tbuckley/cabot-search huggingface dataset:
Integrative high-throughput enhancer surveying and functional verification divulges a YY2-condensed regulatory axis conferring risk for osteoporosis
Authors: Xiao-Feng Chen, Yuan-Yuan Duan, Ying-Ying Jia, Qian-Hua Dong, Wei Shi, Yan Zhang, Shan-Shan Dong, Meng Li, Zhongbo Liu, Fei Chen, Xiao-Ting Huang, Ruo-Han Hao, Dong-Li Zhu, Rui-Hua Jing, Yan Guo, Tie-Lin Yang
Journal: Cell Genomics (2024)

The precise roles of chromatin organization at osteoporosis risk loci remain largely elusive. Here, we combined chromatin interaction conformation (Hi-C) profiling and self-transcribing active regulatory region sequencing (STARR-seq) to qualify enhancer activities of prioritized osteoporosis-associated single-nucleotide polymorphisms (SNPs). We identified 319 SNPs with biased allelic enhancer activity effect (baaSNPs) that linked to hundreds of candidate target genes through chromatin interactions across 146 loci. Functional characterizations revealed active epigenetic enrichment for baaSNPs and prevailing osteoporosis-relevant regulatory roles for their chromatin interaction genes. Further motif enrichment and network mapping prioritized several putative, key transcription factors (TFs) controlling osteoporosis binding to baaSNPs. Specifically, we selected one top-ranked TF and deciphered that an intronic baaSNP (rs11202530) could allele-preferentially bind to YY2 to augment PAPSS2 expression through chromatin interactions and promote osteoblast differentiation. Our results underline the roles of TF-mediated enhancer-promoter contacts for osteoporosis, which may help to better understand the intricate molecular regulatory mechanisms underlying osteoporosis risk loci.
Microbial-derived imidazole propionate links the heart failure-associated microbiome alterations to disease severity
Authors: Sajan C. Raju, Antonio Molinaro, Ayodeji Awoyemi, Silje F. Jørgensen, Peder R. Braadland, Andraz Nendl, Ingebjørg Seljeflot, Per M. Ueland, Adrian McCann, Pål Aukrust, Beate Vestad, Cristiane Mayerhofer, Kaspar Broch, Lars Gullestad, Knut T. Lappegård, Bente Halvorsen, Karsten Kristiansen, Johannes R. Hov, Marius Trøseid
Journal: Genome Medicine (2024)

Abstract Background Interactions between the gut microbiota, diet, and host metabolism contribute to the development of cardiovascular disease, but a firm link between disease-specific gut microbiota alterations and circulating metabolites is lacking. Methods We performed shot-gun sequencing on 235 samples from 166 HF patients and 69 healthy control samples. Separate plasma samples from healthy controls ( n = 53) were used for the comparison of imidazole propionate (ImP) levels. Taxonomy and functional pathways for shotgun sequencing data was assigned using MetaPhlAn3 and HUMAnN3 pipelines. Results Here, we show that heart failure (HF) is associated with a specific compositional and functional shift of the gut microbiota that is linked to circulating levels of the microbial histidine-derived metabolite ImP. Circulating ImP levels are elevated in chronic HF patients compared to controls and associated with HF-related gut microbiota alterations. Contrary to the microbiota composition, ImP levels provide insight into etiology and severity of HF and also associate with markers of intestinal permeability and systemic inflammation. Conclusions Our findings establish a connection between changes in the gut microbiota, the presence, etiology, and severity of HF, and the gut-microbially produced metabolite ImP. While ImP appears promising as a circulating biomarker reflecting gut dysbiosis related to HF, further studies are essential to demonstrate its causal or contributing role in HF pathogenesis. Trial registration NCT02637167, registered December 22, 2015.
Conversion of Host Cell Receptor into Virus Destructor by Immunodisc to Neutralize Diverse SARS‐CoV‐2 Variants
Authors: Jaehyeon Hwang, Beom Kyu Kim, Seokoh Moon, Wonbeom Park, Kyeong Won Kim, Jeong Hyeon Yoon, Hyunseok Oh, Sangwon Jung, Youngseo Park, Suhyun Kim, Misoo Kim, Soomin Kim, Younghun Jung, Myungseo Park, Jun‐Ho Kim, Sang Taek Jung, Sang Jick Kim, Yong‐Sung Kim, Woo‐Jae Chung, Min‐Suk Song, Dae‐Hyuk Kweon
Journal: Advanced Healthcare Materials (2024)

Abstract The decreasing efficacy of antiviral drugs due to viral mutations highlights the challenge of developing a single agent targeting multiple strains. Using host cell viral receptors as competitive inhibitors is promising, but their low potency and membrane‐bound nature have limited this strategy. In this study, the authors show that angiotensin‐converting enzyme 2 (ACE2) in a planar membrane patch can effectively neutralize all tested severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants that emerged during the COVID‐19 pandemic. The ACE2‐incorporated membrane patch implemented using nanodiscs replicated the spike‐mediated membrane fusion process outside the host cell, resulting in virus lysis, extracellular RNA release, and potent antiviral activity. While neutralizing antibodies became ineffective as the SARS‐CoV‐2 evolved to better penetrate host cells the ACE2‐incorporated nanodiscs became more potent, highlighting the advantages of using receptor‐incorporated nanodiscs for antiviral purposes. ACE2‐incorporated immunodisc, an Fc fusion nanodisc developed in this study, completely protected humanized mice infected with SARS‐CoV‐2 after prolonged retention in the airways. This study demonstrates that the incorporation of viral receptors into immunodisc transforms the entry gate into a potent virucide for all current and future variants, a concept that can be extended to different viruses.
Robot-assisted Radical Cystectomy with Totally Intracorporeal Urinary Diversion Versus Open Radical Cystectomy: 3-Year Outcomes from a Randomised Controlled Trial
Authors: Riccardo Mastroianni, Gabriele Tuderti, Mariaconsiglia Ferriero, Umberto Anceschi, Alfredo Maria Bove, Aldo Brassetti, Simone D'Annunzio, Leonardo Misuraca, Giulia Torregiani, Marco Covotta, Salvatore Guaglianone, Michele Gallucci, Giuseppe Simone
Journal: European Urology (2024)
INPP4B ensures that ILC1s and NK cells set up a productive home office
Authors: Zi Yan Chen, Arthur Mortha
Journal: The Journal of Experimental Medicine (2024)

In this issue of JEM, Peng et al. (https://doi.org/10.1084/jem.20230124) identify inositol polyphosphate 4-phosphatase type II (encoded by Inpp4b) as an important enzyme for tissue-resident ILC1 and NK cell survival, signal transduction, and anti-tumor immunity.
Watch-and-Wait strategy vs. resection in patients with radiologic complete response after conversion therapy for initially unresectable hepatocellular carcinoma：a propensity score-matching comparative study
Authors: Binkui Li, Chenwei Wang, Wei He, Jiliang Qiu, Yun Zheng, Ruhai Zou, Zhu Lin, Yunxing Shi, Yichuan Yuan, Rong Zhang, Chao Zhang, Minshan Chen, Wan Yee Lau, Yunfei Yuan
Journal: International Journal of Surgery (2024)

Background: The optimal subsequent management for patients with initially unresectable hepatocellular carcinoma (uHCC) who have achieved complete response (CR) following conversion therapy remains unclear. This study aims to evaluate the feasibility and outcomes of the watch-and-wait (W-W) strategy versus surgical resection (SR) for these patients. Materials and Methods: This retrospective study reviewed patients with initially uHCC who underwent conversion therapy employing transarterial therapies combined with or without systemic therapies. Radiologic CR (rCR), clinical CR (cCR), and pathologic CR (pCR) were evaluated. Overall survival (OS) and progression-free survival (PFS) were compared between the W-W and SR groups. Results: Among 1880 patients with uHCC who underwent conversion therapy, 207 (11.0%) achieved rCR. Finally, we enrolled 149 patients meeting the inclusion criteria, including 74 receiving W-W strategy and 75 undergoing SR. Among the 149 patients with rCR, the W-W group demonstrated comparable 3-year OS rates to the SR group (80.9% vs 83.1%, P =0.77), but demonstrated inferior PFS rates (14.4% vs 46.5%, P =0.002). These results remained consistent after propensity score matching. For the 57 patients who achieved cCR, the W-W group exhibited comparable 3-year OS (88.1% vs 87.9%, P =0.89) and PFS rates (27.8% vs 40.8%, P =0.34) compared to SR group. Among the 75 patients in the SR group, 31 (41.3%) achieved pCR and 44 (58.7%) reached non-pCR. When compared with patients with pCR, those who achieved rCR in the W-W group showed comparable OS but inferior PFS rates. Moreover, patients who achieved rCR in the W-W group displayed both comparable OS and PFS rates to those with non-pCR. Conclusion: The W-W strategy offered comparable survival outcomes to surgical resection in patients with initially uHCC who achieved rCR or cCR after conversion therapy. For these patients, the W-W strategy could be offered as an alternative treatment option.
Regional lymph node mapping in patients with penile cancer undergoing radical inguinal lymph node dissection——retrospective cohort study
Authors: Xingliang Tan, Taonong Cai, Yanjun Wang, Zhiming Wu, Qianghua Zhou, Shengjie Guo, Jing Li, Gangjun Yuan, Zhenhua Liu, Zhiyong Li, Zhicheng Liu, Yi Tang, Yuantao Zou, Sihao Luo, Zike Qin, Fangjian Zhou, Chunhua Lin, Hui Han, Kai Yao
Journal: International Journal of Surgery (2024)

Background: Radical inguinal lymph node dissection (rILND) is the most available treatment to cure penile cancer (PC) with limited inguinal-confined disease. However, guidelines regarding acceptable boundaries of rILND are controversial, and consensus is lacking. We aimed to standardize the surgical boundaries of rILND with definite pathological evidence and explore the distribution pattern of inguinal lymph nodes (ILNs) in PC. Methods: A total of 414 PC patients from two centers who underwent rILND were enrolled. The ILN distribution was divided into seven zones anatomically for pathological examination. Student’s t test and Kaplan‒Meier survival analysis were used. Results: ILNs displayed a funnel-shaped distribution with high density in superior regions. ILNs and metastatic nodes present anywhere within the radical boundaries. Positive ILNs were mainly concentrated in zone I (51.7%) and zone II (41.3%), but there were 8.7 and 12.3% in inferior zones V and VI, respectively, and 7.1% in the deep ILNs. More importantly, a single positive ILN and first-station positive zone was detected in all seven regions. Single positive ILNs were located in zones I through VI in 40.4%, 23.6%, 6.7%, 18.0%, 4.5% and 1.1%, respectively, and 5.6% presented deep ILN metastasis directly. Conclusion: We established a detailed ILN distribution map and displayed lymphatic drainage patterns with definite pathological evidence using a large cohort of PC patients. Single positive ILNs and first-station metastatic zones were observed in any region, even directly with deep ILN metastasis. Only rILND can ensure tumor-free resection without the omission of positive nodes.
A commentary on “Intraoperative endomanometric laparoscopic Nissen fundoplication improves postoperative outcomes in large sliding hiatus hernias with severe gastroesophageal reflux disease: a retrospective cohort study”
Authors: Tingfen Han, Shuai Liu, Xiasang Qiu
Journal: International Journal of Surgery (2024)

aDepartment of Traditional Chinese Medicine, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou, 317000, China bDepartment of Gastrointestinal Surgery, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou, 317000, China Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding author. Address: 150 Ximen Street, Linhai City, Taizhou City, Zhejiang Province, 317000,China. E-mail address: [email protected] (X. Qiu). This is an open access article distributed under the Creative Commons Attribution-ShareAlike License 4.0, which allows others to remix, tweak, and build upon the work, even for commercial purposes, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-sa/4.0/
Implications of endoplasmic reticulum stress and beta-cell loss in immunodeficient diabetic NRG-Akita mice for understanding monogenic diabetes
Authors: Ahmed M. Rashwan, Mohamed M. A. Abumandour, Ramadan Kandyel, Om Prakash Choudhary, Rofaida Mostafa Soliman, Ashraf El Sharaby, Ahmed G. Nomir
Journal: International Journal of Surgery (2024)

Immunodeficient mice models have become increasingly important as in vivo models engrafted with human cells or tissues for research. The NOD-Rag1null Ins2Akita Il2rnull (NRG Akita) mice is a model combined with immunodeficient NRG and monogenic diabetes Akita mice that develop spontaneous hyperglycemia with progressive loss of pancreatic insulin-producing beta-cells with age. This model is one of the monogenic diabetic models, which has been providing a powerful platform for transplantation experiments of stem cells-generated human β-cells. This research aimed to provide insights into the mechanisms underlying this monogenic diabetes, which remains incompletely understood.
Beyond the 510(k): The regulation of novel moderate-risk medical devices, intellectual property considerations, and innovation incentives in the FDA’s De Novo pathway
Authors: Mateo Aboy, Cristina Crespo, Ariel Stern
Journal: npj Digital Medicine (2024)

Abstract Moderate-risk medical devices constitute 99% of those that have been regulated by the U.S. Food and Drug Administration (FDA) since it gained authority to regulate medical technology nearly five decades ago. This article presents an analysis of the interaction between the 510(k) process —the historically dominant path to market for most medical devices— and the De Novo pathway, a more recent alternative that targets more novel devices, including those involving new technologies, diagnostics, hardware, and software. The De Novo pathway holds significant potential for innovators seeking to define new categories of medical devices, as it represents a less burdensome approach than would have otherwise been needed historically. Moreover, it supports the FDA in its effort to modernize the long-established 510(k) pathway by promoting the availability of up-to-date device “predicates” upon which subsequent device applications can be based, reflecting positive spillovers that are likely to encourage manufacturers to adopt current state-of-the-art technologies and modern standards of safety and effectiveness. We analyze the of characteristics all the De Novo classification requests to date, including the submission type, trends, FDA review times, and device types. After characterizing how the De Novo process has been used over time, we discuss its unique challenges and opportunities with respect to medical device software and AI-enabled devices, including considerations for intellectual property, innovation, and competition economics.
Dynamic computational phenotyping of human cognition
Authors: Roey Schurr, Daniel Reznik, Hanna Hillman, Rahul Bhui, Samuel J. Gershman
Journal: Nature Human Behaviour (2024)

Abstract Computational phenotyping has emerged as a powerful tool for characterizing individual variability across a variety of cognitive domains. An individual’s computational phenotype is defined as a set of mechanistically interpretable parameters obtained from fitting computational models to behavioural data. However, the interpretation of these parameters hinges critically on their psychometric properties, which are rarely studied. To identify the sources governing the temporal variability of the computational phenotype, we carried out a 12-week longitudinal study using a battery of seven tasks that measure aspects of human learning, memory, perception and decision making. To examine the influence of state effects, each week, participants provided reports tracking their mood, habits and daily activities. We developed a dynamic computational phenotyping framework, which allowed us to tease apart the time-varying effects of practice and internal states such as affective valence and arousal. Our results show that many phenotype dimensions covary with practice and affective factors, indicating that what appears to be unreliability may reflect previously unmeasured structure. These results support a fundamentally dynamic understanding of cognitive variability within an individual.
Fibroblast heterogeneity in pulmonary fibrosis: a new target for therapeutics development?
Authors: Konstantin Tsoyi, Ivan O. Rosas
Journal: European Respiratory Journal (2024)

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with unknown aetiology [1]. The prevalence of this devastating disease continues to increase, affecting approximately 500 per 100 000 adults over the age of 65 years in the USA, and leading to rising rates of hospital admissions and deaths [2–5]. Two therapies for IPF approved by the US Food and Drug Administration, nintedanib and pirfenidone, can attenuate the decline in lung function. However, neither of these drugs can stop or reverse disease progression [6, 7]. Thus, an improved understanding of the pathogenesis of IPF and its underlying cellular and molecular mechanisms will facilitate the development of more effective therapies against this disorder. Do distinct fibroblast subpopulations contribute differentially to fibrosis progression and are these subsets therapeutic targets? <https://bit.ly/473kxJH>
Duration of cardiopulmonary resuscitation and outcomes for adults with in-hospital cardiac arrest: retrospective cohort study
Authors: Masashi Okubo, Sho Komukai, Lars W Andersen, Robert A Berg, Michael C Kurz, Laurie J Morrison, Clifton W Callaway
Journal: BMJ (2024)

Abstract Objective To quantify time dependent probabilities of outcomes in patients after in-hospital cardiac arrest as a function of duration of cardiopulmonary resuscitation, defined as the interval between start of chest compression and the first return of spontaneous circulation or termination of resuscitation. Design Retrospective cohort study. Setting Multicenter prospective in-hospital cardiac arrest registry in the United States. Participants 348 996 adult patients (≥18 years) with an index in-hospital cardiac arrest who received cardiopulmonary resuscitation from 2000 through 2021. Main outcome measures Survival to hospital discharge and favorable functional outcome at hospital discharge, defined as a cerebral performance category score of 1 (good cerebral performance) or 2 (moderate cerebral disability). Time dependent probabilities of subsequently surviving to hospital discharge or having favorable functional outcome if patients pending the first return of spontaneous circulation at each minute received further cardiopulmonary resuscitation beyond the time point were estimated, assuming that all decisions on termination of resuscitation were accurate (that is, all patients with termination of resuscitation would have invariably failed to survive if cardiopulmonary resuscitation had continued for a longer period of time). Results Among 348 996 included patients, 233 551 (66.9%) achieved return of spontaneous circulation with a median interval of 7 (interquartile range 3-13) minutes between start of chest compressions and first return of spontaneous circulation, whereas 115 445 (33.1%) patients did not achieve return of spontaneous circulation with a median interval of 20 (14-30) minutes between start of chest compressions and termination of resuscitation. 78 799 (22.6%) patients survived to hospital discharge. The time dependent probabilities of survival and favorable functional outcome among patients pending return of spontaneous circulation at one minute’s duration of cardiopulmonary resuscitation were 22.0% (75 645/343 866) and 15.1% (49 769/328 771), respectively. The probabilities decreased over time and were &lt;1% for survival at 39 minutes and &lt;1% for favorable functional outcome at 32 minutes’ duration of cardiopulmonary resuscitation. Conclusions This analysis of a large multicenter registry of in-hospital cardiac arrest quantified the time dependent probabilities of patients’ outcomes in each minute of duration of cardiopulmonary resuscitation. The findings provide resuscitation teams, patients, and their surrogates with insights into the likelihood of favorable outcomes if patients pending the first return of spontaneous circulation continue to receive further cardiopulmonary resuscitation.
Anorexia nervosa: diagnostic, therapeutic, and risk biomarkers in clinical practice
Authors: Hubertus Himmerich, Janet Treasure
Journal: Trends in Molecular Medicine (2024)

In anorexia nervosa (AN), measurable biological parameters can inform the process of treating patients. Such biomarkers include established laboratory parameters as well as a range of potential future biomarkers, including genetic, metabolomic, microbiomic, endocrine, immunological, hematological, electrophysiological, and neuroimaging parameters. In this opinion article we discuss how these biomarkers can support diagnosic and therapeutic processes at specific steps during the AN treatment cycle, that is, the diagnosis, diagnostic specification, risk management, choice of therapy, therapy monitoring, and treatment review. History-taking, physical and neuropsychological examination, clinical observation, and judgment about treatment success by the patient, their carers, and members of the multidisciplinary team are essential to interpret laboratory and imaging data appropriately and to assess the full clinical picture.
Risk Factors for Meeting Criteria for Switching from Bevacizumab to Aflibercept When Treating Eyes with Diabetic Macular Edema and Visual Acuity of &lt; 20/40
Authors: Chirag D. Jhaveri, Danni Liu, Maureen G. Maguire, Adam R. Glassman, Ruben A. Grigorian, Lee M. Jampol, Ronald M. Kingsley, Mathew W. MacCumber, Daniel F. Martin, Raj K. Maturi, Gisela Velez, Jennifer K. Sun
Journal: Ophthalmology (2024)
Ibrutinib-associated focal segmental glomerulosclerosis and the impact of podocin mutations in chronic lymphocytic leukemia
Authors: Jan Czogalla, Simon Schliffke, Shun Lu, Maria Schwerk, Helena Petereit, Tianran Zhang, Shuya Liu, Bernhard Dumoulin, Sydney Gies, Guochao Wu, Sonja Hänzelmann, Marlies Bode, Florian Grahammer, Markus Gödel, Minna Voigtländer, Linus Butt, Carsten Bokemeyer, Carsten Bergmann, Thomas Benzing, Thorsten Wiech, Victor G. Puelles, Tobias B. Huber
Journal: Kidney International (2024)
Using Two Predictive Models to Capture Two Types of Poor Outcomes in Knee Arthroplasty: A Multisite Longitudinal Cohort Study
Authors: Daniel L. Riddle, Levent Dumenci
Journal: Arthritis & Rheumatology (2024)

Poor outcome after knee arthroplasty (KA), a common major surgery worldwide, reportedly occurs in approximately 20% of patients. These patients demonstrate minimal improvement, at least moderate knee pain, and difficulty performing many routine daily activities. The purposes of our study were to comprehensively determine poor outcome risk after KA and to identify predictors of poor outcome.