tbuckley/cabot-search huggingface dataset:
Identification of digital twins to guide interpretable AI for diagnosis and prognosis in heart failure
Authors: Feng Gu, Andrew J. Meyer, Filip Ježek, Shuangdi Zhang, Tonimarie Catalan, Alexandria Miller, Noah A. Schenk, Victoria E. Sturgess, Domingo Uceda, Rui Li, Emily Wittrup, Xinwei Hua, Brian E. Carlson, Yi-Da Tang, Farhan Raza, Kayvan Najarian, Scott L. Hummel, Daniel A. Beard
Journal: npj Digital Medicine (2025)

Heart failure (HF) is a highly heterogeneous condition, and current methods struggle to synthesize extensive clinical data for personalized care. Using data from 343 HF patients, we developed mechanistic computational models of the cardiovascular system to create digital twins. These twins, consisting of optimized measurable and unmeasurable parameters alongside simulations of cardiovascular function, provided comprehensive representations of individual disease states. Unsupervised machine learning applied to digital twin-derived features identified interpretable phenogroups and mechanistic drivers of cardiovascular death risk. Incorporating these features into prognostic AI models improved performance, transferability, and interpretability compared to models using only clinical variables. This framework demonstrates potential to enhance prognosis and guide therapy, paving the way for more precise, individualized HF management.
Donor selection in T-cell-replete haploidentical donor peripheral blood stem cell transplantation
Authors: Fumiya Wada, Makoto Iwasaki, Masahiro Hirayama, Koji Kawamura, Katsuji Kaida, Noriko Doki, Hirohisa Nakamae, Yuta Hasegawa, Takahiro Fukuda, Tetsuya Eto, Nobuhiro Hiramoto, Yumiko Maruyama, Koji Nagafuji, Shuichi Ota, Jun Ishikawa, Toshihiko Ando, Tatsuo Ichinohe, Yoshiko Atsuta, Hideki Nakasone, Junya Kanda
Journal: Leukemia (2025)
Differential expression of the MYC‐Notch axis drives divergent responses to the front‐line therapy in central and peripheral extensive‐stage small‐cell lung cancer
Authors: Libo Luo, Rui Xia, Shiqi Mao, Qian Liu, He Du, Tao Jiang, Shuo Yang, Yan Wang, Wei Li, Fei Zhou, Jia Yu, Guanghui Gao, Xuefei Li, Chao Zhao, Lei Cheng, Jingyun Shi, Xiaoxia Chen, Caicun Zhou, Luonan Chen, Shengxiang Ren, Fengying Wu
Journal: MedComm (2025)

Abstract Central and peripheral extensive‐stage small‐cell lung cancer (ES‐SCLC) are reported to be two distinct tumor entities, but their responses to the front‐line therapies and underlying biological mechanisms remain elusive. In this study, we first compared the outcomes of central and peripheral ES‐SCLC receiving front‐line chemotherapy or chemo‐immunotherapy with a cohort of 265 patients. Then we performed single‐cell RNA sequencing (scRNA‐seq) on nine treatment‐naïve ES‐SCLC samples to investigate potential mechanisms underlying the response differences. Under chemotherapy, the peripheral type had a lower objective response rate (44.8% vs. 71.2%, p = 0.008) and shorter progression‐free survival (median 3.4 vs. 5.1 months, p = 0.001) than the central type. When comparing chemo‐immunotherapy with chemotherapy, the peripheral type showed a greater potential to reduce progression (HR, 0.18 and 0.52, respectively) and death (HR, 0.44 and 0.91 respectively) risks than the central type. Concerning the scRNA‐seq data, the peripheral type was associated with chemo‐resistant and immune‐responsive tumoral and microenvironmental features, including a higher expression level of MYC‐Notch‐non‐neuroendocrine (MYC‐Notch‐non‐NE) axis and a more potent antigen presentation and immune activation status. Our results revealed that central and peripheral ES‐SCLC had distinct responses to front‐line treatments, potentially due to differential activation statuses of the MYC‐Notch‐non‐NE axis.
Noncanonical feedback loop between “RIP3–MLKL” and “4EBP1–eIF4E” promotes neuronal necroptosis
Authors: Shuchao Wang, Yun Zhang, Meijuan Wang, Zhihao Zhai, Yating Tan, Weiye Xu, Xiaozhen Ren, Ximin Hu, Jinyou Mo, Jia Liu, Yunfeng Yang, Dan Chen, Bing Jiang, Hualin Huang, Jufang Huang, Kun Xiong
Journal: MedComm (2025)

Stroke is a leading risk factor for disability and death. Necroptosis is involved in stroke pathogenesis. However, the molecular mechanisms underlying necroptosis in stroke remain unclear. The mammalian target of rapamycin complex 1 (mTORC1) modulates necroptosis in the gut epithelium. Eukaryotic translation initiation factor 4E (eIF4E)-binding protein-1 (4EPB1) is one of the main downstream molecules of mTORC1. This study addresses the role of the 4EBP1-eIF4E pathway in necroptosis. The 4EBP1-eIF4E pathway was found to be activated in both necroptotic HT-22 and mouse middle cerebral artery occlusion (MCAO) models. Functionally, 4EBP1 overexpression, eIF4E knockdown, and eIF4E inhibition suppressed necroptosis, respectively. Furthermore, a positive feedback circuit was observed between the 4EBP1-eIF4E and receptor-interacting protein-3 (RIP3)-mixed lineage kinase domain-like protein (MLKL) pathways, in which RIP3-MLKL activates the 4EBP1-eIF4E pathway by degrading 4EBP1 and activating eIF4E. This in turn enhanced RIP3-MLKL pathway activation. The eIF4E activation derived from this loop may stimulate cytokine production, which is a key factor associated with necroptosis. Finally, using a mouse MCAO model, the application of eIF4E, RIP3, and MLKL inhibitors was found to have a regulatory mechanism similar to that in the in vitro study, reducing the infarct volume and improving neurological function in MCAO mice.
TDP‐43/ALKBH5‐mediated m<sup>6</sup>A modification of CDC25A mRNA promotes glioblastoma growth by facilitating G1/S cell cycle transition
Authors: Yunxiao Zhang, Sidi Xie, Weizhao Li, Junwei Gu, Xi‐an Zhang, Bowen Ni, Ziyu Wang, Runwei Yang, Haimin Song, Yaxuan Zhong, Peiting Huang, Jinyao Zhou, Yongfu Cao, Jing Guo, Yawei Liu, Songtao Qi, Hai Wang
Journal: MedComm (2025)

Abstract Glioblastoma (GBM) exhibits significant intratumor heterogeneity (ITH), indicating the presence of tumor cells with diverse growth rates. Here, we aimed to identify fast‐growing cells in GBM and elucidate the underlying mechanisms. Precisely targeting these cells could offer an improved treatment option. Our results found that targeting ALKBH5 expression impaired GBM proliferation and tumor stemness. Nuclear but not overall expression of ALKBH5 differs between monoclonal cells derived from the same patient with different proliferation rates. Mechanistically, ALKBH5 interacted with TAR DNA‐binding protein 43 (TDP‐43) in fast‐growing cells. Furthermore, TDP‐43 facilitated the nuclear localization of ALKBH5 and its binding to cell division cycle 25A (CDC25A) pre‐mRNA. The TDP‐43/ALKBH5 complex regulates CDC25A mRNA splicing via N6‐methyladenosine (m 6 A) demethylation to maintain the expression of its oncogenic isoform (CDC25A‐1), ultimately promoting the G1/S phase transition and growth of GBM cells. TRAD01 selectively targeted the interaction between TDP‐43 and ALKBH5, leading to significant antitumor effects both in vitro and in vivo. Our study identified a novel epigenetic mechanism by which TDP‐43/ALKBH5 contributes to GBM growth via m 6 A modification and alternative splicing. Therefore, targeting the TDP‐43/ALKBH5 axis might be a promising therapeutic strategy for GBM patients.
Pan-cancer analysis of oncogenic MET fusions reveals distinct pathogenomic subsets with differential sensitivity to MET-targeted therapy
Authors: Christopher A. Febres-Aldana, Morana Vojnic, Igor Odintsov, Tom Zhang, Ryan Cheng, Catherine Z. Beach, Daniel Lu, Marissa S. Mattar, Andrea M. Gazzo, Leo Gili, Manju Harshan, Ali Ameri, Stephen Machnicki, Xiuying Xiao, William W. Lockwood, Xiao-yan Zhou, Qianlan Yao, Alexander Drilon, Natasha Rekhtman, Nameeta Shah, Anqi Li, Zebing Liu, Soo-Ryum Yang, Monika A. Davare, Marc Ladanyi, Romel Somwar
Journal: Cancer Discovery (2025)

Abstract MET fusions (MET-Fs) are oncogenic drivers that remain poorly characterized. Analysis of 56 MET-F-positive tumors from an institutional cohort of 91,119 patients (79,864 DNA-seq plus 11,255 RNA-seq) uncovered two forms of MET-F pathobiology. The first group featured 5’ partners with homodimerization domains fused in-frame with MET-tyrosine kinase domain (TKD), primarily originated from translocations, frequently excluded MET exon 14, mediated oncogenesis through cytoplasmic aggregation and constitutive activation, and were markedly sensitive to MET tyrosine kinase inhibitors (TKI) in pre-clinical models and patients with lung cancer. The second group lacked partner homodimerization motifs and retained MET transmembrane and extracellular domains. Their pathogenesis involved intrachromosomal rearrangements, resulting in partner selection for promoter hijacking and fusion allele amplification. Membrane-bound fusions were enriched in gliomas with RTK co-alterations. We provide a framework to comprehend the heterogeneous landscape of MET-Fs, supporting that fusion oncogenicity and MET-TKI sensitivity are determined by structural topology and pathogenomic context.
COSMIC-021 Phase Ib Study of Cabozantinib Plus Atezolizumab: Results from the Locally Advanced or Metastatic Urothelial Carcinoma Cohorts
Authors: Sumanta K. Pal, Yohann Loriot, Andrea Necchi, Parminder Singh, Daniel Castellano, Lance Pagliaro, Cristina Suarez, Bradley A. McGregor, Ulka N. Vaishampayan, Ralph J. Hauke, Thomas Powles, Carla M.L. Van Herpen, Kevin D. Courtney, Robert Dreicer, Ramu Sudhagoni, Martin Schwickart, Svetlana Andrianova, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2025)

PURPOSE The COSMIC-021 study assessed the safety and efficacy of cabozantinib plus atezolizumab in advanced solid tumors. Presented here are results from the expansion cohorts with advanced urothelial carcinoma (UC). METHODS This phase Ib study (ClinicalTrials.gov identifier: NCT03170960 ) enrolled patients with inoperable locally advanced/metastatic UC into four tumor cohorts: first-line cisplatin-eligible (cis-eligible), first-line cisplatin-ineligible (cis-ineligible), previous platinum-containing chemotherapy (previous chemotherapy-treated), and previous immune checkpoint inhibitor (ICI)–treated. Patients received oral cabozantinib 40 mg once daily and intravenous atezolizumab 1,200 mg once every 3 weeks. The primary end point was objective response rate (ORR), as assessed by the investigator per RECIST v1.1 every 6 weeks for 12 months and every 12 weeks thereafter; the secondary end point was safety. RESULTS A total of 121 patients (previous ICI-treated cohort, n = 31, and each of the other cohorts, n = 30) received study treatment from March 2018 to November 2021. The ORR (95% CI) was 30% (15 to 49) for cis-eligible, 20% (8 to 39) for cis-ineligible, 27% (12 to 46) for previous chemotherapy-treated, and 10% (2 to 26) for previous ICI-treated cohorts. The median progression-free survival (95% CI) was 5.5 (1.6 to 11.6), 5.6 (3.1 to 11.1), 5.4 (1.6 to 7.6), and 3.0 (1.8 to 5.5) months, respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) were experienced by 43%, 67%, 57%, and 45% of patients, respectively. TRAEs led to discontinuation of all treatment components in 17%, 13%, 3%, and 19%, respectively. No grade 5 TRAEs were reported in any cohort. CONCLUSION The novel combination of cabozantinib plus atezolizumab exhibited clinical activity in advanced UC that is cis-eligible, cis-ineligible, or previously treated with platinum-containing chemotherapy; clinical activity in previous ICI-treated UC was modest. The toxicity profile was consistent with that previously reported for the combination.
Chromosomal instability in tumor suppressor genes–altered prostate cancer.
Authors: Marta Garcia de Herreros, Natalia Jiménez, Joan Padrosa, Òscar Reig, Laia Fernandez-Mañas, Laura Ferrer-Mileo, Samuel García-Esteve, Albert Font Pous, Vicente Ruiz de Porras, Begoña Mellado
Journal: Journal of Clinical Oncology (2025)

226 Background: Metastatic prostate cancer (PC) accumulates significant genomic alterations as the disease progresses, exhibiting the highest levels of chromosomal instability (CIN) among all metastatic tumors (Bakhoum, Nature 2018). Furthermore, tumor suppressor genes (TSG; RB1 , PTEN and TP53 ) are frequently altered in metastatic PC and are associated with adverse outcomes. Here, we aim to investigate CIN in metastatic hormone-sensitive PC (mHSPC) harbouring alterations in TSG. Methods: TSG and whole transcriptome gene expression was assessed by nCounter platform (N=354) and RNA-seq (N=60) in mHPSC samples, respectively. TSG low was considered when ≥2 out of 3 TSG presented low expression of a previously stablished cut-off, and TSG wt in the remaining cases. Differential gene expression analysis between TSG low vs TSG wt tumors of our RNA-seq cohort (N=60) and TCGA cohort (N=333) was performed. Differential expressed genes (DEGs) were considered if FDR &lt;0.05 and log2FoldChange (LFC)&gt;0.5. DEGs were correlated with castration-resistance PC-free survival (CRPC-FS) and overall survival (OS) by Cox analysis. CIN gene signatures were obtained from literature and the rest of Hallmark signatures from MSigDB. Results: In our cohort of mHSPC patients treated with androgen deprivation therapy + docetaxel, TSG low tumors (16.7%) displayed higher levels of CIN compared with TSG wt (CIN25 normalized enrichment score [NES] 2.13, p&lt;0.001 and CIN70 NES 2.54, p&lt;0001). Cell cycle and DNA-repair signatures were also overexpressed in TSG low tumors, contrasting with a low expression of androgen receptor pathway. Results were validated in the TCGA cohort, where TSG low presented also overexpression of CIN signatures. In our RNA-seq cohort, we found 22 DEGs associated with CIN (29.3% of the total DEGs) in TSG low tumors compared with TSG wt . 51 genes were significantly correlated with CRPC-FS in a multivariate analysis and 16 of them (31,3%) were CIN-associated genes. Among these genes, 5 encode proteins that are targetable for metastatic PC, with specific inhibitors already developed: BUB1 (LFC 1.06, FDR 0.034), CDC7 (LFC 12.4 FDR 0.003), KIFC1 , (LFC 11,7, FDR 0.01), PLK1 (LFC 1.08, FDR &lt;0.001) and WEE1 (LFC 0.79, FDR 0.011). Conclusions: TSG-altered mHSPC tumors harbor high levels of CIN, and differentially expressed CIN-associated genes could potentially be targets in mHSPC.
Early identification of weight loss trajectories in advanced cancer and associations with survival
Authors: Sophia Fuller, Stacey Alexeeff, Bette Caan, Marcus Dasilva Goncalves, Richard F Dunne, Tobias Janowitz, Mariam Jamal-Hanjani, Tilak K Sundaresan, Elizabeth M Cespedes Feliciano
Journal: JNCI Journal of the National Cancer Institute (2025)

Consensus criteria to diagnose unintentional weight loss, a condition often termed cachexia that affects most patients with advanced cancer, are based on 6-month changes by which time intervention is often ineffective. Leveraging the large and diverse population in Kaiser Permanente Northern California's community oncology practice, we studied 8,338 patients with advanced lung, pancreatic, or colorectal cancers. We calculated weekly weight change measurements from 2-months pre- to 6-months post-diagnosis to identify 4 weight change trajectories (Gain, Stable, Moderate Loss, and Severe Loss) and associated these trajectories with survival. With high agreement, we classified patients into these trajectories after 3 months and found them to be prognostic; those classified in Moderate (HR = 1.55; 95%CI: 1.45-1.67) or Severe Loss (HR = 2.20; 95%CI: 2.01-2.41) at 3 months had significantly increased risk of death compared to the Stable trajectory. Weight loss at 3 months post-diagnosis can accurately classify deleterious weight trajectories, allowing for earlier clinical intervention.
Biomarkers of radioresistance in head and neck cancer: a new beginning
Authors: Yuan James. Rao
Journal: Clinical Cancer Research (2025)

The development of biomarkers of radioresistance in head and neck cancer may help personalize treatment. This commentary puts in context the findings of a secondary analysis of NRG/RTOG 9512, a trial of fractionation in T2N0 glottic cancer, which observed that NFE2L2/KEAP1/CUL3 mutations are correlated with local recurrence and disease-free survival.
Sustained release of a novel non-fibrate PPARα agonist from microparticles for neuroprotection in murine models of age-related macular degeneration
Authors: Yi Cui, Sagun Poudel, Nuo Xu, Kelu Zhou, Rui Cheng, Wentao Liang, Tian Yuan, Long Zhao, Chaolong Qin, Katelyn G Stevens, Adam S Duerfeldt, Jianzhang Hu, Qingguo Xu, Jian-Xing Ma
Journal: Journal of Controlled Release (2025)
PRO-XL: A phase II study of zanzalintinib (XL092) in patients with metastatic castration-resistant prostate cancer (mCRPC) after progression on lutetium-177 (177Lu)-PSMA-617.
Authors: Umang Swami, Kenneth M Boucher, Yeonjung Jo, Colin Moynier, Susan Clement, Tenzin Kunsang Phunrab, Julia Batten, Joshua Quertinmont, Jon Mahlow, Vinay Mathew Thomas, Sumati Gupta, Manish Kohli, Benjamin L. Maughan, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2025)

TPS285 Background: 177Lu-PSMA-617 has been approved for patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy after demonstrating improvement in overall survival (OS) in the phase III VISION trial (PMID: 34161051). However, the tumor eventually develops resistance to 177Lu-PSMA-617 and progresses, and therefore, therapies are needed to treat 177Lu-PSMA-617 refractory mCRPC. Prior studies have demonstrated a significant VEGF expression in LNCaP tumors and locally recurrent prostate cancer after radiotherapy. Also, tumor recurrence largely depends on new vessel formation through angiogenesis when radiation inhibits angiogenesis. Zanzalintinib is a novel, potent, orally bioavailable small molecule multi-targeted inhibitor of kinases, including the receptor tyrosine kinases (RTKs), VEGFR2, MET, and TAM kinases AXL, and MER, which have been shown to be overexpressed in radiation-resistant tumors. Therefore, zanzalintinib is expected not only to inhibit tumor angiogenesis but also to mitigate resistance to antiangiogenic therapy over time. We initiated a phase 2 trial of zanzalintinib in pts with mCRPC after progression on 177Lu-PSMA-617. Methods: This IRB-approved, investigator-initiated, single-arm, single-center, non-randomized, open-label study will enroll 30 patients. Zanzalintinib will be administered orally at 100 mg once daily. Eligibility criteria: ≥ 18 years of age, mCRPC with histologically/cytologically confirmed adenocarcinoma without small cell histology, progression on or after prior treatment with 177Lu-PSMA-617, ECOG performance status ≤ 2, and adequate organ function. Any number of prior therapies will be allowed. Primary Endpoint: Proportion of participants with non-progressive disease at 16 weeks of treatment with zanzalintinib as assessed by Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1. Thirty patients will ensure that the disease control rate can be estimated via a 95% confidence interval with a margin of error &lt;0.20. Secondary Endpoints: safety, tolerability, PSA 50% response rate, and OS. Tissue and blood samples will be collected for correlative studies. Clinical trial information: NCT06568562 .
Targeting the soluble epoxide hydrolase (sEH) enzyme to relieve painful docetaxel-induced peripheral neuropathy.
Authors: Nicholas Mitsiades, Karen M Wagner, Jun Yang, Bruce D. Hammock
Journal: Journal of Clinical Oncology (2025)

126 Background: Docetaxel is an important chemotherapeutic agent used for the treatment of several cancers, including metastatic prostate cancer. Unfortunately, it shares the side effect profile of other taxanes, including causing painful chemotherapy-induced peripheral neuropathy (CIPN). The pain of CIPN is notoriously difficult to treat, can lead to discontinuation of life-prolonging cancer treatments and can become a debilitating, chronic condition. Notably, African American (AA) cancer patients have increased (2-3-fold) risk and increased severity of CIPN. The enzyme soluble epoxide hydrolase (sEH) functions as a master regulator of inflammation, by converting epoxy fatty acids (EpFAs), which are polyunsaturated fatty acid (PUFA) derivatives with inflammation-resolving, analgesic and anti-cancer properties, into corresponding inactive or pro-inflammatory diols. As sEH inhibition has demonstrated efficacy in several models of neuropathy, here we assessed its potential to relieve and/or prevent docetaxel-induced CIPN specifically. Methods: We established a model of docetaxel-induced painful neuropathy in male Sprague Dawley rats, by administering 3 doses of docetaxel (10 mg/kg intraperitoneally, once weekly, for 3 doses). We tested the efficacy of the small molecule sEH inhibitor EC5026 (EicOsis, Inc, Davis, CA) both (1) as a single dose administered via oral gavage and (2) via chronic administration (1 mg/kg/day) in the drinking water started 1 week prior to and continuing during the period of docetaxel treatments. To examine the analgesic efficacy of EC5026, the rats were assessed for responses in nociceptive (von Frey assay and cold plate assay) and functional (open field test) behavior assays. Tail vein blood was sampled, and the blood concentration of docetaxel (measured by mass spectrometry) was compared between vehicle-treated and EC5026-treated cohorts. Results: Oral dosing of the sEH inhibitor EC5026 dose-dependently relieved docetaxel-induced painful neuropathy. Additionally, chronic treatment with EC5026 via the drinking water blocked both tactile allodynia and cold sensitivity compared to vehicle-treated rats. The open field assay revealed that EC5026 has no negative effect on motor skills. Moreover, EC5026 did not affect the blood levels of docetaxel in rats. Conclusions: sEH is a novel target for achieving pain relief in our CIPN model. Our results indicate robust response to therapeutic treatment of the CIPN model and additionally improved outcomes with prophylactic administration of the sEH inhibitor EC5026 in docetaxel-induced painful CIPN, without effect of EC5026 on animal motor skills or docetaxel pharmacokinetics.