Role of Established Type 2 Diabetes–Susceptibility Genetic Variants in a High Prevalence American Indian Population

Several single nucleotide polymorphisms (SNPs) associated with type 2 diabetes mellitus (T2DM) have been identified, but there is little information on their role in populations at high risk for T2DM. We genotyped SNPs at 63 T2DM loci in 3,421 individuals from a high-risk American Indian population. Nominally significant (P < 0.05) associations were observed at nine SNPs in a direction consistent with the established association. A genetic risk score derived from all loci was strongly associated with T2DM (odds ratio 1.05 per risk allele, P = 6.2 × 10⁻⁶) and, in 292 nondiabetic individuals, with lower insulin secretion (by 4% per copy, P = 4.1 × 10⁻⁶). Genetic distances between American Indians and HapMap populations at T2DM markers did not differ significantly from genomic expectations. Analysis of U.S. national survey data suggested that 66% of the difference in T2DM prevalence between African Americans and European Americans, but none of the difference between American Indians and European Americans, was attributable to allele frequency differences at these loci. These analyses suggest that, in general, established T2DM loci influence T2DM in American Indians and that risk is mediated in part through an effect on insulin secretion. However, differences in allele frequencies do not account for the high population prevalence of T2DM.     

Characteristics and Prognosis of Colorectal Cancer Associated With Rheumatic Disease

It is well known that host immunity plays an important role in the defense against colorectal cancer (CRC) progression. The effects of autoimmune diseases, such as rheumatic disease (RD) in which the immune system is deregulated, on this immunity have not been fully investigated. The medical records of 1299 consecutive patients diagnosed with primary colorectal cancer who underwent surgical resection were retrospectively reviewed. The clinicopathologic factors of 28 subjects with RD (RD group) were compared with those of 1271 patients without RD (non-RD group). Compared to the non-RD group, the RD group was typified by a predominance of females (P < 0.01), older age (P < 0.01), and a lower incidence of rectal cancer (P = 0.02). Although no difference was observed between the groups in terms of TNM classification, disease-free and overall survival were significantly poorer in the RD group in both univariate and multivariate analyses. Subjects who had RD for more than 10 years tended to have a higher frequency of lymph node metastasis (P = 0.06) and a significantly higher incidence of synchronous distant metastasis (P = 0.035) at the time of cancer diagnosis. RD was associated with a significantly poorer prognosis of colorectal cancer, suggesting that deregulation of the immune system by autoimmune diseases may adversely affect the host immune defense against colorectal cancer progression.Key words: Colorectal cancer, Rheumatic disease, Host immunity, PrognosisIt is well known that host immunity plays an important role in defenses against the development and progression of cancer. The degree of lymphocyte infiltration into tumors has been reported to correlate with improvements of patient survival.¹ In carcinogen-induced mouse models of cancer, primary tumor susceptibility has been found to be enhanced in immunocompromised mice; conversely, the capacity for such tumors to grow after transplantation into wild-type mice is reduced.^2,3 Although cancer cells originate from autologous normal tissue, the immune system can recognize even minimal cellular alterations, distinguish cancerous from normal cells, and elicit an immune response.In autoimmune diseases represented by rheumatic disease (RD), the immune system loses the ability to distinguish nonself from self, eliciting an immune response against self-antigens; in this process, there is a possibility that immune defenses against non-normal cells are lost or impaired, facilitating the development and progression of cancer. In addition, the development of RD associated with cancer has been reported, and as its development is dependent on the production of substances such as hormones, peptides, autocrine and paracrine mediators, and antibodies or the stimulation of cytotoxic lymphocytes, the condition is known as paraneoplastic rheumatic syndrome. In such cases, RD tends to be less responsive to therapy than its nonparaneoplastic equivalents, and instead, treatment of the underlying cancer usually results in regression of RD.^4,5 Thus, it is postulated that RD and cancer are closely associated. However, only a few reports on the incidence and risk of cancer among patients with RD exist,^6,7 and the characteristics and prognosis of colorectal cancer (CRC) in these patients remain to be elucidated.In the present study, we investigated the development of CRC in the background of an immunologic disorder caused by RD, with the hypothesis that patients with CRC and autoimmune diseases such as RD will have a poorer prognosis than those without RD, as a result of depressed antitumor immunity caused by immune system incompetence. Thus, we aimed to clarify the features and prognosis of CRC-associated RD, and for this purpose, we compared the clinicopathologic features of patients with CRC with or without underlying RD.     

Integrating trauma,self-disturbances,cognitive biases,and personality into a model for the risk of psychosis: a longitudinal study in a non-clinical sample

European Archives of Psychiatry and Clinical Neuroscience - The hypothesis of the psychosis continuum enables to study the mechanisms of psychosis risk not only in clinical samples but in...     

Diabetes mellitus contribution to the remodeling of the tumor microenvironment in gastric cancer

Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial contribution of diabetes mellitus (DM) as a risk factor associated with increased cancer incidence and mortality in many human neoplasms, including gastric cancer (GC). DM is considered a systemic inflammatory disease and therefore, this inflammatory status may have profound effects on the tumor microenvironment (TME), particularly by driving many molecular mechanisms to generate a more aggressive TME. DM is an active driver in the modification of the behavior of many cell components of the TME as well as altering the mechanical properties of the extracellular matrix (ECM), leading to an increased ECM stiffening. Additionally, DM can alter many cellular signaling mechanisms and thus favoring tumor growth, invasion, and metastatic potential, as well as key elements in regulating cellular functions and cross-talks, such as the microRNAs network, the production, and cargo of exosomes, the metabolism of cell stroma and resistance to hypoxia. In the present review, we intend to highlight the mechanistic contributions of DM to the remodeling of TME in GC.     

Extent of Laminin-5 Assembly and Secretion Effect Junctional Epidermolysis Bullosa Phenotype

Junctional epidermolysis bullosa (JEB) is an autosomal recessive skin blistering disease with both lethal and nonlethal forms, with most patients shown to have defects in laminin-5. We analyzed the location of mutations, gene expression levels, and protein chain assembly of the laminin-5 heterotrimer in six JEB patients to determine how the type of genetic lesion influences the pathophysiology of JEB. Mutations within laminin-5 genes were diversely located, with the most severe forms of JEB correlating best with premature termination codons, rather than mapping to any particular protein domain. In all six JEB patients, the laminin-5 assembly intermediates we observed were as predicted by our previous work indicating that the α3β3γ2 heterotrimer assembles intracellularly via a β3γ2 heterodimer intermediate. Since assembly precedes secretion, mutations that disrupt protein–protein interactions needed for assembly are predicted to limit the secretion of laminin-5, and likely to interfere with function. However, our data indicate that typically the most severe mutations diminish mRNA stability, and serve as functional null alleles that block chain assembly by resulting in either a deficiency (in the nonlethal mitis variety) or a complete absence (in lethal Herlitz-JEB) of one of the chains needed for laminin-5 heterotrimer assembly.     

Validation of cardiovascular magnetic resonance assessment of pericardial adipose tissue volume

Background

Pericardial adipose tissue (PAT) has been shown to be an independent predictor of coronary artery disease. To date its assessment has been restricted to the use of surrogate echocardiographic indices such as measurement of epicardial fat thickness over the right ventricular free wall, which have limitations. Cardiovascular magnetic resonance (CMR) offers the potential to non-invasively assess total PAT, however like other imaging modalities, CMR has not yet been validated for this purpose. Thus, we sought to describe a novel technique for assessing total PAT with validation in an ovine model.

Methods

11 merino sheep were studied. A standard clinical series of ventricular short axis CMR images (1.5T Siemens Sonata) were obtained during mechanical ventilation breath-holds. Beginning at the mitral annulus, consecutive end-diastolic ventricular images were used to determine the area and volume of epicardial, paracardial and pericardial adipose tissue. In addition adipose thickness was measured at the right ventricular free wall. Following euthanasia, the paracardial adipose tissue was removed from the ventricle and weighed to allow comparison with corresponding CMR measurements.

Results

There was a strong correlation between CMR-derived paracardial adipose tissue volume and ex vivo paracardial mass (R² = 0.89, p < 0.001). In contrast, CMR measurements of corresponding RV free wall paracardial adipose thickness did not correlate with ex vivo paracardial mass (R² = 0.003, p = 0.878).

Conclusion

In this ovine model, CMR-derived paracardial adipose tissue volume, but not the corresponding and conventional measure of paracardial adipose thickness over the RV free wall, accurately reflected paracardial adipose tissue mass. This study validates for the first time, the use of clinically utilised CMR sequences for the accurate and reproducible assessment of pericardial adiposity. Furthermore this non-invasive modality does not use ionising radiation and therefore is ideally suited for future studies of PAT and its role in cardiovascular risk prediction and disease in clinical practice.