tbuckley/cabot-search huggingface dataset:
Familial uveal melanoma and other tumors in 25 families with monoallelic germline <i>MBD4</i> variants
Authors: Marie-Charlotte Villy, Anaïs Le Ven, Marine Le Mentec, Julien Masliah-Planchon, Alexandre Houy, Ivan Bièche, Sophie Vacher, Anne Vincent-Salomon, Catherine Dubois d’Enghien, Mathias Schwartz, Sophie Piperno-Neumann, Alexandre Matet, Denis Malaise, Virginie Bubien, Alain Lortholary, Amal Ait Omar, Mathias Cavaillé, Dominique Stoppa-Lyonnet, Nathalie Cassoux, Marc-Henri Stern, Manuel Rodrigues, Lisa Golmard, Chrystelle Colas
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Monoallelic germline MBD4 pathogenic variants were recently reported to cause a predisposition to uveal melanoma, associated with a specific tumor mutational signature and good response to immunotherapy. Monoallelic tumor pathogenic variants have also been described in brain tumors, breast cancers, and myxofibrosarcomas, whereas biallelic germline MBD4 pathogenic variants have been involved in a recessive hereditary adenomatous polyposis and a specific type of acute myeloid leukemia. Methods We analyzed MBD4 for all patients with a diagnosis of uveal melanoma at Institut Curie since July 2021 and in the 3240 consecutive female probands explored at the Institut Curie for suspicion of predisposition to breast cancer between July 2021 and February 2023. Results We describe 25 families whose probands carry a monoallelic germline pathogenic variant in MBD4. Eighteen of these families presented with uveal melanoma (including a case patient with multiple uveal melanoma), and 7 families presented with breast cancer. Family histories showed the first familial case of uveal melanoma in monoallelic MBD4 pathogenic variant carriers and other various types of cancers in relatives, especially breast, renal, and colorectal tumors. Conclusions Monoallelic MBD4 pathogenic variant may explain some cases of familial and multiple uveal melanoma as well as various cancer types, expanding the tumor spectrum of this predisposition. Further genetic testing in relatives combined with molecular tumor analyses will help define the tumor spectrum and estimate each tumor’s risk.
Gut microbiota links to serum ferritin and cognition
Authors: Marisel Rosell-Díaz, Elena Santos-González, Anna Motger-Albertí, Lluís Ramió-Torrentà, Josep Garre-Olmo, Vicente Pérez-Brocal, Andrés Moya, Mariona Jové, Reinald Pamplona, Josep Puig, Rafael Ramos, José Manuel Fernández-Real, Jordi Mayneris-Perxachs
Journal: Gut Microbes (2023)

Iron is required for the replication and growth of almost all bacterial species and in the production of myelin and neurotransmitters. Increasing clinical studies evidence that the gut microbiota plays a critical role in iron metabolism and cognition. However, the understanding of the complex iron-microbiome-cognition crosstalk remains elusive. In a recent study in the Aging Imageomics cohort (n = 1,030), we identified a positive association of serum ferritin (SF) with executive function (EF) as inferred from the semantic verbal fluency (SVF,) the total digit span (TDS) and the phonemic verbal fluency tests (PVF). Here, we explored the potential mechanisms by analyzing the gut microbiome and plasma metabolome using shotgun metagenomics and HPLC-ESI-MS/MS, respectively. Different bacterial species belonging to the Proteobacteria phylum (Klebsiella pneumoniae, Klebsiella michiganensis, Unclassified Escherichia) were negatively associated both with SF and executive function. At the functional level, an enrichment of microbial pathways involved in phenylalanine, arginine, and proline metabolism was identified. Consistently, phenylacetylglutamine, a metabolite derived from microbial catabolism of phenylalanine, was negatively associated with SF, EF, and semantic memory. Other metabolites such as ureidobutyric acid and 19,20-DiHDPA, a DHA-derived oxylipin, were also consistently and negatively associated with SF, EF, and semantic memory, while plasma eicosapentaenoic acid was positively associated. The associations of SF with cognition could be mediated by the gut microbiome through microbial-derived metabolites.
European Society of Cardiology Core Curriculum for c<scp>ardio‐oncology</scp>
Authors: Teresa López‐Fernández, Dimitrios Farmakis, Pietro Ameri, Riccardo Asteggiano, Evandro de Azambuja, Marianne Aznar, Ana Barac, Antoni Bayes‐Genis, Jeroen J. Bax, Jutta Bergler‐Klein, Giuseppe Boriani, Jelena Celutkiene, Andrew Coats, Alain Cohen‐Solal, Raúl Córdoba, Bernard Cosyns, Gerasimos Filippatos, Kevin Fox, Geeta Gulati, Riccardo M. Inciardi, Geraldine Lee, Mamas A. Mamas, Giuseppina Novo, Chris Plummer, Amanda Psyrri, Amina Rakisheva, Thomas Suter, Giacomo Tini, Carlo Gabriele Tocchetti, Konstantinos Toutouzas, Matthias Wilhelm, Marco Metra, Alexander R. Lyon, Giuseppe M.C. Rosano
Journal: European Journal of Heart Failure (2023)
A roadmap to establishing global oncology as a priority initiative within a National Cancer Institute–designated cancer center
Authors: Katherine Van Loon, Lindsay Breithaupt, Dianna Ng, Rebecca J DeBoer, Geoffrey C Buckle, Stella Bialous, Robert A Hiatt, Paul Volberding, Michelle L Hermiston, Alan Ashworth
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract As the burden of cancers impacting low- and middle-income countries is projected to increase, formation of strategic partnerships between institutions in high-income countries and low- and middle-income country institutions may serve to accelerate cancer research, clinical care, and training. As the US National Cancer Institute and its Center for Global Health continue to encourage cancer centers to join its global mission, academic cancer centers in the United States have increased their global activities. In 2015, the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, responded to the call for international partnership in addressing the global cancer burden through the establishment of the Global Cancer Program as a priority initiative. In developing the Global Cancer Program, we galvanized institutional support to foster sustained, bidirectional, equitable, international partnerships in global cancer control. Our focus and intent in disseminating this commentary is to share experiences and lessons learned from the perspective of a US-based, National Cancer Institute–designated cancer center and to provide a roadmap for other high-income institutions seeking to strategically broaden their missions and address the complex challenges of global cancer control. Herein, we review the formative evaluation, governance, strategic planning, investments in career development, funding sources, program evaluation, and lessons learned. Reflecting on the evolution of our program during the first 5 years, we observed in our partners a powerful shift toward a locally driven priority setting, reduced dependency, and an increased commitment to research as a path to improve cancer outcomes in resource-constrained settings.
Optimal Irreversible Electroporation Combined with Nano‐Enabled Immunomodulatory to Boost Systemic Antitumor Immunity
Authors: Wencheng Peng, Yanbing Cao, Yuting Zhang, Aoxue Zhong, Cao Zhang, Zuwu Wei, Xiaolong Liu, Shoulong Dong, Jingcheng Wu, Yanan Xue, Ming Wu, Chenguo Yao
Journal: Advanced Healthcare Materials (2023)

Abstract In this work, we proposed nµPEF, a novel pulse configuration combining nanosecond and microsecond pulses (nµPEF), to enhance tumor ablation in irreversible electroporation (IRE) for oncological therapy. nµPEF demonstrated improved efficacy in inducing immunogenic cell death, positioning it as a potential candidate for next‐generation ablative therapy. However, the immune response elicited by nµPEF alone was insufficient to effectively suppress distant tumors. To address this limitation, we developed PPR@CM‐PD1, a genetically engineered nanovesicle. PPR@CM‐PD1 employed a polyethylene glycol‐polylactic acid‐glycolic acid (PEG‐PLGA) nanoparticle encapsulating the immune adjuvant imiquimod and coated with a genetically engineered cell membrane expressing programmed cell death protein 1 (PD1). This design allowed PPR@CM‐PD1 to target both the innate immune system through toll‐like receptor 7 (TLR7) agonism and the adaptive immune system through programmed cell death protein 1/programmed cell death‐ligand 1 (PD1/PDL1) checkpoint blockade. In turn, nµPEF facilitated intratumoral infiltration of PPR@CM‐PD1 by modulating the tumor stroma. The combination of nµPEF and PPR@CM‐PD1 generated a potent and systemic antitumor immune response, resulting in remarkable suppression of both nµPEF‐treated and untreated distant tumors (abscopal effects). This interdisciplinary approach presents a promising perspective for oncotherapy and holds great potential for future clinical applications.
Mitochondria- and NOX4-dependent antioxidant defense mitigates progression to nonalcoholic steatohepatitis in obesity
Authors: Spencer Greatorex, Supreet Kaur, Chrysovalantou E. Xirouchaki, Pei K. Goh, Florian Wiede, Amanda J. Genders, Melanie Tran, YaoYao Jia, Arthe Raajendiran, Wendy A. Brown, Catriona A. McLean, Junichi Sadoshima, Matthew J. Watt, Tony Tiganis
Journal: Journal of Clinical Investigation (2023)

Non-alcoholic fatty liver disease (NAFLD) is prevalent in the majority of obese individuals, but in a subset, this progresses to non-alcoholic steatohepatitis (NASH) and fibrosis. The mechanisms that prevent NASH and fibrosis in the majority of NAFLD patients remain unclear. Here we report that NAD(P)H oxidase (NOX)-4 and nuclear factor erythroid 2-related factor 2 (NFE2L2) were elevated in hepatocytes early in disease progression to prevent NASH/fibrosis. Mitochondrial-derived reactive oxygen species (ROS) activated NFE2L2 to induce the expression of NOX4, which in turn generated H2O2 to exacerbate the NFE2L2 antioxidant defense response. The deletion or inhibition of NOX4 in hepatocytes decreased ROS and attenuated antioxidant defense to promote mitochondrial oxidative stress, damage proteins and lipids, diminish insulin signalling and promote cell death upon oxidant challenge. Hepatocyte NOX4 deletion in high fat fed obese mice, which otherwise develop steatosis, but not NASH, resulted in hepatic oxidative damage, inflammation and T cell recruitment to drive NASH and fibrosis, whereas NOX4 overexpression tempered the development of NASH/fibrosis in mice fed a NASH-promoting diet. Thus, mitochondrial- and NOX4-derived ROS function in concert to drive a NFE2L2 antioxidant defense response to attenuate oxidative liver damage and the progression to NASH/fibrosis in obesity.
<i>Notes from the Field:</i> Responding to the Wartime Spread of Antimicrobial-Resistant Organisms — Ukraine, 2022
Authors: Ihor Kuzin, Oleksandr Matskov, Roman Bondar, Rostyslav Lapin, Tetiana Vovk, Andrea Howard, Arkadii Vodianyk, Robert Skov, Sarah Legare, Marianna Azarskova, Teeb Al-Samarrai, Ezra Barzilay, Charles Vitek
Journal: MMWR Morbidity and Mortality Weekly Report (2023)
Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance
Authors: Dominik J. Schaer, Nadja Schulthess-Lutz, Livio Baselgia, Kerstin Hansen, Raphael M. Buzzi, Rok Humar, Elena Dürst, Florence Vallelian
Journal: Journal of Clinical Investigation (2023)

Microscopic hemorrhage is a common aspect of cancers, yet its potential role as an independent factor influencing both cancer progression and therapeutic response is largely ignored. Recognizing the essential function of macrophages in red blood cell disposal, we explored a pathway that connects intratumoral hemorrhage with the formation of cancer-promoting tumor-associated macrophages (TAMs). Using spatial transcriptomics, we found that NRF2-activated myeloid cells possessing characteristics of procancerous TAMs tend to cluster in peri-necrotic hemorrhagic tumor regions. These cells resembled anti-inflammatory erythrophagocytic macrophages. We identified heme, a red blood cell metabolite, as a pivotal microenvironmental factor steering macrophages toward protumorigenic activities. Single-cell RNA-seq and functional assays of TAMs in 3D cell culture spheroids revealed how elevated intracellular heme signals via the transcription factor NRF2 to induce cancer-promoting TAMs. These TAMs stabilized epithelial-mesenchymal transition, enhancing cancer invasiveness and metastatic potential. Additionally, NRF2-activated macrophages exhibited resistance to reprogramming by IFNγ and anti-CD40 antibodies, reducing their tumoricidal capacity. Furthermore, MC38 colon adenocarcinoma-bearing mice with NRF2 constitutively activated in leukocytes were resistant to anti-CD40 immunotherapy. Overall, our findings emphasize hemorrhage-activated NRF2 in TAMs as a driver of cancer progression, suggesting that targeting this pathway could offer new strategies to enhance cancer immunity and overcome therapy resistance.
Endoscopic mucosal resection for large non-pedunculated colorectal polyps: staying on track with a safe, effective and cost-efficient technique
Authors: Francesco Vito Mandarino, Renato Medas, Julia L Gauci, Clarence Kerrison, Anthony Whitfield, Sunil Gupta, Stephen J Williams, Eric Y Lee, Nicholas G Burgess, Michael J Bourke
Journal: Gut (2023)
Short peripheral blood leukocyte telomere length in rheumatoid arthritis-interstitial lung disease
Authors: Tracy J Doyle, Pierre-Antoine Juge, Anna L Peljto, Seoyeon Lee, Avram D Walts, Anthony Joseph Esposito, Sergio Poli, Ritu Gill, Hiroto Hatabu, Mizuki Nishino, Paul F Dellaripa, Michael E Weinblatt, Nancy A Shadick, M Kristen Demoruelle, Jeffrey A Sparks, Ivan O Rosas, Benjamin Granger, Kevin D Deane, Bruno Crestani, Paul J Wolters, Philippe Dieudé, Joyce S Lee
Journal: Thorax (2023)

Shortened telomere lengths (TLs) can be caused by single nucleotide polymorphisms and loss-of-function mutations in telomere-related genes (TRG), as well as ageing and lifestyle factors such as smoking. Our objective was to determine if shortened TL is associated with interstitial lung disease (ILD) in individuals with rheumatoid arthritis (RA). This is the largest study to demonstrate and replicate that shortened peripheral blood leukocytes-TL is associated with ILD in patients with RA compared with RA without ILD in a multinational cohort, and short PBL-TL was associated with baseline disease severity in RA-ILD as measured by forced vital capacity percent predicted.
<i>Notes from the Field: </i>Undiagnosed Tuberculosis During Pregnancy Resulting in a Neonatal Death — United States, 2021
Authors: Kathryn Miele, R. Bryan Rock, Sylvia M. LaCourse, David Ashkin, Lisa Y. Armitige, William Pomputius, Neela D. Goswami
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

In 2022, the World Health Organization reported 10.6 million new cases of tuberculosis (TB) globally.One third of these new cases were reported in women; however, pregnancy status was not included in these data.*CDC recently added pregnancy status to national TB reporting in the United States; however, because the number of U.S. TB cases during pregnancy is presumed to be low, adverse effects of TB on pregnancy and postpartum outcomes are likely not well characterized.† A 2017 meta-analysis of 13 studies that included approximately 123,000 pregnancies from several countries found that TB disease during pregnancy was associated with increased odds of maternal morbidity and mortality, including hospital admission, anemia of pregnancy, cesarean birth, miscarriage, preterm birth, low birthweight, and neonatal TB (1).TB diagnosis during pregnancy might be delayed because of overlap in symptoms of TB with those of pregnancy, as well as clinician reluctance to use chest radiography during pregnancy.§ Perinatal TB is a life-threatening illness, with a congenital and neonatal TB mortality rate of approximately 50% (2), highlighting the importance of diagnosing and treating TB before and during pregnancy.This report describes a case of fatal neonatal TB after successful in vitro fertilization in 2021.
Large Community Outbreak of Legionnaires Disease Potentially Associated with a Cooling Tower — Napa County, California, 2022
Authors: Nárjara V. Grossmann, Crystal Milne, Melinda R. Martinez, Karen Relucio, Banafsheh Sadeghi, Erica N. Wiley, Samuel N. Holland, Sarah Rutschmann, Duc J. Vugia, Akiko Kimura, Chad Crain, Farhima Akter, Rituparna Mukhopadhyay, John Crandall, Meghann Shorrock, Jessica C. Smith, Namrata Prasad, Rebecca Kahn, Albert E. Barskey, Sooji Lee, Melisa J. Willby, Natalia A. Kozak-Muiznieks, Claressa E. Lucas, Kelley C. Henderson, Jennafer A. P. Hamlin, Eungi Yang, Nakia S. Clemmons, Troy Ritter, Jennifer Henn
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Legionnaires disease is a serious infection acquired by inhalation of water droplets from human-made building water systems that contain Legionella bacteria. On July 11 and 12, 2022, Napa County Public Health (NCPH) in California received reports of three positive urinary antigen tests for Legionella pneumophila serogroup 1 in the town of Napa. By July 21, six Legionnaires disease cases had been confirmed among Napa County residents, compared with a baseline of one or two cases per year. NCPH requested assistance from the California Department of Public Health (CDPH) and CDC to aid in the investigations. Close temporal and geospatial clustering permitted a focused environmental sampling strategy of high-risk facilities which, coupled with whole genome sequencing results from samples and investigation of water system maintenance, facilitated potential linking of the outbreak with an environmental source. NCPH, with technical support from CDC and CDPH, instructed and monitored remediation practices for all environmental locations that tested positive for Legionella. The investigation response to this community outbreak illustrates the importance of interdisciplinary collaboration by public health agencies, laboratory support, timely communication with the public, and cooperation of managers of potentially implicated water systems. Timely identification of possible sources, sampling, and remediation of any facility testing positive for Legionella is crucial to interrupting further transmission.
The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revisions of the T-Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer
Authors: Paul E. Van Schil, Hisao Asamura, Katherine K. Nishimura, Ramon Rami-Porta, Young Tae Kim, Pietro Bertoglio, Ayten K. Cangir, Jessica Donington, Wentao Fang, Dorothy J. Giroux, Yolande Lievens, Hui Liu, Gustavo Lyons, Shuji Sakai, William D. Travis, Paula Ugalde, Chi-Fu Jeffrey Yang, Masaya Yotsukura, Frank Detterbeck
Journal: Journal of Thoracic Oncology (2023)
Influence of age on clinical characteristics, pharmacological management and exacerbations in children with asthma
Authors: Zainab Khalaf, Andrew Bush, Sejal Saglani, Chloe I Bloom
Journal: Thorax (2023)

Background Asthma trials and guidelines often do not distinguish between adolescents and younger children. Using a large English data set, we evaluated the impact of age on asthma characteristics, management and exacerbations. Methods Primary care medical records, 2004–2021, were linked to hospital records. Children were categorised by age at diagnosis and followed until the next age bracket. Ages (based on management guidelines) were 5–8 years, 9–11 years and adolescents (12–16 years). Characteristics evaluated included body mass index, allergies and events before and after diagnosis (symptoms, medication). Exacerbation incidence was calculated. Multivariable Cox proportional hazards determined associations with exacerbations. Results 119 611 children were eligible: 61 940 (51.8%) 5–8 years, 32 316 (27.7%) 9–11 years and 25 355 (21.2%) adolescents. Several characteristics differed by age; children aged 5–8 years had the highest proportion with eczema, food/drug allergy and cough, but adolescents had the highest proportion with overweight/obesity, aeroallergen sensitisation, dyspnoea and short-acting-beta-agonist only use. Exacerbation rates were highest in the youngest children (per 100 person-years (95% CI): 5–8 years =13.7 (13.4–13.9), 9–11 years =10.0 (9.8–10.4), adolescents =6.7 (6.5–7.0)). Exacerbation risk factors also differed by age; 5–8 years: male, eczema and food/drug allergy were strongly associated, but for children ≥9 years old, obesity and aeroallergen sensitisation were strongly associated. For all children, higher socioeconomic deprivation was significantly associated with having an exacerbation. Delayed diagnosis was most common in children aged 5–8 years and was associated with increased exacerbations across all ages. Conclusion Children’s baseline characteristics and exacerbation rates varied according to their age group. Clinical guidelines should consider age at time of diagnosis more discretely than the broad range, 5–16 years, as this appears to impact on asthma severity and management.
Artificial Intelligence–Powered Assessment of Pathologic Response to Neoadjuvant Atezolizumab in Patients With NSCLC: Results From the LCMC3 Study
Authors: Sanja Dacic, William D. Travis, Jennifer M. Giltnane, Filip Kos, John Abel, Stephanie Hilz, Junya Fujimoto, Lynette Sholl, Jon Ritter, Farah Khalil, Yi Liu, Amaro Taylor-Weiner, Murray Resnick, Hui Yu, Fred R. Hirsch, Paul A. Bunn, David P. Carbone, Valerie Rusch, David J. Kwiatkowski, Bruce E. Johnson, Jay M. Lee, Stephanie R. Hennek, Ilan Wapinski, Alan Nicholas, Ann Johnson, Katja Schulze, Mark G. Kris, Ignacio I. Wistuba
Journal: Journal of Thoracic Oncology (2023)
Ambient Heat and Risk of Serious Hypoglycemia in Older Adults With Diabetes Using Insulin in the U.S. and Taiwan: A Cross-National Case-Crossover Study
Authors: Aayush Visaria, Shu-Ping Huang, Chien-Chou Su, David Robinson, John Read, Chuan-Yao Lin, Rachel Nethery, Kevin Josey, Poonam Gandhi, Benjamin Bates, Melanie Rua, Ashwagosha Parthasarathi, Arnab K. Ghosh, Yea-Huei Kao Yang, Soko Setoguchi
Journal: Diabetes Care (2023)

OBJECTIVE To measure the association between ambient heat and hypoglycemia-related emergency department visit or hospitalization in insulin users. RESEARCH DESIGN AND METHODS We identified cases of serious hypoglycemia among adults using insulin aged ≥65 in the U.S. (via Medicare Part A/B/D-eligible beneficiaries) and Taiwan (via National Health Insurance Database) from June to September, 2016–2019. We then estimated odds of hypoglycemia by heat index (HI) percentile categories using conditional logistic regression with a time-stratified case-crossover design. RESULTS Among ∼2 million insulin users in the U.S. (32,461 hypoglycemia case subjects), odds ratios of hypoglycemia for HI &amp;gt;99th, 95–98th, 85–94th, and 75–84th percentiles compared with the 25–74th percentile were 1.38 (95% CI, 1.28–1.48), 1.14 (1.08–1.20), 1.12 (1.08–1.17), and 1.09 (1.04–1.13) respectively. Overall patterns of associations were similar for insulin users in the Taiwan sample (∼283,000 insulin users, 10,162 hypoglycemia case subjects). CONCLUSIONS In two national samples of older insulin users, higher ambient temperature was associated with increased hypoglycemia risk.