tbuckley/cabot-search huggingface dataset:
Mutational signatures define immune and Wnt-associated subtypes of ampullary carcinoma
Authors: Ekaterina Zhuravleva, Monika Lewinska, Colm J O'Rourke, Antonio Pea, Asif Rashid, Ann W Hsing, Andrzej Taranta, David Chang, Yu-Tang Gao, Jill Koshiol, Rui Caetano Oliveira, Jesper B Andersen
Journal: Gut (2024)

Background and objective Ampullary carcinoma (AMPAC) taxonomy is based on morphology and immunohistochemistry. This classification lacks prognostic reliability and unique genetic associations. We applied an approach of integrative genomics characterising patients with AMPAC exploring molecular subtypes that may guide personalised treatments. Design We analysed the mutational landscapes of 170 patients with AMPAC. The discovery included 110 tumour/normal pairs and the validation comprised 60 patients. In a tumour subset, we interrogated the transcriptomes and DNA methylomes. Patients were stratified based on mutational signatures and associated with molecular and clinical features. To evaluate tumour and immune cellularity, 22 tumours were independently assessed histomorphologically and by digital pathology. Results We defined three patient clusters by mutational signatures independent of histomorphology. Cluster 1 (C1) was defined by spontaneous deamination of DNA 5-methylcytosine and defective mismatch repair. C2 and C3 were related to the activity of transcription-coupled nucleotide excision repair but C3 was further defined by the polymerase eta mutational process. C1–2 showed enrichment of Wnt pathway alterations, aberrant DNA methylation profiles, immune cell exclusion and patients with poor prognosis. These features were associated with a hypermutator phenotype caused by C&gt;T alterations at CpGs. C3 patients with improved overall survival were associated with activation of immune-related pathways, immune infiltration and elevated expression of immunoinhibitory checkpoint genes. Conclusion Immunogenicity and Wnt pathway associations, emphasised by the mutational signatures, defined patients with prospective sensitivity to either immunotherapy or Wnt pathway inhibitors. This emphasises a novel mutational signature-based AMPAC classification with prognostic potential, suggesting prospective implications for subgroup-specific management of patients with AMPAC.
Cardiovascular-Liver-Metabolic Health: Recommendations in Screening, Diagnosis, and Management of Metabolic Dysfunction-Associated Steatotic Liver Disease in Cardiovascular Disease via Modified Delphi Approach
Authors: Nicholas W.S. Chew, Anurag Mehta, Rachel Sze Jen Goh, Audrey Zhang, Yiming Chen, Bryan Chong, Han Shi Jocelyn Chew, Asim Shabbir, Adrian Brown, Georgios K. Dimitriadis, Daniel Q. Huang, Roger Foo, Carel W. le Roux, Gemma A. Figtree, Marat Fudim, Ambarish Pandey, Mamas A. Mamas, Derek J. Hausenloy, A. Mark Richards, Stephen J. Nicholls, Mark Y. Chan, Mark D. Muthiah, Arun Sanyal, Laurence S. Sperling
Journal: Circulation (2024)

There is a new awareness of the widespread nature of metabolic dysfunction–associated steatotic liver disease (MASLD) and its connection to cardiovascular disease (CVD). This has catalyzed collaboration between cardiologists, hepatologists, endocrinologists, and the wider multidisciplinary team to address the need for earlier identification of those with MASLD who are at increased risk for CVD. The overlap in the pathophysiologic processes and parallel prevalence of CVD, metabolic syndrome, and MASLD highlight the multisystem consequences of poor cardiovascular–liver–metabolic health. Metabolic dysfunction and associated insulin resistance, together with the predilection for ectopic fat deposition in the liver and surrounding tissues, are associated with elevated risk of endothelial dysfunction, systemic inflammatory response, and ectopic fat deposition in the epicardium. This complex pathophysiology can accelerate atherogenic dyslipidemia, atherogenesis, diastolic dysfunction, valvular calcification, and cardiac arrhythmias. Despite the mounting evidence of mechanistic pathways underpinning MASLD and CVD, current recommendations have not clearly focused upon MASLD as a risk factor or target for intervention in CVD. We have brought together a diverse range of international experts committed to promoting cardiovascular–liver–metabolic health and related outcomes across the globe. The overarching goal of this document is to offer a construct for clinicians in the cardiovascular field with regards to (1) diagnosis and screening of MASLD through the use of noninvasive serum and imaging tests; (2) screening for CVD in all individuals with MASLD regardless of established atherosclerotic risk factors; and (3) the approach to management of MASLD with respect to prevention of CVD through lifestyle, as well as pharmacologic and surgical strategies. To achieve this, the modified Delphi method was applied and a series of evidence-based quality standard recommendations have been identified.
The Financial Burden of Localized and Metastatic Bladder Cancer
Authors: Pietro Scilipoti, Marco Moschini, Roger Li, Seth P Lerner, Peter C Black, Andrea Necchi, Morgan Rouprêt, Shahrokh F Shariat, Shilpa Gupta, Alicia K Morgans, Sarah P Psutka, Ashish M Kamat
Journal: European Urology (2024)
Differential Efficacy of Advanced Therapies in Inducing Remission in Ulcerative Colitis Based on Prior Exposure to TNF Antagonists
Authors: Han Hee Lee, Virginia Solitano, Sujay Singh, Ashwin N Ananthakrishnan, Vipul Jairath, Gaurav Syal, Brigid S Boland, Pradipta Ghosh, John T Chang, Siddharth Singh
Journal: Clinical Gastroenterology and Hepatology (2024)
Comparative efficacy and safety of treatment regimens for Pneumocystis jirovecii pneumonia in people living with HIV – A systematic review and network meta-analysis of randomized controlled trials
Authors: Stefan Hatzl, Florian Posch, Laura Scholz, Christina Geiger, Lisa Kriegl, Philipp Kreuzer, Philipp Eller, Daniele Roberto Giacobbe, Matteo Bassetti, Martin Hoenigl, Robert Krause
Journal: Clinical Microbiology and Infection (2024)

Pneumocystis jirovecii pneumonia (PCP) is a serious opportunistic infection in people living with HIV (PWH) who have low CD4 counts. Despite its side effects, trimethoprim-sulfamethoxazole (TMP-SMX) is currently considered the primary treatment for PCP.
Modified Crohn’s Disease Exclusion Diet Maintains Remission in Pediatric Crohn’s Disease; Randomized Controlled Trial
Authors: Rotem Sigall Boneh, Víctor Manuel Navas-López, Séamus Hussey, Gemma Pujol-Muncunill, Sally Lawrence, Helena Rolandsdotter, Anthony Otley, Javier Martín-de-Carpi, Lee Abramas, Marta Herrador-López, Natalia Egea Castillo, Min Chen, Michelle Hurley, Kirsten Wingate, Ola Olen, Tintin Eurenius Rääf, Michal Yaakov, Nicolette Wierdsma, Johan Van Limbergen, Eytan Wine
Journal: Clinical Gastroenterology and Hepatology (2024)
Contrasting rule and machine learning based digital self triage systems in the USA
Authors: Bilal A. Naved, Yuan Luo
Journal: npj Digital Medicine (2024)

Abstract Patient smart access and self-triage systems have been in development for decades. As of now, no LLM for processing self-reported patient data has been published by health systems. Many expert systems and computational models have been released to millions. This review is the first to summarize progress in the field including an analysis of the exact self-triage solutions available on the websites of 647 health systems in the USA.
N-terminus α-synuclein detection reveals new and more diverse aggregate morphologies in multiple system atrophy and Parkinson’s disease
Authors: James A. Wiseman, YuHong Fu, Richard L. M. Faull, Clinton P. Turner, Maurice A. Curtis, Glenda M. Halliday, Birger V. Dieriks
Journal: Translational Neurodegeneration (2024)

Abstract Background Parkinson’s disease (PD) and multiple system atrophy (MSA) are classified as α-synucleinopathies and are primarily differentiated by their clinical phenotypes. Delineating these diseases based on their specific α-synuclein (α-Syn) proteoform pathologies is crucial for accurate antemortem biomarker diagnosis. Newly identified α-Syn pathologies in PD raise questions about whether MSA exhibits a similar diversity. This prompted the need for a comparative study focusing on α-Syn epitope-specific immunoreactivities in both diseases, which could clarify the extent of pathological overlap and diversity, and guide more accurate biomarker development. Methods We utilised a multiplex immunohistochemical approach to detect multiple structural domains of α-Syn proteoforms across multiple regions prone to pathological accumulation in MSA ( n = 10) and PD ( n = 10). Comparison of epitope-specific α-Syn proteoforms was performed in the MSA medulla, inferior olivary nucleus, substantia nigra, hippocampus, and cerebellum, and in the PD olfactory bulb, medulla, substantia nigra, hippocampus, and entorhinal cortex. Results N-terminus and C-terminus antibodies detected significantly more α-Syn pathology in MSA than antibodies for phosphorylated (pS129) α-Syn, which are classically used to detect α-Syn. Importantly, C-terminus immunolabelling is more pronounced in MSA compared to PD. Meanwhile, N-terminus immunolabelling consistently detected the highest percentage of α-Syn across pathologically burdened regions of both diseases, which could be of biological significance. As expected, oligodendroglial involvement distinguished MSA from PD, but in contrast to PD, no substantial astrocytic or microglial α-Syn accumulation in MSA occurred. These data confirm glial-specific changes between these diseases when immunolabelling the N-terminus epitope. In comparison, N-terminus neuronal α-Syn was present in PD and MSA, with most MSA neurons lacking pS129 α-Syn proteoforms. This explains why characterisation of neuronal MSA pathologies is lacking and challenges the reliance on pS129 antibodies for the accurate quantification of α-Syn pathological load across α-synucleinopathies. Conclusions These findings underscore the necessity of utilising a multiplex approach to detect α-Syn, most importantly including the N-terminus, to capture the entire spectrum of α-Syn proteoforms in α-synucleinopathies. The data provide novel insights toward the biological differentiation of these α-synucleinopathies and pave the way for more refined antemortem diagnostic methods to facilitate early identification and intervention of these neurodegenerative diseases.
SARS-CoV-2 membrane protein induces neurodegeneration via affecting Golgi-mitochondria interaction
Authors: Fang Wang, Hailong Han, Caifang Wang, Jingfei Wang, Yanni Peng, Ye Chen, Yaohui He, Zhouyang Deng, Fang Li, Yikang Rong, Danling Wang, Wen Liu, Hualan Chen, Zhuohua Zhang
Journal: Translational Neurodegeneration (2024)

Abstract Background Neurological complications are a significant concern of Coronavirus Disease 2019 (COVID-19). However, the pathogenic mechanism of neurological symptoms associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is poorly understood. Methods We used Drosophila as a model to systematically analyze SARS-CoV-2 genes encoding structural and accessory proteins and identified the membrane protein (M) that disrupted mitochondrial functions in vivo. The M protein was stereotaxically injected to further assess its effects in the brains of wild-type (WT) and 5 × FAD mice. Omics technologies, including RNA sequencing and interactome analysis, were performed to explore the mechanisms of the effects of M protein both in vitro and in vivo. Results Systematic analysis of SARS-CoV-2 structural and accessory proteins in Drosophila identified that the M protein induces mitochondrial fragmentation and dysfunction, leading to reduced ATP production, ROS overproduction, and eventually cell death in the indirect flight muscles. In WT mice, M caused hippocampal atrophy, neural apoptosis, glial activation, and mitochondrial damage. These changes were further aggravated in 5 × FAD mice. M was localized to the Golgi apparatus and genetically interacted with four wheel drive (FWD, a Drosophila homolog of mammalian PI4KIIIβ) to regulate Golgi functions in flies. Fwd RNAi, but not PI4KIIIα RNAi, reversed the M-induced Golgi abnormality, mitochondrial fragmentation, and ATP reduction. Inhibition of PI4KIIIβ activity suppressed the M-induced neuronal cell death. Therefore, M induced mitochondrial fragmentation and apoptosis likely through disruption of Golgi-derived PI(4)P-containing vesicles. Conclusions M disturbs the distribution and function of Golgi, leading to mitochondrial abnormality and eventually neurodegeneration via a PI4KIIIβ-mediated mechanism. This study reveals a potential mechanism for COVID-19 neurological symptoms and opens a new avenue for development of therapeutic strategies targeting SARS-CoV-2 M or mitochondria.
Empagliflozin in acute myocardial infarction in patients with and without type 2 diabetes: A pre‐specified analysis of the <scp>EMPACT</scp>‐<scp>MI</scp> trial
Authors: Mark C. Petrie, Jacob A. Udell, Stefan D. Anker, Josephine Harrington, W. Schuyler Jones, Michaela Mattheus, Tomasz Gasior, Peter van der Meer, Offer Amir, M. Cecilia Bahit, Johann Bauersachs, Antoni Bayes‐Genis, Vijay K. Chopra, James L. Januzzi, Renato D. Lopes, Piotr Ponikowski, Xavier Rossello, Morten Schou, Shelley Zieroth, Martina Brueckmann, Mikhail Sumin, Deepak L. Bhatt, Adrian F. Hernandez, Javed Butler
Journal: European Journal of Heart Failure (2024)

In the EMPACT-MI trial, empagliflozin reduced heart failure (HF) hospitalizations but not mortality in acute myocardial infarction (MI). Contemporary reports of clinical event rates with and without type 2 diabetes mellitus (T2DM) in acute MI trials are sparse. The treatment effect of empagliflozin in those with and without T2DM in acute MI is unknown.
The transcriptional profile of iron deficiency in patients with heart failure: Heme‐sparing and reduced immune processes
Authors: Niels Grote Beverborg, Ridha I.S. Alnuwaysir, George Markousis‐Mavrogenis, Martijn F. Hoes, Haye H. van der Wal, Simon P.R. Romaine, Mintu Nath, Andrea Koekoemoer, John G.F. Cleland, Chim C. Lang, Stefan D. Anker, Kenneth Dickstein, Marco Metra, Leong L. Ng, Dirk J. van Veldhuisen, Adriaan A. Voors, Nilesh J. Samani, Peter van der Meer
Journal: European Journal of Heart Failure (2024)

Aims Iron deficiency (ID) is highly prevalent in patients with heart failure (HF) and associated with morbidity and poor prognosis, but pathophysiological mechanisms are unknown. We aimed to identify novel biological pathways affected by ID. Methods and results We studied 881 patients with HF from the BIOSTAT‐CHF cohort. ID was defined as a transferrin saturation &lt;20%. Transcriptome profiling was performed in whole blood. Identified targets were validated in a human in vitro stem cell‐derived cardiomyocyte ID model utilizing deferoxamine as iron chelator. ID was identified in 554 (62.9%) patients, and 89 differentially expressed genes between ID and non‐ID were identified, of which 60 were up‐ and 29 were downregulated. Upregulated genes were overrepresented in pathways of erythrocyte development and homeostasis. Heme biosynthetic processes were confirmed as relatively upregulated in ID, while iron–sulfur cluster assembly was downregulated. Downregulated processes further included natural killer cell and lymphocyte mediated immunity. In agreement with patient data, cardiomyocyte iron depletion significantly induced the expression of two genes ( SIAH2 and CLIC4 ), which could be normalized upon iron supplementation. Both SIAH2 and CLIC4 are associated with increased mortality in patients with HF (hazard ratio 2.40, 95% confidence interval 1.86–3.11, p &lt; 0.001 hazard ratio 1.78, 95% confidence interval 1.53–2.07, p &lt; 0.001, respectively). Conclusion Iron deficiency is associated with the preservation of heme‐related processes at the cost of iron–sulfur clusters. Immune processes are downregulated, uncovering another high energy demand system affected. SIAH2 and CLIC4 might be modifiable factors in the relation between ID and impaired prognosis.
Neoadjuvant atezolizumab + chemotherapy for resectable NSCLC: 3-year clinical update of phase II clinical trial results and translational findings
Authors: Brian S Henick, Peter D Koch, Justin F Gainor, Mark M Awad, Codruta Chiuzan, Stephanie Izard, Yohanna Georgis, Samyukta Mallick, Robert F Garofano, Cheryl V Wong, Anjali Saqi, Jessica Grindheim, Katja Schulze, Joshua R Sonett, Naiyer A Rizvi, Benjamin Izar, Alison M Taylor, Catherine A Shu
Journal: Journal for ImmunoTherapy of Cancer (2024)

Introduction Neoadjuvant chemoimmunotherapy has achieved overall survival (OS) benefit for patients with resectable non-small cell lung cancer (NSCLC). Here, we present outcomes after 3 years of follow-up from the first reported study of neoadjuvant atezolizumab+chemotherapy. Methods This open-label, multicenter single-arm investigator-initiated phase II study conducted at three US hospitals tested up to four cycles of atezolizumab, carboplatin, and nab-paclitaxel prior to surgery. Major pathological response (MPR, primary endpoint) was previously reported; here, we report 3-year disease-free survival (DFS), OS, and clinical characteristics of patients developing brain metastases (BM) with integrated data from tumor genomics, gene expression, and quantitative immunofluorescent measurement of immune markers. Results Of 30 enrolled patients, 29 were taken to the operating room. 26 underwent R0 resection, with 17 experiencing MPR (10 pCR). With a median follow-up of 39.5 months, the median OS was 55.8 months, and the median DFS was 34.5 months. Landmark OS at 36 months was 77%. Among 14 patients with recurrent disease, 6 patients had BM. Patients whose tumors had mutations in STK11 and KEAP1 did not have a significantly higher incidence of BM. Reduced copy number of STK11 and KEAP1 , both residing on chromosome 19p, was observed in ~1/3 of tumors. Reduced CN of STK11 was significantly associated with worse pathological response and incidence of BM. Conclusions Consistent with recent phase III studies, 3-year OS data with neoadjuvant atezolizumab+chemotherapy was associated with prolonged PFS and OS. Establishing associations between STK11 and KEAP1 genomic alterations and key clinical outcomes in early-stage NSCLC requires further study.
Gut microbiota-derived 4-hydroxyphenylacetic acid from resveratrol supplementation prevents obesity through SIRT1 signaling activation
Authors: Pan Wang, Ruiqi Wang, Wenting Zhao, Yuanyuan Zhao, Dan Wang, Shuang Zhao, Zhiwen Ge, Yue Ma, Xiaoyan Zhao
Journal: Gut Microbes (2024)

Resveratrol (RSV), a natural polyphenol, has been suggested to influence glucose and lipid metabolism. However, the underlying molecular mechanism of its action remains largely unknown due to its multiple biological targets and low bioavailability. In this study, we demonstrate that RSV supplementation ameliorates high-fat-diet (HFD)-induced gut microbiota dysbiosis, enhancing the abundance of anti-obesity bacterial strains such as Akkermansia, Bacteroides and Blautia. The critical role of gut microbiota in RSV-mediated anti-obesity effects was confirmed through antibiotic-induced microbiome depletion and fecal microbiota transplantation (FMT), which showed that RSV treatment effectively mitigates body weight, histopathological damage, glucose dysregulation and systematic inflammation associated with HFD. Metabolomics analysis revealed that RSV supplementation significantly increases the levels of the gut microbial flavonoid catabolite 4-hydroxyphenylacetic acid (4-HPA). Notably, 4-HPA was sufficient to reverse obesity and glucose intolerance in HFD-fed mice. Mechanistically,4-HPA treatment markedly regulates SIRT1 signaling pathways and induces the expression of beige fat and thermogenesis-specific markers in white adipose tissue (WAT). These beneficial effects of 4-HPA are partially abolished by EX527, a known SIRT1 inhibitor. Collectively, our findings indicate that RSV improve obesity through a gut microbiota-derived 4-HPA-SIRT1 axis, highlighting gut microbiota metabolites as a promising target for obesity prevention.
Bioactive Microspheres to Enhance Sonodynamic-Embolization-Metalloimmune Therapy for Orthotopic Liver Cancer
Authors: Jiachen Xu, Zifan Pei, Yuanjie Wang, Nan Jiang, Yuehan Gong, Fei Gong, Caifang Ni, Liang Cheng
Journal: Biomaterials (2024)
A3AR antagonism mitigates metabolic dysfunction-associated steatotic liver disease by exploiting monocyte-derived Kupffer cell necroptosis and inflammation resolution
Authors: Jeong-Su Park, Yuan-Qiang Ma, Feng Wang, Hwan Ma, Guoyan Sui, Nodir Rustamov, Minyeong Han, Yejin Son, Chun-Woong Park, Sang-Bae Han, Jin Tae Hong, Lak Shin Jeong, Jin Lee, Yoon-Seok Roh
Journal: Metabolism (2024)
Tinea corporis at the injection site of interleukin-17 inhibitor in psoriasis vulgaris
Authors: Keigo Takase, Takayoshi Komatsu-Fujii, Toshiaki Kogame, Atsushi Otsuka, Kenji Kabashima
Journal: British Journal of Dermatology (2024)

We report a patient with psoriasis vulgaris who developed tinea corporis at the injection site of ixekizumab, an IL-17 inhibitor. This case suggests that local inhibition of IL-17 may reduce dermatophyte resistance, leading to site-specific fungal infections.
Haemodynamic and hyperaemic effects of adenosine in patients with atrial fibrillation undergoing quantitative myocardial perfusion cardiovascular magnetic resonance
Authors: Simran Shergill, Charley A Budgeon, Mohamed Elshibly, Peter Kellman, Anvesha Singh, Gerry P McCann, Gaurav S Gulsin, J Ranjit Arnold
Journal:  (2024)

Abstract Aims Patients with atrial fibrillation (AF) are thought to have an attenuated response to adenosine during vasodilator stress testing. We sought to investigate the haemodynamic and hyperaemic effects of adenosine in patients with AF undergoing adenosine-stress cardiovascular magnetic resonance (CMR) assessment. Methods and results We retrospectively examined 318 patients referred for clinical adenosine-stress CMR (AF n = 158, sinus rhythm [SR] n = 160). Baseline and peak heart rate (HR) and quantitative myocardial perfusion were compared between groups. At peak stress, the haemodynamic response was blunted in patients with AF (HR increase 7 ± 10bpm vs. 17 ± 11bpm in SR, P &amp;lt; 0.001). Fewer patients in AF met the threshold for a satisfactory HR response ≥10bpm (40% in AF vs. 76% in SR, P &amp;lt; 0.001). There were no intergroup differences in hyperaemic myocardial blood flow (1.52 ± 0.65 mL/min/g in AF vs. 1.55 ± 0.65 mL/min/g in SR, P = 0.670) or myocardial perfusion reserve (2.66 ± 1.11 in AF vs. 2.66 ± 1.08 in SR, P = 0.981). AF (odds ratio [OR], 0.29 [0.17–0.50], P &amp;lt; 0.001) and left ventricular ejection fraction (OR 1.03 [1.00–1.05], P = 0.023) were independently associated with achieving a satisfactory HR response on multivariable analysis, but only ejection fraction (OR 1.05 [1.02–1.09], P = 0.003) predicted a satisfactory hyperaemic response. Conclusion The heart rate response during adenosine-stress CMR is blunted in AF patients. Despite this, the majority of patients with AF generate a sufficient hyperaemic response with a standard adenosine-stress protocol. Further work is needed to determine the diagnostic accuracy of adenosine-stress CMR in patients with AF.