tbuckley/cabot-search huggingface dataset:
Protein aggregates containing wild-type and mutant NOTCH3 are major drivers of arterial pathology in CADASIL
Authors: Nicolas Dupré, Florian Gueniot, Valérie Domenga-Denier, Virginie Dubosclard, Christelle Nilles, David Hill-Eubanks, Christelle Morgenthaler-Roth, Mark T. Nelson, Céline Keime, Lydia Danglot, Anne Joutel
Journal: Journal of Clinical Investigation (2024)

Loss of arterial smooth muscle cells (SMCs) and abnormal accumulation of the extracellular domain of the NOTCH3 receptor (Notch3ECD) are the two core features of CADASIL, a common cerebral small vessel disease caused by highly stereotyped dominant mutations in NOTCH3. Yet, the relationship between NOTCH3 receptor activity, Notch3ECD accumulation and arterial SMC loss has remained elusive, hampering the development of disease-modifying therapies. Using dedicated histopathological and multiscale imaging modalities, we could detect and quantify previously undetectable CADASIL-driven arterial SMC loss in the central nervous system of mice expressing the archetypal Arg169Cys mutation. We found that arterial pathology was more severe and Notch3ECD accumulation greater in transgenic mice overexpressing the mutation on a wild-type Notch3 background (TgNotch3R169C) than in knock-in Notch3R170C/R170C mice expressing this mutation without a wild-type Notch3 copy. Notably, expression of Notch3-regulated genes was essentially unchanged in TgNotch3R169C arteries. We further showed that wild-type Notch3ECD co-aggregated with mutant Notch3ECD and that elimination of one copy of wild-type Notch3 in TgNotch3R169C was sufficient to attenuate Notch3ECD accumulation and arterial pathology. These findings suggest that Notch3ECD accumulation, involving mutant and wild-type NOTCH3, is a major driver of arterial SMC loss in CADASIL, paving the way for NOTCH3-lowering therapeutic strategies.
Comparative genomics incorporating translocation renal cell carcinoma mouse model reveals molecular mechanisms of tumorigenesis
Authors: Gopinath Prakasam, Akhilesh Mishra, Alana Christie, Jeffrey Miyata, Deyssy Carrillo, Vanina T. Tcheuyap, Hui Ye, Quyen N. Do, Yunguan Wang, Oscar Reig Torras, Ramesh Butti, Hua Zhong, Jeffrey Gagan, Kevin B. Jones, Thomas J. Carroll, Zora Modrusan, Steffen Durinck, Mai-Carmen Requena-Komuro, Noelle S. Williams, Ivan Pedrosa, Tao Wang, Dinesh Rakheja, Payal Kapur, James Brugarolas
Journal: Journal of Clinical Investigation (2024)

Translocation Renal Cell Carcinoma (tRCC) most commonly involves an ASPSCR1-TFE3 fusion, but molecular mechanisms remain elusive and animal models are lacking. Here, we show that human ASPSCR1-TFE3 driven by Pax8-Cre (a credentialed ccRCC driver) disrupted nephrogenesis and glomerular development causing neonatal death, whilst the ccRCC failed driver, Sglt2-Cre, induced aggressive tRCC (as well as ASPS) with complete penetrance and short latency. However, in both contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an EMT program. Electron microscopy of tRCC tumors showed lysosome expansion and functional studies revealed simultaneous activation of autophagy and mTORC1 pathways. Comparative genomic analyses encompassing an institutional human tRCC cohort (including a hitherto unreported SFPQ-TFEB fusion) and a variety of tumorgraft models (ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3, RBM10-TFE3, and MALAT1-TFEB) disclosed significant convergence in canonical (cell cycle, lysosome and mTORC1) and less established pathways such as Myc, E2F and inflammation (IL6/JAK/STAT3, interferon-γ, TLR signaling, systemic lupus, etc). Therapeutic trials (adjusted for human drug exposures) showed anti-tumor activity of cabozantinib. Overall, this study provides insight into MiT/TFE-driven tumorigenesis including the cell of origin and characterizes diverse mouse models available for research.
<i>Notes from the Field:</i> Reemergence of <i>Mycoplasma pneumoniae</i> Infections in Children and Adolescents After the COVID-19 Pandemic, United States, 2018–2024
Authors: Chris Edens, Benjamin R. Clopper, Jourdan DeVies, Alvaro Benitez, Erin R. McKeever, Dylan Johns, Bernard Wolff, Rangaraj Selvarangan, Jennifer E. Schuster, Geoffrey A. Weinberg, Peter G. Szilagyi, Fatimah S. Dawood, Lakshmi Radhakrishnan, Christina Quigley, Leila C. Sahni, Natasha Halasa, Laura S. Stewart, Meredith L. McMorrow, Brett Whitaker, Danielle M. Zerr, Vasanthi Avadhanula, John V. Williams, Marian G. Michaels, Aaron Kite-Powell, Janet A. Englund, Mary Allen Staat, Kathleen Hartnett, Heidi L. Moline, Adam L. Cohen, Maureen Diaz
Journal: MMWR Morbidity and Mortality Weekly Report (2024)
Progress Toward Measles Elimination — World Health Organization Eastern Mediterranean Region, 2019–2022
Authors: Nasrin Musa, Amany Ghoniem, Christopher H. Hsu, Sondos Mubarak, Gerald Sume, Mohammed Sharifuzzaman, JeongEun Bak, Yvan Hutin, Nadia Teleb, Natasha Crowcroft, Patrick O’Connor, Frank Mahoney, Quamrul Hassan
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

In 2015, all 22 World Health Organization Eastern Mediterranean Region (EMR) countries and areas (countries) pledged to achieve measles elimination by 2020.Despite success in several countries, most countries in the region still have not eliminated measles.This report updates a previous report and describes progress toward measles elimination in EMR during 2019-2022.During that period, estimated regional coverage with the first and second doses of a measles-containing vaccine (MCV) was 82%-83% and 76%-78%, respectively.During 2019-2022, approximately 160 million children were vaccinated during national or subnational supplementary immunization activities.Reported confirmed regional measles incidence decreased from 29.8 cases per 1 million population in 2019 to 7.4 in 2020, but then increased 68%, to 50.0 in 2022 because of challenges providing immunization services and conducting surveillance during the COVID-19 pandemic.Surveillance indicators deteriorated in 11 (50%) of the 22 EMR countries.During 2019-2022, four countries in the region were verified as having achieved measles elimination, but other countries reported immunity gaps and increased measles incidence in 2022.To achieve measles elimination in EMR, national immunization programs, especially in those countries with high measles incidence, will need to continue to recover from the COVID-19 pandemic, increase overall vaccination coverage to close immunity gaps, and maintain high-quality disease surveillance.
Ectopic expression of transcription factor ONECUT3 drives complex karyotype in Myelodysplastic Syndromes
Authors: Yingwan Luo, Xiaomin Feng, Wei Lang, Weihong Xu, Wei Wang, Chen Mei, Li Ye, Shuanghong Zhu, Lu Wang, Xinping Zhou, Huimin Zeng, Liya Ma, Yanling Ren, Jie Jin, Rongzhen Xu, Gang Huang, Hongyan Tong
Journal: Journal of Clinical Investigation (2024)

Chromosomal instability is a prominent biological feature of Myelodysplastic Syndromes (MDS), with over 50% of MDS patients harboring chromosomal abnormalities or a complex karyotype. Despite this observation, the mechanisms underlying mitotic and chromosomal defects in MDS remain elusive. In this study, we identified a ectopic expression of transcription factor ONECUT3, associated with complex karyotypes and poorer survival outcomes in MDS. ONECUT3-overexpressing cell models exhibited enrichment of several notable pathways, including signatures of sister chromosome exchange separation and mitotic nuclear division with the upregulation of INCENP and CDCA8 genes. Notably, dysregulation of Chromosome Passenger Complex (CPC) accumulation besides the cell equator and midbody during mitotic phases consequently caused cytokinesis failure and defective chromosome segregation. Mechanistically, the Homeobox (HOX) domain of ONECUT3, serving as the DNA binding domain, occupied the unique genomic regions of INCENP and CDCA8, and transcriptionally activated these two genes. A novel lead compound C5484617, was identified that functionally targeted the HOX domain of ONECUT3 inhibiting its transcriptional activity on downstream genes, and synergistically resensitized MDS cells to hypomethylating agents. This study revealed that ONECUT3 promoted chromosomal instability by transcriptional activation of INCENP and CDCA8, suggesting potential prognosis and therapeutic roles for targeting high-risk MDS patients with complex karyotype.
A Mobile Instant Messaging–Delivered Psychoeducational Intervention for Cancer Caregivers
Authors: Qinqin Cheng, Marques Shek Nam Ng, Kai Chow Choi, Yongyi Chen, Gaoming Liu, Winnie Kwok Wei So
Journal: JAMA Network Open (2024)

Importance Psychoeducational interventions (PEIs), which provide both information and emotional and psychosocial support, may address the unmet needs of the caregivers of adolescent and young adult patients with cancer. Objective To explore the effects of an instant messaging–delivered PEI on anxiety, depression, quality of life (QOL), and coping and determine whether the intervention reduces caregivers’ unmet needs. Design, Setting, and Participants This randomized clinical trial using an intention-to-treat protocol was conducted from April 1 to September 14, 2022, in a tertiary cancer hospital in China and included caregivers of patients diagnosed with cancer at age 15 to 39 years recruited using convenience sampling. Intervention Caregivers were allocated 1:1 using a randomized block scheme to the intervention or control group. The intervention group received a 5-week PEI and usual care, whereas the control group received only usual care. The PEI was delivered through articles and calls through an instant messaging application. Main Outcomes and Measures The primary outcomes were changes in the levels of caregivers’ anxiety and depression, measured using the 7-Item Generalized Anxiety Disorder Scale and the Patient Health Questionnaire 9, respectively. The secondary outcomes were changes in the levels of caregivers’ QOL, coping, and unmet needs. Results Of the 160 participants, 92 (57.5%) were male; mean (SD) age was 40.27 (8.33) years. Compared with the control group, the intervention group had significantly greater reduction in severity of anxiety (B = −3.231; 95% CI, −4.746 to −1.716; P &amp;amp;lt; .001) and depression (B = −3.253; 95% CI, −5.052 to −1.454; P &amp;amp;lt; .001), smaller reduction in QOL (B = 13.574; 95% CI, 0.488-26.661; P = .04), and greater reduction in unmet needs (B = −12.136; 95% CI, −18.307 to −5.965; P &amp;amp;lt; .001) after the intervention. Twelve weeks after baseline, the intervention group demonstrated a significantly greater reduction only in severity of anxiety (B = −1.890; 95% CI, −3.382 to −0.397; P = .01). Conclusions and Relevance In this randomized clinical trial of a mobile instant messaging–delivered PEI, caregivers’ unmet needs, anxiety, and depression decreased significantly and QOL declined at a significantly slower rate immediately after the intervention in the intervention group compared with the control group. A sustained effect on anxiety was observed 12 weeks after baseline. Trial Registration Chinese Clinical Trial Registry identifier: ChiCTR2200055951
Patient and Staff Perspectives on the Impacts and Challenges of Hospital-Based Harm Reduction
Authors: Leah Fraimow-Wong, Marlene Martín, Laura Thomas, Ro Giuliano, Oanh Kieu Nguyen, Kelly Knight, Leslie W. Suen
Journal: JAMA Network Open (2024)

Importance Harm reduction is associated with improved health outcomes among people who use substances. As overdose deaths persist, hospitals are recognizing the need for harm reduction services; however, little is known about the outcomes of hospital-based harm reduction for patients and staff. Objective To evaluate patient and staff perspectives on the impact and challenges of a hospital-based harm reduction program offering safer use education and supplies at discharge. Design, Setting, and Participants This qualitative study consisted of 40-minute semistructured interviews with hospitalized patients receiving harm reduction services and hospital staff at an urban, safety-net hospital in California from October 2022 to March 2023. Purposive sampling allowed inclusion of diverse patient racial and ethnic identities, substance use disorders (SUDs), and staff roles. Exposure Receipt of harm reduction education and/or supplies (eg, syringes, pipes, naloxone, and test strips) from an addiction consult team, or providing care for patients receiving these services. Main Outcomes and Measures Interviews were analyzed using thematic analysis to identify key themes. Results A total of 40 participants completed interviews, including 20 patients (mean [SD] age, 43 [13] years; 1 American Indian or Alaska Native [5%], 1 Asian and Pacific Islander [5%], 6 Black [30%]; 6 Latine [30%]; and 6 White [30%]) and 20 staff (mean [SD] age 37 [8] years). Patients were diagnosed with a variety of SUDs (7 patients with opioid and stimulant use disorder [35%]; 7 patients with stimulant use disorder [35%]; 3 patients with opioid use disorder [15%]; and 3 patients with alcohol use disorder [15%]). A total of 3 themes were identified; respondents reported that harm reduction programs (1) expanded access to harm reduction education and supplies, particularly for ethnically and racially minoritized populations; (2) built trust by improving the patient care experience and increasing engagement; and (3) catalyzed culture change by helping destigmatize care for individuals who planned to continue using substances and increasing staff fulfillment. Black and Latine patients, those who primarily used stimulants, and those with limited English proficiency (LEP) reported learning new harm reduction strategies. Program challenges included hesitancy regarding regulations, limited SUD education among staff, remaining stigma, and the need for careful assessment of patient goals. Conclusions and Relevance In this qualitative study, patients and staff believed that integrating harm reduction services into hospital care increased access for populations unfamiliar with harm reduction, improved trust, and reduced stigma. These findings suggest that efforts to increase access to harm reduction services for Black, Latine, and LEP populations, including those who use stimulants, are especially needed.
Enhancing Neonatal Intensive Care With Rapid Genome Sequencing
Authors: Shan Jiang, Bonny Parkinson, Yuanyuan Gu
Journal: JAMA Network Open (2024)

Daphna Marom, MD; Adi Mory, PhD; Sivan Reytan-Miron, MSc; Yam Amir, MSc; Alina Kurolap, PhD; Julia Grinshpun Cohen, PhD; Yocheved Morhi; Tatiana Smolkin, MD; Lior Cohen, MD; Shmuel Zangen, MD, MHA; Adel Shalata, MD, PhD; Arieh Riskin, MD, MHA, PhD; Amir Peleg, MD; Karen Lavie-Nevo, MD; Dror Mandel, MD; Elana Chervinsky, MD; Clari Felszer Fisch, MD; Vered Fleisher Sheffer, MD; Tzipora C. Falik-Zaccai, MD; Jonathan Rips, MD; Noa Ofek Shlomai, MD; Smadar Eventov Friedman, MD, PhD; Calanit Hershkovich Shporen, MD; Sagie Josefsberg Ben-Yehoshua, MD; Aryeh Simmonds, MD; Racheli Goldfarb Yaacobi, MD; Sofia Bauer-Rusek, MD; Hussam Omari, MD; Karin Weiss, MD; Ori Hochwald, MD; Arie Koifman, MD; Omer Globus, MD; Nurit Assia Batzir, MD; Naveh Yaron, MD; Reeval Segel, MD; Iris Morag, MD; Orit Reish, MD; Aviva Eliyahu, MD; Leah Leibovitch, MD; Marina Eskin Schwartz, MD, PhD; Ramy Abramsky, MD; Amit Hochberg, MD; Anat Oron, MD; Ehud Banne, MD; Igor Portnov, MD; Nadra Nasser Samra, MD; Amihood Singer, MD; Hagit Baris Feldman, MD
National Rapid Genome Sequencing in Neonatal Intensive Care
Authors: Daphna Marom, Adi Mory, Sivan Reytan-Miron, Yam Amir, Alina Kurolap, Julia Grinshpun Cohen, Yocheved Morhi, Tatiana Smolkin, Lior Cohen, Shmuel Zangen, Adel Shalata, Arieh Riskin, Amir Peleg, Karen Lavie-Nevo, Dror Mandel, Elana Chervinsky, Clari Felszer Fisch, Vered Fleisher Sheffer, Tzipora C. Falik-Zaccai, Jonathan Rips, Noa Ofek Shlomai, Smadar Eventov Friedman, Calanit Hershkovich Shporen, Sagie Josefsberg Ben-Yehoshua, Aryeh Simmonds, Racheli Goldfarb Yaacobi, Sofia Bauer-Rusek, Hussam Omari, Karin Weiss, Ori Hochwald, Arie Koifman, Omer Globus, Nurit Assia Batzir, Naveh Yaron, Reeval Segel, Iris Morag, Orit Reish, Aviva Eliyahu, Leah Leibovitch, Marina Eskin Schwartz, Ramy Abramsky, Amit Hochberg, Anat Oron, Ehud Banne, Igor Portnov, Nadra Nasser Samra, Amihood Singer, Hagit Baris Feldman
Journal: JAMA Network Open (2024)

National implementation of rapid trio genome sequencing (rtGS) in a clinical acute setting is essential to ensure advanced and equitable care for ill neonates.
Weight Loss and Physical Activity for Cardiovascular Protection Among Patients With Diabetes
Authors: Lance E. Davidson
Journal: JAMA Network Open (2024)

Zihao Huang, Msc; Xiaodong Zhuang, PhD; Rihua Huang, MD; Menghui Liu, PhD; Xinghao Xu, MD; Ziyan Fan, MD; Rongling Dai, MA; Hansheng Li, MA; Zhenyu Xiong, PhD; Yue Guo, PhD; Qi Liang, PhD; Xinxue Liao, PhD
Outbreak of <i>Mycobacterium orygis</i> in a Shipment of Cynomolgus Macaques Imported from Southeast Asia — United States, February–May 2023
Authors: Samantha D. Swisher, Sara J. Taetzsch, Mark E. Laughlin, William L. Walker, Adam J. Langer, Tyler C. Thacker, Jessica L. Rinsky, Kimberly A. Lehman, Anne Taffe, Nancy Burton, Doris M. Bravo, Emily McDonald, Clive M. Brown, Emily G. Pieracci
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Nonhuman primates (NHP) can become infected with the same species of Mycobacteria that cause human tuberculosis.All NHP imported into the United States are quarantined and screened for tuberculosis; no confirmed cases of tuberculosis were diagnosed among NHP during CDC-mandated quarantine during 2013-2020.In February 2023, an outbreak of tuberculosis caused by Mycobacterium orygis was detected in a group of 540 cynomolgus macaques (Macaca fascicularis) imported to the United States from Southeast Asia for research purposes.Although the initial exposure to M. orygis is believed to have occurred before the macaques arrived in the United States, infected macaques were first detected during CDCmandated quarantine.CDC collaborated with the importer and U.S. Department of Agriculture's National Veterinary Services Laboratories in the investigation and public health response.A total of 26 macaques received positive test results for M. orygis by culture, but rigorous occupational safety protocols implemented during transport and at the quarantine facility prevented cases among caretakers in the United States.Although the zoonotic disease risk to the general population remains low, this outbreak underscores the importance of CDC's regulatory oversight of NHP importation and adherence to established biosafety protocols to protect the health of the United States research animal population and the persons who interact with them.
Features and Factors Associated With Myeloid Neoplasms After Chimeric Antigen Receptor T-Cell Therapy
Authors: Mark Gurney, Anmol Baranwal, Allison Rosenthal, Mohamed A. Kharfan-Dabaja, Saad S. Kenderian, Yi Lin, Mithun Vinod Shah
Journal: JAMA Oncology (2024)

This case-control study examines the incidence and risks of myeloid neoplasms in adults treated for B-cell lymphoproliferative disorders or multiple myeloma.
Physical Activity and Weight Loss Among Adults With Type 2 Diabetes and Overweight or Obesity
Authors: Zihao Huang, Xiaodong Zhuang, Rihua Huang, Menghui Liu, Xinghao Xu, Ziyan Fan, Rongling Dai, Hansheng Li, Zhenyu Xiong, Yue Guo, Qi Liang, Xinxue Liao
Journal: JAMA Network Open (2024)

Importance Prior findings from the Look AHEAD trial showed no significant reduction in the risk of cardiovascular events by lifestyle-induced weight loss among individuals with type 2 diabetes (T2D) and overweight or obesity. However, physical activity (PA) may modify the changes in cardiovascular risk associated with weight loss. Objective To examine the joint association of weight loss and PA with the risk of adverse cardiovascular events in patients with T2D and overweight or obesity. Design, Setting, and Participants This cohort study was a post hoc analysis of the Look AHEAD randomized clinical trial, which compared the cardiovascular effects of weight loss by intensive lifestyle intervention vs diabetes support and education among individuals with T2D and overweight or obesity. The study was conducted from June 2001 to September 2012, and participants were patients in the substudy of accelerometry-measured PA from 8 locations in the United States. Data were analyzed from June to August 2023. Exposures Body weight change and accelerometer-derived PA volume across the first 4 years. Main Outcomes and Measures The primary outcome was a composite cardiovascular outcome including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina. Results Among a total of 1229 participants (mean [SD] age, 60 [7] years; 533 male [43%]), 333 (27%) achieved and maintained weight loss for the first 4 years. Among the individuals who maintained weight loss, 105 (32%) maintained high PA volume. During a median of 9.5 years of follow-up, 198 participants (16.1%) experienced the primary outcome. Compared with those with low PA volume and no weight loss (105 [15.8%]), maintaining high PA volume and weight loss was associated with a 61% lower risk of the primary end point (hazard ratio, 0.39; 95% CI, 0.19-0.81; P = .01). However, there was no significant difference in the risk of the primary end point among those with either weight loss only or high PA only. The multiplicative interaction between weight loss and PA for the risk of cardiovascular events was also significant ( P for interaction = .01). Conclusions and Relevance In this cohort study, maintaining weight loss and higher PA volume was associated with a lower risk of the composite cardiovascular outcome. The findings suggest that the cardiovascular benefits of PA may vary and be enhanced by weight loss among individuals with T2D and overweight or obesity.