keyword
https://read.qxmd.com/read/38498682/the-absence-of-intra-tumoral-tertiary-lymphoid-structures-is-associated-with-a-worse-prognosis-and-mtor-signaling-activation-in-hepatocellular-carcinoma-with-liver-transplantation-a-multicenter-retrospective-study
#1
JOURNAL ARTICLE
Jianhua Li, Li Zhang, Hao Xing, Yan Geng, Shaocheng Lv, Xiao Luo, Weiqiao He, Zhi Fu, Guangming Li, Bin Hu, Shengran Jiang, Zhe Yang, Ningqi Zhu, Quanbao Zhang, Jing Zhao, Yifeng Tao, Conghuan Shen, Ruidong Li, Feng Tang, Shusen Zheng, Yun Bao, Qiang He, Daoying Geng, Zhengxin Wang
Tertiary lymphoid structure (TLS) can predict the prognosis and sensitivity of tumors to immune checkpoint inhibitors (ICIs) therapy, whether it can be noninvasively predicted by radiomics in hepatocellular carcinoma with liver transplantation (HCC-LT) has not been explored. In this study, it is found that intra-tumoral TLS abundance is significantly correlated with recurrence-free survival (RFS) and overall survival (OS). Tumor tissues with TLS are characterized by inflammatory signatures and high infiltration of antitumor immune cells, while those without TLS exhibit uncontrolled cell cycle progression and activated mTOR signaling by bulk and single-cell RNA-seq analyses...
March 18, 2024: Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
https://read.qxmd.com/read/38496361/ectopic-hcn4-provides-a-target-biomarker-for-the-genetic-spectrum-of-mtoropathies
#2
JOURNAL ARTICLE
Matthew Coleman, Paulo Pinares-Garcia, Sarah E Stephenson, Wei Shern Lee, Daniz Kooshavar, Catriona A Mclean, Katherine B Howell, Richard J Leventer, Christopher A Reid, Paul J Lockhart
BACKGROUND AND OBJECTIVES: Pathogenic variants in PI3K-AKT-mTOR pathway and GATOR1 complex genes resulting in hyperactivation of mechanistic target of rapamycin (mTOR) complex 1 are a major cause of drug-resistant epilepsy and focal cortical malformations (FCM). Resective neurosurgery is often required to achieve seizure control in patients with mTORopathies due to lack of effectiveness of nonsurgical therapies, including antiseizure medication and mTOR inhibitors. Elevated hyperpolarization-activated cyclic nucleotide-gated potassium channel isoform 4 (HCN4) has been proposed as a key marker in some mTOR-related brain malformations...
April 2024: Neurology. Genetics
https://read.qxmd.com/read/38460672/l1cam-expression-and-molecular-alterations-distinguish-low-grade-oncocytic-tumor-lot-from-eosinophilic-chromophobe-renal-cell-carcinoma
#3
JOURNAL ARTICLE
Mohammed Alghamdi, Jie-Fu Chen, Achim Jungbluth, Sirma Koutzaki, Matthew B Palmer, Hikmat A Al-Ahmadie, Samson W Fine, Anuradha Gopalan, Judy Sarungbam, S Joseph Sirintrapun, Satish K Tickoo, Victor E Reuter, Ying-Bei Chen
Renal low-grade oncocytic tumor (LOT) is a recently recognized renal cell neoplasm designated within the "other oncocytic tumors" category in the 2022 WHO Classification. While the clinicopathologic, immunohistochemical, and molecular features reported for LOT have been largely consistent, the data is relatively limited. The morphologic overlap between LOT and other low grade oncocytic neoplasms, particularly eosinophilic chromophobe renal cell carcinoma (E-chRCC), remains a controversial area in renal tumor classification...
March 7, 2024: Modern Pathology
https://read.qxmd.com/read/38453353/effects-of-hindlimb-unloading-on-the-mevalonate-and-mechanistic-target-of-rapamycin-complex-1-signaling-pathways-in-a-fast-twitch-muscle-in-rats
#4
JOURNAL ARTICLE
Munehiro Uda, Toshinori Yoshihara, Noriko Ichinoseki-Sekine, Takeshi Baba
Fast-twitch muscles are less susceptible to disuse atrophy, activate the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, and increase protein synthesis under prolonged muscle disuse conditions. However, the mechanism underlying prolonged muscle disuse-induced mTORC1 signaling activation remains unclear. The mevalonate pathway activates the mTORC1 signaling pathway via the prenylation and activation of Ras homolog enriched in brain (Rheb). Therefore, we investigated the effects of hindlimb unloading (HU) for 14 days on the mevalonate and mTORC1 signaling pathways in the plantaris muscle, a fast-twitch muscle, in adult male rats...
March 2024: Physiological Reports
https://read.qxmd.com/read/38452984/an-autophagy-associated-diagnostic-signature-based-on-peripheral-blood-for-antibody-mediated-rejection-in-renal-transplantation
#5
JOURNAL ARTICLE
Yue Xu, Yuxuan Wang, Di Zhang, Hao Zhang, Yicun Wang, Wei Wang, Xiaopeng Hu
BACKGROUND: Antibody-mediated rejection (ABMR) emerged as a major cause of graft loss in renal transplantation. Needle biopsy is the gold standard for diagnosis of ABMR in renal allografts. Thus, noninvasive diagnosis methods of ABMR with high accuracy are urgently needed to prevent unnecessary biopsies. METHODS: We collected peripheral blood transcriptome data from two independent renal transplantation cohorts with patients with ABMR, stable well-functioning transplants (STA), and T-cell mediated rejection (TCMR)...
March 5, 2024: Transplant Immunology
https://read.qxmd.com/read/38448650/the-rapid-proximity-labeling-system-phastid-identifies-atp6ap1-as-an-unconventional-gef-for-rheb
#6
JOURNAL ARTICLE
Ran Feng, Feng Liu, Ruofei Li, Zhifen Zhou, Zhuoheng Lin, Song Lin, Shengcheng Deng, Yingying Li, Baoting Nong, Ying Xia, Zhiyi Li, Xiaoqin Zhong, Shuhan Yang, Gang Wan, Wenbin Ma, Su Wu, Zhou Songyang
Rheb is a small G protein that functions as the direct activator of the mechanistic target of rapamycin complex 1 (mTORC1) to coordinate signaling cascades in response to nutrients and growth factors. Despite extensive studies, the guanine nucleotide exchange factor (GEF) that directly activates Rheb remains unclear, at least in part due to the dynamic and transient nature of protein-protein interactions (PPIs) that are the hallmarks of signal transduction. Here, we report the development of a rapid and robust proximity labeling system named Pyrococcus horikoshii biotin protein ligase (PhBPL)-assisted biotin identification (PhastID) and detail the insulin-stimulated changes in Rheb-proximity protein networks that were identified using PhastID...
March 6, 2024: Cell Research
https://read.qxmd.com/read/38411613/the-mtor-pathway-genes-mtor-rheb-depdc5-pten-and-tsc1-have-convergent-and-divergent-impacts-on-cortical-neuron-development-and-function
#7
JOURNAL ARTICLE
Lena H Nguyen, Youfen Xu, Maanasi Nair, Angelique Bordey
Brain somatic mutations in various components of the mTOR complex 1 (mTORC1) pathway have emerged as major causes of focal malformations of cortical development and intractable epilepsy. While these distinct gene mutations converge on excessive mTORC1 signaling and lead to common clinical manifestations, it remains unclear whether they cause similar cellular and synaptic disruptions underlying cortical network hyperexcitability. Here, we show that in utero activation of the mTORC1 activator genes, Rheb or MTOR , or biallelic inactivation of the mTORC1 repressor genes, Depdc5 , Tsc1 , or Pten in the mouse medial prefrontal cortex leads to shared alterations in pyramidal neuron morphology, positioning, and membrane excitability but different changes in excitatory synaptic transmission...
February 27, 2024: ELife
https://read.qxmd.com/read/38393151/zearalenone-promotes-uterine-hypertrophy-through-ampk-mtor-mediated-autophagy
#8
JOURNAL ARTICLE
Lijie Yang, Wenshuang Liao, Jiuyuan Dong, Xiangjin Chen, Libo Huang, Weiren Yang, Shuzhen Jiang
Zearalenone (ZEN), a non-steroidal Fusarium graminearum with an estrogen effect, can cause damage to the gastrointestinal tract, immune organs, liver, and reproductive system. Further analysis of the mechanism of ZEN has become an important scientific issue. We have established in vivo and in vitro models of ZEN intervention, used AMPK/mTOR as a targeted pathway for ZEN reproductive toxicity, and explored the molecular mechanism by which ZEN may induce uterine hypertrophy in weaned piglets. Our study strongly suggested that ZEN can activate the phosphorylation of AMPK in uterine endometrial epithelium cells, affect the phosphorylation level of mTOR through TSC2 and Rheb, induce autophagy, upregulate the expression of proliferative genes PCNA and BCL2, downregulate the expression of apoptotic gene BAX, promote uterine endometrial epithelium cells proliferation, and ultimately lead to thickening of the endometrial and myometrium, increased density of uterine glands, and induce uterine hypertrophy...
February 1, 2024: Toxins
https://read.qxmd.com/read/38303710/whitening-of-brown-adipose-tissue-inhibits-osteogenic-differentiation-via-secretion-of-s100a8-a9
#9
JOURNAL ARTICLE
Ting Wang, Chaoran Zhao, Jiahuan Zhang, Shengfa Li, Youming Zhang, Yan Gong, Yingyue Zhou, Lei Yan, Sheng Zhang, Zhongmin Zhang, Hongling Hu, Anling Liu, Xiaochun Bai, Zhipeng Zou
The mechanism by which brown adipose tissue (BAT) regulates bone metabolism is unclear. Here, we reveal that BAT secretes S100A8/A9, a previously unidentified BAT adipokine (batokine), to impair bone formation. Brown adipocytes-specific knockout of Rheb ( Rheb BAD KO), the upstream activator of mTOR, causes BAT malfunction to inhibit osteogenesis. Rheb depletion induces NF-κB dependent S100A8/A9 secretion from brown adipocytes, but not from macrophages. In wild-type mice, age-related Rheb downregulation in BAT is associated with enhanced S100A8/A9 secretion...
February 16, 2024: IScience
https://read.qxmd.com/read/38303702/creb3l4-promotes-hepatocellular-carcinoma-progression-and-decreases-sorafenib-chemosensitivity-by-promoting-rheb-mtorc1-signaling-pathway
#10
JOURNAL ARTICLE
Zhengchen Jiang, Bowen Shi, Yun Zhang, Tianming Yu, Yang Cheng, Jiankang Zhu, Guangyong Zhang, Mingwei Zhong, Sanyuan Hu, Xiaomin Ma
This study was designed to explore the roles of CREB3L4 in the pathogenesis and drug resistance of hepatocellular carcinoma (HCC). The proliferation of HCC lines was determined in the presence of CREB3L4 over-expression and silencing. Chromatin immunoprecipitation (ChIP) assay and dual-luciferase reporter assay were performed to screen the potential target of CREB3L4 on mTORC1. Xenografted tumor model was established to define the regulatory effects of CREB3L4 in the tumorigenesis. Then we evaluated the roles of CREB3L4 in chemosensitivity to sorafenib treatment...
February 16, 2024: IScience
https://read.qxmd.com/read/38278976/farnesyl-transferase-inhibitors-show-synergistic-anticancer-effects-in-combination-with-novel-kras-g12c-inhibitors
#11
JOURNAL ARTICLE
Marcell Baranyi, Eszter Molnár, Luca Hegedűs, Zsófia Gábriel, Flóra Gréta Petényi, Fanni Bordás, Violetta Léner, Ivan Ranđelović, Mihály Cserepes, József Tóvári, Balázs Hegedűs, József Tímár
BACKGROUND: Inhibition of mutant KRAS challenged cancer research for decades. Recently, allele-specific inhibitors were approved for the treatment of KRAS-G12C mutant lung cancer. However, de novo and acquired resistance limit their efficacy and several combinations are in clinical development. Our study shows the potential of combining G12C inhibitors with farnesyl-transferase inhibitors. METHODS: Combinations of clinically approved farnesyl-transferase inhibitors and KRAS G12C inhibitors are tested on human lung, colorectal and pancreatic adenocarcinoma cells in vitro in 2D, 3D and subcutaneous xenograft models of lung adenocarcinoma...
January 26, 2024: British Journal of Cancer
https://read.qxmd.com/read/38253890/rheb1-is-required-for-limb-growth-through-regulating-chondrogenesis-in-growth-plate
#12
JOURNAL ARTICLE
Yuwei Zhang, Jiaxin Wen, Ruijun Lai, Jiahuan Zhang, Kai Li, Yue Zhang, Anling Liu, Xiaochun Bai
Ras homology enriched in the brain (Rheb) is well established as a critical regulator of cell proliferation and differentiation in response to growth factors and nutrients. However, the role of Rheb1 in limb development remains unknown. Here, we found that Rheb1 was dynamically expressed during the proliferation and differentiation of chondrocytes in the growth plate. Given that Prrx1+ limb-bud-like mesenchymal cells are the source of limb chondrocytes and are essential for endochondral ossification, we conditionally deleted Rheb1 using Prrx1-Cre and found a limb dwarfism in Prrx1-Cre; Rheb1fl/fl mice...
January 23, 2024: Cell and Tissue Research
https://read.qxmd.com/read/38234670/thada-inhibits-autophagy-and-increases-5-fu-sensitivity-in-gastric-cancer-cells-via-the-pi3k-akt-mtor-signaling-pathway
#13
JOURNAL ARTICLE
Xianke Lin, Jiajia Pan, Hammza Hamoudi, Jiren Yu
OBJECTIVES: 5-Fluorouracil (5-FU) is currently the main drug used in chemotherapy for gastric cancer (GC). The main clinical problems of 5-FU therapy are insensitivity and acquired resistance to 5-FU. The mechanism of GC cell resistance to 5-FU is currently unknown. MATERIALS AND METHODS: This study employed next-generation sequencing (NGS) to analyze the differentially expressed genes (DEGs) in chemotherapy-sensitive and non-sensitive GC tissues. In addition, a bioinformatics analysis was conducted using the GC dataset of GEO, and further validated and explored through in vitro experiments...
2024: Iranian Journal of Basic Medical Sciences
https://read.qxmd.com/read/38195686/tfeb-drives-mtorc1-hyperactivation-and-kidney-disease-in-tuberous-sclerosis-complex
#14
JOURNAL ARTICLE
Nicola Alesi, Damir Khabibullin, Dean M Rosenthal, Elie W Akl, Pieter M Cory, Michel Alchoueiry, Samer Salem, Melissa Daou, William F Gibbons, Jennifer A Chen, Long Zhang, Harilaos Filippakis, Laura Graciotti, Caterina Miceli, Jlenia Monfregola, Claudia Vilardo, Manrico Morroni, Chiara Di Malta, Gennaro Napolitano, Andrea Ballabio, Elizabeth P Henske
Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and lesions  in multiple organs including lung (lymphangioleiomyomatosis) and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in TSC. Here, we generated two mouse models of TSC in which kidney pathology is the primary phenotype. Knockout of TFEB rescues kidney pathology and overall survival, indicating that TFEB is the primary driver of renal disease in TSC...
January 9, 2024: Nature Communications
https://read.qxmd.com/read/38159819/a-study-on-molecular-mechanism-of-xihuang-pill-in-the-treatment-of-glioblastoma-based-on-network-pharmacology-and-validation-in-vitro-and-in-vivo
#15
JOURNAL ARTICLE
Hong-Bin Xu, Xian-Zhen Chen, Su-Yan Zhu, Fei Xue, Yuan-Bin Zhang
ETHNOPHARMACOLOGICAL RELEVANCE: Xihuang pill has been utilized to treat cancer for more than three hundred years in China. The molecular mechanisms of Xihuang pill in treating glioblastoma remains unclear. AIM OF THE STUDY: This study aimed to explore the core molecular mechanisms of Xihuang pill in treating glioblastoma by an integrative pharmacology-based investigation. MATERIALS AND METHODS: The main active compounds of Xihuang pill were identified from TCMSP, BATMAN-TCM, TCMID and CNKI...
December 28, 2023: Journal of Ethnopharmacology
https://read.qxmd.com/read/38153629/loxl3-inhibits-autophagy-of-chondrocytes-by-activating-rheb-in-osteoarthritis
#16
JOURNAL ARTICLE
Guang-Ping Zheng, Chen Liu, Liang Zhang, Qiang Zhong, Yun Zhang, Zhong-Ming Huang
OBJECTIVE: This study aimed to investigate the potential mechanisms by which lysyl oxidase like 3 (LOXL3) affects the autophagy in chondrocytes in osteoarthritis (OA), specifically through the activation of mammalian target of rapamycin complex 1 (mTORC1). METHODS: To establish an OA model, rats underwent anterior cruciate ligament transection (ACLT). Chondrocytes were isolated from cartilage tissues and cultured. Western blotting was performed to assess the expression of LOXL3, Rheb, phosphorylation of p70S6K (p-p70S6K, a downstream marker of mTORC1), and autophagy markers...
December 2023: Current Medical Science
https://read.qxmd.com/read/38147625/small-g-protein-rheb-gates-mtor-signaling-to-regulate-morphine-tolerance-in-mice
#17
JOURNAL ARTICLE
Wenying Wang, Xiaqing Ma, Wenjie Du, Raozhou Lin, Zhongping Li, Wei Jiang, Lu-Yang Wang, Paul F Worley, Tao Xu
BACKGROUND: Analgesic tolerance due to long-term use of morphine remains a challenge for pain management. Morphine acts on μ-opioid receptors and downstream of the phosphatidylinositol-3-kinase signaling pathway to activate the mammalian target of rapamycin (mTOR) pathway. Rheb is an important regulator of growth and cell-cycle progression in the central nervous system owing to its critical role in the activation of mTOR. We hypothesized that signaling via the GTP-binding protein Rheb in the dorsal horn of the spinal cord is involved in morphine-induced tolerance...
December 26, 2023: Anesthesiology
https://read.qxmd.com/read/38100333/anti-seizure-gene-therapy-for-focal-cortical-dysplasia
#18
JOURNAL ARTICLE
Amanda Almacellas Barbanoj, Robert T Graham, Benito Maffei, Jenna C Carpenter, Marco Leite, Justin Hoke, Felisia Hardjo, James Scott-Solache, Christos Chimonides, Stephanie Schorge, Dimitri M Kullmann, Vincent Magloire, Gabriele Lignani
Focal cortical dysplasias are a common subtype of malformation of cortical development, which frequently presents with a spectrum of cognitive and behavioural abnormalities as well as pharmacoresistant epilepsy. Focal cortical dysplasia type II is typically caused by somatic mutations resulting in mammalian target of rapamycin (mTOR) hyperactivity, and is the commonest pathology found in children undergoing epilepsy surgery. However, surgical resection does not always result in seizure freedom, and is often precluded by proximity to eloquent brain regions...
February 1, 2024: Brain
https://read.qxmd.com/read/38079221/nadph-oxidase-2-derived-reactive-oxygen-species-promote-cd8-t-cell-effector-function
#19
JOURNAL ARTICLE
Jing Chen, Chao Liu, Anna V Chernatynskaya, Brittney Newby, Todd M Brusko, Yuan Xu, Jessie M Barra, Nadine Morgan, Christopher Santarlas, Westley H Reeves, Hubert M Tse, Jennifer W Leiding, Clayton E Mathews
Oxidants participate in lymphocyte activation and function. We previously demonstrated that eliminating the activity of NADPH oxidase 2 (NOX2) significantly impaired the effectiveness of autoreactive CD8+ CTLs. However, the molecular mechanisms impacting CD8+ T cell function remain unknown. In the present study, we examined the role of NOX2 in both NOD mouse and human CD8+ T cell function. Genetic ablation or chemical inhibition of NOX2 in CD8+ T cells significantly suppressed activation-induced expression of the transcription factor T-bet, the master transcription factor of the Tc1 cell lineage, and T-bet target effector genes such as IFN-γ and granzyme B...
December 11, 2023: Journal of Immunology
https://read.qxmd.com/read/38019969/martini-3-force-field-parameters-for-protein-lipidation-post-translational-modifications
#20
JOURNAL ARTICLE
Panagiotis I Koukos, Sepehr Dehghani-Ghahnaviyeh, Camilo Velez-Vega, John Manchester, D Peter Tieleman, José S Duca, Paulo C T Souza, Zoe Cournia
Protein lipidations are vital co/post-translational modifications that tether lipid tails to specific protein amino acids, allowing them to anchor to biological membranes, switch their subcellular localization, and modulate association with other proteins. Such lipidations are thus crucial for multiple biological processes including signal transduction, protein trafficking, and membrane localization and are implicated in various diseases as well. Examples of lipid-anchored proteins include the Ras family of proteins that undergo farnesylation; actin and gelsolin that are myristoylated; phospholipase D that is palmitoylated; glycosylphosphatidylinositol-anchored proteins; and others...
November 29, 2023: Journal of Chemical Theory and Computation
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