NAEMSP president discusses impact of the ET3 model

Our co-hosts sit down with the NAEMSP president to discuss how the new reimbursement model will transform all aspects of the industry

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DNA methylation‐regulated and tumor‐suppressive roles of miR‐487b in colorectal cancer via targeting MYC, SUZ12, and KRAS

MiR‐487b is a CRC suppressor that prevents the EMT process and targets to MYC, SUZ12, and KRAS to inhibit the proliferation, migration, and invasion of CRC cells. Meanwhile, DNA methylation might be the reason for the aberrantly low expression of miR‐487b in CRC. Thus, miR‐487b is identified as a diagnosis‐related biomarker and a novel target for CRC therapy.

Abstract

Human colorectal cancer (CRC), characterized by its high morbidity and lethality, seriously threatens human health and lives. MicroRNA‐487b (miR‐487b) is currently reported to be aberrantly expressed in several tumors, but the detailed functions and underlying mechanisms of miR‐487b in CRC remain unclear. Here, we found that miR‐487b is downregulated in CRC cell lines and is markedly decreased in tumor specimens derived from CRC patients. MiR‐487b inhibits cell proliferation, migration and invasion and promotes the apoptosis of CRC cells in vitro. Statistical analysis of clinical samples indicates that miR‐487b may serve as a biomarker for early CRC diagnosis. Inverse correlations between the expression levels of MYC, SUZ12, and KRAS and that of miR‐487b exist in vitro and in CRC patient tissue specimens. Further experiments demonstrated the regulatory effects of miR‐487b on MYC, SUZ12, and KRAS, and the disruption of these genes partially restores the miR‐487b inhibitor‐induced phenotype. Additionally, miR‐487b promoter region is in a DNA hypermethylated condition and the DNA methyltransferase inhibitor 5‐aza‐2'‐deoxycytidine (5‐Aza) increases the levels of miR‐487b but suppresses the expression of MYC, SUZ12, and KRAS in a time‐ and concentration‐dependent manner in CRC cells. Collectively, miR‐487b is regulated by DNA methylation and it functions as a tumor suppressor in CRC mainly through targeting MYC, SUZ12, and KRAS. Our study provides insight into the regulatory network in CRC cells, offering a new target for treating CRC patients.

https://ift.tt/2U3iL6G

SPHK1‐induced autophagy in peritoneal mesothelial cell enhances gastric cancer peritoneal dissemination

SPHK1 overexpressed in HPMC is associated with peritoneal relapse in GC. GC cells promote HPMC autophagy via TGF‐β1. SPHK1 is required for TGF‐β1‐induced HPMCs autophagy and GCPD promotion. SPHK1 regulates HPMCs fibrosis by promoting autophagy.

Abstract

Gastric cancer peritoneal dissemination (GCPD) has been recognized as the most common form of metastasis in advanced gastric cancer (GC), and the survival is pessimistic. The injury of mesothelial cells plays an important role in GCPD. However, its molecular mechanism is not entirely clear. Here, we focused on the sphingosine kinase 1 (SPHK1) in human peritoneal mesothelial cells (HPMCs) which regulates HPMCs autophagy in GCPD progression. Initially, we analyzed SPHK1 expression immunohistochemically in 120 GC peritoneal tissues, and found high SPHK1 expression to be significantly associated with LC3B expression and peritoneal recurrence, leading to poor prognosis. Using a coculture system, we observed that GC cells promoted HPMCs autophagy and this process was inhibited by blocking TGF‐β1 secreted from GC cells. Autophagic HPMCs induced adhesion and invasion of GC cells. We also confirmed that knockdown of SPHK1 expression in HPMCs inhibited TGF‐β1‐induced autophagy. In addition, SPHK1‐driven autophagy of HPMCs accelerated GC cells occurrence of GCPD in vitro and in vivo. Moreover, we explored the relationship between autophagy and fibrosis in HPMCs, observing that overexpression of SPHK1 induced HPMCs fibrosis, while the inhibition of autophagy weakened HPMCs fibrosis. Taken together, our results provided new insights for understanding the mechanisms of GCPD and established SPHK1 as a novel target for GCPD.

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Distinctive incidence patterns of follicular lymphoma in Taiwan: Implications of ethnic differences

Follicular lymphoma in Taiwan is highly distinct when compared to US Caucasians. A strong birth‐cohort effect in Taiwan, corresponding to environmental alterations.

Abstract

Background

Follicular lymphoma (FL) is less prevalent in Asians, but detailed epidemiological analyses were not available. This study aimed to characterize the epidemiologic features of FL in Taiwan to explore the factors relevant to disease development and prognosis.

Methods

We obtained epidemiological data for Taiwanese citizens during 1990‐2012 from Taiwan's National Cancer Registry Database, and the corresponding data for US Caucasians from the Surveillance, Epidemiology, and End Results Program. Changes in incidence rates were evaluated with age‐period‐cohort (APC) analyses. Patient outcomes were compared with 5‐year relative survival rates (RS) estimates.

Results

Incidence rates of FL in Taiwan increased continuously during the study period (0.34 to 0.91 per 100 000 person‐year from 1993‐1997 to 2008‐2012 in men, and from 0.29 [1993‐1997] to 0.81 [2008‐2012] in women), while rates in the US remained stable in both sexes, ranging between 3.73 and 3.96 in men and between 3.24 and 3.55 in women. Estimates of average annual percentage changes in incidence were significantly positive in Taiwan, but not in US Caucasians. Notably, the APC analysis identified a strong birth‐cohort effect in Taiwan, corresponding to environmental alterations present during the study period. The estimated 5‐year RS rates in both populations showed steady improvement, but the RS in Taiwanese patients was consistently 10% lower than in US Caucasians.

Conclusion

A distinct increasing trend of incidence with a strong birth‐cohort effect was identified in Taiwan, providing evidence of the association between environmental factors and disease development.

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Real impact of liver cirrhosis on the development of hepatocellular carcinoma in various liver diseases—meta‐analytic assessment

In this study, we performed a meta‐analysis on how the incidence of developing HCC is increasing in the cirrhotic state due to the various liver diseases, and compared with that in the non‐cirrhotic state.

Abstract

Background

It is well known that the incidence of developing hepatocelluler carcinoma (HCC) is increased in liver cirrhosis of different etiologies. However, comparison of HCC incidence in various liver diseases has not yet been estimated. We surveyed this comparison.

Methods

The PubMed database was examined (1989‐2017) for studies published in English language regarding the prospective follow‐up results for the development of HCC in various liver diseases. A meta‐analysis was performed for each liver disease.

Results

The annual incidence (%) of HCC in the non‐cirrhotic stage and cirrhotic stage, and the ratio of HCC incidence in the cirrhotic stage/non‐cirrhotic stage were as follows. (a) hepatitis B virus liver disease: 0.37%→3.23% (8.73‐fold), (b) hepatitis C virus liver diseases: 0.68%→4.81% (7.07‐fold), (c) primary biliary cholangitis (0.26%→1.79%, 6.88‐fold), (d) autoimmune hepatitis (0.19%→0.53%, 2.79‐fold), and (e) NASH (0.03%→1.35%, 45.00‐fold). Regarding primary hemochromatosis and alcoholic liver diseases, only follow‐up studies in the cirrhotic stage were presented, 1.20% and 2.06%, respectively.

Conclusions

When the liver diseases advance to cirrhosis, the incidence of HCC is markedly increased. The development of HCC must be closely monitored by ultrasonography, magnetic resonance imaging, and computed tomography, irrespective of the different kinds of liver diseases.

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Dysregulation, functional implications, and prognostic ability of the circadian clock across cancers

Circadian clock genes were dysregulated in cancer especially at expression level; expressions of core clock genes were downregulated by higher DNA methylation in tumor; The expression signature of core clock genes was correlated with virus infection; The expression signature of core clock genes was correlated with immunephenotypes; Core clock genes and expression signature were related with cancer survival.

Abstract

It has been proposed that the circadian rhythm generally plays important roles in tumor suppression, but there is also evidence that disruption of the canonical circadian pathway has anticancer effects. In this study, we systematically analyzed the aberrances of circadian clock genes across cancers based on data from The Cancer Genome Atlas (TCGA). These data showed that the frequencies of mutations and copy number alterations in core clock genes (PER1/2/3, CLOCK, CRY1/2, and ARNTL) were low, but that the expression levels of core clock genes were downregulated by the higher levels of DNA methylation in most tumors. The circadian clock index (CCI) was established through a principal component analysis, and this measure well represents the overall expression of the core clock genes. In fact, the CCI was significantly lower in hepatocellular carcinoma with HBV infection than in other cancers. Furthermore, pathways such as the MAPK, JAK‐STAT, and immune‐related signaling pathways were enriched in tumors with high CCI values. Interestingly, the CCI was generally positively related to the immunophenoscores and immunophenotypes of tumors. Additionally, the expression levels of core clock genes and the CCI were also generally positively related to survival across cancers. Taken together, the results of this study provide a comprehensive analysis of circadian clock aberrances in cancer, and the results should aid further investigations of the molecular mechanisms of cancer and the development of therapeutic strategies.

https://ift.tt/2U3iJM6

The diagnostic accuracy of circulating free DNA for the detection of KRAS mutation status in colorectal cancer: A meta‐analysis

Circulating free DNA (cfDNA) has high concordance rate in detecting KRAS mutation status in colorectal cancer (CRC) patients, compared with tumor tissues. cfDNA has adequate diagnostic performance and could act as an effective method to detect KRAS mutation status in CRC patients. Due to its high specificity and non‐invasive nature, cfDNA might be a promising screening tool for CRC.

Abstract

KRAS mutations have been reported as a reliable biomarker for epidermal growth factor receptor (EGFR) targeted therapy and are also associated with poor prognosis in colorectal cancer (CRC) patients. However, limitations of detecting KRAS mutations in tissues are obvious. KRAS mutations in the peripheral blood can be detected as an alternative to tissue analysis. The objective of this meta‐analysis was to evaluate the diagnostic value of cfDNA (circulating free DNA) compared with tissues and to investigate the prognostic potential of cfDNA KRAS mutations in CRC patients. Searches were performed in PubMed, Embase, and Cochrane Library for published studies. We extracted true‐positive (TP), false‐positive (FP), false‐negative (FN), true‐negative (TN) values, survival rate of CRC patients with mutant and wild‐type KRAS and calculated pooled sensitivity and specificity, positive/negative likelihood ratios [PLRs/NLRs], diagnostic odds ratios [DORs], and corresponding 95% confidence intervals [95% CIs]. We also generated a summary receiver operating characteristic (SROC) curve to evaluate the overall diagnostic potential. Totally, 31 relevant studies were recruited and used for the meta‐analysis on the efficacy of cfDNA testing in detecting KRAS mutations. The pooled sensitivity, specificity, PLR, NLR, and DOR were 0.637 (95% CI: 0.607‐0.666), 0.943 (95% CI: 0.930‐0.954), 10.024 (95% CI: 6.912‐14.535), 0.347 (95% CI: 0.269‐0.447), and 37.882 (95% CI: 22.473‐63.857), respectively. The area under the SROC curve was 0.9392. Together, the results suggest that detecting KRAS mutations in cfDNA has adequate diagnostic efficacy in terms of specificity. There is a promising role for cfDNA in the detection of KRAS mutations in CRC patients. However, prospective studies with larger patient cohorts are still required before definitive conclusions of the prognostic potential of cfDNA KRAS mutations in CRC patients were drawn.

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