261 research outputs found
Epidemiological transition of colorectal cancer in developing countries: Environmental factors, molecular pathways, and opportunities for prevention
Colorectal cancer (CRC) is one of the leading causes of cancer and cancer-related mortality worldwide. The disease has been traditionally a major health problem in industrial countries, however the CRC rates are increasing in the developing countries that are undergoing economic growth. Several environmental risk factors, mainly changes in diet and life style, have been suggested to underlie the rise of CRC in these populations. Diet and lifestyle impinge on nuclear receptors, on the intestinal microbiota and on crucial molecular pathways that are implicated in intestinal carcinogenesis. In this respect, the epidemiological transition in several regions of the world offers a unique opportunity to better understand CRC carcinogenesis by studying the disease phenotypes and their environmental and molecular associations in different populations. The data from these studies may have important implications for the global prevention and treatment of CRC. © 2014 Baishideng Publishing Group Inc. All rights reserved
Overweight and obese patients with nickel allergy have a worse metabolic profile compared to weight matched non-allergic individuals
A lack of balance between energy intake and expenditure due to overeating or reduced physical activity does not seem to explain entirely the obesity epidemic we are facing, and further factors are therefore being evaluated. Nickel (Ni) is a ubiquitous heavy metal implied in several health conditions. Regarding this, the European Food Safety Authority has recently released an alert on the possible deleterious effects of dietary Ni on human health given the current levels of Ni dietary intake in some countries. Pre-clinical studies have also suggested its role as an endocrine disruptor and have linked its exposure to energy metabolism and glucose homeostasis dysregulation. Ni allergy is common in the general population, but preliminary data suggest it being even more widespread among overweight patients.
OBJECTIVES:
The aim of this study has been to evaluate the presence of Ni allergy and its association with the metabolic and endocrine profile in overweight and obese individuals.
METHODS:
We have evaluated 1128 consecutive overweight and obese outpatients. 784 were suspected of being allergic to Ni and 666 were assessed for it. Presence of Ni allergy and correlation with body mass index (BMI), body composition, metabolic parameters and hormonal levels were evaluated.
RESULTS:
We report that Ni allergy is more frequent in presence of weight excess and is associated with worse metabolic parameters and impaired Growth Hormone secretion.
CONCLUSIONS:
We confirm that Ni allergy is more common in obese patients, and we report for the first time its association with worse metabolic parameters and impaired function of the GH-IGF1 axis in human subjects
Regulation of miR-483-3p by the O-linked N-acetylglucosamine transferase links chemosensitivity to glucose metabolism in liver cancer cells
The miR-483-3p is upregulated in several tumors, including liver tumors, where it inhibits TP53-dependent apoptosis by targeting the pro-apoptotic gene BBC3/PUMA. The transcriptional regulation of the miR-483-3p could be driven by the β-catenin/USF1 complex, independently from its host gene IGF2, and we previously demonstrated that in HepG2 hepatoblastoma cells carrying wild-type TP53 the upregulation of the miR-483-3p overcomes the antitumoral effects of the tumor-suppressor miR-145-5p by a mechanism involving cellular glucose availability. Here we demonstrate that in HepG2 cells, the molecular link between glucose concentration and miR-483-3p expression entails the O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT), which stabilizes the transcriptional complex at the miR-483 promoter. HepG2 cells showed reduced miR-483-3p expression and increased susceptibility to 5-fluorouracil (5-FU)-induced apoptosis in presence of the inhibitor of glycolysis 2-deoxy-D-glucose (2-DG). However, in vivo experiments showed that HepG2 cells with higher miR-483-3p expression were selected during tumor progression regardless of 5-FU treatment. Furthermore, treatment with 2-DG alone did not significantly reduce HepG2 xenograft load in immunodeficient mice. In conclusion, we show that in HepG2 cells glucose uptake increases the expression of the oncogenic miR-483-3p through the OGT pathway. This suggests that depletion of the miR-483-3p may be a valuable therapeutic approach in liver cancer patients, but the use of inhibitors of glycolysis to achieve this purpose could accelerate the selection of resistant neoplastic cell clones
Analysis of adenomatous polyposis coli gene in thyroid tumours.
Familial adenomatous polyposis (FAP) is known to be associated with neoplasia of various tissues, including thyroid carcinoma. Germline mutations of the tumour-suppressor gene APC, responsible for the predisposition to FAP, may therefore be involved in the pathogenesis of these tumours. In this report the structure of the APC gene has been investigated in 26 thyroid tumours, at different stages of dedifferentiation, that were surgically excised from patients with a negative history of FAP. Approximately 35% of the APC gene coding region, where most of the mutations are clustered, has been analysed by a combination of single-strand conformation polymorphism and direct sequencing. No significant alterations could be demonstrated in any sample examined. It is concluded that, at least in patients not affected by FAP, APC gene abnormalities do not seem to play a relevant role in the pathogenesis of thyroid carcinoma
Analysis of extended genomic rearrangements in oncological research.
Screening for genomic rearrangements is a fundamental task in the genetic diagnosis of many inherited
disorders including cancer-predisposing syndromes. Several methods were developed for analysis of structural
genomic abnormalities, some are targeted to the analysis of one or few specific loci, others are designed to
scan the whole genome. Locus-specific methods are used when the candidate loci responsible for the specific
pathological condition are known. Whole-genome methods are used to discover loci bearing structural
abnormalities when the disease-associated locus is unknown. Three main approaches have been employed for
the analysis of locus-specific structural changes. The first two are based on probe hybridization and include
cytogenetics and DNA blotting. The third approach is based on PCR amplification and includes microsatellite or
single nucleotide polymorphism (SNP) genotyping, relative allele quantitation, real-time quantitative PCR, long
PCR and multiplex PCR-based methods such as multiplex ligation-dependent probe amplification and the
recently developed nonfluorescent multiplex PCR coupled to high-performance liquid chromatography analysis.
Whole-genome methods include cytogenetic methods, array-comparative genomic hybridization, SNP array
and other sequence-based methods. The goal of the present review is to provide an overview of the main
features and advantages and limitations of methods for the screening of structural genomic abnormalities
relevant to oncological research
Controlled laser-induced dehydrogenation of free-standing graphane probed by pump–probe X-ray photoemission
The effects of optical excitation on fully hydrogenated free-standing nanoporous graphene have been characterized by pump–probe X-ray photoemission spectroscopy. Hydrogenated graphene, known as graphane, is characterized by a sp3 hybridization, which induces a sp3 component in the C 1s core level whose intensity can be used to monitor the hydrogen content. Under optical excitation we observe a partial dehydrogenation of graphane, which we attribute to local laser-induced heating; such result allows us to estimate the thermal conductivity of the material, for which we found an upper limit of 0.2 W/(m K), four orders of magnitude smaller than that of graphene. Such stark difference, combined with the possibility of dehydrogenating the graphane substrate via laser exposure, may be exploited to engineer nanostructured heat conduction channels in organic and hybrid organic–inorganic devices. We then explored the sub-nanosecond dynamics of the C 1s core level, which displays a kinetic energy shift and a peak broadening with two different decay constants, 210 ps and 130 ps, respectively. We assign the former to surface photovoltage, and the latter to transient lattice heating
High prevalence of BRCA1 deletions in BRCAPRO-positive patients with high carrier probability.
Mutation screening of the BRCA1 and BRCA2 genes in probands with familial breast/ovarian cancer has been
greatly improved by the multiplex ligation-dependent probe amplification (MLPA) assay able to evidence gene
rearrangements not detectable by standard screening methods. However, no criteria for selection of cases to
be submitted to the MLPA test have been reported yet. We used the BRCAPro software for the selection of
familial breast/ovarian cancer probands investigated with the MLPA approach after negative BRCA1/2
conventional mutation screening. One hundred and seventy-seven probands were investigated for germline
BRCA1/2 mutations after assessment of genetic risk using BRCAPro. Probands were classified as BRCAPro
positive (n = 67) when the carrier probability (CP) was >10% and as BRCAPro negative (n = 110), when the CP
was <10%. Conventional mutational analyses of the BRCA1/2 genes and, in one case, of p53 identified 22
pathogenetic germline mutations, 12 in BRCA1, 9 in BRCA2 and 1 in p53, in 22/177 (12.4%) probands. All the
mutations except one were detected in BRCAPro-positive patients. In the 46 BRCAPro-positive cases that
resulted negative by BRCA1/2 mutation, screening analysis of rearrangements within BRCA1/2 by MLPA was
carried out. Three patients with a very high CP showed BRCA1 deletions, consisting of deletions of exons 1–2 in
two probands and of exon 24 in the third proband. In one case, the exons 1–2 deletion was shown to
cosegregate with disease in the family. No BRCA2 rearrangements were detected, but one patient showed the
1100delC of the CHEK2 gene, whose probe is present in the BRCA2 kit. In our series, the highest carrier
detection rate of mutation screening plus MLPA analysis (52.3%) was in patients with a BRCAPro CP >50%
Gastric adenomas: relationship between clinicopathological findings, Helicobacter pylori infection, APC mutations and COX-2 expression.
Gastric adenomas are rare neoplastic growths characterized by localized polypoid proliferations of dysplastic epithelium that tend to progress to infiltrating adenocarcinoma. Therefore, the identification of molecular markers that could reliably recognize adenomas at risk of progression is advocated in the clinical management. In this study we investigated, in a series of gastric adenoma specimens from an area at high risk of gastric cancer, the relationship between clinicopathological characteristics of adenoma and Helicobacter pylori infection, APC mutational status, and COX-2 and the down-stream enzyme mPGES1 expression. Helicobacter pylori infection, detected in 24%, and 33% by histology and PCR analyses, respectively, did not show any relationship with growth pattern, localization, size, dysplasia grade and presence of synchronous cancer. Pathogenetic mutations of MCR region (codons 1269-1589) of the APC gene were detected only in one case corresponding to a single, small size, low grade, H. pylori-negative adenoma. The expression of COX-2 largely matched that of mPGES(1). Both were overexpressed in 79% of cases showing a relationship with high-grade dysplasia, size >10 mm and presence of a synchronous carcinoma. In conclusion, COX-2 may play a key role in the development and progression of gastric adenoma and could be an attractive target in the management of gastric adenoma at major risk of cancer development
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