tbuckley/cabot-search huggingface dataset:
Letter to the Editor: Regarding terlipressin-related patient outcomes in hepatorenal syndrome-acute kidney injury
Authors: Xin Luo, Jixian Yu
Journal: Hepatology (2024)

To the editor, As we know, terlipressin and albumin were mainstay treatments that could provide survival benefits for patients with hepatorenal syndrome-acute kidney injury (HRS-AKI) but may be associated with cardiopulmonary complications. In a recent issue of Hepatology, Premkumar et al1 analyzed the predictors of terlipressin response and mortality by using point-of-care echocardiography and cardiac and renal biomarkers. By using the predictor statistical analysis, they found and concluded that cirrhotic cardiomyopathy and reduction in cardiac index reliably predict terlipressin nonresponse and cirrhotic cardiomyopathy is independently associated with poor survival in patients with HRS-AKI. Despite their impressive results, in this letter, we raise some statistical concerns in this study, while it may change their predictive results for these patients with HRS-AKI. For the prediction statistical analysis, we should obey the basic statistical rule that 10 outcome events for analyzing 1 variable.2–4 However, for univariate prediction statistical analysis in Supplemental Table S1 of Premkumar and colleagues' study, there were 32 variables for the prediction of only 38 terlipressin nonresponse patients. Importantly, 38 cases at most analyzed 4 variables. Thus, this predictor model was too crowded, and it could get correct statistical results. Moreover, in Supplemental Table S3 of Premkumar and colleagues' study, which showed the Cox proportional hazard—univariable analysis for prediction of mortality, 23 dead patients were used to analyze the prediction model, which consists of 39 variables. In contrast, 23 dead patients at most analyzed 3 variables, not 39 variables in this study. Thus, these statistical results were unreliable. Before the prediction analysis, we could first compare these 32 variables between the terlipressin response patients and terlipressin nonresponse patients in Supplemental Table S1, or compare 39 variables between dead patients and survival patients in Supplemental Table S3 and find the significant variables. Then, using these significant variables to do the following univariate or multivariate prediction analysis it could obtain more accurate prediction statistical results. Without considering this basic statistical rule in this study, cirrhotic cardiomyopathy and reduction in cardiac index may be associated with but not predict the terlipressin nonresponse or mortality of patients with HRS-AKI. Thus, the exact predictive role of cirrhotic cardiomyopathy and reduction in the cardiac index in terlipressin nonresponse and survival of patients with HRS-AKI remain validation cohort or large sample size study to validate. However, we show great respect for Premkumar and colleagues' impressive study despite these comments.
<i>COL10A1</i> expression distinguishes a subset of cancer-associated fibroblasts present in the stroma of high-risk basal cell carcinoma
Authors: Mauro Esposito, Laura Yerly, Prachi Shukla, Victoria Hermes, Federica Sella, Zsolt Balazs, Evelyn Lattmann, Aizhan Tastanova, Patrick Turko, Ramon Lang, Isabel Kolm, Ramon Staeger, François Kuonen, Michael Krauthammer, Juerg Hafner, Mitchell P Levesque, Gaetana Restivo
Journal: British Journal of Dermatology (2024)

Basal cell carcinoma (BCC) is the most frequently diagnosed skin cancer and the most common malignancy in humans. Different morphological subtypes of BCC are associated with a low or high risk of recurrence and aggressiveness, but the underlying biology of how the individual subtypes arise remains largely unknown. As the majority of BCCs appear to arise from mutations in the same pathway, we hypothesized that BCC development, growth and invasive potential is also influenced by the tumour microenvironment and, in particular, by cancer-associated fibroblasts (CAFs) and the factors they secrete.
Forward programming of human induced pluripotent stem cells via the ETS variant transcription factor 2: rapid, reproducible, and cost-effective generation of highly enriched, functional endothelial cells
Authors: Sarah Rieck, Kritika Sharma, Carlotta Altringer, Michael Hesse, Christos Triantafyllou, Yanhui Zhang, Volker Busskamp, Bernd K Fleischmann
Journal: Cardiovascular Research (2024)

Abstract Aims Endothelial cell (EC) dysfunction plays a key role in the initiation and progression of cardiovascular disease. However, studying these disorders in ECs from patients is challenging; hence, the use of human induced pluripotent stem cells (hiPSCs) and their in vitro differentiation into ECs represents a very promising approach. Still, the generation of hiPSC-derived ECs (hECs) remains demanding as a cocktail of growth factors and an intermediate purification step are required for hEC enrichment. Therefore, we probed the utility of a forward programming approach using transgenic hiPSC lines. Methods and results We have used the transgenic hiPSC line PGP1 ETV2 isoform 2 to explore the in vitro differentiation of hECs via doxycycline-dependent induction of the ETS variant transcription factor 2 (ETV2) and compared these with a standard differentiation protocol for hECs using non-transgenic control hiPSCs. The transgenic hECs were highly enriched without an intermediate purification step and expressed—as non-transgenic hECs and human umbilical vein endothelial cells—characteristic EC markers. The viability and yield of transgenic hECs were strongly improved by applying EC growth medium during differentiation. This protocol was successfully applied in two more transgenic hiPSC lines yielding reproducible results with low line-to-line variability. Transgenic hECs displayed typical functional properties, such as tube formation and LDL uptake, and a more mature phenotype than non-transgenic hECs. Transgenic hiPSCs preferentially differentiated into the arterial lineage; this was further enhanced by adding a high concentration of vascular endothelial growth factor to the medium. We also demonstrate that complexing lentivirus with magnetic nanoparticles and application of a magnetic field enables efficient transduction of transgenic hECs. Conclusion We have established a highly efficient, cost-effective, and reproducible differentiation protocol for the generation of functional hECs via forward programming. The transgenic hECs can be genetically modified and are a powerful tool for disease modelling, tissue engineering, and translational purposes.
Biologic and Clinical Analysis of Childhood Gamma Delta T-ALL Identifies <i>LMO2/STAG2</i> Rearrangements as Extremely High Risk
Authors: Shunsuke Kimura, Chun Shik Park, Lindsey E. Montefiori, Ilaria Iacobucci, Petri Pölönen, Qingsong Gao, Elizabeth D. Arnold, Andishe Attarbaschi, Anthony Brown, Barbara Buldini, Kenneth J. Caldwell, Yunchao Chang, Chelsey Chen, Cheng Cheng, Zhongshan Cheng, John Choi, Valentino Conter, Kristine R. Crews, Hester A. de Groot-Kruseman, Takao Deguchi, Mariko Eguchi, Hannah E. Muhle, Sarah Elitzur, Gabriele Escherich, Burgess B. Freeman, Zhaohui Gu, Katie Han, Keizo Horibe, Toshihiko Imamura, Sima Jeha, Motohiro Kato, Kean H. Chiew, Tanya Khan, Michal Kicinski, Stefan Köhrer, Steven M. Kornblau, Rishi S. Kotecha, Chi-Kong Li, Yen-Chun Liu, Franco Locatelli, Selina M. Luger, Elisabeth M. Paietta, Atsushi Manabe, Hanne V. Marquart, Riccardo Masetti, Mellissa Maybury, Pauline Mazilier, Jules P.P. Meijerink, Sharnise Mitchell, Takako Miyamura, Andrew S. Moore, Koichi Oshima, Katarzyna Pawinska-Wasikowska, Rob Pieters, Mollie S. Prater, Shondra M. Pruett-Miller, Ching-Hon Pui, Chunxu Qu, Michaela Reiterova, Noemi Reyes, Kathryn G. Roberts, Jacob M. Rowe, Atsushi Sato, Kjeld Schmiegelow, Martin Schrappe, Shuhong Shen, Szymon Skoczeń, Orietta Spinelli, Jan Stary, Michael Svaton, Masatoshi Takagi, Junko Takita, Yanjing Tang, David T. Teachey, Paul G. Thomas, Daisuke Tomizawa, Jan Trka, Elena Varotto, Tiffaney L. Vincent, Jun J. Yang, Allen E.J. Yeoh, Yinmei Zhou, Martin Zimmermann, Hiroto Inaba, Charles G. Mullighan
Journal: Cancer Discovery (2024)

Abstract Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer–promoter looping, resulting in deregulation of gene expression associated with T-cell differentiation. High-throughput drug screening identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which can be targeted by poly(ADP-ribose) polymerase inhibition. These data provide a diagnostic framework for classification and risk stratification of pediatric γδ T-ALL. Significance: Patients with acute lymphoblastic leukemia expressing the gamma delta T-cell receptor under 3 years old or measurable residual disease ≥1% at end of induction showed dismal outcomes and should be classified as having high-risk disease. The STAG2/LMO2 subtype was enriched in this very young age group. STAG2 inactivation may perturb chromatin conformation and cell differentiation and confer vulnerability to poly(ADP-ribose) polymerase inhibition.
Aramchol improves hepatic fibrosis in metabolic dysfunction–associated steatohepatitis: Results of multimodality assessment using both conventional and digital pathology
Authors: Vlad Ratziu, Yusuf Yilmaz, Don Lazas, Scott L. Friedman, Caroline Lackner, Cynthia Behling, Oscar W. Cummings, Li Chen, Mathieu Petitjean, Yossi Gilgun-Sherki, Tali Gorfine, Shaul Kadosh, Eli Eyal, Arun J. Sanyal
Journal: Hepatology (2024)

Background and Aims: Antifibrotic trials rely on conventional pathology despite recognized limitations. We compared single-fiber digital image analysis with conventional pathology to quantify the antifibrotic effect of Aramchol, a stearoyl-CoA desaturase 1 inhibitor in development for metabolic dysfunction–associated steatohepatitis. Approach and Results: Fifty-one patients with metabolic dysfunction–associated steatohepatitis enrolled in the open-label part of the ARMOR trial received Aramchol 300 mg BID and had paired pre-post treatment liver biopsies scored by consensus among 3 hepatopathologists, and separately assessed by a digital image analysis platform (PharmaNest) that generates a continuous phenotypic Fibrosis Composite Severity (Ph-FCS) score. Fibrosis improvement was defined as: ≥1 NASH Clinical Research Network (NASH-CRN) stage reduction; “improved” by ranked pair assessment; reduction in Ph-FCS (“any” for ≥0.3 absolute reduction and “substantial” for ≥25% relative reduction). Fibrosis improved in 31% of patients (NASH-CRN), 51% (ranked pair assessment), 74.5% (any Ph-FCS reduction), and 41% (substantial Ph-FCS reduction). Most patients with stable fibrosis by NASH-CRN or ranked pair assessment had a Ph-FCS reduction (a third with substantial reduction). Fibrosis improvement increased with treatment duration: 25% for &lt;48 weeks versus 39% for ≥48 weeks by NASH-CRN; 43% versus 61% by ranked pair assessment, mean Ph-FCS reduction −0.54 (SD: 1.22) versus −1.72 (SD: 1.02); Ph-FCS reduction (any in 54% vs. 100%, substantial in 21% vs. 65%). The antifibrotic effect of Aramchol was corroborated by reductions in liver stiffness, Pro-C3, and enhanced liver fibrosis. Changes in Ph-FCS were positively correlated with changes in liver stiffness. Conclusions: Continuous fibrosis scores generated in antifibrotic trials by digital image analysis quantify antifibrotic effects with greater sensitivity and a larger dynamic range than conventional pathology.
Brain gene regulatory networks coordinate nest construction in birds
Authors: Yi-Ting Fang, Hao-Chih Kuo, Cheng-Yu Chen, Shen-Ju Chou, Chia-Wei Lu, Chih-Ming Hung
Journal: Molecular Biology and Evolution (2024)

Nest building is a vital behavior exhibited during breeding in birds, and is possibly induced by environmental and social cues. Although such behavioral plasticity has been hypothesized to be controlled by adult neuronal plasticity, empirical evidence, especially at the neurogenomic level, remains limited. Here, we aim to uncover the gene regulatory networks that govern avian nest construction and examine whether they are associated with circuit rewiring. We designed an experiment to dissect this complex behavior into components in response to pair bonding and nest material acquisition by manipulating the presence of mates and nest materials in 30 pairs of zebra finches. Whole-transcriptome analysis of 300 samples from five brain regions linked to avian nesting behaviors revealed nesting-associated gene expression enriched with neural rewiring functions, including neurogenesis and neuron projection. The enriched expression was observed in the motor/sensorimotor and social behavior networks of female finches, and in the dopaminergic reward system of males. Female birds exhibited predominant neurotranscriptomic changes to initiate the nesting stage, while males showed major changes after entering this stage, underscoring sex-specific roles in nesting behavior. Notably, major neurotranscriptomic changes occurred during pair bonding, with minor changes during nest material acquisition, emphasizing social interactions in nest construction. We also revealed gene expression associated with reproductive behaviors and tactile sensing for nesting behavior. This study presents novel neurogenomic evidence supporting the hypothesis of adult neural plasticity underlying avian nest-construction behavior. By uncovering the genetic toolkits involved, we offer novel insights into the evolution of animals' innate ability to construct nests.
Surface Engineering for Endothelium‐Mimicking Functions to Combat Infection and Thrombosis in Extracorporeal Life Support Technologies
Authors: Morgan Ashcraft, Mark Garren, Orsolya Lautner‐Csorba, Vicente Pinon, Yi Wu, Dagney Crowley, Joseph Hill, Yeniselis Morales, Robert Bartlett, Elizabeth J. Brisbois, Hitesh Handa
Journal: Advanced Healthcare Materials (2024)

Abstract Blood‐contacting medical devices routinely fail from the cascading effects of biofouling toward infection and thrombosis. Nitric oxide (NO) is an integral part of endothelial homeostasis, maintaining platelet quiescence and facilitating oxidative/nitrosative stress against pathogens. Recently, it is shown that the surface evolution of NO can mediate cell‐surface interactions. However, this technique alone cannot prevent the biofouling inherent in device failure with dynamic blood‐contacting applications. This work proposes an endothelium‐mimicking surface design pairing controlled NO release with an inherently antifouling polyethylene glycol interface (NO+PEG). This simple, robust, and scalable platform develops surface‐localized NO availability with surface hydration, leading to a significant reduction in protein adsorption as well as bacteria/platelet adhesion. Further in vivo thrombogenicity studies show a decrease in thrombus formation on NO+PEG interfaces, with preservation of circulating platelet and white blood cell counts, maintenance of activated clotting time, and reduced coagulation cascade activation. It is anticipated that this bio‐inspired surface design will enable a facile alternative to existing surface technologies to address clinical manifestations of infection and thrombosis in dynamic blood‐contacting environments.
Innate and adaptive immune responses that control lymph-borne viruses in the draining lymph node
Authors: Carolina R. Melo-Silva, Luis J. Sigal
Journal: Cellular and Molecular Immunology (2024)

Abstract The interstitial fluids in tissues are constantly drained into the lymph nodes (LNs) as lymph through afferent lymphatic vessels and from LNs into the blood through efferent lymphatics. LNs are strategically positioned and have the appropriate cellular composition to serve as sites of adaptive immune initiation against invading pathogens. However, for lymph-borne viruses, which disseminate from the entry site to other tissues through the lymphatic system, immune cells in the draining LN (dLN) also play critical roles in curbing systemic viral dissemination during primary and secondary infections. Lymph-borne viruses in tissues can be transported to dLNs as free virions in the lymph or within infected cells. Regardless of the entry mechanism, infected myeloid antigen-presenting cells, including various subtypes of dendritic cells, inflammatory monocytes, and macrophages, play a critical role in initiating the innate immune response within the dLN. This innate immune response involves cellular crosstalk between infected and bystander innate immune cells that ultimately produce type I interferons (IFN-Is) and other cytokines and recruit inflammatory monocytes and natural killer (NK) cells. IFN-I and NK cell cytotoxicity can restrict systemic viral spread during primary infections and prevent serious disease. Additionally, the memory CD8 + T-cells that reside or rapidly migrate to the dLN can contribute to disease prevention during secondary viral infections. This review explores the intricate innate immune responses orchestrated within dLNs that contain primary viral infections and the role of memory CD8 + T-cells following secondary infection or CD8 + T-cell vaccination.
Null‐type <i>SH2B3</i> mutations are potential drivers in a subset of Ph‐negative myeloproliferative neoplasms
Authors: Xi Zhang, Yi Ding, Peng Li, Kirk Bourgeois, Aruna Rangan, Jennifer L. Herrick, Animesh Pardanani, Dong Chen, David Viswanatha, Rong He, Gang Zheng
Journal: American Journal of Hematology (2024)
Excess Risk of Injury in Individuals With Type 1 or Type 2 Diabetes Compared With the General Population
Authors: Berhanu Elfu Feleke, Agus Salim, Jedidiah I. Morton, Belinda J. Gabbe, Dianna J. Magliano, Jonathan E. Shaw
Journal: Diabetes Care (2024)

OBJECTIVE To estimate the relative risk (RR) and excess hospitalization rate for injury in individuals with diabetes compared with the general population. RESEARCH DESIGN AND METHODS Data were obtained from the Australian National Diabetes Services Scheme, hospitalization data sets, the Australian Pharmaceutical Benefits Scheme, the National Death Index, and the census spanning from 2011 to 2017. Hospitalizations for injury were coded as head and neck, lower-extremity, upper-extremity, or abdominal and thoracic injury; burns; or other injury. Poisson regression was used to estimate the age- and sex-adjusted RR of hospitalization for injury. RESULTS The total number of hospitalizations for any injury was 117,705 in people with diabetes and 3,463,173 in the general population. Compared with that in the general population, an elevated adjusted risk of admission was observed for any injury (RR 1.22; 95% CI 1.21, 1.22), head and neck (1.28; 1.26, 1.30), lower extremity (1.24; 1.23, 1.26), abdominal and thoracic (1.29; 1.27, 1.30), upper extremity (1.03; 1.02, 1.05), burns (1.52; 1.44, 1.61), and other injury (1.37; 1.33, 1.40). The adjusted RR of any injury was 1.62 (1.58, 1.66) in individuals with type 1 diabetes, 1.65 (1.63, 1.66) in those with type 2 diabetes who were taking insulin, and 1.07 (1.06, 1.08) in individuals with type 2 diabetes not using insulin. Falls were the primary cause of injury in individuals with diabetes. CONCLUSIONS Individuals with diabetes, especially those using insulin, had a higher risk of hospitalization for injury compared with the general population.
Short- and long-term neuropsychiatric outcomes in long COVID in South Korea and Japan
Authors: Sunyoung Kim, Hayeon Lee, Jinseok Lee, Seung Won Lee, Rosie Kwon, Min Seo Kim, Ai Koyanagi, Lee Smith, Guillaume Fond, Laurent Boyer, Masoud Rahmati, Guillermo F. López Sánchez, Elena Dragioti, Samuele Cortese, Ju-Young Shin, Ahhyung Choi, Hae Sun Suh, Sunmi Lee, Marco Solmi, Chanyang Min, Jae Il Shin, Dong Keon Yon, Paolo Fusar-Poli
Journal: Nature Human Behaviour (2024)
A humanized mouse that mounts mature class-switched, hypermutated and neutralizing antibody responses
Authors: Daniel P. Chupp, Carlos E. Rivera, Yulai Zhou, Yijiang Xu, Patrick S. Ramsey, Zhenming Xu, Hong Zan, Paolo Casali
Journal: Nature Immunology (2024)

Humanized mice are limited in terms of modeling human immunity, particularly with regards to antibody responses. Here we constructed a humanized (THX) mouse by grafting non-γ-irradiated, genetically myeloablated Kit
A portable thermal ablation device for cervical cancer prevention in a screen-and-treat setting: a randomized, noninferiority trial
Authors: Partha Basu, Mulindi Mwanahamuntu, Leeya F. Pinder, Richard Muwonge, Eric Lucas, Namakau Nyambe, Samson Chisele, Aaron Lunda Shibemba, Catherine Sauvaget, Rengaswamy Sankaranarayanan, Walter Prendiville, Groesbeck P. Parham
Journal: Nature Medicine (2024)

Abstract Implementing standard-of-care cryotherapy or electrosurgical excision to treat cervical precancers is challenging in resource-limited settings. An affordable technological alternative that is as effective as standard-of-care techniques would greatly improve access to treatment. This randomized controlled trial aims to demonstrate the noninferiority efficacy of a portable, battery-driven thermal ablation (TA) device compared to cryotherapy and electrosurgical excision (large loop excision of transformation zone (LLETZ)) to treat cervical precancer in a screen-and-treat program in Zambia. A total of 3,124 women positive on visual inspection with acetic acid and eligible for ablative therapy were randomized to one of the treatment arms. Human papillomavirus (HPV) testing was performed at baseline and at the follow-up. The primary outcome was treatment success, defined as either type-specific HPV clearance at the follow-up in participants positive for HPV at baseline, or a negative visual inspection with acetic acid test for those who had a negative HPV test at baseline. After a median follow-up of 12 months, treatment success rates were 74.0%, 71.1% and 71.4% for the TA, cryotherapy and LLETZ arms, respectively, thus demonstrating noninferiority ( P = 0.83). TA was a safe and well-accepted procedure. Only 3.6% of those randomized to TA reported moderate-to-severe pain, compared to 6.5% and 1.9% for the cryotherapy and LLETZ arms, respectively. Thus, our randomized controlled trial demonstrates the safety and efficacy of TA, which is not inferior to cryotherapy or surgical excision. ClinicalTrials.gov registration: NCT02956239 .
Adaptive selection at G6PD and disparities in diabetes complications
Authors: Joseph H. Breeyear, Jacklyn N. Hellwege, Philip H. Schroeder, John S. House, Hannah M. Poisner, Sabrina L. Mitchell, Brian Charest, Anjali Khakharia, Til B. Basnet, Christopher W. Halladay, Peter D. Reaven, James B. Meigs, Mary K. Rhee, Yang Sun, Mary G. Lynch, Alexander G. Bick, Otis D. Wilson, Adriana M. Hung, Cari L. Nealon, Sudha K. Iyengar, Daniel M. Rotroff, John B. Buse, Aaron Leong, Josep M. Mercader, Lucia Sobrin, Milam A. Brantley, Neal S. Peachey, Alison A. Motsinger-Reif, Peter W. Wilson, Yan V. Sun, Ayush Giri, Lawrence S. Phillips, Todd L. Edwards
Journal: Nature Medicine (2024)
Strain-specific gut microbial signatures in type 2 diabetes identified in a cross-cohort analysis of 8,117 metagenomes
Authors: Zhendong Mei, Fenglei Wang, Amrisha Bhosle, Danyue Dong, Raaj Mehta, Andrew Ghazi, Yancong Zhang, Yuxi Liu, Ehud Rinott, Siyuan Ma, Eric B. Rimm, Martha Daviglus, Walter C. Willett, Rob Knight, Frank B. Hu, Qibin Qi, Andrew T. Chan, Robert D. Burk, Meir J. Stampfer, Iris Shai, Robert C. Kaplan, Curtis Huttenhower, Dong D. Wang
Journal: Nature Medicine (2024)