tbuckley/cabot-search huggingface dataset:
Paired single-B-cell transcriptomics and receptor sequencing reveal activation states and clonal signatures that characterize B cells in acute myeloid leukemia
Authors: Shengnan Guo, Gopi S Mohan, Bofei Wang, Tianhao Li, Naval Daver, Yuting Zhao, Patrick K Reville, Dapeng Hao, Hussein A Abbas
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Acute myeloid leukemia (AML) is associated with a dismal prognosis. Immune checkpoint blockade (ICB) to induce antitumor activity in AML patients has yielded mixed results. Despite the pivotal role of B cells in antitumor immunity, a comprehensive assessment of B lymphocytes within AML’s immunological microenvironment along with their interaction with ICB remains rather constrained. Methods We performed an extensive analysis that involved paired single-cell RNA and B-cell receptor (BCR) sequencing on 52 bone marrow aspirate samples. These samples included 6 from healthy bone marrow donors (normal), 24 from newly diagnosed AML patients (NewlyDx), and 22 from 8 relapsed or refractory AML patients (RelRef), who underwent assessment both before and after azacitidine/nivolumab treatment. Results We delineated nine distinct subtypes of B cell lineage in the bone marrow. AML patients exhibited reduced nascent B cell subgroups but increased differentiated B cells compared with healthy controls. The limited diversity of BCR profiles and extensive somatic hypermutation indicated antigen-driven affinity maturation within the tumor microenvironment of RelRef patients. We established a strong connection between the activation or stress status of naïve and memory B cells, as indicated by AP-1 activity, and their differentiation state. Remarkably, atypical memory B cells functioned as specialized antigen-presenting cells closely interacting with AML malignant cells, correlating with AML stemness and worse clinical outcomes. In the AML microenvironment, plasma cells demonstrated advanced differentiation and heightened activity. Notably, the clinical response to ICB was associated with B cell clonal expansion and plasma cell function. Conclusions Our findings establish a comprehensive framework for profiling the phenotypic diversity of the B cell lineage in AML patients, while also assessing the implications of immunotherapy. This will serve as a valuable guide for future inquiries into AML treatment strategies.
Nucleosides are overlooked fuels in central carbon metabolism
Authors: Abigail Strefeler, Joan Blanco-Fernandez, Alexis A. Jourdain
Journal: Trends in Endocrinology and Metabolism (2024)

From our daily nutrition and synthesis within cells, nucleosides enter the bloodstream and circulate throughout the body and tissues. Nucleosides and nucleotides are classically viewed as precursors of nucleic acids, but recently they have emerged as a novel energy source for central carbon metabolism. Through catabolism by nucleoside phosphorylases, the ribose sugar group is released and can provide substrates for lower steps in glycolysis. In environments with limited glucose, such as at sites of infection or in the tumor microenvironment (TME), cells can use, and may even require, this alternative energy source. Here, we discuss the implications of these new findings in health and disease and speculate on the potential new roles of nucleosides and nucleic acids in energy metabolism.
VMAT structures reveal exciting targets for drug development
Authors: Shimon Schuldiner, Lucy R. Forrest
Journal: Trends in Pharmacological Sciences (2024)

Vesicular monoamine transporter (VMAT)-2 has a crucial role in the neurotransmission of biogenic amines. Recently, Dalton et al., Pidathala et al., Wu et al., and Wang et al. individually reported cryo-electron microscopy (EM) structures of human VMAT2, offering opportunities for developing improved therapeutics and deep insights into the functioning of this protein.
Helitrons: genomic parasites that generate developmental novelties
Authors: Daniela Barro-Trastoy, Claudia Köhler
Journal: Trends in Genetics (2024)

Helitrons, classified as DNA transposons, employ rolling-circle intermediates for transposition. Distinguishing themselves from other DNA transposons, they leave the original template element unaltered during transposition, which has led to their characterization as 'peel-and-paste elements'. Helitrons possess the ability to capture and mobilize host genome fragments, with enormous consequences for host genomes. This review discusses the current understanding of Helitrons, exploring their origins, transposition mechanism, and the extensive repercussions of their activity on genome structure and function. We also explore the evolutionary conflicts stemming from Helitron-transposed gene fragments and elucidate their domestication for regulating responses to environmental challenges. Looking ahead, further research in this evolving field promises to bring interesting discoveries on the role of Helitrons in shaping genomic landscapes.
The Global Burden of Alcohol-associated Cirrhosis and Cancer in Young and Middle-aged Adults
Authors: Pojsakorn Danpanichkul, Cheng Han Ng, Darren Jun Hao Tan, Karn Wijarnpreecha, Daniel Q. Huang, Mazen Noureddin, Benjamin Nah, Jia Hong Koh, Margaret Teng, Wen Hui Lim, Vijay Ramadoss, Elizabeth Thong, Mark Muthiah, Zhen Yu Wong, Apichat Kaewdech, Kwanjit Duangsonk, Ken Liu, Tomoya Sano, Hirokazu Takahashi, Vincent Chen, Brian P. Lee
Journal: Clinical Gastroenterology and Hepatology (2024)
The health state of France before COVID-19 pandemic between 1990 and 2019: an analysis of the Global Burden of Disease study 2019
Authors: Florence Francis-Oliviero, Panayotis Constantinou, Romana Haneef, Adel Al-Jumaily, Yannick Béjot, Louis Jacob, Julien Magne, Ali Mansour, Ali Mokdad, Manon Pigeolet, Mathieu Raad, Sedighi Mansour, Mathilde Touvier, Jean-David Zeitoun, Michaël Schwarzinger, Anne Gallay, Antoine Rachas, François Alla
Journal: The Lancet Regional Health - Europe (2024)

France faces nowadays some major challenges regarding its health care system including medically underserved areas, social health inequalities, and hospital pressures. Various indicators and sources of data allow us to describe the health status of a population and, consequently, to assess the impact of these challenges. We assessed the burden of diseases before COVID-19 in France in 2019 and its evolution from 1990 to 2019, and compared it with Western European countries. We used specific Global Burden of Diseases (GBD) metrics: socio-demographic index (SDI), life expectancy (LE), healthy life expectancy (HALE), years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) with their 95% uncertainty interval (95% UI). We compared French age-standardized metrics to those for other Western European Countries for both sexes and also between 1990 and 2019. We also described the specific causes of these different metrics. We observed for life expectancy at birth in France a trend to an improvement over time from 77.2 (95% UI: 77.2–77.3) years in 1990 to 82.9 (82.7–83.1) in 2019, which represented the seventh highest life expectancy among 23 Western European countries. HALE at birth in France increased from 67.0 (64.0–69.7) to 71.5 (68.1–74.5), which represented the fourth highest HALE among 23 Western European countries. In France, the total number of DALY per 100.000 population tended to decrease from 25,192 (22,374–28,351) in 1990 to 18,782 (16,408–21,920) in 2019. As compared to other European countries, the burden due to cardiovascular diseases was lower. Neoplasms and cardio-vascular diseases were the two leading causes of YLLs. Mental and musculoskeletal disorders were the two leading causes of YLDs. Overall, these results highlight a clear trend of improvement in the health status in France with certain differences between western European countries. The health policy makers need to devise interventional strategies to reduce the burden of diseases and injuries, with specific attention to causes such as cancers, cardiovascular diseases, mental health and musculoskeletal disorders. Bill & Melinda Gates Foundation.
Supporting the case for a targeted approach for elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis with no F508del CFTR variant: further analysis for the French compassionate use programme
Authors: Michael Dooney, Tarek Saba
Journal: European Respiratory Journal (2024)

We have read with great interest the work of Burgel et al. [1] and applaud them for their innovative use of elexacaftor/tezacaftor/ivacaftor (ETI) in combination with ivacaftor (IVA) in people with significant cystic fibrosis (CF) respiratory disease who were carriers of cystic fibrosis transmembrane conductance regulator (CFTR) variants that did not meet eligibility criteria for funded treatment. The observed response rate of 54% is impressive and regulatory bodies should take note of such a result, especially considering that a profound treatment effect was observed in those who responded. Elexacaftor/tezacaftor/ivacaftor is effective in more people with cystic fibrosis than initially thought with targeted use <https://bit.ly/47YF0QY>
5S-Heudelotinone alleviates experimental colitis by shaping the immune system and enhancing the intestinal barrier in a gut microbiota-dependent manner
Authors: Qing Meng, Jianshuang Guo, Ke Lv, Yang Liu, Jin Zhang, Mingyue Li, Xirui Cheng, Shenghua Chen, Xiaoguang Huo, Quan Zhang, Yue Chen, Jing Li
Journal: Acta Pharmaceutica Sinica B (2024)

Aberrant changes in the gut microbiota are implicated in many diseases, including inflammatory bowel disease (IBD). Gut microbes produce diverse metabolites that can shape the immune system and impact the intestinal barrier integrity, indicating that microbe-mediated modulation may be a promising strategy for preventing and treating IBD. Although fecal microbiota transplantation and probiotic supplementation are well-established IBD therapies, novel chemical agents that are safe and exert strong effects on the gut microbiota are urgently needed. Herein, we report the total synthesis of heudelotinone and the discovery of 5
Reply to: Supporting the case for a targeted approach for elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis with no F508del CFTR variant: further analysis for the French compassionate use programme
Authors: Pierre-Régis Burgel
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>Lists of <i>CFTR</i> variants responsive and non-responsive to elexacaftor/tezacaftor/ivacaftor will help in expanding eligibility for people with cystic fibrosis carrying rare CFTR variants</b>https://bit.ly/3HQioXl
Interalveolar pore morphology in (pre-)COPD stages and associations with small airways
Authors: Stijn E. Verleden, Therese S. Lapperre, Annemiek Snoeckx, Wen Wen, Suresh K. Yogeswaran, Geert M. Verleden, Veronique Verplancke, Reinier R.L. Wener, Senada Koljenovic, Dieter J.E. Peeters, Jeroen M.H. Hendriks
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>There is a severity dependent increase in the size but not the absolute number of interalveolar pores of Kohn in COPD. In addition, the pore size shows important correlations with pulmonary function testing.</b>https://bit.ly/3HL1GJ8
Neutralization of SARS-CoV-2 BA.2.86 and JN.1 by CF501 adjuvant-enhanced immune responses targeting the conserved epitopes in ancestral RBD
Authors: Zezhong Liu, Jie Zhou, Weijie Wang, Guangxu Zhang, Lixiao Xing, Keqiang Zhang, Yuanzhou Wang, Wei Xu, Qian Wang, Qiuhong Man, Qiao Wang, Tianlei Ying, Yun Zhu, Shibo Jiang, Lu Lu
Journal: Cell Reports Medicine (2024)

The emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants BA.2.86 and JN.1 raise concerns regarding their potential to evade immune surveillance and spread globally. Here, we test sera from rhesus macaques immunized with 3 doses of wild-type SARS-CoV-2 receptor-binding domain (RBD)-Fc adjuvanted with the STING agonist CF501. We find that the sera can potently neutralize pseudotyped XBB.1.5, XBB.1.16, CH.1.1, EG.5, BA.2.86, and JN.1, with 50% neutralization titers ranging from 3,494 to 7,424. We also demonstrate that CF501, but not Alum, can enhance immunogenicity of the RBD from wild-type SARS-CoV-2 to improve induction of broadly neutralizing antibodies (bnAbs) with binding specificity and activity similar to those of SA55, BN03, and S309, thus exhibiting extraordinary broad-spectrum neutralizing activity. Overall, the RBD from wild-type SARS-CoV-2 also contains conservative epitopes. The RBD-Fc adjuvanted by CF501 can elicit potent bnAbs against JN.1, BA.2.86, and other XBB subvariants. This strategy can be adopted to develop broad-spectrum vaccines to combat future emerging and reemerging viral infectious diseases.
Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial
Authors: Patrick Yu-Wai-Man, Valerio Carelli, Nancy J. Newman, Magda Joana Silva, Aki Linden, Gregory Van Stavern, Jacek P. Szaflik, Rudrani Banik, Wojciech Lubiński, Berthold Pemp, Yaping Joyce Liao, Prem S. Subramanian, Marta Misiuk-Hojło, Steven Newman, Lorena Castillo, Jarosław Kocięcki, Marc H. Levin, Francisco Jose Muñoz-Negrete, Ali Yagan, Sylvia Cherninkova, David Katz, Audrey Meunier, Marcela Votruba, Magdalena Korwin, Jacek Dziedziak, Neringa Jurkutė, Joshua P. Harvey, Chiara La Morgia, Claudia Priglinger, Xavier Llòria, Livia Tomasso, Thomas Klopstock
Journal: Cell Reports Medicine (2024)

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON.
Follicular lymphoma B cells exhibit heterogeneous transcriptional states with associated somatic alterations and tumor microenvironments
Authors: Jordan E Krull, Kerstin Wenzl, Melissa A Hopper, Michelle K Manske, Vivekananda Sarangi, Matthew J Maurer, Melissa C Larson, Patrizia Mondello, ZhiZhang Yang, Joseph P Novak, Makayla Serres, Kaitlyn R Whitaker, Jose C Villasboas Bisneto, Thomas M Habermann, Thomas E Witzig, Brian K Link, Lisa M Rimsza, Rebecca L King, Stephen M Ansell, James R Cerhan, Anne J Novak
Journal: Cell Reports Medicine (2024)

Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma of germinal center origin, which presents with significant biologic and clinical heterogeneity. Using RNA-seq on B cells sorted from 87 FL biopsies, combined with machine-learning approaches, we identify 3 transcriptional states that divide the biological ontology of FL B cells into inflamed, proliferative, and chromatin-modifying states, with relationship to prior GC B cell phenotypes. When integrated with whole-exome sequencing and immune profiling, we find that each state was associated with a combination of mutations in chromatin modifiers, copy-number alterations to TNFAIP3, and T follicular helper cells (Tfh) cell interactions, or primarily by a microenvironment rich in activated T cells. Altogether, these data define FL B cell transcriptional states across a large cohort of patients, contribute to our understanding of FL heterogeneity at the tumor cell level, and provide a foundation for guiding therapeutic intervention.
Systematic analysis of off-label and off-guideline cancer therapy usage in a real-world cohort of 165,912 US patients
Authors: Ruishan Liu, Lisa Wang, Shemra Rizzo, Marius Rene Garmhausen, Navdeep Pal, Sarah Waliany, Sarah McGough, Yvonne G. Lin, Zhi Huang, Joel Neal, Ryan Copping, James Zou
Journal: Cell Reports Medicine (2024)

Patients with cancer may be given treatments that are not officially approved (off-label) or recommended by guidelines (off-guideline). Here we present a data science framework to systematically characterize off-label and off-guideline usages using real-world data from de-identified electronic health records (EHR). We analyze treatment patterns in 165,912 US patients with 14 common cancer types. We find that 18.6% and 4.4% of patients have received at least one line of off-label and off-guideline cancer drugs, respectively. Patients with worse performance status, in later lines, or treated at academic hospitals are significantly more likely to receive off-label and off-guideline drugs. To quantify how predictable off-guideline usage is, we developed machine learning models to predict which drug a patient is likely to receive based on their clinical characteristics and previous treatments. Finally, we demonstrate that our systematic analyses generate hypotheses about patients' response to treatments.
Genomic evolution shapes prostate cancer disease type
Authors: Dan J. Woodcock, Atef Sahli, Ruxandra Teslo, Vinayak Bhandari, Andreas J. Gruber, Aleksandra Ziubroniewicz, Gunes Gundem, Yaobo Xu, Adam Butler, Ezequiel Anokian, Bernard J. Pope, Chol-Hee Jung, Maxime Tarabichi, Stefan C. Dentro, J. Henry R. Farmery, Peter Van Loo, Anne Y. Warren, Vincent Gnanapragasam, Freddie C. Hamdy, G. Steven Bova, Christopher S. Foster, David E. Neal, Yong-Jie Lu, Zsofia Kote-Jarai, Michael Fraser, Robert G. Bristow, Paul C. Boutros, Anthony J. Costello, Niall M. Corcoran, Christopher M. Hovens, Charlie E. Massie, Andy G. Lynch, Daniel S. Brewer, Rosalind A. Eeles, Colin S. Cooper, David C. Wedge
Journal: Cell Genomics (2024)

The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression.
Multi-omic profiling of follicular lymphoma reveals changes in tissue architecture and enhanced stromal remodeling in high-risk patients
Authors: Andrea J. Radtke, Ekaterina Postovalova, Arina Varlamova, Alexander Bagaev, Maria Sorokina, Olga Kudryashova, Mark Meerson, Margarita Polyakova, Ilia Galkin, Viktor Svekolkin, Sergey Isaev, Daniil Wiebe, Anna Sharun, Alexander Sarachakov, Grigory Perelman, Yaroslav Lozinsky, Ziv Yaniv, Bradley C. Lowekamp, Emily Speranza, Li Yao, Stefania Pittaluga, Arthur L. Shaffer, Danny Jonigk, James D. Phelan, Theresa Davies-Hill, Da Wei Huang, Pavel Ovcharov, Krystle Nomie, Ekaterina Nuzhdina, Nikita Kotlov, Ravshan Ataullakhanov, Nathan Fowler, Michael Kelly, Jagan Muppidi, Jeremy L. Davis, Jonathan M. Hernandez, Wyndham H. Wilson, Elaine S. Jaffe, Louis M. Staudt, Mark Roschewski, Ronald N. Germain
Journal: Cancer Cell (2024)
Retinoic acid receptor activation reprograms senescence response and enhances anti-tumor activity of natural killer cells
Authors: Manuel Colucci, Sara Zumerle, Silvia Bressan, Federico Gianfanti, Martina Troiani, Aurora Valdata, Mariantonietta D’Ambrosio, Emiliano Pasquini, Angelica Varesi, Francesca Cogo, Simone Mosole, Cristina Dongilli, Maria Andrea Desbats, Liliana Contu, Ajinkya Revankdar, Jingjing Chen, Madhuri Kalathur, Maria Luna Perciato, Rossella Basilotta, Laczko Endre, Stefan Schauer, Alaa Othman, Ilaria Guccini, Miriam Saponaro, Luisa Maraccani, Nicolò Bancaro, Ping Lai, Lei Liu, Nicolò Pernigoni, Federico Mele, Sara Merler, Lloyd C. Trotman, Greta Guarda, Bianca Calì, Monica Montopoli, Andrea Alimonti
Journal: Cancer Cell (2024)

Cellular senescence can exert dual effects in tumors, either suppressing or promoting tumor progression. The senescence-associated secretory phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, favoring tumor-suppressive SASP factors over tumor-promoting ones. Here, we identify the retinoic-acid-receptor (RAR) agonist adapalene as an effective pro-senescence compound in prostate cancer (PCa). Reactivation of RARs triggers a robust senescence response and a tumor-suppressive SASP. In preclinical mouse models of PCa, the combination of adapalene and docetaxel promotes a tumor-suppressive SASP that enhances natural killer (NK) cell-mediated tumor clearance more effectively than either agent alone. This approach increases the efficacy of the allogenic infusion of human NK cells in mice injected with human PCa cells, suggesting an alternative therapeutic strategy to stimulate the anti-tumor immune response in "immunologically cold" tumors.
Group-based sleep trajectories in children and adolescents: A systematic review
Authors: Yuhang Wang, Buqun Li, Chenggang Zhang, Orfeu M. Buxton, Susan Redline, Xiaoyu Li
Journal: Sleep Medicine Reviews (2024)

Sleep is crucial for health and development. Evidence indicates that sleep changes over time and distinct subgroups may experience different longitudinal patterns. This study systematically reviewed the studies that used latent trajectory modeling to investigate sleep trajectories of children and adolescents aged 0–18 years, and summarized the associated determinants and health-related outcomes. We searched PubMed, Embase, CENTRAL, PsycINFO, and Web of Science, identifying 46 articles that met our criteria. To ensure the reliability of the review, only studies rated as good or fair in terms of methodological quality were included, resulting in a total of 36 articles. Group-based trajectories were identified on several sleep dimensions (i.e., sleep duration, general and specific sleep problems, and bed-sharing behavior) and three or four trajectories were reported in most studies. There was a convergence trend across sleep duration trajectories during the first six years of life. Studies on specific sleep problem (i.e., insomnia, night-waking, and sleep-onset difficulties) typically identified two trajectories: consistent minimal symptoms or chronic yet fluctuating symptoms. Lower socioeconomic status, maternal depression, and night feeding behaviors were the most frequently reported potential determinants of sleep trajectories. Membership in a group with certain adverse patterns (e.g., persistent short sleep duration) was associated with increased risks of multiple negative health-related conditions, such as obesity, compromised immunity, neurological problems, substance use, or internalizing/externalizing symptoms. Generally, there is potential to improve the quality of studies in this field. Causality is hard to be inferred within the current body of literature. Future studies could emphasize early life sleep, incorporate more assessment timepoints, use objective measures, and employ experimental design to better understand changes of and mechanisms behind the various sleep trajectories and guide targeted interventions for at-risk subpopulations.