tbuckley/cabot-search huggingface dataset:
Aptamer BT200 blocks interaction of K1405-1408 in the VWF-A1 domain with macrophage LRP1
Authors: Alain Chan Kwo Chion, Ciara Byrne, Ferdows Atiq, Dearbhla Doherty, Sonia Aguila, Judicael Fazavana, Patricia Lopes, Ellie Karampini, Aamir Amin, Roger J.S. Preston, Ross Ian Baker, Thomas AJ McKinnon, Shuhao Zhu, James C. Gilbert, Jonas Emsley, Bernd Jilma, James S. O'Donnell
Journal: Blood (2024)

Abstract Rondaptivon pegol (previously BT200) is a pegylated RNA aptamer that binds to the A1 domain of von Willebrand factor (VWF). Recent clinical trials demonstrated that BT200 significantly increased plasma VWF–factor VIII levels by attenuating VWF clearance. The biological mechanism(s) through which BT200 attenuates in vivo clearance of VWF has not been defined. We hypothesized that BT200 interaction with the VWF-A1 domain may increase plasma VWF levels by attenuating macrophage-mediated clearance. We observed that full-length and VWF-A1A2A3 binding to macrophages and VWF-A1 domain binding to lipoprotein receptor–related protein 1 (LRP1) cluster II and cluster IV were concentration-dependently inhibited by BT200. Additionally, full-length VWF binding to LRP1 expressed on HEK293T (HEK-LRP1) cells was also inhibited by BT200. Importantly, BT200 interacts with the VWF-A1 domain in proximity to a conserved cluster of 4 lysine residues (K1405, K1406, K1407, and K1408). Alanine mutagenesis of this K1405-K1408 cluster (VWF-4A) significantly (P &amp;lt; .001) attenuated binding of VWF to both LRP1 clusters II and IV. Furthermore, in vivo clearance of VWF-4A was significantly (P &amp;lt; .001) reduced than that of wild-type VWF. BT200 did not significantly inhibit binding of VWF-4A to LRP1 cluster IV or HEK-LRP1 cells. Finally, BT200 interaction with the VWF-A1 domain also inhibited binding to macrophage galactose lectin and the SR-AI scavenger receptor. Collectively, our findings demonstrate that BT200 prolongs VWF half-life by attenuating macrophage-mediated clearance and specifically the interaction of K1405-K1408 in the VWF-A1 domain with macrophage LRP1. These data support the concept that targeted inhibition of VWF clearance pathways represents a novel therapeutic approach for von Willebrand disease and hemophilia A.
Risk Prediction for Clonal Cytopenia: Multicenter Real-World Evidence
Authors: Zhuoer Xie, Rami S Komrokji, Najla Al-Ali, Alexandra Regelson, Susan Geyer, Anand A Patel, Caner Saygin, Amer M. Zeidan, Jan Philipp Bewersdorf, Lourdes M Mendez, Ashwin Kishtagari, Joshua F. Zeidner, Catherine C. Coombs, Yazan F Madanat, Stephen S Chung, Talha Badar, James M Foran, Pinkal Desai, Charlton Tsai, Elizabeth A. Griffiths, Monzr M. Al Malki, Idoroenyi Amanam, Catherine Lai, H. Joachim Deeg, Lionel Ades, Cecilia Arana-Yi, Afaf EG Osman, Shira Naomi Dinner, Yasmin Abaza, Justin Taylor, Namrata S Chandhok, Deborah Soong, Andrew M. Brunner, Hetty E Carraway, Abhay Singh, Chiara Elena, Jacqueline Ferrari, Anna Galli, Sara Pozzi, Eric Padron, Mrinal M. Patnaik, Luca Malcovati, Michael R. Savona, Aref Al-Kali
Journal: Blood (2024)
Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer: Updated Overall Survival Outcomes From Phase III PRODIGY
Authors: Yoon-Koo Kang, Hyung-Don Kim, Jeong Hwan Yook, Young-Kyu Park, Jong Seok Lee, Young-Woo Kim, Jin Young Kim, Min-Hee Ryu, Sun Young Rha, Ik Joo Chung, In-Ho Kim, Sang Cheul Oh, Young Soo Park, Jae-Ho Cheong, Oh Jeong, Mi Hwa Heo, Hark Kyun Kim, ChoHyun Park, Chang Hak Yoo, Seok Yun Kang, Dae Young Zang, You Jin Jang, Ji Young Sul, Jong Gwang Kim, Beom Su Kim, Seung-Hoon Beom, Jun-Eul Hwang, Seung Wan Ryu, Myeong-Cherl Kook, Baek-Yeol Ryoo, Hyunki Kim, Moon-Won Yoo, Nam Su Lee, Sang Ho Lee, Sung Hoon Noh
Journal: Journal of Clinical Oncology (2024)

JCO
Prevalence Increases as Treatments Improve: An Evolutionary Perspective on the Treatment–Prevalence Paradox in Depression
Authors: Iony D. Ezawa, Noah Robinson, Steven D. Hollon
Journal: Annual Review of Clinical Psychology (2024)

Depression is an eminently treatable disorder that responds to psychotherapy or medications; the efficacy of each has been established in hundreds of controlled trials. Nonetheless, the prevalence of depression has increased in recent years despite the existence of efficacious treatments—a phenomenon known as the treatment–prevalence paradox. We consider several possible explanations for this paradox, which range from a misunderstanding of the very nature of depression, inflated efficacy of the established treatments, and a lack of access to efficacious delivery of treatments. We find support for each of these possible explanations but especially the notion that large segments of the population lack access to efficacious treatments that are implemented as intended. We conclude by describing the potential of using lay therapists and digital technologies to overcome this lack of access and to reach historically underserved populations and simultaneously guarantee the quality of the interventions delivered.
A confusion of pathways: Discerning cell death mechanisms in SARS-CoV-2 infection
Authors: Lok-Yin Roy Wong, Stanley Perlman
Journal: Science Immunology (2024)

Upon SARS-CoV-2 infection, infected cells undergo necroptosis, whereas delayed apoptosis and pyroptosis occur in uninfected, bystander cells, thus providing a plausible explanation for the extensive injury among myriad uninfected cells.
MHC heterozygosity limits T cell receptor variability in CD4 T cells
Authors: Alexander J. Brown, Janice White, Laura Shaw, Jimmy Gross, Andrei Slabodkin, Ella Kushner, Victor Greiff, Jennifer Matsuda, Laurent Gapin, James Scott-Browne, John Kappler, Philippa Marrack
Journal: Science Immunology (2024)

αβ T cell receptor (TCR) V(D)J genes code for billions of TCR combinations. However, only some appear on peripheral T cells in any individual because, to mature, thymocytes must react with low affinity but not high affinity with thymus expressed major histocompatibility (MHC)/peptides. MHC proteins are very polymorphic. Different alleles bind different peptides. Therefore, any individual might express many different MHC alleles to ensure that some peptides from an invader are bound to MHC and activate T cells. However, most individuals express limited numbers of MHC alleles. To explore this, we compared the TCR repertoires of naïve CD4 T cells in mice expressing one or two MHC alleles. Unexpectedly, the TCRs in heterozygotes were less diverse that those in the sum of their MHC homozygous relatives. Our results suggest that thymus negative selection cancels out the advantages of increased thymic positive selection in the MHC heterozygotes.
Initiator cell death event induced by SARS-CoV-2 in the human airway epithelium
Authors: Kaixin Liang, Katherine C. Barnett, Martin Hsu, Wei-Chun Chou, Sachendra S. Bais, Kristina Riebe, Yuying Xie, Tuong Thien Nguyen, Thomas H. Oguin, Kevin M. Vannella, Stephen M. Hewitt, Daniel S. Chertow, Maria Blasi, Gregory D. Sempowski, Amelia Karlsson, Beverly H. Koller, Deborah J. Lenschow, Scott H. Randell, Jenny P.-Y. Ting
Journal: Science Immunology (2024)

Virus-induced cell death is a key contributor to COVID-19 pathology. Cell death induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well studied in myeloid cells but less in its primary host cell type, angiotensin-converting enzyme 2 (ACE2)–expressing human airway epithelia (HAE). SARS-CoV-2 induces apoptosis, necroptosis, and pyroptosis in HAE organotypic cultures. Single-cell and limiting-dilution analysis revealed that necroptosis is the primary cell death event in infected cells, whereas uninfected bystanders undergo apoptosis, and pyroptosis occurs later during infection. Mechanistically, necroptosis is induced by viral Z-RNA binding to Z-DNA–binding protein 1 (ZBP1) in HAE and lung tissues from patients with COVID-19. The Delta (B.1.617.2) variant, which causes more severe disease than Omicron (B1.1.529) in humans, is associated with orders of magnitude–greater Z-RNA/ZBP1 interactions, necroptosis, and disease severity in animal models. Thus, Delta induces robust ZBP1-mediated necroptosis and more disease severity.
Infection and chronic disease activate a systemic brain-muscle signaling axis
Authors: Shuo Yang, Meijie Tian, Yulong Dai, Rong Wang, Shigehiro Yamada, Shengyong Feng, Yunyun Wang, Deepak Chhangani, Tiffany Ou, Wenle Li, Xuan Guo, Jennifer McAdow, Diego E. Rincon-Limas, Xin Yin, Wanbo Tai, Gong Cheng, Aaron Johnson
Journal: Science Immunology (2024)

Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood. We developed multiple models to investigate the impact of CNS stressors on motor function and found that Escherichia coli infections and SARS-CoV-2 protein expression caused reactive oxygen species (ROS) to accumulate in the brain. ROS induced expression of the cytokine Unpaired 3 (Upd3) in Drosophila and its ortholog, IL-6, in mice. CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, which caused muscle mitochondrial dysfunction and impaired motor function. We observed similar phenotypes after expressing toxic amyloid-β (Aβ42) in the CNS. Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.
Analysis and Validation of Image Search Engines in Histopathology
Authors: Isaiah Lahr, Saghir Alfasly, Peyman Nejat, Jibran Khan, Luke Kottom, Vaishnavi Kumbhar, Areej Alsaafin, Abubakr Shafique, Sobhan Hemati, Ghazal Alabtah, Nneka Comfere, Dennis Murphree, Aaron Mangold, Saba Yasir, Chady Meroueh, Lisa Boardman, Vijay H. Shah, Joaquin J. Garcia, H.R. Tizhoosh
Journal: IEEE Reviews in Biomedical Engineering (2024)

Searching for similar images in archives of histology and histopathology images is a crucial task that may aid in patient tissue comparison for various purposes, ranging from triaging and diagnosis to prognosis and prediction. Whole slide images (WSIs) are highly detailed digital representations of tissue specimens mounted on glass slides. Matching WSI to WSI can serve as the critical method for patient tissue comparison. In this paper, we report extensive analysis and validation of four search methods bag of visual words (BoVW), Yottixel, SISH, RetCCL, and some of their potential variants. We analyze their algorithms and structures and assess their performance. For this evaluation, we utilized four internal datasets (1269 patients) and three public datasets (1207 patients), totaling more than 200, 000 patches from 38 different classes/subtypes across five primary sites. Certain search engines, for example, BoVW, exhibit notable efficiency and speed but suffer from low accuracy. Conversely, search engines like Yottixel demonstrate efficiency and speed, providing moderately accurate results. Recent proposals, including SISH, display inefficiency and yield inconsistent outcomes, while alternatives like RetCCL prove inadequate in both accuracy and efficiency. Further research is imperative to address the dual aspects of accuracy and minimal storage requirements in histopathological image search.
Fitness-related physical activity intensity explains most of the association between accelerometer data and cardiometabolic health in persons 50–64 years old
Authors: Jonatan Fridolfsson, Elin Ekblom-Bak, Örjan Ekblom, Göran Bergström, Daniel Arvidsson, Mats Börjesson
Journal: British Journal of Sports Medicine (2024)

To investigate the physical activity (PA) intensity associated with cardiometabolic health when considering the mediating role of cardiorespiratory fitness (CRF).
Ketogenic Diet and Progression of Kidney Disease in Animal Models of Nephropathic Cystinosis
Authors: Francesco Bellomo, Sara Pugliese, Sara Cairoli, Patrick Krohn, Cristiano De Stefanis, Roberto Raso, Laura Rita Rega, Anna Taranta, Ester De Leo, Andrea Ciolfi, Nicolò Cicolani, Stefania Petrini, Alessandro Luciani, Bianca Maria Goffredo, Ottavia Porzio, Olivier Devuyst, Carlo Dionisi-Vici, Francesco Emma
Journal: Journal of the American Society of Nephrology (2024)

Key Points Ketogenic diet can change the metabolism in the body and helped restore the function of altered pathways in nephropathic cystinosis. Ketogenic diet had significant benefits for preventing kidney damage, even when initiated after the onset of kidney impairment. Ketogenic diet may provide a partial therapeutic alternative in countries where cysteamine therapy is too expensive. Background Nephropathic cystinosis is a rare inherited lysosomal storage disorder caused by mutations in the CTNS gene that encodes for cystinosin, a lysosomal cystine/H + symporter. From the standpoint of the kidneys, patients develop early-onset renal Fanconi syndrome and progressive CKD. Current therapy with cysteamine delays but does not prevent kidney failure and has significant side effects that limit adherence and reduce the quality of life of patients. Methods We have tested biochemically and histologically the effects of ketogenic diet on kidney disease of two animal models of nephropathic cystinosis. Results When Ctns −/− mice were fed with ketogenic diet from 3 to 12 months of age, we observed significant nearly complete prevention of Fanconi syndrome, including low molecular weight proteinuria, glycosuria, and polyuria. Compared with wild-type animals, BUN at 12 months was higher in cystinotic mice fed with standard diet ( P &lt; 0.001), but not with ketogenic diet. At sacrifice, kidneys of knockout mice fed with ketogenic diet appeared macroscopically similar to those of wild-type animals, which was reflected microscopically by a significant reduction of interstitial cell infiltration (CD3 and CD68 positive cells, P &lt; 0.01), of interstitial fibrosis (Masson and α -smooth muscle actin staining, P &lt; 0.001), and of apoptosis (cleaved caspase-3 levels; P &lt; 0.001), and by indirect evidence of restoration of a normal autophagic flux (SQSTM1/p62 and LC3-II expression, P &lt; 0.05). Beneficial effects of ketogenic diet on tubular function were also observed after mice were fed with this ketogenic diet from the age of 6 months to the age of 15 months, after they had developed proximal tubular dysfunction. Although slightly less pronounced, these results were replicated in Ctns −/− rats fed with ketogenic diet from 2 to 8 months of life. Conclusions These results indicate significant mitigation of the kidney phenotype in cystinotic animals fed with ketogenic diet.
Effects of Zibotentan Alone and in Combination with Dapagliflozin on Fluid Retention in Patients with CKD
Authors: J. David Smeijer, Victor S. Wasehuus, Neeraj Dhaun, José Luis Górriz, Maria José Soler, Magnus Åstrand, Anne-Kristina Mercier, Peter J. Greasley, Phil Ambery, Hiddo J.L. Heerspink
Journal: Journal of the American Society of Nephrology (2024)

Endothelin receptor antagonists (ERAs) reduce albuminuria but are limited by fluid retention risk, particularly in patients with chronic kidney disease (CKD). Combining ERAs with sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have diuretic effects, offers a promising strategy to mitigate fluid retention. In this post-hoc analysis of the ZENITH-CKD trial, we assessed fluid dynamics in patients with CKD treated with the ERA zibotentan alone, and in combination with the SGLT2 inhibitor dapagliflozin.
Mendelian Randomization Unveils Drug Targets for IgA Nephropathy
Authors: Atlas Khan, Tze Y. Lim, Simone Sanna-Cherchi
Journal: Journal of the American Society of Nephrology (2024)

1Division of Nephrology, Department of Medicine, Columbia University, New York, New York 2Unit of Genomic Variability and Complex Diseases, Department of Medical Sciences, University of Turin, Turin, Italy Correspondence: Dr. Simone Sanna-Cherchi, email: [email protected] See related article, "Circulating Proteins and IgA Nephropathy: A Multiancestry Proteome-Wide Mendelian Randomization Study," on pages 1045–1057.
Mediterranean Diet and Cardiometabolic Biomarkers in Children and Adolescents
Authors: José Francisco López-Gil, Antonio García-Hermoso, Miguel Ángel Martínez-González, Fernando Rodríguez-Artalejo
Journal: JAMA Network Open (2024)

No prior systematic review and meta-analysis has specifically verified the association of Mediterranean diet (MedDiet)-based interventions with biomarkers of cardiometabolic health in children and adolescents.
Refining Colon Cancer Screening, Antibody Therapy for Lung Cancer, and More—Highlights From ASCO 2024
Authors: Jennifer Abbasi
Journal: JAMA (2024)

This Medical News article is an interview about JAMA Network highlights from the American Society of Clinical Oncology’s annual meeting, hosted by Nora Disis, MD, editor in chief of JAMA Oncology and a JAMA deputy editor.
Screen Media Use and Mental Health of Children and Adolescents
Authors: Jesper Schmidt-Persson, Martin Gillies Banke Rasmussen, Sarah Overgaard Sørensen, Sofie Rath Mortensen, Line Grønholt Olesen, Søren Brage, Peter Lund Kristensen, Niels Bilenberg, Anders Grøntved
Journal: JAMA Network Open (2024)

Importance Excessive screen media use has been associated with poorer mental health among children and adolescents in several observational studies. However, experimental evidence supporting this hypothesis is lacking. Objective To investigate the effects of a 2-week screen media reduction intervention on children’s and adolescents’ mental health. Design, Setting, and Participants This prespecified secondary analysis of a cluster randomized clinical trial with a 2-week follow-up included 89 families (with 181 children and adolescents) from 10 Danish municipalities in the region of Southern Denmark. All study procedures were carried out in the home of the participants. Enrollment began on June 6, 2019, and ended on March 30, 2021. This analysis was conducted between January 1 and November 30, 2023. Intervention Families were randomly allocated to a screen media reduction group or a control group. The 2-week screen media reduction intervention was designed to ensure a high level of compliance to the reduction in leisure-time screen media use. Participants allocated to the intervention group had to reduce their leisure-time screen media use to 3 hours per week or less per person and hand over smartphones and tablets. Main Outcomes and Measures The main outcome was the between-group mean difference in change in total behavioral difficulties, measured by the Strengths and Difficulties Questionnaire at 2-week follow-up. Results were estimated using mixed-effects tobit regression models. Analyses were carried out as both intention to treat and complete case. Results In the sample of 89 families including 181 children and adolescents (intervention group [45 families]: 86 children; mean [SD] age, 8.6 [2.7] years; 42 girls [49%]; control group [44 families]: 95 children; mean [SD] age, 9.5 [2.5] years; 57 girls [60%]), there was a statistically significant between-group mean difference in the total difficulties score, favoring the screen media reduction intervention (−1.67; 95% CI, −2.68 to −0.67; Cohen d , 0.53). The greatest improvements were observed for internalizing symptoms (emotional symptoms and peer problems; between-group mean difference, −1.03; 95% CI, −1.76 to −0.29) and prosocial behavior (between-group mean difference, 0.84; 95% CI, 0.39-1.30). Conclusions and Relevance This secondary analysis of a randomized clinical trial found that a short-term reduction in leisure-time screen media use within families positively affected psychological symptoms of children and adolescents, particularly by mitigating internalizing behavioral issues and enhancing prosocial behavior. More research is needed to confirm whether these effects are sustainable in the long term. Trial Registration ClinicalTrials.gov Identifier: NCT04098913
Representation of Older Adults in the ACC/AHA/SCAI Guideline for Coronary Artery Revascularization
Authors: Yasser Jamil, Cosmas Sibindi, Dae Yong Park, Jennifer Frampton, Abdulla A. Damluji, Michael G. Nanna
Journal: JAMA Network Open (2024)

This cross-sectional study assesses the generalizability of the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) guideline by examining the representation of older adults in studies cited in the guideline.
Few Medicare Beneficiaries Receive Needed Opioid Use Disorder Meds
Authors: Emily Harris
Journal: JAMA (2024)

Christopher M. Jones, PharmD, DrPH; Carla Shoff, PhD; Carlos Blanco, MD, PhD; Jan L. Losby, PhD, MSW; Shari M. Ling, MD; Wilson M. Compton, MD, MPE
Medicaid Coverage in Early Childhood for Children With Sickle Cell Disease
Authors: Sophia S. Horiuchi, Sarah L. Reeves, Allison P. Plaxco, Hannah K. Peng, Mei Zhou, Mariam Kayle, Mary Hulihan
Journal: JAMA Network Open (2024)

This cohort study examines patterns of Medicaid coverage in the first 3 years of life among children with sickle cell disease across 5 states.
A Family-Based Intervention With a Digital Break to Improve Child Psychiatric Symptoms
Authors: Henning Tiemeier
Journal: JAMA Network Open (2024)

Jesper Schmidt-Persson, PhD; Martin Gillies Banke Rasmussen, PhD; Sarah Overgaard Sørensen, MSc; Sofie Rath Mortensen, MSc; Line Grønholt Olesen, PhD; Søren Brage, PhD; Peter Lund Kristensen, PhD; Niels Bilenberg, PhD; Anders Grøntved, PhD
COVID-19 Pandemic Quarantines and Mental Health Among Adolescents in Norway
Authors: Johanne H. Pettersen, Laurie J. Hannigan, Kristin Gustavson, Ingunn O. Lund, Rebecca M. Pearson, Pia Jensen, Ragnar Nesvåg, Ragnhild E. Brandlistuen, Helga Ask
Journal: JAMA Network Open (2024)

Adolescence is a critical developmental phase when mental health disorders, such as anxiety and depression, often emerge. Stringent public health measures and quarantine mandates during the COVID-19 pandemic could threaten adolescent mental health.
Errors in the Strength and Limitations and Supplement 2
Journal: JAMA Network Open (2024)

Clinical Trial" 1 published on May 16, 2024, there were errors in the Strengths and Limitations section and Supplement 2."Attrition" was omitted after a percentage in the Strengths and Limitations section.The sentence should be as follows: "Notably, 1 site had high retention (12 of 54 = 22% attrition), showing that it is possible in principle to keep contact with families over a longer time span."Additionally, there was a typographical error in the eFigure 3 caption in Supplement 2. This article has been corrected.