tbuckley/cabot-search huggingface dataset:
Polycystic Kidney Disease
Authors: Fabian Braun, Roman-Ulrich Müller
Journal: Journal of the American Society of Nephrology (2025)

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 3Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 4Department II of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany 5Center for Rare Diseases Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany 6Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases, Cologne, Germany Correspondence: Dr. Roman-Ulrich Müller, email: [email protected] See related article, "Circadian Clock Disruption and Growth of Kidney Cysts in Autosomal Dominant Polycystic Kidney Disease," on pages XXX–XXX.
In situ RAS:RAF binding correlates with response to KRASG12C inhibitors in <i>KRASG12C</i>­-mutant non–small cell lung cancer
Authors: Ryoji Kato, Hitendra S. Solanki, Hilal Ozakinci, Bina Desai, Harika Gundlapalli, Yu Chi Yang, Ida Aronchik, Mallika Singh, Joseph Johnson, Andriy Marusyk, Theresa A. Boyle, Eric B. Haura
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Therapeutic efficacy of KRASG12C(OFF) inhibitors (KRASG12Ci) in KRASG12C-mutant non–small cell lung cancer (NSCLC) varies widely. The activation status of RAS signaling in tumors with KRASG12C mutation remains unclear, as its ability to cycle between the active GTP-bound and inactive GDP-bound states may influence downstream pathway activation and therapeutic responses. We hypothesized that the interaction between RAS and its downstream effector RAF in tumors may serve as indicators of RAS activity, rendering NSCLC tumors with a high degree of RAS engagement and downstream effects more responsive to KRASG12Ci compared to tumors with lower RAS­­–RAF interaction. Experimental Design: We developed a method for measuring in situ RAS binding to RAF in cancer samples using proximity ligation assays (PLAs) designed to detect panRAS–CRAF interactions. Results: The panRAS–CRAF PLA signal correlated with levels of both RAS-GTP and phosphorylated ERK protein, suggesting that this assay can effectively assess active RAS signaling. We found that elevated panRAS–CRAF PLA signals were associated with increased sensitivity to KRASG12Ci in KRASG12C-mutant NSCLC cell lines, xenograft models, and patient samples. Applying a similar PLA approach to measure the interactions between EGFR and its adaptor protein GRB2 as a surrogate for EGFR activity, we found no relationship between EGFR activity and response to KRASG12Ci in the same samples. Conclusions: Our study highlights the importance of evaluating in situ RAS–RAF interactions as a potential predictive biomarker for identifying NSCLC patients most likely to benefit from KRASG12Ci. The PLA developed for quantifying these interactions represents a valuable tool for guiding treatment strategies.
Population Pharmacokinetics of Orvacabtagene Autoleucel, an Autologous BCMA-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Hongxiang Hu, Yan Li, Julia Piasecki, Daniela Hosseyni, Zhicheng Yan, Xianghong Liu, Ken Ogasawara, Simon Zhou, Yiming Cheng
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Orvacabtagene autoleucel (orva-cel; JCARH125), a CAR T-cell therapy targeting B-cell maturation antigen (BCMA), was evaluated in relapsed/refractory multiple myeloma (RRMM) patients in the EVOLVE phase 1/2 study (NCT03430011). We applied a modified piecewise model to characterize orva-cel transgene kinetics and assessed the impact of various covariates on its pharmacokinetics (PK). Experimental Design: The population PK analysis included 159 patients from the EVOLVE study. Traditional piecewise models, employing a first-order expansion rate with or without lag time followed by a bi-exponential contraction phase, were compared with a modified model incorporating a cell number-dependent expansion phase aligned with cellular physiology. Covariates assessed encompassed baseline demographics, dose levels (50 to 600 × 106 CD3+ CAR+ T cells), prior/concomitant medications, baseline disease burden, and anti-therapeutic antibody (ATA) status. Results: Traditional piecewise models failed to accurately describe maximum orva-cel transgene level (Cmax) and underestimated the time to Cmax (Tmax). Our modified model incorporating a cell number-dependent expansion rate outperformed traditional models by 1) more accurately capturing the cellular expansion phase, and 2) yielding a Tmax that closely matches observed values. Additionally, dose level, percentage of plasma cells in bone marrow, and treatment-induced ATA were identified as statistically significant covariates and associated with orva-cel expansion and/or persistence. Conclusions: Orva-cel PK were adequately described by the modified piecewise model incorporating a cell number-dependent expansion phase, which aligns closely with T cell biology.
Randomized phase II study of bevacizumab with weekly anetumab ravtansine or weekly paclitaxel in platinum-resistant/refractory high grade ovarian cancer (NCI trial)
Authors: Husam A. Alqaisi, David E. Cohn, Jing-Yi Chern, Linda R. Duska, Andrea Jewell, Bradley R. Corr, Ira Seth. Winer, Eugenia Girda, Marta A. Crispens, Neesha C. Dhani, Ainhoa Madariaga, Robert C. Grant, Matthew Malaguti, Crystal Lee, Valerie Bowering, Horace Wong, Andrew Poothullil, Vanessa Speers, Lisa Wang, Philippe L. Bedard, John C. Brady, Andrew B. Nixon, Li Chen, Claire O'Connor, William Zamboni, Tawyna McKee, Jeffrey A. Moscow, Amit M. Oza, Stephanie Lheureux
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Mesothelin (MSLN) is highly expressed in high grade serous/ endometrioid ovarian cancers (HGOC). Anetumab ravtansine (AR) is an antibody drug conjugate directed at MSLN antigen with a tubulin polymerization inhibitor. We assessed safety, activity and pharmacokinetics of the combination AR/bevacizumab (Bev) (ARB) versus weekly paclitaxel (wP)/Bev (PB) in patients with platinum resistant/refractory HGOC (prrHGOC). Expiremental design: Following a run-in phase I study to assess ARB safety, prrHGOC patients with centrally confirmed MSLN positive expression were randomized to ARB or PB (wP 80mg/m2 with Bev 10mg/kg biweekly). Patients were stratified by platinum resistance/refractory and prior Bev. The primary endpoint was progression-free survival (PFS), secondary endpoints were overall response rate (ORR), safety, and blood-based angiome biomarker assessment. A futility analysis was planned after 35 PFS events. Results: The combination of Bev (10mg/kg) biweekly with AR (2.2mg/kg) weekly was well tolerated. Regarding phase II results, mesothelin positivity was 88% and 57 pts were randomized (28 ARB, 29 PB). 42% pts received prior Bev and 23% were platinum refractory. At futility analysis, the median PFS was 5.3 and 12.7 months for ARB and PB respectively (p=0.03, HR= 2.02 [1.06-3.86]). ORR was 21% with ARB and 65% with PB. The most common treatment-related grade ≥ 3 adverse events were anemia (18%) with ARB, and neutropenia (24%) with PB. Higher baseline levels of circulating IL-6 were associated with worse PFS, and its levels decreased with PB treatment. Conclusion: Our study stopped at interim analysis highlighting the benefit of PB in prrHGOC as standard of care.
CA-125 as a Biomarker in Renal Medullary Carcinoma: Integrated Molecular Profiling, Functional Characterization, and Prospective Clinical Validation
Authors: Sandra L. Grimm, Menuka Karki, Kyle A. Blum, Jean-Philippe Bertocchio, Rong He, Durga N. Tripathi, Niki M. Zacharias, Justin M. Lebenthal, Rahul A. Sheth, Priya Rao, Giannicola Genovese, Zhen Lu, Robert C. Bast, Davis R. Ingram, Rossana Lazcano, Khalida M. Wani, Wei-Lien Wang, Alexander J. Lazar, Nizar M. Tannir, Cheryl L. Walker, Cristian Coarfa, Pavlos Msaouel
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Renal medullary carcinoma (RMC) is a highly aggressive malignancy defined by the loss of the SMARCB1 tumor suppressor. It mainly affects young individuals of African descent with sickle cell trait, and it is resistant to conventional therapies used for other renal cell carcinomas. This study aimed to identify potential biomarkers for early detection and disease monitoring of RMC. Experimental Design: Integrated profiling of primary untreated RMC tumor tissues and paired adjacent kidney controls was performed using RNA-sequencing (RNA-seq) and histone Chromatin Immunoprecipitation Sequencing (ChIP-seq). The expression of serum cancer antigen 125 (CA-125), was prospectively evaluated in 47 patients with RMC. Functional studies were conducted in RMC cell lines to assess the effects of SMARCB1 re-expression. Results: MUC16, encoding for CA-125, was identified as one of the top upregulated genes in RMC tissues, with concomitant enrichment of active histone marks H3K4me3 and H3K27ac at its promoter. Elevated serum CA-125 levels were found in 31 of 47 (66%) RMC patients and correlated significantly with metastatic tumor burden (p = 0.03). Functional studies in RMC cell lines demonstrated that SMARCB1 re-expression significantly reduced MUC16 expression. Conclusions: The correlation between serum CA-125 levels and metastatic burden suggests that CA-125 is a clinically relevant biomarker for RMC. These findings support further exploration of CA-125 for disease monitoring and targeted therapeutics in RMC.
MAPK pathway activating alteration and immunotherapy efficacy in squamous cell lung carcinoma: results from the randomized, prospective SQUINT trial
Authors: Federico Cappuzzo, Biagio Ricciuti, Angelo Delmonte, Laura Bonanno, Xiaoyue Wang, Weng Kit Lye, Andreas Görtz, Kalliopi Andrikou, Alessandro Dal Maso, Gabriele Minuti, Maximilian Papi, Joao Victor. Alessi, Alessandro Di Federico, Scott Rodig, Mark Magdi. Awad, Giulio Metro, Ilaria Attili, Fabiana Vitiello, Sara Pilotto, Stefania Gori, Giulio Rossi, Simonetta Buglioni, Diana Giannarelli, Lorenza Landi
Journal: Clinical Cancer Research (2025)

Abstract Background: The role of activating alterations in the MAPK pathway in predicting immunotherapy efficacy in lung squamous cell carcinoma (LSCC) patients is largely unknown. The aims of the randomized, phase II SQUINT trial were to assess the efficacy of nivolumab plus ipilimumab (NI) versus platinum-based chemotherapy plus nivolumab (N-CT) and to identify clinically available biomarkers of response to immunotherapy in patients with advanced or metastatic LSCC. Methods: SQUINT was an open-label, randomized, parallel, non-comparative, phase II trial of NI versus N-CT in chemo-naïve, metastatic or recurrent LSCC adult patients. The study was conducted across 15 Italian centers from September 2017 to February 2022 (ClinicalTrials.gov ID: NCT03823625). Results: 45 patients were included in the NI arm and 46 in the N-CT arm. At 12 months, the overall survival (OS) rate was 62% in the NI arm and 50% in the N-CT arm. 74 patients were included in the analyses for individual biomarkers. In patients with mutations or copy number variations of genes involved in the MAPK pathway, we observed higher response to immunotherapy (43% vs 15%), longer progression-free survival (PFS) (p=0.03) and OS (p&amp;lt;0.001). A higher density of CD8+PD1+ T cells (p=0.04) among MAPK-altered tumors versus wild-type, together with an increased CD8+PD1+/FOXP3 ratio (p=0.047) were observed. In the validation cohort of patients not exposed to immunotherapy, OS was similar between MAPK13 mutant and wild-type LSCC. Conclusion: We showed for the first time that MAPK pathway activating alteration influences the outcome of LSCC treated with immunotherapy, highlighting the relevance of gene profiling.
The Splice Index as a prognostic biomarker of strength and function in myotonic dystrophy type 1
Authors: Marina Provenzano, Kobe Ikegami, Kameron Bates, Alison Gaynor, Julia M Hartman, Aileen S Jones, Amanda Butler, Kiera N Berggren, Jeanne Dekdebrun, Man Hung, Dana M Lapato, Michael Kiefer, Charles A Thornton, Nicholas E Johnson, Melissa A Hale
Journal: Journal of Clinical Investigation (2025)

Myotonic dystrophy type 1 (DM1) is a multisystemic, CTG repeat expansion disorder characterized by a slow, progressive decline in skeletal muscle function. A biomarker correlating RNA mis-splicing, the core pathogenic disease mechanism, and muscle performance is crucial for assessing response to disease-modifying interventions. We evaluated the Myotonic Dystrophy Splice Index (SI), a composite RNA splicing biomarker incorporating 22 disease-specific events, as a potential biomarker of DM1 muscle weakness. Total RNA sequencing of tibialis anterior biopsies from 58 DM1 participants and 33 unaffected/disease controls was used to evaluate RNA splicing events across the disease spectrum. Targeted RNA sequencing was used to derive the SI from biopsies collected at baseline (n = 52) or a 3-month (n = 37) follow-up visit along with clinical measures of muscle performance. The SI demonstrated significant associations with measures of muscle strength and ambulation, including ankle dorsiflexion strength (ADF) and 10-meter run/fast walk (Pearson r = -0.719 and -0.680, respectively). The SI was relatively stable over 3-months (ICC = 0.863). Latent-class analysis identified three DM1 subgroups stratified by baseline SI (SIMild, SIModerate, SISevere); SIModerate individuals had a significant increase in the SI over 3-months. Multiple linear regression modeling revealed that baseline ADF and SI were predictive of strength at 3-months (adjusted R² = 0.830). The SI is a reliable biomarker that captures associations of RNA mis-splicing with physical strength and mobility and has prognostic utility to predict future function, establishing it as a potential biomarker for assessment of therapeutic target engagement. NCT03981575Funding: FDA (7R01FD006071), Myotonic Dystrophy Foundation, Wyck Foundation, Muscular Dystrophy Association, Novartis, Dyne, Avidity, PepGen, Takeda, Sanofi Genzyme, Pfizer, Arthex, and Vertex Pharmaceuticals.
Melanoma: Assessment and Management summary of 2022 update of the NICE guidelines
Authors: Myles J Smith, Howard Peach, Steve Keohane, John Lear, Lynne A Jamieson, Hesham S Mohamed, Andrew Molyneux, John Lear, Will Bolland, Guy Burkill, Susan Cheetham, Fiona Collier, Gillian Godsell, Sarah HemingtonGorse, Ian James, Lynne Jamieson, Stephen Keohane, Christine Parkinson, Howard Peach, Saskia Reeken, Myles J Smith, Delia Sworm, Steven Watkins, Dharmisha Chauhan, Sophie Wilne
Journal: British Journal of Dermatology (2025)

Abstract Melanoma is the fifth most common skin cancer in the UK, accounting for 4% of all new cancer cases, with a predicted 7% increase in incidence between 2014-35. In parallel, since the initial publication of the Melanoma NICE Guidelines in 2015, there has been a paradigm shift in the management of the disease, with the introduction of effective systemic therapies. These innovations have reshaped the management of melanoma throughout the patient journey, and improved clinical outcomes. Surgical management has evolved, with the role of sentinel node biopsy in staging and management of regional lymph nodes becoming clearly defined, and a reduction in the need and indications for morbid block dissections. In advanced disease, effective therapies have allowed a de-escalation of surgery, changing the role and sequencing of local therapies. Regional therapies for in-transit disease have expanded and are effective in controlling this pattern of disease as part of multidisciplinary care. These advances have undoubtedly improved the care for people with melanoma, but have also increased the complexity of management. In this context, this article seeks to summarizes the most relevant of the recent updates to the NICE guidelines.
Single-cell and spatial transcriptomics illuminate bat immunity and barrier tissue evolution
Authors: Roy Levinger, Dafna Tussia-Cohen, Sivan Friedman, Yan Lender, Yomiran Nissan, Evgeny Fraimovitch, Yuval Gavriel, Jacqueline Tearle, Aleksandra A Kolodziejczyk, Kyung-Mee Moon, Tomás Gomes, Natalia Kunowska, Maya Weinberg, Giacomo Donati, Leonard J Foster, Kylie R James, Yossi Yovel, Tzachi Hagai
Journal: Molecular Biology and Evolution (2025)

Abstract Bats have adapted to pathogens through diverse mechanisms, including increased resistance – rapid pathogen elimination, and tolerance – limiting tissue damage following infection. In the Egyptian fruit bat (an important model in comparative immunology) several mechanisms conferring disease tolerance were discovered, but mechanisms underpinning resistance remain poorly understood. Previous studies on other species suggested that elevated basal expression of innate immune genes may lead to increased resistance to infection. Here, we test whether such transcriptional patterns occur in Egyptian fruit bat tissues through single-cell and spatial transcriptomics of gut, lung and blood cells, comparing gene expression between bat, mouse and human. Despite numerous recent loss and expansion events of interferons in the bat genome, interferon expression and induction are remarkably similar to that of mouse. In contrast, central complement system genes are highly and uniquely expressed in key regions in bat lung and gut epithelium, unlike in human and mouse. Interestingly, the unique expression of these genes in the bat gut is strongest in the crypt, where developmental expression programs are highly conserved. The complement system genes also evolve rapidly in their coding sequence across the bat lineage. Finally, the bat complement system displays strong hemolytic activity. Together, these results indicate a distinctive transcriptional divergence of the complement system, which may be linked to bat resistance, and highlight the intricate evolutionary landscape of bat immunity.
A 61-Year-Old Man With Weakness and Gait Dysfunction
Authors: Felipe J. S. Jones, Christyn Edmundson, Jennifer Orthmann-Murphy
Journal: JAMA Neurology (2025)

A man aged 61 years presented with chronic progressive weakness and gait dysfunction over a 4-year period. He had Ashkenazi Jewish ancestry and a history of memory loss, inappropriate laughter, dysarthria, and hypertension. Examination revealed impaired recall, extremity spasticity, distal sensory loss, and normal cerebellar function, and imaging showed hyperintensities in the periventricular white matter of the corticospinal tracts of the pons and medulla. What is your diagnosis?
Use of Albumin-Adjusted Calcium Measurements in Clinical Practice
Authors: Noémie Desgagnés, James A. King, Gregory A. Kline, Isolde Seiden-Long, Alexander A. Leung
Journal: JAMA Network Open (2025)

Importance Using albumin-adjusted calcium is commonly recommended for for measuring calcium, but with little empirical evidence to support the practice. Objective To assess the correlation between total calcium measurements (with or without adjustment) vs the ionized calcium level as a reference standard. Design, Setting, and Participants This was a population-based cross-sectional study in the province of Alberta, Canada, including adults tested for serum total calcium and ionized calcium simultaneously between January 1, 2013, and October 31, 2019. Statistical analysis was performed from March 2023 to October 2024. Main Measures and Outcomes The correlation between unadjusted and adjusted total calcium measurements (using 10 formulas) and the ionized calcium level was evaluated, along with the potential association with the classification of calcium status. Results Among 22 658 patients included, 11 889 (52.5%) were female and 10 769 (47.5%) were male; the median (IQR) age was 60 (47-72) years. The unadjusted total calcium ( R 2 = 71.7%; 95% CI, 71.1%-72.2%) had a stronger correlation with ionized calcium than the commonly used simplified Payne formula (ie, total calcium [mmol/L] + 0.02 [40 − albumin (g/L)]) ( R 2 = 68.9%; 95% CI, 68.0%-69.6%) and correlated similarly to other formulas (Payne: lowest R 2 = 60.3%; 95% CI, 59.3%-61.3%; and James: highest R 2 = 76.7%; 95% CI, 76.1%-77.3%). When classifying patients into categories of hypocalcemia, normocalcemia, or hypercalcemia, unadjusted total calcium had the best overall agreement (74.5%) with ionized calcium compared with albumin-adjusted calcium using the original Payne and simplified Payne formulas (agreement 63.0% and 58.7%, respectively). Misclassification using the adjustment formulas was worse in the presence of hypoalbuminemia (albumin level &amp;amp;lt;30 g/L). Conclusions and Relevance In this cross-sectional study drawn from a contemporaneous population, there appeared to be heavy reliance on adjustment formulas for calcium in clinical practice with little gain but considerable risk of misclassification of true calcium status, especially in the presence of hypoalbuminemia. These results suggest that unadjusted total calcium was the best and most practical alternative to ionized calcium.
Age at Menopause and Development of Type 2 Diabetes in Korea
Authors: Byung-Joon Ko, Jin-Hyung Jung, Kyungdo Han, Ga Eun Nam
Journal: JAMA Network Open (2025)

Importance There is limited evidence regarding the association between age at menopause and incident type 2 diabetes (T2D). Objective To investigate whether age at menopause and premature menopause are associated with T2D incidence in postmenopausal Korean women. Design, Setting, and Participants This population-based cohort study was conducted among a nationally representative sample from the Korean National Health Insurance Service database of 1 125 378 postmenopausal women without T2D who enrolled in 2009. The median (IQR) follow-up was 8.4 (8.1-8.7) years. Data were analyzed in March 2024. Exposures Age at menopause and premature menopause (menopause onset at age &amp;amp;lt;40 years). Main Outcomes and Measures The primary outcome was incident T2D. Multivariable Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs) and 95% CIs for incident T2D by age at menopause, adjusting for potential confounders. Results Of 1 125 378 participants (mean [SD] age at enrollment, 61.2 [8.4] years), 113 864 individuals (10.1%) were diagnosed with T2D at least 1 year after enrollment. Women with menopause onset at ages younger than 40 years (premature menopause; HR, 1.13; 95% CI, 1.08-1.18) and ages 40 to 44 years (HR, 1.03; 95% CI, 1.00-1.06) had increased risk of T2D compared with those with onset at age 50 years or older, with adjustment for sociodemographic, lifestyle, cardiometabolic, psychiatric, and reproductive factors; a younger age at menopause was associated with increased risk of developing T2D ( P for trend &amp;amp;lt;.001). Body mass index, depressive disorder, and prediabetes modified the association in subgroup analyses; for example, for individuals with premature menopause vs those with menopause at ages 50 years or older, HRs were 1.54 (95% CI, 1.14-2.06) for a BMI less than 18.5 and 1.14 (95% CI, 1.00-1.30) for a BMI of 30 or greater ( P &amp;amp;lt; .001), 1.28 (95% CI, 1.12-1.45) for individuals with depression and 1.11 (95% CI, 1.07-1.16) for those without depression ( P = .01), and 1.25 (95% CI, 1.18-1.33) for individuals who were not prediabetic and 1.04 (95% CI, 0.99-1.11) those who were prediabetic ( P &amp;amp;lt; .001). Conclusions and Relevance In this study, premature and early menopause were associated with a higher risk of T2D, highlighting the need for targeted public health strategies aimed at preventing or delaying T2D among postmenopausal women.