tbuckley/cabot-search huggingface dataset:
Quantifying interstitial fluid by direct osmotic pressure measurements in vivo via telemetry-enabled Nanofluidic implants
Authors: Ilaria Facchi, Nicola Di Trani, Nathanael Hernandez, Ashley L Joubert, Anthony M Wood, Danilo Demarchi, Alessandro Grattoni
Journal: Journal of Controlled Release (2024)

Interstitial fluid (IF) is pivotal in maintaining balance within tissues and organs, facilitating molecular transport and supporting homeostasis. Various drug delivery systems, such as long-acting depots or implants, rely on IF to distribute drugs locally before they enter the bloodstream. The volume and accessibility of this fluid directly influence how drugs diffuse and the build-up of the osmotic pressure in areas with high drug concentration, ultimately impacting the performance of the delivery systems. Consequently, differences in free fluid availability contribute to discrepancies in drug delivery in vitro versus in vivo. Accurately estimating the volume of IF in vivo would significantly improve the design of in vitro drug release experiments and enhance the outcomes of animal studies. However, accurately measuring free IF and its effect on drug delivery systems in living organisms poses challenges. In response, we developed a reservoir-membrane subcutaneous (SQ) implant similar to a long-acting drug delivery system. The implant measures fluid availability in surrounding tissues by measuring real-time osmotic pressure changes resulting from fluid permeating through a nanoporous membrane, using an integrated pressure transducer and Bluetooth connectivity. By correlating in vitro and in vivo data using a computational model of molecular transport across the membrane, we estimated a 93 % reduction in free fluid availability in the subcutaneous tissue surrounding the implant as compared to our ideal in vitro setting with implant immersed within sink fluids. Applicable to various implantation sites, our study highlights a practical approach to directly assessing free fluid availability in different tissues, enhancing in vitro drug delivery experimental design and evaluating the performance of drug delivery systems in physiological contexts.
Tumor-derived CCL2 drives tumor growth and immunosuppression in IDH1-mutant cholangiocarcinoma
Authors: Daniel J. Zabransky, Emma Kartalia, Jae W. Lee, James M. Leatherman, Soren Charmsaz, Sara E. Young, Yash Chhabra, Sebastià Franch-Expósito, Martin Kang, Saumya Maru, Noushin Rastkari, Michael Davis, William Brian Dalton, Kiyoko Oshima, Marina Baretti, Nilofer S. Azad, Elizabeth M. Jaffee, Mark Yarchoan
Journal: Hepatology (2024)

Background and aims: Isocitrate dehydrogenase 1 ( IDH1 )-mutant cholangiocarcinoma (CCA) is a highly lethal subtype of hepatobiliary cancer that is often resistant to immune checkpoint inhibitor therapies. We evaluated the effects of IDH1 -mutations in CCA cells on the tumor immune microenvironment and identify opportunities for therapeutic intervention. Approach and results: Analysis of 2,606 human CCA tumors using deconvolution of RNA-sequencing data identified decreased CD8 T cell and increased M2-like tumor-associated macrophage (TAM) infiltration in IDH1 -mutant compared to IDH1 -wild type tumors. To model the tumor immune microenvironment of IDH1- mutant CCA in vivo , we generated an isogenic cell line panel of mouse SB1 CCA cells containing a heterozygous IDH1 R132C (SB1 mIDH1 ) or control (SB1 WT ) cells using CRISPR-mediated homology directed repair. SB1 mIDH1 cells recapitulated features of human IDH1 -mutant CCA including D-2-HG production and increased M2-like TAM infiltration. SB1 mIDH1 cells and tumors produced increased levels of CCL2, a chemokine involved in recruitment and polarization of M2-like TAMs compared to wild type controls. In vivo neutralization of CCL2 led to decreased M2-like TAM infiltration, reduced tumor size, and improved overall survival in mice harboring SB1 mIDH1 tumors. Conclusions: IDH1- mutant CCA is characterized by increased abundance of M2-like TAMs. Targeting CCL2 remodels the tumor immune microenvironment and improves outcomes in preclinical models of IDH1 -mutant CCA, highlighting the role for myeloid-targeted immunotherapies in the treatment of this cancer.
Multimodal multiphasic pre-operative image-based deep-learning predicts hepatocellular carcinoma outcomes after curative surgery
Authors: Rex Wan-Hin Hui, Keith Wan-Hang Chiu, I-Cheng Lee, Chenlu Wang, Ho-Ming Cheng, Jianliang Lu, Xianhua Mao, Sarah Yu, Lok-Ka Lam, Lung-Yi Mak, Tan-To Cheung, Nam-Hung Chia, Chin-Cheung Cheung, Wai-Kuen Kan, Tiffany Cho-Lam Wong, Albert Chi-Yan Chan, Yi-Hsiang Huang, Man-Fung Yuen, Philip Leung-Ho Yu, Wai-Kay Seto
Journal: Hepatology (2024)

Background: Hepatocellular carcinoma (HCC) recurrence frequently occurs after curative surgery. Histological microvascular-invasion (MVI) predicts recurrence but cannot provide pre-operative prognostication, whereas clinical prediction scores have variable performances. Methods: Recurr-NET, a multimodal multiphasic residual-network random survival forest deep-learning model incorporating pre-operative CT and clinical parameters, was developed to predict HCC recurrence. Pre-operative triphasic CT scans were retrieved from patients with resected histology-confirmed HCC from four centers in Hong Kong (Internal-cohort). The internal-cohort was randomly divided in an 8:2 ratio into training and internal-validation. External-testing was performed in an independent cohort from Taiwan. Results: Among 1231 patients (Age 62.4, 83.1% male, 86.8% viral hepatitis, median follow-up 65.1 months), cumulative HCC recurrence at years 2 and 5 were 41.8% and 56.4% respectively. Recurr-NET achieved excellent accuracy in predicting recurrence from years 1-5 (Internal cohort AUROC 0.770-0.857; External AUROC 0.758-0.798), significantly out-performing MVI (Internal AUROC 0.518-0.590; External AUROC 0.557-0.615) and multiple clinical risk scores (ERASL-PRE, ERASL-POST, DFT, and Shim scores) (Internal AUROC 0.523-0.587, External AUROC: 0.524-0.620) respectively (all p &lt;0.001). Recurr-NET was superior to MVI in stratifying recurrence risks at year 2 (Internal: 72.5% vs. 50.0% in MVI; External: 65.3% vs. 46.6% in MVI) and year 5 (Internal: 86.4% vs. 62.5% in MVI; External: 81.4% vs. 63.8% in MVI) (all p &lt;0.001). Recurr-NET was also superior to MVI in stratifying liver-related and all-cause mortality (all p &lt;0.001). The performance of Recurr-NET remained robust in subgroup analyses. Conclusion: Recurr-NET accurately predicted HCC recurrence, out-performing MVI and clinical prediction scores respectively, highlighting its potential in pre-operative prognostication.
miRNAs in HCC, pathogenesis, and targets
Authors: Guisheng Song, Xiaofan Yu, Hongtao Shi, Bo Sun, Stuart Amateau
Journal: Hepatology (2024)

Liver cancer is the third leading cause of cancer-related mortality worldwide. HCC, the most common type of primary liver cancer, is driven by complex genetic, epigenetic, and environmental factors. MicroRNAs, a class of naturally occurring small noncoding RNAs, play crucial roles in HCC by simultaneously modulating the expression of multiple genes in a fine-tuning manner. Significant progress has been made in understanding how miRNAs influence key oncogenic pathways, including cell proliferation, apoptosis, angiogenesis, and epithelial-mesenchymal transition (EMT), as well as their role in modulating the immune microenvironment in HCC. Due to the unexpected stability of miRNAs in the blood and fixed HCC tumors, recent advancements also highlight their potential as noninvasive diagnostic tools. Restoring or inhibiting specific miRNAs has offered promising strategies for targeted HCC treatment by suppressing malignant hepatocyte growth and enhancing antitumor immunity. In this comprehensive review, we consolidate previous research and provide the latest insights into how miRNAs regulate HCC and their therapeutic and diagnostic potential. We delve into the dysregulation of miRNA biogenesis in HCC, the roles of miRNAs in the proliferation and apoptosis of malignant hepatocytes, angiogenesis and metastasis of HCC, the immune microenvironment in HCC, and drug resistance. We also discuss the therapeutic and diagnostic potential of miRNAs and delivery approaches of miRNA drugs to overcome the limitations of current HCC treatment options. By thoroughly summarizing the roles of miRNAs in HCC, our goal is to advance the development of effective therapeutic drugs with minimal adverse effects and to establish precise tools for early diagnosis of HCC.
Racial Bias in Clinical and Population Health Algorithms: A Critical Review of Current Debates
Authors: Madison Coots, Kristin A. Linn, Sharad Goel, Amol S. Navathe, Ravi B. Parikh
Journal: Annual Review of Public Health (2024)

Among health care researchers, there is increasing debate over how best to assess and ensure the fairness of algorithms used for clinical decision support and population health, particularly concerning potential racial bias. Here we first distill concerns over the fairness of health care algorithms into four broad categories: ( a ) the explicit inclusion (or, conversely, the exclusion) of race and ethnicity in algorithms, ( b ) unequal algorithm decision rates across groups, ( c ) unequal error rates across groups, and ( d ) potential bias in the target variable used in prediction. With this taxonomy, we critically examine seven prominent and controversial health care algorithms. We show that popular approaches that aim to improve the fairness of health care algorithms can in fact worsen outcomes for individuals across all racial and ethnic groups. We conclude by offering an alternative, consequentialist framework for algorithm design that mitigates these harms by instead foregrounding outcomes and clarifying trade-offs in the pursuit of equitable decision-making.
Is there a place for natural agents with anti-inflammatory and antioxidative properties in critically ill patients? Potential usefulness of Xanthohumol
Authors: Wojciech Dabrowski, Carmen Andrea Pfortmueller, Katarzyna Kotfis, Andrzej Jaroszynski, Mariusz Gagos, Wlodzimierz Plotek, Manu L N G Malbrain
Journal: Pharmacology & Therapeutics (2024)
Genetic Discovery and Risk Prediction for Type 1 Diabetes in Individuals Without High-Risk HLA-DR3/DR4 Haplotypes
Authors: Carolyn McGrail, Joshua Chiou, Ruth Egamal, Amber M. Luckett, Richard A. Oram, Paola Benaglio, Kyle J. Gaulton
Journal: Diabetes Care (2024)

OBJECTIVE More than 10% of patients with type 1 diabetes (T1D) do not have high-risk HLA-DR3 or -DR4 haplotypes with distinct clinical features, such as later onset and reduced insulin dependence. We aimed to identify genetic drivers of T1D in the absence of DR3/DR4 and improve prediction of T1D risk in these individuals. RESEARCH DESIGN AND METHODS We performed T1D association and fine-mapping analyses in 12,316 non-DR3/DR4 samples. Next, we performed heterogeneity tests to examine differences in T1D risk variants in individuals without versus those with DR3/DR4 haplotypes. We further assessed genome-wide differences in gene regulatory element and biological pathway enrichments between the non-DR3/DR4 and DR3/DR4 cohorts. Finally, we developed a genetic risk score (GRS) to predict T1D in individuals without DR3/DR4 and compared with an existing T1D GRS. RESULTS A total of 18 T1D risk variants in non-DR3/DR4 samples were identified. Risk variants at the MHC and multiple other loci genome wide had heterogeneity in effects on T1D dependent on DR3/DR4 status, and non-DR3/DR4 T1D had evidence for a greater polygenic burden. T1D-assocated variants in non-DR3/DR4 were more enriched for regulatory elements and pathways involved in antigen presentation, innate immunity, and β-cells and depleted in T cells compared with DR3/DR4. A non-DR3/DR4 GRS outperformed an existing risk score GRS2 in discriminating non-DR3/DR4 T1D from no diabetes (area under the curve 0.867; P = 7.48 × 10−32) and type 2 diabetes (0.907; P = 4.94 × 10−44). CONCLUSIONS In total, we identified heterogeneity in T1D genetic risk dependent on high-risk HLA-DR3/DR4 haplotype, which uncovers disease mechanisms and enables more accurate prediction of T1D across the HLA background.
Tolerability and effectiveness of low-dose oral minoxidil for alopecia in patients with breast cancer: a retrospective cohort study
Authors: Devyn Zaminski, Michelle Sikora, Ambika Nohria, Deesha Desai, Michael Buontempo, Avrom S. Caplan, Mario Lacouture, Michael Garshick, Elise A. Olsen, Jerry Shapiro, Daniel R. Mazori, Kristen I. Lo Sicco
Journal: Journal of the American Academy of Dermatology (2024)
Changes in Physical Activity and Cardiovascular Disease Risk in Cancer Survivors
Authors: Wonyoung Jung, In Young Cho, Jinhyung Jung, Mi Hee Cho, Hye Yeon Koo, Yong-Moon Mark Park, Kyungdo Han, Dong Wook Shin
Journal: JACC CardioOncology (2024)

Cancer survivors face an elevated risk of cardiovascular disease, with physical inactivity after cancer treatment potentially worsening this risk. The aim of this study was to investigate the association between physical activity before and after a cancer diagnosis and the risk for heart disease. A nationwide cohort of 269,943 cancer survivors (mean age 56.3, 45.7% men) was evaluated for physical activity adherence 2 years before and after diagnosis. The primary outcomes were the incidence of myocardial infarction (MI), heart failure (HF), and atrial fibrillation. Subdistribution HRs (sHRs) and 95% CIs were calculated using Gray's method, accounting for death as a competing risk. Over a follow-up period of 1,111,329.28 person-years, compared with those who remained inactive, persistent physical activity was associated with a 20% reduction in MI risk (sHR: 0.80; 95% CI: 0.70-0.91) and a 16% reduction risk in HF risk (sHR: 0.84; 95% CI: 0.78-0.90). Initiating physical activity after a cancer diagnosis was linked to an 11% lower risk for MI (sHR: 0.89; 95% CI: 0.79-0.99) and a 13% lower risk for HF (sHR: 0.87; 95% CI: 0.82-0.93). Being active only before diagnosis was associated with a 20% lower risk for MI (sHR: 0.80; 95% CI: 0.71-0.91) and a 6% lower risk for HF (sHR: 0.94; 95% CI: 0.88-1.00). No association was observed between physical activity and atrial fibrillation risk. Associations varied by primary cancer site. These findings underscore the importance of maintaining physical activity for cardiovascular health in cancer survivors and suggest that physical activity before a diagnosis may offer enduring protection against ischemic heart disease and cardiac dysfunction.
Serum Proteins Predict Treatment-Related Cardiomyopathy Among Survivors of Childhood Cancer
Authors: Suresh Poudel, Him Shrestha, Yue Pan, Qian Li, Kendrick Li, Cindy Im, Stephanie B Dixon, Matthew J Ehrhardt, Daniel A Mulrooney, Suiping Zhou, Haiyan Tan, Anthony A High, Paul W Burridge, Smita Bhatia, John L Jefferies, Kirsten K Ness, Melissa M Hudson, Leslie L Robison, Gregory T Armstrong, Junmin Peng, Bonnie Ky, Yutaka Yasui, Yadav Sapkota
Journal: JACC CardioOncology (2024)

Anthracyclines, a highly effective chemotherapy for many pediatric malignancies, cause cardiomyopathy, a major late effect in adult survivors. Biomarkers are needed for early detection and targeted interventions for anthracycline-associated cardiomyopathy. The aim of this study was to determine if serum proteins and/or metabolites in asymptomatic childhood cancer survivors can discriminate symptomatic cardiomyopathy. Using an untargeted mass spectrometry-based approach, 867 proteins and 218 metabolites were profiled in serum samples of 75 asymptomatic survivors with subclinical cardiomyopathy and 75 individually matched survivors without cardiomyopathy from SJLIFE (St. Jude Lifetime Cohort Study). Models were developed on the basis of the most influential differentially expressed proteins and metabolites, using conditional logistic regression with a least absolute shrinkage and selection operator penalty. The best performing model was evaluated in 23 independent survivors with severe or symptomatic cardiomyopathy and 23 individually matched cardiomyopathy-free survivors. A 27-protein model identified using conditional logistic regression with a least absolute shrinkage and selection operator penalty discriminated symptomatic or severe cardiomyopathy requiring heart failure medications in independent survivors; 19 of 23 individually matched survivors with and without cardiomyopathy were correctly discriminated with 82.6% (95% CI: 71.4%-93.8%) accuracy. Pathway enrichment analysis revealed that the 27 proteins were enriched in various biological processes, many of which have been linked to anthracycline-related cardiomyopathy. A risk model was developed on the basis of the differential expression of serum proteins in subclinical cardiomyopathy, which accurately discriminated the risk for severe cardiomyopathy in an independent, matched sample. Further assessment of these proteins as biomarkers of cardiomyopathy risk should be conducted in external larger cohorts and through prospective studies.
Clonal Hematopoiesis and Risk of Heart Failure After Autologous Hematopoietic Cell Transplantation for Lymphoma
Authors: June-Wha Rhee, Raju Pillai, Sitong Chen, Alysia Bosworth, Artem Oganesyan, Liezl Atencio, Kendall Freeman, Caitlyn Estrada, Tati Guzman, Kara Lukas, Kelly Peng, Brianna Sigala, Aleksi Lukuridze, Lanie Lindenfeld, Faizi Jamal, Pradeep Natarajan, Smita Bhatia, Alex F Herrera, Matthew G Mei, Ryotaro Nakamura, F Lennie Wong, Stephen J Forman, Saro H Armenian
Journal: JACC CardioOncology (2024)

Patients with lymphoma are at high risk for developing heart failure (HF) after autologous hematopoietic cell transplantation (HCT). More accurate risk determination pre-HCT may facilitate screening and prevention of HF. The aim of this study was to examine the association between clonal hematopoiesis of indeterminate potential (CHIP) and the risk for HF after HCT for lymphoma. This was a retrospective cohort study of 861 patients who underwent autologous HCT for lymphoma between 2010 and 2016 at City of Hope Comprehensive Cancer Center. Targeted DNA sequencing was performed to determine the presence of CHIP (variant allele frequency ≥ 2%). The primary outcome of interest was the 5-year cumulative incidence of de novo HF. Other outcomes of interest included overall and cause-specific mortality. Overall, 186 patients (21.7% of the cohort) had at least 1 CHIP variant, and 59 (6.9%) had ≥2 variants. DNMT3A, PPM1D, and TET2 were the most frequently mutated genes. The 5-year incidence of HF was significantly higher in patients with CHIP compared with those without CHIP (13.8% vs 4.7%; P < 0.001; sub-distribution hazard ratio [sHR]: 2.48; 95% CI: 1.32-4.68); the HF incidence increased by variant allele frequency: 0-2% (4.7%), 2-10% (11.7%), and >10% (18.5%), P < 0.001. Patients with CHIP had significantly worse overall survival after HCT, compared with those without (63.4% vs 80.3%; P < 0.001), due primarily to the higher risk for nonrelapse mortality (subdistribution HR: 5.37; 95% CI: 2.34-12.35). CHIP was highly prevalent and associated with risk for HF and nonrelapse mortality after HCT. These findings highlight the role of CHIP as a novel biomarker and potential target for intervention to improve outcomes after autologous HCT.
Why is endoscopic reintervention easier using a braided metal stent than a laser-cut stent in stent-in-stent placement? A bench study
Authors: Mitsuru Okuno, Fumiya Kataoka, Atsushi Tagami, Hiroshi Araki, Eiichi Tomita, Hisataka Moriwaki, Masahito Shimizu
Journal: Endoscopy (2024)

Bilateral stent placement results in better clinical palliation than unilateral placement for unresectable malignant hilar biliary obstruction [1]. Moreover, for simultaneous bilateral drainage, the stent-in-stent method with self-expandable metal stents (SEMSs) shows longer stent patency than side-by-side-placement [1] [2]; however, endoscopic reintervention in stent-in-stent cases is challenging because the additional drainage device must pass through the crossed-wire wall of the inner SEMS ([Fig. 1]). In such conditions, endoscopic reintervention is more difficult in cases where a laser-cut SEMS has been placed than in those where a braided SEMS was placed [3], although the reason for this difference has not been satisfactorily explained. We conducted a bench study to address this question, using a video that directly recorded the path of the inserted drainage device, a plastic stent, through the crossed-wire wall of two SEMSs ([Video 1]).
Endoscopic full-thickness resection with local injection into tissue outside the capsule of a gastrointestinal stromal tumor
Authors: Makoto Kobayashi, Tatsuma Nomura, Junki Toyoda, Yuto Ikadai, Tomohiro Sase, Tomonori Saito, Katsumi Mukai
Journal: Endoscopy (2024)

Recently, the usefulness of endoscopic full-thickness resection (EFTR) of gastrointestinal stromal tumor (GIST) has been demonstrated [1] [2]. However, the R0 resection rate of endoscopy alone is problematic. We previously reported a method for achieving R0 resection during endoscopic muscularis dissection of an intraluminal growth type GIST using local injection of a hyaluronic acid solution into the muscle layer to attach the muscle layer to the tumor side using a knife capable of delivering the fluid [3]. In this report, we describe the first case of local injection of hyaluronic acid solution into tissue outside the GIST capsule to achieve R0 resection.
Correction: Palliative procedures for malignant gastric outlet obstruction: a network meta-analysis
Authors: Khoi Van Tran, Nguyen-Phong Vo, Hung Song Nguyen, Nhi Thi Vo, Thi Bao Trang Thai, Vu Anh Pham, El-Wui Loh, Ka-Wai Tam
Journal: Endoscopy (2024)
Exploration of the feasibility of the tunneling technique for colonic lesions originating from the muscularis propria
Authors: Bin-Yang Luo, Xia-Fei Gu, Zhu Wang
Journal: Endoscopy (2024)

Submucosal tunneling endoscopic resection (STER) was developed for treatment of upper gastrointestinal submucosal tumors originating from the muscularis propria, with its safety well-established through extensive clinical evidence. However, reports of its application in the resection of colonic lesions have been scarce. The thinner colonic wall, combined with the presence of colonic folds, substantially increases the complexity of the tunneling technique. In a recent case, we successfully employed the STER technique to treat a mass originating from the muscularis propria in the colon, demonstrating its feasibility in this context ([Video 1]).
Endoscopic retrieval of a huge gastric trichobezoar after thermally induced cutting with a hook knife
Authors: Ting Wei, Deliang Li, Saif Ullah, Dan Liu, Qingfen Zheng, Bingrong Liu
Journal: Endoscopy (2024)

Trichobezoars, composed of ingested hair, may lead to severe complications, including gastrointestinal obstruction, perforation, and gastric bleeding [1] [2] [3]. Herein, we report a case of successful endoscopic retrieval of a trichobezoar after thermally induced cutting with a hook knife.
Implementation and validation of single-cell genomics experiments in neuroscience
Authors: Marco Colonna, Genevieve Konopka, Shane A. Liddelow, Tomasz Nowakowski, Rajeshwar Awatramani, Helen S. Bateup, Cathryn R. Cadwell, Emre Caglayan, Jerry L. Chen, Jesse Gillis, Martin Kampmann, Fenna Krienen, Samuel E. Marsh, Michelle Monje, Michael R. O’Dea, Rickie Patani, Alex A. Pollen, Francisco J. Quintana, Marissa Scavuzzo, Matthew Schmitz, Steven A. Sloan, Paul J. Tesar, Jessica Tollkuhn, Maria Antonietta Tosches, Madeleine E. Urbanek, Jonathan M. Werner, Omer A. Bayraktar, Ozgun Gokce, Naomi Habib
Journal: Nature Neuroscience (2024)
Applying single-cell and single-nucleus genomics to studies of cellular heterogeneity and cell fate transitions in the nervous system
Authors: Igor Adameyko, Trygve Bakken, Aparna Bhaduri, Chintan Chhatbar, Mariella G. Filbin, David Gate, Hannah Hochgerner, Chang Nam Kim, Jordan Krull, Gioele La Manno, Qingyun Li, Sten Linnarsson, Qin Ma, Christian Mayer, Vilas Menon, Patricia Nano, Marco Prinz, Steve Quake, Christopher A. Walsh, Jin Yang, Omer Ali Bayraktar, Ozgun Gokce, Naomi Habib, Genevieve Konopka, Shane A. Liddelow, Tomasz J. Nowakowski
Journal: Nature Neuroscience (2024)