tbuckley/cabot-search huggingface dataset:
TRIM15 drives chondrocyte senescence and osteoarthritis progression
Authors: Zhuang Li, Weituo Zhang, Xiao ying Wei, Jun zheng Hu, Xinyue Hu, Haoyang Liu, Jun Lu, Shuying Shen, Ming-liang Ji
Journal: Science Translational Medicine (2025)

Osteoarthritis (OA) is a prevalent joint disease characterized by pain, disability, and loss of physical function, posing a challenge to public health. However, molecular mechanisms of OA pathogenesis have not been fully described. We report that tripartite motif containing 15 (TRIM15) is a regulator in chondrocyte senescence and OA. Our study revealed heightened expression of TRIM15 in chondrocytes of senescent cartilage from patients with OA and in aged wild-type mice. Using gain- and loss-of-function studies, we found that TRIM15 facilitated human chondrocyte senescence. Conditional deletion of Trim15 in mouse chondrocytes severely impaired skeletal growth, partially because of impaired embryonic chondrocyte senescence. Compared with conditionally knocked out Col2a1-CreER T2 /Trim15 flox/flox mice, Trim15 flox/flox control mice exhibited accelerated OA phenotypes, increased senescence markers, and senescence-associated secretory phenotype during aging. Mechanistically, TRIM15 bound with yes-associated protein (YAP) and mediated K48-linked YAP ubiquitination at K254, which interrupted the interaction between YAP and angiomotin, leading to enhanced YAP nuclear translocation. Dysregulation of TRIM15-YAP and transcriptional coactivator with PDZ-binding motif (TAZ) signaling promoted OA progression in both the surgery-induced and natural aging–induced mouse OA model. Intra-articular injection of adeno-associated virus 5 (AAV5)– Trim15 shRNA decelerated OA progression in mice. In particular, YAP and TAZ protein amounts were increased in chondrocytes of patients with OA. Our preclinical results demonstrated that the AAV5- TRIM15 shRNA treatment protected human OA explants against degeneration through inhibiting chondrocyte senescence. Together, our findings underscore the potential of targeting TRIM15 in reshaping the aging cartilage microenvironment and suggest a promising therapeutic avenue for OA.
CAR T cells based on fully human T cell receptor–mimetic antibodies exhibit potent antitumor activity in vivo
Authors: Robert Salzler, David J. DiLillo, Kei Saotome, Kevin Bray, Katja Mohrs, Haun Hwang, Kamil J. Cygan, Darshit Shah, Anna Rye-Weller, Kunal Kundu, Ashok Badithe, Xiaoqin Zhang, Elena Garnova, Marcela Torres, Ankur Dhanik, Robert Babb, Frank J. Delfino, Courtney Thwaites, Drew Dudgeon, Michael J. Moore, Thomas Craig Meagher, Corinne E. Decker, Tomasz Owczarek, John A. Gleason, Xiaoran Yang, David Suh, Wen-Yi Lee, Richard Welsh, Douglas MacDonald, Johanna Hansen, Chunguang Guo, Jessica R. Kirshner, Gavin Thurston, Tammy Huang, Matthew C. Franklin, George D. Yancopoulos, John C. Lin, Lynn E. Macdonald, Andrew J. Murphy, Gang Chen, Olav Olsen, William C. Olson
Journal: Science Translational Medicine (2025)

Monoclonal antibody therapies have transformed the lives of patients across a diverse range of diseases. However, antibodies can usually only access extracellular proteins, including the extracellular portions of membrane proteins that are expressed on the cell surface. In contrast, T cell receptors (TCRs) survey the entire cellular proteome when processed and presented as peptides in association with human leukocyte antigen (pHLA complexes). Antibodies that mimic TCRs by recognizing pHLA complexes have the potential to extend the reach of antibodies to this larger pool of targets and provide increased binding affinity and specificity. A major challenge in developing TCR mimetic (TCRm) antibodies is the limited sequence differences between the target pHLA complex relative to the large global repertoire of pHLA complexes. Here, we provide a comprehensive strategy for generating fully human TCRm antibodies across multiple HLA alleles, beginning with pHLA target discovery and validation and culminating in the engineering of TCRm-based chimeric antigen receptor T cells with potent antitumor activity. By incorporating mass spectrometry, bioinformatic predictions, HLA-humanized mice, antibody screening, and cryo–electron microscopy, we have established a pipeline to identify additional pHLA complex–specific antibodies with therapeutic potential.
<i>Anopheles</i> mosquito survival and pharmacokinetic modeling show the mosquitocidal activity of nitisinone
Authors: Lee R. Haines, Anna Trett, Clair Rose, Natalia García, Marcos Sterkel, Dagmara McGuinness, Clément Regnault, Michael P. Barrett, Didier Leroy, Jeremy N. Burrows, Giancarlo Biagini, Lakshminarayan R. Ranganath, Ghaith Aljayyoussi, Álvaro Acosta-Serrano
Journal: Science Translational Medicine (2025)

One approach to interrupting the transmission of insect-borne diseases that is successfully used in veterinary medicine is exploiting the ability of antiparasitic drugs to make vertebrate blood toxic for blood-feeding insects. Recent studies have identified 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme of the tyrosine detoxification pathway, as essential for hematophagous arthropods to digest their blood meals. Such blood-feeding insects include anopheline mosquitoes, which transmit malaria-causing Plasmodium parasites. A US Food and Drug Administration–approved HPPD enzyme inhibitor called nitisinone is a drug used to treat rare human-inherited disorders of the tyrosine pathway. Here, we demonstrate that feeding human blood containing nitisinone to insectary-reared female Anopheles gambiae mosquitoes was mosquitocidal to both young and old mosquitoes as well as insecticide-resistant Anopheles strains. Pharmacokinetic-pharmacodynamic (PK/PD) modeling of nitisinone’s dose-response relationship (when administered at the highest recommended doses for adults and children) demonstrated improved efficacy against mosquitoes compared with the gold standard endectocidal drug, ivermectin. Furthermore, blood samples from individuals with alkaptonuria (a rare genetic metabolic disorder in the tyrosine degradation pathway), who were taking a daily low dose of 2 milligrams of nitisinone, were shown to be lethal to mosquitoes. Thus, inhibiting the Anopheles HPPD enzyme with nitisinone warrants further investigation as a complementary intervention for vector control and the prevention of malaria transmission.
Implementation of standard of care CAR-T-cell treatment for patients with aggressive B-cell lymphoma and acute lymphoblastic leukemia in Sweden
Authors: Mats Jerkeman, Karin Mellgren, Kristina Sonnevi, Mikael Lisak, Ingemar Lagerlöf, Balazs Kapas, Hanna Sjölund, Jacek Toporski, Hans Hagberg, Stephan Mielke, Gunilla Enblad
Journal: Leukemia (2025)
Identification and characterization of human retinal stem cells capable of retinal regeneration
Authors: Hui Liu, Yunlong Ma, Na Gao, Yijun Zhou, Gen Li, Qunyan Zhu, Xiaoyu Liu, Shasha Li, Chunyu Deng, Cheng Chen, Yuhe Yang, Qing Ren, Huijuan Hu, Yaoyao Cai, Ming Chen, Yuanchao Xue, Kang Zhang, Jia Qu, Jianzhong Su
Journal: Science Translational Medicine (2025)

Human retinal stem cells hold great promise in regenerative medicine, yet their existence and characteristics remain elusive. Here, we performed single-cell multiomics and spatial transcriptomics of human fetal retinas and uncovered a cell subpopulation, human neural retinal stem-like cells (hNRSCs), distinct from retinal pigment epithelium stem-like cells and traditional retinal progenitor cells. We found that these hNRSCs reside in the peripheral retina in the ciliary marginal zone, exhibiting substantial self-renewal and differentiation potential. We conducted single-cell and spatial transcriptomic analyses of human retinal organoids (hROs) and revealed that hROs contain a population of hNRSCs with similar transcriptional profiles and developmental trajectories to hNRSCs in the fetal retina potentially capable of regenerating all retinal cells. Furthermore, we identified crucial transcription factors, such as MECOM , governing hNRSC commitment to neural retinogenesis and regulating repair processes in hROs. hRO-derived hNRSCs transplanted into the rd10 mouse model of retinitis pigmentosa differentiated and were integrated into the retina, alleviated retinal degeneration, and improved visual function. Overall, our work identifies and characterizes a distinct category of retinal stem cells from human retinas, underscoring their regenerative potential and promise for transplantation therapy.
The Liver Transplant Comorbidity Index (LTCI) : A composite index of ambulatory Pre-LT factors to identify patients at increased risk of Post-LT Mortality
Authors: Jennifer C Lai, Amy M Shui, Michele Molinari, Robert Rahimi, Daniela Ladner, Daniel Ganger, Matthew Kappus, Elizabeth King, Amit Tevar, Michael Volk, Andres Duarte-Rojo, Elizabeth C Verna
Journal: Hepatology (2025)

Background: Frailty is strongly associated with mortality after liver transplantation. However, national guidelines discourage its use as a sole reason to decline a patient for liver transplantation, as some frail patients have acceptable outcomes. We aimed to develop a composite index, the Liver Transplant Comorbidity Index (LTCI), integrating frailty and other comorbidities, as a risk factor for longer-term (3-year) post-transplant mortality. Methods: This 8-center prospective Functional Assessment in Liver Transplantation (FrAILT) Study included adult recipients of a primary deceased donor liver transplant from 2012-2022. Frailty was measured using the Liver Frailty Index (LFI ≥4.5=frail). Other candidate variables included demographics, laboratories, and comorbidities. Cox proportional hazards regression with best subset selection was used to identify risk factors of 3-year post-transplant death. The final model was selected based on Aikaike Information Criterion and clinical pragmatism. Results: Of 1,472 liver transplant recipients. 290 (20%) were frail. Three-year post-transplant mortality was higher in frail versus non-frail patients (13 vs. 8%; p =0.03). The final LTCI included 5 variables: frailty, coronary artery disease, hepatocellular carcinoma, renal dysfunction, and diabetes. Three-year post-transplant mortality in low-, moderate-, and high-risk LTCI groups was 93%, 87%, and 80% respectively. In multivariable analysis, after adjusting for donor factors (age, DCD), both moderate- (HR 2.23; 95% CI 1.46-3.40; p &lt;0.001) and high-risk (HR 2.78; 95% CI 1.67-4.64; p &lt;0.001) status were associated with 3-year post-transplant mortality. Conclusion: The LTCI, comprising 5 pre-transplant clinical parameters, effectively identifies patients at increased risk of post-transplant mortality. By integrating frailty in the context of other co-morbidities, the LTCI can help providers better weigh the relative transplant risks and benefits and standardize selection of transplant candidates.
Exploring the impact of Metacognitive Interpersonal Therapy on borderline personality disorder: a retrospective observational study using a latent transition analysis of symptoms and functional changes over 12 months
Authors: Matteo Aloi, Antonio Semerari, Giulio Amadei, Ilaria Bucci, Livia Colle, Giuseppe Nicolò, Ilaria Riccardi, Cristina Segura-Garcia, Antonino Carcione
Journal: Psychotherapy and Psychosomatics (2025)

Introduction: Borderline personality disorder (BPD) is marked by emotional instability, interpersonal dysfunction, and high comorbidity, posing significant treatment challenges. Metacognitive Interpersonal Therapy (MIT) targets core features of BPD, including metacognitive impairments and emotional dysregulation. This study uses Latent Transition Analysis (LTA) to assess changes in BPD symptoms and psychological factors over a 12-month MIT intervention, hypothesizing that MIT will reduce symptom severity and improve emotional regulation, metacognitive abilities, and interpersonal functioning. Methods: This single-center, retrospective observational study included 98 patients, all diagnosed with BPD according to DSM-IV-TR criteria, without severe psychiatric comorbidities or concurrent psychotherapy. These patients underwent a 12-month MIT intervention, delivered in five phases targeting metacognitive and emotional regulation skills. Clinical assessments included SCID-II for BPD diagnosis, SCL-90-R for symptom severity, MAI for metacognitive abilities, and IIP for interpersonal difficulties. Results: Latent Class Analysis (LCA) identified three baseline profiles: "Affective dysregulation and anger" (14.3%), "Low symptomatic" (7.1%), and "Identity and interpersonal sensitivity" (78.6%). After 12 months of treatment, most participants (58.2%) transitioned to a "Recovered" class, with significant reductions in BPD symptoms. The "Recovered" class showed the greatest improvements in metacognitive abilities, emotional regulation, and interpersonal functioning compared to other groups. Conclusions: MIT was associated with significant improvements in BPD symptoms, with over half of participants achieving full recovery. These findings suggest that MIT may play a role in enhancing emotional regulation and interpersonal functioning. However, residual symptoms in some participants confirm the complexity of BPD, suggesting the need for further research into long-term outcomes and comorbidities.
Cost-Effectiveness Analysis of 3D Total-Body Photography for People at High Risk of Melanoma
Authors: Daniel Lindsay, H. Peter Soyer, Monika Janda, David C. Whiteman, Sonya Osborne, Anna Finnane, Liam J. Caffery, Louisa G. Collins
Journal: JAMA Dermatology (2025)

Importance Greater use of novel digital technologies could be associated with improved health outcomes and save health care costs by detecting smaller melanomas earlier (needing less treatment) or benign tumors (needing no treatment). Objective To compare costs and health effects of 3-dimensional (3D) total-body photography (TBP) and sequential digital dermoscopy imaging (SDDI) vs usual care for early detection of melanoma. Design, Setting, and Participants This prespecified cost-effectiveness analysis using randomized clinical trial (n = 309) data with 2 years of follow-up was conducted at a research hospital in Brisbane, Australia, and took a health system perspective. It included adults 18 years or older at high risk of developing a primary or subsequent melanoma. Intervention The intervention group received usual care plus clinical skin examinations by junior clinicians at baseline and 6, 12, 18, and 24 months with 3D TBP-SDDI reviewed by a teledermatologist. The control group continued to receive usual care and completed online surveys every 6 months. Main Outcomes and Measures Government health care costs, patient out-of-pocket costs, numbers of benign and malignant skin tumor excisions, and quality-adjusted life-years. Skin biopsy, excisions, pathology, and their costs were collected using administrative claims data. Quality of life was collected using the EuroQol-5D-5L. Results The trial included 314 participants (mean [SD] age, 51.6 [12.8] years; 194 female individuals [62%]) who completed all of the study procedures (158 in the intervention and 156 in the control groups). Compared with controls, intervention group participants had fewer melanoma excisions, more keratinocyte carcinomas and benign excisions, and more biopsy specimens. Over 24 months, mean per-person costs (analyzed in Australian dollars and converted to US$) for the intervention group were $1708 (95% CI, $1455-$1961) vs $763 (95% CI, $655-$870) for controls, an incremental cost of $945 (95% CI, $738-$1157) to provide the intervention. Total quality-adjusted life-years per person were similar for the intervention (1.84; 95% CI, 1.82-1.86) and control groups (1.84; 95% CI, 1.83-1.86). The incremental cost per additional malignant skin tumor excised was $40 (95% CI, $34-$48). Conclusions and Relevance Over 2 years of the trial, the 3D TBP-SDDI model by junior clinicians and teledermatologist review generated higher costs and detected similar numbers of malignant tumors than usual care in a high-risk melanoma cohort. Cost-effectiveness is a necessary but not sufficient consideration for implementation. Other benefits of 3D TBP-SDDI may arise once artificial intelligence clinician support systems are integrated, and more research is needed to understand factors associated with costs and whether there are other benefits of 3D TBP-SDDI.
Health-Related Social Needs Discussions in Primary Care Encounters in Safety-Net Clinics
Authors: Elaine De Leon, Sneha Panganamamula, Antoinette Schoenthaler
Journal: JAMA Network Open (2025)

Importance Health-related social needs (HRSN) influence health outcomes and health care utilization. Clinicians face challenges addressing HRSN due to limited skills, expertise, and time. Further insight is needed on how patients and clinicians navigate HRSN in clinical encounters. Objective This study examines outpatient primary care encounters predating widespread HRSN screening to identify how discussions on HRSN are initiated and addressed. Design, Setting, and Participants This qualitative analysis was conducted on transcripts of 97 audiotaped English-speaking patient encounters from 3 clinics in New York City within a municipal health care system from January 2011 through April 2015. Patients were eligible if they were older than 18 years, self-identified as Black or White, had a diagnosis of hypertension, and had at least one prior encounter with the participating clinician. Codes were developed from social needs domains addressed by the Accountable Health Communities HRSN Screening Tool. Codes were added for further social needs identified, whether a patient or clinician initiated the HRSN discussion, and how a social need was addressed, if at all. Encounters were analyzed between June 2023 and February 2024. Main Outcomes and Measures Characterization of the content and nature of HRSN discussions during clinical encounters within safety-net clinics. Results A total of 97 patients (55 [56.7%] women, 58 [59.8%] Black, mean [SD] age, 59.7 [10.6] years) had audiotaped encounters with 27 clinicians (18 [66.7%] women, 15 [55.6%] White, mean [SD] age, 36 [5.8] years). Physical activity (36% of encounters), financial strain (35%), mental health (34%), and substance use (28%) were the most discussed HRSN domains across the 97 encounters. Patients introduced financial strain most often (70% of the time), while clinicians led substance use (75%), physical activity (51%) and mental health (51%) discussions. Patients initiated conversations on employment (77%), food insecurity (62%), and housing instability (52%). Interventions included prescriptions, forms, counseling, and referrals. Domains frequently intervened on included health care navigation needs (85% of discussions), substance use (33%), and mental health (27%). Conclusions and Relevance In this qualitative study of HRSN discussions in primary care encounters, clinicians were more likely to initiate discussions on substance use, physical activity, and mental health, behaviors routinely assessed in primary care, but different from topics introduced by patients. Findings underscore the need for standardized screening to improve identification of domains less frequently addressed by clinicians. Additional interventions are also needed, including clinician training for how to address HRSN in resource-constrained settings and integration of other health care team members, to enhance HRSN identification and intervention.
Combining faecal haemoglobin, iron deficiency anaemia status and age can improve colorectal cancer risk prediction in patients attending primary care with bowel symptoms: a retrospective observational study
Authors: Jayne Digby, Jennifer Nobes, Judith A Strachan, Rebecca McCann, Christopher Hall, Callum G Fraser, Craig Mowat
Journal: Gut (2025)

Background In primary care, National Institute for Health and Care Excellence suspected cancer guidelines recommend measuring faecal haemoglobin (f-Hb) if colorectal cancer (CRC) is suspected, with a referral threshold of ≥10 µg Hb/g faeces defining a 3% risk, but most have a normal colonoscopy. Objective Examine whether combining f-Hb, patient age and iron-deficient anaemia (IDA) status improves risk prediction. Design Retrospective single-centre observational study of symptomatic patients who submitted contemporaneous f-Hb and full blood count (FBC) samples between December 2015 and December 2019. f-Hb was estimated using HM-JACKarc (Hitachi Chemical Diagnostics Systems). Patients were categorised by presence/absence of IDA. Incident CRC was identified via record linkage to the Scottish Cancer Registry. Kaplan-Meier estimates determined cumulative 1-year CRC risk by patient age, f-Hb result and presence of IDA. Results Of 34 647 valid f-Hb results retrieved; 7889 (22.8%) had f-Hb≥10 µg Hb/g. Of these, 33 285 samples (96.1%) had associated FBC results of which 3000 (9.0%) had IDA. Overall, 571 incident CRC were recorded. The risk of CRC breached 3% in patients with f-Hb&gt;99 µg Hb/g aged &gt;40 years and reached 30% (19.4–41.0) with f-Hb&gt;99 µg Hb/g in age &gt;55 years plus IDA. 2029 f-Hb results (25.7%) were in the 10–19 µg Hb/g range of which 27 (1.3%) had CRC. In this subgroup, CRC risk did not exceed 3% in patients &lt;85 years and no IDA. Conclusion Combining f-Hb, patient age and IDA status improves CRC risk prediction, identifies a low-risk group with f-Hb&lt;20 µg Hb/g and no IDA and could inform revised referral guidance.