tbuckley/cabot-search huggingface dataset:
New Advances in the Pharmacology and Toxicology of Lithium: A Neurobiologically Oriented Overview
Authors: Analia Bortolozzi, Giovanna Fico, Michael Berk, Marco Solmi, Michele Fornaro, Joao Quevedo, Carlos A. Zarate, Lars V. Kessing, Eduard Vieta, Andre F. Carvalho
Journal: Pharmacological Reviews (2024)

Over the last six decades, lithium has been considered the gold standard treatment for the long-term management of bipolar disorder due to its efficacy in preventing both manic and depressive episodes as well as suicidal behaviors. Nevertheless, despite numerous observed effects on various cellular pathways and biologic systems, the precise mechanism through which lithium stabilizes mood remains elusive. Furthermore, there is recent support for the therapeutic potential of lithium in other brain diseases. This review offers a comprehensive examination of contemporary understanding and predominant theories concerning the diverse mechanisms underlying lithium's effects. These findings are based on investigations utilizing cellular and animal models of neurodegenerative and psychiatric disorders. Recent studies have provided additional support for the significance of glycogen synthase kinase-3 (GSK3) inhibition as a crucial mechanism. Furthermore, research has shed more light on the interconnections between GSK3-mediated neuroprotective, antioxidant, and neuroplasticity processes. Moreover, recent advancements in animal and human models have provided valuable insights into how lithium-induced modifications at the homeostatic synaptic plasticity level may play a pivotal role in its clinical effectiveness. We focused on findings from translational studies suggesting that lithium may interface with microRNA expression. Finally, we are exploring the repurposing potential of lithium beyond bipolar disorder. These recent findings on the therapeutic mechanisms of lithium have provided important clues toward developing predictive models of response to lithium treatment and identifying new biologic targets. <h3>Significance Statement</h3> Lithium is the drug of choice for the treatment of bipolar disorder, but its mechanism of action in stabilizing mood remains elusive. This review presents the latest evidence on lithium's various mechanisms of action. Recent evidence has strengthened glycogen synthase kinase-3 (GSK3) inhibition, changes at the level of homeostatic synaptic plasticity, and regulation of microRNA expression as key mechanisms, providing an intriguing perspective that may help bridge the mechanistic gap between molecular functions and its clinical efficacy as a mood stabilizer.
Age-associated CD4 <sup>+</sup> T cells with B cell–promoting functions are regulated by ZEB2 in autoimmunity
Authors: Manaka Goto, Hideyuki Takahashi, Ryochi Yoshida, Takahiro Itamiya, Masahiro Nakano, Yasuo Nagafuchi, Hiroaki Harada, Toshiaki Shimizu, Meiko Maeda, Akatsuki Kubota, Tatsushi Toda, Hiroaki Hatano, Yusuke Sugimori, Kimito Kawahata, Kazuhiko Yamamoto, Hirofumi Shoda, Kazuyoshi Ishigaki, Mineto Ota, Tomohisa Okamura, Keishi Fujio
Journal: Science Immunology (2024)

Aging is a significant risk factor for autoimmunity, and many autoimmune diseases tend to onset during adulthood. We conducted an extensive analysis of CD4
Integrated Proteogenomics Uncover Mechanisms of Glioblastoma Evolution, Pointing to Novel Therapeutic Targets
Authors: Jiabo Li, Ling-Kai Shih, Daniel J. Brat
Journal: Cancer Research (2024)

Abstract Nearly all glioblastoma (GBM) patients relapse following standard treatment and eventually succumb to disease. While large-scale, integrated multiomic studies have tremendously advanced the understanding of primary GBM at the cellular and molecular level, the posttherapeutic trajectory and biological properties of recurrent GBM remain poorly understood. This knowledge gap was addressed in a recent Cancer Cell article in which Kim and colleagues report on a highly integrative proteogenomic analysis performed on 123 matched primary and recurrent GBMs that uncovered a dramatic evolutionary shift from a proliferative state at initial diagnosis to the activation of neuronal and synaptogenic pathways at recurrence following therapy. Neuronal transition was characterized by posttranslational activation of WNT/PCP signaling and BRAF kinase, while many canonical oncogenic pathways, and EGFR in particular, were downregulated. Parallel multiomics analyses of patient-derived xenograft (PDX) models corroborated this evolutionary trajectory, allowing in vivo experiments for translational significance. Notably, targeting BRAF kinase disrupted both the neuronal transition and migration capabilities of recurrent gliomas, which were key characteristics of posttreatment progression. Furthermore, combining BRAF inhibitor vemurafenib with temozolomide prolonged survival in PDX models. Overall, the results reveal novel biological mechanisms of GBM evolution and therapy resistance, and suggest promising therapeutic intervention.
Discovery of a Novel Potent EGFR Inhibitor Against EGFR Activating Mutations and On-Target Resistance in NSCLC
Authors: Eun Ji Lee, Seung Yeon Oh, You Won Lee, Ju Young Kim, Min-Je Kim, Tae Ho Kim, Jii Bum Lee, Min Hee Hong, Sun Min Lim, Anke Baum, Lydia Woelflingseder, Harald Engelhardt, Mark Petronczki, Flavio Solca, Mi Ran Yun, Byoung Chul Cho
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) serve as the standard first-line therapy for EGFR-mutated non-small cell lung cancer (NSCLC). Despite the sustained clinical benefits achieved through optimal EGFR-TKI treatments, including the third-generation EGFR-TKI osimertinib, resistance inevitably develops. Currently, there are no targeted therapeutic options available postprogression on osimertinib. Here, we assessed the preclinical efficacy of BI-4732, a novel fourth-generation EGFR-TKI, using patient-derived preclinical models reflecting various clinical scenarios. Experimental Design: The antitumor activity of BI-4732 was evaluated using Ba/F3 cells and patient-derived cell/organoid/xenograft models with diverse EGFR mutations. Intracranial antitumor activity of BI-4732 was evaluated in a brain-metastasis mouse model. Results: We demonstrated the remarkable antitumor efficacy of BI-4732 as a single agent in various patient-derived models with EGFR_C797S-mediated osimertinib resistance. Moreover, BI-4732 exhibited activity comparable to osimertinib in inhibiting EGFR-activating (E19del and L858R) and T790M mutations. In a combination treatment strategy with osimertinib, BI-4732 exhibited a synergistic effect at significantly lower concentrations than those used in monotherapy. Importantly, BI-4732 displayed potent antitumor activity in an intracranial model, with low efflux at the blood–brain barrier. Conclusions: Our findings highlight the potential of BI-4732, a selective EGFR-TKI with high blood–brain barrier penetration, targeting a broad range of EGFR mutations, including C797S, warranting clinical development.
Single-cell transcriptome analyses reveal disturbed decidual homoeostasis in obstetric antiphospholipid syndrome
Authors: Chenyang Lu, Rui Gao, Pingying Qing, Xun Zeng, Xin Liao, Meng Cheng, Lang Qin, Yi Liu
Journal: Annals of the Rheumatic Diseases (2024)

Objectives Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disease characterised by the presence of antiphospholipid antibodies in circulation and pathological pregnancy. However, the pathogenesis of OAPS remains unknown. We aimed to reveal cellular compositions and molecular features of decidual cells involved in the development of OAPS using single-cell RNA sequencing (scRNA-seq). Methods We performed unbiased scRNA-seq analysis on the first-trimester decidua from five OAPS patients and five healthy controls (HCs), followed by validations with flow cytometry, immunohistochemical staining and immunofluorescence in a larger cohort. Serum chemokines and cytokines were measured by using ELISA. Results A higher ratio of macrophages but a lower ratio of decidual natural killer (dNK) cells was found in decidua from OAPS compared with HCs. Vascular endothelial cells shrinked in OAPS decidua while having upregulated chemokine expression and conspicuous responses to IFN-γ and TNF-α. Macrophages in OAPS had stronger phagocytosis function, complement activation signals and relied more on glycolysis. dNK cells were more activated in OAPS and had enhanced cytotoxicity and IFN-γ production. Downregulation of granules in OAPS dNK cells could be associated with suppressed glycolysis. Moreover, stromal cells had a prosenescent state with weakened immune surveillance for senescent cells in OAPS. In addition, the cellular interactions between decidual immune cells and those of immune cells with non-immune cells under disease state were altered, especially through chemokines, IFN-γ and TNF-α. Conclusion This study provided a comprehensive decidual cell landscape and identified aberrant decidual microenvironment in OAPS, providing some potential therapeutic targets for this disease.
Lower airway microbiota in COPD and healthy controls
Authors: Solveig Tangedal, Rune Nielsen, Marianne Aanerud, Christine Drengenes, Gunnar R Husebø, Sverre Lehmann, Kristel S Knudsen, Pieter S Hiemstra, Tomas ML Eagan
Journal: Thorax (2024)

Background The lower airway microbiota in patients with chronic obstructive pulmonary disease (COPD) are likely altered compared with the microbiota in healthy individuals. Information on how the microbiota is affected by smoking, use of inhaled corticosteroids (ICS) and COPD severity is still scarce. Methods In the MicroCOPD Study, participant characteristics were obtained through standardised questionnaires and clinical measurements at a single centre from 2012 to 2015. Protected bronchoalveolar lavage samples from 97 patients with COPD and 97 controls were paired-end sequenced with the Illumina MiSeq System. Data were analysed in QIIME 2 and R. Results Alpha-diversity was lower in patients with COPD than controls (Pielou evenness: COPD=0.76, control=0.80, p=0.004; Shannon entropy: COPD=3.98, control=4.34, p=0.01). Beta-diversity differed with smoking only in the COPD cohort (weighted UniFrac: permutational analysis of variance R 2 =0.04, p=0.03). Nine genera were differentially abundant between COPD and controls. Genera enriched in COPD belonged to the Firmicutes phylum. Pack years were linked to differential abundance of taxa in controls only (ANCOM-BC (Analysis of Compositions of Microbiomes with Bias Correction) log-fold difference/q-values: Haemophilus −0.05/0.048; Lachnoanaerobaculum −0.04/0.03). Oribacterium was absent in smoking patients with COPD compared with non-smoking patients (ANCOM-BC log-fold difference/q-values: −1.46/0.03). We found no associations between the microbiota and COPD severity or ICS. Conclusion The lower airway microbiota is equal in richness in patients with COPD to controls, but less even. Genera from the Firmicutes phylum thrive particularly in COPD airways. Smoking has different effects on diversity and taxonomic abundance in patients with COPD compared with controls. COPD severity and ICS use were not linked to the lower airway microbiota.
Comorbidity clusters in patients with rheumatoid arthritis identify a patient phenotype with a favourable prognosis
Authors: Cynthia S Crowson, Elizabeth J Atkinson, Vanessa L Kronzer, Bradly A Kimbrough, Courtney A Arment, Lynne S Peterson, Kerry Wright, Thomas G Mason, Delamo I Bekele, John M Davis, Elena Myasoedova
Journal: Annals of the Rheumatic Diseases (2024)

Objectives We aimed to cluster patients with rheumatoid arthritis (RA) based on comorbidities and then examine the association between these clusters and RA disease activity and mortality. Methods In this population-based study, residents of an eight-county region with prevalent RA on 1 January 2015 were identified. Patients were followed for vital status until death, last contact or 31 December 2021. Diagnostic codes for 5 years before the prevalence date were used to define 55 comorbidities. Latent class analysis was used to cluster patients based on comorbidity patterns. Standardised mortality ratios were used to assess mortality. Results A total of 1643 patients with prevalent RA (72% female; 94% white; median age 64 years, median RA duration 7 years) were studied. Four clusters were identified. Cluster 1 (n=686) included patients with few comorbidities, and cluster 4 (n=134) included older patients with 10 or more comorbidities. Cluster 2 (n=200) included patients with five or more comorbidities and high prevalences of depression and obesity, while cluster 3 (n=623) included the remainder. RA disease activity and survival differed across the clusters, with cluster 1 demonstrating more remission and mortality comparable to the general population. Conclusions More than 40% of patients with prevalent RA did not experience worse mortality than their peers without RA. The cluster with the worst prognosis (&lt;10% of patients with prevalent RA) was older, had more comorbidities and had less disease-modifying antirheumatic drug and biological use compared with the other clusters. Comorbidity patterns may hold the key to moving beyond a one-size-fits-all perspective of RA prognosis.
Prognostic factors for survival in unresectable stage III EGFR mutation-positive lung adenocarcinoma: impact of pre-CCRT PET-CT
Authors: Wei-Chun Lin, Wan-Ming Chen, Ben-Chang Shia, Szu-Yuan Wu
Journal: Thorax (2024)

To assess the survival impact of pre-concurrent chemoradiotherapy (CCRT) staging with positron emission tomography-CT (PET-CT) in patients with unresectable epidermal growth factor receptor (EGFR) mutation-positive adenocarcinoma.
Annals of the Rheumatic Diseases collection on pregnancy 2018–2023: observational data-driven knowledge
Authors: Kate Duhig, Kimme L Hyrich
Journal: Annals of the Rheumatic Diseases (2024)

Pregnancy can be an exciting time but for those living with rheumatic musculoskeletal diseases (RMDs), it can also be a time fraught with concern, including what effect pregnancy will have on the underlying RMD and what effect the RMD may have on the pregnancy and the baby, including the effects of medications. Generating an evidence base in pregnancy is challenging. Few interventional trials of medications in RMD pregnancies have ever been conducted, often for concerns of safety for both the mother and the child. Therefore, observational research remains important for informing clinical practice and helping women with RMDs make decisions regarding their health preconception and during pregnancy. The Annals of the Rheumatic Diseases (ARD) continues to publish important research on pregnancy in RMDs to increase the evidence base on this subject. Here we present an overview of papers published on this topic between January 2018 and December 2023. Our focus includes papers on pregnancy and RMD outcome, the effects of drug exposure, fetal outcomes as well as fertility.
“RIPping” off Pancreas Cancer's Blockage of Immune Surveillance
Authors: Xiuting Liu, Blake E. Sells, David G. DeNardo
Journal: Cancer Discovery (2024)

Summary: MHC-I downregulation is correlated with immunotherapy resistance in PDAC, but efficient strategies to increase cell-surface MHC-I are still lacking. This study by Sang, Zhou, Chen, Yu, and colleagues identified inhibition of tumor-intrinsic RIPK2 as a pharmacologic target to block the degradation of MHC-I on tumor cells and improved PDAC responses to anti–PD-1 immunotherapy. See related article by Sang et al., p. 326 (1) .
Highlighted research articles
Journal: Cancer Discovery (2024)

In This Issue| February 08 2024 Highlighted research articles Author & Article Information Online ISSN: 2159-8290 Print ISSN: 2159-8274 ©2024 American Association for Cancer Research2024American Association for Cancer Research Cancer Discov (2024) 14 (2): 201–203. https://doi.org/10.1158/2159-8290.CD-14-2-ITI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record February 8 2024 Citation Highlighted research articles. Cancer Discov 1 February 2024; 14 (2): 201–203. https://doi.org/10.1158/2159-8290.CD-14-2-ITI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search PI3Kα-selective inhibitors have received FDA approval for use in breast cancer, but clinical-acquired resistance to these inhibitors is not well understood. Using serial liquid biopsies and molecular profiling of rapid autopsies from 39 patients with advanced breast cancer that developed acquired resistance to orthosteric PI3Kα inhibitors, Varkaris, Fece de la Cruz, Martin, and colleagues showed that 50% of patients acquire genomic alterations in the PI3K pathway and identified secondary resistance mutations in PIK3CA that alter the inhibitor binding pocket. Use of the allosteric, pan-mutant-selective PI3Kα inhibitor RLY-2608 was able to overcome resistance induced by all mutations, providing insight into potential strategies to improve outcomes. See article, p. 227. PIK3CA is mutated in approximately 40% of hormone receptor-positive (HR+) breast cancer. Standard-of-care treatment with the orthosteric inhibitor alpelisib leads to dose-limiting hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Varkaris and colleagues discovered a cryptic allosteric pocket that... You do not currently have access to this content.
Injury incidence and prevalence in elite short-course triathletes: a 4-year prospective study
Authors: Melissa Leith Crunkhorn, Liam Anthony Toohey, Paula Charlton, Michael Drew, Kate Watson, Naroa Etxebarria
Journal: British Journal of Sports Medicine (2024)

Objective To characterise the prevalence, incidence rate (IR) and burden of injuries in elite short-course triathletes over a 4-year training and competition period. Methods Fifty elite Australian triathletes were prospectively monitored for injury during four consecutive seasons (2018–2021). Injuries requiring medical attention were prospectively recorded and further subcategorised according to time loss. The IR and burden (injury IR×mean injury severity) were calculated per 365 athlete days, with sex differences in IR compared using IR ratios (IRR) from negative binomial regression models. Results Two hundred and sixty-six injuries were reported in 46 (92.0%) athletes, of which 67.3% resulted in time loss. The injury IR was 1.87 injuries per 365 athlete days (95% CI 1.70 to 2.80), and comparable between sexes (IRR 0.82, 95% CI 0.64 to 1.04, p=0.109). Most injuries (70.7%) were training related. The most frequently injured body sites were the ankle (15.8%), foot (12.4%) and lower leg (12.0%). Bone stress injuries (BSIs) were the most burdensome injury type with 31.38 days of time loss per 365 days (95% CI 24.42 to 38.34). Twenty athletes (40.0%) reported at least one bone stress injury (BSI) (range 0–3). The rate of BSIs in female athletes was three times greater compared with male athletes (IRR 2.99, 95% CI 1.26 to 7.07, p=0.013). Conclusion Two-thirds of injuries reported in elite short-course triathletes resulted in time loss, with the majority occurring during training activities. Foot, ankle and other lower leg injuries had the highest incidence, with BSIs carrying the highest injury burden. The considerably higher rate of BSI observed in female athletes warrants consideration for future prevention strategies in female triathletes.
Long covid: Online rehabilitation can improve quality of life, study reports
Authors: Gareth Iacobucci
Journal: BMJ (2024)

A group online rehabilitation programme including gentle exercise and mental health support can improve quality of life for adults with long covid, a trial 1 published in The BMJ has reported.The eight week Regain programme led to sustained improvements in fatigue, pain, and depression compared with usual care in people who had been admitted to hospital with their initial covid infection, researchers found.Gordon McGregor, professor of clinical exercise physiology and rehabilitation at the University of Warwick, who led the clinical trial, told a media briefing that there was "no precedent" for how best to treat people with long covid, which was a complex and diverse condition or group of conditions.
<i>Notes from the Field</i>: Rapidly Linking an Outbreak of <i>Salmonella</i> Typhimurium Infections to Domestically Grown Cantaloupes Through Early Collaboration — United States, 2022
Authors: Colin Schwensohn, Benjamin Schneider, Erin Jenkins, Allison Wellman, Sharon Seelman Federman, Oluwakemi Oni, Nicole Stone, Jennifer Adams, Laura Gieraltowski
Journal: MMWR Morbidity and Mortality Weekly Report (2024)
Stigmatizing Language for Alcohol Use Disorder and Liver Disease on Liver Transplant Center Websites
Authors: Rachael Mahle, Adedayo Okanlawon, Jay Luther, Jeremy Louissaint, Wei Zhang
Journal: JAMA Network Open (2024)

This cross-sectional study investigates the adoption of recommendations for the use of nonstigmatizing language to describe alcohol use disorder and alcohol-related liver disease among liver transplant centers in the US.
Safety Profile and Adverse Event Management for Futibatinib, An Irreversible FGFR1–4 Inhibitor: Pooled Safety Analysis of 469 Patients
Authors: Funda Meric-Bernstam, Antoine Hollebecque, Junji Furuse, Do-Youn Oh, John A. Bridgewater, Masashi Shimura, Bailey Anderson, Nanae Hangai, Volker Wacheck, Lipika Goyal
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Futibatinib, a covalently-binding inhibitor of fibroblast growth factor receptor (FGFR)1-4 gained approval for the treatment of refractory, advanced intrahepatic cholangiocarcinoma (iCCA) harboring an FGFR2 fusion/other rearrangement. An integrated analysis was performed to evaluate safety and provide guidance on the management of futibatinib-associated adverse events (AEs) in patients with unresectable/metastatic tumors, including iCCA. Patients and Methods: Data from three global phase I or II studies of futibatinib (NCT02052778; JapicCTI-142552) were pooled. AEs were graded per NCI CTCAE v4.03, where applicable. Safety was analyzed for patients receiving any futibatinib starting dose (overall population) and in those receiving the approved starting dose of 20 mg once every day. Results: In total, 469 patients with one of 33 known tumor types were analyzed, including 318 patients who received futibatinib 20 mg every day. AEs of clinical interest (AECI; any grade/grade ≥3) in the overall population included hyperphosphatemia (82%/19%), nail disorders (27%/1%), hepatic AEs (27%/11%), stomatitis (19%/3%), palmar-plantar erythrodysesthesia syndrome (PPES; 13%/3%), rash (9%/0%), retinal disorders (8%/0%), and cataract (4%/1%). Median time to onset of grade ≥3 AECIs ranged from 9 days (hyperphosphatemia) to 125 days (cataract). Grade ≥3 hyperphosphatemia, hepatic AEs, PPES, and nail disorders resolved to grade ≤2 within a median of 7, 7, 8, and 28 days, respectively. Discontinuations due to treatment-related AEs were rare (2%), and no treatment-related deaths occurred. AE management included phosphate-lowering medication and dose adjustments. Conclusions: Futibatinib showed a consistent and manageable safety profile across patients with various tumor types. AECIs were mostly reversible with appropriate clinical management.
Fever, Rash, and Shortness of Breath in a 69-Year-Old
Authors: Vivekanand Tiwari, Alexander T. Miller
Journal: JAMA (2024)

A 69-year-old had fever, fatigue, rash, right periorbital swelling, and shortness of breath. Chest computed tomography revealed numerous small, bilateral pulmonary nodules; laboratory testing revealed mean corpuscular volume, 96.1 fL; hemoglobin level, 12.4 mg/dL; and leukopenia. What is the diagnosis and what would you do next?