Lung cancer is the leading cause of cancer‐related death worldwide. As well as the identified role of epidermal growth factor receptor (EGFR), its association with driver mutations has improved the ...therapeutics for patients with lung cancer harboring EGFR mutations. These patients usually display shorter overall survival and a higher tendency to develop distant metastasis compared with those carrying the wild‐type EGFR. Nevertheless, the way to control mutated EGFR signaling remains unclear. Here, we performed membrane proteomic analysis to determine potential components that may act with EGFR mutations to promote lung cancer malignancy. Expression of transmembrane glycoprotein non‐metastatic melanoma protein B (GPNMB) was positively correlated with the status of mutated EGFR in non‐small‐cell lung cancer (NSCLC). This protein was not only overexpressed but also highly glycosylated in EGFR‐mutated, especially EGFR‐L858R mutated, NSCLC cells. Further examination showed that GPNMB could activate mutated EGFR without ligand stimulation and could bind to the C‐terminus of EGFR, assist phosphorylation at Y845, turn on downstream STAT3 signaling, and promote cancer metastasis. Moreover, we also found that Asn134 (N134) glycosylation of GPNMB played a crucial role in this ligand‐independent regulation. Depleting N134‐glycosylation on GPNMB could dramatically inhibit binding of GPNMB to mutated EGFR, blocking its downstream signaling, and ultimately inhibiting cancer metastasis in NSCLC. Clarifying the role of N‐glycosylated GPNMB in regulating the ligand‐independent activation of mutated EGFR may soon give new insight into the development of novel therapeutics for NSCLC.
In this study, we used membrane proteomic analysis to identify that GPNMB is overexpressed and highly N‐glycosylated in the EGFR mutant, especially the EGFR‐L858R mutated, NSCLC. GPNMB could bind to mutated EGFR without ligand stimulation, activate its downstream signaling and promote cancer metastasis. N134 glycosylation of GPNMB also plays a crucial role in controlling this ligand‐independent regulation.
Long noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) ...progression and could be a potential therapeutic target.
We screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact with LINRIS (Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells with LINRIS inhibited were tested in vitro and in vivo.
LINRIS was upregulated in CRC tissues from patients with poor overall survival (OS), and LINRIS inhibition led to the impaired CRC cell line growth. Moreover, knockdown of LINRIS resulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N
-methyladenosine (m
A) 'reader'. LINRIS blocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown of LINRIS attenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription of LINRIS could be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition of LINRIS suppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models.
LINRIS is an independent prognostic biomarker for CRC. The LINRIS-IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target.
Research has found that many people view climate change as a psychologically distant, future threat, which leads them to be less motivated to engage in pro-environmental behavior. Engaging in ...episodic future thinking (EFT; projecting the self into the future to pre-experience future events) may facilitate the perception of future events as psychologically close, thereby increasing the perceived risk associated with those events. Therefore, engagement in EFT regarding climate change–related risks should induce higher risk perceptions and lead to acting pro-environmentally. In two experiments, we demonstrated that engaging in EFT to pre-experience climate change–related risk events was associated with a higher level of risk perception and a greater tendency toward pro-environmental behavior, including energy-saving use of air-conditioning (Experiment 1), willingness to participate in beach cleaning (Experiment 2), and choice of a meal with lower environmental impact (Experiment 2). The current research provides experimental evidence for an innovative approach to improving public engagement with climate change.
Lower heart rate variability (HRV) is associated with a higher risk of cardiovascular events and mortality, although the extent of the association is uncertain. We performed a meta-analysis of cohort ...studies to elucidate the association between HRV and the risk of all-cause death or cardiovascular events in patients with cardiovascular disease (CVD) during a follow-up of at least 1 year. We searched four databases (PubMed, MEDLINE, Embase, and Cochrane Central Register of Controlled Trials) and extracted the adjusted hazard ratio (HR) from eligible studies. We included 28 cohort studies involving 3,094 participants in the meta-analysis. Results revealed that lower HRV was associated with a higher risk of all-cause death and cardiovascular events; the pooled HRs were 2.12 (95% confidence interval CI = 1.64, 2.75) and 1.46 (95% CI 1.19, 1.77), respectively. In subgroup analyses, the pooled HR of all-cause death was significant for patients with acute myocardial infarction (AMI) but not for those with heart failure. The pooled HR for cardiovascular events was significant for the subgroup of patients with AMI and acute coronary syndrome but not for those with coronary artery disease and heart failure. Additionally, both time and frequency domains of HRV were significantly associated with risk of all-cause death and cardiovascular events in patients with CVD.
Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct ...disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma.
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•First deep proteogenomic landscape of non-smoking lung adenocarcinoma in East Asia•Identified age, sex-related endogenous, and environmental carcinogen mutagenic processes•Proteome-informed classification distinguished clinical features within early stages•Protein networks identified tumorigenesis hallmarks, biomarkers, and druggable targets
Deep proteogenomic landscape of early stage lung adenocarcinoma in a cohort of mostly non-smokers reveals unique drivers and biomarkers, as well as gender-associated mutagenesis.
The initial presentation of non-alcoholic steatohepatitis (NASH) is hepatic steatosis. The dysfunction of lipid metabolism within hepatocytes caused by genetic factors, diet, and insulin resistance ...causes lipid accumulation. Lipotoxicity, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress would further contribute to hepatocyte injury and death, leading to inflammation and immune dysfunction in the liver. During the healing process, the accumulation of an excessive amount of fibrosis might occur while healing. During the development of NASH and liver fibrosis, the gut-liver axis, adipose-liver axis, and renin-angiotensin system (RAS) may be dysregulated and impaired. Translocation of bacteria or its end-products entering the liver could activate hepatocytes, Kupffer cells, and hepatic stellate cells, exacerbating hepatic steatosis, inflammation, and fibrosis. Bile acids regulate glucose and lipid metabolism through Farnesoid X receptors in the liver and intestine. Increased adipose tissue-derived non-esterified fatty acids would aggravate hepatic steatosis. Increased leptin also plays a role in hepatic fibrogenesis, and decreased adiponectin may contribute to hepatic insulin resistance. Moreover, dysregulation of peroxisome proliferator-activated receptors in the liver, adipose, and muscle tissues may impair lipid metabolism. In addition, the RAS may contribute to hepatic fatty acid metabolism, inflammation, and fibrosis. The treatment includes lifestyle modification, pharmacological therapy, and non-pharmacological therapy. Currently, weight reduction by lifestyle modification or surgery is the most effective therapy. However, vitamin E, pioglitazone, and obeticholic acid have also been suggested. In this review, we will introduce some new clinical trials and experimental therapies for the treatment of NASH and related fibrosis.
The catalyst‐controlled diversity‐oriented synthesis of spirohydroquinoline‐indandiones and 3‐methylenehydroquinoline‐indandiones from ortho‐sulfonamidophenyl‐substituted para‐quinone methides and ...allylidene‐indandiones is reported. The strategies utilized an organobase such as DMAP or TMG to control the reaction pathway chemoselectively, furnishing the corresponding products in 40–99% yields with excellent diastereoselectivities. The mechanistic studies revealed that spirohydroquinoline‐indandione was the kinetic product to afford 3‐methylenehydroquinoline‐indandione in the presence of TMG, which probably involved an unusual base‐initiated 1,3‐nitrogen rearrangement process.
Hypoxia which commonly exists in solid tumors, leads to cancer cells chemoresistance via provoking adaptive responses including autophagy. Therefore, we sought to evaluate the role of autophagy and ...hypoxia as well as the underlying mechanism in the cisplatin resistance of lung cancer cells. Our study demonstrated that hypoxia significantly protected A549 and SPC-A1 cells from cisplatin-induced cell death in a Hif-1α- and Hif-2α-dependent manner. Moreover, compared with normoxia, cisplatin-induced apoptosis under hypoxia was markedly reduced. However, when autophagy was inhibited by 3-MA or siRNA targeted ATG5, this reduction was effectively attenuated, which means autophagy mediates cisplatin resisitance under hypoxia. In parallel, we showed that hypoxia robustly augmented cisplatin-induced autophagy activation, accompanying by suppressing cisplatin-induced BNIP3 death pathways, which was due to the more efficient autophagic process under hypoxia. Consequently, we proposed that autophagy was a protective mechanism after cisplatin incubation under both normoxia and hypoxia. However, under normoxia, autophagy activation 'was unable to counteract the stress induced by cisplatin, therefore resulting in cell death, whereas under hypoxia, autophagy induction was augmented that solved the cisplatin-induced stress, allowing the cells to survival. In conclusion, augmented induction of autophagy by hypoxia decreased lung cancer cells susceptibility to cisplatin-induced apoptosis.
Cognitive dysfunction has been reported in individuals with fibromyalgia. However, findings regarding cognitive function examined using neuropsychological tests have been inconsistent. The aim of the ...study was to determine domain-specific cognitive impairment in patients with fibromyalgia compared with healthy controls.
We conducted a meta-analysis that systematically searched six databases (PubMed, Ovid MEDLINE, Embase, CINAHL, PsycINFO, and Web of Science) for articles published before September 2017.
Twenty-three case-control studies with a total of 2096 participants were included in the meta-analysis. Cognitive function was significantly lower (g = 0.87, 95% confidence interval CI = 0.60-1.15) in individuals with fibromyalgia than in healthy controls. Large effect sizes were found in learning/memory and attention/psychomotor speed (g = 0.94, p = .013; g = 1.22, p < .001, respectively); medium effect sizes were reported in executive function and working memory (g = 0.72, p < .001; g = 0.75, p < .001, respectively). Depression and anxiety scores were associated with the effect size of group differences in cognitive function (B = 0.11, p < .001, 95% CI = 0.09-0.13; B = 0.02, p < .001, 95% CI = 0.01-0.02, respectively).
Cognitive impairment across different cognitive domains was found in individuals with fibromyalgia compared with healthy controls. Mood states (depression and anxiety) may explain the heterogeneity across studies.
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