tbuckley/cabot-search huggingface dataset:
PD-1<sup>IR2</sup>promotes tumor evasion via deregulating CD8<sup>+</sup>T cell function
Authors: Haojing Zang, Tongfeng Liu, Xiaodong Wang, Shuwen Cheng, Xiaofeng Zhu, Chang Huang, Liqiang Duan, Xujie Zhao, Fang Guo, Xuetong Wang, Chang Zhang, Facai Yang, Yinmin Gu, Hongbo Hu, Shan Gao
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background The programmed cell death 1 (PD-1) is an immune checkpoint that mediates immune evasion of tumors. Alternative splicing (AS) such as intron retention (IR) plays a crucial role in the immune-related gene processing and its function. However, it is not clear whether PDCD1 encoding PD-1 exists as an IR splicing isoform and what underlying function of such isoform plays in tumor evasion. Methods An AS isoform of human PDCD1 , characterized by the second IR and named PD-1 IR2 , was identified by reverse transcription-PCR (RT-PCR) and Sanger sequencing. The expression profile of PD1 IR2 was assessed by quantitative RT-PCR and flow cytometry, while its function was evaluated through immune cell proliferation, cytokine interleukin 2 secretion, and tumor cell killing assays. PDCD1 IR2 CKI mice which specifically conditional knock-in PDCD1 IR2 in T cells and humanized peripheral blood mononuclear cells (PBMC)-NOG (NOD.Cg-PrkdcscidIL2rgtm1Sug/JicCrl) mice were utilized to further confirm the physiological function of PD-1 IR2 in vivo. Results PD-1 IR2 is expressed in a variety of human leukemia cell lines and tumor-infiltrating lymphocytes. PD-1 IR2 expression is induced on T cell activation and regulated by the RNA-binding protein hnRNPLL. PD-1 IR2 negatively regulates the immune function of CD8 + T cells, indicated by inhibiting T cell proliferation, cytokine production, and tumor cell killing in vitro. PD-1 IR2+ CD8 + T cells show impaired antitumor function, which consequently promote tumor evasion in a conditional knock-in mouse model and a PBMC-engrafted humanized NOG mouse model. PD-1 IR2 mice exhibit resistance to anti-PD-L1 therapy compared with wild-type mice. Conclusions PD-1 IR2 is a potential immune checkpoint that may mediate potential resistance to immune checkpoint therapy.
Cell-intrinsic PD-L1 signaling drives immunosuppression by myeloid-derived suppressor cells through IL-6/Jak/Stat3 in PD-L1-high lung cancer
Authors: Hyein Jeong, Jaemoon Koh, Sehui Kim, Jeemin Yim, Seung Geun Song, Hanbyeol Kim, Yingying Li, Soo Hyun Lee, Yeon Kyu Chung, Hongsoon Kim, Chul-Hwan Lee, Hye Young Kim, Bhumsuk Keam, Se-Hoon Lee, Doo Hyun Chung, Yoon Kyung Jeon
Journal: Journal for ImmunoTherapy of Cancer (2025)

Some patients with non-small-cell lung cancer (NSCLC) benefit from immune checkpoint inhibitors (ICIs) despite programmed death-ligand 1 (PD-L1) expression. To address the mechanism of ICI resistance in PD-L1-positive NSCLC, we investigated the role of tumor-cell-intrinsic function of PD-L1 in interleukin (IL)-6-mediated immunosuppression. Cohorts of NSCLC patients treated with ICI and public datasets were analyzed. PD-L1-overexpressing and PD-L1-knockdown NSCLC cells were submitted to RNA-seq, in vitro analyses, chromatin immunoprecipitation-qPCR, CUT&Tag, and biochemical assays. Human myeloid-derived suppressor cells (MDSCs) sorted from peripheral blood mononuclear cells were co-cultured with NSCLC cells and then assessed for their immunosuppressive activity on T-cells. Mouse Lewis lung carcinoma (LLC) cells with PD-L1 overexpression or knockdown were subcutaneously injected into wild-type or PD-1-knockout C57BL/6 mice in the presence of IL-6 and/or PD-1 blockade. In the ICI cohort with RNA-seq data, the IL-6/Jak/Stat3 pathway was enriched, and IL-6 expression was higher in patients with PD-L1-high NSCLCs who did not respond to ICIs. In another cohort, a higher baseline serum IL-6 level was associated with poor clinical outcomes after ICI therapy. IL-6 expression and the IL-6/Jak/Stat3 pathway were enhanced in PD-L1-high NSCLCs in the ICI cohorts and The Cancer Genome Atlas analysis. IL-6 expression correlated positively with tumor-infiltrating MDSCs in NSCLCs. In NSCLC cells, PD-L1 activated Jak2/Stat3 signaling by binding to and inhibiting protein tyrosine phosphatase 1B. PD-L1 also bound to p-Stat3 in the nucleus, thus promoting the activity of p-Stat3 in the transcription of several cytokines (IL-6, TGF-β, TNF-α, IL-1β) and chemokines. PD-L1-overexpressing NSCLC cells enhanced the migration and immunosuppressive activity of human MDSCs in vitro, mediated by IL-6 and CXCL1. In both wild-type and PD-1-knockout mice, PD-L1-overexpressing LLC tumors were infiltrated by increased MDSCs with high immunosuppressive function, increased Tregs, and decreased granzyme B+ or IFNγ+ CD8 T-cells. These responses were mediated by IL-6 secreted from PD-L1-overexpressing tumor cells. Combined blockade of PD-1 and IL-6 was effective in tumor control and decreased MDSCs while increasing granzyme B+ or IFNγ+ CD8 T-cells. The tumor-cell-intrinsic function of PD-L1 drives immunosuppression and tumor progression through the PD-L1/Jak/Stat3/IL-6/MDSC axis. This pathway represents a potential therapeutic target to improve ICI efficacy in PD-L1-high NSCLC.
A unified acoustic-to-speech-to-language embedding space captures the neural basis of natural language processing in everyday conversations
Authors: Ariel Goldstein, Haocheng Wang, Leonard Niekerken, Mariano Schain, Zaid Zada, Bobbi Aubrey, Tom Sheffer, Samuel A. Nastase, Harshvardhan Gazula, Aditi Singh, Aditi Rao, Gina Choe, Catherine Kim, Werner Doyle, Daniel Friedman, Sasha Devore, Patricia Dugan, Avinatan Hassidim, Michael Brenner, Yossi Matias, Orrin Devinsky, Adeen Flinker, Uri Hasson
Journal: Nature Human Behaviour (2025)

This study introduces a unified computational framework connecting acoustic, speech and word-level linguistic structures to study the neural basis of everyday conversations in the human brain. We used electrocorticography to record neural signals across 100 h of speech production and comprehension as participants engaged in open-ended real-life conversations. We extracted low-level acoustic, mid-level speech and contextual word embeddings from a multimodal speech-to-text model (Whisper). We developed encoding models that linearly map these embeddings onto brain activity during speech production and comprehension. Remarkably, this model accurately predicts neural activity at each level of the language processing hierarchy across hours of new conversations not used in training the model. The internal processing hierarchy in the model is aligned with the cortical hierarchy for speech and language processing, where sensory and motor regions better align with the model's speech embeddings, and higher-level language areas better align with the model's language embeddings. The Whisper model captures the temporal sequence of language-to-speech encoding before word articulation (speech production) and speech-to-language encoding post articulation (speech comprehension). The embeddings learned by this model outperform symbolic models in capturing neural activity supporting natural speech and language. These findings support a paradigm shift towards unified computational models that capture the entire processing hierarchy for speech comprehension and production in real-world conversations. This study links acoustic, speech and linguistic data with brain activity during real-life conversations to create a model that predicts neural responses during speech with high accuracy.
Letter to the editor: Viral load decline time offers theoretical insight rather than practical value
Authors: Nawfal R. Hussein, Delovan S. Mahfodh
Journal: Eurosurveillance (2025)

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Health inequalities in incidence of bacteraemias: a national surveillance and data linkage study, England, 2018 to 2022
Authors: Andrea Mazzella, Zahin Amin-Chowdhury, Amelia Andrews, Andre Charlett, Colin S Brown, Russell Hope, Dimple Chudasama
Journal: Eurosurveillance (2025)

BackgroundHealth inequalities exist globally, but limited data exist on this topic for bacteraemia.AimIn this study we investigated health inequalities surrounding bacteraemia in England, to identify high-risk population groups and areas of intervention.MethodsWe retrospectively analysed English surveillance data between 2018 and 2022 for Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, and both meticillin-sensitive and resistant Staphylococcus aureus (MSSA, MRSA) bacteraemia. Crude incidence rates stratified by index of multiple deprivation and ethnic groups were calculated; age-adjusted rate ratios were estimated using negative binomial regression models.ResultsWe identified 342,787 bacteraemia cases. Across all pathogens, as the level of deprivation rose, so did the age-adjusted bacteraemia incidence rate ratio. Compared with residents of the 20% least deprived areas of England, residents of the 20% most deprived areas had a 2.68-fold increased bacteraemia rate for MRSA (95% CI: 2.29-3.13) and 1.95-fold for E. coli (95% CI: 1.84-2.05), and 15% higher odds of dying within 30 days of any bacteraemia (95% CI: 1.13-1.19). After age adjustment, the incidence of all bacteraemia was higher in the Asian and Black groups compared with the White group: for MRSA, 79% higher in the Asian (95% CI: 1.51-2.10) and 59% higher in the Black (95% CI: 1.29-1.95) groups. The exception was MSSA, whose incidence was highest in the White group.ConclusionDisproportionately higher age-adjusted incidence of bacteraemia occurred in deprived areas and ethnic minorities. These disparities are likely multifactorial, possibly including socioeconomic, cultural, and systemic risk factors and different burden of comorbidities. Better understanding these factors can enable targeted interventions.
Retrospective case–case study investigation of a significant increase in Cryptosporidium spp. in England and Wales, August to September 2023
Authors: Sarah V Williams, Eve Matthews, Thomas Inns, Christopher Roberts, Joshua Matizanadzo, Paul Cleary, Richard Elson, Chris J Williams, Reece Jarratt, Rachel M Chalmers, Roberto Vivancos
Journal: Eurosurveillance (2025)

BackgroundLaboratory surveillance detected an unprecedented increase in Cryptosporidium spp. (predominantly Cryptosporidium hominis) in England and Wales in August 2023. Cases are not routinely followed up in all of England and Wales, and initial investigations identified no common exposures.AimTo perform a retrospective case-case study investigation of the increase in Cryptosporidium spp. in England and Wales.MethodsWe conducted an unmatched case-case study with 203 cases of laboratory-confirmed C. hominis and 614 comparator cases of laboratory-confirmed Campylobacter spp. reported between 14 August and 30 September 2023. We fitted a multilevel logistic regression model, with random intercepts for geographical region, to estimate adjusted odds ratios (aOR) for exposures. We present the final model as aOR and 95% confidence intervals (CI).ResultsMultivariable analysis identified associations with swimming pool use (aOR: 5.3, 95% CI: 2.3-9.3), travel to Spain (aOR: 6.5, 95% CI: 3.5-12.3) and young age, with children 0-4 years having the strongest association of being a case (aOR: 3.6, 95% CI: 1.5-8.6). We also identified associations with swimming in a river, and travel to France or Türkiye, but there was low frequency of exposure among cases and comparator cases.ConclusionsFollowing the largest recorded increase of Cryptosporidium spp. and in particular C. hominis cases in England and Wales, we identified several exposures, suggesting that causation was likely to be multifactorial. We recommend development of a standardised questionnaire to enable rapid investigation of future case increases, which will improve existing surveillance and inform public health actions.
Author’s response: Viral load decline time offers theoretical insight rather than practical value
Authors: Jakob Jonnerby, Ajit Lalvani
Journal: Eurosurveillance (2025)

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Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: 5-year outcomes of the randomized DYNAMIC trial
Authors: Jeanne Tie, Yuxuan Wang, Serigne N. Lo, Kamel Lahouel, Joshua D. Cohen, Rachel Wong, Jeremy D. Shapiro, Samuel J. Harris, Adnan Khattak, Matthew E. Burge, Margaret Lee, Marion Harris, Sue-Anne McLachlan, Lisa Horvath, Christos Karapetis, Jenny Shannon, Madhu Singh, Desmond Yip, Sumitra Ananda, Craig Underhill, Janine Ptak, Natalie Silliman, Lisa Dobbyn, Maria Popoli, Nickolas Papadopoulos, Cristian Tomasetti, Kenneth W. Kinzler, Bert Vogelstein, Peter Gibbs
Journal: Nature Medicine (2025)
A torpor-like state in mice slows blood epigenetic aging and prolongs healthspan
Authors: Lorna Jayne, Aurora Lavin-Peter, Julian Roessler, Alexander Tyshkovskiy, Mateusz Antoszewski, Erika Ren, Aleksandar Markovski, Senmiao Sun, Hanqi Yao, Vijay G. Sankaran, Vadim N. Gladyshev, Robert T. Brooke, Steve Horvath, Eric C. Griffith, Sinisa Hrvatin
Journal: Nature Aging (2025)

Torpor and hibernation are extreme physiological adaptations of homeotherms associated with pro-longevity effects. Yet the underlying mechanisms of how torpor affects aging, and whether hypothermic and hypometabolic states can be induced to slow aging and increase healthspan, remain unknown. Here we demonstrate that the activity of a spatially defined neuronal population in the preoptic area, which has previously been identified as a torpor-regulating brain region, is sufficient to induce a torpor-like state (TLS) in mice. Prolonged induction of TLS slows epigenetic aging across multiple tissues and improves healthspan. We isolate the effects of decreased metabolic rate, long-term caloric restriction, and decreased core body temperature (Tb) on blood epigenetic aging and find that the decelerating effect of TLSs on aging is mediated by decreased Tb. Taken together, our findings provide novel mechanistic insight into the decelerating effects of torpor and hibernation on aging and support the growing body of evidence that Tb is an important mediator of the aging processes. Dissecting the effects of hypothermic and hypometabolic states on aging processes, the authors show that activation of neurons in the preoptic area induces a torpor-like state in mice that slows epigenetic aging and improves healthspan. These pro-longevity effects are mediated by reduced Tb, reinforcing evidence that Tb is a key mediator of aging processes.
Anti-obesity medication for weight loss in early nonresponders to behavioral treatment: a randomized controlled trial
Authors: Jena S. Tronieri, Eleanor Ghanbari, Jonathan Chevinsky, Erica M. LaFata, Alyssa M. Minnick, Simran Rajpal, Seamus Y. Wang, Kylie Burcaw, Robert I. Berkowitz, Thomas A. Wadden
Journal: Nature Medicine (2025)

Current guidelines recommend behavioral treatment (BT) as the first intervention for patients with obesity. However, a substantial minority (35–50%) do not achieve a clinically meaningful loss of ≥5%. Anti-obesity medications (AOMs) are recommended when target weight loss is not achieved; however, their efficacy among BT nonresponders has not been established. This double-blind, randomized controlled proof-of-principle study evaluated whether augmenting BT with AOM improved 24-week weight loss compared to BT with placebo in early nonresponders to BT. A total of 147 adults with a body mass index ≥31 kg m−2 (≥28 kg m−2 with obesity-related comorbidity) completed an initial 4-week BT run-in. The 76 early nonresponders who lost <2.0% of initial weight were then randomized to 24 weeks of either BT plus placebo (BT + P, n = 38) or BT plus AOM (phentermine = 15.0 mg d−1, n = 38). Early responders received ongoing BT and were not part of the randomized trial. The primary outcome was met; early nonresponders assigned to BT + AOM had a greater mean (±s.e.) reduction in weight of 5.9 ± 0.7% from randomization to week 24, as compared to 2.8 ± 0.7% for those assigned to BT + P (mean difference = 3.1 ± 1.0, 95% confidence interval = 1.1–5.1%, Cohen's d = 0.73, P = 0.003). Stepping up early BT nonresponders to BT + AOM improves their 24-week weight loss. ClinicalTrials.gov registration: NCT03779048 . A randomized clinical trial showing the superiority of behavioral treatment plus phentermine to behavioral treatment plus placebo for weight loss in those that previously had not responded to behavioral treatment.
Neutrophils physically interact with tumor cells to form a signaling niche promoting breast cancer aggressiveness
Authors: Sandra Camargo, Ori Moskowitz, Amir Giladi, Maiia Levinson, Roi Balaban, Shani Gola, Alice Raizman, Kelly Lipczyc, Alon Richter, Noa Keren-Khadmy, Oren Barboy, Yael Dugach, Yaron Carmi, Amir Sonnenblick, Merav Cohen
Journal: Nature Cancer (2025)
Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity
Authors: Benjamin Klein, Mack B. Reynolds, Bin Xu, Mehrnaz Gharaee-Kermani, Yiqing Gao, Celine C. Berthier, Svenja Henning, Lam C. Tsoi, Shannon N. Loftus, Kelsey E. McNeely, Christine M. Goudsmit, Amanda M. Victory, Craig Dobry, Grace A. Hile, Feiyang Ma, Jessica L. Turnier, Johann E. Gudjonsson, Mary X. O’Riordan, J. Michelle Kahlenberg
Journal: Science Immunology (2025)

Photosensitivity is observed in numerous autoimmune diseases and drives poor quality of life and disease flares. Elevated epidermal type I interferon (IFN) production primes for photosensitivity and enhanced inflammation, but the substrates that sustain and amplify this cycle remain undefined. We show that IFN-induced Z-DNA binding protein 1 (ZBP1) stabilizes ultraviolet (UV) B–induced cytosolic Z-DNA derived from oxidized mitochondrial DNA. ZBP1 is up-regulated in the epidermis of adult and pediatric patients with autoimmune photosensitivity. In patient-derived samples, lupus keratinocytes accumulate extensive cytosolic Z-DNA after UVB exposure, and transfection of keratinocytes with Z-DNA results in stronger IFN production through cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS-STING) activation compared with the more conventional B-DNA. ZBP1 knockdown abrogates UVB-induced IFN responses, whereas overexpression results in a lupus-like phenotype with spontaneous Z-DNA accumulation and IFN production. Our results highlight Z-DNA and ZBP1 as critical mediators for UVB-induced inflammation and uncover how type I IFNs prime for cutaneous inflammation in photosensitivity.
Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: exploratory biomarker analyses of a randomized phase 3 trial
Authors: Kohei Shitara, Yelena Y. Janjigian, Jaffer Ajani, Markus Moehler, Jin Yao, Xuya Wang, Aparna Chhibber, Dimple Pandya, Lin Shen, Marcelo Garrido, Carlos Gallardo, Lucjan Wyrwicz, Kensei Yamaguchi, Tomasz Skoczylas, Arinilda Bragagnoli, Tianshu Liu, Michael Schenker, Patricio Yañez, Ruben Kowalyszyn, Michalis Karamouzis, Thomas Zander, Kynan Feeney, Elena Elimova, Parul Doshi, Mingshun Li, Ming Lei
Journal: Nature Medicine (2025)

First-line nivolumab-plus-chemotherapy demonstrated superior overall survival (OS) and progression-free survival versus chemotherapy for advanced gastroesophageal adenocarcinoma with programmed death ligand 1 combined positive score ≥ 5, meeting both primary end points of the randomized phase 3 CheckMate 649 trial. Nivolumab-plus-ipilimumab provided durable responses and higher survival rates versus chemotherapy; however, the prespecified OS significance boundary was not met. To identify biomarkers predictive of differential efficacy outcomes, post hoc exploratory analyses were performed using whole-exome sequencing and RNA sequencing. Nivolumab-based therapies demonstrated improved efficacy versus chemotherapy in hypermutated and, to a lesser degree, Epstein–Barr virus-positive tumors compared with chromosomally unstable and genomically stable tumors. Within the KRAS-altered subgroup, only patients treated with nivolumab-plus-chemotherapy demonstrated improved OS benefit versus chemotherapy. Low stroma gene expression signature scores were associated with OS benefit with nivolumab-based regimens; high regulatory T cell signatures were associated with OS benefit only with nivolumab-plus-ipilimumab. Our analyses suggest that distinct and overlapping pathways contribute to the efficacy of nivolumab-based regimens in gastroesophageal adenocarcinoma. Exploratory post hoc analysis of molecular residual disease (MRD) from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR-mutated stage IB–IIIA non-small cell lung cancer shows that MRD detection predicts disease recurrence with long term adjuvant osimertinib treatment.
Comments on “worldwide research trends on tumor burden and immunotherapy: a bibliometric analysis”
Authors: Guangtao Han, Lijun Cai, Qin Wang, Shuo Sun, Pengde Kang
Journal: International Journal of Surgery (2025)

aWest China hospital of sichuan university *West China hospital of sichuan university, Email: ([email protected]) (P. Kang). Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. This is an open access article distributed under the Creative Commons Attribution-ShareAlike License 4.0, which allows others to remix, tweak, and build upon the work, even for commercial purposes, as long as the author is credited and the new creations are licensed under the identical terms.
Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate
Authors: Yinghui J. Huang, Shin Foong Ngiow, Amy E. Baxter, Sasikanth Manne, Simone L. Park, Jennifer E. Wu, Omar Khan, Josephine R. Giles, E. John Wherry
Journal: Science Immunology (2025)

Although checkpoint blockade temporarily improves exhausted CD8 T (Tex) cell function, the underlying Tex epigenetic landscape remains largely unchanged, preventing durable Tex "reinvigoration" in cancer and chronic infections. The transcription factor TOX initiates Tex epigenetic programming, yet it remains unclear whether TOX continually preserves Tex biology after Tex establishment. Here, we demonstrated that induced TOX ablation in committed Tex cells resulted in apoptotic-driven loss of Tex cells, reduced expression of inhibitory receptors, and decreased terminal differentiation. Gene expression and epigenetic profiling revealed a critical role for TOX in maintaining chromatin accessibility and transcriptional patterns in committed Tex cells. Moreover, TOX removal endows established Tex cells with greater fate flexibility to differentiate into more functional effector-like T cells. Thus, continuous TOX expression in established Tex cells acts as a durable epigenetic barrier reinforcing the Tex developmental fate. TOX manipulation even after Tex establishment could therefore provide therapeutic opportunities to rewire Tex cells in chronic infections or cancer.
Comparison of the multivariate genetic architecture of eight major psychiatric disorders across sex
Authors: Ted Schwaba, Travis T. Mallard, Adam X. Maihofer, Mijke Rhemtulla, Phil H. Lee, Jordan W. Smoller, Lea K. Davis, Michel G. Nivard, Andrew D. Grotzinger, Elliot M. Tucker-Drob
Journal: Nature Genetics (2025)