tbuckley/cabot-search huggingface dataset:
Estrogen induces LCAT to maintain cholesterol homeostasis and suppress hepatocellular carcinoma development
Authors: Wenzhi He, Min Wang, Xuechun Zhang, Yilan Wang, Dongli Zhao, Wenhua Li, Fang Lei, Min Peng, Zhonglin Zhang, Yufeng Yuan, Zan Huang
Journal: Cancer Research (2024)

Abstract Hepatocellular carcinoma (HCC) is an aggressive disease that occurs predominantly in men. Estrogen elicits protective effects against HCC development. Elucidation of the estrogen-regulated biological processes that suppress HCC could lead to improved prevention and treatment strategies. Here, we performed transcriptomic analyses on mouse and human liver cancer and identified lecithin cholesterol acyltransferase (LCAT) as the most highly estrogen-upregulated gene and a biomarker of favorable prognosis. LCAT upregulation inhibited HCC in vitro and in vivo and mediated estrogen-induced suppression of HCC in an ESR1-dependent manner. LCAT facilitated high-density lipoprotein cholesterol production and uptake via the LDLR and SCARB1 pathways. Consistently, high HDL-C levels corresponded to a favorable prognosis in HCC patients. The enhanced HDL-C absorption induced by LCAT impaired SREBP2 maturation, which ultimately suppressed cholesterol biosynthesis and dampened HCC cell proliferation. HDL-C alone inhibited HCC growth comparably to the cholesterol-lowering drug lovastatin, and SREBF2 overexpression abolished the inhibitory activity of LCAT. Clinical observations and cross-analyses of multiple databases confirmed the correlation of elevated LCAT and HDL-C levels to reduced cholesterol synthesis and improved HCC patient prognosis. Furthermore, LCAT deficiency mimicked whereas LCAT overexpression abrogated the tumor growth–promoting effects of ovariectomy in HCC-bearing female mice. Most importantly, HDL-C and LCAT delayed the development of subcutaneous tumors in nude mice, and HDL-C synergized with lenvatinib to eradicate orthotopic liver tumors. Collectively, this study reveals that estrogen upregulates LCAT to maintain cholesterol homeostasis and to dampen hepatocarcinogenesis. LCAT and HDL-C represent potential prognostic and therapeutic biomarkers for targeting cholesterol homeostasis as a strategy for treating HCC. Significance: Estrogen mediates the sex differences in hepatocellular carcinoma development by reducing cholesterol biosynthesis through activation of an LCAT/HDL-C axis, providing strategies for improving liver cancer prevention, prognosis, and treatment.
A Virus-Inspired Inhalable Liponanogel Induces Potent Antitumor Immunity and Regression in Metastatic Lung Tumors
Authors: Junyao Li, Lanqing Luo, Jia He, Jinchao Yu, Xinyan Li, Xueying Shen, Junxia Zhang, Sai Li, Jeffrey M. Karp, Rui Kuai
Journal: Cancer Research (2024)

Pulmonary delivery of immunostimulatory agents such as poly(I:C) to activate double-stranded RNA sensors MDA5 and RIG-I within lung-resident antigen-presenting cells is a potential strategy to enhance antitumor immunity by promoting type I interferon secretion. Nevertheless, following pulmonary delivery, poly(I:C) suffers from rapid degradation and poor endosomal escape, thus limiting its potency. Inspired by the structure of a virus that utilizes internal viral proteins to tune the loading and cytosolic delivery of viral nucleic acids, we developed a liponanogel (LNG)-based platform to overcome the delivery challenges of poly(I:C). The LNG comprised an anionic polymer hyaluronic acid-based nanogel core coated by a lipid shell, which served as a protective layer to stabilize the nanogel core in the lungs. The nanogel core was protonated within acidic endosomes to enhance the endosomal membrane permeability and cytosolic delivery of poly(I:C). After pulmonary delivery, LNG-poly(I:C) induced 13.7-fold more IFNβ than poly(I:C) alone and two-fold more than poly(I:C) loaded in the state-of-art lipid nanoparticles [LNP-poly(I:C)]. Additionally, LNG-poly(I:C) induced more potent CD8+ T-cell immunity and stronger therapeutic effects than LNP-poly(I:C). The combination of LNG-poly(I:C) and PD-L1 targeting led to regression of established lung metastases. Due to the ease of manufacturing and the high biocompatibility of LNG, pulmonary delivery of LNG may be broadly applicable to the treatment of different lung tumors and may spur the development of innovative strategies for cancer immunotherapy. Significance: Pulmonary delivery of poly(I:C) with a virus-inspired inhalable liponanogel strongly activates cytosolic MDA5 and RIG-I and stimulates antitumor immunity, representing a promising strategy for safe and effective treatment of metastatic lung tumors.
LGR6 frameshift variant abrogates receptor expression on select leukocyte subsets and associates with viral infections
Authors: Esteban Alberto Gomez Cifuentes, Roberta De Matteis, Palita Udomjarumanee, Genes and Health Queen Mary University of London, Patricia B Munroe, Jesmond Dalli
Journal: Blood (2024)

The leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6) was recently identified as the cognate receptor for the pro-resolving mediator Maresin (MaR)1. To address the biological role of LGR6 in humans, we investigated the functional impact of a genetic variant in the gene encoding for LGR6, which is predicted to lead to a frameshift mutation in one of the receptor isoforms, on both receptor expression and immune cell responses. In neutrophils, monocytes, and NK cells from volunteers homozygous for this variant, we found a significant downregulation in the expression of LGR6 when compared with controls without the variant. Whereas LGR6 expression was essentially similar in monocyte-derived macrophages and CD8+ T-cells. Functionally loss of LGR6 expression was linked with a decreased ability of neutrophils and monocytes to phagocytose bacteria. We observed an increase in neutrophil chemotaxis and leukotriene B4 (LTB4) production, and increased expression of activation markers, including markers for platelet-leukocyte phagocyte heterotypic aggregates, such as CD41, in neutrophils and monocytes from the variant group. Using data from the UK Biobank we found that at a population level the rs4266947 variant which is in high linkage disequilibrium with rs74355478 was associated with a higher incidence of viral infections. Intriguingly, neutrophils, NK cells and CD8+ T-cells from volunteers with the LGR6 variant displayed altered viral responses when stimulated with Toll-like receptor (TLR)3, TLR7/TLR8 and TLR9 agonists. Together these findings shed new light on the cell type-specific regulation of LGR6 expression and the role of this receptor in directing host immune responses.
Single-cell analyses reveal the metabolic heterogeneity and plasticity of the tumor microenvironment during head and neck squamous cell carcinoma progression
Authors: Xiaoyan Meng, Yang Zheng, Lingfang Zhang, Peipei Liu, Zhonglong Liu, Yue He
Journal: Cancer Research (2024)

Metabolic reprogramming is a hallmark of cancer. In addition to metabolic alterations in the tumor cells, multiple other metabolically active cell types in the tumor microenvironment (TME) contribute to the emergence of a tumor-specific metabolic milieu. Here, we defined the metabolic landscape of the TME during the progression of head and neck squamous cell carcinoma (HNSCC) by performing single-cell RNA sequencing on 26 human patient specimens, including normal tissue, precancerous lesions, early stage cancer, advanced-stage cancer, lymph node metastases, and recurrent tumors. The analysis revealed substantial heterogeneity at the transcriptional, developmental, metabolic, and functional levels in different cell types. SPP1+ macrophages were identified as a protumor and prometastatic macrophage subtype with high fructose and mannose metabolism, which was further substantiated by integrative analysis and validation experiments. An inhibitor of fructose metabolism reduced the proportion of SPP1+ macrophages, reshaped the immunosuppressive TME, and suppressed tumor growth. In conclusion, this work delineated the metabolic landscape of HNSCC at a single-cell resolution and identified fructose metabolism as a key metabolic feature of a protumor macrophage subpopulation. Significance: Fructose and mannose metabolism is a metabolic feature of a protumor and prometastasis macrophage subtype and can be targeted to reprogram macrophages and the microenvironment of head and neck squamous cell carcinoma.
Development and Implementation of a Digital Quality Measure of Emergency Cancer Diagnosis
Authors: Paarth Kapadia, Andrew J. Zimolzak, Divvy K. Upadhyay, Saritha Korukonda, Riyaa Murugaesh Rekha, Umair Mushtaq, Usman Mir, Daniel R. Murphy, Alexis Offner, Gary A. Abel, Georgios Lyratzopoulos, Luke T.A. Mounce, Hardeep Singh
Journal: Journal of Clinical Oncology (2024)

Missed and delayed cancer diagnoses are common, harmful, and often preventable. Automated measures of quality of cancer diagnosis are lacking but could identify gaps and guide interventions. We developed and implemented a digital quality measure (dQM) of cancer emergency presentation (EP) using electronic health record databases of two health systems and characterized the measure's association with missed opportunities for diagnosis (MODs) and mortality.
RE: The impact of multidisciplinary cancer conferences on overall survival: a meta-analysis
Authors: Bareera Shamsi, Mariam Hina, Sarah Akhtar, Fabiha Shakeel, Bilal Ahmed, Sehrish Abrar, Asim Hafiz, Bilal Mazhar Qureshi, Nasir Ali, Ahmed Nadeem Abbasi
Journal: JNCI Journal of the National Cancer Institute (2024)

Our team has read your article with great interest, aligning with our commitment towards establishment of site specific multidisciplinary tumor boards across our country (1,2).We agree with the inferences made in your article regarding the positive impact that Multidisciplinary Cancer Conferences (MCC) have on patient survival as discussed in cited literature.The inclusion of various cancer types and sub-group analyses offer a clear understanding of the potential benefits of MCC.Processes, such as evaluation of patient outcomes, encompassing diverse perspectives, coordinated care, and personalized treatment approaches may definitely enhance the effectiveness of MCCs.Given our team's keen interest in this topic, we would like to request the authors to elaborate more on the reason of exclusion of the majority of screened studies.With 2949 studies (95%) excluded out of 3089 initially screened, it would be insightful to understand
Prostate cancer incidence and mortality in men exposed to α1-adrenergic receptor antagonists
Authors: Lars Björnebo, Shirin Razdan, Andrea Discacciati, Thorgerdur Palsdottir, Markus Aly, Tobias Nordström, Martin Eklund, Dara Lundon, Henrik Grönberg, Ash Tewari, Peter Wiklund, Natasha Kyprianou, Anna Lantz
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background α1-Adrenergic receptor antagonists are commonly used to treat benign prostatic hyperplasia. Preclinical studies suggest that they induce cell death and inhibit tumor growth. This study evaluated the risk of prostate cancer death in men using α1-adrenergic receptor antagonists. Methods A population-based cohort study in Stockholm, Sweden (January 1, 2007, to December 31, 2019) included 451 779 men with a prostate-specific antigen test result. Study entry was 1 year after the first prostate-specific antigen test. Men were considered exposed at their second filled prescription. The primary outcome was prostate cancer mortality. Secondary outcomes were all-cause mortality and prostate cancer incidence. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all outcomes. Inverse-probability weighting with marginal structural models accounted for time-dependent confounders. Results Of 351 297 men in the final cohort, 39 856 (11.3%) were exposed to α1-adrenergic receptor antagonists. Median (interquartile range) follow-up for prostate cancer mortality was 8.9 (5.1-10.9) years; median (interquartile range) exposure time to α1-adrenergic receptor antagonists was 4.4 (2.0-7.6) years. There was no evidence of an association between α1-adrenergic receptor antagonist use and prostate cancer mortality, all-cause mortality, or high-grade prostate cancer. α1-Adrenergic receptor antagonist use was associated with an increased risk of prostate cancer (HR = 1.11, 95% CI = 1.06 to 1.17) and low-grade prostate cancer (HR = 1.22, 95% CI = 1.11 to 1.33). Men whose prostate cancer was treated with α1-adrenergic receptor antagonists underwent more frequent prostate-specific antigen testing. Conclusions Our findings show no significant association between α1-adrenergic receptor adrenoceptor antagonist exposure and prostate cancer mortality or high-grade prostate cancer. Although the preclinical evidence indicates a potential chemopreventive effect, this study’s findings do not support it.
Long-term cardiovascular disease risk after anthracycline and trastuzumab treatments in US breast cancer survivors
Authors: Jacqueline B Vo, Cody Ramin, Lene H S Veiga, Carolyn Brandt, Rochelle E Curtis, Clara Bodelon, Ana Barac, Véronique L Roger, Heather Spencer Feigelson, Diana S M Buist, Erin J Aiello Bowles, Gretchen L Gierach, Amy Berrington de González
Journal: JNCI Journal of the National Cancer Institute (2024)

Although breast cancer survivors are at risk for cardiovascular disease (CVD) from treatment late effects, evidence to inform long-term and age-specific cardiovascular surveillance recommendations is lacking.
Bioengineered vascular grafts with a pathogenic <i>TGFBR1</i> variant model aneurysm formation in vivo and reveal underlying collagen defects
Authors: Ying Yang, Hao Feng, Ying Tang, Zhenguo Wang, Ping Qiu, Xihua Huang, Lin Chang, Jifeng Zhang, Yuqing Eugene Chen, Dogukan Mizrak, Bo Yang
Journal: Science Translational Medicine (2024)

Thoracic aortic aneurysm (TAA) is a life-threatening vascular disease frequently associated with underlying genetic causes. An inadequate understanding of human TAA pathogenesis highlights the need for better disease models. Here, we established a functional human TAA model in an animal host by combining human induced pluripotent stem cells (hiPSCs), bioengineered vascular grafts (BVGs), and gene editing. We generated BVGs from isogenic control hiPSC-derived vascular smooth muscle cells (SMCs) and mutant SMCs gene-edited to carry a Loeys-Dietz syndrome (LDS)–associated pathogenic variant ( TGFBR1 A230T ). We also generated hiPSC-derived BVGs using cells from a patient with LDS ( Patient A230T/+ ) and using genetically corrected cells ( Patient +/+ ). Control and experimental BVGs were then implanted into the common carotid arteries of nude rats. The TGFBR1 A230T variant led to impaired mechanical properties of BVGs, resulting in lower burst pressure and suture retention strength. BVGs carrying the variant dilated over time in vivo, resembling human TAA formation. Spatial transcriptomics profiling revealed defective expression of extracellular matrix (ECM) formation genes in Patient A230T/+ BVGs compared with Patient +/+ BVGs. Histological analysis and protein assays validated quantitative and qualitative ECM defects in Patient A230T/+ BVGs and patient tissue, including decreased collagen hydroxylation. SMC organization was also impaired in Patient A230T/+ BVGs as confirmed by vascular contraction testing. Silencing of collagen-modifying enzymes with small interfering RNAs reduced collagen proline hydroxylation in SMC-derived tissue constructs. These studies demonstrated the utility of BVGs to model human TAA formation in an animal host and highlighted the role of reduced collagen modifying enzyme activity in human TAA formation.
Nothing about us without us: Advocacy and engagement in genetic medicine
Authors: Olabimpe Olayiwola, Adam Castillejo, Michael Louella, Moses Supercharger, Evelyn Harlow, Lynda Dee, Khadidja Abdallah, Cissy Kityo-Mutuluuza, Jennifer E. Adair, Rimas Orentas, Karine Dubé
Journal: Science Translational Medicine (2024)

The development of new genetic medicines to treat sickle cell disease highlights the need for greater collaboration between researchers and people with lived experiences. Drawing on the adage "Nothing about us, without us," we call for increased investments in community advocacy and engagement.
Surgery is better than nasal sprays for people with severely blocked airways caused by septal deviation
Authors: Helen Saul, Samantha Cassidy, Laura Swaithes, Sean Carrie
Journal: BMJ (2024)

The study Carrie S, O’Hara J, Fouweather T, et al. Clinical effectiveness of septoplasty versus medical management for nasal airways obstruction: multicentre, open label, randomised controlled trial. BMJ 2023;383:e075445. To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/surgery-is-better-than-nasal-sprays-for-people-with-severely-blocked-airways/
MRGPRX4 mediates phospho-drug–associated pruritus in a humanized mouse model
Authors: Daphne Chun-Che Chien, Nathachit Limjunyawong, Can Cao, James Meixiong, Qi Peng, Cheng-Ying Ho, Jonathan F. Fay, Bryan L. Roth, Xinzhong Dong
Journal: Science Translational Medicine (2024)

The phosphate modification of drugs is a common chemical strategy to increase solubility and allow for parenteral administration. Unfortunately, phosphate modifications often elicit treatment- or dose-limiting pruritus through an unknown mechanism. Using unbiased high-throughput drug screens, we identified the Mas-related G protein-coupled receptor X4 (MRGPRX4), a primate-specific, sensory neuron receptor previously implicated in itch, as a potential target for phosphate-modified compounds. Using both G
The translational gap for gene therapies in low- and middle-income countries
Authors: Kevin W. Doxzen, Jennifer E. Adair, Yris Maria Fonseca Bazzo, Daima Bukini, Kenneth Cornetta, Varsha Dalal, Renato Luiz Guerino-Cunha, Suradej Hongeng, Geeta Jotwani, Cissy Kityo-Mutuluuza, Krishnamurti Lakshmanan, Johnny Mahlangu, Julie Makani, Vikram Mathews, Margareth C. Ozelo, Savita Rangarajan, Janine Scholefield, João Batista Silva Júnior, Joseph M. McCune
Journal: Science Translational Medicine (2024)

Gene therapies are designed to address the root cause of disease. As scientific understanding of disease prevention, diagnosis, and treatment improves in tandem with technological innovation, gene therapies have the potential to become safe and effective treatment options for a wide range of genetic and nongenetic diseases. However, as the medical scope of gene therapies expands, consideration must be given to those who will benefit and what proactive steps must be taken to widen development and access potential, particularly in regions carrying a high disease burden.
Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2− advanced breast cancer: final overall survival results of MONARCH 3
Authors: M.P. Goetz, M. Toi, J. Huober, J. Sohn, O. Trédan, I.H. Park, M. Campone, S.-C. Chen, L.M. Manso, S. Paluch-Shimon, O.C. Freedman, J. O’Shaughnessy, X. Pivot, S.M. Tolaney, S.A. Hurvitz, A. Llombart-Cussac, V. André, A. Saha, G. van Hal, A. Shahir, H. Iwata, S.R.D. Johnston
Journal: Annals of Oncology (2024)

Highlights•This phase III trial evaluated abemaciclib + NSAI versus placebo + NSAI as initial therapy for HR+, HER2− ABC.•Addition of abemaciclib to an NSAI resulted in numerically longer OS; however, statistical significance was not reached.•Absolute improvement in median OS was clinically meaningful (ITT: 13.1 months; sVD: 14.9 months).•The previously demonstrated PFS benefit with the addition of abemaciclib was sustained (median improvement 14.3 months).•The addition of abemaciclib delayed subsequent receipt of chemotherapy (median improvement 16.1 months).AbstractBackgroundIn MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) with disease progression on prior endocrine therapy. In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) as initial therapy for HR+, HER2− ABC significantly improved PFS. Here, we present the prespecified final OS results for MONARCH 3.Patients and methodsMONARCH 3 is a randomized, double-blind, phase III study of abemaciclib plus NSAI (anastrozole or letrozole) versus placebo plus NSAI in postmenopausal women with HR+, HER2− ABC without prior systemic therapy in the advanced setting. The primary objective was investigator-assessed PFS; OS was a gated secondary endpoint, and chemotherapy-free survival was an exploratory endpoint.ResultsA total of 493 women were randomized 2 : 1 to receive abemaciclib plus NSAI (n = 328) or placebo plus NSAI (n = 165). After a median follow-up of 8.1 years, there were 198 OS events (60.4%) in the abemaciclib arm and 116 (70.3%) in the placebo arm (hazard ratio, 0.804; 95% confidence interval 0.637-1.015; P = 0.0664, non-significant). Median OS was 66.8 versus 53.7 months for abemaciclib versus placebo. In the subgroup with visceral disease, there were 113 OS events (65.3%) in the abemaciclib arm and 65 (72.2%) in the placebo arm (hazard ratio, 0.758; 95% confidence interval 0.558-1.030; P = 0.0757, non-significant). Median OS was 63.7 months versus 48.8 months for abemaciclib versus placebo. The previously demonstrated PFS benefit was sustained, and chemotherapy-free survival numerically improved with the addition of abemaciclib. No new safety signals were observed.ConclusionsAbemaciclib combined with an NSAI resulted in clinically meaningful improvement in median OS (intent-to-treat population: 13.1 months; subgroup with visceral disease: 14.9 months) in patients with HR+ HER2− ABC; however, statistical significance was not reached.
Decitabine in Older Patients with AML: Quality of Life Results of the EORTC-GIMEMA-GMDS-SG Randomized Phase III Trial
Authors: Fabio Efficace, Michal Kicinski, Corneel Coens, Stefan Suciu, Walter J. F. M. van der Velden, Richard Noppeney, Sylvain Chantepie, Laimonas Griskevicius, Andreas Neubauer, Ernesta Audisio, Mario Luppi, Stephan Fuhrmann, Robin Foà, Martina Crysandt, Gianluca Gaidano, Radovan Vrhovac, Adriano Venditti, Eduardus F. M. Posthuma, Anna Candoni, Frédéric Baron, Olivier Legrand, Andrea Mengarelli, Paola Fazi, Marco Vignetti, Anne Giraut, Pierre W. Wijermans, Gerwin Huls, Michael Lübbert
Journal: Blood (2024)
Undernutrition increases the risk of unsuccessful treatment outcomes of patients with tuberculosis in Ethiopia: A multicenter retrospective cohort study
Authors: Fasil Wagnew, Kefyalew Addis Alene, Matthew Kelly, Darren Gray
Journal: Journal of Infection (2024)

While undernutrition has been identified as a common risk factor for tuberculosis (TB), its impact on treatment outcomes has yet to be investigated in high TB burden and low-income countries such as Ethiopia. Therefore, this study aimed to investigate the effect of undernutrition on treatment outcomes among patients with TB in northwest Ethiopia.
The evolutionary conserved miR-137/325 tandem mediates obesity-induced hypogonadism and metabolic comorbidities by repressing hypothalamic kisspeptin
Authors: María S. Avendaño, Cecilia Perdices-Lopez, Yolanda Guerrero-Ruiz, Francisco Ruiz-Pino, Ana B. Rodriguez-Sanchez, María J. Sanchez-Tapia, Verónica Sobrino, Rafael Pineda, Alexia Barroso, Alejandro Correa-Sáez, Maribel Lara-Chica, José C. Fernandez-Garcia, Ana B. García-Redondo, Raquel Hernanz, Miguel Ruiz-Cruz, David Garcia-Galiano, Nelly Pitteloud, Marco A. Calzado, Ana M. Briones, María J. Vázquez, Manuel Tena-Sempere
Journal: Metabolism (2024)