Emerging evidence suggests that PIWI-interacting RNAs (piRNAs) may be important epigenetic regulators of gene expression in human cancers; however, their functional and clinical significance in ...colorectal cancer (CRC) remains unknown.
We performed piRNA expression profiling in paired cancer and normal tissues through small RNA-sequencing. The clinical significance of candidate piRNAs was investigated, and independently validated in 771 CRC patients from three independent cohorts. The biological function of piRNAs was characterized in cell lines, followed by identification and validation of downstream target genes in CRC tissues.
We identified piR-1245 as a novel and frequently overexpressed noncoding RNA in CRC, and its expression significantly correlated with advanced and metastatic disease. Patients with high piR-1245 expression experienced significantly shorter overall survival, and multivariate analysis identified its expression to serve as an independent prognostic biomarker in CRC. Functionally, piR-1245 acts as an oncogene and promotes tumor progression, and gene expression profiling results identified a panel of downstream target-genes involved in regulating cell survival pathway. Based upon piRNA:mRNA sequence complementarity, we identified a panel of tumor suppressor genes (ATF3, BTG1, DUSP1, FAS,NFKBIA, UPP1, SESN2, TP53INP1 and MDX1) as direct targets of piR-1245, and successfully validated an inverse correlation between their expression and piR-1245 in CRC.
We for the first time have identified the role for a PIWI-interacting noncoding RNA, piR-1245, as a novel oncogene and a potential prognostic biomarker in colorectal cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
It is well-documented that the Affordable Care Act Medicaid expansion increased health care utilization by low-income Americans. Emerging studies also found that the expansion changed the ...geographical distribution of new physicians. However, the effect of the expansion on physician compensation has not been studied.
We aimed to assess how the Medicaid expansion affected the compensation of new primary care physicians (PCPs) and whether the effect differed by specialty, gender, and geography.
We used a quasiexperimental difference-in-differences design to assess changes in compensation for new PCPs from before to after the Medicaid expansion in states that expanded Medicaid compared with states that did not expand.
Our study included 2003 new PCPs who responded to the Survey of Residents Completing Training in New York between 2009 and 2018.
Our primary outcome was respondents' self-reported starting salary for their first year of practice. Our secondary outcomes were respondents' self-reported additional anticipated income and incentives they received for accepting the job offer.
We found that starting salaries for new PCPs, especially new general internists and family physicians, grew faster in expansion states than in nonexpansion states. In addition, we found that the expansion was associated with a statistically significant increase in receiving additional anticipated income as part of the compensation package for new PCPs practicing in rural areas.
Colorectal cancer (CRC) is a major cause of cancer mortality worldwide. There is an urgent need to search for specific and sensitive biomarkers for early diagnosis of CRC. We carried out a ...comprehensive systematic review of published studies that compared the miRNA expression profiles between CRC tissue and paired neighboring noncancerous colorectal tissue to determine candidate miRNA biomarkers for CRC. A miRNA ranking system that takes the number of comparisons in agreement, total study sizes and direction of differential expression into the consideration was devised and used. One of the most up‐regulated miRNAs, miRNA‐106a, was consistently reported to be differentially expressed in six studies and the five most down‐regulated miRNAs, miR‐30a‐3p, miR‐139, miR‐145, miR‐125a and miR‐133a, were consistently reported to be differentially expressed in four studies. Moreover, we further validated five miRNAs in a clinical setting using qRT‐PCR, which demonstrated that miR‐106a expression was increased, whereas the expression of miR‐30a‐3p, miR‐145, miR‐125a and miR‐133a was decreased in the CRC tissues. Therefore, these miRNAs may be the candidates to develop a panel of biomarkers with sufficient sensitivity and specificity for the diagnosis of CRC in a clinical setting.
The initiation and progression of colorectal cancer (CRC) involves genetic and epigenetic alterations influenced by dietary and environmental factors. Increasing evidence has linked the intestinal ...microbiota and colorectal cancer. More recently,
(Fn), an opportunistic commensal anaerobe in the oral cavity, has been associated with CRC. Several research teams have reported an overabundance of Fn in human CRC and have elucidated the possible mechanisms by which Fn is involved in colorectal carcinogenesis
and in mouse models. However, the mechanisms by which Fn promotes colorectal carcinogenesis remain unclear. To provide new perspectives for early diagnosis, the identification of high risk populations and treatment for colorectal cancer, this review will summarize the relative research progresses regarding the relationship between Fn and colorectal cancer.
•
Introduction
•
Embryonic origin of cancer
‐
Early embryo development and tumourigenesis
•
Similarity in cell invasive behaviours
•
Similarity in epigenetic regulation
•
Similarity in gene ...expression
•
Similarity in protein profiling
•
Similarity in other biological behaviours
•
Conclusion
With the recent substantial progress in developmental biology and cancer biology, the similarities between early embryo development and tumourigenesis, as well as the important interaction between tumours and embryos become better appreciated. In this paper, we review in detail the embryonic origin of tumour, and the similarities between early embryo development and tumourigenesis with respect to cell invasive behaviours, epigenetic regulation, gene expression, protein profiling and other important biological behaviours. Given an improved understanding of the relationship between early embryo development and tumourigenesis, now we have better and broader resources to attack cancer from the perspective of developmental biology and develop next generation of prognostic and therapeutic approaches for this devastating disease.
Abstract
Digestive system diseases arise primarily through the interplay of genetic and environmental influences; there is an urgent need in elucidating the pathogenic mechanisms of these diseases ...and deploy personalized treatments. Traditional and long-established model systems rarely reproduce either tissue complexity or human physiology faithfully; these shortcomings underscore the need for better models. Organoids represent a promising research model, helping us gain a more profound understanding of the digestive organs; this model can also be used to provide patients with precise and individualized treatment and to build rapid in vitro test models for drug screening or gene/cell therapy, linking basic research with clinical treatment. Over the past few decades, the use of organoids has led to an advanced understanding of the composition of each digestive organ and has facilitated disease modeling, chemotherapy dose prediction, CRISPR-Cas9 genetic intervention, high-throughput drug screening, and identification of SARS-CoV-2 targets, pathogenic infection. However, the existing organoids of the digestive system mainly include the epithelial system. In order to reveal the pathogenic mechanism of digestive diseases, it is necessary to establish a completer and more physiological organoid model. Combining organoids and advanced techniques to test individualized treatments of different formulations is a promising approach that requires further exploration. This review highlights the advancements in the field of organoid technology from the perspectives of disease modeling and personalized therapy.
The present study was designed to search for potential diagnostic biomarkers in the serum of colorectal cancer (CRC).
CRC is the third most common cancer worldwide, and its prognosis is poor at early ...stages. A panel of novel biomarkers is urgently needed for early diagnosis of CRC.
An integrated proteomics and metabolomics approach was performed to define oncofetal biomarkers in CRC by protein and metabolite profiling of serum samples from CRC patients, healthy control adults, and fetus. The differentially expressed proteins were identified by a 2-D DIGE (2-Dimensional Difference Gel Electrophoresis) coupled with a Finnigan LTQ-based proteomics approach. Meanwhile, the serum metabolome was analyzed using gas chromatography-mass spectrometry integrated with a commercial mass spectral library for peak identification.
Of the 28 identified proteins and the 34 analyzed metabolites, only 5 protein spots and 6 metabolites were significantly increased or decreased in both CRC and fetal serum groups compared with the healthy adult group. Data from supervised predictive models allowed a separation of 93.5% of CRC patients from the healthy controls using the 6 metabolites. Finally, correlation analysis was applied to establish quantitative linkages between the 5 individual metabolite 3-hydroxybutyric acid, L-valine, L-threonine, 1-deoxyglucose, and glycine and the 5 individual proteins MACF1, APOH, A2M, IGL@, and VDB. Furthermore, 10 potential oncofetal biomarkers were characterized and their potential for CRC diagnosis was validated.
The integrated approach we developed will promote the translation of biomarkers with clinical value into routine clinical practice.
A recent study found that states that expanded Medicaid under the Affordable Care Act (ACA) gained new general internists who were establishing their first practices, whereas nonexpansion states lost ...them.
The objective of this study was to examine the level of social disadvantage of the areas of expansion states that gained new physicians and the areas of nonexpansion states that lost them.
We used American Community Survey data to classify commuting zones as high, medium, or low social disadvantage. Using 2009-2019 data from the AMA Physician Masterfile and information on states' Medicaid expansion status, we estimated conditional logit models to compare where new physicians located during the 6 years following the expansion to where they located during the 5 years preceding the expansion.
A total of 32,102 new general internists.
Compared with preexpansion patterns, new general internists were more likely to locate in expansion states after the expansion, a finding that held for high, medium, and low disadvantage areas. We estimated that, between 2014 and 2019, nonexpansion states lost 371 new general internists (95% confidence interval, 203-540) to expansion states. However, 62.5% of the physicians lost by nonexpansion states were lost from high disadvantage areas even though these areas only accounted for 17.9% of the population of nonexpansion states.
States that opted not to expand Medicaid lost new general internists to expansion states. A highly disproportionate share of the physicians lost by nonexpansion states were lost from high disadvantage areas, potentially compromising access for all residents irrespective of insurance coverage.
Cancer cells are usually characterized by hyperactive glucose metabolism, which can often lead to glucose scarcity; thus, alternative pathways to rewire cancer metabolism are required. Here, we ...demonstrated that GLUT3 was highly expressed in colorectal cancer (CRC) and negatively linked to CRC patient outcomes, whereas GLUT1 was not associated with CRC prognosis. Under glucose-limiting conditions, GLUT3 expedited CRC cell growth by accelerating glucose input and fuelling nucleotide synthesis. Notably, GLUT3 had a greater impact on cell growth than GLUT1 under glucose-limiting stress. Mechanistically, low-glucose stress dramatically upregulated GLUT3 via the AMPK/CREB1 pathway. Furthermore, high GLUT3 expression remarkably increased the sensitivity of CRC cells to treatment with vitamin C and vitamin C-containing regimens. Together, the results of this study highlight the importance of the AMPK/CREB1/GLUT3 pathway for CRC cells to withstand glucose-limiting stress and underscore the therapeutic potential of vitamin C in CRC with high GLUT3 expression.
Background
Abnormal expression of protein tyrosine phosphatases (PTPs) has been reported to be a crucial cause of cancer. As a member of PTPs, protein tyrosine phosphatase receptor type O (PTPRO) has ...been revealed to play tumor suppressive roles in several cancers, while its roles in colorectal cancer (CRC) remains to be elucidated. Hence, we aimed to explore the roles and mechanisms of PTPRO in CRC initiation and progression.
Methods
The influences of PTPRO on the growth and liver metastasis of CRC cells and the expression patterns of different lipid metabolism enzymes were evaluated in vitro and in vivo. Molecular and biological experiments were conducted to uncover the underpinning mechanisms of dysregulated de novo lipogenesis and fatty acid β‐oxidation.
Results
PTPRO expression was notably downregulated in CRC liver metastasis compared to the primary cancer, and such a downregulation was associated with poor prognosis of patients with CRC. PTPRO silencing significantly promoted cell growth and liver metastasis. Compared with PTPRO wild‐type mice, PTPRO‐knockout mice developed more tumors and harbored larger tumor loads under treatment with azoxymethane and dextran sulfate sodium. Gene set enrichment analysis revealed that PTPRO downregulation was significantly associated with the fatty acid metabolism pathways. Blockage of fatty acid synthesis abrogated the effects of PTPRO silencing on cell growth and liver metastasis. Further experiments indicated that PTPRO silencing induced the activation of the AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling axis, thus promoting de novo lipogenesis by enhancing the expression of sterol regulatory element‐binding protein 1 (SREBP1) and its target lipogenic enzyme acetyl‐CoA carboxylase alpha (ACC1) by activating the AKT/mTOR signaling pathway. Furthermore, PTPRO attenuation decreased the fatty acid oxidation rate by repressing the expression of peroxisome proliferator‐activated receptor alpha (PPARα) and its downstream enzyme peroxisomal acyl‐coenzyme A oxidase 1 (ACOX1) via activating the p38/extracellular signal‐regulated kinase (ERK) mitogen‐activated protein kinase (MAPK) signaling pathway.
Conclusions
PTPRO could suppress CRC development and metastasis via modulating the AKT/mTOR/SREBP1/ACC1 and MAPK/PPARα/ACOX1 pathways and reprogramming lipid metabolism.
PDF
