tbuckley/cabot-search huggingface dataset:
Urine proteomics defines an immune checkpoint-associated nephritis signature
Authors: James P Long, Shailbala Singh, Yanlan Dong, Cassian Yee, Jamie S Lin
Journal: Journal for ImmunoTherapy of Cancer (2025)

Immune checkpoint inhibitor (ICI) therapy is a cornerstone treatment for many cancers, but it can induce severe immunotoxicity, including acute interstitial nephritis (AIN). Currently, kidney biopsy is required to differentiate ICI-AIN from other causes of acute kidney injury (AKI). However, this invasive approach can lead to morbidity, delayed glucocorticoid treatment for patients with AIN, and unnecessarily prolonged suspension of ICI therapy in non-AIN patients. Delayed or incorrect diagnosis of ICI-AIN is particularly detrimental, as over 50% of patients are at risk of permanent renal damage. Thus, there is an urgent need for non-invasive biomarkers that can rapidly and accurately distinguish ICI-AIN from other causes of AKI. The urine and plasma proteome contain actively secreted proteins that provide real-time insights into dynamic physiological processes. However, identification of effective biomarkers of disease using established technologies such as proximity ligation assays (PLA) and bead-based immunoassays is challenging due to their limited sensitivity and loss of precision in multiplex analysis. To address this, we employed cutting-edge NUcleic acid Linked Immuno-Sandwich Assay (NULISA) technology to measure protein expression in urine and plasma samples from AKI patients undergoing ICI therapy. NULISA offers 10,000-fold greater precision than PLA, enabling quantification of over 200 inflammatory proteins with unprecedented precision. Our analysis revealed that urine was more sensitive and specific than plasma in distinguishing ICI-AIN from non-AIN cases. Pathway analyses highlighted the involvement of JAK-STAT and tumor necrosis factor (TNF) signaling in ICI-AIN pathogenesis. We identified several novel urine biomarkers, including IL-5, Fas, TNFSF4, CD274, IL-20, TNFSF15, TSLP, TREM1 and CCL1 while confirming previously reported markers such as CXCL9 and TNF-α. Using statistical and machine learning methods, we constructed a novel urine biomarker signature—IL-5+Fas—that achieved an area under the curve of 0.94 for diagnosing ICI-AIN. By leveraging high-sensitivity proteomics, we developed a non-invasive strategy for diagnosing ICI-AIN. This approach will enable earlier intervention to mitigate immunotoxicity, preservation of antitumor efficacy of ICI therapy in non-AIN patients, and safe rechallenge of ICI therapy in patients previously treated for ICI-AIN.
Novel B7-H3 CAR T cells show potent antitumor effects in glioblastoma: a preclinical study
Authors: Thananya Inthanachai, Chatikorn Boonkrai, Tanapati Phakham, Trairak Pisitkun, Rattapoom Thaiwong, Vichaya Chuthaphakdikun, Nithidol Sakunrangsit, Vudhiporn Limprasutr, Thanyavi Chinsuwan, Nattiya Hirankarn, Koramit Suppipat, Norihiro Watanabe, Supannikar Tawinwung
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background B7 homolog 3 (B7-H3), an overexpressed antigen across multiple solid cancers, represents a promising target for CAR T cell therapy. This study investigated the expression of B7-H3 across various solid tumors and developed novel monoclonal antibodies (mAbs) targeting B7-H3 for CAR T cell therapy. Methods Expression of B7-H3 across various solid tumors was evaluated using RNA-seq data from TCGA, TARGET, and GTEx datasets and by flow cytometry staining. B7-H3-specific mAbs were developed by immunizing mice with human B7-H3, screening with ELISA, and analyzing kinetics with surface plasmon resonance. These mAbs were used to create second-generation CAR constructs, which were evaluated in vitro and in vivo for their antitumor function. Results We identified four mAb clones from immunized mice, with three demonstrating high specificity and affinity. The second-generation B7-H3 CAR T cells derived from these mAbs exhibited robust cytotoxicity against B7-H3-positive targets and successfully infiltrated and eliminated tumor spheroids in vitro. In a xenograft mouse model of glioblastoma, these CAR T cells, particularly those derived from clone A2H4, eradicated the primary tumor, and effectively controlled rechallenge tumor, resulting in prolonged survival of the xenograft mice. In vivo T cell trafficking revealed high accumulation and persistence of A2H4-derived CAR T cells at the tumor site. Conclusions Our results provide novel B7-H3-targeted CAR T cells with high efficacy, paving the way for clinical translation of solid tumor treatment.
Exploring the Clinical Diversity of Castleman Disease and <scp>TAFRO</scp> Syndrome: A Japanese Multicenter Study on Lymph Node Distribution Patterns
Authors: Mizuna Otsuka, Tomohiro Koga, Remi Sumiyoshi, Shoichi Fukui, Yuko Kaneko, Takayuki Shimizu, Atsushi Katsube, Shingo Yano, Yasufumi Masaki, Makoto Ide, Hajime Yoshifuji, Masayasu Kitano, Yasuharu Sato, Naoki Sawa, Hiroaki Niiro, Naoya Nakamura, David C. Fajgenbaum, Frits van Rhee, Atsushi Kawakami
Journal: American Journal of Hematology (2025)

ABSTRACT Individuals diagnosed with Castleman disease (CD) and TAFRO syndrome (characterized by thrombocytopenia, anasarca, fever, bone marrow fibrosis, and organomegaly) displays a wide range of clinical symptoms, including varying patterns of lymph node enlargement, systemic inflammation, and impaired organ function. Some patients may present with both CD and TAFRO syndrome concurrently. A retrospective study conducted across multiple centers in Japan examined 321 cases to determine if the quantity and position of swollen lymph nodes could forecast the clinical progression and intensity of these conditions. Interestingly, the study revealed that patients with TAFRO syndrome exhibited lymphadenopathy across all ranges of lymph node region counts. Moreover, no specific clinical patterns were associated with the number of affected lymph node regions in CD patients, regardless of whether they also had TAFRO syndrome. These results enhance our understanding of the clinical variability in CD and TAFRO syndrome, suggesting that a comprehensive clinical evaluation, rather than relying solely on lymph node count, is crucial for effectively managing these conditions. Additional studies are required to establish reliable diagnostic markers and to predict disease severity at the time of diagnosis, ultimately improving patient outcomes.
Divergent transcriptional states and kinetics of circulating tumor-infiltrating lymphocyte repertoires with highly homologous T-cell receptor sequences in a patient during immunotherapy
Authors: Ryutaro Kajihara, Mark D Long, Toshifumi Hoki, Hongbin Chen, Takayoshi Yamauchi, Hisashi Kanemaru, Brahm H Segal, Grace K Dy, Fumito Ito
Journal: Journal for ImmunoTherapy of Cancer (2025)

Evidence has shown that T-cell receptors (TCRs) that recognize the same epitopes may not be the exact TCR clonotypes but have slightly different TCR sequences. However, the changes in the genomic and transcriptomic signatures of these highly homologous T cells during immunotherapy remain unknown. Here, we examined the evolutionary features in circulating TCR clonotypes observed in tumors (tumor-infiltrating lymphocyte (TIL)-TCRs) by combining single-cell RNA/TCR sequencing of longitudinal blood samples and TCR sequencing of tumor tissue from a patient treated with anti-cytotoxic T-lymphocyte-associated protein 4/programmed cell death protein-1 therapy. We found frequent circulating CD8 + TIL-TCRs with identical complementarity determining region 3 (CDR3)α amino acid sequences but quasi-identical CDR3β and TCR α/β (TRA/TRB) sequences. Despite their sequence similarities, these highly homologous TIL-TCRs responded differently to immunotherapy, and exhibited distinct transcriptional signatures that were uniquely distinguished by the expression of GZMK . Overall, the expression of IFNG in CD8 + T-cell subsets including highly homologous TIL-TCRs increased when the patient achieved a response, but gradually decreased as the patient developed acquired resistance. Our findings provide insight into the cross-talk between T cells in the tumor microenvironment and those in the blood, and highlight that CD8 + T cells with highly homologous TCR sequences might display divergent transcriptional states and kinetics in response to immunotherapy.
Interleukin-34 orchestrates bone formation through its binding to bone morphogenic proteins
Authors: Dominique Heymann, Muñoz-Garcia Javier, Vargas-Franco Jorge W., Schiavone Kristina, Keatinge Marcus T., Robin Young, Amiaud Jérôme, Fradet Laurie, Yagita Hideo, Jégou Jean-François, Blin-Wakkach Claudine, Wakkach Abdelilah, Cochonneau Denis, Ollivier Emilie, Pugière Martine, Henriquet Corinne, Legendre Marie, Amselem Serge, Giurgea Irina, Heymann Marie-Françoise, Télétchéa Stéphane, Lézot Frédéric, Heymann. Dominique
Journal: Theranostics (2025)

Rationale: During development, the contribution of IL34, a ligand of macrophage colony stimulating factor receptor (MCSFR), has not been fully defined. Together with its twin cytokine MCSF, they display an essential role in macrophage differentiation and activation, including tissue specialized macrophages. The mechanism of action of each molecule involves the phosphorylation of MCSFR in varying intensity and kinetics. Furthermore, IL34 can interact with other receptors and cofactors, opening a wide range of modulations during development. The aim of this work was to investigate these effects through the suppression of IL34 in different animal models and study molecular interactions, with a particular focus on osteoclast / osteoblast regulation. Methods: Two different and unique models of IL34-/- were generated in zebrafish and mouse. The skeleton of both species was analyzed and compared by histological and morphometric (Micro-CT) approaches. The role of IL34 and new partners in osteoclast and osteoblast differentiation was analyzed by multiple techniques including mineralization assays, tartrate resistant acid phosphatase (TRAP) staining, receptor phosphorylation and activation assays, and gene expression (real-time quantitative PCR) studies. Furthermore, protein interactions were studied by surface plasmon resonance approach and protein-protein docking ClusPro analysis. Results: Significant growth delay and hypo-mineralization of skeletal elements were observed in both IL34-/- models, as well as craniofacial dysmorphoses in mice. With regard to bone cells, an unexpected increase in the number of osteoclasts and an accumulation of pre-osteoblasts were observed in mice lacking IL34. For the first time, in vitro analyses complemented by protein binding and molecular docking studies established that IL34 interacts directly with certain Bone Morphogenetic Proteins (BMPs), modulating their various activities such as the stimulation of osteoblast differentiation. Conclusions: A new mechanism of action for IL34 through BMPs has been characterized. IL34 interactions with MCSFR and BMPs appear crucial for both osteoclastogenesis and osteoblastogenesis, impacting bone tissue homeostasis and development. The potential interaction of IL34 with different members of the BMP family and their functional impact, including pathological situations such as cancer, should be further explored, opening new therapeutic perspectives.
Roles of Cellular Neighborhoods in Hepatocellular Carcinoma Pathogenesis
Authors: Lichun Ma, Cherry Caiyi Li, Xin Wei Wang
Journal: Annual Review of Pathology Mechanisms of Disease (2025)

The development of hepatocellular carcinoma (HCC) involves an intricate interplay among various cell types within the liver. Unraveling the orchestration of these cells, particularly in the context of various etiologies, may hold the key to deciphering the underlying mechanisms of this complex disease. The advancement of single-cell and spatial technologies has revolutionized our ability to determine cellular neighborhoods and understand their crucial roles in disease pathogenesis. In this review, we highlight the current research landscape on cellular neighborhoods in chronic liver disease and HCC, as well as the emerging computational approaches applicable to delineate disease-associated cellular neighborhoods, which may offer insights into the molecular mechanisms underlying HCC pathogenesis and pave the way for effective disease interventions.
Apoptosis in Cancer Biology and Therapy
Authors: Allison Moyer, Kosuke Tanaka, Emily H. Cheng
Journal: Annual Review of Pathology Mechanisms of Disease (2025)

Since its inception, the study of apoptosis has been intricately linked to the field of cancer. The term apoptosis was coined more than five decades ago following its identification in both healthy tissues and malignant neoplasms. The subsequent elucidation of its molecular mechanisms has significantly enhanced our understanding of how cancer cells hijack physiological processes to evade cell death. Moreover, it has shed light on the pathways through which most anticancer therapeutics induce tumor cell death, including targeted therapy and immunotherapy. These mechanistic studies have paved the way for the development of therapeutics directly targeting either pro- or antiapoptotic proteins. Notably, the US Food and Drug Administration (FDA) approved the BCL-2 inhibitor venetoclax in 2016, with additional agents currently undergoing clinical trials. Recent research has brought to the forefront both the anti- and proinflammatory effects of individual apoptotic pathways. This underscores the ongoing imperative to deepen our comprehension of apoptosis, particularly as we navigate the evolving landscape of immunotherapy.
Pathogenesis of Focal Segmental Glomerulosclerosis and Related Disorders
Authors: Mehmet M. Altintas, Shivangi Agarwal, Yashwanth Sudhini, Ke Zhu, Changli Wei, Jochen Reiser
Journal: Annual Review of Pathology Mechanisms of Disease (2025)

Focal segmental glomerulosclerosis (FSGS) is the morphologic manifestation of a spectrum of kidney diseases that primarily impact podocytes, cells that create the filtration barrier of the glomerulus. As its name implies, only parts of the kidney and glomeruli are affected, and only a portion of the affected glomerulus may be sclerosed. Although the diagnosis is based primarily on microscopic features, patient stratification relies on clinical data such as proteinuria and etiological criteria. FSGS affects both children and adults and has an elevated risk of progression to end-stage renal disease. The prevalence of FSGS is rising among various populations, and the efficacy of various therapies is limited. Therefore, understanding the pathophysiology of FSGS and developing targeted therapies to address the complex needs of FSGS patients are topics of great interest that are currently being studied across various clinical trials. We discuss the etiology of FSGS, describe the major contributing pathophysiological pathways, and outline emerging therapeutic strategies along with their pitfalls.
Role of Fungi in Tumorigenesis: Promises and Challenges
Authors: Silvia Guglietta, Xin Li, Deepak Saxena
Journal: Annual Review of Pathology Mechanisms of Disease (2025)

The mycobiome plays a key role in the host immune responses in homeostasis and inflammation. Recent studies suggest that an imbalance in the gut's fungi contributes to chronic, noninfectious diseases such as obesity, metabolic disorders, and cancers. Pathogenic fungi can colonize specific organs, and the gut mycobiome has been linked to the development and progression of various cancers, including colorectal, breast, head and neck, and pancreatic cancers. Some fungal species can promote tumorigenesis by triggering the complement system. However, in immunocompromised patients, fungi can also inhibit this activation and establish life-threatening infections. Interestingly, the interaction of the fungi and bacteria can also induce unique host immune responses. Recent breakthroughs and advancements in high-throughput sequencing of the gut and tumor mycobiomes are highlighting novel diagnostic and therapeutic opportunities for cancer. We discuss the latest developments in the field of cancer and the mycobiome and the potential benefits and challenges of antifungal therapies.
Targeting Protein–Protein Interactions in Hematologic Malignancies
Authors: Tomasz Cierpicki, Jolanta Grembecka
Journal: Annual Review of Pathology Mechanisms of Disease (2025)

Over the last two decades, there have been extensive efforts to develop small-molecule inhibitors of protein-protein interactions (PPIs) as novel therapeutics for cancer, including hematologic malignancies. Despite the numerous challenges associated with developing PPI inhibitors, a significant number of them have advanced to clinical studies in hematologic patients in recent years. The US Food and Drug Administration approval of the very first PPI inhibitor, venetoclax, demonstrated the real clinical value of blocking protein-protein interfaces. In this review, we discuss the most successful examples of PPI inhibitors that have reached clinical studies in patients with hematologic malignancies. We also describe the challenges of blocking PPIs with small molecules, clinical resistance to such compounds, and the lessons learned from the development of successful PPI inhibitors. Overall, this review highlights the remarkable success and substantial promise of blocking PPIs in hematologic malignancies.
Immune Dysregulation in Obesity
Authors: Zewen Jiang, Chihiro Tabuchi, Sarah G. Gayer, Sagar P. Bapat
Journal: Annual Review of Pathology Mechanisms of Disease (2025)

The immune system plays fundamental roles in maintaining physiological homeostasis. With the increasing prevalence of obesity-a state characterized by chronic inflammation and systemic dyshomeostasis-there is growing scientific and clinical interest in understanding how obesity reshapes immune function. In this review, we propose that obesity is not merely an altered metabolic state but also a fundamentally altered immunological state. We summarize key seminal and recent findings that elucidate how obesity influences immune function, spanning its classical role in microbial defense, its contribution to maladaptive inflammatory diseases such as asthma, and its impact on antitumor immunity. We also explore how obesity modulates immune function within tissue parenchyma, with a particular focus on the role of T cells in adipose tissue. Finally, we consider areas for future research, including investigation of the durable aspects of obesity on immunological function even after weight loss, such as those observed with glucagon-like peptide-1 (GLP-1) receptor agonist treatment. Altogether, this review emphasizes the critical role of systemic metabolism in shaping immune cell functions, with profound implications for tissue homeostasis across various physiological contexts.
Unraveling Mechanisms of Genetic Risks in Metabolic Dysfunction–Associated Steatotic Liver Diseases: A Pathway to Precision Medicine
Authors: Xiang Zhang, Kyong-Mi Chang, Jun Yu, Rohit Loomba
Journal: Annual Review of Pathology Mechanisms of Disease (2025)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health problem, affecting ∼1 billion people. This condition is well established to have a heritable component with strong familial clustering. With the extraordinary breakthroughs in genetic research techniques coupled with their application to large-scale biobanks, the field of genetics in MASLD has expanded rapidly. In this review, we summarize evidence regarding genetic predisposition to MASLD drawn from family and twin studies. Significantly, we delve into detailed genetic variations associated with diverse pathogenic mechanisms driving MASLD. We highlight the interplay between these genetic variants and their connections with metabolic factors, the gut microbiome, and metabolites, which collectively influence MASLD progression. These discoveries are paving the way for precise medicine, including noninvasive diagnostics and therapies. The promising landscape of novel genetically informed drug targets such as RNA interference is explored. Many of these therapies are currently under clinical validation, raising hopes for more effective MASLD treatment.
CXCR4 antagonist-loaded nanoparticles reprogram the tumor microenvironment and enhance immunotherapy in hepatocellular carcinoma
Authors: Sheng-Liang Cheng, Chien-Huang Wu, Yun-Jen Tsai, Jen-Shin Song, Hsin-Min Chen, Teng-Kuang Yeh, Chia-Tung Shen, Jou-Chien Chiang, Hsin-Mei Lee, Kuan-Wei Huang, Yuling Chen, J Timothy Qiu, Yu-Ting Yen, Kak-Shan Shia, Yunching Chen
Journal: Journal of Controlled Release (2025)
GenAI synthesis of histopathological images from Raman imaging for intraoperative tongue squamous cell carcinoma assessment
Authors: Bing Yan, Zhining Wen, Lili Xue, Tianyi Wang, Zhichao Liu, Wulin Long, Yi Li, Runyu Jing
Journal: International Journal of Oral Science (2025)

Abstract The presence of a positive deep surgical margin in tongue squamous cell carcinoma (TSCC) significantly elevates the risk of local recurrence. Therefore, a prompt and precise intraoperative assessment of margin status is imperative to ensure thorough tumor resection. In this study, we integrate Raman imaging technology with an artificial intelligence (AI) generative model, proposing an innovative approach for intraoperative margin status diagnosis. This method utilizes Raman imaging to swiftly and non-invasively capture tissue Raman images, which are then transformed into hematoxylin-eosin (H&amp;E)-stained histopathological images using an AI generative model for histopathological diagnosis. The generated H&amp;E-stained images clearly illustrate the tissue’s pathological conditions. Independently reviewed by three pathologists, the overall diagnostic accuracy for distinguishing between tumor tissue and normal muscle tissue reaches 86.7%. Notably, it outperforms current clinical practices, especially in TSCC with positive lymph node metastasis or moderately differentiated grades. This advancement highlights the potential of AI-enhanced Raman imaging to significantly improve intraoperative assessments and surgical margin evaluations, promising a versatile diagnostic tool beyond TSCC.
The Global Prevalence of Reported Penicillin Allergy: A Systematic Review and Meta-Analysis
Authors: Akish Luintel, Joseph Healy, Michael Blank, Aashika Luintel, Simon Dryden, Abhishek Das, Ara Darzi, Graham Cooke
Journal: Journal of Infection (2025)

Patients labelled with penicillin allergy (PenA) often receive broader spectrum antibiotics, associated with antimicrobial resistance and poorer outcomes. However, ~95% of patients are likely mis-labelled. Whilst de-labelling programmes are gaining momentum, they have been restricted to a few countries. Here, we address the global prevalence of PenA, to inform the wider potential impact for de-labelling programmes. We conducted a systematic review and meta-analysis including all studies on adult PenA prevalence between January 2003-June 2023. Data on PenA prevalence, allergy recording methods, healthcare setting, and country income were extracted. This study is registered on PROSPERO (CRD42023437718). 174 studies from 28 countries were included (18,352 screened). Global PenA prevalence was 9·4% (95% CI 8·4-10·4%). 92% of peer-reviewed publications were from high-income countries(HICs), with 72% from the UK, USA or Australia. HICs had higher PenA prevalence 9·9% (95% CI 8·8-11·0%), compared to middle-income countries (MICs), 4·4% (95% CI 2·8-6·2%), p<0.0001. Primary care data was seldom reported (16% of studies) and the method of allergy recording significantly influenced reported prevalence. Studies reporting PenA prevalence are skewed towards HICs and secondary care, with little data from Africa, most of Asia and South America. This highlights an unmet need to broaden epidemiological analysis in under-represented regions.