tbuckley/cabot-search huggingface dataset:
Porustobart (HBM4003) plus toripalimab as second-line therapy in patients with advanced hepatocellular carcinoma: a multicenter, open-label, phase I study
Authors: Ningning Zhang, Tian Liu, Ming Luo, Jihui Hao, Shukui Qin, Yanqiao Zhang, Gang Wang, Yajin Chen, Jingdong Zhang, Shanzhi Gu, Junqi Niu, Guijie Xin, Ge Yu, Yabing Guo, Chongyuan Xu, Jun Yao, Jie Shen, Aibing Xu, Shuwen Zhang, Di Yang, Meijuan Gao, Ruixuan Luo, Yebo He, Fei Zheng, Nan Cao, Xiaolu Tao
Journal: Clinical Cancer Research (2025)

Abstract Purpose: To evaluate porustobart (HBM4003), a novel anti-CTLA-4 monoclonal antibody, combined with toripalimab as second-line therapy in advanced HCC. Patients and Methods: This phase I study included two cohorts of patients with advanced HCC: cohort 1 included patients who were anti-PD-1/PD-L1 naïve and had received first-line anti-VEGFR- tyrosine kinase inhibitor; cohort 2 included patients who had failed prior first-line anti-PD-1/PD-L1 and anti-VEGF/VEGFR therapies. Porustobart (0.45 mg/kg) and toripalimab (240 mg) were administered every 21 days. The primary endpoint was the objective response rate (ORR). Results: Totally, 16 patients were enrolled in cohort 1 and 12 in cohort 2. In the 26 patients with evaluable efficacy data, ORR was 23.1% (95% CI 9.0-43.6). Cohort 1 exhibited an ORR of 40.0%, while cohort 2 presented no objective response. The median progression-free survival was 4.2 months, with 5.7 months for cohort 1 and 3.8 for cohort 2. Biomarker exploration revealed higher abundance of intratumoral Tregs in responders before treatment, and a substantial elevation of CD4+Ki67+ and CD8+Ki67+ T cells after treatment. For safety, treatment-emergent adverse events were reported in 27 (96.4%) patients, treatment-related adverse events (TRAEs) were reported in 25 patients (89.3%), among whom 13 (46.5%) had grade ≥3 TRAEs. Serious adverse events (SAEs) were observed in 12 patients (42.9%), and treatment-related SAEs were observed in 9 (32.1%) patients. Conclusions: The combination of porustobart and toripalimab shows promising efficacy as a second-line therapy in anti-PD-1/PD-L1 naïve patients with advanced HCC and a manageable safety profile. Trial Registration: ClinicalTrials.gov identifier: NCT05149027.
Clinicogenomic characterization of inflammatory breast cancer
Authors: Nolan Priedigkeit, Beth Harrison, Robert Shue, Melissa E. Hughes, Yvonne Li, Alinés Lebrón-Torres, Gregory J. Kirkner, Liam F. Spurr, Marie Claire. Remolano, Sarah Strauss, Janet Files, Anne-Marie Feeney, Libby Grant, Ayesha Mohammed-Abreu, Ana Garrido-Castro, Romualdo Barroso Sousa, Brittany Bychkovsky, Faina Nakhlis, Jennifer R. Bellon, Tari A. King, Eric P. Winer, Neal Lindeman, Bruce E. Johnson, Lynette Sholl, Deborah Dillon, Beth Overmoyer, Sara M. Tolaney, Andrew D. Cherniack, Nancy U. Lin, Filipa Lynce
Journal: Clinical Cancer Research (2025)

Abstract Background: Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to limited large-scale genomic studies that directly compare IBC to non-IBC cases. Patients and Methods: We conducted a retrospective analysis of 140 patients with IBC (68 primary tumors, 72 metastatic tumors) and 2,317 patients with non-IBC (700 primary tumors, 65 local recurrences, 1,552 metastases). Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV), tumor mutational burden (TMB), and exploratory survival outcomes were compared between IBC and non-IBC. Results: The most frequent somatic alterations in IBC were detected in TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%) and GATA3 (8%). Multivariate logistic regression revealed a significant enrichment in TP53 SNVs in IBC, particularly in HER2+ and hormone receptor-positive (HR+) disease. TMB did not differ between IBC and non-IBC cases. In HER2+ disease, a pathway analysis revealed an enrichment in NOTCH pathway alterations. TP53, CCND1 and RB1 alterations were associated with poor outcomes in IBC. Conclusion: This study provides a comprehensive resource of somatic alterations in a large cohort of patients with metastatic IBC and non-IBC; highlighting genomic features associated with worse outcomes. Our findings reveal a significant enrichment of TP53 mutations, reinforcing its critical role in IBC pathogenesis. Few other distinct differences in IBC were observed, suggesting further investigations—beyond bulk sequencing of the somatic genome—are required to better understand the biology driving this aggressive disease.
Innovative Therapeutic Strategies Targeting the Network Architecture of Glioblastoma
Authors: Julius Beichert, Dirk C. Hoffmann, Frank Winkler, Miriam Ratliff
Journal: Clinical Cancer Research (2025)

Abstract Recent discoveries concerning the network architecture of glioblastoma, including tumor microtubules (TMs) and neuron-glioma synapses, have underscored critical pathways that sustain tumor growth, enhance resistance, and integrate glioblastoma with the surrounding neural environment. This review explores emerging therapeutic strategies targeting these pathways, including inhibitors of gap junctions, AMPA receptors, and glutamate signaling, which are currently being tested in clinical trials. By consolidating these advances, this review seeks to bridge the gap between neurobiology, cancer neuroscience, and oncology, proposing novel approaches to overcome resistance and improve patient outcomes. The insights derived from this comprehensive review hold the potential to significantly influence the future management of glioblastoma.
Genomic Editing of a Pathogenic Mutation in ACTA2 Rescues Multisystemic Smooth Muscle Dysfunction Syndrome in Mice
Authors: Qianqian Ding, Peiheng Gan, Zhisheng Xu, Hui Li, Lei Guo, Camryn MacDonald, Wei Tan, Efrain Sanchez-Ortiz, John R. McAnally, Yu Zhang, Dileep Karri, Lin Xu, Ning Liu, Eric N. Olson
Journal: Circulation (2025)

Background: Vascular smooth muscle cells (vSMCs), the predominant cell type in the aortic wall, play a crucial role in maintaining aortic integrity, blood pressure, and cardiovascular function. vSMC contractility and function depend on smooth muscle alpha-actin 2 ( ACTA2 ). The pathogenic variant ACTA2 c.536G&gt;A (p. R179H) causes multisystemic smooth muscle dysfunction syndrome (MSMDS), a severe disorder marked by widespread smooth muscle abnormalities, resulting in life-threatening aortic disease and high-risk early mortality from aneurysms or stroke. No effective treatments exist for MSMDS. Methods: To develop a comprehensive therapy for MSMDS, we utilized CRISPR-Cas9 adenine base editing to correct the ACTA2 R179H mutation. We generated isogenic human induced pluripotent stem cell (iPSC) lines and humanized mice carrying this pathogenic missense mutation. iPSC-SMCs were evaluated for key functional characteristics, including proliferation, migration, and contractility. The adenine base editor (ABE) ABE8e-SpCas9-VRQR under control of either a SMC-specific promoter or a CMV promoter, and an optimized single guide RNA (sgRNA) under control of U6 promoter were delivered intravenously to humanized R179H mice using adeno-associated virus serotype 9 (AAV9) and phenotypic outcomes were evaluated. Results: The R179H mutation causes a dramatic phenotypic switch in human iPSC-SMCs from a contractile to a synthetic state, a transition associated with aneurysm formation. Base editing prevented this pathogenic phenotypic switch and restored normal SMC function. In humanized mice, the ACTA2 R179H/+ mutation caused widespread smooth muscle dysfunction, manifesting as decreased blood pressure, aortic dilation and dissection, bladder enlargement, gut dilation, and hydronephrosis. In vivo base editing rescued these pathological abnormalities, normalizing smooth muscle function. Conclusions: This study demonstrates the effectiveness of adenine base editing to treat MSMDS and restore aortic smooth muscle function. By correcting the ACTA2 R179H mutation, the pathogenic phenotypic shift in SMCs was prevented, key aortic smooth muscle functions were restored, and life-threatening aortic dilation and dissection were mitigated in humanized mice. These findings underscore the promise of gene-editing therapies in addressing the underlying genetic causes of smooth muscle disorders and offer a potential transformative treatment for patients facing severe vascular complications.
Tumor progression locus 2, a new potential prognostic factor and therapeutic target in activated B-cell-like diffuse large B-cell lymphoma
Authors: Kota Yoshifuji, Yotaro Motomura, Makiko Saito, Genji Kawade, Shiori Watabe, Kouhei Yamamoto, Mai Soejima, Ayako Nogami, Satoru Aoyama, Takehiko Mori, Toshikage Nagao
Journal: Blood Cancer Journal (2025)
Unravelling the tumor microenvironment and PD-L1 expression across tissue type in high-grade serous ovarian cancer in the NeoPembrOV/GINECO phase II randomized trial
Authors: Laetitia Collet, Maude Ardin, David Venet, Justine Berthet, Sarah Ghamry-Barrin, Isabelle Treilleux, Jean-Christophe Noel, Marianne Leheurteur, Jérôme Meunier, Leïla Bengrine Lefevre, Mathilde Martinez, Frank Priou, Frédéric Selle, Pierre-Alexandre Just, Guillaume Bataillon, Françoise Rothé, Christos Sotiriou, Christophe Caux, Bertrand Dubois, Isabelle Ray-Coquard, Olivia Le Saux
Journal: Clinical Cancer Research (2025)

Abstract Purpose: To describe PD-L1 expression across tissue types and its associated tumor microenvironment (TME) and to investigate how it impacts its predictive value for response to pembrolizumab in treatment-naïve ovarian cancer (OC) patients included in the NeoPembrOV phase II trial (NCT03275506). Methods: PD-L1 expression was assessed for 85 patients (56 on metastasis, 29 on tubo-ovary) using tumor proportion score (TPS) and immune cell (IC) score, considering positivity if ≥ 1% and high expression if ≥ 5%. RNA sequencing and multiplex immunofluorescence were conducted. The Australian Ovarian Cancer Study (AOCS) was used as an external validation cohort. Results: PD-L1 was primarily expressed by tumor cells (TCs) in tubo-ovaries and by ICs in metastases. IC-score assessed on the metastases was associated with a longer PFS in the pembrolizumab arm compared to the control arm. Compared to tubo-ovaries, metastases were enriched in T and B cells as well as in GZMBCD8 cytotoxic T cell signatures. In metastases, IC-score was associated with immune infiltration and overexpression of additional immune checkpoints such as IDO1, LAG3, ICOS while TPS was associated with cell proliferation, immune infiltration and interferon-gamma pathways. In tubo-ovaries, TPS was associated with pathways linked to cell proliferation and antigen presentation but depleted in activated immune pathways, and CD274 expression was correlated with hypoxia and PI3K/Akt/mTOR signaling. Discussion: Distinct PD-L1 expression patterns across tissue type are associated with different biological pathways and TME in OC impacting PD-L1 predictive value. Our results provide novel insights in HGSC biology for tailoring immunotherapy in OC patients.
Enabling technologies for in situ biomanufacturing using probiotic yeast
Authors: William Parker, Amanda Taylor, Aryan Razdan, Jose Escarce, Nathan Crook
Journal: Advanced Drug Delivery Reviews (2025)

Saccharomyces boulardii (Sb) is a Generally Regarded As Safe (GRAS) probiotic yeast currently used to alleviate symptoms from various gastrointestinal diseases. Sb is a promising platform for probiotic and biotherapeutic engineering as it is the only probiotic eukaryote and carries with it a unique set of advantages compared to bacterial strains, including resistance to phage, high protein secretion abilities, and intrinsic resistance to antibiotics. While engineered Sb has not been studied as extensively as its close relative Saccharomyces cerevisiae (Sc), many genetic engineering tools developed for Sc have also shown promise in Sb. In this review, we address recent research to develop tools for genetic engineering, colonization modulation, biomarker sensing, and drug production in Sb. Ongoing efforts, especially those that overcome gut-specific challenges to engineered performance, are highlighted as they advance this chassis as a scalable platform for treating gastrointestinal diseases.
The metabolite alpha-ketoglutarate inhibits vascular calcification partially through modulation of TET2/NLRP3 inflammasome signaling pathway
Authors: Mingwei Fu, Zirong Lan, Yuanzhi Ye, Yuan Gong, Qingchun Liang, Mingxi Li, Liyun Feng, An Chen, Qianqian Dong, Yining Li, Siyi Wang, Xiaoyu Liu, Xiuli Zhang, Jing-Song Ou, Lihe Lu, Jianyun Yan
Journal: Kidney International (2025)
Racial and Ethnic Disparities in Mother’s Milk Provision Among Mothers of Preterm Infants
Authors: Nikita S. Kalluri, Erika G. Cordova-Ramos, Sunah S. Hwang, Katherine R. Standish, Margaret G. Parker
Journal: JAMA Network Open (2025)

Importance The extent of mother’s milk provision by race and ethnicity and its change over time is poorly understood in the US preterm population. Objective To examine US prevalence and trends over time of mother’s milk initiation and continuation at 12 weeks after birth (2009-2019) by maternal race and ethnicity and to examine associations of maternal race and ethnicity and mother’s milk initiation and continuation among mothers of preterm infants. Design, Setting, and Participants This cross-sectional study used data from the nationally representative Pregnancy Risk Assessment Monitoring System database. Participants included mothers of preterm infants identifying as non-Hispanic Asian, non-Hispanic Black, Hispanic any race, or non-Hispanic White, with survey completion 12 or more weeks post partum from 2009 to 2019. Data were analyzed from February 2022 to June 2024. Exposure Maternal race and ethnicity obtained from birth certificate data. Main Outcomes and Measures Mother’s milk initiation and continuation at 12 weeks were assessed using survey questions. The overall prevalence and trends over time by maternal race and ethnicity were determined. Multivariable regression was used to analyze independent associations between maternal race and ethnicity and mother’s milk initiation and continuation. Results Among 1 523 131 (weighted) mother-preterm infant dyads, mother’s milk initiation increased significantly from 2009 to 2019 for White and Black mothers but not for Asian or Hispanic mothers. Mother’s milk provision at 12 weeks increased significantly among all groups. There were significant differences in mother’s milk outcomes between groups. Initiation was highest for Asian mothers (92.8%; 95% CI, 91.1%-94.4%), followed by Hispanic (88.1%; 95% CI, 86.5%-89.8%), White (84.1%; 95% CI, 83.3%-84.9%), and Black (75.3%; 95% CI, 73.4%-76.6%) mothers. After adjusting for covariates of interest, compared with White mothers, initiation remained higher for Asian (adjusted relative risk [aRR], 1.09; 95% CI, 1.06-1.12) and Hispanic (aRR, 1.10; 95% CI, 1.08-1.12) mothers. Continuation at 12 weeks was highest for Asian mothers (65.4%; 95% CI, 62.7%-68.0%), followed by Hispanic (48.2%; 95% CI, 46.1%-50.3%), White (47.7%; 95% CI, 46.7%-48.7%), and Black (34.3%; 95% CI, 32.9%-35.7%) mothers. After adjustment, continuation was higher for Asian (aRR, 1.37; 95% CI, 1.24-1.47) and Hispanic (aRR, 1.33; 95% CI, 1.27-1.41) mothers compared with White mothers. Conclusions and Relevance In this cross-sectional study, mother’s milk provision among preterm infants increased from 2009 to 2019, but notable racial and ethnic disparities persist. Future work should address barriers to continued provision of mother’s milk for preterm infants.
Anopheles mosquito exposure is associated with age, gender and bed net use in areas in Uganda experiencing varying malaria transmission intensity
Authors: Sara Lynn Blanken, Maxwell Kilama, Jordache Ramjith, Alex K Musiime, Kjerstin Lanke, Daniel Ayo, Kristiaan Huijbers, Tom Hofste, Melissa Conrad, Paul Krezanoski, Grant Dorsey, Moses R Kamya, Emmanuel Arinaitwe, Teun Bousema
Journal: Journal of Infection (2025)

The number of Anopheles mosquito bites a person receives determines the risk of acquiring malaria and the likelihood of transmitting infections to mosquitoes. We assessed heterogeneity in Anopheles biting and associated factors in two settings in Uganda with different endemicity. Plasmodium falciparum parasites in blood-fed indoor caught Anopheles mosquitoes were quantified using qPCR targeting the Pf18S rRNA gene. Human DNA in dried blood spots from household occupants and mosquito blood meals was profiled using 15 short-tandem repeats (STRs) and analysed using a log-likelihood approach for matching of both single and multi-sourced blood meals and incomplete DNA profiles. The distribution of mosquito bites was non-random; school-age children (5-15 years) and adults (≥16 years) had a mosquito biting rate ratio (BRR) 1.76 (95%CI 1.27-2.44, P < 0.001) and 1.96 (95%CI 1.41-2.73, P < 0.0001) times that of children under 5 years, respectively. Biting rates were lower in bed net users (BRR: 0.80, 95%CI 0.65-0.99, P = 0.042), and higher in males (BRR: 1.30, 95%CI 1.01-1.66, P = 0.043) and individuals infected with P. falciparum (BRR: 1.42, 95%CI 1.03-1.96, P = 0.030), though the latter effect lost statistical significance in sensitivity analyses. Adults and school-age children are at higher risk of receiving mosquito bites, and this has implications for the relative importance of demographic populations to onward malaria transmission to mosquitoes.
Regulation of immune cell metabolism by therapeutic normal IgG intravenous immunoglobulin
Authors: Naresh Rambabu, Fawaz Alzaid, Boban D Anđelković, Sruthi Vijaya Retnakumar, Anupama Karnam, Srinivasa Reddy Bonam, Lucie Orliaguet, Tina Ejlalmanesh, Dorothy Tonui, Emeline Chu-Van, Ludovic Brunet, Nina Bozinovic, Ivan Nemazanyy, Fabian Käsermann, Nicolas Venteclef, Srini V Kaveri, Thibaut Léger, François Fenaille, Benoit Colsch, Jagadeesh Bayry
Journal: Journal of Allergy and Clinical Immunology (2025)

Immune cell metabolism and metabolic end-products influence the nature and magnitude of immune responses. Various autoimmune and inflammatory diseases are associated with dysregulated cellular metabolism. Intravenous immunoglobulin (IVIG), a therapeutic pooled normal IgG, is extensively used for the immunotherapy of a wide-range of autoimmune and inflammatory diseases. Although several cellular and molecular mechanisms of action of IVIG have been reported, the role of IVIG in modulating the immune cell metabolism remains unknown. To investigate the influence of IVIG on the metabolic events of human immune cells. We performed metabolic flux analyses on inflammatory mediators-stimulated human peripheral blood mononuclear cells (PBMCs). Further, intracellular metabolites were extracted from activated PBMCs and subjected to liquid chromatography coupled to high-resolution mass spectrometry. Untargeted global metabolic profiling of PBMCs was performed to determine the metabolic landscape of immune cells and metabolic reprogramming by IVIG. Targeted lipidomics was used for the mechanistic studies on IVIG-induced lipogenesis. IVIG, and its Fc and F(ab')2 fragments regulate the Warburg effect in activated PBMCs depending on the glucose availability. Untargeted global metabolic profiling revealed that IVIG alters the overall metabolic landscape of inflammatory mediators-stimulated PBMCs, blocks prenylation of amino acid cysteine and promotes lipogenesis of well-known anti-inflammatory lipids like diacylglycerol and triacylglycerol by shuttling acetyl-CoA away from the mevalonate pathway. Mechanistically, IVIG-induced lipogenesis was mediated via F(ab')2 fragments and dependent on the sialylated glycans of IgG. Our data indicate that IVIG targets immune cell metabolism and highlights a novel mechanism of action of IVIG in the context of immunotherapy of autoimmune and inflammatory diseases.
Exercise Communication for Breast Cancer Survivors
Authors: Oliver W. A. Wilson, Kaitlyn M. Wojcik, Jinani Jayasekera, Laura Q. Rogers, Wendy Demark-Wahnefried, David Farrell, Gisela Butera, Charles E. Matthews, Richard L. Street
Journal: JAMA Network Open (2025)

Importance Exercise may offer various clinical benefits to breast cancer survivors. However, exercise participation among survivors is low. Discussions about exercise can increase participation, but details regarding implementation of exercise communication for breast cancer survivors are unclear. Objective To examine the development and implementation of explicitly reported exercise communication for breast cancer survivors. Evidence Review The Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews was used. Six databases (PubMed/MEDLINE, Cochrane Library, Embase, Web of Science, Communication and Mass Media Complete, and PsycINFO) were searched for articles describing exercise communication for female breast cancer survivors in any geographical location or setting published up to April 2024. Information about study and participant characteristics, exercise communication, and intervention components and effects were extracted. Findings Thirty-nine studies were included. Information consistent with exercise guidelines was communicated in 32 studies for aerobic exercise (82.1%) and 7 studies for muscle-strengthening exercise (17.9%). More studies communicated information about exercise benefits (20 [51.3%]) compared with exercise safety (3 [7.7%]). Studies included breast cancer survivors who were predominantly White (median [range], 85.5% [47.4%-98.7%]). Most included breast cancer survivors were educated (median percentage, 50.7% were college graduates) and had completed primary treatment (eg, median percentage, 66.7% had completed chemotherapy). Seventeen individualized (ie, tailored) information based on demographic or clinical characteristics (43.6%), and 5 considered contextual factors, such as the environment (12.8%). Most interventions reported an increase in exercise (19 of 21 [90.4%]). Heterogeneity in intervention design (eg, dietary advice or exercise trackers in addition to exercise information) and evaluation (eg, intervention length and outcomes) prevented quantitative synthesis of intervention effects. Conclusions and Relevance In this systematic scoping review of exercise communication for breast cancer survivors, interventions including exercise communication appeared to show a favorable effect. However, data were limited about the development and implementation of these interventions among underrepresented breast cancer survivors. Interest in research involving exercise communication for breast cancer survivors in clinical settings remains strong.