tbuckley/cabot-search huggingface dataset:
Stochastic method based on copulas for predicting severe road traffic interactions
Authors: Zhankun Chen, Oksana Yastremska-Kravchenko, Aliaksei Laureshyn, Carl Johnsson, Carmelo D’Agostino
Journal: Analytic Methods in Accident Research (2024)

A major difficulty in assessing road traffic safety is the scarcity of historical accident data. xxThis is a common problem in contexts where a certain level of safety has been reached or where exposure is low, such as mixed traffic conditions with different levels of transport automation. Recent studies have demonstrated how severe interactions between road users and/or road users and infrastructure can be a direct measure of safety. However, limiting the investigation to only the most extreme events may lead to inconclusive results considering the lack of prediction robustness and the possible selection bias. In this context, extreme value theory (EVT) is commonly used to extrapolate crashes from road traffic interactions, even combining several indicators. The present work extends the EVT paradigm by proposing a method based on copula functions and EVT, which enables a more specific and continuous evaluation of interaction severity. Compared with pure EVT, this new approach extends the boundary to interactions of all severities while implicitly assuming that the relationship between safety-relevant events and road casualties is stochastic. This EVT-copula approach was also compared with bivariate peaks over threshold (BPOT). It was found that the two approaches yield similar prediction results for crash probabilities. Furthermore, the proposed approach applies to events not properly defined in BPOT and provides more accurate predictions for severe (and less severe) interactions compared with BPOT, when benchmarked against observations.
Spatial intra-tumour heterogeneity and treatment-induced genomic evolution in oesophageal adenocarcinoma: implications for prognosis and therapy
Authors: Sandra Brosda, Lauren G Aoude, Vanessa F Bonazzi, Kalpana Patel, James M Lonie, Clemence J Belle, Felicity Newell, Lambros T Koufariotis, Venkateswar Addala, Marjan M Naeini, John V Pearson, Lutz Krause, Nicola Waddell, Andrew P Barbour
Journal: Genome Medicine (2024)

Oesophageal adenocarcinoma (OAC) is a highly heterogeneous cancer with poor survival. Standard curative treatment is chemotherapy with or without radiotherapy followed by oesophagectomy. Genomic heterogeneity is a feature of OAC and has been linked to treatment resistance.
Pulmonary congestion assessed by lung ultrasound in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation: Prevalence and prognostic implications
Authors: Rosa Lillo, Stefano Cangemi, Francesca Graziani, Gabriella Locorotondo, Daniela Pedicino, Cristina Aurigemma, Enrico Romagnoli, Silvia Malara, Maria Chiara Meucci, Giulia Iannaccone, Francesco Bianchini, Marialisa Nesta, Piergiorgio Bruno, Antonella Lombardo, Carlo Trani, Francesco Burzotta
Journal: European Journal of Heart Failure (2024)

Abstract Aims Lung ultrasound (LUS) is a sensitive tool to assess pulmonary congestion (PC). Few data are available on LUS‐PC evaluation in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). The aim of this study was to assess the prevalence and prognostic impact of LUS‐PC in patients with severe AS before and after TAVI. Methods and results We designed a single‐centre prospective study in patients referred for TAVI for severe AS ( ClinicalTrials.gov identification number: NCT05024942). All patients underwent echocardiography and LUS (according to a simplified 8‐zone scanning protocol) the day before and within 72 h after the procedure. The primary endpoint was the composite of all‐cause mortality, hospitalization for heart failure and urgent medical visits for worsening dyspnoea at 12‐month follow‐up. A total of 127 patients were enrolled (mean age 81.1 ± 5.8 years; 54.3% female). Pre‐TAVI LUS‐PC was documented in 65 patients (51%). After TAVI, the prevalence of LUS‐PC significantly decreased as compared to pre‐TAVI evaluation, being documented in only 28 patients (22% vs. 51%, p &lt; 0.001) with a median B‐lines score of 4 (interquartile range [IQR] 0–11) versus 11 (IQR 6–19) pre‐TAVI ( p &lt; 0.001). During a median follow‐up of 12 (12–17) months, 25 patients (19.6%) met the composite endpoint. On multivariable Cox regression analysis, pre‐TAVI LUS‐PC was independently associated with cardiovascular events (hazard ratio 2.764, 95% confidence interval 1.114–6.857; p = 0.028). Conclusions Lung ultrasonography reveals a high prevalence of PC in patients with severe AS undergoing TAVI, which is significantly reduced by the procedure. Pre‐TAVI PC, measured by LUS, is an independent predictor of 1‐year clinical outcome.
Prevalence of irritable bowel syndrome and functional dyspepsia after acute gastroenteritis: systematic review and meta-analysis
Authors: Serena Porcari, Maria Rosa Ingrosso, Marcello Maida, Leonardo Henry Eusebi, Christopher Black, Antonio Gasbarrini, Giovanni Cammarota, Alexander Charles Ford, Gianluca Ianiro
Journal: Gut (2024)

Disorders of gut-brain interaction may arise after acute gastroenteritis. Data on the influence of pathogen type on the risk of postinfection IBS (PI-IBS), as on postinfection functional dyspepsia (PI-FD), are limited. We conducted a systematic review and meta-analysis to determine prevalence of PI-IBS or PI-FD after acute gastroenteritis.
Frailty and socioeconomic position: A systematic review of observational studies
Authors: Peter Hanlon, Marina Politis, Heather Wightman, Stella Kirkpatrick, Caitlin Jones, Maryam Khan, Cara Bezzina, Shona Mackinnon, Heidi Rennison, Lili Wei, Davide Liborio Vetrano, David N. Blane, Elsa Dent, Emiel O. Hoogendijk
Journal: Ageing Research Reviews (2024)

Frailty, an age-related state of reduced physiological reserve, is often associated with lower socio-economic position (SEP). This systematic review synthesised observational studies assessing (i) the association between SEP and frailty prevalence; (ii) how changes in frailty status over time vary by SEP; and (iii) whether the association between frailty and clinical outcomes is modified by SEP.
Mucosal Healing with Vedolizumab in Patients with Chronic Pouchitis: EARNEST, a Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Vipul Jairath, Brian G. Feagan, Mark S. Silverberg, Silvio Danese, Paolo Gionchetti, Mark Löwenberg, Brian Bressler, Marc Ferrante, Ailsa Hart, Dirk Lindner, Armella Escher, Stephen Jones, Bo Shen, Simon Travis
Journal: Clinical Gastroenterology and Hepatology (2024)

Vedolizumab is indicated for the treatment of chronic pouchitis in the European Union. We assessed whether vedolizumab induced mucosal healing (MH) and if MH was associated with clinical improvements.
Reflections on a Career in Pediatric Neuropathology, with a Note of Gratitude
Authors: Hannah C. Kinney
Journal: Annual Review of Pathology Mechanisms of Disease (2024)

I am honored to be asked by the journal to write this personal essay about my career in pediatric neuropathology-a life of immense satisfaction, meaning, and fulfillment. My motivation to enter this discipline is highlighted, as is my decision to perform brain research in the sudden infant death syndrome, the leading cause of postneonatal infant mortality in the United States today. I also touch upon collaborations, mentoring, and experiences along the way-especially with the light microscope. I close with thoughts about the future of the discipline from my perspective as a lifelong devotee.
Beneficial normalization of cardiac repolarization by carnitine in transgenic short QT syndrome type 1 rabbit models
Authors: Ilona Bodi, Lea Mettke, Konstantin Michaelides, Tibor Hornyik, Stefan Meier, Saranda Nimani, Stefanie Perez-Feliz, Ibrahim El-Battrawy, Heiko Bugger, Manfred Zehender, Michael Brunner, Jordi Heijman, Katja E Odening
Journal: Cardiovascular Research (2024)

Abstract Aims Short QT syndrome type 1 (SQT1) is a genetic channelopathy caused by gain-of-function variants in human-ether-a-go-go (HERG) underlying the rapid delayed-rectifier K+ current (IKr), leading to QT-shortening, ventricular arrhythmias, and sudden cardiac death. Data on efficient pharmacotherapy for SQT1 are scarce. In patients with primary carnitine-deficiency, acquired-short QT syndrome (SQTS) has been observed and rescued by carnitine supplementation. Here, we assessed whether carnitine exerts direct beneficial (prolonging) effects on cardiac repolarization in genetic SQTS. Methods and results Adult wild-type (WT) and transgenic SQT1 rabbits (HERG-N588K, gain of IKr) were used. In vivo electrocardiograms (ECGs), ex vivo monophasic action potentials (APs) in Langendorff-perfused hearts, and cellular ventricular APs and ion currents were assessed at baseline and during L-Carnitine/C16-Carnitine-perfusion. Two-dimensional computer simulations were performed to assess re-entry-based ventricular tachycardia-inducibility. L-Carnitine/C16-Carnitine prolonged QT-intervals in WT and SQT1, leading to QT-normalization in SQT1. Similarly, monophasic and cellular AP duration (APD) was prolonged by L-Carnitine/C16-Carnitine in WT and SQT1. As underlying mechanisms, we identified acute effects on the main repolarizing ion currents: IKr-steady, which is pathologically increased in SQT1, was reduced by L-Carnitine/C16-Carnitine and deactivation kinetics were accelerated. Moreover, L-Carnitine/C16-Carnitine decreased IKs-steady and IK1. In silico modelling identified IKr changes as the main factor for L-Carnitine/C16-Carnitine-induced APD-prolongation. 2D simulations revealed increased sustained re-entry-based arrhythmia formation in SQT1 compared to WT, which was decreased to the WT-level when adding carnitine-induced ion current changes. Conclusion L-Carnitine/C16-Carnitine prolong/normalize QT and whole-heart/cellular APD in SQT1 rabbits. These beneficial effects are mediated by acute effects on IKr. L-Carnitine may serve as a potential future QT-normalizing, anti-arrhythmic therapy in SQT1.
A versatile attention-based neural network for chemical perturbation analysis and its potential to aid surgical treatment: A experimental study
Authors: Zheqi Fan, Houming Zhao, Jingcheng Zhou, Dingchang Li, Yunlong Fan, Yiming Bi, Shuaifei Ji
Journal: International Journal of Surgery (2024)

Deep learning models have emerged as rapid, accurate, and effective approaches for clinical decisions. Through a combination of drug screening and deep learning models, drugs that may benefit patients before and after surgery can be discovered to reduce the risk of complications or speed recovery. However, most existing drug prediction methods have high data requirements and lack interpretability, which has a limited role in adjuvant surgical treatment. To address these limitations, we propose the attention-based convolution transpositional interfusion network (ACTIN) for flexible and efficient drug discovery. ACTIN leverages the graph convolution and the transformer mechanism, utilizing drug and transcriptome data to assess the impact of chemical pharmacophores containing certain elements on gene expression. Remarkably, just with only 393 training instances, only one-tenth of the other models, ACTIN achieves state-of-the-art performance, demonstrating its effectiveness even with limited data. By incorporating chemical element embedding disparity and attention mechanism-based parameter analysis, it identifies the possible pharmacophore containing certain elements that could interfere with specific cell lines, which is particularly valuable for screening useful pharmacophores for new drugs tailored to adjuvant surgical treatment. To validate its reliability, we conducted comprehensive examinations by utilizing transcriptome data from the lung tissue of fatal COVID-19 patients as additional input for ACTIN, we generated novel lead chemicals that align with clinical evidence. In summary, ACTIN offers insights into the perturbation biases of elements within pharmacophore on gene expression, which holds the potential for guiding the development of new drugs that benefit surgical treatment.
Correlation of endoscopic ultrasound-guided portal pressure gradient measurements with hepatic venous pressure gradient: a prospective study
Authors: Belen Martinez-Moreno, Juan Martínez Martínez, Ivan Herrera, Lucía Guilabert, María Rodríguez, Pablo Bellot, Cayetano Miralles, Sonia Pascual, Javier Irurzun, José María Palazón, Vicente Gil Guillén, Pedro Zapater, Rodrigo Jover, José Ramón Aparicio
Journal: Endoscopy (2024)

Hepatic venous portal gradient (HVPG) measurement remains the gold standard for estimating portal pressure gradient (PPG). This study aimed to evaluate the correlation between endoscopic ultrasound (EUS)-guided PPG and HVPG in patients with chronic portal hypertension.
Palladium nanocrystals regulates scleral extracellular matrix remodeling in myopic progression by modulating the hypoxia signaling pathway Nrf-2/Ho-1
Authors: Li Zhang, Kun Yi, Qiuyun Sun, Zhijun Chen, Yongguo Xiang, Wenyang Ren, Peijuan Wu, Shan He, Yanlin Yang, Lili Feng, Ke Hu, Wenjuan Wan
Journal: Journal of Controlled Release (2024)
Clinical effectiveness and safety of time-lapse imaging systems for embryo incubation and selection in in-vitro fertilisation treatment (TILT): a multicentre, three-parallel-group, double-blind, randomised controlled trial
Authors: Priya Bhide, David Y L Chan, Doris Lanz, Odai Alqawasmeh, Eleanor Barry, Dominic Baxter, Francisco Gonzalez Carreras, Yasmin Choudhury, Ying Cheong, Jacqueline Pui Wah Chung, Bonnie Collins, Luping Cong, Sally Doidge, James Heighway, Deepali Patel, M Carmen Pardo, Annabel Rattos, Annie Wright, Julie Dodds, Teresa Perez, Khalid S Khan, Shakila Thangaratinam
Journal: The Lancet (2024)
Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in patients with B-cell malignancies: analysis of the Richter transformation subgroup from the multicentre, open-label, phase 1/2 BRUIN study
Authors: William G Wierda, Nirav N Shah, Chan Y Cheah, David Lewis, Marc S Hoffmann, Catherine C Coombs, Nicole Lamanna, Shuo Ma, Deepa Jagadeesh, Talha Munir, Yucai Wang, Toby A Eyre, Joanna M Rhodes, Matthew McKinney, Ewa Lech-Maranda, Constantine S Tam, Wojciech Jurczak, Koji Izutsu, Alvaro J Alencar, Manish R Patel, John F Seymour, Jennifer A Woyach, Philip A Thompson, Paolo B Abada, Caleb Ho, Samuel C McNeely, Narasimha Marella, Bastien Nguyen, Chunxiao Wang, Amy S Ruppert, Binoj Nair, Hui Liu, Donald E Tsai, Lindsey E Roeker, Paolo Ghia
Journal: The Lancet Haematology (2024)
Low dose lenalidomide versus placebo in non-transfusion dependent patients with low risk, del(5q) myelodysplastic syndromes (SintraREV): a randomised, double-blind, phase 3 trial
Authors: María Díez-Campelo, Félix López-Cadenas, Blanca Xicoy, Eva Lumbreras, Teresa González, Mónica Del Rey González, Joaquín Sánchez-García, Rosa Coll Jordà, Bohrane Slama, Jose-Ángel Hernández-Rivas, Sylvain Thepot, Teresa Bernal, Agnès Guerci-Bresler, Joan Bargay, María Luz Amigo, Claude Preudhomme, Laurene Fenwarth, Uwe Platzbecker, Katharina S Götze, Ali Arar, Sofía Toribio, Consuelo Del Cañizo, Jesús María Hernández-Rivas, Pierre Fenaux
Journal: The Lancet Haematology (2024)
Efficacy and safety of delgocitinib cream in adults with moderate to severe chronic hand eczema (DELTA 1 and DELTA 2): results from multicentre, randomised, controlled, double-blind, phase 3 trials
Authors: Robert Bissonnette, Richard B Warren, Andreas Pinter, Tove Agner, Melinda Gooderham, Marie L A Schuttelaar, Marie-Noëlle Crépy, Luca Stingeni, Esther Serra-Baldrich, Keith Baranowski, Sofie Korn, Merle Kurvits, Ursula Plohberger, Natacha Strange Vest, Sibylle Schliemann
Journal: The Lancet (2024)
CCN6 suppresses metaplastic breast carcinoma by antagonizing WNT/β-catenin signaling to inhibit EZH2-driven EMT
Authors: Maria E. Gonzalez, Bryce Brophy, Ahmad Eido, Adele E. Leonetti, Sabra I. Djomehri, Giuseppina Augimeri, Nicholas J. Carruthers, Raymond G. Cavalcante, Francesca Giordano, Sebastiano Andò, Alexey I. Nesvizhskii, Eric R. Fearon, Celina G. Kleer
Journal: Cancer Research (2024)

Abstract Metaplastic breast carcinomas (mBrCA) are a highly aggressive subtype of triple-negative breast cancer with histologic evidence of epithelial-to-mesenchymal transition and aberrant differentiation. Inactivation of the tumor suppressor gene cellular communication network factor 6 (CCN6; also known as Wnt1-induced secreted protein 3) is a feature of mBrCAs, and mice with conditional inactivation of Ccn6 in mammary epithelium (Ccn6-KO) develop spindle mBrCAs with epithelial-to-mesenchymal transition. Elucidation of the precise mechanistic details of how CCN6 acts as a tumor suppressor in mBrCA could help identify improved treatment strategies. In this study, we showed that CCN6 interacts with the Wnt receptor FZD8 and coreceptor LRP6 on mBrCA cells to antagonize Wnt-induced activation of β-catenin/TCF-mediated transcription. The histone methyltransferase EZH2 was identified as a β-catenin/TCF transcriptional target in Ccn6-KO mBrCA cells. Inhibiting Wnt/β-catenin/TCF signaling in Ccn6-KO mBrCA cells led to reduced EZH2 expression, decreased histone H3 lysine 27 trimethylation, and deregulation of specific target genes. Pharmacologic inhibition of EZH2 reduced growth and metastasis of Ccn6-KO mBrCA mammary tumors in vivo. Low CCN6 is significantly associated with activated β-catenin and high EZH2 in human spindle mBrCAs compared with other subtypes. Collectively, these findings establish CCN6 as a key negative regulator of a β-catenin/TCF/EZH2 axis and highlight the inhibition of β-catenin or EZH2 as a potential therapeutic approach for patients with spindle mBrCAs. Significance: CCN6 deficiency drives metaplastic breast carcinoma growth and metastasis by increasing Wnt/β-catenin activation to upregulate EZH2, identifying EZH2 inhibition as a mechanistically guided treatment strategy for this deadly form of breast cancer.
Targeting the Sodium-Potassium Pump as a Therapeutic Strategy in Acute Myeloid Leukemia
Authors: Constanze Schneider, Hermes Spaink, Gabriela Alexe, Neekesh V. Dharia, Ashleigh Meyer, Lucy A. Merickel, Delan Khalid, Sebastian Scheich, Björn Häupl, Louis M. Staudt, Thomas Oellerich, Kimberly Stegmaier
Journal: Cancer Research (2024)

Abstract Tissue-specific differences in the expression of paralog genes, which are not essential in most cell types due to the buffering effect of the partner pair, can make for highly selective gene dependencies. To identify selective paralogous targets for acute myeloid leukemia (AML), we integrated the Cancer Dependency Map with numerous datasets characterizing protein–protein interactions, paralog relationships, and gene expression in cancer models. In this study, we identified ATP1B3 as a context-specific, paralog-related dependency in AML. ATP1B3, the β-subunit of the sodium–potassium pump (Na/K-ATP pump), interacts with the α-subunit ATP1A1 to form an essential complex for maintaining cellular homeostasis and membrane potential in all eukaryotic cells. When ATP1B3’s paralog ATP1B1 is poorly expressed, elimination of ATP1B3 leads to the destabilization of the Na/K-ATP pump. ATP1B1 expression is regulated through epigenetic silencing in hematopoietic lineage cells through histone and DNA methylation in the promoter region. Loss of ATP1B3 in AML cells induced cell death in vitro and reduced leukemia burden in vivo, which could be rescued by stabilizing ATP1A1 through overexpression of ATP1B1. Thus, ATP1B3 is a potential therapeutic target for AML and other hematologic malignancies with low expression of ATP1B1. Significance: ATP1B3 is a lethal selective paralog dependency in acute myeloid leukemia that can be eliminated to destabilize the sodium–potassium pump, inducing cell death.
Targeting Cholesterol Biosynthesis with Statins Synergizes with AKT Inhibitors in Triple-Negative Breast Cancer
Authors: Alissandra L. Hillis, Timothy D. Martin, Haley E. Manchester, Jenny Högström, Na Zhang, Emmalyn Lecky, Nina Kozlova, Jonah Lee, Nicole S. Persky, David E. Root, Myles Brown, Karen Cichowski, Stephen J. Elledge, Taru Muranen, David A. Fruman, Simon T. Barry, John G. Clohessy, Ralitsa R. Madsen, Alex Toker
Journal: Cancer Research (2024)

Abstract Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer patient deaths due to extensive molecular heterogeneity, high recurrence rates, and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. Here, we performed a genome-wide CRISPR/Cas9 screen with PI3Kα and AKT inhibitors to find targetable synthetic lethalities in TNBC. Cholesterol homeostasis was identified as a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicity in vitro in mouse TNBC xenografts and in patient-derived estrogen receptor (ER)–negative breast cancer organoids. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBC cells showed impaired sterol regulatory element-binding protein 2 (SREBP-2) activation in response to single-agent or combination treatment with AKT inhibitor and pitavastatin, which was rescued by inhibition of the cholesterol-trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss caused lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels, and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. These findings support combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC. Significance: Two FDA-approved compounds, AKT inhibitors and pitavastatin, synergize to induce cell death in triple-negative breast cancer, motivating evaluation of the efficacy of this combination in clinical trials.