Induction chemotherapy followed by neoadjuvant chemoradiotherapy and surgery in locally advanced rectal cancer: preliminary results of a phase II study

PURPOSE: To report preliminary results of induction chemotherapy (IC) followed by neoadjuvant chemoradiotherapy (CRT) and surgery in locally advanced rectal cancer (LARC) patients.MATERIALS AND METHODS: This is the preliminary evaluation of a phase II study. Patients with histologically proven rectal adenocarcinoma, stage II-III disease, who met the inclusion criteria, received induction FOLFOXIRI (5-FU, leucovorin, oxaliplatin and irinotecan) regimen in combination with targeted agents followed by CRT and surgery. Analysis of the first 8 patients was required to confirm the treatment feasibility before the accrual of 20 additional patients. RESULTS: The first 8 patients were evaluated. The median follow-up time was 23 months. There were no treatment-related deaths. Trimodality strategy was well tolerated with high compliance and a good level of toxicity. There were no evidence of febrile neutropenia and any grade 4 adverse events were recorded. Three patients had pathologic complete response (pCR) and 1 patient had a nearly pCR (ypT1 ypN0). CONCLUSION: Preliminary results are encouraging. FOLFOXIRI regimen plus targeted agents followed by CRT and surgery seems a safe approach. Longer follow-up and higher number of patients are mandatory to confirm such findings

LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease

Lipopolysaccharide (LPS) is currently considered one of the major players in non-alcoholic fatty liver disease (NAFLD) pathogenesis and progression. Here, we aim to investigate the possible role of LPS-induced TNF-α factor (LITAF) in inducing a pro-inflammatory and pro-fibrogenic phenotype of non-alcoholic steatohepatitis (NASH).We found that children with NAFLD displayed, in different liver-resident cells, an increased expression of LITAF which correlated with histological traits of hepatic inflammation and fibrosis. Total and nuclear LITAF expression increased in mouse and human hepatic stellate cells (HSCs). Moreover, LPS induced LITAF-dependent transcription of IL-1β, IL-6 and TNF-α in the clonal myofibroblastic HSC LX-2 cell line, and this effect was hampered by LITAF silencing. We showed, for the first time in HSCs, that LITAF recruitment to these cytokine promoters is LPS dependent. However, preventing LITAF nuclear translocation by p38MAPK inhibitor, the expression of IL-6 and TNF-α was significantly reduced with the aid of p65NF-ĸB, while IL-1β transcription exclusively required LITAF expression/activity. Finally, IL-1β levels in plasma mirrored those in the liver and correlated with LPS levels and LITAF-positive HSCs in children with NASH.In conclusion, a more severe histological profile in paediatric NAFLD is associated with LITAF over-expression in HSCs, which in turn correlates with hepatic and circulating IL-1β levels outlining a panel of potential biomarkers of NASH-related liver damage. The in vitro study highlights the role of LITAF as a key regulator of the LPS-induced pro-inflammatory pattern in HSCs and suggests p38MAPK inhibitors as a possible therapeutic approach against hepatic inflammation in NASH

Echocardiographic nomograms for chamber diameters and areas in Caucasian children

BACKGROUND: Although a quantitative evaluation of cardiac chamber dimensions in pediatric echocardiography is often important, nomograms for these structures are limited. The aim of this study was to establish reliable echocardiographic nomograms of cardiac chamber diameters and areas in a wide population of children. METHODS: A total of 1,091 Caucasian Italian healthy children (age range, 0 days to 17 years; 44.8% female) with body surface areas (BSAs) ranging from 0.12 to 1.8 m(2) were prospectively enrolled. Twenty-two two-dimensional and M-mode measurements of atrial and ventricular chamber diameters and areas were performed. Models using linear, logarithmic, exponential, and square-root relationships were tested. Heteroscedasticity was tested by the White test and the Breusch-Pagan test. Age, weight, height, and BSA, calculated by the Haycock formula, were used as the independent variables in different analyses to predict the mean value of each echocardiographic measurement. The influence of various confounders, including gender, type of delivery, prematurity, and interobserver variability, was also evaluated. Structured Z scores were then computed. RESULTS: The Haycock formula provided the best fit and was used when presenting data as predicted values (mean ? 2 SDs) for a given BSA and within equations relating echocardiographic measurements to BSA. Confounders were not included in the final models, because they did not show significant effects for most of the measurements. CONCLUSIONS: Echocardiographic reference values are presented for chamber area and diameters, derived from a large population of healthy children. These data partly cover a gap in actual pediatric echocardiographic nomograms. Further studies are required to reinforce these data, as well as to evaluate other parameters and ethnicities

Large-scale genetic variation of the symbiosis-required megaplasmid pSymA revealed by comparative genomic analysis of Sinorhizobium meliloti natural strains

BACKGROUND: Sinorhizobium meliloti is a soil bacterium that forms nitrogen-fixing nodules on the roots of leguminous plants such as alfalfa (Medicago sativa). This species occupies different ecological niches, being present as a free-living soil bacterium and as a symbiont of plant root nodules. The genome of the type strain Rm 1021 contains one chromosome and two megaplasmids for a total genome size of 6 Mb. We applied comparative genomic hybridisation (CGH) on an oligonucleotide microarrays to estimate genetic variation at the genomic level in four natural strains, two isolated from Italian agricultural soil and two from desert soil in the Aral Sea region. RESULTS: From 4.6 to 5.7 percent of the genes showed a pattern of hybridisation concordant with deletion, nucleotide divergence or ORF duplication when compared to the type strain Rm 1021. A large number of these polymorphisms were confirmed by sequencing and Southern blot. A statistically significant fraction of these variable genes was found on the pSymA megaplasmid and grouped in clusters. These variable genes were found to be mainly transposases or genes with unknown function. CONCLUSION: The obtained results allow to conclude that the symbiosis-required megaplasmid pSymA can be considered the major hot-spot for intra-specific differentiation in S. meliloti

Melusin is a new muscle-specific interactor for beta(1) integrin cytoplasmic domain.

Here we describe the isolation and partial characterization of a new muscle-specific protein (Melusin) which interacts with the integrin cytoplasmic domain. The cDNA encoding Melusin was isolated in a two-hybrid screening of a rat neonatal heart library using beta(1)A and beta(1)D integrin cytoplasmic regions as baits. Melusin is a cysteine-rich cytoplasmic protein of 38 kDa, with a stretch of acidic amino acid residues at the extreme carboxyl-terminal end. In addition, putative binding sites for SH3 and SH2 domains are present in the amino-terminal half of the molecule. Chromosomic analysis showed that melusin gene maps at Xq12.1/13 in man and in the synthenic region X band D in mouse. Melusin is expressed in skeletal and cardiac muscles but not in smooth muscles or other tissues. Immunofluorescence analysis showed that Melusin is present in a costamere-like pattern consisting of two rows flanking alpha-actinin at Z line. Its expression is up-regulated during in vitro differentiation of the C2C12 murine myogenic cell line, and it is regulated during in vivo skeletal muscle development. A fragment corresponding to the tail region of Melusin interacted strongly and specifically with beta(1) integrin cytoplasmic domain in a two-hybrid test, but the full-length protein did not. Because the tail region of Melusin contains an acidic amino acid stretch resembling high capacity and low affinity calcium binding domains, we tested the possibility that Ca(2+) regulates Melusin-integrin association. In vitro binding experiments demonstrated that interaction of full-length Melusin with detergent-solubilized integrin heterodimers occurred only in absence of cations, suggesting that it can be regulated by intracellular signals affecting Ca(2+) concentration

Spatial and temporal expressions of prune reveal a role in Muller gliogenesis during Xenopus retinal development

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Association between Serum Atypical Fibroblast Growth Factors 21 and 19 and Pediatric Nonalcoholic Fatty Liver Disease

Atypical fibroblast growth factors (FGF) 21 and 19 play a central role in energy metabolism through the mediation of Klotho coreceptor. Contradictory findings are available about the association of FGF21 and FGF19 with nonalcoholic fatty liver disease (NAFLD) in humans. We investigated the association of serum FGF21, FGF19 and liver Klotho coreceptor with non-alcoholic steatohepatitis (NASH) and fibrosis in children with NAFLD. Serum FGF21 and FGF19 were measured in 84 children with biopsy-proven NAFLD and 23 controls (CTRL). The hepatic expression of Klotho coreceptor was measured in 7 CTRL, 9 patients with NASH (NASH+) and 11 patients without NASH (NASH-). FGF21 and FGF19 showed a tendency to decrease from CTRL (median FGF21 = 196 pg/mL; median FGF19 = 201 pg/mL) to NASH- (FGF21 = 89 pg/mL; FGF19 = 81 pg/mL) to NASH+ patients (FGF21 = 54 pg/mL; FGF19 = 41 pg/mL) (p<0.001 for all comparisons) and were inversely associated with the probability of NASH and fibrosis in children with NAFLD. The hepatic expression of Klotho coreceptor was inversely associated with NASH (R2 = 0.87, p<0.0001) and directly associated with serum FGF21 (R2 = 0.57, p<0.0001) and FGF19 (R2 = 0.67, p<0.0001). In conclusion, serum FGF19 and FGF21 and hepatic Klotho expression are inversely associated with hepatic damage in children with NAFLD and these findings may have important implications for understanding the mechanisms of NAFLD progression. © 2013 Alisi et al

Effects of a probiotic suspension Symprove™ on a rat early-stage Parkinson’s disease model

An increasing number of studies in recent years have focused on the role that the gut may play in Parkinson’s Disease (PD) pathogenesis, suggesting that the maintenance of a healthy gut may lead to potential treatments of the disease. The health of microbiota has been shown to be directly associated with parameters that play a potential role in PD including gut barrier integrity, immunity, function, metabolism and the correct functioning of the gut-brain axis. The gut microbiota (GM) may therefore be employed as valuable indicators for early diagnosis of PD and potential targets for preventing or treating PD symptoms. Preserving the gut homeostasis using probiotics may therefore lead to a promising treatment strategy due to their known benefits in improving constipation, motor impairments, inflammation, and neurodegeneration. However, the mechanisms underlying the effects of probiotics in PD are yet to be clarified. In this project, we have tested the efficacy of an oral probiotic suspension, Symprove™, on an established animal model of PD. Symprove™, unlike many commercially available probiotics, has been shown to be resistant to gastric acidity, improve symptoms in gastrointestinal diseases and improve gut integrity in an in vitro PD model. In this study, we used an early-stage PD rat model to determine the effect of Symprove™ on neurodegeneration and neuroinflammation in the brain and on plasma cytokine levels, GM composition and short chain fatty acid (SCFA) release. Symprove™ was shown to significantly influence both the gut and brain of the PD model. It preserved the gut integrity in the PD model, reduced plasma inflammatory markers and changed microbiota composition. The treatment also prevented the reduction in SCFAs and striatal inflammation and prevented tyrosine hydroxylase (TH)-positive cell loss by 17% compared to that observed in animals treated with placebo. We conclude that Symprove™ treatment may have a positive influence on the symptomology of early-stage PD with obvious implications for the improvement of gut integrity and possibly delaying/preventing the onset of neuroinflammation and neurodegeneration in human PD patients

The role of HMGA1 protein in gastroenteropancreatic neuroendocrine tumors

Neuroendocrine tumors (NETs) are neoplasms derived from neuroendocrine cells. One of their main features is to often remain asymptomatic and clinically undetectable. High Mobility Group A (HMGA) proteins belong to a family of non-histone chromatinic proteins able to modulate gene expression through the interaction with DNA and transcription factors. They are overexpressed in most of the human malignancies, playing a critical role in carcinogenesis. However, their expression levels and their role in neuroendocrine carcinogenesis has not been exhaustively evaluated until now. Therefore, in this study, we have addressed the validity of using the expression of HMGA1 as a diagnostic marker and have investigated its role in NET carcinogenesis. The expression of HMGA1 has been evaluated by qRT-PCR and immunohistochemistry, using NET tissue microarrays, in a cohort of gastroenteropancreatic (GEP)-NET samples. The expression levels of HMGA1 have been then correlated with the main clinical features of NET samples. Finally, the contribution of HMGA1 overexpression to NET development has been addressed as far as the modulation of proliferation and migration abilities of NET cells is concerned. Here, we report that HMGA1 is overexpressed in GEP-NET samples, at both mRNA and protein levels, and that the silencing of HMGA1 protein expression interferes with the ability of NET cells to proliferate and migrate through the downregulation of Cyclin E, Cyclin B1 and EZH2. These results propose the HMGA proteins as new diagnostic and prognostic markers