupts p53 inhibition by mouse double minute 2 (MDM2) and MDMX to induce cell-cycle arrest or apoptosis in TP53-wild-type (WT) tumors.Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and antitumor effects in patients with solid tumors or lymphomas. In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B was twice-weekly for 2 weeks every 21 days.Seventy-one patients were enrolled: 41 in arm A (0.16-4.4 mg/kg) and 30 in arm B (0.32-2.7 mg/kg). ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLT) were grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the MTD in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. No DLTs were observed in arm B. No G3/G4 thrombocytopenia was observed in any patient. Seven patients had infusion-related reactions; 3 discontinued treatment. In 41 efficacy-evaluable patients with TP53-WT disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, 2 had confirmed partial responses, and 20 had stable disease. Six patients were treated for >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg.ALRN-6924 was well tolerated and demonstrated antitumor activity.
Dasatinib enhances anti-leukemia efficacy of chimeric antigen receptor T cells by inhibiting cell differentiation and exhaustion
Authors: Hao Zhang, Yongxian Hu, Mi Shao, Xinyi Teng, Penglei Jiang, Xiujian Wang, Hui Wang, Jiazhen Cui, Jian Yu, Zuyu Liang, Lijuan Ding, Yingli Han, Jieping Wei, Yulin Xu, Xiaoqing Li, Wei Shan, Jimin Shi, Yi Luo, Pengxu Qian, He Huang
Journal: Journal of Hematology & Oncology (2021)

Abstract Relapses of CD19-expressing leukemia in patients who achieved initial remission after CART cell treatment have been reported to correlate with poor CART cells persistence. Sustained tonic signaling or strong activation drives CART cell differentiation and exhaustion, which limit the therapeutic efficacy and persistence of CART cells. Here, we identified dasatinib as the optimal candidate to prevent or reverse both CD28/CART and 4-1BB/CART cell differentiation and exhaustion during ex vivo expansion, which profoundly enhanced the therapeutic efficacy and in vivo persistence. Moreover, strong activation-induced CART cells differentiation, exhaustion and apoptosis driven by CD3/CD28 stimulation or antigen exposure were dramatically prevented or reversed by dasatinib treatment. Mechanistically, dasatinib markedly reduced the phosphorylation of Src and Lck, and downregulated the expression of genes involved in CAR signaling pathways, which resulted in the optimization of cell differentiation, exhaustion and apoptosis-related gene expression. Our study proposes a promising pharmacological approach for optimizing CART cells manufacture, and provides an experimental basis for reinvigorating CART cells in clinical application.
Performance evaluation of a prescription medication image classification model: an observational cohort
Authors: Corey A. Lester, Jiazhao Li, Yuting Ding, Brigid Rowell, Jessie ‘Xi’ Yang, Raed Al Kontar
Journal: npj Digital Medicine (2021)

Technology assistance of pharmacist verification tasks through the use of machine intelligence has the potential to detect dangerous and costly pharmacy dispensing errors. National Drug Codes (NDC) are unique numeric identifiers of prescription drug products for the United States Food and Drug Administration. The physical form of the medication, often tablets and capsules, captures the unique features of the NDC product to help ensure patients receive the same medication product inside their prescription bottle as is found on the label from a pharmacy. We report and evaluate using an automated check to predict the shape, color, and NDC for images showing a pile of pills inside a prescription bottle. In a test set containing 65,274 images of 345 NDC classes, overall macro-average precision was 98.5%. Patterns of incorrect NDC predictions based on similar colors, shapes, and imprints of pills were identified and recommendations to improve the model are provided.
IOM Report a Blueprint for Elimination of TB
Authors: J. Stephenson
Journal: JAMA (2000)

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Publisher Correction: Germline de novo mutation clusters arise during oocyte aging in genomic regions with high double-strand-break incidence
Authors: Jakob M. Goldmann, Vladimir B. Seplyarskiy, Wendy S. W. Wong, Thierry Vilboux, Pieter B. Neerincx, Dale L. Bodian, Benjamin D. Solomon, Joris A. Veltman, John F. Deeken, Christian Gilissen, John E. Niederhuber
Journal: Nature Genetics (2021)
The Case | Cardiac tamponade in a kidney transplant recipient with chronic inflammation
Authors: Nathalie Chavarot, Perrine Parize, Isabelle Podglajen, Rebecca Sberro-Soussan, Carole Burger, Lucile Amrouche, Frank Martinez, Christophe Legendre, Julien Zuber, Anne Scemla, Geltrude Giura, Patrick Bruneval, Dany Anglicheau
Journal: Kidney International (2021)
Adult-onset Still's disease following COVID-19 vaccination
Authors: Flavia Leone, Pier Giacomo Cerasuolo, Silvia Laura Bosello, Lucrezia Verardi, Enrica Fiori, Fabrizio Cocciolillo, Biagio Merlino, Angelo Zoli, Maria Antonietta D'Agostino
Journal: The Lancet Rheumatology (2021)
Contingency Measures During the COVID-19 Pandemic in China: An Analysis Based on a New Ethical Framework
Authors: Yuming Wang, Hui Zhang, Yongguang Yang, Zhenxiang Zhang, Zhiping Guo
Journal: The American Journal of Bioethics (2021)

This article is referred to by:Ethics Frameworks and Beyond—Advancing Our Understanding of the Contingency Phase to Improve Health Care Quality During Public Health Emergencies
Cell membrane inspired nano-shell enabling long-acting Glucose Oxidase for Melanoma starvation therapy via microneedles-based percutaneous delivery
Authors: Yang Zeng, Haiyan Zhou, Jinsong Ding, Wenhu Zhou
Journal: Theranostics (2021)

Rationale: Glucose oxidase (GOx) has gained tremendous research interest recently as a glucose-consuming enzyme for tumor starvation therapy, while its in vivo applications are strictly limited by rapid deactivation, as well as side effects of non-specific catalysis.Methods: To address these issues, here we report a protective nano-shell to encapsule GOx for localized melanoma therapy delivered by dissolving microneedles (MNs).Inspired by cell membrane that separates and protects cell organelles and components from outside environment while selectively ingesting nutrition sources, we designed polydopamine (PDA)-structured nano-shell to allow free transportation of glucose for catalytic reaction, while impede the penetration of GOx, proteinase, and other GOx-deactivating macromolecules across the shell membrane.Results: GOx was well protected in core layer with persistent catalytic activity for at least 6 d under various biological matrixes (e.g., PBS, serum, and cell lysate) and surviving different harsh conditions (e.g., acid/base treatments, and proteinase-induced degradation).Such long-acting nano-catalyst can be easily integrated into MNs as topical delivery carrier for effective glucose consumption in melanoma tissue, achieving significant tumor growth inhibition via starvation therapy with minimized side effects as compared to systemic administration. Conclusion:This work provides an elegant platform for in vivo delivery of GOx, and our cell-mimicking nano-system can also be applied for other enzyme-based therapeutics.
Traumatic brain injury and sight loss in military and veteran populations– a review
Authors: Syeda F. Hussain, Zara Raza, Andrew T. G. Cash, Thomas Zampieri, Robert A. Mazzoli, Randy H. Kardon, Renata S. M. Gomes
Journal: Military Medical Research (2021)

Abstract War and combat exposure pose great risks to the vision system. More recently, vision related deficiencies and impairments have become common with the increased use of powerful explosive devices and the subsequent rise in incidence of traumatic brain injury (TBI). Studies have looked at the effects of injury severity, aetiology of injury and the stage at which visual problems become apparent. There was little discrepancy found between the frequencies or types of visual dysfunctions across blast and non-blast related groups, however complete sight loss appeared to occur only in those who had a blast-related injury. Generally, the more severe the injury, the greater the likelihood of specific visual disturbances occurring, and a study found total sight loss to only occur in cases with greater severity. Diagnosis of mild TBI (mTBI) is challenging. Being able to identify a potential TBI via visual symptoms may offer a new avenue for diagnosis.
Comparative Use of Direct Oral Anticoagulants and Warfarin in the Treatment of Atrial Fibrillation and Venous Thromboembolism and Prophylaxis: A Retrospective Single Center Utilization Study
Authors: Linda Hoang, Josephine Pineda Dela Cruz, Stephen Farley, Julia Sessa, Jamie Chin, Rose Calixte, Alexander Hindenburg
Journal: Blood (2017)
A Randomized, Phase III Study of Lenvatinib in Chinese Patients with Radioiodine-Refractory Differentiated Thyroid Cancer
Authors: Xiangqian Zheng, Zhengang Xu, Qinghai Ji, Minghua Ge, Feng Shi, Jianwu Qin, Feng Wang, Guang Chen, Yuan Zhang, Rui Huang, Jian Tan, Tao Huang, Sijin Li, Zhongwei Lv, Yansong Lin, Zhuming Guo, Tomoki Kubota, Takuya Suzuki, Hiroki Ikezawa, Ming Gao
Journal: Clinical Cancer Research (2021)

Lenvatinib has shown efficacy in treating radioiodine-refractory differentiated thyroid cancer (RR-DTC) in the multinational phase III SELECT study; however, it has not been tested in Chinese patients with RR-DTC.
Continuous Glucose Monitoring Improves Glycemic Outcomes in Children With Type 1 Diabetes: Real-World Data From a Population-Based Clinic
Authors: Elaine E. Sanderson, Mary B. Abraham, Grant J. Smith, Jenny A. Mountain, Timothy W. Jones, Elizabeth A. Davis
Journal: Diabetes Care (2021)

Although recent clinical trials of continuous glucose monitoring (CGM) use have shown positive glycemic benefit (1,2), outcomes outside the research setting may differ and real-world studies over a long time period are limited.

In April 2017, CGM was fully subsidized in Australia for people living with type 1 diabetes (T1D) <21 years. Perth Children’s Hospital is the sole pediatric diabetes center in Western Australia and is where almost all patients <18 years of age are seen (1,192 patients in 2019). This provided unique opportunity to determine the glycemic outcomes in a state-wide population-based pediatric cohort before and after commencement of CGM in a real-world setting. The aim of this study was to investigate impact on glycemic control with commencement of subsidized CGM.

An observational longitudinal study of Western Australian children with T1D attending Perth Children’s Hospital between January 2015 and July 2019 was performed, with the following inclusion criteria: age  2 years, and at least 2 pre– and post–CGM clinic visits. Participants were using Dexcom or Medtronic CGM available through subsidy.

The primary outcome was HbA1c measured at 3-monthly clinic visits. Values up to 3 years pre– and up to 2 years post–CGM commencement were included. A multilevel piecewise growth modeling approach with maximum likelihood estimation was used for …