tbuckley/cabot-search huggingface dataset:
TCTN1 Induces Fatty Acid Oxidation to Promote Melanoma Metastasis
Authors: Yinlam Li, Ren Ming, Tianyi Zhang, Zixu Gao, Lu Wang, Yang Yang, Kangjie Shen, Chenlu Wei, Yu Zhu, Jianrui Li, Shaoluan Zheng, Zucheng Luo, Yiteng Ding, Jiangying Xuan, Qianrong Hu, Yanwen Yang, Jianying Gu, Chuanyuan Wei
Journal: Cancer Research (2024)

Abstract Metabolic reprogramming promotes and sustains multiple steps of melanoma metastasis. Identification of key regulators of metabolic reprogramming could lead to the development of treatments for preventing and treating metastatic melanoma. Here, we identified that the tectonic family member TCTN1 promotes melanoma metastasis by increasing fatty acid oxidation (FAO). In clinical melanoma samples, high expression of TCTN1 correlated with increased metastasis and shorter patient survival. Functionally, TCTN1 promoted melanoma invasion and migration in vitro and distant metastasis in vivo, and TCTN1 induced a mesenchymal-like phenotype switch. Mechanistically, TCTN1 acted as a protein scaffold to promote the binding of HADHA and HADHB, subunits of the mitochondrial trifunctional protein complex, thus leading to FAO activation. TCTN1-mediated FAO activated the p38/MAPK signaling pathway in melanoma cells, promoting tumor EMT and stemness. Molecular docking indicated that the prostaglandin F receptor agonist fluprostenol can block HADHA/HADHB binding, which was confirmed experimentally. Treatment with fluprostenol was able to inhibit TCTN1-induced melanoma invasion and metastasis. Taken together, these findings elucidate the mechanism of TCTN1-mediated promotion of melanoma metastasis and support the potential application of fluprostenol for targeted therapy of metastatic melanoma.
The actin-binding protein drebrin disrupts NF2-LATS kinases complex assembly to facilitate liver tumorigenesis
Authors: Yang Sun, Henan Wei, Wentao Yu, Haoran Gao, Jinhui Li, Xiaoyu Li, Haijiao Zhang, Haoen Zhang, Sen Miao, Lihua Zhao, Ruizeng Yang, Jinjin Xu, Yi Lu, Fang Wei, Hu Zhou, Daming Gao, Yunyun Jin, Lei Zhang
Journal: Hepatology (2024)

Background and Aims: The Hippo signaling has emerged as a crucial regulator of tissue homeostasis, regeneration, and tumorigenesis, representing a promising therapeutic target. Neurofibromin 2 (NF2), a component of Hippo signaling, is directly linked to human cancers but has been overlooked as a target for cancer therapy. Approach and Results: Through a high-content RNA interference genome-wide screen, the actin-binding protein Drebrin (DBN1) has been identified as a novel modulator of YAP localization. Further investigations have revealed that DBN1 directly interacts with NF2, disrupting the activation of large tumor suppressor kinases (LATS1/2) by competing with LATS kinases for NF2 binding. Consequently, DBN1 knockout considerably promotes YAP nuclear exclusion and repression of target gene expression, thereby preventing cell proliferation and liver tumorigenesis. We identified three lysine residues (K238, K248, and K252) essential for DBN1-NF2 interaction and developed a mutant DBN1 (DBN1-3K mut ) that is defective in NF2 binding and incompetent to trigger NF2-dependent YAP activation and tumorigenesis both in vitro and in vivo. Furthermore, BTP2, a DBN1 inhibitor, successfully restored NF2-LATS kinase binding and elicited potent antitumor activity. The combination of sorafenib and BTP2 exerted synergistic inhibitory effects against HCC. Conclusions: Our study identifies a novel DBN1-NF2-LATS axis, and pharmacological inhibition of DBN1 represents a promising alternative intervention targeting the Hippo pathway in cancer treatment.
Letter to the Editor: Serum identification of At-Risk MASH: The metabolomics-advanced steatohepatitis fibrosis score (MASEF)
Authors: Mazen Noureddin, Emily Truong, Rebeca Mayo, Ibon Martínez-Arranz, Itziar Mincholé, Jesus M. Banales, Marco Arrese, Kenneth Cusi, María Teresa Arias-Loste, Radan Bruha, Manuel Romero-Gómez, Paula Iruzubieta, Rocio Aller, Javier Ampuero, José Luis Calleja, Luis Ibañez-Samaniego, Patricia Aspichueta, Antonio Marín-Duce, Tatyana Kushner, Pablo Ortiz, Stephen A. Harrison, Quentin M. Anstee, Javier Crespo, José M. Mato, Arun J. Sanyal
Journal: Hepatology (2024)
Long-term air pollution exposure and incident physical disability in older US adults: a cohort study
Authors: Jiaqi Gao, Carlos F Mendes de Leon, Boya Zhang, Jennifer Weuve, Kenneth M Langa, Jennifer D'Souza, Adam Szpiro, Jessica Faul, Joel D Kaufman, Richard Hirth, Sara D Adar
Journal: The Lancet Healthy Longevity (2024)
Disparities in the availability and access to Neuro-Oncology Trial-Supporting infrastructure in the United States
Authors: Yeonju Kim, Terri S Armstrong, Mark R Gilbert, Orieta Celiku
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract We conducted an extensive assessment and quantification of the reach of the oncology clinical trial supporting infrastructure in the United States (US). While our primary focus was on identifying avenues to expand the reach of neuro-oncology clinical trials, we considered infrastructure layers with important implications for broader cancer research and care. Specifically, we examined the geographic, population, and socioeconomic reach of national collaboratives (including over 1,500 institutions), over 600 academic oncology and neurosurgery training programs, and networks of over 25,000 individual neuro-oncology, neurosurgery, and general oncology (including hematology/medical/gynecological oncology, surgical oncology, and radiation oncology) providers. Our study found that over 57% of the US population lacks direct access to trial-supporting infrastructure. More than 71% of the locations with infrastructure are urban, and over 72% are in socioeconomically-advantaged areas. Our findings reveal critical disparities in oncology care access and suggest actionable strategies to optimize and expand the existing infrastructure’s reach.\
Deconstructing Regenerative Medicine: From Mechanistic Studies of Cell Therapy to Novel Bioinspired RNA Drugs
Authors: Eduardo Marbán
Journal: Circulation Research (2024)

All Food and Drug Administration–approved noncoding RNA (ncRNA) drugs (n≈20) target known disease-causing molecular pathways by mechanisms such as antisense. In a fortuitous evolution of work on regenerative medicine, my coworkers and I inverted the RNA drug discovery process: first we identified natural disease-modifying ncRNAs, then used them as templates for new synthetic RNA drugs. Mechanism was probed only after bioactivity had been demonstrated. The journey began with the development of cardiosphere-derived cells (CDCs) for cardiac regeneration. While testing CDCs in a first-in-human trial, we discovered they worked indirectly: ncRNAs within CDC-secreted extracellular vesicles mediate the therapeutic benefits. The vast majority of such ncRNAs are fragments of unknown function. We chose several abundant ncRNA species from CDC-secreted extracellular vesicles, synthesized and screened each of them in vitro and in vivo. Those with exceptional disease-modifying bioactivity inspired new chemical entities that conform to the structural conventions of the Food and Drug Administration–approved ncRNA armamentarium. This discovery arc—Cell-Derived RNA from Extracellular vesicles for bioinspired Drug develOpment, or CREDO—has yielded various promising lead compounds, each of which works via a unique, and often novel, mechanism. The process relies on emergent insights to shape therapeutic development. The initial focus of our inquiry—CDCs—are now themselves in phase 3 testing for Duchenne muscular dystrophy and its associated cardiomyopathy. But the intravenous delivery strategy and the repetitive dosing protocol for CDCs, which have proven key to clinical success, both arose from systematic mechanistic inquiry. Meanwhile, emergent insights have led to multiple cell-free therapeutic candidates: CDC-secreted extracellular vesicles are in preclinical development for ventricular arrhythmias, while the CREDO-conceived RNA drugs are in translation for diseases ranging from myocarditis to scleroderma.
Sexual dimorphism in the relationship between BMI and recent suicidal attempts in first-episode drug-naïve patients with major depressive disorder
Authors: Ze-Zhi Li, Yu-Ping Chen, Xiao-Cui Zang, Denise Zheng, Xiao-E Lang, Yong-Jie Zhou, Feng-Chun Wu, Xiang-Yang Zhang
Journal: Military Medical Research (2024)
A high proportion of germline variants in pediatric chronic myeloid leukemia
Authors: Manuela Krumbholz, Anna Dolnik, Eric Sträng, Tabita Ghete, Sabrina Skambraks, Stephan Hutter, Alfred Simonis, Frank Stegelmann, Meinolf Suttorp, Anselm H C Horn, Heinrich Sticht, Torsten Haferlach, Lars Bullinger, Markus Metzler
Journal: Molecular Cancer (2024)
Streamlining the Conduct of Cancer Clinical Trials: New Standard Data Collection Practices for National Cancer Institute Late Phase Clinical Studies
Authors: Sheila A Prindiville, Sumithra J Mandrekar, Neal J Meropol, Andrea Denicoff, Oren Grad, Judith A Hautala, James H Doroshow
Journal: JNCI Journal of the National Cancer Institute (2024)

The increase in the complexity of cancer clinical trials over the past several decades has led to a dramatic growth in trial cost and operational burden. The extent and frequency of data collection, particularly in late phase trials which enroll many participants, have been major contributors to this problem. The Clinical Trials and Translational Research Advisory Committee of the National Cancer Institute (NCI) recently assessed the impact of these stressors on the NCI National Clinical Trials Network (NCTN) and recommended that data collection in late phase NCTN trials be limited to data elements essential to address the primary and secondary objectives of the trial. The purpose of this commentary is to describe the rationale for this recommendation, progress towards implementation, and the development of new streamlined standard practices for data collection for late phase NCTN trials effective January 1, 2025.
Activating mutations remodel the chromatin accessibility landscape to drive distinct regulatory networks in <i>KMT2A</i>‐rearranged acute leukemia
Authors: Qirui Zhang, Ton Falqués‐Costa, Mattias Pilheden, Helena Sturesson, Tina Ovlund, Vendela Rissler, Anders Castor, Hanne V. H. Marquart, Birgitte Lausen, Thoas Fioretos, Axel Hyrenius‐Wittsten, Anna K. Hagström‐Andersson
Journal: HemaSphere (2024)

Abstract Activating FLT3 and RAS mutations commonly occur in leukemia with KMT2A ‐gene rearrangements ( KMT2A ‐r). However, how these mutations cooperate with the KMT2A ‐r to remodel the epigenetic landscape is unknown. Using a retroviral acute myeloid leukemia (AML) mouse model driven by KMT2A::MLLT3 , we show that FLT3 ITD , FLT3 N676K , and NRAS G12D remodeled the chromatin accessibility landscape and associated transcriptional networks. Although the activating mutations shared a common core of chromatin changes, each mutation exhibits unique profiles with most opened peaks associating with enhancers in intronic or intergenic regions. Specifically, FLT3 N676K and NRAS G12D rewired similar chromatin and transcriptional networks, distinct from those mediated by FLT3 ITD . Motif analysis uncovered a role for the AP‐1 family of transcription factors in KMT2A::MLLT3 leukemia with FLT3 N676K and NRAS G12D , whereas Runx1 and Stat5a/Stat5b were active in the presence of FLT3 ITD . Furthermore, transcriptional programs linked to immune cell regulation were activated in KMT2A ‐r AML expressing NRAS G12D or FLT3 N676K , and the expression of NKG2D‐ligands on KMT2A ‐r cells rendered them sensitive to CAR T cell‐mediated killing. Human KMT2A ‐r AML cells could be pharmacologically sensitized to NKG2D‐CAR T cells by treatment with the histone deacetylase inhibitor LBH589 (panobinostat) which caused upregulation of NKG2D‐ligand levels. Co‐treatment with LBH589 and NKG2D‐CAR T cells enabled robust AML cell killing, and the strongest effect was observed for cells expressing NRAS G12D . Finally, the results were validated and extended to acute leukemia in infancy. Combined, activating mutations induced mutation‐specific changes in the epigenetic landscape, leading to changes in transcriptional programs orchestrated by specific transcription factor networks.
Axillary clearance and chemotherapy rates in ER+HER2− breast cancer: secondary analysis of the SENOMAC trial
Authors: Tove Filtenborg Tvedskov, Robert Szulkin, Sara Alkner, Yvette Andersson, Leif Bergkvist, Jan Frisell, Oreste Davide Gentilini, Michalis Kontos, Thorsten Kühn, Dan Lundstedt, Birgitte Vrou Offersen, Roger Olofsson Bagge, Toralf Reimer, Malin Sund, Lisa Rydén, Peer Christiansen, Jana de Boniface
Journal: The Lancet Regional Health - Europe (2024)
Protein kinase N1 deficiency results in upregulation of cerebral energy metabolism and is highly protective in in vivo and in vitro stroke models
Authors: Stephanie Zur Nedden, Motahareh S Safari, Dido Weber, Louisa Kuenkel, Carolin Garmsiri, Luisa Lang, Cyrille Orset, Tom Freret, Benoît Haelewyn, Madlen Hotze, Marcel Kwiatkowski, Bettina Sarg, Klaus Faserl, Dragana Savic, Ira-Ida Skvortsova, Anne Krogsdam, Sandro Carollo, Zlatko Trajanoski, Herbert Oberacher, Dominik Zlotek, Florian Ostermaier, Angus Cameron, Gottfried Baier, Gabriele Baier-Bitterlich
Journal: Metabolism (2024)
Levels and functionality of Pacific Islanders’ hybrid humoral immune response to BNT162b2 vaccination and delta/omicron infection: A cohort study in New Caledonia
Authors: Catherine Inizan, Adrien Courtot, Chloé Sturmach, Anne-Fleur Griffon, Antoine Biron, Timothée Bruel, Vincent Enouf, Thibaut Demaneuf, Sandie Munier, Olivier Schwartz, Ann-Claire Gourinat, Georges Médevielle, Marc Jouan, Sylvie van der Werf, Yoann Madec, Valérie Albert-Dunais, Myrielle Dupont-Rouzeyrol
Journal: PLoS Medicine (2024)

Pacific Islanders are underrepresented in vaccine efficacy trials. Few studies describe their immune response to COVID-19 vaccination. Yet, this characterization is crucial to re-enforce vaccination strategies adapted to Pacific Islanders singularities.
Impact of public health and patient‐centered prevention strategies on periodontitis and caries as causes of tooth loss in high‐income countries
Authors: Thomas Kocher, Peter Meisel, Sebastian Baumeister, Birte Holtfreter
Journal: Periodontology 2000 (2024)

Abstract In high‐income countries, the oral health of the population is influenced by public health interventions, widespread use of oral care products, dental practice measures, and the cost of dental treatment. We compiled information on changes of the prevalence of proximal and upstream determinants of periodontitis, caries, and tooth loss over the last three decades to outline their potential effects on changes of oral health during this period. Information was retrieved from repeated cross‐sectional studies and from published literature. While both the prevalence of edentulism and the number of missing teeth (from the DMF‐T index) decreased, the number of sound teeth as well as the total number of teeth increased. The prevalence of severe periodontitis was unchanged, whereas the prevalence of periodontal health and moderate periodontitis may have increased to a minor extent. Concerning oral health risk factors, the proportion of individuals with tertiary education increased, while smoking prevalence declined. More and more people used oral care products. Whether one reimbursement system worked better than another one in terms of tooth retention could not be elucidated. In tooth retention, population‐wide use of fluoridated toothpastes had the greatest impact. To some extent, the higher number of teeth present may be related to the more frequent use of interdental cleaning aids and powered toothbrushes. Since there was no decrease in severe periodontitis in most cohorts, periodontal interventions probably contributed little to improved tooth retention.
The roles of patient‐derived xenograft models and artificial intelligence toward precision medicine
Authors: Venkatachalababu Janitri, Kandasamy Nagarajan ArulJothi, Vijay Murali Ravi Mythili, Sachin Kumar Singh, Parteek Prasher, Gaurav Gupta, Kamal Dua, Rakshith Hanumanthappa, Karthikeyan Kaliappan, Krishnan Anand
Journal: MedComm (2024)

Patient-derived xenografts (PDX) involve transplanting patient cells or tissues into immunodeficient mice, offering superior disease models compared with cell line xenografts and genetically engineered mice. In contrast to traditional cell-line xenografts and genetically engineered mice, PDX models harbor the molecular and biologic features from the original patient tumor and are generationally stable. This high fidelity makes PDX models particularly suitable for preclinical and coclinical drug testing, therefore better predicting therapeutic efficacy. Although PDX models are becoming more useful, the several factors influencing their reliability and predictive power are not well understood. Several existing studies have looked into the possibility that PDX models could be important in enhancing our knowledge with regard to tumor genetics, biomarker discovery, and personalized medicine; however, a number of problems still need to be addressed, such as the high cost and time-consuming processes involved, together with the variability in tumor take rates. This review addresses these gaps by detailing the methodologies to generate PDX models, their application in cancer research, and their advantages over other models. Further, it elaborates on how artificial intelligence and machine learning were incorporated into PDX studies to fast-track therapeutic evaluation. This review is an overview of the progress that has been done so far in using PDX models for cancer research and shows their potential to be further improved in improving our understanding of oncogenesis.
Dedicator of cytokinesis 8 (DOCK8) mutation impairs the differentiation of helper T cells by regulating the glycolytic pathway of CD4<sup>+</sup> T cells
Authors: Panpan Jiang, Siyu Zhao, Xiaoyu Li, Shiyan Hu, Shuhan Chen, Yinming Liang, Lichen Zhang, Liaoxun Lu, Guofeng Fang, Lu Yang, Yanmei Huang, Heather Miller, Fei Guan, Jiahui Lei, Chaohong Liu
Journal: MedComm (2024)

Abstract Dedicator of cytokinesis 8 (DOCK8) deficiency is a primary immunodeficiency disease caused by mutations in exon 45 of the DOCK8 gene. The clinical signs primarily consist of increased serum IgE levels, eczema, repeated skin infections, allergies, and upper respiratory tract infections. Using CRISPR/Cas9 technology, we generated a DOCK8 exon 45 mutation in mice, mirroring the mutation found in patients. The results indicated that DOCK8 mutation impairs peripheral T cell homeostasis, disrupts regulatory T cells (Tregs) development, increases ICOS expression in Tregs within peripheral lymph nodes (pLn), and promotes Th17 cell differentiation within the spleen and pLn. Upon virus infection, DOCK8 mutation CD4 + T cells have a Th2 effector fate. RNA‐bulk sequencing data revealed alternations in the mTOR pathway of DOCK8 mutant CD4 + T cells. We observed that DOCK8 mutation upregulates the glycolysis levels in CD4 + T cells, which is related to the Akt/mTOR/S6/HIF‐1α pathway. In summary, our research elucidates that DOCK8 regulates the differentiation of helper T cells by modulating the glycolytic pathway in CD4 + T cells, thereby advancing the comprehension and offering potential treatment of diseases in DOCK8‐deficient patients.
The role of ubiquitination in health and disease
Authors: Yan Liao, Wangzheqi Zhang, Yang Liu, Chenglong Zhu, Zui Zou
Journal: MedComm (2024)

Ubiquitination is an enzymatic process characterized by the covalent attachment of ubiquitin to target proteins, thereby modulating their degradation, transportation, and signal transduction. By precisely regulating protein quality and quantity, ubiquitination is essential for maintaining protein homeostasis, DNA repair, cell cycle regulation, and immune responses. Nevertheless, the diversity of ubiquitin enzymes and their extensive involvement in numerous biological processes contribute to the complexity and variety of diseases resulting from their dysregulation. The ubiquitination process relies on a sophisticated enzymatic system, ubiquitin domains, and ubiquitin receptors, which collectively impart versatility to the ubiquitination pathway. The widespread presence of ubiquitin highlights its potential to induce pathological conditions. Ubiquitinated proteins are predominantly degraded through the proteasomal system, which also plays a key role in regulating protein localization and transport, as well as involvement in inflammatory pathways. This review systematically delineates the roles of ubiquitination in maintaining protein homeostasis, DNA repair, genomic stability, cell cycle regulation, cellular proliferation, and immune and inflammatory responses. Furthermore, the mechanisms by which ubiquitination is implicated in various pathologies, alongside current modulators of ubiquitination are discussed. Enhancing our comprehension of ubiquitination aims to provide novel insights into diseases involving ubiquitination and to propose innovative therapeutic strategies for clinical conditions.
Partial hepatectomy versus interventional treatment in patients with hepatitis B virus‐related hepatocellular carcinoma and clinically significant portal hypertension: a randomized comparative clinical trial
Authors: Yichuan Yuan, Hong Peng, Wei He, Yun Zheng, Jiliang Qiu, Bin Chen, Ruhai Zou, Chenwei Wang, Wan Yee Lau, Binkui Li, Yunfei Yuan
Journal: Cancer Communications (2024)

Abstract Background The widely accepted view that portal hypertension (PHT) is a contraindication to hepatectomy for patients with hepatocellular carcinoma (HCC) is being increasingly challenged. The long‐term survival outcomes and safety of partial hepatectomy versus interventional treatment using ablation with or without pre‐ablation transarterial chemoembolization (TACE) in patients with HBV‐related HCC within the Milan criteria and with clinically significant PHT were compared in this study. Methods This open‐label randomized clinical trial was conducted on consecutive patients with clinically PHT and hepatitis B virus (HBV)‐related HCC with tumors which were within the Milan criteria. These patients were randomized 1:1 to receive either partial hepatectomy or interventional treatment between December 2012 and June 2018. The primary endpoint was overall survival (OS); secondary endpoints included recurrence‐free survival (RFS) and therapeutic safety. Results Each of the 2 groups had 80 patients. The 1‐, 3‐ and 5‐year OS rates in the partial hepatectomy group and the interventional treatment group were 95.0%, 86.2%, 69.5% versus 93.8%, 77.5%, 64.9%, respectively ( P = 0.325). The corresponding RFS rates were 78.8%, 55.0%, 46.2% versus 71.3%, 52.5%, 45.0%, respectively ( P = 0.783). The partial hepatectomy group had a higher complication rate compared to the interventional group (67.5% vs. 20%, P &lt; 0.001). However, the differences were mainly in Clavien‐Dindo Grade I complications ( P &lt; 0.001), while not significant in Grade II/III/IV/V (All P &gt; 0.05). Conclusions This study shows that partial hepatectomy treatment did not meet prespecified significance for improved OS and RFS compared to interventional treatment for patients with HBV‐related HCC within the Milan criteria and with clinically significant PHT. However, partial hepatectomy is still a safe procedure and should be considered as a treatment option rather than a contraindication.