tbuckley/cabot-search huggingface dataset:
Aberrant single-cell phenotype and clinical implications of genotypically defined polyclonal plasma cells in myeloma
Authors: Matteo Claudio Da Viá, Francesca Lazzaroni, Antonio Matera, Alessio Marella, Akihiro Maeda, Claudio De Magistris, Loredana Pettine, Antonio Giovanni Solimando, Vanessa Desantis, Giuseppe M Peretti, Laura Mangiavini, Riccardo Giorgino, Sonia Fabris, Stefania Pioggia, Alfredo Marchetti, Marzia Barbieri, Silvia Lonati, Alessandra Cattaneo, Marta Tornese, Margherita Scopetti, Emanuele Calvi, Nayyer Latifinavid, Giancarlo Castellano, Federica Torricelli, Antonino Neri, Cathelijne Fokkema, Tom Cupedo, Marta Lionetti, Francesco Passamonti, Niccolò Bolli
Journal: Blood (2025)

Multiple Myeloma is driven by clonal plasma cell (cPC)-intrinsic factors and changes in the tumorigenic microenvironment (TME). To investigate if residual polyclonal PCs (pPCs) are disrupted, single-cell (sc) RNAseq and sc B-cell receptor analysis were applied in a cohort of 46 samples with PC dyscrasias and 21 healthy donors (HDs). Out of n=234,789 PCs, 64,432 were genotypically identified as pPCs with frequencies decreasing over different disease stages, from 23.66% in monoclonal gammopathy of undetermined significance (MGUS) to 3.23% in MMs (p=0.00012). Both cPCs and pPCs had a comparable expression of typical lineage markers (i.e. CD38, CD138), while others were more variable (CD27, ITGB7). Only cPCs overexpressed oncogenes (e.g. CCND1/2, NSD2), but CCND3 was often expressed in pPCs. BCMA was expressed on both p- and cPCs, while GPRC5D was mostly upregulated in cPCs with implications for on-target, off-tumor activity of targeted immunotherapies. In comparison with HDs, pPCs from patients showed upregulated autophagy and disrupted interaction with TME. Importantly, interferon related pathways where significantly enriched in pPCs from patients vs HDs (p-adjusted &amp;lt; 0.05) showing an inflamed phenotype affecting genotypically normal PCs. Function of pPCs was consequently impacted and correlated with immunoparesis, driven by disrupted cellular interactions with TME. Leveraging our scRNAseq data, we derived a "healthy PC signature" that could be applied to bulk transcriptomics from the CoMMpass dataset and predicted significantly better PFS and OS (log rank p &amp;lt; 0.05 for both). Our findings show that genotypic, single-cell identification of pPCs in PC dyscrasias has relevant pathogenic and clinical implications.
Ibrutinib Lead-in followed by Venetoclax Plus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia - SAKK 34/17
Authors: Adalgisa Condoluci, Ilaria Romano, Daniel Dietrich, Katia Pini, Georg Stussi, Gisela Müller, Nathan Cantoni, Richard Cathomas, Ulrich J.M. Mey, Anouk Andrea Widmer, Thorsten Zenz, Michael Gregor, Dominik Heim, Martin Andres, Rudolf Benz, Davide Rossi
Journal: Blood (2025)

The rationale for combining ibrutinib and venetoclax (IV) in chronic lymphocytic leukemia (CLL) treatment lies in their complementary mechanisms of action. Studies investigating IV typically begin with a short initial course of ibrutinib, followed by venetoclax introduction for a limited duration, typically 12 months. SAKK34/17 (NCT03708003) is a single-arm, open-label, multicenter, phase 2 trial evaluating the effectiveness of a modified IV schedule in patients with relapsed/refractory (R/R) CLL. No prior exposure to BTK- or BCL2-inhibitors was allowed. The lead-in phase with ibrutinib was extended to six months to reduce the tumor burden and related tumor lysis syndrome (TLS) risk. Additionally, the treatment phase with IV is prolonged to a minimum of 24 months to enhance the undetectable minimal residual disease (uMRD, 10-4) rate. The primary endpoint was the rate of complete response or complete response with incomplete bone marrow recovery (CR/CRi) with uMRD in both bone marrow (BM) and peripheral blood (PB). Secondary endpoints included assessing the proportion of patients who transitioned to a low-risk category for TLS after receiving ibrutinib lead-in. Out of the 30 patients with R/R CLL who were enrolled, 40.0% achieved a status of uMRD CR/CRi according to the intention-to-treat analysis, and 53.3% showed uMRD in the BM and PB. Following the lead-in period with ibrutinib, 57.1% of patients achieved a low-risk for TLS. At cycle 31, the progression-free survival rate was 89.9%. These results contribute to the increasing body of evidence supporting the idea that a longer IV duration is beneficial for enhancing therapeutic effectiveness.
Authors' Reply: Unlocking the Potential of SC0062: A New Horizon in IgA Nephropathy Treatment?
Authors: Jianghua Chen, Hiddo J.L. Heerspink
Journal: Journal of the American Society of Nephrology (2025)

We thank Xiong and Zhao1 for their interest in our JASN article about the albuminuria-lowering effects of the selective endothelin receptor antagonist SC0062 in patients with IgA nephropathy.2 Our trial enrolled participants with a biopsy-proven IgA nephropathy with similar inclusion criteria compared with other recent clinical trials that enrolled patients with IgA nephropathy.3–5 We did not record Oxford mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, crescents scores as the main goal of the study was to find optimal doses of SC0062 for future phase 3 clinical trials. In these future trials, we will consider collection of Oxford mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, crescents scores. Since our trial was a phase 2 dose-finding trial of 24-week duration, we were unable to assess the longer-term efficacy and safety of SC0062, which is the main objective of a recently started phase 3 clinical trial in participants with IgA nephropathy (NCT06819826). This trial will also enroll more patients with a GFR below 60 ml/min per 1.73 m2 to assess the efficacy and safety of SC0062 in people with more severe kidney impairment. Finally, the finding that the albuminuria-lowering effects were consistent in participants using and not using sodium-glucose cotransporter 2 inhibitors is in keeping with the results from clinical trials with other endothelin receptor antagonists, including atrasentan and zibotentan.4,6 We therefore do not consider our results a chance finding because of the small sample size. We agree that larger clinical trials, such as the ongoing SC0062 phase 3 trial, will provide more robust evidence.
Uremic Toxins, Chronic Kidney Disease, and Cognitive Dysfunction
Authors: Taylor D. Andrews, Gregory S. Day, Sarosh R. Irani, Takahisa Kanekiyo, LaTonya J. Hickson
Journal: Journal of the American Society of Nephrology (2025)

Abstract Cognitive impairment involves alterations to one’s cognitive status that affects their everyday life. Individuals with chronic kidney disease (CKD), and in particular kidney failure, experience higher rates of cognitive impairment compared to the general population. In CKD, 20-70% of individuals have cognitive impairment, but the highest prevalence is described in kidney failure such that dialysis-dependent patients have twice the prevalence of aged-matched controls. In the past 5 years, the number of investigations examining the “kidney-brain axis”, mechanisms of CKD-related cognitive impairment, and potential therapeutics have exponentially increased. This review article summarizes recent literature on direct and indirect effects of CKD-associated cognitive impairment with emphasis on uremic toxins; brain injury mechanisms; overlap between CKD-associated cognitive impairment, Alzheimer’s disease, and other neurodegenerative diseases; and promising therapeutics. Reviewed therapeutic interventions include: AST-120 [indoxyl sulfate absorbent], CH-223191 [aryl hydrocarbon receptor antagonist], TRAM34 [Kca3.1-specific inhibitor], anakinra [IL-1R inhibitor], marimastat, exercise, supplements, and kidney transplantation. Special focus is placed on translational studies examining uremic toxin-associated pathogenic processes including brain oxidative stress, neuroinflammation, and blood brain barrier dysfunction through in vitro and in vivo models of CKD-associated brain injury. Finally, future research directions are suggested including targeting of cellular senescence abundance with senotherapeutics and capitalizing on anti-inflammatory effects of regenerative, cell-based therapeutics (e.g. mesenchymal stem cells and extracellular vesicles), and use of aged murine models. Collectively, CKD-associated cognitive impairment represents a prevalent condition for which remaining knowledge gaps exist, and scientific advancements are needed to preserve cognitive function and improve the lives of in individuals with CKD.
Integrated cross-linking by TG2 and FXIII generates hepatoprotective fibrin(ogen) deposits in injured liver
Authors: Zimu Wei, Nana Kwame Kwabi Boateng, Lauren Schmitt, Holly Cline, Maria Theodora Fernandes Fonseca, Ariana Newberry, Alicia Taylor, Jelle Adelmeijer, Lauren Poole, R. Todd Stravitz, William M. Lee, Ton Lisman, Kirk C Hansen, James P Luyendyk
Journal: Blood (2025)
Rat hepatitis E virus as an aetiological agent of acute hepatitis of unknown origin
Authors: Javier Caballero-Gómez, María Casares-Jiménez, Marina Gallo-Marín, Sara Pereira-Pardo, Adrián Beato-Benítez, Antonio Poyato, Rafael Guerra, Ana Avellón, Katja Schilling-Loeffler, Carolina Freyre-Carrillo, Ignacio García-Bocanegra, Débora Jiménez-Martín, Diana Corona-Mata, Isabel Viciana, Tomás Fajardo, Milagros Muñoz-Chimeno, Miguel Ángel Quevedo, Lucía Ríos-Muñoz, Ana Belén Pérez, David Cano-Terriza, Juan Macías, Ana Fuentes, Reimar Johne, Antonio Rivero-Juarez, Antonio Rivero
Journal: Journal of Hepatology (2025)
Genetic Correlates of Treatment-Resistant Depression
Authors: Bohan Xu, Katherine L. Forthman, Rayus Kuplicki, Jonathan Ahern, Robert Loughnan, Firas Naber, Wesley K. Thompson, Charles B. Nemeroff, Martin P. Paulus, Chun Chieh Fan
Journal: JAMA Psychiatry (2025)

Importance Treatment-resistant depression (TRD) is a major challenge in mental health, affecting a significant number of patients and leading to considerable burdens. The etiological factors contributing to TRD are complex and not fully understood. Objective To investigate the genetic factors associated with TRD using polygenic scores (PGS) across various traits and explore their potential role in the etiology of TRD using large-scale genomic data from the All of Us (AoU) Research Program. Design, Setting, and Participants This study was a cohort design with observational data from participants in the AoU Research Program who have both electronic health records and genomic data. Data analysis was performed from March 27 to October 24, 2024. Exposures PGS for 61 unique traits from 7 domains. Main Outcomes and Measures Logistic regressions to test if PGS was associated with treatment-resistant depression (TRD) compared with treatment-responsive major depressive disorder (trMDD). Cox proportional hazard model was used to determine if the progressions from MDD to TRD were associated with PGS. Results A total of 292 663 participants (median [IQR] age, 57 (41-69) years; 175 981 female [60.1%]) from the AoU Research Program were included in this analysis. In the discovery set (124 945 participants), 11 of the selected PGS were found to have stronger associations with TRD than with trMDD, encompassing PGS from domains in education, cognition, personality, sleep, and temperament. Genetic predisposition for insomnia (odds ratio [OR], 1.11; 95% CI, 1.07-1.15) and specific neuroticism (OR, 1.11; 95% CI, 1.07-1.16) traits were associated with increased TRD risk, whereas higher education (OR, 0.88; 95% CI, 0.85-0.91) and intelligence (OR, 0.91; 95% CI, 0.88-0.94) scores were protective. The associations held across different TRD definitions (meta-analytic R 2 &amp;amp;gt;83%) and were consistent across 2 other independent sets within AoU (the whole-genome sequencing Diversity dataset, 104 388, and Microarray dataset, 63 330). Among 28 964 individuals followed up over time, 3854 developed TRD within a mean of 944 days (95% CI, 883-992 days). All 11 previously identified and replicated PGS were found to be modulating the conversion rate from MDD to TRD. Conclusions and Relevance Results of this cohort study suggest that genetic predisposition related to neuroticism, cognitive function, and sleep patterns had a significant association with the development of TRD. These findings underscore the importance of considering psychosocial factors in managing and treating TRD. Future research should focus on integrating genetic data with clinical outcomes to enhance understanding of pathways leading to treatment resistance.
Genetic Variants and Clinical Features of Patients With Glycogen Storage Disease Type Ib
Authors: Yu Xia, Yu Sun, Taozi Du, Chengkai Sun, Ying Xu, Wensong Ge, Lili Liang, Ruifang Wang, Manqing Sun, Bing Xiao, Wenjuan Qiu
Journal: JAMA Network Open (2025)

Importance Glycogen storage disease type Ib (GSDIb) is a rare metabolic disorder characterized by impaired glucose-6-phosphate transporter function with limited descriptions. Objective To describe the genetic and clinical features of Chinese patients with GSDIb. Design, Setting, and Participants This retrospective cohort study retrieved the medical records of 113 Chinese patients with GSDIb treated at a single institution in Shanghai from November 1, 2000, to June 30, 2024. Main Outcomes and Measures Biochemical parameters and clinical features (infections, inflammatory bowel disease [IBD], kidney and cardiovascular issues, growth and puberty) at baseline and the last follow-up, all-cause mortality, and mental and social development were assessed. Results A total of 113 patients (96 children [85%]; 67 males [59%]) had GSDIb genetically diagnosed at a median age of 1.4 (range, 0.0-35.5) years. Thirty-eight novel SLC37A4 variants were identified. Hypoglycemia and metabolic derangements were the primary concerns in patients aged 2 years or younger (45%). Short stature (75%), infections (75%), and recurrent epistaxis (31%) became more prevalent in patients aged 2.1 to 5.0 years. The frequency of respiratory tract infection decreased after a median age of 7.0 (IQR, 3.5-10.5) years. Forty-four patients (46%) developed IBD at a median age of 6.0 (IQR, 3.0-12.0) years, 14% of whom developed IBD-associated arthritis at a median age of 10.5 (IQR, 5.8-19.6) years. The mean (SD) difference between the z scores of actual height and target height (Δ height z scores) at the final visit (−2.11 [1.76]) did not significantly increase even after uncooked cornstarch treatment. The mean (SD) Δ height z scores of the patients with IBD (−2.99 [1.70]) were significantly lower than those without IBD (mean [SD], −1.36 [1.44]) ( P &amp;amp;lt; .001). Ten patients (9%) died due to complications of GSDIb, including metabolic derangements, sepsis, and/or severe pneumonia (n = 8), IBD (n = 1), and pulmonary hypertension (n = 1). Conclusions and Relevance In this cohort study, the genetic and clinical spectra of GSDIb were broadened, suggesting associations between GSDIb and bowel, growth, and survival outcomes. To date, no previous study reported IBD-associated arthritis.
Stories Matter: Finding Poetry, and Ourselves, in Medicine
Authors: Rafael Campo
Journal: JAMA (2025)

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Social Media Posts About Medical Tests With Potential for Overdiagnosis
Authors: Brooke Nickel, Ray Moynihan, Emma Grundtvig Gram, Tessa Copp, Melody Taba, Patti Shih, Raffael Heiss, Mingyao Gao, Joshua R. Zadro
Journal: JAMA Network Open (2025)

Importance Social media is an influential source of medical information, but little is known about how posts discuss medical tests that carry potential for overdiagnosis or overuse. Objective To investigate how social media posts discuss 5 popular medical tests: full-body magnetic resonance imaging, the multicancer early detection test, and tests for antimullerian hormone, gut microbiome, and testosterone. Design, Setting, and Participants This cross-sectional study assessed posts on Instagram and TikTok between April 30, 2015, and January 23, 2024, that discussed full-body magnetic resonance imaging, the multicancer early detection test, and tests for antimullerian hormone, gut microbiome, and testosterone. Using keywords on newly created accounts, posts were searched and screened until 100 posts for each test on each platform were identified (n = 1000). Posts were excluded if they did not discuss 1 of the 5 tests or were not in English or if the account holders had fewer than 1000 followers. Main Outcomes and Measures The main outcome was information about benefits, harms, and overall tone discussed in the post. All outcomes were summarized descriptively. Logistic regression was used to assess whether the use of evidence or the account holder being a physician or having financial interests influenced how tests were discussed. Results A total of 982 posts from account holders with a combined 194 200 000 followers were analyzed. Across all tests, benefits were mentioned in 855 posts (87.1%) and harms in 144 (14.7%), with 60 (6.1%) mentioning overdiagnosis or overuse. Overall, 823 posts (83.8%) had a promotional (vs neutral or negative) tone. Evidence was explicitly used in 63 posts (6.4%), personal anecdotes were used in 333 (33.9%), 498 posts (50.7%) encouraged viewers to take action and get the test, and 668 account holders (68.0%) had financial interests. Posts from physicians were more likely to mention harms (odds ratio, 4.49; 95% CI, 2.85-7.06) and less likely to have an overall promotional tone (odds ratio, 0.53; 95% CI, 0.35-0.80). Conclusions and Relevance In this cross-sectional study of social media posts about 5 popular medical tests, most posts were misleading or failed to mention important harms, including overdiagnosis or overuse. These data demonstrate a need for stronger regulation of misleading medical information on social media.
Trends in Guideline-Concordant Care for Inflammatory Breast Cancer
Authors: Audree Tadros, Brian Diskin, Varadan Sevilimedu, Amy Xu, Perri Vingan, Jonas Nelson, Yoshiko Iwai, Monica Morrow, Oluwadamilola M. Fayanju
Journal: JAMA Network Open (2025)

Importance Inflammatory breast cancer (IBC) is an aggressive variant for which trimodality treatment (ie, neoadjuvant systemic therapy [NST] followed by modified radical mastectomy without immediate reconstruction and postmastectomy radiotherapy [PMRT]) represents guideline-concordant care (GCC) and is associated with improved overall survival (OS). However, it is unclear whether there are disparities in trimodality treatment receipt among patients with IBC and how such disparities might affect OS. Objective To assess trends in IBC trimodality treatment receipt in a contemporary cohort. Design, Setting, and Participants A retrospective cohort study was conducted using data from the National Cancer Database. Women with nonmetastatic IBC treated from calendar years 2010 to 2018 were included. Data analysis was performed from April 1, 2023, to March 1, 2024. Exposures Guideline-concordant care (ie, trimodality treatment administered in the correct sequence with time to NST initiation &amp;amp;lt;60 days post diagnosis). Main Outcomes and Measures The main outcomes were associations between patient-, disease-, treatment-, and facility-level factors and receipt of overall and modality-specific GCC and associations between these factors and adjusted OS. Results Of 6945 patients identified (median age, 57 [IQR, 47-66] years; 2.4% Asian or Pacific Islander, 7.8% Hispanic, 17.1% non-Hispanic Black, and 71.5% non-Hispanic White), only 1740 (25.1%) received all forms of GCC: 91.3% (n = 5662) received NST initiation less than 60 days post diagnosis, 63.3% (n = 4395) received PMRT, and 51.3% (n = 3564) underwent guideline-concordant surgery (ie, modified radical mastectomy without immediate reconstruction with &amp;amp;gt;6 lymph nodes removed). Receipt of GCC did not differ significantly by race and ethnicity, insurance status, or location. Asian (odds ratio [OR], 0.48; 95% CI, 0.27-0.84), Black (OR, 0.53; 95% CI, 0.41-0.68), and Hispanic (OR, 0.40; 95% CI, 0.29-0.55) patients were less likely to have NST initiation less than 60 days post diagnosis vs White patients (all P ≤ .001). Recipients of GCC had improved adjusted OS vs nonrecipients (hazard ratio [HR], 0.75; 95% CI, 0.68-0.84; P &amp;amp;lt; .001). Black patients had significantly lower adjusted OS ,compared with White recipients (HR, 1.41; 95% CI, 1.26-1.58; P &amp;amp;lt; .001). When GCC was received for triple-negative IBC, there was no racial and ethnic disparity in OS. Conclusions and Relevance In this cohort study of women with nonmetastatic IBC, there were no disparities observed in GCC receipt, but only 25.1% of patients with IBC received all forms of GCC for which they were eligible. Among those who received GCC, there was no racial disparity in survival for triple-negative IBC, suggesting opportunities to improve equity through standardization of care.