tbuckley/cabot-search huggingface dataset:
A Glycemic Threshold Above Which the Improvement of β-Cell Function and Glycemia in Response to Insulin Therapy Is Amplified in Early Type 2 Diabetes: The Reversal of Glucotoxicity
Authors: Ravi Retnakaran, Jiajie Pu, Chang Ye, Alexandra Emery, Stewart B. Harris, Sonja M. Reichert, Hertzel C. Gerstein, Natalia McInnes, Caroline K. Kramer, Bernard Zinman
Journal: Diabetes Care (2024)

OBJECTIVE Alleviation of unrecognized glucotoxicity, with resultant recovery of β-cell function, could amplify the glucose-lowering effect of pharmacotherapy and contribute to the variable therapeutic response observed among patients with type 2 diabetes (T2D). However, clinical evidence supporting this concept is lacking. Short-term intensive insulin therapy (IIT) can ameliorate glucotoxicity and improve β-cell function in early T2D. Thus, for evidence of recovery of glucotoxicity-associated β-cell dysfunction, we sought to determine whether there exists a baseline fasting glucose threshold above which the post-IIT improvement in both β-cell function and glycemia is amplified. RESEARCH DESIGN AND METHODS IIT (glargine, lispro) was administered for 3 weeks to 108 adults with T2D (mean duration 1.8 ± 1.4 years). Oral glucose tolerance tests before and after IIT enabled assessment of β-cell function by Insulin Secretion-Sensitivity Index-2 and insulinogenic index/HOMA-insulin resistance. For each level of baseline fasting glycemia from 6.0 to 10.5 mmol/L, we modeled the difference in IIT-induced percentage change in β-cell function between those at/above the indicated glucose level and those below it. RESULTS The relationship between baseline fasting glucose and the differential change in β-cell function was nonlinear. Instead, this relationship was best fit by a cubic regression model with inflection (amplification) at fasting glucose at 9.3 mmol/L. Moreover, baseline fasting glucose at 9.3 mmol/L also identified the inflection point at which nonlinear reductions in fasting glucose and 2-h glucose, respectively, were both amplified. CONCLUSIONS The respective improvements in β-cell function and glycemia in response to short-term IIT are amplified in those in whom baseline fasting glucose exceeds a defined threshold, consistent with reversal of glucotoxicity.
Family History of Diabetes and Clinical Characteristics in Children at Diagnosis of Type 1 Diabetes—A Swedish Population-Based Study
Authors: Emma Hedlund, Jasaman Tojjar, Lisa Lilja, Helena Elding Larsson, Gun Forsander, Johnny Ludvigsson, Claude Marcus, Fredrik Norström, Martina Persson, Annelie Carlsson
Journal: Diabetes Care (2024)

To compare the prevalence of parental diabetes between children with and without type 1 diabetes (T1D), and to compare clinical characteristics at diagnosis of T1D in children with, versus without, a family history of diabetes.
Long-term autonomy, professional activities, cognition, and overall survival after awake functional-based surgery in patients with IDH-mutant grade 2 gliomas: a retrospective cohort study
Authors: Sam Ng, Valérie Rigau, Sylvie Moritz-Gasser, Catherine Gozé, Amélie Darlix, Guillaume Herbet, Hugues Duffau
Journal: The Lancet Regional Health - Europe (2024)
Cardiac Localized Polycystin-2 in the Natriuretic Peptide Signaling Pathway and Hypertension
Authors: Karla M. Márquez-Nogueras, Brandon Elliott, Paula Thuo, Elisabeth DiNello, Ryne M. Knutila, Geena E. Fritzmann, Virdjinija Vuchkovska, Sarah Flury, Monte Willis, Arlene B. Chapman, Quan Cao, David Y. Barefield, Ivana Y. Kuo
Journal: Journal of the American Society of Nephrology (2024)

Key Points Cardiac localized polycystin facilitates natriuretic peptide signaling pathways. Hypertension associated with autosomal dominant polycystic kidney disease may arise from impaired cardiac natriuretic peptide signaling. Background Hypertension is seen in 70% of patients with autosomal dominant polycystic kidney disease by age of 30 years before decline in kidney function. However, cardiac origins of hypertension, such as the natriuretic peptide signaling pathway, have not been fully investigated. We hypothesized that cardiomyocyte localized polycystin proteins contribute to production of natriuretic peptides, and loss of this pathway would contribute to hypertension. Methods Telemetry, echocardiography, and a molecular analysis of the natriuretic peptide pathway from left ventricular tissue of cardiomyocyte specific knockout models of polycystin-2 (cPC2-KO) mice and Cre control littermates were conducted. Complementary studies were conducted in ex vivo murine hearts, engineered heart tissue with human iPSCs driven into cardiomyocytes with CRISPR/Cas9 knockout of PKD2 and in in vitro cell lines. Results cPC2-KO mice demonstrated diurnal hypertension. Circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide were unchanged between cPC2-KO and Cre mice. Analysis of the pathways involved in production, maturation, and activity of natriuretic peptides identified decreased transcription of chromogranin B, PCSK6, NPR1, and NFAT genes in cPC2-KOs. Human iPSC-derived cardiomyocytes with PC2-KO failed to produce ANP. Re-expression of polycystin-2 in a myoblast cell line, but not pathogenic forms of polycystin-2, restored ANP production. Conclusions Natriuretic peptide production required cardiac localized polycystin-2, and loss of this pathway may contribute to the development of hypertension in autosomal dominant polycystic kidney disease.
Production of Acetylcholine by Podocytes and its Protection from Kidney Injury in Glomerulonephritis
Authors: Luan D. Truong, Jessica Trostel, Carlos Roncal, Gabriel Cara-Fuentes, Makoto Miyazaki, Shinobu Miyazaki-Anzai, Ana Andres-Hernando, Fumihiko Sasai, Miguel Lanaspa, Richard J. Johnson, Gabriela E. Garcia
Journal: Journal of the American Society of Nephrology (2024)

Background: One of the most important factors modulating endothelial health is acetylcholine, and while it is associated as a cholinergic neurotransmitter; it is also expressed by non-neuronal cells. However, its role in the kidney, which does not receive cholinergic innervation, remains unknown. Methods: To determine if acetylcholine is produced in the kidney, we used ChAT(BAC)-eGFP (ChAT mice) transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed under the control of the endogenous choline acetyltransferase (ChAT) transcriptional regulatory elements. We then investigated the role of acetylcholine in kidney disease by inducing anti- glomerular basement membrane glomerulonephritis (anti-GBM GN) in ChAT transgenic mice. Results: We demonstrate ChAT, the sole enzyme responsible for acetylcholine production, was expressed in glomerular podocytes and produced acetylcholine. We also show during anti-GBM GN in ChAT transgenic mice, ChAT expression was induced in the glomeruli, mainly in podocytes and protects mice from kidney injury with marked reduction of glomerular proliferation/fibrinoid necrosis (by 71%) crescent formation (by 98%), and tubular injury (by 78%). In contrast, specific knockout of podocyte ChAT worsened the severity of the disease. The mechanism of protection included reduction of inflammation, attenuation of angiogenic factors reduction, and increase of eNOS expression. In vitro and in vivo studies demonstrated available drugs like cholinesterase inhibitors and ChAT inducers increased the expression of podocyte-ChAT and acetylcholine production. Conclusions: These findings suggest de novo synthesis of acetylcholine by podocytes protected against inflammation and glomerular endothelium damage in anti-GBM glomerulonephritis.
AI-Safe-C Score: Assessing Liver-Related Event Risks in Non-Cirrhotic Patients after Successful Direct-Acting Antiviral Treatment
Authors: Huapeng Lin, Terry Cheuk-Fung Yip, Hye Won Lee, Xiangjun Meng, Jimmy Che-To Lai, Sang Hoon Ahn, Wenjing Pang, Grace Lai-Hung Wong, Lingfeng Zeng, Vincent Wai-Sun Wong, Victor de Lédinghen, Seung Up Kim
Journal: Journal of Hepatology (2024)
Gastrointestinal adverse events associated with use of biologic therapies available for psoriasis: a systematic review of pharmacovigilance studies
Authors: Siddhartha Sood, Nawar Tarafdar, Jonah Perlmutter, Khalad Maliyar, Muskaan Sachdeva, Asfandyar Mufti, Jensen Yeung
Journal: Journal of the American Academy of Dermatology (2024)
Clinical and Molecular Analysis of Longitudinal Rhinitis Phenotypes in an Urban Birth Cohort
Authors: Sima K Ramratnam, Molly Johnson, Cynthia M Visness, Agustin Calatroni, Mathew C Altman, Tomasz Janczyk, Kathryn E McCauley, Claire Schachtschneider, Kei E Fujimura, Douglas W Fadrosh, Susan V Lynch, Leonard B Bacharier, George T O'Connor, Megan T Sandel, Meyer Kattan, Robert A Wood, Peter J Gergen, Daniel J Jackson, Alkis Togias, James E Gern
Journal: Journal of Allergy and Clinical Immunology (2024)
How Dermatologic Surgeons Decide to Proceed with Surgery for Nonmelanoma Skin Cancer When Site Identification is Initially Uncertain: A Nationwide, Multicenter, Prospective Study
Authors: Areeba Ahmed, Amanda Maisel-Campbell, Victoria J Shi, Eric Koza, Melissa Ma, Misha Haq, Umer Nadir, Michael D Yi, Loma Dave, Farhana Ikmal Hisham, Katherine A Lin, Sarah A Ibrahim, Bianca Y Kang, McKenzie A Dirr, Juliet L Aylward, Omar Bari, Hamza Bhatti, Diana Bolotin, Basil S Cherpelis, Joel L Cohen, Sean Condon, Sheila Farhang, Bahar Firoz, Algin B Garrett, Roy G Geronemus, Nicholas J Golda, Dyann Helming, Tatyana R Humphreys, Eva A Hurst, Oren H Jacobson, S Brian Jiang, Pritesh S Karia, Arash Kimyai-Asadi, David J Kouba, M Laurin Council, Marilyn Le, Deborah F MacFarlane, Ian A Maher, Stanley J Miller, Eduardo K Moioli, Meghan Morrow, Julia Neckman, Timothy Pearson, Samuel R Peterson, Christine Poblete-Lopez, Chad L Prather, Jennifer S Ranario, Ashley G Rubin, Chrysalyne D Schmults, Andrew M Swanson, Christopher Urban, Y Gloria Xu, Ross Pearlman, Simon Yoo, Vishnu Harikumar, Alexandra Weil, Matthew Schaeffer, Sanjana Iyengar, Emily Poon, Brian A Cahn, Murad Alam
Journal: Journal of the American Academy of Dermatology (2024)
Conversion of vaccines from low to high immunogenicity by antibodies with epitope complementarity
Authors: Alexandra R Dvorscek, Craig I McKenzie, Vera C Stäheli, Zhoujie Ding, Jacqueline White, Stewart A Fabb, Leonard Lim, Kristy O'Donnell, Catherine Pitt, Daniel Christ, Danika L Hill, Colin W Pouton, Deborah L Burnett, Robert Brink, Marcus J Robinson, David M Tarlinton, Isaak Quast
Journal: Immunity (2024)
Diversity in Recombination Hotspot Characteristics and Gene Structure Shape Fine-Scale Recombination Patterns in Plant Genomes
Authors: Thomas Brazier, Sylvain Glémin
Journal: Molecular Biology and Evolution (2024)

During the meiosis of many eukaryote species, crossovers tend to occur within narrow regions called recombination hotspots. In plants, it is generally thought that gene regulatory sequences, especially promoters and 5' to 3' untranslated regions, are enriched in hotspots, but this has been characterized in a handful of species only. We also lack a clear description of fine-scale variation in recombination rates within genic regions and little is known about hotspot position and intensity in plants. To address this question, we constructed fine-scale recombination maps from genetic polymorphism data and inferred recombination hotspots in 11 plant species. We detected gradients of recombination in genic regions in most species, yet gradients varied in intensity and shape depending on specific hotspot locations and gene structure. To further characterize recombination gradients, we decomposed them according to gene structure by rank and number of exons. We generalized the previously observed pattern that recombination hotspots are organized around the boundaries of coding sequences, especially 5' promoters. However, our results also provided new insight into the relative importance of the 3' end of genes in some species and the possible location of hotspots away from genic regions in some species. Variation among species seemed driven more by hotspot location among and within genes than by differences in size or intensity among species. Our results shed light on the variation in recombination rates at a very fine scale, revealing the diversity and complexity of genic recombination gradients emerging from the interaction between hotspot location and gene structure.
<b>Neuroactive Kynurenines as Pharmacological Targets: New Experimental Tools and Exciting Therapeutic Opportunities</b>
Authors: Ana Pocivavsek, Robert Schwarcz, Sophie Erhardt
Journal: Pharmacological Reviews (2024)

Both preclinical and clinical studies implicate functional impairments of several neuroactive metabolites of the kynurenine pathway (KP), the major degradative cascade of the essential amino acid tryptophan in mammals, in the pathophysiology of neurologic and psychiatric diseases. A number of KP enzymes, such as tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenases (IDO1 and IDO2), kynurenine aminotransferases (KATs), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3-HAO), and quinolinic acid phosphoribosyltransferase (QPRT), control brain KP metabolism in health and disease and are therefore increasingly considered to be promising targets for the treatment of disorders of the nervous system. Understanding the distribution, cellular expression, and regulation of KP enzymes and KP metabolites in the brain is therefore critical for the conceptualization and implementation of successful therapeutic strategies. SIGNIFICANCE STATEMENT: Studies have implicated the kynurenine pathway of tryptophan in the pathophysiology of neurologic and psychiatric diseases. Key enzymes of the kynurenine pathway regulate brain metabolism in both health and disease, making them promising targets for treating these disorders. Therefore, understanding the distribution, cellular expression, and regulation of these enzymes and metabolites in the brain is critical for developing effective therapeutic strategies. This review endeavors to describe these processes in detail.
Faecal intestinal permeability and intestinal inflammatory markers in older adults with age-related disorders: a systematic review and meta-analysis
Authors: Nurul Izzati Ahmad Fadzuli, Siong Meng Lim, Chin Fen Neoh, Abu Bakar Abdul Majeed, Maw Pin Tan, Hui Min Khor, Ai Huey Tan, Kalavathy Ramasamy
Journal: Ageing Research Reviews (2024)
Epidemiological associations between periodontitis and cancer
Authors: Jon Higham, Frank A. Scannapieco
Journal: Periodontology 2000 (2024)

Abstract There is a postulated association of periodontitis with a number of human cancers. This narrative review provides current epidemiological evidence on the association between periodontitis and cancer. A PubMed search with the relevant keywords (periodontal disease, periodontitis, cancer, and malignancy) was completed to identify relevent articles. We present a narrative review on the association between periodontal disease and a range of cancers, including oral cancer, stomach and esophageal cancer, colorectal cancer, lung cancer, pancreatic cancer, prostate cancer, hematological malignancies, liver cancer, breast cancer, and ovarian cancer. While there is a considerable body of epidemiological evidence that supports the association between periodontal disease and cancer, this is largely from cohort and case–control studies and the association may therefore be circumstantial as little evidence exists in the form of treatment trials that would validate the role of periodontal disease in the process of cancer initiation and development.
Physical, cognitive, and social triggers of symptom fluctuations in people living with long COVID: an intensive longitudinal cohort study
Authors: Darren C Greenwood, Maedeh Mansoubi, Nawar D Bakerly, Aishwarya Bhatia, Johnny Collett, Helen E Davies, Joanna Dawes, Brendan Delaney, Leisle Ezekiel, Phaedra Leveridge, Ghazala Mir, Willie Muhlhausen, Clare Rayner, Flo Read, Janet T Scott, Manoj Sivan, Ian Tucker-Bell, Himanshu Vashisht, Tomás Ward, Daryl B O'Connor, Helen Dawes
Journal: The Lancet Regional Health - Europe (2024)
Optimizing Adoptive Cell Therapy for Solid Tumors via Epigenetic Regulation of T‐cell Destiny
Authors: Xuemeng Guo, Xiang Li, Sijie Wang, Yingying Shi, Jiaxin Huang, Xu Liu, Yichao Lu, Junlei Zhang, Lihua Luo, Jian You
Journal: Advanced Healthcare Materials (2024)

Abstract Adoptive cell therapy (ACT) emerged as a promising approach for cancer treatment, yet its application in solid tumors faced challenges such as inadequate tumor infiltration and cellular dysfunction. Histone acetylation is reported to play a crucial role in restoring T‐cell function within tumor tissues. Building upon previous research, a novel strategy involving the co‐loading of two drugs, G3C12 and vorinostat (SAHA), into PLGA microspheres to form G3C12+SAHA@PLGA is developed for intratumoral injection. The G3C12 peptide enhances adoptive T‐cell recruitment to the tumor site by modulating the binding state of IFN‐γ. While SAHA, a histone deacetylase inhibitor, promotes memory phenotypes of infiltrating T‐cells and prevents their transition to an exhausted state. This synergistic approach effectively augmentes the efficacy of ACT in the “cold” tumor model (4T1) or the “hot” tumor model (CT26). These findings highlight the potential of combining epigenetic regulation with recruitment signaling as a means to enhance the therapeutic impact of ACT in treating solid tumors.
Intensification Approaches and Treatment Sequencing in Metastatic Castration-resistant Prostate Cancer: A Systematic Review
Authors: Edoardo Francini, Neeraj Agarwal, Elena Castro, Heather H Cheng, Kim N Chi, Noel Clarke, Joaquin Mateo, Dana Rathkopf, Fred Saad, Bertrand Tombal
Journal: European Urology (2024)
Adjuvant Nivolumab for Localized Renal Cell Carcinoma at High Risk of Recurrence After Nephrectomy: Part B of the Randomized, Placebo-Controlled, Phase III CheckMate 914 Trial
Authors: Robert J. Motzer, Axel Bex, Paul Russo, Yoshihiko Tomita, Hernan Javier Cutuli, Carlos Rojas, Marine Gross-Goupil, Giovanni Schinzari, Bohuslav Melichar, Philippe Barthélémy, Abraham Ruiz Garcia, Jeffrey Sosman, Marc-Oliver Grimm, Jeffrey C. Goh, Cristina Suarez, Christian K. Kollmannsberger, Suresh G. Nair, Brian M. Shuch, Jian Huang, Burcin Simsek, Julia Spiridigliozzi, Chung-Wei Lee, Maximiliano van Kooten Losio, Viktor Grünwald
Journal: Journal of Clinical Oncology (2024)

PURPOSE CheckMate 914 is a two-part, randomized phase III trial evaluating adjuvant nivolumab plus ipilimumab (part A) or adjuvant nivolumab monotherapy (part B) versus placebo in mutually exclusive populations of patients with localized renal cell carcinoma (RCC) at high risk of postnephrectomy recurrence. Part A showed no disease-free survival (DFS) benefit for adjuvant nivolumab plus ipilimumab versus placebo. We report results from part B. METHODS Patients were randomly assigned (2:1:1) to nivolumab (240 mg once every 2 weeks for up to 12 doses), placebo, or nivolumab (240 mg once every 2 weeks for up to 12 doses) plus ipilimumab (1 mg/kg once every 6 weeks for up to four doses). The planned treatment duration was 24 weeks (approximately 5.5 months). The primary end point was DFS per blinded independent central review (BICR) for nivolumab versus placebo; safety was a secondary end point. RESULTS Overall, 825 patients were randomly assigned to nivolumab (n = 411), placebo (n = 208), or nivolumab plus ipilimumab (n = 206). With a median follow-up of 27.0 months (range, 18.0-42.4), the primary end point of improved DFS per BICR with nivolumab versus placebo was not met (hazard ratio [HR], 0.87 [95% CI, 0.62 to 1.21]; P = .40); the median DFS was not reached in either arm, and 18-month DFS rates were 78.4% versus 75.4%. The HR for DFS per investigator was 0.80 (95% CI, 0.58 to 1.12; P = .19). Grade 3-4 all-cause adverse events (AEs) occurred in 17.2%, 15.0%, and 28.9% of patients with nivolumab, placebo, and nivolumab plus ipilimumab, respectively. Any-grade treatment-related AEs led to discontinuation in 9.6%, 1.0%, and 28.4%, respectively. CONCLUSION Part B of CheckMate 914 did not meet the primary end point of improved DFS for nivolumab versus placebo in patients with localized RCC at high risk of postnephrectomy recurrence.
Navigating Hormone Therapy in Postmenopausal Women: Balancing Symptom Relief With Cancer Risk
Authors: Mali Barbi, Megan Gorman, Veena S. John
Journal: Journal of Clinical Oncology (2024)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
The potential of federated learning for public health purposes: a qualitative analysis of GDPR compliance, Europe, 2021
Authors: Natalie Lieftink, Carolina dos S Ribeiro, Mark Kroon, George B Haringhuizen, Albert Wong, Linda HM van de Burgwal
Journal: Eurosurveillance (2024)

Background The wide application of machine learning (ML) holds great potential to improve public health by supporting data analysis informing policy and practice. Its application, however, is often hampered by data fragmentation across organisations and strict regulation by the General Data Protection Regulation (GDPR). Federated learning (FL), as a decentralised approach to ML, has received considerable interest as a means to overcome the fragmentation of data, but it is yet unclear to which extent this approach complies with the GDPR. Aim Our aim was to understand the potential data protection implications of the use of federated learning for public health purposes. Methods Building upon semi-structured interviews (n = 14) and a panel discussion (n = 5) with key opinion leaders in Europe, including both FL and GDPR experts, we explored how GDPR principles would apply to the implementation of FL within public health. Results Whereas this study found that FL offers substantial benefits such as data minimisation, storage limitation and effective mitigation of many of the privacy risks of sharing personal data, it also identified various challenges. These challenges mostly relate to the increased difficulty of checking data at the source and the limited understanding of potential adverse outcomes of the technology. Conclusion Since FL is still in its early phase and under rapid development, it is expected that knowledge on its impracticalities will increase rapidly, potentially addressing remaining challenges. In the meantime, this study reflects on the potential of FL to align with data protection objectives and offers guidance on GDPR compliance.