tbuckley/cabot-search huggingface dataset:
Biosynthesis and Metabolism of ApoB-Containing Lipoproteins
Authors: Jan Borén, Marja-Riitta Taskinen, Chris J. Packard
Journal: Annual Review of Nutrition (2024)

Recent advances in human genetics, together with a substantial body of epidemiological, preclinical and clinical trial evidence, strongly support a causal relationship between triglyceride-rich lipoproteins (TRLs) and atherosclerotic cardiovascular disease. Consequently, the secretion and metabolism of TRLs have a significant impact on cardiovascular health. This knowledge underscores the importance of understanding the molecular mechanisms and regulation of very-low-density lipoprotein (VLDL) and chylomicron biogenesis. Fortunately, there has been a resurgence of interest in the intracellular assembly, trafficking, degradation, and secretion of VLDL, leading to many ground-breaking molecular insights. Furthermore, the identification of molecular control mechanisms related to triglyceride metabolism has greatly advanced our understanding of the complex metabolism of TRLs. In this review, we explore recent advances in the assembly, secretion, and metabolism of TRLs. We also discuss available treatment strategies for hypertriglyceridemia.
Development of the Binocular Circuit
Authors: Eloísa Herrera, Alain Chédotal, Carol Mason
Journal: Annual Review of Neuroscience (2024)

Seeing in three dimensions is a major property of the visual system in mammals. The circuit underlying this property begins in the retina, from which retinal ganglion cells (RGCs) extend to the same or opposite side of the brain. RGC axons decussate to form the optic chiasm, then grow to targets in the thalamus and midbrain, where they synapse with neurons that project to the visual cortex. Here we review the cellular and molecular mechanisms of RGC axonal growth cone guidance across or away from the midline via receptors to cues in the midline environment. We present new views on the specification of ipsi- and contralateral RGC subpopulations and factors implementing their organization in the optic tract and termination in subregions of their targets. Lastly, we describe the functional and behavioral aspects of binocular vision, focusing on the mouse, and discuss recent discoveries in the evolution of the binocular circuit.
CRISPR-Cas9 screening identifies KRAS-induced COX-2 as a driver of immunotherapy resistance in lung cancer
Authors: Jesse Boumelha, Andrea de Castro, Nourdine Bah, Hongui Cha, Sophie de Carné Trécesson, Sareena Rana, Mona Tomaschko, Panayiotis Anastasiou, Edurne Mugarza, Christopher Moore, Robert Goldstone, Phil East, Kevin Litchfield, Se-Hoon Lee, Miriam Molina-Arcas, Julian Downward
Journal: Cancer Research (2024)

Abstract Oncogenic KRAS impairs antitumor immune responses. As effective strategies to combine KRAS inhibitors and immunotherapies have so far proven elusive, a better understanding of the mechanisms by which oncogenic KRAS drives immune evasion is needed to identify approaches that could sensitize KRAS-mutant lung cancer to immunotherapy. In vivo CRISPR–Cas9 screening in an immunogenic murine lung cancer model identified mechanisms by which oncogenic KRAS promotes immune evasion, most notably via upregulation of immunosuppressive COX2 in cancer cells. Oncogenic KRAS potently induced COX2 in both mouse and human lung cancer, which was suppressed using KRAS inhibitors. COX2 acted via prostaglandin E2 (PGE2) to promote resistance to immune checkpoint blockade (ICB) in lung adenocarcinoma. Targeting COX2/PGE2 remodeled the tumor microenvironment by inducing proinflammatory polarization of myeloid cells and influx of activated cytotoxic CD8+ T cells, which increased the efficacy of ICB. Restoration of COX2 expression contributed to tumor relapse after prolonged KRAS inhibition. These results provide the rationale for testing COX2/PGE2 pathway inhibitors in combination with KRASG12C inhibition or ICB in patients with KRAS-mutant lung cancer. Significance: COX2 signaling via prostaglandin E2 is a major mediator of immune evasion driven by oncogenic KRAS that promotes immunotherapy and KRAS-targeted therapy resistance, suggesting effective combination treatments for KRAS-mutant lung cancer.
<i>ERJ</i>Podcast April 2024: Allergic bronchopulmonary aspergillosis
Journal: European Respiratory Journal (2024)

As part of the April issue, the European Respiratory Journal presents the latest in its series of podcasts. Chief Editor James Chalmers interviews Ritesh Agarwal (Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India) about the revised International Society for Human and Animal Mycology ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses.
Structural Lung Disease and Clinical Phenotype in Bronchiectasis Patients: The EMBARC CT Study
Authors: Angelina L. P. Pieters, Tjeerd van der Veer, Jennifer J. Meerburg, Eleni-Rosalina Andrinopoulou, Menno M. van der Eerden, Pierluigi Ciet, Stefano Aliberti, Pierre-Regis Burgel, Megan L. Crichton, Amelia Shoemark, Pieter C. Goeminne, Michal Shteinberg, Michael R. Loebinger, Charles S. Haworth, Francesco Blasi, Harm A. W. M. Tiddens, Daan Caudri, James D. Chalmers
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Chest computed tomography (CT) scans are essential to diagnose and monitor bronchiectasis (BE). To date, few quantitative data are available about the nature and extent of structural lung abnormalities (SLAs) on CT scans of patients with BE.
A 700 nm LED Light Activated Ru(II) Complex Destroys Tumor Cytoskeleton via Photosensitization and Photocatalysis
Authors: Anyi Dao, Shiyan Chen, Li Pan, Qingyan Ren, Xun Wang, Haorui Wu, Qiufang Gong, Zeduan Chen, Shaomin Ji, Jiaxi Ru, HaoTu Zhu, Chao Liang, Pingyu Zhang, Haiping Xia, Huaiyi Huang
Journal: Advanced Healthcare Materials (2024)

Abstract Photoactivable chemotherapy (PACT) using metallic complexes provides spatiotemporal selectivity over drug activation for targeted anticancer therapy. However, the poor absorption in near‐infrared (NIR) light region of most metallic complexes renders tissue penetration challenging. Herein, an NIR light triggered dinuclear photoactivable Ru(II) complex ( Ru2 ) is presented and the antitumor mechanism is comprehensively investigated. The introduction of a donor–acceptor–donor (D–A–D) linker greatly enhances the intramolecular charge transition, resulting in a high molar extinction coefficient in the NIR region with an extended triplet excited state lifetime. Most importantly, when activated by 700 nm NIR light, Ru2 exhibits unique slow photodissociation kinetics that facilitates synergistic photosensitization and photocatalytic activity to destroy diverse intracellular biomolecules. In vitro and in vivo experiments show that when activated by 700 nm NIR light, Ru2 exhibits nanomolar photocytotoxicity toward 4T1 cancer cells via the induction of calcium overload and endoplasmic reticulum (ER) stress. These findings provide a robust foundation for the development of NIR‐activated Ru(II) PACT complexes for phototherapeutic application.
Omental Preadipocytes Stimulate Matrix Remodeling and IGF Signaling to Support Ovarian Cancer Metastasis
Authors: Jennifer A. Waters, Mikella Robinson, Omar Lujano-Olazaba, Cassidy Lucht, Samuel F. Gilbert, Carrie D. House
Journal: Cancer Research (2024)

Abstract Ovarian cancer can metastasize to the omentum, which is associated with a complex tumor microenvironment. Omental stromal cells facilitate ovarian cancer colonization by secreting cytokines and growth factors. An improved understanding of the tumor-supportive functions of specific cell populations in the omentum could identify strategies to prevent and treat ovarian cancer metastasis. Here, we showed that omental preadipocytes enhance the tumor initiation capacity of ovarian cancer cells. Secreted factors from preadipocytes supported cancer cell viability during nutrient and isolation stress and enabled prolonged proliferation. Coculturing with preadipocytes led to the upregulation of genes involved in extracellular matrix (ECM) organization, cellular response to stress, and regulation of insulin-like growth factor (IGF) signaling in ovarian cancer cells. IGF1 induced ECM genes and increased alternative NF-κB signaling by activating RelB. Inhibiting the IGF1 receptor initially increased tumor omental adhesion but decreased the growth of established preadipocyte-induced subcutaneous tumors as well as established intraperitoneal tumors. Together, this study shows that omental preadipocytes support ovarian cancer progression, which has implications for targeting metastasis. Significance: Omental preadipocyte-mediated IGF1 signaling promotes ovarian cancer tumorigenesis and metastasis via extracellular matrix remodeling, revealing a role for preadipocytes in regulating ovarian cancer progression and highlighting potential therapeutic targets for metastatic disease.
CD58 alterations govern antitumor immune responses by inducing PD-L1 and IDO in diffuse large B-cell lymphoma
Authors: Xiyue Xu, Yidan Zhang, Yaxiao Lu, Xiaoyan Zhang, Cuicui Zhao, Jiesong Wang, Qingpei Guan, Yingfang Feng, Meng Gao, Jingwei Yu, Zheng Song, Xia Liu, Zahra Golchehre, Lanfang Li, Weicheng Ren, Qiang Pan-Hammarström, Huilai Zhang, Xianhuo Wang
Journal: Cancer Research (2024)

Recurrent abnormalities in immune surveillance-related genes affect the progression of diffuse large B-cell lymphoma (DLBCL) and modulate the response to therapeutic interventions. CD58 interacts with the CD2 receptor on T cells and NK cells and is recurrently mutated and deleted in DLBCL, suggesting that it may play a role in regulating antitumor immunity. In this study, we comprehensively analyzed the genomic characteristics of CD58 through targeted next-generation sequencing, RNA sequencing (RNA-seq), whole-exome sequencing, and single-cell RNA-seq in patients with newly diagnosed DLBCL. The CD58 mutation rate was 9.1%, and the copy number loss rate was 44.7% among all enrolled patients with DLBCL. Notably, CD58 genetic alterations, along with low CD58 expression, significantly correlated with reduced rates of response to R-CHOP therapy and inferior progression-free survival and overall survival. Single-cell RNA-seq revealed that CD58 expression in tumor cells was negatively correlated with CD8+ T-cell exhaustion/dysfunction status. Insufficient T-cell activation resulting from CD58 alterations could not be attributed solely to CD2 signaling. CD58 inhibited the activity of the JAK2/STAT1 pathway by activating the LYN/CD22/SH2 domain-containing phosphatase 1 (SHP1) axis, thereby limiting PDL1 and IDO expression. Elevated PDL1 and IDO expression in CD58-deficient DLBCL cells led to immune evasion and tumor-intrinsic resistance to chimeric antigen receptor T-cell therapy. Direct activation of CD58-CD2 costimulatory signaling in combination with anti-PDL1 blockade or IDO inhibitor sensitized CD58-deficient DLBCL to chimeric antigen receptor T-cell therapy. Collectively, this work identified the multiple roles of CD58 in regulating antitumor immune responses in DLBCL. Significance: Loss of CD58 mediates immune evasion and therapy resistance in diffuse large B-cell lymphoma by upregulating PDL1 and IDO through LYN/CD22/SHP1 signaling, providing potential targets and therapeutic strategies to improve patient treatment.
Effect of 5:2 Regimens: Energy-Restricted Diet or Low-Volume High-Intensity Interval Training Combined With Resistance Exercise on Glycemic Control and Cardiometabolic Health in Adults With Overweight/Obesity and Type 2 Diabetes: A Three-Arm Randomized Controlled Trial
Authors: Mian Li, Jie Li, Yu Xu, Jinli Gao, Qiuyu Cao, Yi Ding, Zhuojun Xin, Ming Lu, Xiaoting Li, Haihong Song, Jue Shen, Tianzhichao Hou, Ruixin He, Ling Li, Zhiyun Zhao, Min Xu, Jieli Lu, Tiange Wang, Shuangyuan Wang, Hong Lin, Ruizhi Zheng, Jie Zheng, Callum John Baker, Shenghan Lai, Nathan Anthony Johnson, Guang Ning, Stephen Morris Twigg, Weiqing Wang, Yan Liu, Yufang Bi
Journal: Diabetes Care (2024)

OBJECTIVE We aimed to examine the effects of a 5:2 diet (2 days per week of energy restriction by formula diet) or an exercise (2 days per week of high-intensity interval training and resistance training) intervention compared with routine lifestyle education (control) on glycemic control and cardiometabolic health among adults with overweight/obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS This two-center, open-label, three-arm, parallel-group, randomized controlled trial recruited 326 participants with overweight/obesity and type 2 diabetes and randomized them into 12 weeks of diet intervention (n = 109), exercise intervention (n = 108), or lifestyle education (control) (n = 109). The primary outcome was the change of glycemic control measured as glycated hemoglobin (HbA1c) between the diet or exercise intervention groups and the control group after the 12-week intervention. RESULTS The diet intervention significantly reduced HbA1c level (%) after the 12-week intervention (−0.72, 95% CI −0.95 to −0.48) compared with the control group (−0.37, 95% CI −0.60 to −0.15) (diet vs. control −0.34, 95% CI −0.58 to −0.11, P = 0.007). The reduction in HbA1c level in the exercise intervention group (−0.46, 95% CI −0.70 to −0.23) did not significantly differ from the control group (exercise vs. control −0.09, 95% CI −0.32 to 0.15, P = 0.47). The exercise intervention group was superior in maintaining lean body mass. Both diet and exercise interventions induced improvements in adiposity and hepatic steatosis. CONCLUSIONS These findings suggest that the medically supervised 5:2 energy-restricted diet could provide an alternative strategy for improving glycemic control and that the exercise regimen could improve body composition, although it inadequately improved glycemic control.
Real-world and clinical trial outcomes in large B-cell lymphoma with axicabtagene ciloleucel across race and ethnicity
Authors: Frederick L. Locke, Tanya Siddiqi, Caron A. Jacobson, Armin Ghobadi, Sairah Ahmed, David B. Miklos, Miguel-Angel Perales, Javier Munoz, Warren B. Fingrut, Martina Pennisi, Jordan Gauthier, Mazyar Shadman, Lohith Gowda, Abu-Sayeef Mirza, Muhammad Bilal Abid, Sanghee Hong, Navneet S. Majhail, Mohamed A. Kharfan-Dabaja, Arushi Khurana, Talha Badar, Yi Lin, N. Nora Bennani, Megan M. Herr, Zhen-Huan Hu, Hai-Lin Wang, Anjani Baer, Elande Baro, Harry Miao, Clare Spooner, Hairong Xu, Marcelo C. Pasquini
Journal: Blood (2024)

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% CI, 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell-associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with CAR T-cell therapy across different racial and ethnic groups. ZUMA-1 and ZUMA-7 (ClinicalTrials.gov identifiers: #NCT02348216 and #NCT03391466, respectively) are registered on ClinicalTrials.gov.
Corneal fibrosis: From in vitro models to current and upcoming drug and gene medicines
Authors: Laura Trujillo Cubillo, Mehmet Gurdal, Dimitrios I. Zeugolis
Journal: Advanced Drug Delivery Reviews (2024)

Fibrotic diseases are characterised by myofibroblast differentiation, uncontrolled pathological extracellular matrix accumulation, tissue contraction, scar formation and, ultimately tissue / organ dysfunction. The cornea, the transparent tissue located on the anterior chamber of the eye, is extremely susceptible to fibrotic diseases, which cause loss of corneal transparency and are often associated with blindness. Although topical corticosteroids and antimetabolites are extensively used in the management of corneal fibrosis, they are associated with glaucoma, cataract formation, corneoscleral melting and infection, imposing the need of far more effective therapies. Herein, we summarise and discuss shortfalls and recent advances in in vitro models (e.g. transforming growth factor-β (TGF-β) / ascorbic acid / interleukin (IL) induced) and drug (e.g. TGF-β inhibitors, epigenetic modulators) and gene (e.g. gene editing, gene silencing) therapeutic strategies in the corneal fibrosis context. Emerging therapeutical agents (e.g. neutralising antibodies, ligand traps, receptor kinase inhibitors, antisense oligonucleotides) that have shown promise in clinical setting but have not yet assessed in corneal fibrosis context are also discussed.
O-GlcNAcylation promotes the progression of nonalcoholic fatty liver disease by upregulating the expression and function of CD36
Authors: Hanlong Zhu, Tianming Zhao, Si Zhao, Suzhen Yang, Kang Jiang, Shupei Li, Ying Kang, Zhuoxin Yang, Jiajia Shen, Si Shen, Hui Tao, Ji Xuan, Miaofang Yang, Bing Xu, Fangyu Wang, Mingzuo Jiang
Journal: Metabolism (2024)
Alternative models to support weight loss in chronic musculoskeletal conditions: effectiveness of a physiotherapist-delivered intensive diet programme for knee osteoarthritis, the POWER randomised controlled trial
Authors: Kim Allison, Sarah Jones, Rana S Hinman, Jesse Pardo, Peixuan Li, Anurika DeSilva, Jonathan George Quicke, Priya Sumithran, Jodie Prendergast, Elena George, Melanie A Holden, Nadine E Foster, Kim L Bennell
Journal: British Journal of Sports Medicine (2024)

Objectives To determine if physiotherapists can deliver a clinically effective very low energy diet (VLED) supplementary to exercise in people with knee osteoarthritis (OA) and overweight or obesity. Methods 88 participants with knee OA and body mass index (BMI) &gt;27 kg/m 2 were randomised to either intervention (n=42: VLED including two daily meal replacement products supplementary to control) or control (n=46: exercise). Both interventions were delivered by unblinded physiotherapists via six videoconference sessions over 6 months. The primary outcome was the percentage change in body weight at 6 months, measured by a blinded assessor. Secondary outcomes included BMI, waist circumference, waist-to-hip ratio, self-reported measures of pain, function, satisfaction and perceived global change, and physical performance tests. Results The intervention group lost a mean (SD) of 8.1% (5.2) body weight compared with 1.0% (3.2) in the control group (mean (95% CI) between-group difference 7.2% (95% CI 5.1 to 9.3), p&lt;0.001), with significantly lower BMI and waist circumference compared with control group at follow-up. 76% of participants in the intervention group achieved ≥5% body weight loss and 37% acheived ≥10%, compared with 12% and 0%, respectively, in the control group. More participants in the intervention group (27/38 (71.1%)) reported global knee improvement than in the control group (20/42 (47.6%)) (p=0.02). There were no between-group differences in any other secondary outcomes. No serious adverse events were reported. Conclusion A VLED delivered by physiotherapists achieved clinically relevant weight loss and was safe for people with knee OA who were overweight or obese. The results have potential implications for future service models of care for OA and obesity. Trial registration number NIH, US National Library of Medicine, Clinicaltrials.gov NCT04733053 (1 February 2021).
First, do no harm: a call to action to improve the evaluation of harms in clinical exercise research
Authors: Simon Nørskov Thomsen, Alejandro Lucia, Rosalind R Spence, Fabiana Braga Benatti, Michael J Joyner, Ronan Martin Griffin Berg, Mathias Ried-Larsen, Casper Simonsen
Journal: British Journal of Sports Medicine (2024)
Cost-Related Non-Adherence to Prescribed Medicines: What Are Physicians’ Moral Duties?
Authors: Narcyz Ghinea, Katrina Hutchison, Mianna Lotz, Wendy A. Rogers
Journal: The American Journal of Bioethics (2024)

As the price of pharmaceuticals and biologicals rises so does the number of patients who cannot afford them. In this article, we argue that physicians have a moral duty to help patients access affordable medicines. We offer three grounds to support our argument: (i) the aim of prescribing is to improve health and well-being which can only be realized with secure access to treatment; (ii) there is no morally significant difference between medicines being unavailable and medicines being unaffordable, so the steps physicians are willing to take in the first case should extend to the second; and (iii) as the primary stakeholder with a duty to put the individual patient's interests first, the medical professional has a duty to address cost-barriers to patient care. In articulating this duty, we take account of important epistemic and control conditions that must be met for the attribution of this duty to be justified.
Predicting non-muscle invasive bladder cancer outcomes using artificial intelligence: a systematic review using APPRAISE-AI
Authors: Jethro C. C. Kwong, Jeremy Wu, Shamir Malik, Adree Khondker, Naveen Gupta, Nicole Bodnariuc, Krishnateja Narayana, Mikail Malik, Theodorus H. van der Kwast, Alistair E. W. Johnson, Alexandre R. Zlotta, Girish S. Kulkarni
Journal: npj Digital Medicine (2024)

Abstract Accurate prediction of recurrence and progression in non-muscle invasive bladder cancer (NMIBC) is essential to inform management and eligibility for clinical trials. Despite substantial interest in developing artificial intelligence (AI) applications in NMIBC, their clinical readiness remains unclear. This systematic review aimed to critically appraise AI studies predicting NMIBC outcomes, and to identify common methodological and reporting pitfalls. MEDLINE, EMBASE, Web of Science, and Scopus were searched from inception to February 5th, 2024 for AI studies predicting NMIBC recurrence or progression. APPRAISE-AI was used to assess methodological and reporting quality of these studies. Performance between AI and non-AI approaches included within these studies were compared. A total of 15 studies (five on recurrence, four on progression, and six on both) were included. All studies were retrospective, with a median follow-up of 71 months (IQR 32−93) and median cohort size of 125 (IQR 93−309). Most studies were low quality, with only one classified as high quality. While AI models generally outperformed non-AI approaches with respect to accuracy, c-index, sensitivity, and specificity, this margin of benefit varied with study quality (median absolute performance difference was 10 for low, 22 for moderate, and 4 for high quality studies). Common pitfalls included dataset limitations, heterogeneous outcome definitions, methodological flaws, suboptimal model evaluation, and reproducibility issues. Recommendations to address these challenges are proposed. These findings emphasise the need for collaborative efforts between urological and AI communities paired with rigorous methodologies to develop higher quality models, enabling AI to reach its potential in enhancing NMIBC care.