tbuckley/cabot-search huggingface dataset:
Advancing Clinical Response Against Glioblastoma: Evaluating SHP1705 CRY2 Activator Efficacy in Preclinical Models and Safety in Phase I Trials
Authors: Priscilla Chan, Yoshiko Nagai, Qiulian Wu, Anahit Hovsepyan, Seda Mkhitaryan, Jiarui Wang, Gevorg Karapetyan, Theodore Kamenecka, Laura A Solt, Jamie Cope, Rex A Moats, Tsuyoshi Hirota, Jeremy N Rich, Steve A Kay
Journal: Neuro-Oncology (2025)

Abstract Background It has been reported that circadian clock components, Brain and Muscle ARNT-Like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK), are essential for glioblastoma (GBM) stem cell (GSC) biology and survival. Consequently, we developed a novel Cryptochrome (CRY) activator SHP1705, which inhibits BMAL1-CLOCK transcriptional activity. Methods We utilized GlioVis to determine which circadian genes are differentially expressed in non-tumor versus GBM tissues. We employed in vitro and in vivo methods to test the efficacy of SHP1705 against patient-derived GSCs and xenografts in comparison to earlier CRY activator scaffolds. We applied a novel REV-ERB agonist SR29065, which inhibits BMAL1 transcription, to determine whether targeting both negative limbs of the circadian transcription-translation feedback loop (TTFL) would yield synergistic effects against various GBM cells. Results SHP1705 is the first circadian clock-modulating compound to be found safe and well-tolerated in Phase I clinical trials. SHP1705 has increased selectivity for the CRY2 isoform and potency against GSC viability compared to previously published CRY activators, making it promising for applications in GBM where CRY2 levels are found to be low. SHP1705 prolonged survival in mice bearing GBM tumors established with GSCs. When combined with novel REV-ERB agonist SR29065, SHP1705 displayed synergy against multiple GSC lines and differentiated GSCs (DGCs). Conclusions We demonstrate the efficacy of SHP1705 against GSCs, which pose as a major source of chemoradiation resistance leading to poor GBM patient prognosis. Novel circadian clock compounds have high potential for targeting GBM as single agents or in combination with each other or current standard-of-care.
Exercise as a renal-protective strategy: slowing chronic kidney disease progression and optimising dialysis care (PhD Academy Award)
Authors: Hugo de Luca Corrêa, Thiago dos Santos Rosa
Journal: British Journal of Sports Medicine (2025)

My PhD investigated the effects of resistance training (RT) on physiological, molecular and clinical profile in patients with chronic kidney disease (CKD). This work encompassed six studies, including randomised controlled trials,1 2 epidemiological analyses,3–5 and an umbrella review,6 exploring the role of muscle mass and exercise in preserving renal function and improving health outcomes in patients with CKD across different disease stages. In total, data from over 1000 patients were analysed, covering a wide spectrum of disease severity and intervention strategies. CKD affects >10% of the global population, leading to progressive renal function decline, increased morbidity and high healthcare costs. Muscle loss is prevalent in CKD, contributing to frailty, inflammation and cardiovascular disease, yet exercise remains underutilised in renal care. RT has shown promise in mitigating CKD-related muscle atrophy, but its feasibility and long-term impact remain unclear. My research aimed to fill this gap by evaluating how RT affects renal function, inflammation and metabolic health, with the goal of establishing exercise as a key therapeutic strategy in CKD management. This PhD included a series of experimental and observational studies:
Correction: Potential public health impacts of gonorrhea vaccination programmes under declining incidences: A modeling study
Authors: Lin Geng, Lilith K. Whittles, Borame L. Dickens, Martin T. W. Chio, Yihao Chen, Rayner Kay Jin Tan, Azra Ghani, Jue Tao Lim
Journal: PLoS Medicine (2025)

[This corrects the article DOI: 10.1371/journal.pmed.1004521.].
<i>TP53</i> deletion as an MRD‐dependent risk factor in childhood B‐ALL: A post hoc analysis from a prospective cohort
Authors: Yangyang Gao, Jun Li, Ning Wang, Wenbin An, Zixi Yin, Junxia Wang, Xia Chen, Yumei Chen, Ye Guo, Wenyu Yang, Li Zhang, Yao Zou, Xiaojuan Chen, Xiaofan Zhu
Journal: HemaSphere (2025)

Abstract The effect of TP53 alterations on childhood B‐cell acute lymphoblastic leukemia (B‐ALL) remains unclear. To investigate the prognostic value of TP53 deletion ( TP53 del ) and TP53 mutation ( TP53 mut ), this post hoc study used fluorescence in situ hybridization test to detect TP53 del in 907 newly diagnosed B‐ALL patients from a prospective cohort of Chinese Children's Cancer Group ALL‐2015 trial. Targeted gene sequencing was used to identify TP53 mut in 342 out of the 907 patients. TP53 del was detected in 4.4% of patients. The frequency of hypodiploidy was higher in TP53 del subgroup (7.5% vs. 0.5%, p = 0.002), but patients with TP53 del were less likely to have other recurrent genetic abnormalities, including BCR::ABL1, ETV6::RUNX1, TCF3::PBX1 and KMT2A rearrangements. Univariable and multivariable analyses indicated that TP53 del was an independent risk factor for overall survival (OS) and disease‐free survival (DFS). Furthermore, stratification analysis revealed that TP53 del was associated with lower 5‐year DFS in patients with positive minimal residual disease (MRD) after induction in the intermediate‐risk group (0.0% vs. 58.0% [95% confidence interval [CI] 49.2%–68.3%], p &lt; 0.001), suggesting an MRD‐dependent pattern. However, somatic TP53 mut was not associated with poor survival (81.8% [95% CI 61.9%–100.0%] vs. 84.9% [95% CI 81.1%‐89.0%], p = 0.971). In summary, TP53 del may serve as a predictor for poor prognosis in pediatric B‐ALL. In particular, children in the intermediate‐risk group with positive MRD and TP53 del may require more aggressive treatment.
Sociodemographic Disparities in Exposures to Inorganic Contaminants in United States Public Water Systems
Authors: Mona Q. Dai, Xindi C. Hu, Brent A. Coull, Chris Campbell, David Q. Andrews, Olga V. Naidenko, Elsie M. Sunderland
Journal: Environmental Health Perspectives (2025)

Maximum contaminant level violations occur more frequently among some public water systems (PWS) serving marginalized communities across the United States. Spatially resolved PWS service area data are now available, allowing for better understanding of relationships between sociodemographic factors and water quality.
Epidemiological and economical burden of cholestatic liver disease
Authors: Bregje Mol, Ellen Werner, Emma L. Culver, Adriaan J. van der Meer, Johannes A. Bogaards, Cyriel Y. Ponsioen
Journal: Hepatology (2025)

The main cholestatic liver diseases comprise primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and IgG4-related cholangitis (IgG4-C). Despite being classified as rare diseases these are becoming gradually more important in the field of hepatology since their incidence is slowly rising while viral hepatitis burden is declining. Cholestatic liver diseases now rank among the three most frequent indications for liver transplantation in many Western countries. An accurate understanding of the epidemiology and burden of disease on both the individual and society of cholestatic diseases is of great importance. This review aims at providing a comprehensive overview of the current literature on the epidemiology, health related quality of life, and economical burden of PSC, PBC, and IgG4-C.
Getting to HBV Cure – will new biomarkers help?
Authors: Jordan J. Feld, Adam J. Gehring, Fabien Zoulim
Journal: Hepatology (2025)

The natural history and response to therapy in chronic hepatitis B (CHB) infection have been defined by a combination of serological and virological biomarkers along with liver biochemistry and/or histology. A number of novel biomarkers including HBV RNA, hepatitis B core-related antigen (HBcrAg), hepatitis B core antigen (HBcAg) and quantitative hepatitis B surface antigen (qHBsAg) have been developed and evaluated in different clinical settings. Novel immunological biomarkers have also been studied but have been less well characterized. In addition to providing insights into HBV biology, these novel biomarkers may significantly aid in the design, development and assessment of novel antiviral strategies aiming for cure of CHB. Biomarkers can be used to confirm the mechanism of action or target engagement of a novel agent but also may be used for patient selection for trials and clinical use. Ideally, biomarkers can be used to more accurately define stages of CHB, particularly degrees of virological control. In this review, the serological, virological and immunological biomarkers are described with a focus on how they can be used to guide development of HBV cure strategies. New terminology is proposed for clinical endpoints, including Sustained Control to replace the concept of partial cure and Resolved Chronic Infection to replace Functional Cure, reserving the term Cure for clearance or silencing of all cccDNA and integrated HBV DNA.
European Cancer Organisation Essential Requirements for Quality Cancer Care: Hematological malignancies
Authors: John G. Gribben, Leticia Quintanilla‐Martinez, Simon Crompton, Jann Arends, Christophe Bardin, Heiko Becker, Frederic Castinetti, Dégi L. Csaba, Melvin D'Anastasi, Thomas Frese, Jan Geissler, Reda Matuzeviciene, Marius E. Mayerhoefer, Rui Medeiros, Kate Morgan, Šarūnas Narbutas, Samantha Nier, Umberto Ricardi, Eugenia Trigoso Arjona, Mehmet Ungan, Lorna Warwick, Emanuele Zucca
Journal: HemaSphere (2025)
Chromosome-level genome assembly and single-cell analysis unveil molecular mechanisms of arm regeneration in the ophiuroid Ophiura sarsii vadicola
Authors: Qin-Zeng Xu, Yi-Xuan Li, Wen-Ge Shi, Yue Dong, Zhong Li, Jack Chi-Ho Ip, Matthew P. Galaska, Chen Han, Qian Zhang, Yu-Yao Sun, Lin-Lin Zhao, Kai-Ming Sun, Zong-Ling Wang, Jian-Wen Qiu, Xue-Lei Zhang
Journal: Genome biology (2025)

Abstract Background Ophiuroids, belonging to Ophiuroidea in Echinodermata, possess remarkable regenerative capacities in their arms, relying on cellular recruitment and de-differentiation. However, limited high-quality genomic resources have hindered the investigation of the underlying molecular mechanisms of ophiuroid regeneration. Results Here, we report a chromosome-level genome of Ophiura sarsii vadicola , 259.28 Mbp in length with a scaffold N50 length of 66.91 Mbp. We then perform bulk and single-cell RNA sequencing analysis to investigate gene expression and cellular dynamics during arm regeneration. We identify five distinct cellular clusters involved in the arm regeneration and infer the dynamic transformations from sensory stimulation to injury response, wound healing, and tissue regeneration. We find that progenitor cells derived from connective tissue cells differentiate into muscle, cartilage, endothelial, and epithelial cells. Pseudotime analysis indicates that muscle differentiation occurs early in the regeneration process. Conclusions Our genomic resource and single-cell atlas shed light on the mechanisms of organ regeneration in ophiuroids.
Exposure to ethylene oxide and relative rates of female breast cancer mortality: 62 years of follow-up in a large US occupational cohort
Authors: Kaitlin Kelly-Reif, Stephen J Bertke, Leslie Stayner, Kyle Steenland
Journal: Environmental Health Perspectives (2025)

Ethylene oxide (EtO) is a recognized carcinogen of concern in occupational and environmental settings, but evidence of cancer risks in humans remains limited. Since new EtO emission standards and mitigation measures have been proposed, further investigation of EtO cancer risks is needed to inform quantitative risk assessment.
Tumour-intrinsic alterations and stromal matrix remodelling promote Wnt-niche independence during diffuse-type gastric cancer progression
Authors: Lars J S Kemp, Jooske L Monster, Colin S Wood, Martijn Moers, Marjolein J Vliem, Antoine A Khalil, Nigel B Jamieson, Lodewijk A A Brosens, Liudmila L Kodach, Jolanda M van Dieren, Tanya M Bisseling, Rachel S van der Post, Martijn Gloerich
Journal: Gut (2025)

Background Development of diffuse-type gastric cancer (DGC) starts with intramucosal lesions that are primarily composed of differentiated, non-proliferative signet ring cells (SRCs). These indolent lesions can advance into highly proliferative and metastatic tumours, which requires suppression of DGC cell differentiation. Objective Our goal was to identify molecular changes contributing to the progression of indolent to aggressive DGC lesions. Design We conducted spatial transcriptomic analysis of patient tumours at different stages of hereditary DGC, comparing transcriptional differences in tumour cell populations and tumour-associated cells. We performed functional analysis of identified changes in a human gastric ( CDH1 KO ) organoid model recapitulating DGC initiation. Results Our analysis reveals that distinct DGC cell populations exhibit varying levels of Wnt-signalling activity, and high levels of Wnt signalling prevent differentiation into SRCs. We identify multiple adaptations during DGC progression that converge on Wnt signalling, allowing tumour cells to remain in an undifferentiated state as they disseminate away from the gastric stem cell niche. First, DGC cells establish a cell-autonomous source for Wnt-pathway activation through upregulated expression of Wnt-ligands and ‘secreted frizzled-related protein 2’ ( SFRP2 ) that potentiates ligand-induced Wnt signalling. Second, early tumour development is marked by extracellular matrix remodelling, including increased deposition of collagen I whose interactions with DGC cells suppress their differentiation in the absence of exogenous Wnt ligands. Conclusions Our findings demonstrate that tumour cell-derived ligand expression and extracellular matrix remodelling sustain Wnt signalling during DGC progression. These complementary mechanisms promote niche independence enabling expansion of undifferentiated DGC cells needed for the development of advanced tumours.
Foundation Model for Predicting Prognosis and Adjuvant Therapy Benefit From Digital Pathology in GI Cancers
Authors: Xiyue Wang, Yuming Jiang, Sen Yang, Fang Wang, Xiaoming Zhang, Wei Wang, Yijiang Chen, Xiaoyan Wu, Jinxi Xiang, Yuchen Li, Xiaofeng Jiang, Wei Yuan, Jing Zhang, Kun-Hsing Yu, Robyn L. Ward, Nicholas Hawkins, Jitendra Jonnagaddala, Guoxin Li, Ruijiang Li
Journal: Journal of Clinical Oncology (2025)

PURPOSE Artificial intelligence (AI) holds significant promise for improving cancer diagnosis and treatment. Here, we present a foundation AI model for prognosis prediction on the basis of standard hematoxylin and eosin–stained histopathology slides. METHODS In this multinational cohort study, we developed AI models to predict prognosis from histopathology images of patients with GI cancers. First, we trained a foundation model using over 130 million patches from 104,876 whole-slide images on the basis of self-supervised learning. Second, we fine-tuned deep learning models for predicting survival outcomes and validated them across seven cohorts, including 1,619 patients with gastric and esophageal cancers and 2,594 patients with colorectal cancer. We further assessed the model for predicting survival benefit from adjuvant chemotherapy. RESULTS The AI models predicted disease-free survival and disease-specific survival with a concordance index of 0.726-0.797 for gastric cancer and 0.714-0.757 for colorectal cancer in the validation cohorts. The models stratified patients into high-risk and low-risk groups, with 5-year survival rates of 49%-52% versus 76%-92% in gastric cancer and 43%-72% versus 81%-98% in colorectal cancer. In multivariable analysis, the AI risk scores remained an independent prognostic factor after adjusting for clinicopathologic variables. Compared with stage alone, an integrated model consisting of stage and image information improved prognosis prediction across all validation cohorts. Finally, adjuvant chemotherapy was associated with improved survival in the high-risk group but not in the low-risk group (treatment-model interaction P = .01 and .006) for stage II/III gastric and colorectal cancer, respectively. CONCLUSION The pathology foundation model can accurately predict survival outcomes and complement clinicopathologic factors in GI cancers. Pending prospective validation, it may be used to improve risk stratification and inform personalized adjuvant therapy.
Effect of ANGPTL3 Inhibition With Solbinsiran in Preclinical and Early Human Studies
Authors: Kausik K Ray, Helle Linnebjerg, Laura F Michael, Xi Shen, Xiaosu Ma, Shufen Lim, Eugene Y Zhen, Henryk Dudek, Marc Abrams, Utsav Saxena, Anton Turanov, Stephen J Nicholls, Giacomo Ruotolo
Journal: Journal of the American College of Cardiology (2025)

The residual cardiovascular risk associated with hypertriglyceridemia and remnant particles supports efforts to develop effective novel therapeutic approaches. Angiopoietin-like protein 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases, and Mendelian randomization studies associate lower ANGPTL3 activity with lower triglycerides, and lower cardiovascular risk. The aim of this study was to evaluate the impact of solbinsiran, an N-acetylgalactosamine-conjugated small interfering RNA developed to inhibit hepatic translation of ANGPTL3 messenger RNA (mRNA), on ANGPTL3 and lipid levels in preclinical models and humans. In preclinical studies, the impact of solbinsiran on ANGPTL3 levels was assessed in mouse and nonhuman primate models. The phase 1 clinical study enrolled participants with mixed dyslipidemia. In the single-ascending-dose study, participants received single subcutaneous doses of solbinsiran (24-960 mg) or matching placebo. In the repeat-dose study, subcutaneous solbinsiran (208 or 480 mg) or matching placebo on days 1 and 29 was evaluated. Safety, pharmacokinetics, and effect on levels of ANGPTL3 and lipid parameters were evaluated over 169 days. In mice transiently expressing human ANGPTL3, a single dose of solbinsiran reduced hepatocyte ANGPTL3 mRNA expression by 65% vs vehicle-treated mice. In cynomolgus monkeys, mean ± SEM reductions in hepatic ANGPTL3 mRNA expression up to 73% ± 2% (P < 0.0001) and serum ANGPTL3 protein expression up to 69% ± 4% (P < 0.001) were seen vs vehicle-treated monkeys. In humans, a single dose of solbinsiran resulted in dose-dependent mean ± SD percentage reductions from baseline in ANGPTL3 up to 86% ± 4%, triglycerides up to 73% ± 7%, low-density lipoprotein (LDL) cholesterol up to 30% ± 16%, non-high-density lipoprotein cholesterol up to 41% ± 12%, and apolipoprotein B up to 30% ± 11%, with sustained effects at higher doses (P < 0.0001 for all). The repeat-dose study demonstrated reductions in ANGPTL3 of 89% ± 6%, triglycerides up to 70% ± 13%, LDL cholesterol up to 42% ± 14%, non-high-density lipoprotein cholesterol up to 46% ± 14%, and apolipoprotein B up to 36% ± 13% (P < 0.0001 for all). Nuclear magnetic resonance lipoprotein analysis demonstrated reductions in the total number of triglyceride-rich lipoprotein and LDL particles with solbinsiran. Adverse events were mostly mild in severity, with similar incidence in solbinsiran- and placebo-treated participants. Solbinsiran inhibits hepatic ANGPTL3 translation and results in significant reductions in all atherogenic lipoproteins in mixed dyslipidemia. The impact of this approach on cardiovascular outcomes remains to be determined. (A Study of LY3561774 in Participants With Dyslipidemia; NCT04644809).
A comprehensive evaluation of stability and safety for HEK293F-derived extracellular vesicles as promising drug delivery vehicles
Authors: Zhi-Qing Chen, Tao-Tao Tang, Ri-Ning Tang, Yue Zhang, Yi-Lin Zhang, Hong-Bin Yang, Jing Song, Qin Yang, Suo-Fu Qin, Feng Chen, Yu-Xia Zhang, Yu-Jia Wang, Bin Wang, Lin-Li Lv, Bi-Cheng Liu
Journal: Journal of Controlled Release (2025)
Non-relapse mortality with bispecific antibodies: A systematic review and meta-analysis in lymphoma and multiple myeloma
Authors: Tobias Tix, Mohammad Alhomoud, Roni Shouval, Gloria Iacoboni, Edward R Scheffer Cliff, Doris K Hansen, Saad Z Usmani, Gilles Salles, Miguel-Angel Perales, David M Cordas Dos Santos, Kai Rejeski
Journal: Molecular Therapy (2025)

Bispecific antibodies (BsAb) are associated with distinct immune-related toxicities that impact morbidity and mortality. This systematic review and meta-analysis examined non-relapse mortality (NRM) with BsAb therapy in B-cell non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). A PubMed and Embase search up to October 2024 identified 29 studies (21 NHL, 8 MM) involving 2,535 patients. The overall NRM point estimate was 4.7% (95% CI 3.4-6.4%) with a median follow-up of 12.0 months. We noted no significant difference in NRM across disease entities (NHL: 4.2%, MM: 6.2%, p=0.22). In NHL, prespecified subgroup analyses revealed increased NRM in real-world studies compared to clinical trials. For MM, an association between NRM and higher response rates and longer follow-up was noted. Meta-regression comparing BsAb and CAR-T therapies (n=8,592) showed no significant NRM difference when accounting for key study-level confounders (p=0.96). Overall, infections were the leading cause of NRM, accounting for 71.8% of non-relapse deaths. Of the infection-related deaths, 48% were attributed to COVID-19. In a pre-specified sensitivity analysis excluding COVID-19-fatalities, the overall NRM estimate was 3.5% (95% CI 2.6-4.6%). Taken together, these results provide a benchmark for the estimated NRM with BsAb therapy and highlight the paramount importance of infection reporting, prevention, and mitigation.
Redefining Quality in Cell and Gene Therapies: Lessons from Implementing Electronic QMS in Academic cGMP Facility
Authors: Xia Wu, Amaia Cadinanos-Garai, Vivian Quach, Eric Jurado, Alix Vaissié, Mohamed Abou-El-Enein
Journal: Molecular Therapy (2025)

Manufacturing cell and gene therapies (CGTs) involves complex processes that require robust quality management, especially within academic current Good Manufacturing Practice (cGMP) facilities, where resources are often limited. Traditional paper-based quality management systems (QMS), while initially convenient, often become burdensome, leading to errors, poor traceability, and compliance risks. Electronic Quality Management Systems (eQMS) are gaining recognition for their ability to centralize and automate key quality processes, significantly enhancing operational efficiency. Through an in-depth case study of the USC/CHLA academic cGMP facility, this review demonstrates tangible improvements achieved by adopting an eQMS. Practical insights gained from this experience are shared, including careful selection of eQMS platforms, phased rollout strategies, and comprehensive staff training. The review also addresses common implementation challenges and suggests practical solutions to overcome them. Lessons learned and strategies discussed here can serve as valuable guidance for other academic institutions considering eQMS adoption. Ultimately, adopting an eQMS equips academic CGT manufacturers to enhance sustainability, continuously optimize operations, and strengthen their strategic position within this rapidly evolving field.
Orbital atherectomy versus balloon angioplasty before drug-eluting stent implantation in severely calcified lesions eligible for both treatment strategies (ECLIPSE): a multicentre, open-label, randomised trial
Authors: Ajay J Kirtane, Philippe Généreux, Bruce Lewis, Richard A Shlofmitz, Suhail Dohad, Jithendra Choudary, Thom Dahle, Andres M Pineda, Kendrick Shunk, Akiko Maehara, Alexandra Popma, Bjorn Redfors, Ziad A Ali, Mitchell Krucoff, Ehrin Armstrong, David E Kandzari, William O'Neill, Carlye Kraemer, Krista M Stiefel, Denise E Jones, Jeff Chambers, Gregg W Stone
Journal: The Lancet (2025)