tbuckley/cabot-search huggingface dataset:
Maternal folic acid over-supplementation impairs cardiac function in mice offspring by inhibiting SOD1 expression
Authors: Ke Cai, Feng Wang, Hai-Qun Shi, An-Na Shen, Rui Zhao, Hao-Ran Geng, Jia-Quan Lu, Yong-Hao Gui, Yan Shi, Jian-Yuan Zhao
Journal: Cardiovascular Research (2024)

Abstract Aims Folic acid (FA) supplementation during pregnancy aims to protect foetal development. However, maternal over-supplementation of FA has been demonstrated to cause metabolic dysfunction and increase the risk of autism, retinoblastoma, and respiratory illness in the offspring. Moreover, FA supplementation reduces the risk of congenital heart disease. However, little is known about its possible adverse effects on cardiac health resulting from maternal over-supplementation. In this study, we assessed the detrimental effects of maternal FA over-supplementation on the cardiac health of the offspring. Methods and results Eight-week-old C57BL/6J pregnant mice were randomly divided into control and over-supplemented groups. The offspring cardiac function was assessed using echocardiography. Cardiac fibrosis was assessed in the left ventricular myocardium by histological analysis. Proteomic, protein, RNA, and DNA methylation analyses were performed by liquid chromatography–tandem mass spectrometry, western blotting, real-time quantitative PCR, and bisulfite sequencing, respectively. We found that maternal periconceptional FA over-supplementation impaired cardiac function with the decreased left ventricular ejection fraction in the offspring. Biochemical indices and tissue staining further confirmed impaired cardiac function in offspring caused by maternal FA over-supplementation. The combined proteomic, RNA expression, and DNA methylation analyses suggested that key genes involved in cardiac function were inhibited at the transcriptional level possibly due to increased DNA methylation. Among these, superoxide dismutase 1 was down-regulated, and reactive oxygen species (ROS) levels increased in the mouse heart. Inhibition of ROS generation using the antioxidant N-acetylcysteine rescued the impaired cardiac function resulting from maternal FA over-supplementation. Conclusions Our study revealed that over-supplementation with FA during mouse pregnancy is detrimental to cardiac function with the decreased left ventricular ejection fraction in the offspring and provides insights into the mechanisms underlying the association between maternal FA status and health outcomes in the offspring.
Brain tumoroids: treatment prediction and drug development for brain tumors with fast, reproducible and easy-to-use personalized models
Authors: Aurélie Soubéran, Carine Jiguet-Jiglaire, Soline Toutain, Philippe Morando, Nathalie Baeza-Kallee, Romain Appay, Céline Boucard, Thomas Graillon, Mikael Meyer, Kaissar Farah, Dominique Figarella-Branger, Emeline Tabouret, Aurélie Tchoghandjian
Journal: Neuro-Oncology (2024)

Abstract Background The generation of patient avatars is critically needed in neuro-oncology for treatment prediction and preclinical therapeutic development. Our objective was to develop a fast, reproducible, low-cost, and easy-to-use method of tumoroids generation and analysis, efficient for all types of brain tumors, primary and metastatic. Methods Tumoroids were generated from 89 patients: 81 primary tumors including 77 gliomas, and 8 brain metastases. Tumoroids morphology and cellular and molecular characteristics were compared with the ones of the parental tumor by using histology, methylome profiling, pTERT mutations, and multiplexed spatial immunofluorescences. Their cellular stability over time was validated by flow cytometry. Therapeutic sensitivity was evaluated and predictive factors of tumoroid generation were analyzed. Results All the tumoroids analyzed had similar histological (n = 21) and molecular features (n = 7) to the parental tumor. The median generation time was 5 days. The success rate was 65 %: it was higher for high-grade gliomas and brain metastases versus IDH mutated low-grade gliomas. For high-grade gliomas, neither other clinical, neuro-imaging, histological nor molecular factors were predictive of tumoroid generation success. The cellular organization inside tumoroids analyzed by MACSima revealed territories dedicated to specific cell subtypes. Finally, we showed the correlation between tumoroid and patient treatment responses to radio-chemotherapy and their ability to respond to immunotherapy thanks to a dedicated and reproducible 3D analysis workflow. Conclusions Patient-derived tumoroid model that we developed offers a robust, user-friendly, low-cost, and reproducible preclinical model valuable for therapeutic development of all types of primary or metastatic brain tumors, allowing their integration into forthcoming early-phase clinical trials.
Microbiome 2.0: lessons from the 2024 Gut Microbiota for Health World Summit
Authors: Sushrut Jangi, Gail Hecht
Journal: Gut Microbes (2024)

This Meeting Summary highlights the key insights from the 12th meeting of the Gut Microbiota for Health World Summit, held in Washington, DC, organized by the American Gastroenterological Association (AGA) and the European Society of Neurogastroenterology and Motility (ESNM). Through a 2-day series of plenary sessions, workshops, a poster session, and live discussions involving thought leaders, physicians, researchers, and representatives from the Food and Drug Administration and the pharmaceutical industry, the conference attendees focused on the strategies and challenges in developing microbiome-based therapies to prevent and treat human disease. The conference highlighted progress in the field, including the recently successful introduction of 2 new fecal microbial transplantation-based products into the clinical setting, and the continuing development of next-generation probiotics. However, to continue to advance microbiome-directed treatments, three key themes emerged during the meeting, including (1) better methods to identify actionable targets in the microbiome (2) developing effective strategies to manipulate the microbiome (3) aligning microbiome-based therapies with existing treatment paradigms in the real world.
Impact of induction regimens intensity and allogeneic stem cell transplantation on survival of patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia: A multi‐institutional study
Authors: Talha Badar, Ravi Narra, Alice S Mims, Michael G Heckman, Rory M Shallis, Sheikh Fahad, Cameron Hunter, Vamsi Kota, Tamer Adel Othman, Brian Jonas, Shreya Desai, Guilherme Sacchi de Camargo Correia, Anand Patel, Adam S DuVall, Neil Palmisiano, Emily Curran, Zulfa Omer, Anjali Advani, Ehab Atallah, Mark Litzow
Journal: American Journal of Hematology (2024)

Intensive chemotherapy (IC) combination with second- or third-generation TKI improves survival compared to non-IC with first-generation TKI. Allo-HCT was suggestive of improving RFS/OS after propensity score matching and multivariable analysis.
In-situ nanoplatform with synergistic neutrophil intervention and chemotherapy to prevent postoperative tumor recurrence and metastasis
Authors: Wenxia Zheng, Jianye Li, Jiaojiao Li, Nana Bie, Zhaohan Wei, Jiaqi Qin, Shiyu Li, Tuying Yong, Qing Du, Xiangliang Yang, Lu Gan
Journal: Journal of Controlled Release (2024)
The Mayo ATTR‐CM score versus other diagnostic scores and cardiac biomarkers in patients with suspected cardiac amyloidosis
Authors: Giovanni Battista Bonfioli, Daniela Tomasoni, Giuseppe Vergaro, Vincenzo Castiglione, Marianna Adamo, Iacopo Fabiani, Victor Loghin, Carlo Mario Lombardi, Alessio Nicolai, Marco Metra, Michele Emdin, Alberto Aimo
Journal: European Journal of Heart Failure (2024)

Several scores were developed to help the diagnosis of cardiac amyloidosis (CA). The most recent one, being the Mayo transthyretin amyloidosis cardiomyopathy (ATTR-CM) score, was not externally validated. We compared the diagnostic performance of the ATTR-CM score with previous tools (increased wall thickness [IWT] score, AMYLoidosis Index [AMYLI] score, and cardiac biomarkers) in a cohort of patients evaluated for a suspicion of CA.
Zinc-alpha2-glycoprotein modulates blood pressure by regulating renal lipid metabolism reprogramming - mediated urinary Na+ excretion in hypertension
Authors: Xiaoxin Zhou, Chunyan Deng, Lin Chen, Lifu Lei, Xiaoliang Wang, Shuo Zheng, Caiyu Chen, Chengfeng Du, Valérie B Schini-Kerth, Jian Yang
Journal: Cardiovascular Research (2024)

Abstract Aims Organs modulating blood pressure are associated with a common cytokine known as adipokines. We chose Zinc-alpha2-glycoprotein (ZAG) due to its prioritized transcriptional level in the database. Previous studies showed that ZAG is involved in metabolic disorders. The aim of this study was to investigate its role in hypertension. Methods and results Serum ZAG levels were assessed in hypertensive and healthy participants. Blood pressure was monitored in Azgp1−/− mice and other animal models by 24-hour ambulatory implanted telemetric transmitters and tail-cuff method. Multi-omics analysis of proteomics and metabolomics were performed to explore possible mechanisms. Serum ZAG levels were significantly decreased and associated with morning urine Na+ excretion in hypertensive participants in a cross-sectional study. This study firstly reported that Azgp1−/− mice exhibited increased blood pressure and impaired urinary Na+ excretion, which were restored by AAV9-mediated renal tubule Azgp1 rescue. Azgp1 knockout caused the reprogramming of renal lipid metabolism, and increased Na+/H+-exchanger (NHE) activity in the renal cortex. Administration with a NHE inhibitor EIPA reversed the impaired urinary Na+ excretion in Azgp1−/− mice. Moreover, the activity of carnitine palmitoyltransferase 1 (CPT1), a key enzyme of fatty acid β-oxidation, was decreased, and the levels of malonyl-CoA, an inhibitor of CPT1, were increased in renal cortex of Azgp1−/− mice. Renal Cpt1 rescue improved urinary Na+ excretion and blood pressure in Azgp1−/− mice, accompanied by decreased renal fatty acid levels and NHE activity. Finally, administration of recombinant ZAG protein improved blood pressure and urinary Na+ excretion in spontaneous hypertension rats. Conclusion Deficiency of Azgp1 increased the malonyl CoA-mediated inhibition of CPT1 activity, leading to renal lipid metabolism reprogramming, resulting in accumulated fatty acids and increased NHE activity, subsequently decreasing urinary Na+ excretion and causing hypertension. These findings may provide a potential kidney-targeted therapy in the prevention and treatment of hypertension.
CC-Connect: Identifying solutions to elevating the cancer experience for adolescents and young adults (AYA) with cancer
Authors: Michael E Roth, Douglas S Hawkins, Janette K Merrill, Tara O Henderson
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Adolescents and young adults with cancer (AYAs, aged 15 to 39 years) experience unique challenges due to their developmental life stage, and many have limited access to support and resources. CC-Connect, the patient assistance component of the White House Cancer Moonshot CC-DIRECT initiative that aims to help childhood cancer families find the best care for their child, undertook a multipronged effort to identify key strategies for addressing the unique needs of AYAs with cancer. This paper describes the four strategies that emerged to form a comprehensive framework for addressing the unmet needs of AYAs with cancer, which can improve outcomes and enhance the cancer care experience for this vulnerable population.
Pan-cancer genomic analysis reveals <i>FOXA1</i> amplification is associated with adverse outcomes in non-small cell lung, prostate, and breast cancers
Authors: Alexander G Goglia, Mohammed Alshalalfa, Anwar Khan, Danielle R Isakov, Helen Y Hougen, Nishwant Swami, Jasmine Kannikal, Sean M Mcbride, Daniel R Gomez, Sanoj Punnen, Paul L Nguyen, Puneeth Iyengar, Emmanuel S Antonarakis, Brandon A Mahal, Edward Christopher Dee
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Introduction Alterations in forkhead box A1 (FOXA1), a pioneer transcription factor, are associated with poor prognosis in breast cancer (BC) and prostate cancer (PC). We characterized FOXA1 genomic alterations and their clinical impacts in a large pan-cancer cohort from the AACR GENIE database. Methods FOXA1 alterations were characterized across &amp;gt;87,000 samples from &amp;gt;30 cancer types for primary and metastatic tumors alongside patient characteristics and clinical outcomes. FOXA1 alterations were queried in the MSK-MET cohort (a GENIE subset), allowing definition of hazard ratios (HRs) and survival estimates based on Cox proportional hazard models. Results FOXA1 was altered in 1,869 samples (2.1%), with distinct patterns across different cancers: PC enriched with indel-inframe alterations, BC with missense mutations, and lung cancers with copy number (CN) amplifications. Of 74,715 samples with FOXA1 CN profiles, amplification was detected in 834 (1.1%). Amplification was most common in non-small cell lung cancer (NSCLC, 3% in primary; 6% in metastatic) and small cell lung cancer (4.1% primary; 3.5% metastatic), followed by BC (2% primary; 1.6% metastatic) and PC (2.2% primary; 1.6% metastatic). CN amplifications were associated with decreased overall survival in NSCLC (HR: 1.45, 95%CI: 1.06-1.99, p = .02), BC (HR: 3.04, 95%CI: 1.89-4.89, p = 4e−6), and PC (HR: 1.94, 95%CI: 1.03-3.68, p = .04). Amplifications were associated with wide-spread metastases in NSCLC, BC, and PC. Conclusions FOXA1 demonstrates distinct alteration profiles across cancer sites. Our findings suggest an association between FOXA1 amplification and both enhanced metastatic potential and decreased survival, highlighting prognostic and therapeutic potential in breast cancer, prostate cancer, and NSCLC.
The effect of economic downturn, financial hardship, unemployment, and relevant government responses on suicide
Authors: Mark Sinyor, Morton Silverman, Jane Pirkis, Keith Hawton
Journal: The Lancet Public Health (2024)

Economic circumstances and related factors, including unemployment and poverty, can have substantial effects on suicide rates. This relationship applies in all countries, irrespective of their World Bank income status or level of development. Therefore, means of mitigating such influences are essential components of strategies to reduce suicides. In this Series paper, we consider examples of such initiatives, including national policies to try to reduce the effect of economic downturns, efforts to maintain employment and avoid damaging austerity measures, maintenance of reasonable minimum wage levels, and specific policies to assist those most affected by poverty. We also highlight upstream measures such as investment in transport infrastructure, industries, and retraining programmes. Positive public health messaging that encourages coping, together with discouragement of media stories with messages that could contribute to hopelessness in those experiencing economic difficulties, can also be important components of strategies to try to reduce the effect of economic downturn on suicide.
Restriction of access to means used for suicide
Authors: Keith Hawton, Duleeka Knipe, Jane Pirkis
Journal: The Lancet Public Health (2024)

One of the most effective public health measures to prevent suicide is the restriction of access to means used in suicidal acts. This approach can be especially effective if a method is common and readily accessible. Suicide methods vary widely, and there have been several examples where means restriction has been applied, often with considerable success. Factors contributing to availability of suicide methods can include access to physical means as well as cognitive awareness of methods. In this paper, which is the second in a Series on a public health approach to suicide prevention, we focus primarily on examples of restricting access to physical means of suicide, such as pesticides, firearms, and medication. We also discuss restricting the cognitive availability of means through attention to media and other representations of suicide methods. There are challenges associated with restricting access to means, including resistance to measures required to change the availability of some methods (which might, in part, be commercially determined) and method substitution, whereby one suicide method is replaced by another. Nevertheless, means restriction must be an integral part of all national and local suicide prevention strategies.
Stepwise de novo establishment of inactive X chromosome architecture in early development
Authors: Zhenhai Du, Liangjun Hu, Zhuoning Zou, Meishuo Liu, Zihan Li, Xukun Lu, Clair Harris, Yunlong Xiang, Fengling Chen, Guang Yu, Kai Xu, Feng Kong, Qianhua Xu, Bo Huang, Ling Liu, Qiang Fan, Haifeng Wang, Sundeep Kalantry, Wei Xie
Journal: Nature Genetics (2024)
Neoadjuvant gemcitabine–cisplatin plus tislelizumab in persons with resectable muscle-invasive bladder cancer: a multicenter, single-arm, phase 2 trial
Authors: Kaiwen Li, Wenlong Zhong, Jinhai Fan, Shaogang Wang, Dexin Yu, Tao Xu, Jiaju Lyu, Shaoxu Wu, Tao Qin, Zhuo Wu, Longhao Xu, Kaijie Wu, Zheng Liu, Zhiquan Hu, Fan Li, Jinyou Wang, Qi Wang, Jie Min, Zhiqiang Zhang, Luping Yu, Sentai Ding, Longfei Huang, Tingting Zhao, Jian Huang, Tianxin Lin
Journal: Nature Cancer (2024)
Liver-targeted <i>Angptl4</i> silencing by antisense oligonucleotide treatment attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice
Authors: Melanie Modder, Wietse In het Panhuis, Mohan Li, Salwa Afkir, Alexandra L Dorn, Amanda C M Pronk, Trea C M Streefland, Reshma A Lalai, Stefan Pierrou, Stefan K Nilsson, Gunilla Olivecrona, Sander Kooijman, Patrick C N Rensen, Milena Schönke
Journal: Cardiovascular Research (2024)

Abstract Background and Aims Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase to regulate tissue fatty acid uptake from triglyceride-rich lipoproteins such as VLDL. While pharmacological inhibition of ANGPTL3 is being evaluated as lipid-lowering strategy, systemic ANGPTL4 inhibition is not pursued due to adverse effects. This study aimed to compare the therapeutic potential of liver-specific Angptl3 and Angptl4 silencing to attenuate hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established humanized model for lipoprotein metabolism. Methods and results Mice were subcutaneously injected twice-weekly with saline or liver-targeted antisense oligonucleotides against Angptl3, Angptl4, both, or a scrambled oligonucleotide. Plasma lipid levels, VLDL clearance and hepatic VLDL production were determined, and atherosclerosis development was assessed. For toxicological evaluation, cynomolgus monkeys were treated with three dosages of liver-targeted ANGPTL4-silencing oligonucleotides. Liver-targeted Angptl4 silencing reduced plasma triglycerides (-48%) and total cholesterol (-56%), explained by higher VLDL-derived fatty acid uptake by brown adipose tissue and lower VLDL production by the liver. Accordingly, Angptl4 silencing reduced atherosclerotic lesion size (-86%) and improved lesion stability. Hepatic Angptl3 silencing similarly attenuated hyperlipidemia and atherosclerosis development. While Angptl3 and Angptl4 silencing lowered plasma triglycerides in the refed and fasted state, respectively, combined Angptl3/4 silencing lowered plasma triglycerides independent of nutritional state. In cynomolgus monkeys, anti-ANGPTL4 ASO treatment was well tolerated without adverse effects. Conclusions Liver-targeted Angptl4 silencing potently attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, and liver-targeted ANGPTL4 silencing is well-tolerated in non-human primates. These data warrant further clinical development of liver-targeted ANGPTL4 silencing.
Gut Microbiota–Related Biomarkers in Immuno-Oncology
Authors: Carolina Alves Costa Silva, Marine Fidelle, Andrew A. Almonte, Lisa Derosa, Laurence Zitvogel
Journal: The Annual Review of Pharmacology and Toxicology (2024)

Carcinogenesis is associated with the emergence of protracted intestinal dysbiosis and metabolic changes. Increasing evidence shows that gut microbiota–related biomarkers and microbiota-centered interventions are promising strategies to overcome resistance to immunotherapy. However, current standard methods for evaluating gut microbiota composition are cost- and time-consuming. The development of routine diagnostic tools for intestinal barrier alterations and dysbiosis constitutes a critical unmet medical need that can guide routine treatment and microbiota-centered intervention decisions in patients with cancer. In this review, we explore the influence of gut microbiota on cancer immunotherapy and highlight gut-associated biomarkers that have the potential to be transformed into simple diagnostic tools, thus guiding standard treatment decisions in the field of immuno-oncology. Mechanistic insights toward leveraging the complex relationship between cancer immunosurveillance, gut microbiota, and metabolism open exciting opportunities for developing novel biomarkers in immuno-oncology.
Treating Sickle Cell Disease: Gene Therapy Approaches
Authors: Marina Cavazzana, Alice Corsia, Megane Brusson, Annarita Miccio, Michaela Semeraro
Journal: The Annual Review of Pharmacology and Toxicology (2024)

Sickle cell disease (SCD) is a hereditary blood disorder characterized by the presence of abnormal hemoglobin molecules and thus distortion (sickling) of the red blood cells. SCD causes chronic pain and organ damage and shortens life expectancy. Gene therapy emerges as a potentially curative approach for people with SCD who lack a matched sibling donor for hematopoietic stem cell transplantation. Here, we review recent progress in gene therapy for SCD and focus on innovative technologies that target the genetic roots of the disease. We also review the challenges associated with gene therapy, including oncogenic risks, and the need for refined delivery methods. Despite these hurdles, the rapidly evolving landscape of gene therapy for SCD raises hope for a paradigm shift in the treatment of this debilitating disease. As research progresses, a deeper understanding of the molecular mechanisms involved and continuous improvements in gene-editing technologies promise to bring gene therapy for SCD closer to mainstream clinical application, offering a transformative, curative option for patients with this genetic disorder.
Sequencing-Based Detection of Avian Influenza A(H5N1) Virus in Wastewater in Ten Cities
Authors: Michael J. Tisza, Blake M. Hanson, Justin R. Clark, Li Wang, Katelyn Payne, Matthew C. Ross, Kristina D. Mena, Anna Gitter, Sara J. Javornik Cregeen, Juwan Cormier, Vasanthi Avadhanula, Austen Terwilliger, John Balliew, Fuqing Wu, Janelle Rios, Jennifer Deegan, Pedro A. Piedra, Joseph F. Petrosino, Eric Boerwinkle, Anthony W. Maresso
Journal: New England Journal of Medicine (2024)
Immunoregulation of Liver Fibrosis: New Opportunities for Antifibrotic Therapy
Authors: Helene Gilgenkrantz, Rola Al Sayegh, Sophie Lotersztajn
Journal: The Annual Review of Pharmacology and Toxicology (2024)

Liver fibrosis develops in response to chronic liver injury and is characterized by a sustained inflammatory response that leads to excessive collagen deposition by myofibroblasts. The fibrogenic response is governed by the release of inflammatory mediators from innate, adaptive, and innate-like lymphoid cells and from nonprofessional immune cells (i.e., epithelial cells, hepatic myofibroblasts, and liver sinusoidal endothelial cells). Upon removal of the underlying cause, liver fibrosis can resolve via activation of specific immune cell subsets. Despite major advances in the understanding of fibrosis pathogenesis, there is still no approved antifibrotic therapy. This review summarizes our current knowledge of the immune cell landscape and the inflammatory mechanisms underlying liver fibrosis progression and regression. We discuss how reprogramming immune cell phenotype, in particular through targeting selective inflammatory pathways or modulating cell-intrinsic metabolism, may be translated into antifibrogenic therapies.