tbuckley/cabot-search huggingface dataset:
Father’s occupation and colorectal cancer in his adult offspring
Authors: Caitlin C Murphy, Emanuelle M Dias, Piera M Cirillo, Nickilou Y Krigbaum, Barbara A Cohn
Journal: JNCI Journal of the National Cancer Institute (2025)

Abstract Background Growing evidence suggests transmission of colorectal cancer risk through the maternal line. There is scant information about transmission through the paternal line, despite plausible evidence from mammal experiments. Methods We examined the association between paternal occupation and colorectal cancer in the Child Health and Development Studies, a multi-generational cohort followed for 60 years. Pregnant mothers completed in-person interviews at enrollment (1959–1966) and reported demographic and health-related information for her and her husband, including occupation. Colorectal cancer in adult (age ≥18 years) offspring was ascertained from a population-based cancer registry. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHR), with follow-up accrued from birth through cancer diagnosis, death, or last contact. Results Paternal occupations included: 37.0% professional, technical, or managerial; 13.7% clerical or sales; 30.5% crafts or operative; and 17.5% service work or labor. Over 716,133.5 person-years of follow-up, 79 offspring were diagnosed with colorectal cancer (median age at diagnosis: 50 years [range: 23–59 years]). Offspring of fathers employed in crafts, operative, service, or labor occupations had higher incidence rates of colorectal cancer (15.66 per 100,000 person-years; 95% CI 11.47, 20.89) compared to professional, technical, or managerial occupations (6.84 per 100,000 person-years; 95% CI 3.73, 11.47). Risk associated with these occupations remained elevated after adjustment for maternal race, paternal education, and offspring year of birth (aHR 1.99; 95% CI 1.03, 3.87). Conclusion Our findings support possible transmission of cancer risk through the paternal line.
Ketogenesis mitigates metabolic dysfunction-associated steatotic liver disease through mechanisms that extend beyond fat oxidation
Authors: Eric D Queathem, David B Stagg, Alisa B Nelson, Alec B Chaves, Scott B Crown, Kyle Fulghum, D Andre d'Avignon, Justin R Ryder, Patrick J Bolan, Abdirahman Hayir, Jacob R Gillingham, Shannon Jannatpour, Ferrol I Rome, Ashley S Williams, Deborah M Muoio, Sayeed Ikramuddin, Curtis C Hughey, Patrycja Puchalska, Peter A Crawford
Journal: Journal of Clinical Investigation (2025)

The progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH) involves alterations in both liver-autonomous and systemic metabolism that influence the liver's balance of fat accretion and disposal. Here, we quantify the contributions of hepatic oxidative pathways to liver injury in MASLD-MASH. Using NMR spectroscopy, UHPLC-MS, and GC-MS, we performed stable-isotope tracing and formal flux modeling to quantify hepatic oxidative fluxes in humans across the spectrum of MASLD-MASH, and in mouse models of impaired ketogenesis. In humans with MASH, liver injury correlated positively with ketogenesis and total fat oxidation, but not with turnover of the tricarboxylic acid cycle. Loss-of-function mouse models demonstrated that disruption of mitochondrial HMG-CoA synthase (HMGCS2), the rate-limiting step of ketogenesis, impairs overall hepatic fat oxidation and induces a MASLD-MASH-like phenotype. Disruption of mitochondrial β-hydroxybutyrate dehydrogenase (BDH1), the terminal step of ketogenesis, also impaired fat oxidation, but surprisingly did not exacerbate steatotic liver injury. Taken together, these findings suggest that quantifiable variations in overall hepatic fat oxidation may not be a primary determinant of MASLD-to-MASH progression, but rather, that maintenance of ketogenesis could serve a protective role through additional mechanisms that extend beyond overall rates of fat oxidation.
Outcomes after solid organ transplantation in survivors of childhood, adolescent and young adult cancer: A population-based study
Authors: Paul C Nathan, Cindy Lau, Vicky L Ng, Mar Miserachs, Chia Wei Teoh, Melinda Solomon, Anne I Dipchand, Maria Locke, Sumit Gupta
Journal: JNCI Journal of the National Cancer Institute (2025)

Abstract Background Cancer treatment can lead to organ toxicity requiring solid organ transplant (SOT). Transplant teams must evaluate the appropriateness of SOT in survivors of childhood, or adolescent/young adult (AYA) cancer. Methods Children treated at a provincial (Ontario, Canada) pediatric center for any cancer between 1986-2021, and AYA (15-21 years) treated in an adult center for four common cancer types between 1992-2012, were identified using population-based databases. Outcomes were determined by linkage to administrative databases. Transplanted cancer survivors (cases) were matched 1:2 to SOT recipients without a prior cancer (controls). Post-SOT overall survival (OS), subsequent cancers, severe cardiovascular disease and graft loss/death were compared between groups. Results Among 16,533 cancer survivors, 52 received a SOT: 13 liver, 18 kidney, 11 lung, and 10 heart. Median age at SOT was 18 (IQR 14-27). Transplanted cancer survivors experienced lower 10-year post-SOT OS than controls (67.7 vs. 86.0%; p = 0.003). 10-year cumulative incidence of developing another de novo malignancy was 8.6%, similar to the incidence of first cancers among controls (12.9%; HR 1.05, p = 0.91). 10-year cumulative incidence of primary cancer recurrence was 10.5%. Cases (excluding heart transplants) were at risk for graft loss/death (HR = 2.00, 95% confidence interval 1.01-3.94), but not severe cardiovascular disease (HR = 1.10, CI 0.50-2.41). Conclusion Survivors treated with SOT had inferior survival than SOT recipients without a cancer history, but most achieved long-term cancer-free survival. These data can inform decisions around the suitability of cancer survivors for SOT.
Identification of pulmonary artery stiffening due to left heart disease by ultrasonography
Authors: Mariya M Kucherenko, Marian Kukucka, Pengchao Sang, Niklas Hegemann, Qiuhua Li, Felix Hennig, Ruhi Yeter, Tara Gransar, Alexander Mladenow, Anna Emmerich, Andrea Orsenigo, Jana Grune, Volkmar Falk, Wolfgang M Kuebler, Christoph Knosalla
Journal: Cardiovascular Research (2025)

Abstract Aims Pulmonary hypertension (PH) is a common complication of left heart disease (LHD) that leads to right heart failure and death. Pulmonary artery (PA) stiffening has recently emerged as an important diagnostic and prognostic parameter in PH. The present study aimed to develop and validate an ultrasonographic index to identify PA stiffening in PH due to left heart disease (PH-LHD). Methods and Results First, ultrasonographic stiffness index (US-SI) was derived from pulmonary arterial (PA) radial strain (PA-RS), diameter, and stroke volume in rat model, and correlated to ex vivo measured “true” PA stiffness E. Then, US-SI was validated in a cohort of 24 LHD patients with or without PH prior to heart transplantation and again compared to “true” PA stiffness measured ex vivo in collected PA specimens. In rats, ultrasonographic PA-RS and US-SI correlated closely with E, and both were able to detect “true” PA stiffening with ≥ 80% sensitivity and specificity. In LHD patients, even though ultrasonographic right PA radial strain (rPA-RS) or US-SI correlated similarly with E, observer assessment and testing for diagnostic validity identified US-SI as more robust and accurate method that detects “true” PA stiffening with 83.3% sensitivity and 95.8% specificity. Conclusion(s) Both PA strain and US-SI allow for ultrasonographic detection of PA stiffening in patients or animal models with LHD, however, US-SI identifies patients with stiffened PA with higher diagnostic validity and accuracy. Translational Perspective Clinical implementation of US-SI may improve risk stratification in LHD patients and longitudinal monitoring of progression or treatment efficiency in PH-LHD. The animal-to-beside approach used in this study may promote the rapid translation of bio- and pathomechanical insights between the clinical and preclinical scenarios.
Effects of Long-Term Air Pollution Exposure on Disease Outcomes and Hybrid Immune Responses in SARS-CoV-2 Breakthrough Infections: A Study of the Yichang COVID-19 Antibody Longitudinal Survey (YC-CALS) in China
Authors: Xiaolong Yan, Yin Du, Ke Li, Xin Zhao, Hao Wang, Li Liu, Qi Wang, Jianhua Liu, Sheng Wei
Journal: Environmental Health Perspectives (2025)

As immunity wanes and viral mutations continue, the risk of endemic SARS-CoV-2 breakthrough infections (BTIs) remains. Air pollution is considered a risk factor for respiratory infection, but evidence of its association with SARS-CoV-2 BTIs is limited. We aimed to examine the effects of long-term exposure to air pollution on disease outcomes, immune responses, and antibody dynamics of SARS-CoV-2 BTIs. We gathered data on self-reported SARS-CoV-2 infections through questionnaires and measured IgG antibody levels using serological assays from a total of 6,875 participants from the Yichang COVID-19 Antibody Longitudinal Survey cohort in China. Air pollutant exposure (PM2.5, PM10, PM1, SO2, NO2, O3, and CO) was quantified using validated models for the past five years (2018 to 2022). Logistic and linear regression models were applied to analyze the associations between air pollutant levels and SARS-CoV-2 BTIs, Long COVID, COVID-19 hospitalization, and antibody responses. Quantile g-computation was used to assess the combined effects of pollutant mixtures. A linear mixed model was used to evaluate the effect of air pollution on antibody dynamics. Per interquartile range (IQR) increase in PM2.5, SO2, NO2, and CO, the adjusted odds ratios (ORs) for SARS-CoV-2 BTIs were 1.65(95% CI: 1.30, 2.08), 1.30 (95% CI: 1.12, 1.50), 1.63 (95% CI: 1.20, 2.20), and 1.24 (95% CI: 1.06, 1.45). The ORs for PM2.5 were 1.78 (95% CI: 1.07, 3.02) and 2.02 (95% CI: 1.18, 3.54) for Long COVID and hospitalization. Per IQR increase in PM1 and NO2, IgG antibody percentages decreased by -2.31% (95% CI: -4.49%, -0.13%) and -2.69% (95% CI: -5.35%, -0.03%). Effects were stronger in older adults, those with comorbidities, and the under-vaccinated. The combined effect on SARS-CoV-2 BTIs was mainly driven by PM2.5 (59.4%), while the impact on IgG response was largely attributed to NO2 (63.7%). Exposure to the highest levels of PM2.5 (p = 0.002), PM1 (p < 0.001), and NO2 (p = 0.002) was associated with a faster IgG decline than the lowest. Long-term exposure to air pollution increases the risk of SARS-CoV-2 BTIs and disease severity while weakening the immune response, particularly for vulnerable populations. https://doi.org/10.1289/EHP15660.
PFS24 as a prognostic milestone in patients with newly diagnosed primary CNS lymphoma
Authors: Vanja Zeremski, Tobias R Haage, Hanno M Witte, Louisa Adolph, Sina A Beer, Gerhard Behre, Benedikt Jacobs, Christoph Kahl, Chrysavgi Lalayanni, Jens Panse, Sotirios Papageorgiou, Marina P Siakantaris, Jessica Schneider, Ulf Schnetzke, Alexander Schulz, Theodoros P Vassilakopoulos, Jeanette Walter, Dimitrios Mougiakakos
Journal: Journal of Hematology & Oncology (2025)
Effectiveness and safety of fexinidazole for gambiense human African trypanosomiasis and exploration of adherence in outpatients: a phase 3b, prospective, open-label, non-randomised, cohort study
Authors: Victor Kande Betu Kumeso, Christelle Perdrieu, Caroline Menétrey, Médard Ilunga Wa Kyhi, Digas Ngolo Tete, Mamadou Camara, John Tampwo, Papy Kavunga, Mariame Layba Camara, Ansoumane Kourouma, Willy Kuziena Mindele, Felix Akwaso Masa, Hélène Mahenzi, Joseph Makaya, Tim Mayala Malu, Guylain Mandula, Dieudonné Mpoyi Muamba Nzambi, Serge Luwawu Ntoya, Anne Reymondier, Wilfried Mutombo Kalonji, Bruno Scherrer, Olaf Valverde Mordt
Journal: The Lancet Global Health (2025)
Supply-side and demand-side factors affecting allopathic primary care service delivery in low-income and middle-income country cities
Authors: Richard J Lilford, Benjamin Daniels, Barbara McPake, Zulfiqar A Bhutta, Robert Mash, Frances Griffiths, Akinyinka Omigbodun, Elzo Pereira Pinto, Radhika Jain, Gershim Asiki, Eika Webb, Katie Scandrett, Peter J Chilton, Jo Sartori, Yen-Fu Chen, Peter Waiswa, Alex Ezeh, Catherine Kyobutungi, Gabriel M Leung, Cristani Machado, Kabir Sheikh, Sam I Watson, Jishnu Das
Journal: The Lancet Global Health (2025)
Improving primary health-care services in LMIC cities
Authors: Richard J Lilford, Benjamin Daniels, Barbara McPake, Zulfiqar A Bhutta, Robert Mash, Frances Griffiths, Akinyinka Omigbodun, Elzo Pereira Pinto, Radhika Jain, Gershim Asiki, Eika Webb, Katie Scandrett, Peter J Chilton, Jo Sartori, Yen-Fu Chen, Peter Waiswa, Alex Ezeh, Catherine Kyobutungi, Gabriel M Leung, Cristiani Machado, Kabir Sheikh, Sam I Watson, Jishnu Das
Journal: The Lancet Global Health (2025)
Multi-region brain transcriptomic analysis of amyotrophic lateral sclerosis reveals widespread RNA alterations and substantial cerebellum involvement
Authors: Natalie Grima, Andrew N Smith, Claire E Shepherd, Lyndal Henden, Thiri Zaw, Luke Carroll, Dominic B Rowe, Matthew C Kiernan, Ian P Blair, Kelly L Williams
Journal: Molecular Neurodegeneration (2025)

Abstract Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor neurons, causing progressive muscle weakness and paralysis. While research has focused on understanding pathological mechanisms in the motor cortex and spinal cord, there is growing evidence that extra-motor brain regions may also play a role in the pathogenesis or progression of ALS. Methods We generated 165 sample-matched post-mortem brain transcriptomes from 22 sporadic ALS patients with pTDP-43 pathological staging and 11 non-neurological controls. For each individual, five brain regions underwent mRNA sequencing: motor cortex (pTDP-43 inclusions always present), prefrontal cortex and hippocampus (pTDP-43 inclusions sometimes present), and occipital cortex and cerebellum (pTDP-43 inclusions rarely present). We examined gene expression, cell-type composition, transcript usage (% contribution of a transcript to total gene expression) and alternative splicing, comparing ALS-specific changes between brain regions. We also considered whether post-mortem pTDP-43 pathological stage classification defined ALS subgroups with distinct gene expression profiles. Results Significant gene expression changes were observed in ALS cases for all five brain regions, with the cerebellum demonstrating the largest number of total (&gt; 3,000) and unique (60%) differentially expressed genes. Pathway enrichment and predicted activity were largely concordant across brain regions, suggesting that ALS-linked mechanisms, including inflammation, mitochondrial dysfunction and oxidative stress, are also dysregulated in non-motor brain regions. Switches in transcript usage were identified for a small set of genes including increased usage of a POLDIP3 transcript, associated with TDP-43 loss-of-function, in the cerebellum and a XBP1 transcript, indicative of unfolded protein response activity, in the motor cortex. Extensive variation in RNA splicing was identified in the ALS brain, with 26–41% of alternatively spliced genes unique to a given brain region. This included detection of TDP-43-associated cryptic splicing events such as the STMN2 cryptic exon which was shown to have a pTDP-43 pathology-specific expression pattern. Finally, ALS patients with stage 4 pTDP-43 pathology demonstrated distinct gene and protein expression changes in the cerebellum. Conclusions Together our findings highlighted widespread transcriptome alterations in ALS post-mortem brain and showed that, despite the absence of pTDP-43 pathology in the cerebellum, extensive and pTDP-43 pathological stage-specific RNA changes are evident in this brain region.
Metformin for Knee Osteoarthritis in Patients With Overweight or Obesity
Authors: Feng Pan, Yuanyuan Wang, Yuan Z. Lim, Donna M. Urquhart, Mahnuma Mahfuz Estee, Anita E. Wluka, Rory Wolfe, Flavia M. Cicuttini
Journal: JAMA (2025)

Importance Preclinical and preliminary human evidence suggests that metformin, a first-line treatment for type 2 diabetes, reduces inflammation, preserves cartilage, and improves knee pain in knee osteoarthritis. Objective To evaluate the effects of metformin on knee pain at 6 months in participants with symptomatic knee osteoarthritis and overweight or obesity. Design, Setting, and Participants Community-based randomized, parallel-group, double-blind, placebo-controlled clinical trial that used telemedicine to recruit and follow up participants remotely. Individuals with knee pain for 6 months or longer, a pain score greater than 40 mm on a 100-mm visual analog scale (VAS), and body mass index of 25 or higher were recruited from the community through local and social media advertisements in Victoria, Australia, between June 16, 2021, and August 1, 2023. Final follow-up occurred on February 8, 2024. Interventions Participants were randomly assigned to receive either oral metformin, 2000 mg/d (n = 54), or identical placebo (n = 53) for 6 months. Main Outcomes and Measures The primary outcome was change in knee pain, measured using a 100-mm VAS (score range, 0-100; 100 = worst; minimum clinically important difference = 15) at 6 months. Results Of 225 participants assessed for eligibility, 107 (48%) were randomized (mean age, 58.8 [SD, 9.5] years; 68% female) and assigned to receive metformin or placebo. Eighty-eight participants (82%) completed the trial. At 6 months, the mean change in VAS pain was −31.3 mm in the metformin group and −18.9 mm in the placebo group (between-group difference, −11.4 mm; 95% CI, −20.1 to −2.6 mm; P = .01), corresponding to an effect size (standardized mean difference) of 0.43 (95% CI, 0.02-0.83). The most common adverse events were diarrhea (8 [15%] in the metformin group and 4 [8%] in the placebo group) and abdominal discomfort (7 [13%] in the metformin group and 5 [9%] in the placebo group). Conclusions and Relevance These results support use of metformin for treatment of symptomatic knee osteoarthritis in people with overweight or obesity. Because of the modest sample size, confirmation in a larger clinical trial is warranted. Trial Registration ANZCTR Identifier: ACTRN12621000710820
A T7 autogene-mediated DNA vaccine platform for SARS-CoV-2: Overcoming DNA vaccine limitations with enhanced spike mRNA production
Authors: Sang Won Cho, Sang Chul Shin, Yunju Nam, Hyung Jun Ahn
Journal: Journal of Controlled Release (2025)

The COVID-19 pandemic has underscored the urgent need for innovative vaccine platforms that combine potent immunogenicity, thermal stability, and global accessibility. While mRNA vaccines have proven highly efficacious, their fragility and reliance on ultracold storage complicates distribution in resource-constrained settings. DNA vaccines, by contrast, are more stable and easier to distribute but suffer from low immunogenicity due to inefficient nuclear translocation. Here, we introduce the mRNA Factory (mRF) vaccine platform, a DNA-based system that enables direct cytoplasmic transcription of spike mRNA via self-amplifying T7 RNA polymerase. The Rpol/spk mRF vaccine elicited markedly enhanced immunogenicity compared to conventional plasmid DNA vaccines, as evidenced by elevated spike protein expression, robust T cell activation, Th1-biased cytokine profiles, and higher titers of SARS-CoV-2-specific IgG. Compared with an IVT spike mRNA vaccine, the mRF vaccine elicited comparable levels of overall immune responses, including T effector cell activation, IFNγ+CD8+ cytotoxic T cell activation, Th1 polarization, and specific IgG production. These results highlight the mRF platform's potential to overcome key limitations of conventional DNA vaccines while addressing distribution challenges associated with mRNA vaccines. Our findings support the mRF platform as a promising strategy for global vaccine deployment and future pandemic preparedness.
Recurrent Invasive Pneumococcal Disease in Children: a retrospective cohort study, England, 2006/07-2017/18
Authors: Marta Bertran, Fariyo Abdullahi, Joshua C D'Aeth, Zahin Amin-Chowdhury, Nick J Andrews, Seyi Eletu, David Litt, Mary E Ramsay, Godwin Oligbu, Shamez N Ladhani
Journal: Journal of Infection (2025)

Recurrent invasive pneumococcal disease (IPD) is rare in children and usually associated with underlying comorbidities. We aimed to assess the risk and describe the characteristics of children with recurrent IPD over a 12-year-period covering the introduction of the 7-valent (PCV7) followed by the 13-valent (PCV13) pneumococcal conjugate vaccine (PCV) in the national childhood immunisation programme in England. We used enhanced national surveillance data for England and included all laboratory-confirmed IPD cases in children (<15 years) during 2006/07-2017/18. We assessed the risk and rate of recurrent IPD, the serotypes responsible and the demographics, comorbidity status and prevalence, vaccination status, clinical presentation and outcomes in children with recurrent IPD compared to those with a single IPD episode. There were 5,158 IPD episodes reported in 5,033 children over 12 years and 2.2% (105/4,814) of those surviving their first IPD had at least one recurrence. Recurrence risk decreased with increasing age and over time. During 2015/16-2017/18, five years after PCV13 replaced PCV7, IPD recurrence rate was 229.0 (95% CI 154.8-339.0) per 100,000 person years, with all recurrent cases caused by non-PCV13 serotypes. Where serotype information was available, recurrence was due to the same serotype in 25 cases, with a shorter median (IQR) interval of 88 (57-177) days between recurrent episodes, and in 60 cases due to different serotypes, with a median (IQR) interval of 223 (125-574) days (p=0.001). Compared to healthy children (103.0 95%CI 63.1-168.1), recurrence rate per 100,000 person-years was 10 times higher in children with any comorbidity (1,061.02; 95% CI 827.2-1,360.9; 62/78 [79.5%] with available information had comorbidities), and almost 30 times higher in immunosuppressed children (2,788.5; 95%CI 2,029.0-3,832.2; 38/78 [48.7%] were immunosuppressed). The 30-day case-fatality rate after recurrent IPD was 2.9% (3/105) compared to 4.4% (219/4,928; P=0.63) after single-episode IPD. Recurrent IPD is rare in children and occurs mainly in children with comorbidities, especially immunosuppression. Higher-valent PCVs have the potential to further reduce the risk recurrent IPD in children.
Centrifugally spun and ZnO-infiltrated PVA fibers with antibacterial activity for treatment of Acne vulgaris
Authors: Martina Rihova, Susan Azpeitia, Kristyna Cihalova, Jan Michalicka, Pavan Kumar Chennam, Eva Kolibalova, Roman Svoboda, Zbynek Heger, Mato Knez, Jan M Macak
Journal: Journal of Controlled Release (2025)
Regarding Wu et al’s “Response to Cepica et al’s ‘Smoking status is a negative predictor of six-month cutaneous lupus activity trends: a prospective cohort study.’”
Authors: Tyler B Cepica, Lillian Xie, Daniella F Faden, Caroline J Stone, Rui Feng, Victoria P Werth, Benjamin F Chong
Journal: Journal of the American Academy of Dermatology (2025)
Age sensitive response of systemic AAV-mediated gene therapy in a newly characterized feline model of mucolipidosis II
Authors: Nettie K Pyne, Jessica Bagel, Charles Shyng, Patricia Odonnell, Keiko Miyadera, Jennifer Srnak, Gary Swain, Jill P Pesayco, G Diane Shelton, Charles-Antoine Assenmacher, Patricia Dickson, Joshua Stern, Heather Flanagan-Steet, Steven J Gray, Allison M Bradbury
Journal: Molecular Therapy (2025)
IL2-independent expansion, persistence, and antitumor activity in TIL expressing regulatable membrane-bound IL15
Authors: Rachel A Burga, Bulent Arman Aksoy, Zheng Ao, Jeremy H Tchaicha, Dhruv K Sethi, Alonso Villasmil Ocando, Gauri S Kulkarni, Scott Lajoie, Kyle D Pedro, Jack Ryan Tremblay, Meghan Langley, Benjamin Primack, Violet A Young, Theresa Ross, Mithun Khattar, Dexue Sun, Dan Jun Li, Shyam Subramanian, Michelle Ols, Jan Ter Meulen
Journal: Molecular Therapy (2025)