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Merkel cell polyomavirus (MCPyV) is the foremost causative factor of Merkel cell carcinoma (MCC), a rare yet highly aggressive skin cancer. Although the evaluation of circulating IgG antibodies against Merkel cell polyomavirus (MCPyV) LT/sT oncoproteins is clinically useful for MCC diagnosis/prognosis, a limited number of assays for identifying such antibodies have been developed. Herein, a novel indirect immunoassay with synthetic epitopes/mimotopes of MCPyV oncoproteins was computationally designed and experimentally validated on control sera and sera from healthy individuals and MCC patients. Upon computational design of five synthetic peptides, the performance of the immunoassay in detecting anti‐oncoprotein IgGs in MCPyV‐positive and ‐negative control sera was evaluated. The immunoassay was afterwards extended on sera from healthy individuals, and, for longitudinal analysis, MCC patients. Performance properties such as sensitivity and specificity and positive/negative predictive values were adequate. Receiver‐operating characteristic (ROC) curves indicated that the areas under the curves (AUCs) were within the low/moderately accurate ranges. Immunoassay was repeatable, reproducible and accurate. As expected, the serum anti‐oncoprotein IgG prevalence in healthy individuals was low (2%–5%). Anti‐oncoprotein IgGs slightly increased when MCC patients experienced partial tumour remission and/or stable disease, compared to baseline. Our data indicate that the newly developed immunoassay is reliable for detecting circulating anti‐oncoprotein IgGs both in healthy individuals and MCC patients. [ABSTRACT FROM AUTHOR]

Background: The limited therapies available for treating Merkel cell carcinoma (MCC), a highly aggressive skin neoplasm, still pose clinical challenges, and novel treatments are required. Targeting retinoid signalling with retinoids, such as all‐trans retinoic acid (ATRA), is a promising and clinically useful antitumor approach. ATRA drives tumour cell differentiation by modulating retinoid signalling, leading to anti‐proliferative and pro‐apoptotic effects. Although retinoid signalling is dysregulated in MCC, ATRA activity in this tumour is unknown. This study aimed to evaluate the impact of ATRA on the pathological phenotype of MCC cells. Methods: The effect of ATRA was tested in various Merkel cell polyomavirus‐positive and polyomavirus‐negative MCC cell lines in terms of cell proliferation, viability, migration and clonogenic abilities. In addition, cell cycle, apoptosis/cell death and the retinoid gene signature were evaluated upon ATRA treatments. Results: ATRA efficiently impaired MCC cell proliferation and viability in MCC cells. A strong effect in reducing cell migration and clonogenicity was determined in ATRA‐treated cells. Moreover, ATRA resulted as strongly effective in arresting cell cycle and inducing apoptosis/cell death in all tested MCC cells. Enrichment analyses indicated that ATRA was effective in modulating the retinoid gene signature in MCC cells to promote cell differentiation pathways, which led to anti‐proliferative and pro‐apoptotic/cell death effects. Conclusions: These results underline the potential of retinoid‐based therapy for MCC management and might open the way to novel experimental approaches with other retinoids and/or combinatorial treatments. [ABSTRACT FROM AUTHOR]

Limited molecular knowledge of Merkel cell polyomavirus (MCPyV)‐positive and ‐negative Merkel cell carcinoma (MCC) subsets (MCCP/MCCN) has prevented so far the identification of the MCC origin cell type and, therefore, the development of effective therapies. The retinoic gene signature was investigated in various MCCP, MCCN, and control fibroblast/epithelial cell lines to elucidate the heterogeneous nature of MCC. Hierarchical clustering and principal component analysis indicated that MCCP and MCCN cells were clusterizable from each other and control cells, according to their retinoic gene signature. MCCP versus MCCN differentially expressed genes (n = 43) were identified. Protein–protein interaction network indicated SOX2, ISL1, PAX6, FGF8, ASCL1, OLIG2, SHH, and GLI1 as upregulated hub genes and JAG1 and MYC as downregulated hub genes in MCCP compared to MCCN. Numerous MCCP‐associated hub genes were DNA‐binding/‐transcription factors involved in neurological and Merkel cell development and stemness. Enrichment analyses indicated that MCCP versus MCCN differentially expressed genes predominantly encode for to DNA‐binding/‐transcription factors involved in development, stemness, invasiveness, and cancer. Our findings suggest the neuroendocrine origin of MCCP, by which neuronal precursor cells could undergo an MCPyV‐driven transformation. These overarching results might open the way to novel retinoid‐based MCC therapies. [ABSTRACT FROM AUTHOR]

Oncogenic Merkel cell polyomavirus (MCPyV) provokes a widespread and asymptomatic infection in humans. Herein, sera from healthy children and young adults (HC, n = 344) aged 0–20 years old were evaluated for anti‐MCPyV immunoglobulin G (IgG) and IgM antibodies employing a recently developed immunoassay. Serum MCPyV IgG data from healthy subjects (HS, n = 510) and elderlies (ES, n = 226), aged 21–65/66–100 years old, from our previous studies, were included. The anti‐MCPyV IgG and IgM rates in HC sera were 40.7% and 29.7%, respectively. A lower prevalence of anti‐MCPyV IgGs was found in HC aged 0–5 years old (13%) compared to 6–10 (52.3%), 11–15 (60.5%) and 16–20 years old (61.6%) cohorts. Age‐stratified HCs exhibited similar anti‐MCPyV IgM rates (27.9%–32.9%). Serological profiles indicated that anti‐MCPyV IgGs and IgMs had low optical densities (ODs) during the first years of life, while IgM ODs appeared to decrease throughout young adulthood. A lower anti‐MCPyV IgGs rate was found in HC (40.7%) than HS (61.8%) and ES (63.7%). Upon the 5‐years range age‐stratification, a lower anti‐MCPyV IgGs rate was found in the younger HC cohort aged 0–5 years old compared to the remaining older HC/HS/ES cohorts (52.3%–72%). The younger HC cohort exhibited the lowest anti‐MCPyV IgG ODs than the older cohorts. Low anti‐MCPyV IgMs rates and ODs were found in the 21–25 (17.5%) and 26–30 (7.7%) years old cohorts. Our data indicate that, upon an early‐in‐life seroconversion, the seropositivity for oncogenic MCPyV peaks in late childhood/young adulthood and remains at high prevalence and relatively stable throughout life. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma (MCC) is an aggressive skin malignancy with two distinct etiologies. The first, which accounts for the highest proportion, is caused by Merkel cell polyomavirus (MCPyV), a DNA tumor virus. A second, UV‐induced, MCC form has also been identified. Few MCC diagnostic, prognostic, and therapeutic options are available. MicroRNAs (miRNAs) are small noncoding RNA molecules, which play a key role in regulating various physiologic cellular functions including cell cycling, proliferation, differentiation, and apoptosis. Numerous miRNAs are dysregulated in cancer, by acting as either tumor suppressors or oncomiRs. The aim of this review is to collect, summarize, and discuss recent findings on miRNAs whose dysregulation has been assumed to play a role in MCC. The potential clinical application of miRNAs as diagnostic and prognostic biomarkers in MCC is also described. In the future, miRNAs will potentially gain clinical significance for the improvement of MCC diagnostic, prognostic, and therapeutic options. [ABSTRACT FROM AUTHOR]

Aim. We purposed to evaluate the KCTD10 effects of angiogenesis in diabetic retinopathy (DR). Methods. We induced a DR cell model using high glucose (HG) treatment of HRECs and ARPE-19 cells. A DR rat was established by injecting streptozotocin. Small interference RNA targeted KCTD10 (si-KCTD10) was used to mediate KCTD10 inhibition in cell and animal models. The roles of KCTD10 on cell viability, apoptosis, angiogenesis, and related proteins (VEGF and HIF-1 α) were observed by RT-qPCR, Western blot, CCK-8 assay, TUNEL staining, tube formation assay, ELISA, and immunohistochemistry assay. Results. KCTD10 expression was upregulated in DR cells and retinal tissue of DR rats. Treatment of the cells with si-KCTD10 increased cell viability and decreased apoptosis and angiogenesis in DR cells. Inhibition of KCTD10 could reduce the expression of VEGF and HIF-1 α in DR cells. Furthermore, KCTD10 inhibition reduced VEGF levels in the retinal tissue of DR rats. Conclusion. This work showed that inhibition of KCTD10 relieved angiogenesis in DR. [ABSTRACT FROM AUTHOR]

Objective. Clopidogrel is widely used for preventing ischemic complications related to cardiovascular diseases. However, many patients experience clopidogrel resistance (CR). The polymorphisms of CYP2C19 have been implicated in CR, but CYP2C19 polymorphism considerably varies with both ethnic group and geographical location. This study aimed to investigate the association between CYP2C19 polymorphisms and clopidogrel resistance (CR) in patients with coronary heart disease and ischemic stroke among Han and Tibetan populations in Qinghai Province, China. Methods. From June 2019 to January 2020, patients who were diagnosed with coronary heart disease or cerebral infarction in internal medicine of Qinghai Provincial People's Hospital and had taken dual antiplatelet drugs were included in this study. Blood was collected and routine items were completed. Whole exome sequencing was performed for CYP2C19 genetic polymorphisms of CYP2C19 ∗ 2 (rs4244285), CYP2C19 ∗ 3 (rs4986893), and CYP2C19 ∗ 17 (rs12248560). Results. A total of 91 patients with coronary heart disease or cerebral infarction (67 Han people (65.99 ± 12.25 years old) and 24 Tibetan (63.6324 Tib years old)) including 52 cases with CR and 39 cases with non-CR were enrolled in this study. For the Han population, the differences in age, glycosylated hemoglobin, activated partial thromboplastin time (APTT), gender, aspirin resistance, and diabetes were significant between the CR and non-CR groups. For the Tibetan population, the two groups showed no significant difference in all indicators. There was no significant difference between CR and non-CR groups for all genotypes (CYP2C19 ∗ 2, ∗ 3, and ∗ 17) in either Han or Tibetan populations. For the Han populations, age, APTT, and aspirin resistance were significantly correlated with CR. Conclusion. The present study indicated that CYP2C19 ∗ 2, CYP2C19 ∗ 3, and CYP2C19 ∗ 17 alleles were not correlated with CR for both Han and Tibetan populations in Qinghai Province, while age, APTT, and aspirin resistance were independent risk factors of CR in this region. [ABSTRACT FROM AUTHOR]

Arthritis is a genetic disorder characterized by bones and joint degradation assisted by severe pain and inflammation. It is evident by the studies that 0 candidate genes variations play vital role in its development and progression. Therefore, we investigated the genetic variation of TLR-8, TNF, and ESR-1α genes in the Pakistani population. A case-control study comprising 300 RA, 316 OA, and 412 control subjects was conducted. PCR-RFLP and direct sequencing methods were used for determining genetic variations. Analysis was performed by using PLINK and MEGA 6.0 software. Allelic and genetic frequencies of polymorphisms identified on rs3764879 (TLR-8), rs3764880 (TLR-8), rs5744080 (TLR-8), rs1800629 (TNF), rs2228480 (ESR-1α), and rs1451501590 (ESR-1α) were significantly varied among RA, OA, and controls. Novel functional mutations SCV000844945 and SCV000844946 on TLR-8 as well as a non-functional SCV000804801 and functional variation SCV000804802 on ESR-1α were also identified and reported for the first time in the studied population. Multiple site analyses indicated that polymorphisms on TLR-8 and ESR-1α genes were significant risk factors in disease onset to the next generation. In conclusion, TLR-08 and ESR-1α were significant in the onset of arthritis whereas the TNF was not found as a significant risk factor in the onset of RA and OA. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is one of the leading cancers in the world, which has become an increasing serious problem. In this context, reports demonstrate that some long noncoding RNAs (lncRNAs) play significant regulatory roles in breast tumorigenesis and BC progression via various pathways and act as endogenous RNAs. Finding their dysregulation in cancer and evaluating their interaction with other molecules, such as short noncoding RNAs "microRNA (miRNAs)" as well as various genes, are the most important parts in cancer diagnostics. In this study, after performing GSEA and microarray analysis on the GSE71053 dataset, a new ceRNA network of CCDC18-AS1, LINC01343, hsa-miR4462, and SFN in BC was detected by bioinformatics analysis. Therefore, the expression of SFN, CCDC18-AS1, and LINC01343 was quantitatively measured in 24 BC and normal paired tissues using qRT-PCR. CCDC18-AS1, LINC01343, and SFN were expressed higher in BC than in the control (normal paired) tissues based on qRT-PCR data. Furthermore, a significant positive correlation was observed between CCDC18-AS1 and LINC01343 expression in the samples investigated in this study. The investigation of clinicopathological parameters showed that SFN was highly expressed in tumor size of <5 cm and in nonmenopausal ages, while CCDC18-AS1 and LINC01343 indicated a high expression in stages II-III and III of BC, respectively. The overall survival analysis displayed high and low survival in patients with high expression of SFN and CCDC18-AS1, respectively. The ROC curve analysis disclosed that SFN, CCDC18-AS1, and LINC01343 might be suggested as potential biological markers in BC patients. The high expression of CCDC18-AS1, LINC01343, and SFN in BC samples suggests their potential role in BC tumorigenesis and could be considered hallmarks for the diagnosis and prognosis of BC, although this will require further clinical investigations. [ABSTRACT FROM AUTHOR]