Molecular interplay between mechanical and humoral signalling in cardiac hypertrophy

Heart failure is a major clinical problem, only partly mitigated by current pharmacological therapy. An early marker of heart failure is hypertrophic remodelling of the heart, which represents a compensatory mechanism for the mechanical stress imposed by haemodynamic overload, but can eventually affect cardiac function. Recently, using genetically modified animals, have we started to identify the molecular components that elaborate the mechanical stimulus leading to cardiac hypertrophy, with its beneficial and detrimental effects. Characterization of the relative roles of the molecules implicated in the signalling pathways involved in the hypertrophic process might allow us to control the hypertrophic response to haemodynamic overload, directing it to more favourable outcomes.     

New water soluble pyrroloquinoline derivatives as new potential anticancer agents

A new class of water soluble 3H-pyrrolo[3,2-f]quinoline derivatives has been synthesized and investigated as potential anticancer drugs. Water solubility profiles have been used to select the most promising derivatives. The novel compound 10, having two (2-diethylamino-ethyl) side chains linked through positions 3N and 9O, presents a suitable water solubility profile, and it was shown to exhibit cell growth inhibitory properties when tested against the in-house panel of cell lines, in particular those obtained from melanoma.     

Probiotic abilities of riboflavin-overproducing Lactobacillus strains: a novel promising application of probiotics

The probiotic potential of Lactobacillus plantarum and Lactobacillus fermentum strains, capable of overproducing riboflavin, was investigated. The riboflavin production was quantified in co-cultures of lactobacilli and human intestinal epithelial cells, and the riboflavin overproduction ability was confirmed. When milk and yogurt were used as carrier matrices, L. plantarum and L. fermentum strains displayed a significant ability to survive through simulated gastrointestinal transit. Adhesion was studied on both biotic and abiotic surfaces. Both strains adhered strongly on Caco-2 cells, negatively influenced the adhesion of Escherichia coli O157:H7, and strongly inhibited the growth of three reference pathogenic microbial strains. Resistance to major antibiotics and potential hemolytic activity were assayed. Overall, this study reveals that these Lactobacillus stains are endowed with promising probiotic properties and thus are candidates for the development of novel functional food which would be both enriched in riboflavin and induce additional health benefits, including a potential in situ riboflavin production, once the microorganisms colonize the host intestine.     

Is time on our side? Strengthening the link between field efforts and conservation needs

The collection and organization of distributional data is the first crucial stage of any conservation planning action: therefore the decline in field research has implications in both the systematic, floristic and conservation fields. The aim of this paper is to analyze the effects of data updating on conservation planning and priorities. Focusing on the short time frame ranging from 2006 to 2011, we present a case study showing the rate of increase of collected data (taxa and records) and the consequential effects on the definition of areas of priority interest for plant conservation (Important Plant Areas—IPAs). We gathered data on a total of 193 taxa and 849 records with a mean rate of increase of +97 % for taxa and +166 % for records (2006/2011). This increase caused a positive rate of change in high ranking cells (+78 %) defining IPAs, while the number of low ranking cells and no data cells slightly decreased (?12 and ?8 %, respectively). Our results suggest that specific investment to complete the knowledge on the distribution of selected taxa (e.g. 193 taxa represent the 7.5 % of the total vascular flora of Sardinia) would dramatically reduce both the Linnean and Wallacean shortfalls and would allow robust conservation programs to preserve the diversity of the island. Updating the IPAs on a regular basis is a good example of a process that has a low impact as well as a big potential gain especially when field research can only be performed with low intensity and small monetary investments.     

Structure–function relationship and evolutionary history of the human selenoprotein M (SelM) found over-expressed in hepatocellular carcinoma

In humans we know 25 selenoproteins that play important roles in redox regulation, detoxification, immune-system protection and viral suppression. In particular, selenoprotein M (SelM) may function as thiol disulfide oxidoreductase that participates in the formation of disulfide bonds, and can be implicated in calcium responses. However, it presents a redox motif (CXXU), where U is a selenocysteine, and may also function as redox regulator because its decreased or increased expression regulated by dietary selenium alters redox homeostasis. No data are reported in literature about its involvement in cancer but only in neurodegenerative diseases. In this paper we evaluated the SelM expression in two hepatoma cell lines, HepG2 and Huh7, compared to normal hepatocytes. The results suggested its involvement in hepatocellular carcinoma (HCC) as well as its possible use to follow the progression of this cancer as putative marker. The aim of this study has been to analyze the structure–function relationships of SelM. Hence, firstly we studied the evolutionary history of this protein by phylogenetic analysis and GC content of genes from various species. So, we modeled the three-dimensional structure of the human SelM evaluating its energetic stability by molecular dynamics simulations. Moreover, we modeled some of its mutants to obtain structural information helpful for structure-based drug design.     

Role of inflammation and oxidative stress in post‐menopausal oestrogen‐dependent breast cancer

Weight gain and obesity are among the most important risk factors for post-menopausal oestrogen-dependent breast cancer (EDBC). Weight gain is associated with oxidative stress, which in turn promotes breast cancer progression. We carried out a prospective study in 216 consecutive post-menopausal breast cancer patients aiming to examine the correlations between traditional prognostic factors (tumour size, T, nodal, N, grading, G, and metastasis status, M), and body mass index (BMI), leptin, pro-inflammatory cytokines (Interleukin, IL,-6 and tumour necrosis factor-alpha, TNF-α), and oxidative stress (reactive oxygen species, ROS, glutathione peroxidase, GPx, superoxide dismutase, SOD) among patients with oestrogen receptor (ER)+ and ER− breast cancers. Distribution of T, N and M categories did not differ between ER+ and ER− breast cancer patients. ER− patients showed a higher incidence of G3 tumours. Weight, BMI, leptin, IL-6 and ROS were higher in ER+ compared with ER− patients. Among ER+ patients, BMI, leptin, IL-6 and ROS correlated with T and M. Leptin, IL-6 and ROS were positively correlated also with N. Among ER− patients, BMI and leptin did not correlate with any of prognostic parameters, whereas a positive correlation between IL-6, ROS and M was found. Multivariate regression analysis showed that BMI, leptin, IL-6 and ROS were predictive for T, N and M in ER+ patients. Weight gain, inflammation and oxidative stress are involved in EDBC prognosis. Their modulation through antidiabetic, anti-inflammatory and antioxidants drugs combined with endocrine therapy may constitute a targeted approach in post-menopausal EDBC.     

Genome stability: recent insights in the topoisomerase reverse gyrase and thermophilic DNA alkyltransferase

Repair and defence of genome integrity from endogenous and environmental hazard is a primary need for all organisms. Natural selection has driven the evolution of multiple cell pathways to deal with different DNA damaging agents. Failure of such processes can hamper cell functions and induce inheritable mutations, which in humans may cause cancerogenicity or certain genetic syndromes, and ultimately cell death. A special case is that of hyperthermophilic bacteria and archaea, flourishing at temperatures higher than 80 °C, conditions that favor genome instability and thus call for specific, highly efficient or peculiar mechanisms to keep their genome intact and functional. Over the last few years, numerous studies have been performed on the activity, function, regulation, physical and functional interaction of enzymes and proteins from hyperthermophilic microorganisms that are able to bind, repair, bypass damaged DNA, or modify its structure or conformation. The present review is focused on two enzymes that act on DNA catalyzing unique reactions: reverse gyrase and DNA alkyltransferase. Although both enzymes belong to evolutionary highly conserved protein families present in organisms of the three domains (Eucarya, Bacteria and Archaea), recently characterized members from hyperthermophilic archaea show both common and peculiar features.     

Fish consumption and risk of rheumatoid arthritis: a dose-response meta-analysis

Introduction

The association between fish consumption and rheumatoid arthritis (RA) is unclear. The aim of this paper was to summarize the available evidence on the association between fish consumption and risk of RA using a dose-response meta-analysis.

Methods

Relevant studies were identified by a search of MEDLINE and EMBASE through December 2013, with no restrictions. A random-effects dose-response meta-analysis was conducted to combine study specific relative risks. Potential non-linear relation was investigated using restricted cubic splines. A stratified analysis was conducted by study design.

Results

Seven studies (four case-controls and three prospective cohorts) involving a total of 174 701 participants and 3346 cases were included in the meta-analysis. For each one serving per week increment in fish consumption, the relative risk (RR) of RA was 0.96 (95% confidence interval (CI) 0.91 to 1.01). Results did not change when stratifying by study design. No heterogeneity or publication bias was observed. When fish consumption was modeled using restricted cubic splines, the risk of RA was 20 to 24% lower for 1 up to 3 servings per week of fish (RR =0.76, 95% CI: 0.57 to 1.02) as compared to never consumption.

Conclusions

Results from this dose-response meta-analysis showed a non-statistically significant inverse association between fish consumption and RA.     

Identification of Histological Patterns in Clinically Affected and Unaffected Palm Regions in Dupuytren's Disease

Dupuytren''s disease is a fibro-proliferative disease characterized by a disorder of the extracellular matrix (ECM) and high myofibroblast proliferation. However, studies failed to determine if the whole palm fascia is affected by the disease. The objective of this study was to analyze several components of the extracellular matrix of three types of tissues—Dupuytren''s diseased contracture cords (DDC), palmar fascia clinically unaffected by Dupuytren''s disease contracture (NPF), and normal forehand fascia (NFF). Histological analysis, quantification of cells recultured from each type of tissue, mRNA microarrays and immunohistochemistry for smooth muscle actin (SMA), fibrillar ECM components and non-fibrillar ECM components were carried out. The results showed that DDC samples had abundant fibrosis with reticular fibers and few elastic fibers, high cell proliferation and myofibroblasts, laminin and glycoproteins, whereas NFF did not show any of these findings. Interestingly, NPF tissues had more cells showing myofibroblasts differentiation and more collagen and reticular fibers, laminin and glycoproteins than NFF, although at lower level than DDC, with similar elastic fibers than DDC. Immunohistochemical expression of decorin was high in DDC, whereas versican was highly expressed NFF, with no differences for aggrecan. Cluster analysis revealed that the global expression profile of NPF was very similar to DDC, and reculturing methods showed that cells corresponding to DDC tissues proliferated more actively than NPF, and NPF more actively than NFF. All these results suggest that NPF tissues may be affected, and that a modification of the therapeutic approach used for the treatment of Dupuytren''s disease should be considered.     

Complication Probability Models for Radiation-Induced Heart Valvular Dysfunction: Do Heart-Lung Interactions Play a Role?

Purpose

The purpose of this study is to compare different normal tissue complication probability (NTCP) models for predicting heart valve dysfunction (RVD) following thoracic irradiation.

Methods

All patients from our institutional Hodgkin lymphoma survivors database with analyzable datasets were included (n = 90). All patients were treated with three-dimensional conformal radiotherapy with a median total dose of 32 Gy. The cardiac toxicity profile was available for each patient. Heart and lung dose-volume histograms (DVHs) were extracted and both organs were considered for Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP model fitting using maximum likelihood estimation. Bootstrap refitting was used to test the robustness of the model fit. Model performance was estimated using the area under the receiver operating characteristic curve (AUC).

Results

Using only heart-DVHs, parameter estimates were, for the LKB model: D₅₀ = 32.8 Gy, n = 0.16 and m = 0.67; and for the RS model: D₅₀ = 32.4 Gy, s = 0.99 and γ = 0.42. AUC values were 0.67 for LKB and 0.66 for RS, respectively. Similar performance was obtained for models using only lung-DVHs (LKB: D₅₀ = 33.2 Gy, n = 0.01, m = 0.19, AUC = 0.68; RS: D₅₀ = 24.4 Gy, s = 0.99, γ = 2.12, AUC = 0.66). Bootstrap result showed that the parameter fits for lung-LKB were extremely robust. A combined heart-lung LKB model was also tested and showed a minor improvement (AUC = 0.70). However, the best performance was obtained using the previously determined multivariate regression model including maximum heart dose with increasing risk for larger heart and smaller lung volumes (AUC = 0.82).

Conclusions

The risk of radiation induced valvular disease cannot be modeled using NTCP models only based on heart dose-volume distribution. A predictive model with an improved performance can be obtained but requires the inclusion of heart and lung volume terms, indicating that heart-lung interactions are apparently important for this endpoint.