tbuckley/cabot-search huggingface dataset:
An AAV variant selected through NHP screens robustly transduces the brain and drives secreted protein expression in NHPs and mice
Authors: Luis Tecedor, Yong Hong Chen, David E. Leib, Paul T. Ranum, Megan S. Keiser, Brian C. Lewandowski, Elli M. Carrell, Elena Lysenko, Icnelia Huerta-Ocampo, Sakshi Arora, Congsheng Cheng, Xueyuan Liu, Beverly L. Davidson
Journal: Science Translational Medicine (2025)

Recent work has shown that prolonged expression of recombinant proteins after adeno-associated virus (AAV)–mediated delivery of gene therapy to long-lived, ventricle-lining ependymal cells can profoundly affect disease phenotypes in animal models of neurodegenerative diseases. Here, we performed in vivo screens of millions of peptide-modified capsid variants of AAV1, AAV2, and AAV9 parental serotypes in adult nonhuman primates (NHPs) to identify capsids with potent transduction of key brain tissues, including ependyma, after intracerebroventricular injection. Through these screens, we identified an AAV capsid, AAV-Ep + , with markedly increased potency in transducing ependymal cells and cerebral neurons in NHPs. AAV-Ep + ’s potency was conserved in three species of NHP, two mouse strains, and human neurons derived from induced pluripotent stem cells. To apply AAV-Ep + to the treatment of ceroid lipofuscinosis type 2 disease, a lysosomal storage disorder caused by loss-of-function mutations in tripeptidyl-peptidase 1 ( TPP1 ), we used the capsid to package the human TPP1 transgene (AAV-Ep + .hTPP1) and delivered the construct by intracerebroventricular injection into mice lacking TPP1 activity. AAV-Ep + provided robust and therapeutically relevant TPP1 protein concentrations in these mice, significantly improving tremor and life span. In NHPs, high cerebrospinal fluid (CSF) TPP1 concentrations were achieved after intracerebroventricular delivery of AAV-Ep + .hTPP1 at a total dose of 1 × 10 12 viral genomes, which was more than 30× lower than previously reported doses in NHPs. These results suggest that AAV-Ep + may be a potent vector for gene therapy applications where CSF protein expression is required.
An oral norovirus vaccine generates mucosal immunity and reduces viral shedding in a phase 2 placebo-controlled challenge study
Authors: Becca A. Flitter, Joshua Gillard, Susan N. Greco, Maria D. Apkarian, Nick P. D’Amato, Lam Quynh Nguyen, Elena D. Neuhaus, Darreann Carmela M. Hailey, Marcela F. Pasetti, Mallory Shriver, Christina Quigley, Robert W. Frenck, Lisa C. Lindesmith, Ralph S. Baric, Lee-Jen Wei, Sean N. Tucker, James F. Cummings
Journal: Science Translational Medicine (2025)

There are currently no licensed vaccines for norovirus, a leading cause of epidemic and endemic gastroenteritis worldwide. Clinical advancement of promising vaccine candidates from phase 2 studies to phase 3 field trials has been hampered by the lack of robust immunological correlates of protection. Here, we conducted a phase 2b randomized, placebo-controlled vaccination and challenge study to assess the safety, efficacy, immunogenicity, and correlates of protection of VXA-G1.1-NN, an oral tablet norovirus vaccine. VXA-G1.1-NN was safe and well tolerated, conferred protection against norovirus GI.1 challenge, and reduced viral shedding in stool and emesis. Norovirus VP1-specific serum immunoglobulin A (IgA), IgG, and functional blocking antibody titers increased substantially after oral vaccination. Moreover, oral immunization stimulated VP1-specific IgA antibodies in nasal lining fluid, saliva, and fecal samples. Serum and mucosal antibody responses 7 days after vaccination were correlated with the induction of antibody-secreting, α4β7 + mucosal-homing B cells. Machine learning analyses of vaccine-stimulated immune components identified serum functional blocking antibody and fecal IgA as robust correlates of protection. These results demonstrate the potential of VXA-G1.1-NN as a safe and effective oral norovirus vaccine and reveal critical immunological features underpinning vaccine efficacy.
Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory celiac disease
Authors: Mandeep Singh, Raymond H. Y. Louie, Jerome Samir, Matthew A. Field, Claire Milthorpe, Thiruni Adikari, Joseph Mackie, Ellise Roper, Megan Faulks, Katherine J. L. Jackson, Andrew Calcino, Melinda Y. Hardy, Piers Blombery, Timothy G. Amos, Ira W. Deveson, Helen Vander Wende, Stephen N. Floor, Scott A. Read, Dmitri Shek, Antoine Guerin, Cindy S. Ma, Stuart G. Tangye, Antonio Di Sabatino, Marco V. Lenti, Alessandra Pasini, Rachele Ciccocioppo, Golo Ahlenstiel, Dan Suan, Jason A. Tye-Din, Christopher C. Goodnow, Fabio Luciani
Journal: Science Translational Medicine (2025)

Intestinal inflammation continues in a subset of patients with celiac disease despite a gluten-free diet. Here, by applying multi-omic single-cell analysis to duodenal biopsies, we found that low-grade malignancies with lymphoma driver mutations in patients with refractory celiac disease type 2 (RCD2) are comprised by surface CD3-negative (sCD3 − ) lymphocytes stalled at an innate lymphoid cell (ILC)–progenitor T cell stage undergoing extensive TRA , TRB , and TRD TCR recombination. In people with refractory celiac disease type 1 (RCD1), a disease currently lacking explanation, we identified sCD3 + T cells with lymphoma driver mutations in 6 of 10 individuals with RCD1 and in one of the patients with active, recently diagnosed celiac disease. Furthermore, the mutant T cells formed large TCRαβ clones and displayed inflammatory and cytotoxic molecular profiles. Thus, accumulation of lymphoma driver–mutated T cells and sCD3 − progenitors may contribute to chronic, nonresponsive celiac disease.
Intra-amniotic antisense oligonucleotide treatment improves phenotypes in preclinical models of spinal muscular atrophy
Authors: Beltran Borges, Stephen M. Brown, Wan-Jin Chen, Maria T. Clarke, Akos Herzeg, Jae Hong Park, Joshua Ross, Lingling Kong, Madeline Denton, Amy K. Smith, Tony Lum, Fareha Moulana Zada, Marco Cordero, Nalin Gupta, Sarah E. Cook, Heather Murray, John Matson, Stephanie Klein, C. Frank Bennett, Adrian R. Krainer, Tippi C. MacKenzie, Charlotte J. Sumner
Journal: Science Translational Medicine (2025)

Neurological disorders with onset before or at birth are a leading cause of morbidity and mortality in infants and children. Prenatal treatment has the potential to reduce or prevent irreversible neuronal loss and facilitate normal neurodevelopment. We hypothesized that antisense oligonucleotides (ASOs) delivered to the amniotic fluid by intra-amniotic (IA) injection could safely distribute to the fetal central nervous system (CNS) and provide therapeutic benefit in the motor neuron disease spinal muscular atrophy (SMA), caused by mutations of the survival of motor neuron 1 gene ( SMN1 ), leading to deficiency of SMN protein. Although the splice-switching ASO nusinersen ameliorates SMA when delivered postnatally, substantial deficits can remain in severely affected infants. Here, IA injection of ASOs into two mouse models of severe SMA increased SMN expression in the CNS. In SMAΔ7 mice, which manifest pathology in utero, prenatal treatment improved motor neuron numbers, motor axon development, motor behavioral tests, and survival when compared with those in mice treated postnatally (between P1 and P3). To assess the feasibility of prenatal treatment in a large-animal model, ASOs were delivered midgestation to fetal sheep by IA or intracranial injection. ASOs delivered by IA injection distributed to the spinal cord at therapeutic concentrations and to multiple peripheral tissues without evidence of substantial toxicity to the fetus or mother. These data demonstrated that IA delivery of ASOs holds potential as a minimally invasive approach for prenatal treatment of SMA and possibly other severe, early-onset neurological disorders.
Added value of pathology consultations in cutaneous lymphomas: a 2-year review from the Dutch national referral and expertise centre
Authors: Thom Doeleman, Elise S M Beljaards, Rosanne Ottevanger, Patty Jansen, Maarten H Vermeer, Koen D Quint, Rein Willemze, Anne M R Schrader
Journal: British Journal of Dermatology (2025)

Abstract Background The accurate diagnosis of cutaneous lymphomas (CLs) and lymphoproliferative disorders presents significant challenges due to their rarity, the diversity of clinicopathological entities, and the necessity of integrating clinical, immunophenotypic, and molecular analyses with histopathology. Misdiagnosis and diagnostic delays are common, potentially leading to inappropriate treatments. The contribution of an expertise centre specifically for the pathology of CL has not been previously investigated. Objectives To evaluate the value of pathology consultations at the Dutch national referral centre for CLs focusing on diagnostic agreement and identifying common diagnostic pitfalls. Methods We retrospectively reviewed all pathology consultations concerning CLs received at the Leiden University Medical Centre during 2020 and 2021. Cases were categorized into informative and ambiguous conclusions. Diagnostic agreement between submitting and expert pathologists was assessed and categorized as essential agreement, more specific conclusion, minor disagreement, or major disagreement. Results A total of 239 consultations from 230 patients, were analysed. The submitted conclusion was categorized as informative in 64% of the consultations and as ambiguous in 36%. Most (59%) consultations in our study exhibited essential agreement with the submitting pathologist. The expert centre reduced ambiguous conclusions from 36% to 13%, primarily by resolving differential diagnostic considerations between lymphoma and pseudolymphomatous infiltrates. However, major diagnostic disagreements, with a potentially significant impact on treatment or prognosis, were found in 12% of consultations mostly involving reclassification from benign dermatoses to lymphomas. Mycosis fungoides, primary cutaneous follicle centre lymphoma, CD30-positive lymphoproliferative disorders, and pseudolymphomas were delineated as specific areas of diagnostic difficulty. Conclusions The findings indicate that a national referral and expertise centre for CL pathology contributes to ensuring accurate diagnoses and appropriate patient management. Our data encourage low-threshold consultation in an expert centre for all patients with clinical and/or histological suspicion of CL.
Risk of exacerbations, hospitalisation, and mortality in adults with physician-diagnosed chronic obstructive pulmonary disease with normal spirometry and adults with preserved ratio impaired spirometry in Sweden: retrospective analysis of data from a nationwide cohort study
Authors: Oskar Wallström, Caroline Stridsman, Helena Backman, Sigrid Vikjord, Anne Lindberg, Fredrik Nyberg, Lowie E.G.W. Vanfleteren
Journal: The Lancet Regional Health - Europe (2025)
HydroWrap for T2DM-Related Fractures: A smart H2S-delivery controller modulating Macrophage senescence
Authors: Siqi Zhang, Hannan Cui, Jing Wang, Jie Zhou, Hongli Chen, Xinli Wang, Qian Yang, Jiahao Cao, Kaili Hao, Shanshan Fu, Wuyang Zhang, Xu Wang, Xinsen Lin, Xiqing Sun, Wei Lei, Tengjiao Wang, Yafei Feng
Journal: Bioactive Materials (2025)
Molecular characterization and predictors of relapse in patients with Ph + ALL after frontline ponatinib and blinatumomab
Authors: Nicholas J Short, Hagop Kantarjian, Ken Furudate, Nitin Jain, Farhad Ravandi, Omer Karrar, Sanam Loghavi, Lewis Nasr, Fadi G Haddad, Jayastu Senapati, Rebecca Garris, Koichi Takahashi, Elias Jabbour
Journal: Journal of Hematology & Oncology (2025)

Abstract Background Several studies have suggested that chemotherapy-free regimens consisting of blinatumomab and a BCR::ABL1 tyrosine kinase inhibitor are highly effective in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). However, the clinical and molecular characteristics that predict for relapse with these chemotherapy-free regimens are largely unknown. Methods We conducted a prospective phase II clinical trial of the combination of blinatumomab and ponatinib in 76 patients with newly diagnosed Ph + ALL. Patients received 12–15 doses of intrathecal chemotherapy as central nervous systemic (CNS) prophylaxis. The patterns of relapse and the clinical and molecular predictors of relapse were analyzed. Results With a median follow-up of 29 months, the estimated 3-year event-free survival rate was 78% and the 3-year overall survival rate was 88%. Ten patients (13%) relapsed, with a median time to relapse of 18 months (range, 8–24 months). Six relapses occurred only in extramedullary sites (CNS, n = 5; peritoneum and lymph nodes, n = 1). CD19 expression remained high at relapse in all patients. On univariate analysis, factors associated with an increased risk of relapse were: white blood cell (WBC) ≥ 70 × 10 9 /L at diagnosis (sHR 8.86 [95% CI 2.33–33.70]; P = 0.001), CNS involvement at diagnosis (sHR 6.87 [95% CI 1.54–30.68]; P = 0.01), and VPREB1 deletion (sHR 4.06 [95% CI 1.05–15.76]; P = 0.04). WBC ≥ 70 × 10 9 /L was present in 22% of the cohort and was associated with a 53% cumulative incidence of relapse (CIR), as compared with a CIR rate of 6% for patients with WBC &lt; 70 × 10 9 /L. Neither IKZF1 plus genotype, BCR::ABL1 transcript type, nor measurable residual disease kinetics by next-generation sequencing for IG/TR rearrangements significantly impacted the risk of relapse. High WBC at diagnosis was the only variable significantly associated with relapse on multivariate analysis (sHR 16.29 [95% CI 2.35–113.00; P = 0.005). Conclusions WBC ≥ 70 × 10 9 /L is a high-risk feature in patients with Ph + ALL receiving frontline blinatumomab and ponatinib and may supersede the prognostic importance of baseline molecular features. Alternative frontline treatment strategies may be needed for these patients to reduce the risk of relapse and improve long-term outcomes. Trial registration ClinicalTrials.gov (NCT03263572).
Deep learning-based detection of bacterial swarm motion using a single image
Authors: Yuzhu Li, Hao Li, Weijie Chen, Keelan O’Riordan, Neha Mani, Yuxuan Qi, Tairan Liu, Sridhar Mani, Aydogan Ozcan
Journal: Gut Microbes (2025)

Motility is a fundamental characteristic of bacteria. Distinguishing between swarming and swimming, the two principal forms of bacterial movement, holds significant conceptual and clinical relevance. Conventionally, the detection of bacterial swarming involves inoculating samples on an agar surface and observing colony expansion, which is qualitative, time-intensive, and requires additional testing to rule out other motility forms. A recent methodology that differentiates swarming and swimming motility in bacteria using circular confinement offers a rapid approach to detecting swarming. However, it still heavily depends on the observer's expertise, making the process labor-intensive, costly, slow, and susceptible to inevitable human bias. To address these limitations, we developed a deep learning-based swarming classifier that rapidly and autonomously predicts swarming probability using a single blurry image. Compared with traditional video-based, manually processed approaches, our method is particularly suited for high-throughput environments and provides objective, quantitative assessments of swarming probability. The swarming classifier demonstrated in our work was trained on Enterobacter sp. SM3 and showed good performance when blindly tested on new swarming (positive) and swimming (negative) test images of SM3, achieving a sensitivity of 97.44% and a specificity of 100%. Furthermore, this classifier demonstrated robust external generalization capabilities when applied to unseen bacterial species, such as Serratia marcescens DB10 and Citrobacter koseri H6. This competitive performance indicates the potential to adapt our approach for diagnostic applications through portable devices, which would facilitate rapid, objective, on-site screening for bacterial swarming motility, potentially enhancing the early detection and treatment assessment of various diseases, including inflammatory bowel diseases (IBD) and urinary tract infections (UTI).
MYLK-AS1 Enhances Glutamine Metabolism to Promote EGFR Inhibitor Resistance in Non-Small Cell Lung Cancer
Authors: Tianyu Qu, Lei Song, Jiali Xu, Xiyi Lu, Dandan Yin, Jiali Dai, Chen Zhang, Renhua Guo, Erbao Zhang
Journal: Cancer Research (2025)

Abstract Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) limits the efficacy of molecular targeted therapy in non-small cell lung cancer (NSCLC). Metabolic reprogramming is a hallmark of lung cancer that could contribute to TKI resistance. Through systematic screening and verification, we identified a role for the long noncoding RNA (lncRNA) MYLK-AS1 supporting acquired TKI resistance in lung cancer. Elevated expression of MYLK-AS1 correlated with TKI resistance in NSCLC patient samples and cell lines. c-Myc mediated transcriptional activation of MYLK-AS1, and m6A modification promoted post transcriptional upregulation. Mechanistically, MYLK-AS1 bound and directly drove phase separation of interleukin enhancer binding factor 3 (ILF3), thus interacting with the 3’UTR of glutamate dehydrogenase 1 (GLUD1) to post-transcriptionally promote its mRNA stability. MYLK-AS1-mediated GLUD1 upregulation accelerated mitochondrial glutamine catabolism, promoting TKI resistance. Inhibition of GLUD1 with the small-molecule inhibitor R162 in TKI resistant models suppressed cell proliferation in vitro and tumor growth in vivo. Moreover, knockdown of MYLK-AS1 also enhanced drug sensitivity in TKI resistant patient-derived xenograft models, suggesting its therapeutic potential. Collectively, these findings offer insights into the regulation of TKI resistance from the perspective of phase separation and metabolism and highlight targeting the MYLK-AS1/ILF3/GLUD1 axis as a potential strategy for improving the efficacy of EGFR TKIs in NSCLC.
Detection of Early-Stage Colorectal Cancer Using Cell-Free oncRNA Biomarkers and Artificial Intelligence
Authors: Amir Momen-Roknabadi, Mehran Karimzadeh, Nae-Chyun Chen, Taylor B. Cavazos, Jieyang Wang, Jeremy Ku, Alex Degtiar, Akshaya Krishnan, Martha Hernandez, Magdalena Gebala, Alice Huang, Selina Chen, Dang Nguyen, Ti Lam, Rose Hanna, Lisa Fish, Alexx J. Smith, Sukh Sekhon, Jennifer Yen, Jeff Gregg, Helen Li, Fereydoun Hormozdiari, Babak Behsaz, Anna Hartwig, Hani Goodarzi, Lee Schwartzberg, Babak Alipanahi
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, and early detection significantly improves treatment outcomes, but existing blood-based tests often have limited sensitivity in early-stage disease. We developed a blood-based test combining oncRNAs, a group of small cell-free RNAs (cfRNAs), with generative AI to detect CRC. Experimental Design: We leveraged a cohort of 613 CRC cases and controls to train a model that demonstrated both high clinical performance as well as minimal technical variability in robustness testing. We further validated our model in an independent, single-source cohort of 192 CRC cases and controls. Model performance was assessed by sensitivity, specificity, and area under the ROC curve (AUROC), with attention to early-stage detection. Results: In our independent validation set, we achieved an overall sensitivity of 89% at 90% specificity, with an 80% sensitivity for stage I—an important milestone, as early-stage CRC detection remains a challenge for other blood-based technologies. Performance was consistent across demographic subgroups. Conclusions: Our oncRNA-based blood test, powered by AI, offers strong performance for early CRC detection, including in stage I disease where existing blood-based assays are limited. These findings support further development toward a minimally invasive CRC screening tool.
Outcomes of Allogeneic Hematopoietic Stem Cell Transplant in Monogenic Inflammatory Bowel Disease
Authors: Alyssa Baccarella, Trusha Patel, Maire A Conrad, Marina Macchi, Brooke Boyer, Oliver Pickering, Yelizaveta Borodyanskaya MPh, Shreya Gaddipati, Maya Cohen, Andrea Cubero, Noor Dawany, Jennifer Heimall, Nancy Bunin, Kathleen E Sullivan, None Judith R Kelsen
Journal: Clinical Gastroenterology and Hepatology (2025)
Simplifying Diagnosis of Bile Acid Diarrhea with Clinical and Biochemical Measurements on Blood and Single Stool Sample
Authors: Saam Dilmaghani, Camille Lupianez-Merly, Joelle BouSaba, Priya Vijayvargiya, Irene Busciglio, Monique Ferber, Paula Carlson, Leslie J Donato, Michael Camilleri
Journal: Clinical Gastroenterology and Hepatology (2025)
Tobacco Smoking Rewires Cell Metabolism by Inducing GAPDH Succinylation to Promote Lung Cancer Progression
Authors: Kun Wang, Jingzhuo Li, Hai Zhang, Hongyan Ma, Hong-Yong Cui, Huai-Qiang Ju, Jing Zhang, Qing-zhi Ma, Ming Zhao, Qing-mei Zeng, Jie Zou, Xiu-Xuan Sun, Gang Nan, Meirui Qian, Lin Jing, Yiming Li, Cai-feng Xiong, Qiu-zi Yang, Hao Wang, Jian-Li Jiang, Zhi-Nan Chen, Liang Chen, Wan Huang
Journal: Cancer Research (2025)

Abstract Patient behavior and physiology can directly affect cancer metabolism. Smoking is the leading risk factor for non-small cell lung cancer (NSCLC). Here, we identified that smoking modulates lung cancer cell metabolism through altered protein post-translational modification. Proteomic analyses identified elevated K251 succinylation (K251-Su) of GAPDH, a key enzyme in glycolysis, in NSCLC samples, and GAPDH K251-Su was significantly higher in patients who smoke compared to non-smokers. Exposure of lung cancer cells to cigarette smoke extract led to increased uptake of glutamine and enhanced GAPDH K251-Su. Glutamine uptake by cancer cells in hypoxic and nutrient-deficient microenvironments provided succinyl-CoA donors for GAPDH succinylation at K251, which was catalyzed by acyltransferase p300. K251-Su increased GAPDH stability by suppressing TRIM4-mediated K254 ubiquitination. GAPDH K251-Su enhanced glycolysis and glutamine reductive carboxylation to meet the demands for cell growth and to support survival in hypoxic and nutrient-depleted conditions, promoting tumor growth and metastasis. These findings indicate that tobacco smoking mediates metabolic reprogramming of cancer cells through succinylation of GAPDH to drive NSCLC progression.