tbuckley/cabot-search huggingface dataset:
Patient-derived Organoids and Xenografts Uncover Therapeutic Vulnerabilities in Colorectal Signet Ring Cell Carcinomas
Authors: Nazia Chaudhary, Alessandro La Ferlita, Bhagya Shree. Choudhary, Eeshrita Jog, Mufaddal Kazi, Showket Yahya, Afiya Dalwai, Vikas Ostwal, Satishkumar Kumar, Siddhi Redkar, Nileema Khapare, Vaishali Kailaje, Akshaya B, Poonam Gera, Munita Bal, Nandini Verma, Rahul Thorat, Avanish Saklani, Lalit Sehgal, Sorab N. Dalal
Journal: Clinical Cancer Research (2025)

Identifying therapeutic targets for Signet Ring Cell Carcinoma (SRCC) of the colon and rectum is a clinical challenge due to the lack of Patient-Derived Organoids (PDO) or Xenografts (PDX). We present a robust method to establish PDO and PDX models to answer address this unmet need. We demonstrate that these models identify novel therapeutic strategies targeting therapy resistance and peritoneal metastasis. We derived nine PDO and PDX models from colorectal SRCC patients. Detailed histopathological characterization confirmed the fidelity of these models to the original tumors. Drug sensitivity assays were conducted in-vitro and in-vivo to assess therapeutic efficacy and impact on peritoneal metastasis. An RNA-seq analysis was performed to identify critical pathways contributing to therapy resistance and metastatic progression. We successfully developed and characterized PDO and PDX models from nine SRCC patients. The SRCC PDO and PDX models exhibited histopathological features consistent with the original tumors, including high mucin content and eccentric nuclei. They demonstrated increased sensitivity to FOLFIRI combined with Paclitaxel or vincristine, reducing peritoneal metastasis. RNA-seq analysis revealed the upregulation of autophagy genes in SRCC. Treatment with Chloroquine alone resulted in decreased tumor growth and peritoneal metastasis. Our study establishes PDO and PDX models as robust platforms for studying SRCC and identifying potential therapeutic strategies. Combining FOLFIRI with paclitaxel/ vincristine or Chloroquine alone inhibits tumor growth and prevents peritoneal metastasis, showing promise for clinical translation. These findings suggest that combining FOLFIRI with IP paclitaxel warrants further investigation in Phase-I clinical trials for SRCC patients.
Phase I Clinical Trial of High Doses of Seleno-L-methionine in Combination with Axitinib in Patients with Previously Treated Metastatic Clear Cell Renal Cell Carcinoma
Authors: Yousef Zakharia, Ryan J. Reis, Matthew R. Kroll, Aseel O. Rataan, Srija Manchkanti, Bilal Rahim, Rohan Garje, Umang Swami, Sarah L. Mott, K.D. Zamba, Jessica C. Sieren, Aliasger K. Salem, Youcef Rustum
Journal: Clinical Cancer Research (2025)

Data in clear cell renal cell carcinoma (ccRCC) xenografts defined the seleno-L-methionine (SLM) dose and the plasma selenium concentrations associated with the enhancement of HIF1α/2α degradation, stabilization of tumor vasculature, enhanced drug delivery, and efficacy of axitinib. The data provided the rationale for the development of this phase I clinical trial of SLM and axitinib in advanced or metastatic relapsed ccRCC. Patients were ≥18 years with histologically and radiologically confirmed advanced or metastatic ccRCC who had received at least one prior systemic therapy, which could include axitinib (last dose ≥6 months prior to enrollment). Escalating dose levels of SLM (2500, 3000 and 4000 μg) were administered orally twice daily for 14 days, then once daily concurrently with axitinib 5 mg twice daily using a 3+3 design in Phase I. Patients were treated at the 4000 μg dose level in the expansion cohort to obtain preliminary estimates of efficacy. No dose limiting toxicities occurred at the 4000 μg SLM dose level. Among the 27 patients treated with 4000 μg of SLM, the overall response rate was 55.6%, median duration of response was 18.4 months, median progression-free survival was 14.8 months, and median overall survival was 19.6 months. Preliminary results have shown that plasma selenium concentrations, inhibition of TGF-β1 and stabilization of tumor vasculature by SLM are time dependent. SLM (4000 μg) in sequential combination with axitinib is well tolerated with encouraging efficacy.
Targeting AXL inhibits the growth and metastasis of prostate cancer in bone
Authors: Chun-Lung Chiu, Dalin Zhang, Hongjuan Zhao, Yi Wei, Alexandra Lapat. Polasko, Mikkel Thy. Thomsen, Vanessa Yang, Kasie Kexin. Yang, Spencer Hauck, Eric E. Peterson, Ru M. Wen, Zhengyuan Qiu, Eva Corey, Yu Rebecca Miao, Erinn B. Rankin, Donna M. Peehl, Jiaoti Huang, Amato J. Giaccia, James D. Brooks
Journal: Clinical Cancer Research (2025)

After failing primary and secondary hormonal therapy, castration-resistant and neuroendocrine prostate cancer metastatic to the bone is invariably lethal, although treatment with docetaxel and carboplatin can modestly improve survival. Therefore, agents targeting biologically relevant pathways in PCa and potentially synergizing with docetaxel and carboplatin in inhibiting bone metastasis growth are urgently needed. Phosphorylated (activated) AXL expression in human prostate cancer bone metastases was assessed by immunohistochemical staining. We evaluated the effects of a novel soluble AXL signaling inhibitor, sAXL (batiraxcept or AVB-S6-500), on the tumor growth and lung metastases in PCa patient-derived xenograft models (PDX) that implanted intratibally. After injection of LuCaP cells into the tibiae, tumors were treated with batiraxcept and docetaxel or carboplatin alone or in combination, and tumor growth was monitored by serum PSA or bioluminescence. Tumor burden was quantified by human-specific Ku70 staining, and metastasis to the lung was determined using qPCR. Transcriptomic profiling, western blotting and immunohistochemistry were performed to identify treatment-regulated gene and protein profile changes. High AXL phosphorylation in human PCa bone metastases correlated with shortened survival. Batiraxcept alone or in combination with docetaxel or carboplatin significantly suppressed intratibial tumor growth and suppressed metastasis to the lung through multiple mechanisms, including repression of cancer stemness genes (CD44, ALDH1A1, TACSTD2, ATXN1) and the PI3K, JAK, MAPK, and E2F1/NUSAP1 signaling pathways. Our study provides a robust preclinical rationale and mechanisms of action for using batiraxcept as a single agent or in combination with docetaxel or carboplatin to treat lethal mPCa.
Comparison of Investigator-Reported and Centrally Adjudicated Heart Failure Outcomes in the EMPEROR-Preserved Trial
Authors: Peter Carson, John R Teerlink, Michel Komajda, Inder Anand, Milton Packer, Javed Butler, Wolfram Doehner, João Pedro Ferreira, Gerasimos Filippatos, Markus Haass, Alan Miller, Steen Pehrson, Stuart J Pocock, Tomoko Iwata, Martina Brueckmann, Tomasz Gasior, Faiez Zannad, Stefan D Anker
Journal: JACC Heart Failure (2025)
Correcting a pathogenic mitochondrial DNA mutation by base editing in mice
Authors: Jose D. Barrera-Paez, Sandra R. Bacman, Till Balla, Derek Van Booven, Durga P. Gannamedi, James B. Stewart, Beverly Mok, David R. Liu, David B. Lombard, Anthony J. Griswold, Danny D. Nedialkova, Carlos T. Moraes
Journal: Science Translational Medicine (2025)

Primary mitochondrial disorders are most often caused by deleterious mutations in the mitochondrial DNA (mtDNA). Here, we used a mitochondrial DddA-derived cytosine base editor (DdCBE) to introduce a compensatory edit in a mouse model that carries the pathological mutation in the mitochondrial transfer RNA (tRNA) alanine (mt-tRNAAla) gene. Because the original m.5024C→T mutation (G→A in the mt-tRNAAla) destabilizes the mt-tRNAAla aminoacyl stem, we designed a compensatory m.5081G→A edit (C→T in the mt-tRNAAla) that could restore the secondary structure of the tRNAAla aminoacyl stem. For this, the DdCBE gene construct was initially tested in an m.5024C→T mutant cell line. The reduced mt-tRNAAla amounts in these cells were increased after editing up to 78% of the mtDNA. Then, DdCBE was packaged in recombinant adeno-associated virus 9 (AAV9) and intravenously administered by retro-orbital injections into mice. Expression of the transduced DdCBE was observed in the heart and skeletal muscle. Total mt-tRNAAla amounts were restored in heart and muscle by the m.5081G→A edit in a dose-dependent manner. Lactate amounts, which were increased in the heart, were also decreased in treated mice. However, the highest dose tested of AAV9-DdCBE also induced severe adverse effects in vivo because of the extensive mtDNA off-target editing that it generated. These results show that although DdCBE is a promising gene therapy tool for mitochondrial disorders, the doses of the therapeutic constructs must be carefully monitored to avoid deleterious off-target editing.
Early-onset sleep alterations found in patients with amyotrophic lateral sclerosis are ameliorated by orexin antagonist in mouse models
Authors: Simon J. Guillot, Christina Lang, Marie Simonot, Daniel Beckett, Dorothée Lulé, Luisa T. Balz, Antje Knehr, Geoffrey Stuart-Lopez, Pauline Vercruysse, Stéphane Dieterlé, Patrick Weydt, Johannes Dorst, Katharina Kandler, Jan Kassubek, Laura Wassermann, Caroline Rouaux, Sébastien Arthaud, Sandrine Da Cruz, Pierre-Hervé Luppi, Francesco Roselli, Albert C. Ludolph, Luc Dupuis, Matei Bolborea
Journal: Science Translational Medicine (2025)

Sleep alterations have been described in several neurodegenerative diseases yet are currently poorly characterized in amyotrophic lateral sclerosis (ALS). This study investigates sleep macroarchitecture and related hypothalamic signaling disruptions in ALS. Using polysomnography, we found that both patients with ALS as well as asymptomatic C9ORF72 and SOD1 mutation carriers exhibited increased wakefulness and reduced non–rapid eye movement sleep. Increased wakefulness correlated with diminished cognitive performance in both clinical cohorts. Similar changes in sleep macroarchitecture were observed in three ALS mouse models ( Sod1 G86R , Fus Δ NLS/+ , and TDP43 Q331K ). A single oral administration of a dual-orexin receptor antagonist or intracerebroventricular delivery of melanin-concentrating hormone (MCH) through an osmotic pump over 15 days partially normalized sleep patterns in mouse models. MCH treatment did not extend the survival of Sod1 G86R mice but did decrease the loss of lumbar motor neurons. These findings suggest MCH and orexin signaling as potential targets to treat sleep alterations that arise in early stages of the disease.
Prior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection
Authors: Leslie Chan, Kassandra Pinedo, Mikayla A. Stabile, Rebecca E. Hamlin, Shaun M. Pienkos, Kalani Ratnasiri, Samuel Yang, Andra L. Blomkalns, Kari C. Nadeau, Bali Pulendran, Ruth O’Hara, Angela J. Rogers, Susan P. Holmes, Catherine A. Blish, Thanmayi Ranganath, Nancy Q. Zhao, Aaron J. Wilk, Rosemary Vergara, Julia L. McKechnie, Lauren de la Parte, Kathleen Whittle Dantzler, Maureen Ty, Nimish Kathale, Giovanny J. Martínez-Colón, Arjun Rustagi, Geoff Ivison, Ruoxi Pi, Madeline J. Lee, Rachel E. Brewer, Taylor Hollis, Andrea Baird, Michele Ugur, Michal C. Tal, Drina Bogusch, Georgie Nahass, Kazim Haider, Kim Quyen Thi Tran, Laura Simpson, Hena N. Din, Jonasel Roque, Rosen Mann, Iris Chang, Evan Do, Andrea Fernandes, Shu-Chen Lyu, Wenming Zhang, Monali Manohar, James W. Krempski, Anita Visweswaran, Elizabeth J. Zudock, Kathryn Jee, Komal Kumar, Jennifer A. Newberry, James V. Quinn, Donald Schreiber, Euan A. Ashley
Journal: Science Translational Medicine (2025)

At this stage in the COVID-19 pandemic, most infections are "breakthrough" infections that occur in individuals with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To refine long-term vaccine strategies against emerging variants, we examined both innate and adaptive immunity in breakthrough infections. We performed single-cell transcriptomic, proteomic, and functional profiling of primary and breakthrough infections to compare immune responses from unvaccinated and vaccinated individuals during the SARS-CoV-2 Delta wave. Breakthrough infections were characterized by a less activated transcriptomic profile in monocytes and natural killer cells, with induction of pathways limiting monocyte migratory potential and natural killer cell proliferation. Furthermore, we observed a female-specific increase in transcriptomic and proteomic activation of multiple innate immune cell subsets during breakthrough infections. These insights suggest that prior SARS-CoV-2 vaccination prevents overactivation of innate immune responses during breakthrough infections with discernible sex-specific patterns and underscore the potential of harnessing vaccines in mitigating pathologic immune responses resulting from overactivation.
AGER-dependent macropinocytosis drives resistance to KRAS-G12D–targeted therapy in advanced pancreatic cancer
Authors: Changfeng Li, Yuanda Liu, Chang Liu, Fangquan Chen, Yangchun Xie, Herbert J. Zeh, Chunhua Yu, Jiao Liu, Daolin Tang, Rui Kang
Journal: Science Translational Medicine (2025)

Pancreatic ductal adenocarcinoma (PDAC) driven by the KRAS-G12D mutation presents a formidable health challenge because of limited treatment options. MRTX1133 is a highly selective and first-in-class KRAS-G12D inhibitor under clinical development. Here, we report that the advanced glycosylation end product-specific receptor (AGER) plays a key role in mediating MRTX1133 resistance in PDAC cells. The up-regulation of AGER within cancer cells instigates macropinocytosis, facilitating the internalization of serum albumin and subsequent amino acid generation. These amino acids are then used to synthesize the antioxidant glutathione, leading to resistance to MRTX1133 treatment due to the inhibition of apoptosis. The underlying molecular mechanism involves AGER's interaction with diaphanous-related formin 1 (DIAPH1), a formin protein responsible for driving Rac family small GTPase 1 (RAC1)-dependent macropinosome formation. The effectiveness and safety of combining MRTX1133 with pharmacological inhibitors of the AGER-DIAPH1 complex (using RAGE299) or macropinocytosis (using EIPA) were confirmed in patient-derived xenografts, orthotopic models, and genetically engineered mouse PDAC models. This combination therapy also induces high-mobility group box 1 (HMGB1) release, resulting in a subsequent antitumor CD8+ T cell response in immunocompetent mice. Collectively, the study findings underscore the potential to enhance the efficacy of KRAS-G12D blockade therapy by targeting AGER-dependent macropinocytosis.
Organ-specific microenvironments drive divergent T cell evolution in acute graft-versus-host disease
Authors: Kayleigh Ingersoll Omdahl, Rene S. Bermea, Ryan Fleming, Kyle Kimler, James Kaminski, Lida P. Hariri, Amy Ly, Xianliang Rui, Lorenzo Cagnin, Jennifer Lane, Ulrike Gerdemann, Bruce R. Blazar, Victor Tkachev, Leslie S. Kean
Journal: Science Translational Medicine (2025)

Tissue-specific T cell immune responses play a critical role in maintaining organ health but can also drive immune pathology during both autoimmunity and alloimmunity. The mechanisms controlling intratissue T cell programming remain unclear. Here, we leveraged a nonhuman primate model of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation to probe the biological underpinnings of tissue-specific alloimmune disease using a comprehensive systems immunology approach including multiparameter flow cytometry, population-based transcriptional profiling, and multiplexed single-cell RNA sequencing and TCR sequencing. Transcriptional profiling revealed substantial biological differences between T cells infiltrating the lung and liver during aGVHD. These included enrichment for transcriptional pathways controlling extracellular matrix remodeling and chemotaxis in the lung and enrichment for transcriptional pathways linked to nucleic acid metabolism and proliferation in the liver. Single-cell RNA sequencing and TCR sequencing substantiated divergent organ-specific transcriptional programing of tissue-infiltrating T cells, which was linked to clonal expansion, with expanded clones progressively enriched for C-X3-C motif chemokine receptor 1 (CX3CR1)-expressing CD8 effector T cells in the lung and eomesodermin (EOMES)-expressing CD8 effector-memory T cells in the liver. This divergent evolution of T cells was maintained even for T cells sharing the same TCRs, indicating its independence from antigen specificity. Together, these results provide insights into the role that tissue microenvironment-derived signals play in local T cell transcriptional programming during alloimmune-mediated clonal expansion and suggest potential opportunities to develop tissue-specific therapeutics to curtail pathogenic immunity after transplant.
Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia
Authors: Steven L. Brody, Jiehong Pan, Tao Huang, Jian Xu, Huihui Xu, Jeffrey R. Koenitizer, Steven K. Brennan, Rashmi Nanjundappa, Thomas G. Saba, Nisreen Rumman, Andrew Berical, Finn J. Hawkins, Xiangli Wang, Rui Zhang, Moe R. Mahjoub, Amjad Horani, Susan K. Dutcher
Journal: Science Translational Medicine (2025)

Primary ciliary dyskinesia is a rare monogenic syndrome that is associated with chronic respiratory disease, infertility, and laterality defects. Although more than 50 genes causative of primary ciliary dyskinesia have been identified, variants in the genes encoding coiled-coil domain-containing 39 (CCDC39) and CCDC40 in particular cause severe disease that is not explained by loss of ciliary motility alone. Here, we sought to understand the consequences of these variants on cellular functions beyond impaired motility. We used human cells with pathogenic variants in CCDC39 and CCDC40, Chlamydomonas reinhardtii genetics, cryo-electron microscopy, and proteomics to define perturbations in ciliary assembly and cilia stability, as well as multiple motility-independent pathways. Analysis of proteomics of cilia from patient cells identified that the absence of the axonemal CCDC39/CCDC40 heterodimer resulted in the loss of a network of more than 90 ciliary structural proteins, including 14 that were defined as ciliary address recognition proteins, which provide docking for the missing structures. The absence of the network impaired microtubule architecture, activated cell quality control pathways, switched multiciliated cell fate to mucus-producing cells and resulted in a defective periciliary barrier. In CCDC39 variant cells, these phenotypes were reversed through expression of a normal CCDC39 transgene. These findings indicate that the CCDC39/CCDC40 heterodimer functions as a scaffold to support the assembly of an extensive network of ciliary proteins, whose loss results in both motility-dependent and motility-independent phenotypes that may explain the severity of disease. Gene therapy might be a potential treatment option to be explored in future studies.
Islet Autoantibody Screening Throughout Australia Using In-Home Blood Spot Sampling: 2-Year Outcomes of Type1Screen
Authors: John M. Wentworth, Anna B. E. Sing, Gaetano Naselli, Dexing Huang, Elizabeth Azidis-Yates, Batsho Mandlebe, James D. Brown, Kelly McGorm, Candice Hall, Leanne Redl, Renee Kludas, Aniruddh Haldar, Felicity Healy, Abbey Gilbert, Kelly Watson, Cherie Chiang, Jennifer J. Couper, Tony Huynh, Elizabeth A. Davis, Maria E. Craig, Fergus J. Cameron, Thomas W. Kay, Leonard C. Harrison, Peter G. Colman
Journal: Diabetes Care (2025)

Type1Screen offers islet autoantibody testing to Australians with a family history of type 1 diabetes (T1D) with the dual aims of preventing diabetic ketoacidosis (DKA) and enabling use of disease-modifying therapy. We describe screening and monitoring outcomes 2 years after implementing in-home capillary blood spot sampling. Data from 2,064 participants who registered between July 2022 and June 2024 were analyzed: 1,507 and 557 chose blood spot and venipuncture screening respectively. We compared baseline characteristics and outcomes for 1,243 participants (967 blood spot and 276 venipuncture) whose samples were tested by June 2024. One blood spot and five venous participants reported unsuccessful sample collections. The median (quartile 1, quartile 3) age of blood spot registrants was lower (12.1 [7.1, 27.1] vs. 17.2 [9, 38.4] years; P < 0.0001), and a higher proportion lived in regional Australia (39% vs. 29%; P = 0.0037). Among 72 participants (5.9%) with a positive screening test, 5 screened by blood spot and 2 by venipuncture had no autoantibodies on confirmatory testing. Blood spot screening identified the expected 2.1% prevalence of multiple autoantibodies and a 2.5% prevalence of a single autoantibody compared with 1.5% and 4.1%, respectively, for venipuncture screening. Clinical diabetes developed in 12 participants. All had screened positive and none had DKA. Type1Screen has national reach. In-home blood spot screening is feasible, particularly for younger participants living regionally, and identifies the expected prevalence of preclinical T1D. The lower cost, increased convenience, and greater reach of blood spot screening could help meet increasing demand for early T1D diagnosis.
68Ga-FAPI-04 Versus 18F-FDG PET/CT in Duodenal Synovial Sarcoma
Authors: Fenglin Zhan, Xin Liu, Hangcheng Zhou, Xuemei Wang, Xiaobo Yao
Journal: Clinical Nuclear Medicine (2025)

Abstract A previously healthy 18-year-old man with a 9-month history of upper abdominal pain and significant weight loss underwent gastroscopy, revealing an ulcerative lesion in the duodenal bulb. Enrolled in a clinical trial, both 18 F-FDG and 68 Ga-FAPI-04 PET/CT demonstrated similar metabolic activity, though 68 Ga-FAPI-04 offered superior lesion delineation. Pathology confirmed synovial sarcoma. This case highlights the potential utility of 68 Ga-FAPI-04 as a radiopharmaceutical for evaluating rare gastrointestinal synovial sarcomas.
Genome‐wide aggregated <i>trans</i>‐ effects analysis identifies genes encoding immune checkpoints as core genes for rheumatoid arthritis
Authors: Athina Spiliopoulou, Andrii Iakovliev, Darren Plant, Megan Sutcliffe, Seema Sharma, Cankut Cubuk, Myles Lewis, Costantino Pitzalis, Anne Barton, Paul M McKeigue
Journal: Arthritis & Rheumatology (2025)

Objectives The sparse effector “omnigenic” hypothesis postulates that the polygenic effects of common SNPs on a typical complex trait are mediated by trans ‐ effects that coalesce on expression of a relatively sparse set of core genes. The objective of this study was to identify core genes for rheumatoid arthritis by testing for association of rheumatoid arthritis with genome‐wide aggregated trans ‐ effects (GATE) scores for expression of each gene as transcript in whole blood or as circulating protein levels. Methods GATE scores were calculated for 5400 cases and 453705 non‐cases of primary rheumatoid arthritis in UK Biobank participants of European ancestry. Results Testing for association with GATE scores identified 16 putative core genes for rheumatoid arthritis outside the HLA region, of which six – TP53BP1 , PDCD1 , TNFRSF14 , LAIR1 , LILRA4 , and IDO1 – were supported by Mendelian randomization analysis based on the marginal likelihood of the causal effect parameter. Five of these 16 genes were validated by a reported association of rheumatoid arthritis with SNPs within 200 kb of the transcription site, 8 by association of the measured protein level with rheumatoid arthritis in UK Biobank, 10 by experimental perturbation in mouse models of inflammatory arthritis, and two – CTLA4 and PDCD1 – by evidence that drugs targeting the gene cause or ameliorate inflammatory arthritis in humans. 14 of these 16 genes are in pathways affecting immunity or inflammation and six – CD5 , CTLA4 , TIGIT , LAIR1 , TNFRSF14 , PDCD1 – encode receptors that have been characterized as immune checkpoints exploited by cancer cells to escape the immune response. Conclusion These results highlight the key role of immune checkpoints in rheumatoid arthritis and identify possible therapeutic targets.