Intestinal Ca~(2+) absorption revisited: A molecular and clinical approach

Ca~(2+) has an important role in the maintenance of the skeleton and is involved in the main physiological processes. Its homeostasis is controlled by the intestine,kidney, bone and parathyroid glands. The intestinal Ca~(2+) absorption occurs mainly via the paracellular and the transcellular pathways. The proteins involved in both ways are regulated by calcitriol and other hormones as well as dietary factors. Fibroblast growth factor 23(FGF-23) is a strong antagonist of vitamin D action. Part of the intestinal Ca~(2+) movement seems to be vitamin D independent.Intestinal Ca~(2+) absorption changes according to different physiological conditions.It is promoted under high Ca~(2+) demands such as growth, pregnancy, lactation,dietary Ca~(2+) deficiency and high physical activity. In contrast, the intestinal Ca~(2+)transport decreases with aging. Oxidative stress inhibits the intestinal Ca~(2+)absorption whereas the antioxidants counteract the effects of prooxidants leading to the normalization of this physiological process. Several pathologies such as celiac disease, inflammatory bowel diseases, Turner syndrome and others occur with inhibition of intestinal Ca~(2+) absorption, some hypercalciurias show Ca~(2+)hyperabsorption, most of these alterations are related to the vitamin D endocrine system. Further research work should be accomplished in order not only to know more molecular details but also to detect possible therapeutic targets to ameliorate or avoid the consequences of altered intestinal Ca~(2+) absorption.     

MicroRNA expression profiling identifies miR-31-5p/3p as associated with time to progression in wild-type RAS metastatic colorectal cancer treated with cetuximab

The aim of our study was to investigate whether microRNAs (miRNAs) could serve as predictive biomarkers to anti-EGFR therapy (cetuximab, panitumumab) in patients with RAS wild-type (wt-RAS) metastatic colorectal cancer (mCRC). Historical cohort of 93 patients with mCRC (2006–2009) was included and further divided into exploratory and validation cohorts. MiRNAs expression profiling was performed on the exploratory cohort of 41 wt-KRAS mCRC patients treated with cetuximab to identify miRNAs associated with time to progression (TTP). The validation was performed on two independent cohorts: 28 patients of wt-RAS mCRC treated with cetuximab and 24 patients of wt-RAS mCRC treated with panitumumab. We identified 9 miRNAs with significantly different expression between responders and non-responders to cetuximab therapy (P ≤ 0.01). These 9 miRNAs were further evaluated in two independent cohorts of patients and miR-31-3p (P < 0.001) and miR-31-5p (P < 0.001) were successfully confirmed as strongly associated with TTP in wt-RAS mCRC patients treated with cetuximab but not panitumumab. When evaluated on the complete cohort of cetuximab patients (N = 69), miR-31-3p (HR, 5.10; 95% CI, 2.52–10.32; P < 0.001) and miR-31-5p (HR, 4.80; 95% CI, 2.50–9.24; P < 0.001) were correlated with TTP on the comparable level of significance. There was no difference in miR-31-5p/3p expression levels in RAS mutated and wild-type tumor samples. MiR-31-5p/3p are promising predictive biomarkers of cetuximab response in wt-RAS mCRC patients.     

Predictors of first and second dose acceptance of hepatitis B vaccine among STD clinic patients

Our goal was to identify attitudinal, behavioural and pragmatic factors predictive of receipt of the first and second doses of hepatitis B virus (HBV) vaccine. In this study, 431 adult sexually transmitted disease clinic patients with no reported history of prior HBV vaccination or infection completed a computer-assisted questionnaire, then were offered free HBV vaccine. Those who accepted were scheduled for follow-up doses. Twenty-nine percent received the first dose of vaccine. Of these individuals, 21% returned for the second dose. Seven participants received all three doses. Health beliefs and caring for three or more children predicted first dose acceptance. Less travel time to the clinic and caring for two or fewer children predicted return for the second dose. HBV vaccination rates were low in this study. Interventions designed to modify health beliefs may increase first dose uptake. Increases in receipt of subsequent vaccine doses might best be accomplished through approaches designed to decrease pragmatic barriers to vaccine access.     

Detection and identification of Rickettsia species in the northeast of Italy

This study was carried out using Ixodes ricinus ticks collected during 2005 and 2006 from the Friuli Venezia Giulia (FVG) region in the northeastern part of Italy and an area along the Slovenian side of the western border of Italy. The results indicate that Rickettsia spp. is widely distributed throughout these areas, with the greatest prevalence in the central part of the FVG region. The prevalence of Rickettsia spp. was 4.5% during 2005 and 6.1% during 2006. By sequencing the 16S rRNA gene, we show for the first time the presence of Rickettsia helvetica in I. ricinus ticks in the FVG region and the presence of R. monacensis in ticks in both areas. Furthermore, we detected a sequence with a high homology with that of R. limoniae in a tick obtained from the alpine zone.     

The role of the microbiota in inflammation,carcinogenesis, and cancer therapy

Commensal microorganisms colonize barrier surfaces of all multicellular organisms, including those of humans. For more than 500 million years, commensal microorganisms and their hosts have coevolved and adapted to each other. As a result, the commensal microbiota affects many immune and nonimmune functions of their hosts, and de facto the two together comprise one metaorganism. The commensal microbiota communicates with the host via biologically active molecules. Recently, it has been reported that microbial imbalance may play a critical role in the development of multiple diseases, such as cancer, autoimmune conditions, and increased susceptibility to infection. In this review, we focus on the role of the commensal microbiota in the development, progression, and immune evasion of cancer, as well as some modulatory effects on the treatment of cancer. In particular, we discuss the mechanisms of microbiota‐mediated regulation of innate and adaptive immune responses to tumors, and the consequences on cancer progression and whether tumors subsequently become resistant or susceptible to different anticancer therapeutic regiments.     

Real‐world clinical applicability of pathogenicity predictors assessed on SERPINA1 mutations in alpha‐1‐antitrypsin deficiency

The growth of publicly available data informing upon genetic variations, mechanisms of disease, and disease subphenotypes offers great potential for personalized medicine. Computational approaches are likely required to assess a large number of novel genetic variants. However, the integration of genetic, structural, and pathophysiological data still represents a challenge for computational predictions and their clinical use. We addressed these issues for alpha‐1‐antitrypsin deficiency, a disease mediated by mutations in the SERPINA1 gene encoding alpha‐1‐antitrypsin. We compiled a comprehensive database of SERPINA1 coding mutations and assigned them apparent pathological relevance based upon available data. “Benign” and “pathogenic” variations were used to assess performance of 31 pathogenicity predictors. Well‐performing algorithms clustered the subset of variants known to be severely pathogenic with high scores. Eight new mutations identified in the ExAC database and achieving high scores were selected for characterization in cell models and showed secretory deficiency and polymer formation, supporting the predictive power of our computational approach. The behavior of the pathogenic new variants and consistent outliers were rationalized by considering the protein structural context and residue conservation. These findings highlight the potential of computational methods to provide meaningful predictions of the pathogenic significance of novel mutations and identify areas for further investigation.