tbuckley/cabot-search huggingface dataset:
Rare loss-of-function variants in HECTD2 and AKAP11 confer risk of bipolar disorder
Authors: Thorgeir E Thorgeirsson, Vinicius Tragante, Gardar Sveinbjornsson, Gudrun A Jonsdottir, G Bragi Walters, Erna V Ivarsdottir, Gudny A Arnadottir, Arni Sturluson, Brynjar O Jensson, Run Fridriksdottir, Astros Th Skuladottir, Gudmundur Einarsson, Gyda Bjornsdottir, Arni F Gunnarsson, Rosa S Gisladottir, Asgeir Sigurdsson, Asmundur Oddsson, Hakon Jonsson, Olafur Th Magnusson, Hannes Helgason, Gudmundur Norddahl, Gudmar Thorleifsson, Magnus Haraldsson, Engilbert Sigurdsson, Hilma Holm, Gisli Masson, Daniel F Gudbjartsson, Hreinn Stefansson, Patrick Sulem, Kari Stefansson
Journal: Nature Genetics (2025)

Bipolar disorder is a highly heritable psychiatric disorder; genome-wide association studies of bipolar disorder have yielded over 60 risk loci harboring common variants. To harness the information contained in rare loss-of-function (LOF) variants, holding promise for informing on the underlying biology, we performed a variant burden analysis for bipolar disorder using gene-based aggregation of LOF variants in whole-genome sequencing data from Iceland (4,197 cases, more than 200,000 controls) and the UK Biobank (1,881 cases, 426,622 controls). We found that HECTD2 was associated with bipolar disorder and confirmed it using the Bipolar Exome dataset. Meta-analysis with Bipolar Exome also revealed that LOF variants in AKAP11 were associated with bipolar disorder. Both associations with bipolar disorder are new, but AKAP11 has previously been associated with psychosis and schizophrenia. The products of AKAP11 and HECTD2 interact with GSK3β, a protein inhibited by lithium, the most effective mood stabilizer available to treat bipolar disorder. Analysis of whole-genome sequencing data from Iceland and the UK Biobank identifies an excess burden of rare loss-of-function variants in HECTD2 and AKAP11 in individuals diagnosed with bipolar disorder.
Correspondence on ‘The Assessment of SpondyloArthritis International Society (ASAS) consensus-based expert definition of difficult-to-manage, including treatment-refractory, axial spondyloarthritis’ by Poddubnyy D, et al
Authors: Daniel Wendling, Olivier Fakih, Frank Verhoeven, Clément Prati
Journal: Annals of the Rheumatic Diseases (2025)
Tissue-specific properties of type 1 dendritic cells in lung cancer: implications for immunotherapy
Authors: Lucía Ines Lopez Rodriguez, Roberto Amadio, Giulia Maria Piperno, Federica Benvenuti
Journal: Journal for ImmunoTherapy of Cancer (2025)

Checkpoint inhibitors have led to remarkable benefits in non-small cell lung cancer (NSCLC), yet response rates remain below expectations. High-dimensional analysis and mechanistic experiments in clinical samples and relevant NSCLC models uncovered the immune composition of lung cancer tissues, providing invaluable insights into the functional properties of tumor-infiltrating T cells and myeloid cells. Among myeloid cells, type 1 conventional dendritic cells (cDC1s) stand out for their unique ability to induce effector CD8 T cells against neoantigens and coordinate antitumoral immunity. Notably, lung resident cDC1 are particularly abundant and long-lived and express a unique tissue-specific gene program, underscoring their central role in lung immunity. Here, we discuss recent insights on the induction and regulation of antitumoral T cell responses in lung cancer, separating it from the tissue-agnostic knowledge generated from heterogeneous tumor models. We focus on the most recent studies dissecting functional states and spatial distribution of lung cDC1 across tumor stages and their impact on T cell responses to neoantigens. Finally, we highlight relevant gaps and emerging strategies to harness lung cDC1 immunostimulatory potential.
Single-cell analysis of oncolytic virotherapy in adult T-cell leukemia/lymphoma
Authors: Jianhong An, Erqiang Hu, Yang Shi, Yanan Fang, Naijia Liu, Qiang Liu, Qing Wang, Yanhua Wang, Wu He, Angelina Wang, Yinghui Song, Jidong Shan, Jinghang Zhang, Yiyu Zou, Haiying Cheng, Rafi Kabarriti, Wei Cai, Amit Verma, Roberto Alejandro Sica, Wenjun Deng, Shanye Yin
Journal: Journal for ImmunoTherapy of Cancer (2025)

Adult T-cell leukemia/lymphoma (ATLL), an aggressive T-cell malignancy associated with human T-cell leukemia virus type 1, presents significant therapeutic challenges due to high relapse rates and resistance to therapy. Here, we present the first reported case of ATLL treated with talimogene laherparepvec (T-VEC), an oncolytic viral immunotherapy approved for unresectable melanoma. The patient, who had experienced disease progression despite multiple lines of chemotherapy, radiotherapy, immunotherapy, and targeted therapy, underwent experimental virotherapy with two intratumoral T-VEC injections. The treatment was well-tolerated, with no significant adverse effects, and led to substantial tumor regression and clinical stabilization, suggesting potential remission. Single-cell analysis revealed that T-VEC treatment induced robust local and systemic immune responses, including tumor necrosis, activation of M1 macrophages, and infiltration of CD8+ effector memory T cells. These findings demonstrate T-VEC’s safety and efficacy in generating both localized oncolysis and systemic anti-tumor immune response, highlighting its promise as a novel therapeutic approach for refractory ATLL.
Selective activation of interleukin-2/interleukin-15 receptor signaling in tumor microenvironment using paired bispecific antibodies
Authors: Julien Montorfani, Eric Hatterer, Laurence Chatel, Adeline Lesnier, Alizée Viandier, Bruno Daubeuf, Lise Nouveau, Pauline Malinge, Sebastien Calloud, Krzysztof Masternak, Walter Ferlin, Nicolas Fischer, Camilla Jandus, Limin Shang
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Owing to their roles in promoting T cell and natural killer (NK) cell activation and proliferation, interleukins-2 (IL-2) and interleukins-15 (IL-15) have been pursued as promising pathways to target in cancer immunotherapy. Nonetheless, their wider therapeutic application has been hampered by severe dose-limiting toxicities including systemic cytokine release and organ edema for IL-2, and inconvenient intratumoral administration for IL-15. To address these safety issues, we generated IL-2R/IL-15R×TAA (tumor-associated antigen) bispecific antibody (bsAb) pairs to selectively activate IL-2R signaling in the tumor microenvironment. Methods Each bsAb pair is composed of one bsAb targeting CD122 and a TAA epitope, and the other bsAb targeting CD132 and the same or a different TAA epitope. In vitro assays were performed to characterize the IL-2R/IL-15R agonistic activity of the bsAb pairs, as well as their capacity to enhance T-cell-mediated killing of TAA + malignant cells. Using a syngeneic mouse tumor model, in vivo biological activity and systemic toxicity of the bsAb pairs were assessed in comparison with IL-2. The in vivo antitumor activity was assessed in combination with an anti-mouse programmed cell death protein 1 (mPD-1) monoclonal antibody. Results We demonstrated with two different TAAs (human epidermal growth factor receptor 2 (HER2) and mesothelin (MSLN)) that the CD122×TAA/CD132×TAA bsAb pairs mediate effective activation of immune cells exclusively in the presence of TAA + tumor cells. In syngeneic hMSLN-MC38 tumor-bearing mice, the CD122×MSLN-1/CD132×MSLN-2 bsAb pair promotes selective activation and expansion of NK cells and central memory CD8 + T cells inside the tumor without inducing organ edema or systemic cytokine release, two well-known manifestations of IL-2 associated toxicity. In combination with checkpoint inhibitor anti-mPD-1, the bsAb pair boosts the accumulation of CD8 + effector T cells and NK cells, leading to a favorable CD8 + T cell to CD4 + regulatory T cell ratio for a more robust inhibition of tumor growth. Conclusions Overall, the findings suggest that this innovative therapeutic approach effectively leverages the antitumor activity of IL-2 and IL-15 pathways while minimizing their associated systemic toxicities. This dual bsAb format holds potential for broader application in other immune-activating pathways.
Anti-Nephrin Antibodies in Adult Chinese Patients with Minimal Change Disease and Primary Focal Segmental Glomerulosclerosis
Authors: Yue Shu, Jing Huang, Lei Jiang, Yi-Miao Zhang, Fang Wang, Xin Wang, Li-Qiang Meng, Xu-Yang Cheng, Gang Liu, Su-Xia Wang, Ming-Hui Zhao, Pierre Ronco, Zhao Cui
Journal: Kidney International (2025)
Bispecific receptor decoy proteins inhibit ocular neovascularization via simultaneous blockade of vascular endothelial growth factor A and C
Authors: Paul R Sargunas, Emily Ariail, Raquel Lima E Silva, Akash Patil, Mingliang Zhang, Jikui Shen, Beatriz Silva Lopes, Yuseong Oh, Amelia C McCue, Ranjani Ramasubramanian, A Carson Stephenson, Aleksander S Popel, Peter A Campochiaro, Jamie B Spangler
Journal: Molecular Therapy (2025)
Outcomes in patients with classic Hodgkin lymphoma refractory or intolerant to brentuximab vedotin and anti-PD-1 therapy: a real world analysis from 15 U.S. academic centers
Authors: Timothy J. Voorhees, Eric M. McLaughlin, Pallawi Torka, Jorge Florindez, Na Hyun Kim, Tamara K. Moyo, Heather Reves, Nuttavut Sumransub, Saarang Deshpande, Ashley Rose, Cassandra Duarte, Muhammad Salman Faisal, Showkat Hamid, Suki Subbiah, Sabarish Ayyappan, Lauren Shea, Matt Cortese, Krish Patel, Ajay Major, Hayder Saeed, Jakub Svoboda, Sanjal Desai, Praveen Ramakrishnan Geethakumari, Mehdi Hamadani, Natalie Grover, Narendranath Epperla
Journal: Blood Cancer Journal (2025)

Anti-PD-1 based therapies and brentuximab vedotin (BV) have significantly improved survival in patients with classic Hodgkin lymphoma (cHL) and have been incorporated into earlier lines of therapy. However, there is insufficient data regarding the clinical outcomes in patients who develop refractory disease or who become intolerant of BV and anti-PD-1 therapies (double refractory/intolerant; DR/INT). Here, we evaluated outcomes in patients with DR/INT cHL from 15 US academic medical centers. A total of 173 patients were identified as DR/INT. The median overall survival from the time of cHL diagnosis (OS-1) was 14.8 years (95% CI: 10.9–20.9 years) and the 10-year OS-1 estimate was 62% (95% CI: 52–70%). After accounting for differences in age, patients who underwent autologous stem cell transplant prior to developing DR/INT had significantly longer OS-1 (HR 0.53, 95% CI: 0.29–0.96, p = 0.04). Median OS from time of DR/INT (OS-2) was 7.4 years (95% CI: 4.3-NR) and the 5-year OS-2 estimate was 57% (95% CI: 48-66%). Both anti-PD-1 and BV based therapy rechallenge were effective with median PFS of 237 days (95% CI: 155-357 days) and 183 days (95% CI: 108–273 days), respectively. Finally, advanced therapy options such as CD30 directed chimeric antigen receptor T-cell therapy and allogeneic stem cell transplant after DR/INT were associated with improved OS-2 (p < 0.001). To our knowledge, this represents the largest cohort of patients with DR/INT cHL. OS-2 will serve as a benchmark for future studies aiming to improve survival in DR/INT cHL.
Erratum: Health-Related Quality of Life in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma: Findings From the Phase III MAIA Trial
Authors: Aurore Perrot, Thierry Facon, Torben Plesner, Saad Z. Usmani, Shaji Kumar, Nizar J. Bahlis, Cyrille Hulin, Robert Z. Orlowski, Hareth Nahi, Peter Mollee, Karthik Ramasamy, Murielle Roussel, Arnaud Jaccard, Michel Delforge, Lionel Karlin, Bertrand Arnulf, Ajai Chari, Jianming He, Kai Fai Ho, Rian Van Rampelbergh, Clarissa M. Uhlar, Jianping Wang, Rachel Kobos, Katharine S. Gries, John Fastenau, Katja Weisel
Journal: Journal of Clinical Oncology (2025)
Phase I, First-in-Human Study of FOR46 (FG-3246), an Immune-Modulating Antibody-Drug Conjugate Targeting CD46, in Patients With Metastatic Castration-Resistant Prostate Cancer
Authors: Rahul R. Aggarwal, Jacqueline Vuky, David VanderWeele, Matthew Rettig, Elisabeth I. Heath, David Quigley, Jiaoti Huang, Arun Chumber, Alexander Cheung, Adam Foye, Stanley Leung, Jill Abbey, Andrew Dorr, Marc Nasoff, John Hunter, Steven Wang, Robert R. Flavell, Lawrence Fong, Bin Liu, Eric J. Small
Journal: Journal of Clinical Oncology (2025)

PURPOSE FOR46, a fully human antibody conjugated to monomethyl auristatin E, targets a tumor-selective epitope of CD46, which is overexpressed in metastatic castration-resistant prostate cancer (mCRPC). FOR46 demonstrates potent nonclinical activity in enzalutamide-resistant CRPC models. PATIENTS AND METHODS This was a phase I, first-in-human, dose escalation/expansion study in patients with progressive mCRPC after treatment with ≥one androgen signaling inhibitors (ClinicalTrials.gov identifier: NCT03575819 ). The starting dose of FOR46 was 0.1 mg/kg given intravenously every 3 weeks. The primary objective was to determine the maximally tolerated dose (MTD). Whole-blood mass cytometry (cytometry by time of flight) was used to characterize peripheral immune response and CD46 expression in CRPC tissue that underwent central pathology review. RESULTS Fifty-six patients were enrolled. Dose-limiting toxicities included neutropenia (n = 4), febrile neutropenia (n = 1), and fatigue (n = 1). The MTD was 2.7 mg/kg using adjusted body weight. The most common grade ≥3 adverse events across all dose levels were neutropenia (59%), leukopenia (27%), lymphopenia (7%), anemia (7%), and fatigue (5%). One grade 3 febrile neutropenia event was observed. There were no treatment-related deaths. In the efficacy evaluable subset (patients with adenocarcinoma treated with a starting dose ≥1.2 mg/kg, n = 40), the median radiographic progression-free survival was 8.7 months (range, 0.1-33.9). Fourteen of 39 evaluable patients (36%) achieved a PSA50 response. The confirmed objective response rate was 20% (5 of 25 RECIST-evaluable patients). The median duration of response was 7.5 months. Responders had a significantly higher on-treatment frequency of circulating effector CD8 + T cells. CONCLUSION FOR46 demonstrated encouraging preliminary clinical activity with a manageable safety profile. Targeting CD46 elicited an immune priming effect that was associated with clinical outcomes.
Cancer-Associated Fibroblasts Foster a High-Lactate Microenvironment to Drive Perineural Invasion in Pancreatic Cancer
Authors: Tingting Li, Chonghui Hu, Tianhao Huang, Yu Zhou, Qing Tian, Huimou Chen, Rihua He, Yuan Yuan, Yong Jiang, Honghui Jiang, Kaijun Huang, Di Cheng, Rufu Chen, Shangyou Zheng
Journal: Cancer Research (2025)

Abstract Perineural invasion (PNI) is a pivotal prognostic factor in pancreatic cancer associated with aggressive tumor behavior and adverse patient outcomes. The recognized clinical impact of PNI highlights the need to better understand the molecular mechanisms underlying PNI-induced phenotypes. In this study, we isolated PNI-associated cancer-associated fibroblasts (pCAFs), which demonstrated a markedly enhanced capacity to promote neural invasion in pancreatic cancer compared to non-perineural invasion-associated CAFs (npCAFs). Single-cell, high-throughput sequencing and metabolomics data showed a significant upregulation of glycolysis in pCAFs, fostering a high-lactate tumor microenvironment conducive to cancer progression. pCAF-derived lactate was absorbed by tumor cells, facilitating histone H3K18 lactylation. The lactate-induced epigenetic modification activated the transcription of neural invasion-associated genes, such as L1CAM and SLIT1, thereby driving PNI in pancreatic cancer. Further exploration of metabolic reprogramming in pCAFs revealed enhanced acetylation of the glycolytic enzyme GAPDH, which correlated with increased enzymatic activity and glycolytic flux. Targeting of GAPDH and lactylation modifications significantly inhibited neural invasion in a genetically engineered mouse model. Clinical data suggested that high levels of H3K18 lactylation correlate with severe PNI and poorer patient prognosis. Together, these findings provide critical insights into the role of CAFs in promoting PNI of pancreatic cancer, highlighting glycolytic reprogramming and lactate-driven histone modifications as potential therapeutic targets for PDAC.
Beyond Glucocorticoids for IgG4-Related Disease
Authors: Robert Spiera
Journal: New England Journal of Medicine (2025)

IgG4-related disease is an increasingly recognized fibroinflammatory condition with protean manifestations. The disorder is characterized by inflammatory mass lesions that can involve many different organs and organ systems — including the pancreas and biliary tract, orbital structures, salivary and lacrimal glands, lungs, retroperitoneum, and kidneys — and can also cause aortitis and periaortitis.1 The effects of the disease relate to resultant damage in the affected organ systems. It often can be a relapsing disorder, and the optimal approach to inducing or maintaining remission has not been well defined. The etiologic factors of IgG4-related disease are uncertain, but the histopathological characteristics . . .
Methotrexate, Doxorubicin, and Cisplatin Versus Methotrexate, Doxorubicin, and Cisplatin + Ifosfamide in Poor Responders to Preoperative Chemotherapy for Newly Diagnosed High-Grade Osteosarcoma (JCOG0905): A Multicenter, Open-Label, Randomized Trial
Authors: Hiroaki Hiraga, Ryunosuke Machida, Akira Kawai, Toshiyuki Kunisada, Tsukasa Yonemoto, Makoto Endo, Yoshihiro Nishida, Akihito Nagano, Keisuke Ae, Shinichirou Yoshida, Kunihiro Asanuma, Junya Toguchida, Taisuke Furuta, Robert Nakayama, Toshihiro Akisue, Toru Hiruma, Takeshi Morii, Hideki Nishimura, Koji Hiraoka, Masanobu Takeyama, Makoto Emori, Satoshi Tsukushi, Hiroshi Hatano, Hiroyuki Kawashima, Kazuo Isu, Kazuhiro Tanaka, Tomoko Kataoka, Haruhiko Fukuda, Yukihide Iwamoto, Toshifumi Ozaki
Journal: Journal of Clinical Oncology (2025)

PURPOSE Our previous NECO phase II studies on high-grade osteosarcoma suggested that administering ifosfamide (IF; 16 g/m 2 [4g/m 2 once on day 1, then 2g/m 2 once on days 2-7] × six) to patients showing a poor response (PrRsp) to preoperative chemotherapy with methotrexate, doxorubicin, and cisplatin (MAP) improves their prognoses. In this Japan Clinical Oncology Group (JCOG) study, JCOG0905, we aimed to investigate the efficacy and safety of IF in patients with PrRsp. METHODS JCOG0905 is a multicenter, open-label, multi-institutional, randomized trial. Eligible patients (50 years and younger) had resectable, high-grade osteosarcoma (stage II or III, Union for International Cancer Control TNM) of the extremities, limb girdles, and thoracic wall. After two MAP cycles and tumor resection, patients with PrRsp were randomly assigned to either the MAP or MAP plus 15 g/m 2 (3g/m 2 once daily on days 1-5) × six IF (MAP + IF [MAPIF]) group. The primary end point was disease-free survival (DFS); secondary end points were overall survival (OS) and safety. The planned sample size was 100 patients with a one-sided α of .1 and a power of 0.7, assuming a 3-year DFS of 50% and 65% for MAP and MAPIF, respectively. This trial is registered with the Japan Registry of Clinical Trials (jRCT; jRCTs031180126). RESULTS Of the 287 patients registered between February 2010 and August 2020, 51 and 52 patients with PrRsp were assigned to the MAP and MAPIF groups, respectively. As of March 2022, DFS did not differ between groups (hazard ratio [HR], 1.05 [95% CI, 0.55 to 1.98]) and OS was numerically inferior in the MAPIF group (HR, 1.48 [95% CI, 0.68 to 3.22]). Nine and zero patients in the MAPIF and MAP groups discontinued treatment because of adverse events, respectively. CONCLUSION Evidence from JCOG0905 does not support the addition of IF for patients with PrRsp.
Neurological outcomes of joint exposure to polystyrene micro/nanospheres and silver nanoparticles in zebrafish
Authors: Jie Song, Qian Pu, Chen Chen, Xingcheng Liu, Xinlei Zhang, Zejun Wang, Jin Yan, Xuedong Wang, Huili Wang, Qiuhui Qian
Journal: Environmental Health Perspectives (2025)

Micro/nanoplastics and silver nanoparticles (AgNPs) are emerging environmental contaminants widely detected in aquatic environments. However, previous research has primarily focused on the interactions between micro/nanoplastics and organic substances or heavy metals, while the interactions and combined toxic effects of micro/nanoplastics with AgNPs remain unclear.
Authors' Reply: Association between CKD and Kidney Stones: A Reliable Relationship?
Authors: Le-Ting Zhou, Muthuvel Jayachandran, Nicholas B. Larson, John C. Lieske
Journal: Journal of the American Society of Nephrology (2025)

We thank Zheng and Zeng1 for their insightful comments regarding our recent Mendelian randomization (MR)–based study, published in JASN, to re-examine the relationship between CKD and kidney stones.2 We particularly agree with the assessment that the intriguing results offer new directions for future etiological research and clinical interventions for this population of patients. In response to their methodologic observation and suggestions, we would like to stress that we used a literature-based approach to exclude single-nucleotide polymorphisms (SNPs) with potential pleiotropy rather than a purely statistical method. This approach is more specific and avoids overgeneralizing pleiotropy. For example, while fat mass and obesity associated gene-related SNPs are statistically associated with both obesity and diabetes, it is primarily considered an obesity-related gene.3 Removing these SNPs in MR analysis could potentially underestimate the effect of obesity on diabetes. After literature reviewing of the related genes of SNPs selected as instrumental variables, we only excluded UMOD-related SNPs in the MR analysis focused on CKD since its association with CKD is well-established.4 In addition, the UMOD locus may be associated with kidney stones independently of kidney function, despite inconsistent findings in observational studies on urinary uromodulin levels in stone formers.4 Reassuringly, our sensitivity analysis (Supplemental Figures 7 and 8) confirmed consistent results, even after excluding UMOD-related SNPs in the MR analysis of the effect of CKD on kidney stone risk.2 We entirely agree that MR statistical analysis methods are a rapidly evolving field. Nevertheless, multivariable MR remains a well-established, valid, versatile, and thus widely used approach.5 Importantly, the instrumental variables for kidney stones and CKD used in the multivariable MR are generally not associated with cardiometabolic conditions, ensuring a more accurate estimation of their effect sizes. Nevertheless, our group remains open to using these newer methods in future studies. Most importantly, regardless of the modeling method used, MR is not a perfect tool for establishing causality. To partially address this concern, we included additional observational analyses in this article, which showed consistent results and serve to help validate our main findings.