tbuckley/cabot-search huggingface dataset:
Meis transcription factors regulate cardiac conduction system development and adult function
Authors: Noelia Muñoz-Martín, Ana Simon-Chica, Covadonga Díaz-Díaz, Vanessa Cadenas, Susana Temiño, Isaac Esteban, Andreas Ludwig, Barbara Schormair, Juliane Winkelmann, Veronika Olejnickova, David Sedmera, David Filgueiras-Rama, Miguel Torres
Journal: Cardiovascular Research (2024)

Abstract Aims The Cardiac Conduction System (CCS) is progressively specified during development by interactions among a discrete number of Transcriptions Factors that ensure its proper patterning and the emergence of its functional properties. Meis genes encode homeodomain transcription factors (TFs) with multiple roles in mammalian development. In humans, Meis genes associate with congenital cardiac malformations and alterations of cardiac electrical activity, however the basis for these alterations has not been established. Here we studied the role of Meis transcription factors in cardiomyocyte development and function during mouse development and adult life. Methods and Results We studied Meis1 and Meis2 conditional deletion mouse models that allowed cardiomyocyte-specific elimination of Meis function during development and inducible elimination of Meis function in cardiomyocytes of the adult CCS. We studied cardiac anatomy, contractility and conduction. We report that Meis factors are global regulators of cardiac conduction, with a predominant role in the CCS. While constitutive Meis deletion in cardiomyocytes led to congenital malformations of the arterial pole and atria, as well as defects in ventricular conduction, Meis elimination in cardiomyocytes of the adult CCS produced sinus node dysfunction and delayed atrio-ventricular conduction. Molecular analyses unraveled Meis-controlled molecular pathways associated with these defects. Finally, we studied in transgenic mice the activity of a Meis1 human enhancer related to an SNP associated by GWAS to PR elongation and found that the transgene drives expression in components of the atrio-ventricular conduction system. Conclusions Our study identifies Meis TFs as essential regulators of the establishment of cardiac conduction function during development and its maintenance during adult life. In addition, we generated animal models and identified molecular alterations that will ease the study of Meis-associated conduction defects and congenital malformations in humans.
Regorafenib for Hepatocellular Carcinoma in Real-World Practice (REFINE): A Prospective, Observational Study
Authors: Yoon Jun Kim, Philippe Merle, Richard S. Finn, Masatoshi Kudo, Heinz-Josef Klümpen, Ho Yeong Lim, Masafumi Ikeda, Alessandro Granito, Gianluca Masi, René Gerolami, Sung Bum Cho, Chih-Hung Hsu, Yi-Hsiang Huang, Long-Bin Jeng, Do Young Kim, Shi-Ming Lin, Matthias Pinter, Guoliang Shao, Naoya Kato, Masayuki Kurosaki, Kazushi Numata, Kung-Kai Kuo, Yilei Mao, Yih-Jyh Lin, Kangshun Zhu, Philip Twumasi-Ankrah, Javeed Khan, Maria Awan, Kirhan Ozgurdal, Shukui Qin
Journal: Liver Cancer (2024)

Introduction: In the phase 3 RESORCE trial, regorafenib prolonged overall survival (OS) in patients with unresectable hepatocellular carcinoma (uHCC) whose disease progressed on prior sorafenib. The prospective, observational REFINE study aimed to evaluate the safety and effectiveness of regorafenib in a broader population of patients in real-world clinical practice, including patients with Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, Child–Pugh B liver status, and sorafenib-intolerance. Methods: This international, prospective, multicenter study (NCT03289273) enrolled patients with uHCC for whom the decision to treat with regorafenib was made by their physician before enrollment, according to the local health authority-approved label. The primary aim was to evaluate the safety of regorafenib, including the incidence of treatment-emergent adverse events (TEAEs) and dose modifications due to TEAEs. Results: Of the 1,028 patients enrolled, 1,005 initiated regorafenib and were eligible for analysis. Median age was 66 years (range 21–94); most patients were male (83%), Child–Pugh A (61%), and had an ECOG PS of 0 or 1 (82%) at study entry. Overall, 47%, 11%, and 40% of patients initiated regorafenib at 160, 120, and 80 mg/day, respectively. Median treatment duration was 3.7 months (range 1 day–38.9 months). Dose modifications and permanent discontinuation of regorafenib due to TEAEs occurred in 45% and 31% of patients, respectively. The most common drug-related TEAEs were hand–foot skin reaction (31%), diarrhea (26%), and fatigue (15%). Median OS was 13.2 months (95% confidence interval 11.6, 14.8). Conclusion: The results of the real-world REFINE study confirmed the safety and effectiveness of regorafenib in a broad population of patients with uHCC. Of patients who received standard regorafenib dosing in REFINE, safety and efficacy findings were consistent with those reported in the RESORCE trial.
Systematic review and meta-analysis of adverse events in clinical trials of mental health apps
Authors: Jake Linardon, Matthew Fuller-Tyszkiewicz, Joseph Firth, Simon B. Goldberg, Cleo Anderson, Zoe McClure, John Torous
Journal: npj Digital Medicine (2024)

Mental health apps are efficacious, yet they may pose risks in some. This review (CRD42024506486) examined adverse events (AEs) from mental health apps. We searched (May 2024) the Medline, PsycINFO, Web of Science, and ProQuest databases to identify clinical trials of mental health apps. The risk of bias was assessed using the Cochrane Risk of Bias tool. Only 55 of 171 identified clinical trials reported AEs. AEs were more likely to be reported in trials sampling schizophrenia and delivering apps with symptom monitoring technology. The meta-analytic deterioration rate from 13 app conditions was 6.7% (95% CI = 4.3, 10.1, I2 = 75%). Deterioration rates did not differ between app and control groups (OR = 0.79, 95% CI = 0.62–1.01, I2 = 0%). Reporting of AEs was heterogeneous, in terms of assessments used, events recorded, and detail provided. Overall, few clinical trials of mental health apps report AEs. Those that do often provide insufficient information to properly judge risks related to app use.
Mystery of gamma wave stimulation in brain disorders
Authors: Qianting Deng, Chongyun Wu, Emily Parker, Jing Zhu, Timon Cheng-Yi Liu, Rui Duan, Luodan Yang
Journal: Molecular Neurodegeneration (2024)

Abstract Neuronal oscillations refer to rhythmic and periodic fluctuations of electrical activity in the central nervous system that arise from the cellular properties of diverse neuronal populations and their interactions. Specifically, gamma oscillations play a crucial role in governing the connectivity between distinct brain regions, which are essential in perception, motor control, memory, and emotions. In this context, we recapitulate various current stimulation methods to induce gamma entrainment. These methods include sensory stimulation, optogenetic modulation, photobiomodulation, and transcranial electrical or magnetic stimulation. Simultaneously, we explore the association between abnormal gamma oscillations and central nervous system disorders such as Alzheimer’s disease, Parkinson’s disease, stroke, schizophrenia, and autism spectrum disorders. Evidence suggests that gamma entrainment-inducing stimulation methods offer notable neuroprotection, although somewhat controversial. This review comprehensively discusses the functional role of gamma oscillations in higher-order brain activities from both physiological and pathological perspectives, emphasizing gamma entrainment as a potential therapeutic approach for neuropsychiatric disorders. Additionally, we discuss future opportunities and challenges in implementing such strategies.
Asciminib add-on to imatinib demonstrates sustained high rates of ongoing therapy and deep molecular responses with prolonged follow-up in the ASC4MORE study
Authors: Timothy P. Hughes, Giuseppe Saglio, Jan Geissler, Dong-Wook Kim, Elza Lomaia, Jiri Mayer, Anna Turkina, Shruti Kapoor, Ana Paula Cardoso, Becki Nieman, Sara Quenet, Jorge E. Cortes
Journal: Journal of Hematology & Oncology (2024)

Up to 65% of patients with chronic myeloid leukemia (CML) who are treated with imatinib do not achieve sustained deep molecular response, which is required to attempt treatment-free remission. Asciminib is the only approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket. This unique mechanism of action allows asciminib to be combined with adenosine triphosphate–competitive tyrosine kinase inhibitors to prevent resistance and enhance efficacy. The phase II ASC4MORE trial investigated the strategy of adding asciminib to imatinib in patients who have not achieved deep molecular response with imatinib. In ASC4MORE, 84 patients with CML in chronic phase not achieving deep molecular response after ≥ 1 year of imatinib therapy were randomized to asciminib 40 or 60 mg once daily (QD) add-on to imatinib 400 mg QD, continued imatinib 400 mg QD, or switch to nilotinib 300 mg twice daily. More patients in the asciminib 40- and 60-mg QD add-on arms (19.0% and 28.6%, respectively) achieved MR4.5 (BCR::ABL1 ≤ 0.0032% on the International Scale) at week 48 (primary endpoint) than patients in the continued imatinib (0.0%) and switch to nilotinib (4.8%) arms. Fewer patients discontinued asciminib 40- and 60-mg QD add-on treatment (14.3% and 23.8%, respectively) than imatinib (76.2%, including crossover patients) and nilotinib (47.6%). Asciminib add-on was tolerable, with rates of AEs and AEs leading to discontinuation less than those with nilotinib, although higher than those with continued imatinib (as expected in these patients who had already been tolerating imatinib for ≥ 1 year). No new or worsening safety signals were observed with asciminib add-on vs the known asciminib monotherapy safety profile. Overall, these results support asciminib add-on as a treatment strategy to help patients with CML in chronic phase stay on therapy to safely achieve rapid and deep response, although further investigation is needed before this strategy is incorporated into clinical practice. NCT03578367
Tumor-derived G-CSF induces an immunosuppressive microenvironment in an osteosarcoma model, reducing response to CAR.GD2 T-cells
Authors: Michele Pezzella, Concetta Quintarelli, Maria C. Quadraccia, Andrea Sarcinelli, Simona Manni, Laura Iaffaldano, Alessio Ottaviani, Roselia Ciccone, Antonio Camera, Maria L. D’Amore, Stefano Di Cecca, Matilde Sinibaldi, Marika Guercio, Mariasole Aurigemma, Pamela De Falco, Valentina Fustaino, Rossella Rota, Silvia Pomella, Matteo Cassandri, Angela Di Giannatale, Chiara Agrati, Veronica Bordoni, Federica Guarracino, Michele Massa, Giada Del Baldo, Marco Becilli, Giuseppe M. Milano, Francesca Del Bufalo, Franco Locatelli, Biagio De Angelis
Journal: Journal of Hematology & Oncology (2024)

Sarcomas are rare, mesenchymal tumors, representing about 10–15% of all childhood cancers. GD2 is a suitable target for chimeric antigen receptor (CAR) T-cell therapy due to its overexpression in several solid tumors. In this preclinical study, we investigated the potential use of iCasp9.2A.GD2.CAR-CD28.4–1BBζ (CAR.GD2) T-cells as a treatment option for patients who have GD2-positive sarcomas and we sought to identify factors shaping hostile tumor microenvironment in this setting. GD2 expression was evaluated by flow-cytometry on primary tumor biopsies of pediatric sarcoma patients. GD2 expression in sarcoma cells was also evaluated in response to an enhancer of zeste homolog 2 (EZH2) inhibitor (Tazemetostat). The antitumor activity of CAR.GD2 T-cells was evaluated both in vitro and in vivo preclinical models of orthotopic and/or metastatic soft-tissue and bone sarcomas. GD2 expression was detected in 55% of the primary tumors. Notably, the Osteosarcoma and Alveolar Rhabdomyosarcomas subtypes exhibited the highest GD2 expression levels, while Ewing sarcoma showed the lowest. CAR.GD2 T-cells show a significant tumor control both in vitro and in vivo models of GD2-expressing tumors. Pretreatment with an EZH2 inhibitor (Tazemetostat) upregulating GD2 expression, sensitizes GD2dim sarcoma cells to CAR.GD2 T-cells cytotoxic activity. Moreover, in mouse models of disseminated Rhabdomyosarcomas and orthotopic Osteosarcoma, CAR.GD2 T-cells showed both a vigorous anti-tumor activity and long-term persistence as compared to un-transduced T-cells. The presence of immunosuppressive murine myeloid-derived suppressor (MDSC) cells significantly reduces long-term anti-tumour activity of infused CAR.GD2 T-cells. Tumor-derived G-CSF was found to be one of the key factors driving expansion of immunosuppressive murine and human MDSC, thus indirectly limiting the efficacy of CAR.GD2 T-cells. Our preclinical data strongly suggest that CAR.GD2 T-cells hold promise as a potential therapeutic option for the treatment of patients with GD2-positive sarcomas. Strategies to tackle hostile immunosuppressive MDSC are desirable to optimize CAR.GD2 T-cell activity.
An influenza mRNA vaccine protects ferrets from lethal infection with highly pathogenic avian influenza A(H5N1) virus
Authors: Masato Hatta, Yasuko Hatta, Angela Choi, Jaber Hossain, Chenchen Feng, Matthew W. Keller, Jana M. Ritter, Ying Huang, Emma Fang, Elizabeth A. Pusch, Thomas Rowe, Juan A. De La Cruz, Monique C. Johnson, Jimma Liddell, Nannan Jiang, Daniel Stadlbauer, Li Liu, Arindam K. Bhattacharjee, Joseph R. Rouse, Michael Currier, Li Wang, Min Z. Levine, Marie K. Kirby, John Steel, Han Di, John R. Barnes, Carole Henry, C. Todd Davis, Raffael Nachbagauer, David E. Wentworth, Bin Zhou
Journal: Science Translational Medicine (2024)

The global spread of the highly pathogenic avian influenza (HPAI) A(H5N1) virus poses a serious pandemic threat, necessitating the swift development of effective vaccines. The success of messenger RNA (mRNA) vaccine technology in the COVID-19 pandemic, marked by its rapid development and scalability, demonstrates its potential for addressing other infectious threats, such as HPAI A(H5N1). We therefore evaluated mRNA vaccine candidates targeting panzootic influenza A(H5) clade 2.3.4.4b viruses, which have been shown to infect a range of mammalian species, including most recently being detected in dairy cattle. Ferrets were immunized with mRNA vaccines encoding either hemagglutinin alone or hemagglutinin and neuraminidase, derived from a 2.3.4.4b prototype vaccine virus recommended by the World Health Organization. Kinetics of the immune responses, as well as protection against a lethal challenge dose of A(H5N1) virus, were assessed. Two doses of mRNA vaccination elicited robust neutralizing antibody titers against a 2022 avian isolate and a 2024 human isolate. Further, mRNA vaccination conferred protection from lethal challenge, whereas all unvaccinated ferrets succumbed to infection. It also reduced viral titers in the upper and lower respiratory tracts of infected ferrets. These results underscore the effectiveness of mRNA vaccines against HPAI A(H5N1), showcasing their potential as a vaccine platform for future influenza pandemics.
Dextromethorphan inhibits collagen and collagen-like cargo secretion to ameliorate lung fibrosis
Authors: Muzamil M. Khan, George Galea, Juan Jung, Joanna Zukowska, David Lauer, Nadine Tuechler, Aliaksandr Halavatyi, Christian Tischer, Per Haberkant, Frank Stein, Ferris Jung, Jonathan J. M. Landry, Arif M. Khan, Viola Oorschot, Isabelle Becher, Beate Neumann, Thomas Muley, Hauke Winter, Julia Duerr, Marcus A Mall, Alessandro Grassi, Ernesto de la Cueva, Vladimir Benes, Janine Gote-Schniering, Mikhail Savitski, Rainer Pepperkok
Journal: Science Translational Medicine (2024)

Excessive deposition of fibrillar collagen in the interstitial extracellular matrix (ECM) of human lung tissue causes fibrosis, which can ultimately lead to organ failure. Despite our understanding of the molecular mechanisms underlying the disease, no cure for pulmonary fibrosis has yet been found. We screened a drug library and found that dextromethorphan (DXM), a cough expectorant, reduced the amount of excess fibrillar collagen deposited in the ECM in cultured primary human lung fibroblasts, a bleomycin mouse model, and a cultured human precision-cut lung slice model of lung fibrosis. The reduced extracellular fibrillar collagen upon DXM treatment was due to reversible trafficking inhibition of collagen type I (COL1) in the endoplasmic reticulum (ER) in TANGO1- and HSP47-positive structures. Mass spectrometric analysis showed that DXM promoted hyperhydroxylation of proline and lysine residues on various collagens (COL1, COL3, COL4, COL5, COL7, and COL12) and latent transforming growth factor–β–binding protein (LTBP1 and LTBP2) peptides, coinciding with their secretion block. Additionally, proteome profiling of DXM-treated cells showed increased thermal stability of prolyl-hydroxylases P3H2, P3H3, P3H4, P4HA1, and P4HA2, suggesting a change in their activity. Transcriptome analysis of profibrotic stimulated primary human lung fibroblasts and human ex vivo lung slices after DXM treatment showed activation of an antifibrotic program through regulation of multiple pathways, including the MMP-ADAMTS axis, WNT signaling, and fibroblast-to-myofibroblast differentiation. Together, these data obtained from in vitro, in vivo, and ex vivo models of lung fibrogenesis show that DXM has the potential to limit fibrosis through inhibition of COL1 membrane trafficking in the ER.
Interleukin 8-CXCR2 mediated neutrophil extracellular trap (NET) formation in biliary atresia associated with NET-Induced stellate cell activation
Authors: Yuhuan Luo, Lisa Fraser, Julia Jezykowski, Nitika A. Gupta, Alexander G. Miethke, Sarah A. Taylor, Estella M. Alonso, Simon Horslen, Rohit Kohli, Jean P. Molleston, Binita M. Kamath, Stephen L. Guthery, Kathleen M. Loomes, John C. Magee, Phillip Rosenthal, Pamela Valentino, Ronald J. Sokol, Cara L. Mack
Journal: Hepatology (2024)

Background &amp; Aims: Biliary atresia (BA) entails an inflammatory sclerosing lesion of the biliary tree, with prominent fibrosis in infancy. Previous studies revealed neutrophil-activating IL-8 and neutrophil extracellular traps (NETs) positively correlated with bilirubin and risk of liver transplant. The aims of this study were to determine the mechanism of NET formation (NETosis) in BA and if NETs induce stellate cell activation. Approach: BA and other liver disease control plasma and tissue were obtained at diagnosis and transplant. Elastase, NETs, &amp; IL-8 were quantified by ELISA for plasma and by immunohistochemistry (IHC) for liver tissue. FACS analysis of neutrophils co-cultured with BA or control plasma measured BA-specific NETosis. Stellate cell activation from co-culture studies of stellate cells with NETs was measured by RT-qPCR, ELISA and FACS. Results: Liver neutrophils, NETs and plasma elastase, NETs and IL-8 were significantly increased in BA at diagnosis and transplant. Normal neutrophils co-cultured with BA plasma had increased NETosis and activation of CXCR2, an IL-8 receptor; CXCR2 inhibition decreased NET production. IHC identified increased NET expression of pro-fibrogenic tissue factor and IL-17. NETs co-cultured with stellate cells resulted in stellate cell activation, based on increased ACTA2 &amp; COL1A1 mRNA, collagen protein and cell surface expression of actin, collagen1A and PDGFRβ. Conclusions: BA patients have persistent IL-8-CXCR2-mediated NETosis that correlates with biomarkers of injury and fibrosis and NETs induce stellate cell activation, suggesting a role for NETs in the immunopathogenesis of disease. Future investigations should focus on therapeutic agents that inhibit NETs in BA.
Lhx2 specifically expressed in hepatic stellate cells promotes liver regeneration and inhibits liver fibrosis
Authors: Jiawang Tao, Zichao Wu, Yanran Liang, Jiongliang Wang, Miaoxiu Tang, Sunan Huang, Fan Jiang, Guangqi Zhou, Lin Guo, Shengxian Yuan, Yinxiong Li, Jie Wang
Journal: Hepatology (2024)

Promoting liver regeneration while inhibiting fibrogenesis represented an attractive strategy for treating liver diseases, with hepatic stellate cells (HSCs) being crucial to both processes. This study aimed to identify specific targets in HSCs that simultaneously facilitated regeneration and suppressed fibrosis, and elucidated their molecular mechanisms. Through comparing acute and chronic liver injury mouse models induced by CCl4 injections, we revealed that HSCs exhibited dual functionality, expressing pro-regenerative and pro-fibrogenic genes following injury. Analyzing RNA-seq data from primary HSCs of these models, along with publicly available single-cell RNA-seq data of HSCs, we identified transcription factor Lhx2, specifically expressed in HSCs, emerged as a potential regulator of the dual functions. Notably, Lhx2 showed significantly higher expression in HSCs from healthy liver tissue compared to fibrotic liver, in both mouse and human models. Lhx2 knockdown impaired liver function recovery and cellular proliferation after acute liver injury. Consistent changes were observed in mice with HSC-specific Lhx2 overexpression. Additionally, Lhx2 overexpression not only promoted hepatocyte proliferation but also exhibited an anti-fibrogenic function after chronic injury. Mechanistically, Lhx2 suppressed multiple functions of activated HSCs, including fibrogenesis, proliferation and migration, and up-regulated SMAD6 to block TGF-β signaling pathway. Moreover, Lhx2 was an upstream regulator of various pro-regenerative factors, especially HGF, which is crucial for liver regeneration. We demonstrated that Lhx2 had pro-regenerative and anti-fibrogenic functions, and elucidated its regulatory mechanism. The study provided a potential target with dual effects for treating liver diseases.
The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron
Authors: Kyle W. Sloop, Amy L. Cox, David B. Wainscott, Alex White, Brian A. Droz, Cynthia Stutsman, Aaron D. Showalter, Todd M. Suter, James D. Dunbar, Brandy M. Snider, Libbey S. O’Farrell, Natalie Hewitt, J. Craig Ruble, Leah R. Padgett, Eric M. Woerly, Jeffrey A. Peterson, Tamer Coskun, Zhaomin Liu, David E. Coutant, Minrong Ai, Paul J. Emmerson, Panjamaporn Sangwung, Francis S. Willard
Journal: Science Translational Medicine (2024)

Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address the metabolic disease epidemic. One of the first molecules in the emerging class of GLP-1R NPAs is orforglipron, which is in clinical development for treating type 2 diabetes and obesity. Here, we characterized the pharmacological properties of orforglipron in comparison with peptide-based GLP-1R agonists and other NPAs. Competition binding experiments using either [ 125 I]GLP-1(7-36)NH 2 or [ 3 H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant ( K i ) = 1 nM], selective ligand of the human GLP-1R. Signal transduction assays showed that orforglipron has low intrinsic efficacy for effector activation and negligible β-arrestin recruitment. To evaluate GLP-1R engagement in vivo, mice expressing the human GLP-1R were administered orforglipron and subjected to a glucose tolerance test. Predicted receptor occupancy was calculated using the receptor K i value of orforglipron and its unbound concentration in vivo that reduces hyperglycemia. These experiments revealed that low GLP-1R occupancy by orforglipron is sufficient to yield a full biological response. Moreover, in a model where CRISPR-Cas9 gene editing was used to sensitize the rat GLP-1R ( Glp1r S33W ) to GLP-1R NPAs, target engagement by orforglipron in the pancreas and brain was consistent with peptide-based GLP-1R agonists. Diet-induced obesity in Glp1r S33W rats enabled studies showing weight loss in animals orally administered orforglipron versus subcutaneous injection of GLP-1R agonist semaglutide. Furthermore, crossover studies indicated oral orforglipron can sustain efficacy initiated by parenteral semaglutide. The pharmacological properties of orforglipron may inform targeting of other peptide receptors with NPAs.