tbuckley/cabot-search huggingface dataset:
Economic inequalities in adolescents’ internalising symptoms: longitudinal evidence from eight countries
Authors: Thomas Steare, Sara Evans-Lacko, Mesele Araya, Santiago Cueto, Hai-Anh H Dang, Revathi Ellanki, Emily Garman, Gemma Lewis, Kelly Rose-Clarke, Praveetha Patalay
Journal: The Lancet Psychiatry (2024)

Research, mainly conducted in Europe and North America, has shown an inequitable burden of internalising mental health problems among adolescents from poorer households. We investigated whether these mental health inequalities differ across a diverse range of countries and multiple measures of economic circumstances.
Associations between white matter microstructure and cognitive decline in major depressive disorder versus controls in Germany: a prospective case-control cohort study
Authors: Kira Flinkenflügel, Susanne Meinert, Christopher Hirtsiefer, Dominik Grotegerd, Marius Gruber, Janik Goltermann, Nils R Winter, Frederike Stein, Katharina Brosch, Elisabeth J Leehr, Joscha Böhnlein, Katharina Dohm, Jochen Bauer, Ronny Redlich, Tim Hahn, Jonathan Repple, Nils Opel, Robert Nitsch, Hamidreza Jamalabadi, Benjamin Straube, Nina Alexander, Andreas Jansen, Igor Nenadić, Martijn P van den Heuvel, Tilo Kircher, Udo Dannlowski
Journal: The Lancet Psychiatry (2024)
Aberrant fragmentomic features of circulating cell-free mitochondrial DNA enable early detection and prognosis prediction of hepatocellular carcinoma
Authors: Yang Liu, Fan Peng, Siyuan Wang, Huanmin Jiao, Kaixiang Zhou, Wenjie Guo, Shanshan Guo, Miao Dang, Huanqin Zhang, Weizheng Zhou, Xu Guo, Jinliang Xing
Journal: Clinical and Molecular Hepatology (2024)

Early detection and effective prognosis prediction in patients with hepatocellular carcinoma (HCC) provides an avenue for survival improvement, yet more effective approaches are greatly needed. We sought to develop the detection and prognosis models with ultra-sensitivity and low cost based on fragmentomic features of circulating cell free mtDNA (ccf-mtDNA).
Multiple System Atrophy: Pathology, Pathogenesis, and Path Forward
Authors: Alain Ndayisaba, Glenda M. Halliday, Vikram Khurana
Journal: Annual Review of Pathology Mechanisms of Disease (2024)

Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by autonomic failure and motor impairment. The hallmark pathologic finding in MSA is widespread oligodendroglial cytoplasmic inclusions rich in aggregated α-synuclein (αSyn). MSA is widely held to be an oligodendroglial synucleinopathy, and we outline lines of evidence to support this assertion, including the presence of early myelin loss. We consider emerging data that support the possibility of neuronal or immune dysfunction as primary drivers of MSA. These hypotheses are placed in the context of a major recent discovery that αSyn is conformationally distinct in MSA versus other synucleinopathies such as Parkinson's disease. We outline emerging techniques in epidemiology, genetics, and molecular pathology that will shed more light on this mysterious disease. We anticipate a future in which cutting-edge developments in personalized disease modeling, including with pluripotent stem cells, bridge mechanistic developments at the bench and real benefits at the bedside.
<b>Glatiramer Acetate for the Treatment of Multiple Sclerosis: From First Generation Therapy to Elucidation of Immunomodulation and Repair</b>
Authors: Rina Aharoni, Ron Milo, Ruth Arnon
Journal: Pharmacological Reviews (2024)

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), with a putative autoimmune origin and complex pathogenesis. Modification of the natural history of MS by reducing relapses and slowing disability accumulation was first attained in the 1990 s with the development of the first-generation disease-modifying therapies. Glatiramer acetate (GA), a copolymer of L-alanine, L-lysine, L-glutamic acid, and L-tyrosine, was discovered due to its ability to suppress the animal model of MS, experimental autoimmune encephalomyelitis. Extensive clinical trials and long-term assessments established the efficacy and the safety of GA. Furthermore, studies of the therapeutic processes induced by GA in animal models and in MS patients indicate that GA affects various levels of the innate and the adaptive immune response, generating deviation from proinflammatory to anti-inflammatory pathways. This includes competition for binding to antigen presenting cells; driving dendritic cells, monocytes, and B-cells toward anti-inflammatory responses; and stimulating T-helper 2 and T-regulatory cells. The immune cells stimulated by GA reach the CNS and secrete in situ anti-inflammatory cytokines alleviating the pathological processes. Furthermore, cumulative findings reveal that in addition to its immunomodulatory effect, GA promotes neuroprotective repair processes such as neurotrophic factors secretion, remyelination, and neurogenesis. This review aims to provide an overview of MS pathology diagnosis and treatment as well as the diverse mechanism of action of GA. <h3>Significance Statement</h3> Understanding the complex MS immune pathogenesis provided multiple targets for therapeutic intervention, resulting in a plethora of agents, with various mechanisms of action, efficacy, and safety profiles. However, promoting repair beyond the body's limited spontaneous extent is still a major challenge. GA, one of the first approved disease-modifying therapies, induces diverse immunomodulatory effects. Furthermore, GA treatment results in elevated neurotrophic factors secretion, remyelination and neurogenesis, supporting the notion that immunomodulatory treatment can support in situ a growth-promoting and repair environment.
Reply to Chung <i>et al.</i> and to Rogliani and Calzetta
Authors: Chloë I Bloom, Freda Yang, Jadwiga A. Wedzicha
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Reply to Chung et al. and to Rogliani and Calzetta." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
<b>Innovation in cancer pharmacotherapy through integrative consideration of germline and tumor genomes</b>
Authors: Roman Tremmel, Daniel Hübschmann, Elke Schaeffeler, Sebastian Pirmann, Stefan Fröhling, Matthias Schwab
Journal: Pharmacological Reviews (2024)

Precision cancer medicine is widely established, and numerous molecularly targeted drugs for various tumor entities are approved or in development. Personalized pharmacotherapy in oncology has so far been based primarily on tumor characteristics, e.g., somatic mutations. However, the response to drug treatment also depends on pharmacological processes summarized under the term ADME (absorption, distribution, metabolism, and excretion). Variations in ADME genes have been the subject of intensive research for more than five decades, considering individual patients9 genetic makeup, referred to as pharmacogenomics (PGx). The combined impact of a patient9s tumor and germline genome is only partially understood and often not adequately considered in cancer therapy. This may be attributed, in part, to the lack of methods for combined analysis of both data layers. Optimized personalized cancer therapies should, therefore, aim to integrate molecular information about the tumor and the germline, taking into account existing PGx guidelines for drug therapy. Moreover, such strategies should provide the opportunity to consider genetic variants of previously unknown functional significance. Bioinformatic analysis methods and corresponding algorithms for data interpretation need to be developed to consider PGx data in interdisciplinary molecular tumor boards, where cancer patients are discussed to provide evidence-based recommendations for clinical management based on individual tumor profiles. <b>Significance Statement</b> The era of personalized oncology has seen the emergence of drugs tailored to genetic variants associated with cancer biology. However, full potential of targeted therapy remains untapped due to the predominant focus on acquired tumor-specific alterations. Optimized cancer care must integrate tumor and patient genomes, guided by pharmacogenomic principles. An essential prerequisite for realizing truly personalized drug treatment of cancer patients is the development of bioinformatic tools for comprehensive analysis of all data layers generated in modern precision oncology programs.
<b>Biochemistry, pharmacology and<i>in vivo</i>function of arginases</b>
Authors: Sophia K Heuser, Junjie Li, Silke Pudewell, Anthea LoBue, Zhixin Li, Miriam M Cortese-Krott
Journal: Pharmacological Reviews (2024)

Arginase catalyzes the hydrolysis of L-arginine into L-ornithine and urea. The two existing isoforms Arg1 and Arg2 show different cellular localizations and metabolic functions. Arginase activity is crucial for nitrogen detoxification in the urea cycle, synthesis of polyamines, and control of l-arginine bioavailability and nitric oxide production. Despite significant progress in the understanding of the biochemistry and function of arginases, several open questions remain. Recent studies have revealed that the regulation and function of Arg1 and Arg2 are cell-type-specific, species-specific, and profoundly different in mice and humans. The main differences were found in the distribution and function of Arg1 and Arg2 in immune and erythroid cells. Contrary to what was previously thought, Arg1 activity appears to be only partially related to vascular NO signaling under homeostatic conditions in the vascular wall, but its expression is increased under disease conditions and may be targeted by treatment with arginase inhibitors. Arg2 appears to be mainly a catabolic enzyme involved in the synthesis of L-ornithine, polyamine, and proline but may play a putative role in blood pressure control, at least in mice. The immunosuppressive role of arginase-mediated arginine depletion is a promising target for cancer treatment. This review critically revises and discusses the biochemistry, pharmacology, and in vivo function of arginase, focusing on the insights gained from the analysis of cell-specific Arg1 and Arg2 knockout mice and human studies using arginase inhibitors or pegylated recombinant arginase. <b>Significance Statement</b> The review emphasizes the need for further research to deepen our understanding of the regulation of Arg1 and Arg 2 in different cell types under consideration of their localization, species-specificity, and multiple biochemical and physiological roles. This could lead to better pharmacological strategies to target arginase activity in liver, cardiovascular, hematological, immune/infection diseases and cancer.
<i>Promising tools for future drug discovery and development in antiarrhythmic therapy</i>
Authors: Gema Mondéjar-Parreño, Patricia Sánchez-Pérez, Francisco Miguel Cruz, José Jalife
Journal: Pharmacological Reviews (2024)

Arrhythmia refers to irregularities in the rate and rhythm of the heart, with symptoms spanning from mild palpitations to life-threatening arrhythmias and sudden cardiac death (SCD). The complex molecular nature of arrhythmias complicates the selection of appropriate treatment. Current therapies involve the use of antiarrhythmic drugs (class I-IV) with limited efficacy and dangerous side effects and implantable pacemakers and cardioverter-defibrillators with hardware-related complications and inappropriate shocks. The number of novel antiarrhythmic drug in the development pipeline has decreased substantially during the last decade and underscores uncertainties regarding future developments in this field. Consequently, arrhythmia treatment poses significant challenges, prompting the need for alternative approaches. Remarkably, innovative drug discovery and development technologies show promise in helping advance antiarrhythmic therapies. Here, we review unique characteristics and the transformative potential of emerging technologies that offer unprecedented opportunities for transitioning from traditional antiarrhythmics to next-generation therapies. We assess stem cell technology, emphasizing the utility of innovative cell profiling using multi-omics, high-throughput screening, and advanced computational modeling in developing treatments tailored precisely to individual genetic and physiological profiles. We offer insights into gene therapy, peptide and peptibody approaches for drug delivery. We finally discuss potential strengths and weaknesses of such techniques in reducing adverse effects and enhancing overall treatment outcomes, leading to more effective, specific, and safer therapies. Altogether, this comprehensive overview introduces innovative avenues for personalized rhythm therapy, with particular emphasis on drug discovery, aiming to advance the arrhythmia treatment landscape and the prevention of SCD. <b>Significance Statement</b> Arrhythmias and sudden cardiac death account for 15–20% of deaths worldwide. However, current antiarrhythmic therapies are ineffective and with dangerous side effects. Here, we review the field of arrhythmia treatment underscoring the slow progress in advancing the cardiac rhythm therapy pipeline and the uncertainties regarding evolution of this field. We provide information on how emerging technological and experimental tools can help accelerate progress and address the limitations of antiarrhythmic drug discovery.
Call to Action: How Can We Promote the Development of New Pharmacologic Treatments in COPD?
Authors: Daniel C. Belz, Nirupama Putcha, Patricia Alupo, Trishul Siddharthan, Aaron Baugh, Nick Hopkinson, Peter Castaldi, Alberto Papi, David Mannino, Marc Miravitlles, MeiLan K. Han, Leonardo M. Fabbri, Maria Montes de Oca, Jerry A Krishnan, Dave Singh, Fernando J. Martinez, Nadia N Hansel, Peter M. A. Calverley
Journal: American Journal of Respiratory and Critical Care Medicine (2024)
Impact of Syringe and Needle Reuse on the Clinical Outcomes of Patients With Type 2 Diabetes: A 12-Week Randomized Clinical Trial
Authors: Gabriela Berlanda, Gabriela H. Telo, Agnes Nogueira Gossenheimer, Andrea Auler, Eduardo Sturmer da Silva, Paula Godinho Rodrigues, Ana Carolina Krum dos Santos, Sandro Campos Amico, Beatriz D. Schaan
Journal: Diabetes Care (2024)

OBJECTIVE To evaluate the clinical and laboratory outcomes of patients with type 2 diabetes by comparing the no reuse or reuse of syringes and needles for insulin injection. RESEARCH DESIGN AND METHODS Adults with type 2 diabetes who had reused syringes and needles at least three times were randomly instructed either to not reuse or to reuse insulin syringes and needles five times. The primary outcomes assessed were glycemic control, pain scores, and skin complications (ecchymosis, lipohypertrophy, nodules, infection) at baseline and 4, 8, and 12 weeks after the intervention. Secondary outcomes included treatment adherence, quality of life, microbiological contamination of syringes and needles, needle quality, and insulin injection technique. RESULTS Among the 71 participants (mean ± SD age 59.7 ± 8.8 years), 59% were women with a median duration of diabetes of 18 years (interquartile range 10–25 years) and a mean BMI of 31.7 ± 6.7 kg/m2. The group that reused syringes and needles experienced an increase in lipohypertrophy/nodules (0.16 ± 0.08, P = 0.040) but did not experience worsening pain or glycemic control, even when the syringes and needles were inserted into the skin with great effort. There was no difference in the total number of skin complications, quality of life, or microbiological contamination. Both groups improved treatment adherence, with a greater increase in the reuse group. CONCLUSIONS The reuse of syringes and needles is associated with a modest increase in lipohypertrophy/nodules but does not have a short-term impact on glycemic control in patients with type 2 diabetes.
Epidemiology of periportal fibrosis and relevance of current Schistosoma mansoni infection within the context of repeated mass drug administration in rural Uganda: a population-based, cross-sectional study
Authors: Seun Anjorin, Betty Nabatte, Simon Mpooya, Benjamin Tinkitina, Christopher K Opio, Narcis B Kabatereine, Goylette F Chami
Journal: The Lancet Microbe (2024)
Area-level socioeconomic inequalities in mortality in China: a nationwide cohort study based on the ChinaHEART project
Authors: Wenyao Peng, Siqi Lin, Bowang Chen, Xueke Bai, Chaoqun Wu, Xiaoyan Zhang, Yang Yang, Jianlan Cui, Wei Xu, Lijuan Song, Hao Yang, Wenyan He, Yan Zhang, Xi Li, Jiapeng Lu
Journal: The Lancet Public Health (2024)
Mass incarceration as a driver of the tuberculosis epidemic in Latin America and projected effects of policy alternatives: a mathematical modelling study
Authors: Yiran E Liu, Yasmine Mabene, Sergio Camelo, Zulma Vanessa Rueda, Daniele Maria Pelissari, Fernanda Dockhorn Costa Johansen, Moises A Huaman, Tatiana Avalos-Cruz, Valentina A Alarcón, Lawrence M Ladutke, Marcelo Bergman, Ted Cohen, Jeremy D Goldhaber-Fiebert, Julio Croda, Jason R Andrews
Journal: The Lancet Public Health (2024)
Design, synthesis and pharmacological evaluation of 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine derivatives as p21-activated kinase 4 inhibitors for treatment of pancreatic cancer
Authors: Yang Li, Yan Fang, Xiaoyu Chen, Linjiang Tong, Fang Feng, Qianqian Zhou, Shulun Chen, Jian Ding, Hua Xie, Ao Zhang
Journal: Acta Pharmaceutica Sinica B (2024)

The p21-activated kinase 4 (PAK4), a key regulator of malignancy, is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy. Given the lack of high efficacy PAK4 inhibitors, we herein reported the identification of a novel inhibitor 13 bearing a tetrahydrobenzofuro[2,3-c]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC50 values of 0.38 and 0.50 μmol/L, respectively. This compound directly binds to PAK4 in a non-ATP competitive manner. In the mouse Pan02 model, compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg, accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue. Overall, compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo, thus making it worthy of further exploration.
Re: Amanda A. Myers, Wei Shen Tan, Valentina Grajales, et al. Challenging the Paradigm of “BCG-unresponsive” Bladder Cancer: Does Additional Bacillus Calmette-Guérin Have an Effect? Eur Urol. In press. https://doi.org/10.1016/j.eururo.2024.05.027
Authors: Christopher Guske, Seyed Behzad Jazayeri, Roger Li
Journal: European Urology (2024)
Anagrelide and idarubicin combination induces GSDME-mediated pyroptosis as a potential therapy for high-PDE3A acute myeloid leukemia
Authors: Chenwei Yang, Yixin Hu, Li Gao, Zhiheng Li, Yongping Zhang, Ran Zhuo, Yayun Du, Hu Liu, Qi Ji, Minyuan Liu, Jian Pan, Jun Lu, Peifang Xiao, Yuanyuan Tian, Sudan He, Jing Ling, Shaoyan Hu
Journal: Leukemia (2024)
Ultraprocessed food (UPF), health, and mechanistic uncertainty: What should we be advising the public to do about UPFs?
Authors: Eric Robinson, Alexandra M Johnstone
Journal: PLoS Medicine (2024)

In this perspective, we discuss why current mechanistic uncertainty on ultraprocessed foods (UPFs) and health acts as a major challenge to providing informed dietary guidelines and public advice on UPFs. Based on the balance of current evidence, we do not believe it is appropriate to be advising consumers to avoid all UPFs and we await further evidence to inform consumer guidance on the need to limit consumption of specifics foods based on their degree or type of processing.
Histology-specific clinical trial of lenvatinib and pembrolizumab in patients with sarcoma
Authors: Sujana Movva, Kenneth Seier, Viswatej Avutu, Lauren B. Banks, Jason Chan, Ping Chi, Mark A. Dickson, Mrinal M. Gounder, Ciara M. Kelly, Mary L. Keohan, Robert Maki, Evan Rosenbaum, Tiffany Salcito, Kaithleen Rodriguez, Rebecca Dempsey, Paul A. Meyers, Seth M. Cohen, Martee L. Hensley, Jason A. Konner, Alison M. Schram, Robert A. Lefkowitz, Joseph P. Erinjeri, Li-Xuan Qin, William D. Tap, Sandra P. D’Angelo
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Survival of patients with metastatic sarcoma remains poor, and there is a pressing need for new therapies. Most sarcoma subtypes are not responsive to immune checkpoint inhibition alone. Lenvatinib, a multireceptor tyrosine kinase inhibitor targeting tumor vasculature, has an immunomodulatory activity that contributes to its antitumor effects. Therefore, we hypothesized that a combination of lenvatinib and pembrolizumab would lead to improved clinical outcomes in patients with sarcoma. Patients and Methods: This was an open-label, single-arm study of lenvatinib and pembrolizumab in the following cohorts: (A) leiomyosarcoma, (B) undifferentiated pleomorphic sarcoma (UPS), (C) vascular sarcomas (angiosarcoma and epithelioid hemangioendothelioma), (D) synovial sarcoma or malignant peripheral nerve sheath tumor (MPNST), and (E) bone sarcomas (osteosarcoma and chondrosarcoma). The primary endpoint was the best overall response (BOR) rate documented by RECIST v1.1 by 27 weeks in each cohort, with a threshold of ≥2 responses among 10 patients. Secondary endpoints included progression-free survival, overall survival, duration of response, and safety. Results: Forty-six patients were evaluable for the primary endpoint, which was met in the UPS and MPNST/synovial cohorts (BOR rates by 27 weeks of 25% and 30%, respectively). There were seven partial responses overall with additional responses noted in angiosarcoma and osteosarcoma. Treatment-related adverse events of any grade and grade 3 or higher occurred in 50/51 (98%) and 29/51 (57%) of patients, respectively. Conclusions: We observed durable responses in MPNST, synovial sarcoma, and osteosarcoma. Patients with UPS and angiosarcoma also responded. Further exploration of this approach is warranted to confirm activity and determine optimal dosing schedules.