tbuckley/cabot-search huggingface dataset:
Anticholinergic Burden and Cognitive Function in Psychosis: A Systematic Review and Meta-Analysis
Authors: Valentina Mancini, Caren Latreche, Jack B. Fanshawe, Ioana Varvari, Chambrez-Zita Zauchenberger, Nova McGinn, Ana Catalan, Toby Pillinger, Philip K. McGuire, Robert A. McCutcheon
Journal: American Journal of Psychiatry (2025)

The authors synthesized evidence from studies quantifying the relationship between anticholinergic medication and cognitive function in psychosis, and additionally explored studies that investigated whether reducing anticholinergic medications affects cognitive function in individuals with psychosis. A database search was conducted in MEDLINE, Embase, and PsycINFO, from database inception to October 2023, for studies reporting objective cognitive assessment and quantification of anticholinergic burden using clinical scales, serological anticholinergic activity, or tapering of anticholinergic medications. Analyses were carried out in R using the metafor package. Random-effects meta-analysis models were employed, along with assessment of heterogeneity, study quality, and meta-regressions (age, sex, and antipsychotic dosage in chlorpromazine equivalents). Of 1,337 citations retrieved, 40 met inclusion criteria, comprising 25 anticholinergic burden studies (4,620 patients), six serological anticholinergic activity studies (382 patients), and nine tapering studies (186 patients). A negative correlation was identified between anticholinergic burden and global cognition (r=-0.37, 95% CI=-0.48, -0.25), verbal learning (r=-0.28, 95% CI=-0.36, -0.21), visual learning (r=-0.17, 95% CI=-0.28, -0.06), working memory (r=-0.22, 95% CI=-0.29, -0.14), processing speed (r=-0.24, 95% CI=-0.35, -0.13), attention (r=-0.19, 95% CI=-0.29, -0.08), executive functions (r=-0.17, 95% CI=-0.27, -0.06), and social cognition (r=-0.12, 95% CI=-0.19, -0.05), and between serological anticholinergic activity and verbal learning (r=-0.26, 95% CI=-0.38, -0.14), working memory (r=-0.19, 95% CI=-0.35, -0.03), and executive functions (r=-0.16, 95% CI=-0.27, -0.04). Finally, tapering off anticholinergic medication improved the scores in verbal learning (d=0.77, 95% CI=0.44, 1.1), working memory (d=0.94, 95% CI=0.63, 1.26), and executive functions (d=0.44, 95% CI=0.26, 0.62). Anticholinergic burden is associated with the cognitive impairments observed in psychosis. From a clinical perspective, tapering off anticholinergic medication in patients with psychosis may improve cognition. However, randomized clinical trials are needed for an unbiased quantification of benefit.
Estimating Multimodal Structural Brain Variability in Schizophrenia Spectrum Disorders: A Worldwide ENIGMA Study
Authors: Wolfgang Omlor, Finn Rabe, Simon Fuchs, Werner Surbeck, Giacomo Cecere, Gao-Yang Huang, Stephanie Homan, Nils Kallen, Foivos Georgiadis, Tobias Spiller, Erich Seifritz, Thomas Weickert, Jason Bruggemann, Cynthia Weickert, Steven Potkin, Ryota Hashimoto, Kang Sim, Kelly Rootes-Murdy, Yann Quide, Josselin Houenou, Nerisa Banaj, Daniela Vecchio, Fabrizio Piras, Federica Piras, Gianfranco Spalletta, Raymond Salvador, Andriana Karuk, Edith Pomarol-Clotet, Amanda Rodrigue, Godfrey Pearlson, David Glahn, David Tomecek, Filip Spaniel, Antonin Skoch, Matthias Kirschner, Stefan Kaiser, Peter Kochunov, Feng-Mei Fan, Ole A. Andreassen, Lars T. Westlye, Pierre Berthet, Vince D. Calhoun, Fleur Howells, Anne Uhlmann, Freda Scheffler, Dan Stein, Felice Iasevoli, Murray J. Cairns, Vaughan J. Carr, Stanley V. Catts, Maria A. Di Biase, Assen Jablensky, Melissa J. Green, Frans A. Henskens, Paul Klauser, Carmel Loughland, Patricia T. Michie, Bryan Mowry, Christos Pantelis, Paul E. Rasser, Ulrich Schall, Rodney Scott, Andrew Zalesky, Andrea de Bartolomeis, Annarita Barone, Mariateresa Ciccarelli, Arturo Brunetti, Sirio Cocozza, Giuseppe Pontillo, Mario Tranfa, Annabella Di Giorgio, Sophia I. Thomopoulos, Neda Jahanshad, Paul M. Thompson, Theo van Erp, Jessica Turner, Philipp Homan
Journal: American Journal of Psychiatry (2025)

The clinical diversity of schizophrenia is reflected by structural brain variability. It remains unclear how this variability manifests across different gray and white matter features. In this meta- and mega-analysis, the authors investigated how brain heterogeneity in schizophrenia is distributed across multimodal structural indicators.
Endoscopic Ultrasound‐Guided Brachytherapy of Yttrium‐90 Implantation Into Pancreas: A Dose‐Escalation Pilot Study
Authors: Yuchong Zhao, Yilei Yang, Buchuan Zhang, Haochen Cui, Luyao Liu, Ronghua Wang, Yunfeng Han, Dongling Zhu, Wenliang Ma, Xinxing Zhang, Jinlin Wang, Si Xiong, Shuya Bai, Xiaohua Zhu, Bin Cheng
Journal: MedComm (2025)

ABSTRACT Intratumoral brachytherapy enables higher dose treatment and reduces damage to adjacent tissues. We first validated the feasibility and safety of endoscopic ultrasound (EUS)‐guided Yttrium‐90 ( 90 Y) microspheres implantation in a porcine model. Under EUS guidance, 90 Y‐loaded microspheres were implanted into the pancreas of 10 miniature pigs. The first pig was implanted with 10 MBq particles. Subsequently, nine pigs were sequentially included in the low‐ (20 MBq), medium‐ (40 MBq), and high‐dose (60 MBq) groups. Positron emission tomography (PET)/CT imaging was used to check the occurrence of particle displacement postoperatively. After euthanasia, the pancreas and adjacent organs were excised for histological examination and residue radiation detection. The absorbed doses demonstrated safe in the porcine model were further in the xenograft model and KRAS LSL/+ Trp53 FL/FL Ptfqa Cre/+ mouse model. EUS‐guided implantations of 90 Y‐loaded microspheres were successful in all animals. Two pigs had mild serum amylase elevation in the high‐dose group and the abnormal index returned to baseline without interventions. The volume of necrotic lesions ranged from 255.76 to 745.57 mm 3 . In KPC mouse model, PET/CT imaging demonstrated a significant decrease in maximum standardized uptake value (SUVmax) after 90 Y implantation. EUS‐guided 90 Y‐loaded carbon microsphere implantation could serve as a safe and feasible technique at ultrahigh dose for pancreatic cancer brachytherapy.
Tumor-specific CD8<sup>+</sup>T cells from the bone marrow resist exhaustion and exhibit increased persistence in tumor-bearing hosts as compared with tumor-infiltrating lymphocytes
Authors: Elizabeth M Zawidzka, Luca Biavati, Amy Thomas, Claudio Zanettini, Luigi Marchionni, Robert Leone, Ivan Borrello
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Immunotherapy is now an integral aspect of cancer therapy. Strategies employing adoptive cell therapy (ACT) have seen the establishment of chimeric antigen receptor (CAR)-T cells using peripheral blood lymphocytes as well as tumor-infiltrating lymphocytes (TILs) with significant clinical results. The bone marrow (BM) is an immunological niche housing T cells with specificity for previously encountered antigens, including tumor-associated antigens from certain solid cancers. This study sought to improve our understanding of tumor-specific BM T cells in the context of solid tumors by comparing them with TILs, and to assess whether there is a rationale for using the BM as a source of T cells for ACT against solid malignancies. Methods We used the murine B16 melanoma model examining both the endogenous OVA-specific T cell response using an OVA-specific tetramer or examining the OVA-specific response with OVA-specific transgenic CD8+ (OT-1) T cells. Specifically, we compared baseline intrinsic properties of TILs or BM T cells from tumor-bearing mice and their changes following adoptive transfer in the tumor and bone marrow (as well as other compartments when indicated). Results In tumor-bearing mice, endogenous tumor-specific T cells could be detected in the BM early in the course of tumor progression and possessed a more stem-cell-like and memory phenotype in an unsupervised cluster analysis compared with TILs which appeared more exhausted. The BM and tumor microenvironments significantly impact the fate of T cells. Naïve OT-1 transferred T cells acquired an exhausted phenotype in the tumor but maintained a more memory-like phenotype in the BM with tumor progression. Importantly, in a competitive transfer experiment, BM T cells infiltrated the tumor more efficiently than TILs, displayed a higher polyfunctionality with interleukin-2, interferon-γ, tumor necrosis factor-α production and showed greater persistence compared with TILs. Conclusions T cells from the BM appear superior to TILs as a source of cells for cellular therapy. They possess a memory-enriched phenotype and exhibit improved effector function, greater persistence within a tumor-bearing host, and the capacity for increased tumor infiltration. These data provide a foundation for further exploring the BM as a source of tumor-specific T cells for ACT in solid malignancies.
Immunological biomarkers of response and resistance to treatment with cabozantinib and nivolumab in recurrent endometrial cancer
Authors: Vladimir Roudko, Diane Marie Del Valle, Emir Radkevich, Geoffrey Kelly, Xie Hui, Manishkumar Patel, Edgar Gonzalez-Kozlova, Kevin Tuballes, Howard Streicher, Swati Atale, Lisa Wang, Benito CzinCzin, Seunghee Kim-Schulze, Ignacio I Wistuba, Cara L Haymaker, Gheath Al-Atrash, Ganiraju Manyam, Jianjun Zhang, Ryan Thompson, Mayte Suarez-Farinas, Stephanie Lheureux, Sacha Gnjatic
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Antiangiogenics combined with immune checkpoint blockade have become standard of care for recurrent endometrial cancer after standard platinum-based chemotherapy. To dissect mechanisms and define biomarkers associated with clinical outcomes to these combinations, we applied multidimensional immune monitoring to peripheral blood specimens collected from a randomized phase 2 trial of nivolumab with or without cabozantinib in 75 evaluable patients with recurrent endometrial cancer (NCI ETCTN 10104, NCT03367741 ). This trial demonstrated superiority of the combination to nivolumab alone. Methods and results Using Olink proteomics, mass cytometry, tumor antigen-specific ELISA, and whole exome tumor sequencing, we identified longitudinal immune signatures specific to cabozantinib use, including an increase in plasma HO-1 and reduction in plasma vascular endothelial growth factor receptor 2, interleukin-12, and circulating plasmacytoid dendritic cells. Prior exposure to immunotherapy and carcinosarcoma histology had no adverse impact on clinical benefit or biomarkers, and copy-number high tumors were associated with increased plasma granzymes on combination treatment. Higher baseline plasma levels of myeloid-related markers (chemokine ligand 23/CCL23, colony-stimulating factor-1/macrophage colony-stimulating factor/CSF1) were associated with poor overall and progression-free survival, and lack of clinical benefit (defined as progressive or stable disease &lt;6 months) following combination treatment (Kaplan-Meier, multivariate Cox, false discover rate &lt;0.05). Patients with favorable outcomes had higher levels of activated T-cell markers (plasma ICOS-L, CD28) and exhibited spontaneous autoantibody titers to tumor antigen NY-ESO-1. Patients experiencing severe adverse events from the combination therapy had higher baseline levels of neutrophil-derived markers (CXCL1). Conclusions Overall, this study highlights potential resistance and response mechanisms to nivolumab+cabozantinib and suggests prioritizing combination treatment in patients with activated T-cell immunogenicity profiles while exploring future combinatorial therapies targeting myeloid populations to overcome resistance.
Effector T cells under hypoxia have an altered transcriptome similar to tumor-stressed T cells found in non-responsive melanoma patients
Authors: Mate Z Nagy, Lourdes B Plaza-Rojas, Justin C Boucher, Elena Kostenko, Anna L Austin, Ahmad A Tarhini, Zhihua Chen, Dongliang Du, Awino Maureiq E Ojwang', Joshua Davis, Alyssa Obermayer, Katarzyna A Rejniak, Timothy I Shaw, Jose A Guevara-Patino
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background In the tumor microenvironment (TME), hypoxia stands as a significant factor that modulates immune responses, especially those driven by T cells. As T cell-based therapies often fail to work in solid tumors, this study aims to investigate the effects of hypoxia on T cell topo-distribution in the TME, gene expression association with T cell states, and clinical responses in melanoma. Methods To generate detailed information on tumor oxygenation and T cell accessibility, we used mathematical modeling of human melanoma tissue microarrays that incorporate oxygen supply from vessels, intratumoral diffusion, and cellular uptake. We created tumor maps and derived plots showing the fraction of CD4 and CD8 T cells against the distance to the nearest vessel and oxygen pressure. To assess their function and transcriptional changes caused by hypoxia, effector T cells were generated and cultured under hypoxia (0.5% oxygen) or normoxia (21% oxygen). The T cell hypoxia-transcriptional signature was compared against datasets from msigDB, iATLAS (clinical trials of melanoma patients treated with immune checkpoint inhibitors (ICIs)), ORIEN AVATAR (real-world melanoma patients treated with ICIs), and a single-cell atlas of tumor-infiltrating lymphocytes. Results We made three specific observations: (1) in melanoma T cells preferentially accumulated in oxygenated areas close to blood vessels (50–100 µm from the vasculature in the regions of high oxygen availability) but not in hypoxic areas far from blood vessels. (2) Our analysis confirmed that under hypoxia, T cell functions were significantly reduced compared with normoxic conditions and accompanied by a unique gene signature. Furthermore, this hypoxic gene signature was prevalent in resting and non-activated T cells. Notably and clinically relevant, the hypoxic T cell gene set was found to correlate with reduced overall survival and reduced progression-free survival in melanoma patients, which was more pronounced in non-responder patients undergoing ICI therapy. (3) Finally, compared with a single-cell atlas of tumor-infiltrating T cells, our hypoxia signature aligned with a population of cells at a state termed stress response state (T STR ). Conclusions Our study highlights the critical role of hypoxia in shaping T cell distribution and its correlation with clinical outcomes in melanoma. We revealed a preferential accumulation of T cells in oxygenated areas. Moreover, hypoxic T cells develop a distinct hypoxic gene signature prevalent in resting, non-activated T cells and T STR that was also associated with poorer outcomes, particularly pronounced among non-responders to ICIs.
Phase I study of ribociclib (CDK4/6 inhibitor) with spartalizumab (PD-1 inhibitor) with and without fulvestrant in metastatic hormone receptor-positive breast cancer or advanced ovarian cancer
Authors: Ana C Garrido-Castro, Noah Graham, Lestat R Ali, Christina Herold, Jennifer Desrosiers, Khanh Do, Heather Parsons, Tianyu Li, Shom Goel, Molly DiLullo, Eileen Wrabel, Amy J Williams, Joyce F Liu, Elizabeth A Mittendorf, Stephanie K Dougan, Nabihah Tayob, Geoffrey I Shapiro, Sara M Tolaney
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Preclinical evidence suggests that cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors enhance antitumor immunity. We conducted a phase I trial of ribociclib (CDK4/6 inhibitor) plus spartalizumab (PD-1 inhibitor) in patients with hormone receptor (HR)-positive/HER2-negative metastatic breast cancer (MBC) or advanced ovarian cancer (AOC). The combination was also evaluated with fulvestrant in MBC. Methods In Cohort A, ribociclib was administered on Days 1–21 (28-day cycle) starting at 400 mg, and spartalizumab at 400 mg on Day 1. Dose escalation was followed by expansion in AOC. Fulvestrant was added (Cohort B) with a safety run-in followed by expansion in MBC. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), and safety and tolerability of the combinations. Results 33 patients enrolled (n=18, Cohort A; n=15, Cohort B). The RP2D of ribociclib in both cohorts was 600 mg. Treatment-related adverse events in &gt;20% of patients in either cohort were neutropenia, fatigue, anemia, thrombocytopenia, hypertransaminasemia, maculopapular rash, fatigue, and nausea. Hypertransaminasemia occurred in 66.7% (AST) and 46.7% (ALT) of patients in Cohort B, including 46.7% and 40.0%, respectively, of grade 3 or 4 events. Two confirmed partial responses were observed (13.3%) in Cohort B, in patients with low baseline serum thymidine kinase activity, coupled with an increase on-treatment. Peripheral blood flow cytometry across patients demonstrated on-target drug binding with increases in PD-1 occupancy and activated CD8 + T cells during treatment, irrespective of response. PD-L1-positivity, tumor-infiltrating lymphocytes, or tumor mutational burden did not correlate with progression-free survival (PFS). Several copy-number variations detected with next-generation sequencing correlated with PFS. Conclusions Ribociclib with spartalizumab and fulvestrant showed limited efficacy and elevated hepatotoxicity, precluding further development. Correlative analyses revealed treatment-induced immunological effects, and genomic alterations associated with PFS.
Fc-competent TIGITx4-1BB bispecific antibody exerts potent long-lasting antitumor activity by potentiating CD8<sup>+</sup>T cell activity and Fcγ receptor-mediated modulation of the tumor microenvironment
Authors: Wonjun Son, Yangsoon Lee, Yelim Park, Kyeong-Su Park, Sora Kim, Hyunseong Youn, Arim Seo, Byungje Sung, Sang Hoon Lee, Jonghwa Won
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background TIGIT was identified as a target immune checkpoint for overcoming resistance to PD-(L)1-blocking antibodies. However, the clinical efficacies of TIGIT antibodies were moderate in monotherapy and mixed in combination with PD-(L)1 antibodies. 4-1BB, a strong inducible costimulatory receptor, is another attractive target in antitumor therapeutics. This study investigated whether ABL112, an Fc-competent bispecific antibody targeting TIGIT and 4-1BB (TIGITx4-1BB), would enhance antitumor activity via Fcγ receptor (FcγR)-mediated macrophage activation and antibody-dependent cell-mediated functions. Methods TIGIT-dependent 4-1BB activation and TIGIT-blocking activity were assessed using reporter Jurkat T cell lines expressing 4-1BB and TIGIT, respectively. In vivo antitumor activity was confirmed in h4-1BB knock-in mice. The main immune cell subsets associated with the antitumor activity of ABL112 were identified using antibodies for depleting specific immune cell subtypes or FcγR-blocking antibodies. The effects of a combined pembrolizumab or atezolizumab treatment with ABL112 were assessed in two mouse models with different genetic backgrounds. Statistical analysis was performed using one-way or two-way analysis of variance (ANOVA) with Dunnett’s multiple-comparison test or one-way ANOVA with Fisher’s multiple-comparison test. Results ABL112 restored T cell activity by blocking TIGIT–CD155 interactions, based on a TIGIT blockade reporter assay. ABL112, an Fc-competent TIGITx4-1BB bispecific antibody, showed strong FcγRI-dependent 4-1BB activation along with TIGIT-dependent 4-1BB activation. In H22 tumor models expressing high levels of endogenous CD155, both ABL112 and parent TIGIT single-domain Ab showed potent tumor-suppressive activity; however, only ABL112 exerted long-lasting antitumor activity. ABL112 induced a marked decrease in Treg numbers, while augmenting the absolute number of CD8 + T cells and proportion of CD226 + CD8 + T cells. The expressions of CXCL10, CXCL11, IFN-γ, and TNF-α increased, indicating myeloid cell activation and potential modification of the tumor microenvironment to an inflammatory phenotype. ABL112 not only showed outstanding antitumor activity as a monotherapy, but also showed synergistic effects with PD-(L)1 mAb compared with the combined TIGIT–PD-(L)1 mAb treatments. Conclusions Through multiple mechanisms of action, ABL112 exerted potent tumor-killing activity and immune memory response alone or in combination with anti-PD-(L)1 therapies, representing a promising new cancer treatment strategy.
Disruption of GPSM1/CSF1 signaling reprograms tumor-associated macrophages to overcome anti-PD-1 resistance in colorectal cancer
Authors: Yang Chen, Huiqing Jia, Xiangyan Zhang, Han Zhao, Yujing Xiao, Na Li, Yifan Yao, Xiaoming Xing
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Immune checkpoint blockade (ICB) therapies, particularly anti-PD-1, benefit only a limited subset of colorectal cancer (CRC) patients. G-protein signaling modulator 1 (GPSM1) is implicated in immunity and oncology, yet its role in regulating the CRC tumor microenvironment (TME) and contributing to anti-PD-1 resistance remains poorly understood. Methods We employed single-cell RNA sequencing and multiplex immunofluorescence on tumor samples from anti-PD-1-resistant CRC patients to evaluate GPSM1 expression and its impact on macrophage polarization. An orthotopic CRC xenograft model in C57BL/6 mice was used to assess the role of GPSM1 in vivo. An in vitro co-culture system, alongside mass cytometry and flow cytometry, explored GPSM1’s biological functions within the TME. We further used ChIP-PCR, mass spectrometry, and co-immunoprecipitation to elucidate the mechanisms regulating GPSM1 activity. Results GPSM1 expression was significantly elevated in anti-PD-1-resistant CRC tissues. Enhanced GPSM1 levels promoted anti-PD-1 resistance by driving macrophage polarization toward an immunosuppressive M2 phenotype, facilitating their infiltration into the TME. We identified the deubiquitinase USP9X as a key factor preventing GPSM1 degradation through K63-polyubiquitination. This stabilization of GPSM1 led to MEIS3 nuclear translocation, activating macrophage colony-stimulating factor expression. Importantly, ruxolitinib emerged as a promising GPSM1-targeting candidate, demonstrating improved efficacy in combination with anti-PD-1 therapy in both microsatellite instability-high and microsatellite stable CRC models. Conclusions Our findings highlight the pivotal role of GPSM1-driven M2 macrophage infiltration in mediating anti-PD-1 resistance in CRC. Targeting GPSM1 offers a novel therapeutic strategy to enhance ICB efficacy, potentially broadening the patient population that may benefit from these therapies.