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2022 ◽  
Vol 12 ◽  
Author(s):  
Maolin Yao ◽  
Lanyi Fu ◽  
Xuedong Liu ◽  
Dong Zheng

Aberrant activation of calmodulin 1 (CALM1) has been reported in human cancers. However, comprehensive understanding of the role of CALM1 in most cancer types has remained unclear. We systematically analyzed the expression landscape, DNA methylation, gene alteration, immune infiltration, clinical relevance, and molecular pathway of CALM1 in multiple cancers using various online tools, including The Cancer Genome Atlas, cBioPortal and the Human Protein Atlas databases. Kaplan–Meier and receiver operating characteristic (ROC) curves were plotted to explore the prognostic and diagnostic potential of CALM1 expression. Multivariate analyses were used to evaluate whether the CALM1 expression could be an independent risk factor. A nomogram predicting the overall survival (OS) of patients was developed, evaluated, and compared with the traditional Tumor-Node-Metastasis (TNM) model using decision curve analysis. R language was employed as the main tool for analysis and visualization. Results revealed CALM1 to be highly expressed in most cancers, its expression being regulated by DNA methylation in multiple cancers. CALM1 had a low mutation frequency (within 3%) and was associated with immune infiltration. We observed a substantial positive correlation between CALM1 expression and macrophage and neutrophil infiltration levels in multiple cancers. Different mutational forms of CALM1 hampered immune cell infiltration. Additionally, CALM1 expression had high diagnostic and prognostic potential. Multivariate analyses revealed CALM1 expression to be an independent risk factor for OS. Therefore, our newly developed nomogram had a higher clinical value than the TNM model. The concordance index, calibration curve, and time-dependent ROC curves of the nomogram exhibited excellent performance in terms of predicting the survival rate of patients. Moreover, elevated CALM1 expression contributes to the activation of cancer-related pathways, such as the WNT and MAPK pathways. Overall, our findings improved our understanding of the function of CALM1 in human cancers.


2022 ◽  
Author(s):  
Guo‐Sheng Li ◽  
He‐Qing Huang ◽  
Yao Liang ◽  
Qiu‐Yu Pang ◽  
Hao‐Jia Sun ◽  
...  

Author(s):  
Sofie Bünemann Dalsgaard ◽  
Else Toft Würtz ◽  
Johnni Hansen ◽  
Oluf Dimitri Røe ◽  
Øyvind Omland

Objectives: To examine the asbestos-associated cancer incidence and the risk of multiple cancers in former school children exposed to environmental asbestos in childhood. Methods: A cohort of 12,111 former school children, born 1940–1970, was established using 7th grade school records from four schools located at a distance of 100–750 m in the prevailing wind direction from a large asbestos-cement plant that operated from 1928 to 1984 in Aalborg, Denmark. Using the unique Danish personal identification number, we linked information on employments, relatives’ employments, date of cancer diagnosis, and type of cancer and vital status to data on cohortees extracted from the Supplementary Pension Fund Register (employment history), the Danish Cancer Registry, and the Danish Civil Registration System. We calculated standardized incidence rates (SIRs) for asbestos-associated cancers, all cancers, and multiple cancers using rates for a gender and five-year frequency-matched reference cohort. Results: The overall incidence of cancer was modestly increased for the school cohort (SIR 1.07, 95% confidence interval (CI) 1.02–1.12) compared with the reference cohort. This excess was driven primarily by a significantly increased SIR for malignant mesothelioma (SIR 8.77, 95% CI 6.38–12.05). Former school children who had combined childhood environmental and subsequent occupational exposure to asbestos had a significantly increased risk of lung cancer. Within this group, those with additional household exposure by a relative had a significantly increased SIR for cancer of the pharynx (SIR 4.24, 95% CI 1.59–11.29). We found no significant difference in the number of subjects diagnosed with multiple cancers between the two cohorts. Conclusions: Our study confirms the strong association between environmental asbestos exposure and malignant mesothelioma and suggests that environmental asbestos exposure in childhood may increase the overall cancer risk later in life.


Author(s):  
Zheng Chen ◽  
Yingjie Guo ◽  
Da Zhao ◽  
Quan Zou ◽  
Fusheng Yu ◽  
...  

The CDKN2A (cyclin dependent kinase inhibitor 2A/multiple tumor suppressor 1) gene, also known as the P16 gene, encodes multiple tumor suppressor 1 (MTS1), which belongs to the INK4 family. In tumor tissue, CDKN2A has a high expression level compared with normal tissue and reflects prognosis in tumor patients. Our research targeted the analysis of CDKN2A expression in 33 tumors and clinical parameters, patient prognosis and tumor immunity roles. The CDKN2A expression level was significantly correlated with the tumor mutation burden (TMB) in 10 tumors, and the expression of CDKN2A was also correlated with MSI (microsatellite instability) in 10 tumors. CDKN2A expression was associated with infiltrating lymphocyte (TIL) levels in 22 pancancers, thus suggesting that CDKN2A expression is associated with tumor immunity. Enrichment analysis indicated that CDKN2A expression was involved in natural killer cell-mediated cytotoxicity pathways, antigen processing and presentation, olfactory transduction pathways, and regulation of the autophagy pathway in multiple cancers. CDKN2A was significantly associated with several immune cell infiltrates in pantumors. CDKN2A may serve as a promising prognostic biomarker and is associated with immune infiltrates across cancers.


Author(s):  
Qin Zhang ◽  
Dennis K. Jeppesen ◽  
James N. Higginbotham ◽  
Ramona Graves-Deal ◽  
Vincent Q. Trinh ◽  
...  

AbstractExtracellular vesicles and exomere nanoparticles are under intense investigation as sources of clinically relevant cargo. Here we report the discovery of a distinct extracellular nanoparticle, termed supermere. Supermeres are morphologically distinct from exomeres and display a markedly greater uptake in vivo compared with small extracellular vesicles and exomeres. The protein and RNA composition of supermeres differs from small extracellular vesicles and exomeres. Supermeres are highly enriched with cargo involved in multiple cancers (glycolytic enzymes, TGFBI, miR-1246, MET, GPC1 and AGO2), Alzheimer’s disease (APP) and cardiovascular disease (ACE2, ACE and PCSK9). The majority of extracellular RNA is associated with supermeres rather than small extracellular vesicles and exomeres. Cancer-derived supermeres increase lactate secretion, transfer cetuximab resistance and decrease hepatic lipids and glycogen in vivo. This study identifies a distinct functional nanoparticle replete with potential circulating biomarkers and therapeutic targets for a host of human diseases.


2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Jun Yang ◽  
Manlong Qi ◽  
Xiang Fei ◽  
Xia Wang ◽  
Kefeng Wang

AbstractLong non-coding RNA (lncRNA) X-inactive specific transcript (XIST) is an important lncRNA derived from the XIST gene in mammals. XIST is abnormally expressed in numerous tumors, in most of which XIST functions as an oncogene. XIST is involved in multiple aspects of carcinogenesis, including tumor onset, progression, and prognosis. In our review, we collected and analyzed the recent studies on the impact of XIST in human tumor development. The multilevel molecular functions of XIST in human tumors are comprehensively reviewed to clarify the pathologic mechanisms and to offer a novel direction for further study.


2021 ◽  
Author(s):  
Hua Zhao ◽  
yanbing Li

Abstract Objective MicroRNA (miR)-185-3p roles have been probed in multiple cancers, while the underlying function of miR-185-3p in hyperlipidemia remained obscure. This research was conducted to unravel miR-185-3p function in hyperlipidemia development via modulating mastermind-like 1 (MAML1). Methods The hyperlipidemia rat model was constructed. MiR-185-3p and MAML1 levels in hyperlipidemia rats were detected. Adenoviral vectors altering miR-185-3p and MAML1 levels were injected into hyperlipidemia rats to examine the levels of biochemical indices, inflammatory factors, oxidative stress, lipid accumulation and cellular morphology in liver tissues of hyperlipidemia rats. The targeting relation between miR-185-3p and MAML1 was manifested. Results MiR-185-3p levels were depleted while MAML1 expression was elevated in HH rats. MiR-185-3p overexpression or MAML1 silencing reduced levels of inflammatory factors in serum, mitigated oxidative stress and biochemical response, relieved lipid accumulation and cellular morphology in liver tissues; while up-regulated MAML1 reversed the effects of augmented MAML1 in hyperlipidemia rats. MiR-185-3p targeted MAML1. Conclusion Up-regulated miR-185-3p represses hyperlipidemia development via modulating MAML1. This research provides novel therapeutic candidates for the treatment of hyperlipidemia.


2021 ◽  
Vol 1 (2) ◽  
pp. 56-64
Author(s):  
Kyle A. Cottrell ◽  
Luisangely Soto-Torres ◽  
Michael G. Dizon ◽  
Jason D. Weber

The RNA editing enzyme ADAR is an attractive therapeutic target for multiple cancers. Through its deaminase activity, ADAR edits adenosine to inosine in double-stranded RNAs. Loss of ADAR in some cancer cell lines causes activation of the type I IFN pathway and the PKR translational repressor, leading to inhibition of proliferation and stimulation of cell death. As such, inhibition of ADAR function is a viable therapeutic strategy for many cancers. However, there are no FDA-approved inhibitors of ADAR. Two small molecules have been previously shown to inhibit ADAR or reduce its expression: 8-azaadenosine and 8-chloroadenosine. Here we show that neither molecule is a selective inhibitor of ADAR. Both 8-azaadenosine and 8-chloroadenosine show similar toxicity to ADAR-dependent and -independent cancer cell lines. Furthermore, the toxicity of both small molecules is comparable between cell lines with either knockdown or overexpression of ADAR, and cells with unperturbed ADAR expression. Treatment with neither molecule causes activation of PKR. Finally, treatment with either molecule has no effect on A-to-I editing of multiple ADAR substrates. Together, these data show that 8-azaadenosine and 8-chloroadenosine are not suitable small molecules for therapies that require selective inhibition of ADAR, and neither should be used in preclinical studies as ADAR inhibitors. Significance: ADAR is a good therapeutic target for multiple cancers; neither 8-chloroadenosine nor 8-azaadenosine are selective inhibitors of ADAR.


2021 ◽  
Vol 11 ◽  
Author(s):  
Osmel Companioni ◽  
Cristina Mir ◽  
Yoelsis Garcia-Mayea ◽  
Matilde E. LLeonart

Sphingolipids are an extensive class of lipids with different functions in the cell, ranging from proliferation to cell death. Sphingolipids are modified in multiple cancers and are responsible for tumor proliferation, progression, and metastasis. Several inhibitors or activators of sphingolipid signaling, such as fenretinide, safingol, ABC294640, ceramide nanoliposomes (CNLs), SKI-II, α-galactosylceramide, fingolimod, and sonepcizumab, have been described. The objective of this review was to analyze the results from preclinical and clinical trials of these drugs for the treatment of cancer. Sphingolipid-targeting drugs have been tested alone or in combination with chemotherapy, exhibiting antitumor activity alone and in synergism with chemotherapy in vitro and in vivo. As a consequence of treatments, the most frequent mechanism of cell death is apoptosis, followed by autophagy. Aslthough all these drugs have produced good results in preclinical studies of multiple cancers, the outcomes of clinical trials have not been similar. The most effective drugs are fenretinide and α-galactosylceramide (α-GalCer). In contrast, minor adverse effects restricted to a few subjects and hepatic toxicity have been observed in clinical trials of ABC294640 and safingol, respectively. In the case of CNLs, SKI-II, fingolimod and sonepcizumab there are some limitations and absence of enough clinical studies to demonstrate a benefit. The effectiveness or lack of a major therapeutic effect of sphingolipid modulation by some drugs as a cancer therapy and other aspects related to their mechanism of action are discussed in this review.


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