Prostate cancer is the most common non-cutaneous cancer in men in the United States. Cancer metabolism has emerged as a contemporary topic of great interest for improved mechanistic understanding of tumorigenesis. Prostate cancer is a disease model of great interest from a metabolic perspective. Prostatic tissue exhibits unique metabolic activity under baseline conditions. Benign prostate cells accumulate zinc, and this excess zinc inhibits citrate oxidation and metabolism within the citric acid cycle, effectively resulting in citrate production. Malignant cells, however, actively oxidize citrate and resume more typical citric acid cycle function. Of further interest, prostate cancer does not exhibit the Warburg effect, an increase in glucose uptake, seen in many other cancers. These cellular metabolic differences and others are of clinical interest as they present a variety of potential therapeutic targets. Furthermore, understanding of the metabolic profile differences between benign prostate versus low- and high-grade prostate cancers also represents an avenue to better understand cancer progression and potentially develop new diagnostic testing. In this paper, we review the current state of knowledge on the metabolic phenotypes of prostate cancer.
The coupling of osteoblasts and osteocytes by connexin43 (Cx43) gap junctions permits the sharing of second messengers that coordinate bone cell function and cortical bone acquisition. However, details of how Cx43 converts shared second messengers into signals that converge onto essential osteogenic processes are incomplete. Here, we use in vitro and in vivo methods to show that Cx43 and Runx2 functionally interact to regulate osteoblast gene expression and proliferation, ultimately affecting cortical bone properties. Using compound hemizygous mice for the Gja1 (Cx43) and Runx2 genes, we observed a skeletal phenotype not visible in wild-type or singly hemizygous animals. Cortical bone analysis by microCT revealed that 8-week-old male, compound Gja1+/− Runx2+/− mice have a marked increase in cross-sectional area, endosteal and periosteal bone perimeter, and an increase in porosity compared to controls. These compound Gja1+/− Runx2+/− mice closely approximate the cortical bone phenotypes seen in osteoblast-specific Gja1-conditional knockout models. Furthermore, microCT analysis of skulls revealed an altered interparietal bone geometry in compound hemizygotes. Consistent with this finding, Alizarin red/ Alcian blue staining of 2 day-old Gja1+/− Runx2+/− neonates showed a hypomorphic interparietal bone, an exacerbation of the open fontanelles, and a further reduction in the hypoplastic clavicles compared to Runx2+/− neonates. Expression of osteoblast genes, including osteocalcin, osterix, periostin, and Hsp47, was markedly reduced in tibial RNA extracts from compound hemizygous mice, and osteoblasts from compound hemizygous mice exhibited increased proliferative capacity. Further, the reduced osteocalcin expression and hyperproliferative nature of osteoblasts from Cx43 deficient mice was rescued by Runx2 expression. In summary, these findings provide evidence that Cx43 and Runx2 functionally intersect in vivo to regulate cortical bone properties and affect osteoblast differentiation and proliferation, and likely contributes to aspects of the skeletal phenotype of Cx43 conditional knockout mice.
BackgroundRecent work has shown that the gap junction protein connexin43 (Cx43) is upregulated in cells of the joint during osteoarthritis (OA). Here we examined if the OA-associated increase in Cx43 expression impacts the function of synovial fibroblasts by contributing to the production of catabolic and inflammatory factors that exacerbate joint destruction in arthritic disease.MethodsUsing rabbit and human synovial fibroblast cell lines, we examined the effects of Cx43 overexpression and Cx43 siRNA-mediated knockdown on the gene expression of OA-associated matrix metalloproteinases (MMP1 and MMP13), aggrecanases (ADAMTS4 and ADAMTS5), and inflammatory factors (IL1, IL6 and PTGS2) by quantitative real time RT-PCR. We examined collagenase activity in conditioned media of cultured synovial cells following Cx43 overexpression. Lastly, we assessed the interplay between Cx43 and the NFκB cascade by western blotting and gene expression studies.ResultsIncreasing Cx43 expression enhanced the gene expression of MMP1, MMP13, ADAMTS4, ADAMTS5, IL1, IL6 and PTGS2 and increased the secretion of collagenases into conditioned media of cultured synovial fibroblasts. Conversely, knockdown of Cx43 decreased expression of many of these catabolic and inflammatory genes. Modulation of Cx43 expression altered the phosphorylation of the NFκB subunit, p65, and inhibition of NFκB with chemical inhibitors blocked the effects of increased Cx43 expression on the mRNA levels of a subset of these catabolic and inflammatory genes.ConclusionsIncreasing or decreasing Cx43 expression alone was sufficient to alter the levels of catabolic and inflammatory genes expressed by synovial cells. The NFκB cascade mediated the effect of Cx43 on the expression of a subset of these OA-associated genes. As such, Cx43 may be involved in joint pathology during OA, and targeting Cx43 expression or function may be a viable therapeutic strategy to attenuate the catabolic and inflammatory environment of the joint during OA.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2474-15-425) contains supplementary material, which is available to authorized users.
This research was supported in part by the Proposed Research Initiated by Students and Mentors (PRISM) Program, University of Maryland School of Medicine Office of Student Research.
IntroductionPhysicians are increasingly practicing defensive medicine as a response to society’s litigious climate. This study sought to characterize cardiology malpractice claims and elucidate the allegations underlying the use of defensive medicine.MethodsThe WestlawNext™ database was queried to obtain state and federal jury verdicts and settlements related to medical malpractice and cardiology that occurred in the United States between 2010 and 2015. Cardiology cases were identified using the search terms “medical malpractice” and “cardiology” and reviewed by two individuals utilizing available case documents. Duplicate and nonpertinent cases were excluded. Binary logistic regression models were created to predict the likelihood of defendant verdict, plaintiff verdict, and settlement based on the various reasons for litigation cited.ResultsInclusion criteria were met in 166 cases. The plaintiffs were predominantly male (94 cases; 56.6%), and the average patient age was 53.3±17.5 years. More than half of the cases involved a cardiologist as a defendant. The most common reasons for litigation were: failure to treat (129; 77.7%), failure to diagnose (115; 69.3%), failure to refer/order diagnostic tests (107; 64.5%), and patient death (118; 71.1%). Among cases tried for failure to diagnose, the most commonly missed diagnosis was myocardial infarction. Cases most commonly resulted in a defendant verdict (94; 56.6%). However, odds of a plaintiff verdict were significantly higher when failure to diagnose was alleged with an odds ratio (OR) of 7.60 (95% confidence interval 1.14 - 50.87, p = 0.0365).ConclusionsFailure to diagnose remains a commonly alleged base for litigation. In conclusion, our analysis suggests increased training for non-cardiologists in the recognition of the acute coronary syndrome and enhanced awareness of inherent biases among all physicians may facilitate reducing missed diagnoses.
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