A polymorphic variant of the insulin-like growth factor 1 (IGF-1) receptor correlates with male longevity in the Italian population: a genetic study and evaluation of circulating IGF-1 from the "Treviso Longeva (TRELONG)" study

<p>Abstract</p> <p>Background</p> <p>An attenuation of the insulin-like growth factor 1 (IGF-1) signaling has been associated with elongation of the lifespan in simple metazoan organisms and in rodents. In humans, IGF-1 level has an age-related modulation with a lower concentration in the elderly, depending on hormonal and genetic factors affecting the IGF-1 receptor gene (<it>IGF-1R</it>).</p> <p>Methods</p> <p>In an elderly population from North-eastern Italy (<it>n </it>= 668 subjects, age range 70–106 years) we investigated the <it>IGF-1R </it>polymorphism G3174A (<it>rs2229765</it>) and the plasma concentration of free IGF-1. Frequency distributions were compared using χ²-test "Goodness of Fit" test, and means were compared by one-way analysis of variance (ANOVA); multiple regression analysis was performed using JMP7 for SAS software (SAS Institute, USA). The limit of significance for genetic and biochemical comparison was set at α = 0.05.</p> <p>Results</p> <p>Males showed an age-related increase in the A-allele of <it>rs2229765 </it>and a change in the plasma level of IGF-1, which dropped significantly after 85 years of age (85+ group). In the male 85+ group, A/A homozygous subjects had the lowest plasma IGF-1 level. We found no clear correlation between <it>rs2229765 </it>genotype and IGF-1 in the females.</p> <p>Conclusion</p> <p>These findings confirm the importance of the <it>rs2229765 </it>minor allele as a genetic predisposing factor for longevity in Italy where a sex-specific pattern for IGF-1 attenuation with ageing was found.</p

WHOLE-GENOME RE-SEQUENCING OF TWO TOMATO LANDRACES REVEALS SEQUENCE VARIATIONS UNDERPINNING KEY ECONOMICALLY IMPORTANT TRAITS

In the post-genomic era, one of the major challenges is the identification of alleles directly responsible for phenotype variation among different genotypes within the same species. Tomato is a model crop for understanding the development and ripening of climacteric fleshy fruits, and it is also known to be an important source of health-promoting compounds. In addition, cultivated tomato germplasm shows a high phenotypic variation despite its very low genetic diversity. Toward the identification of sequence variations responsible for stress tolerance, high fruit quality and long shelf life, we re-sequenced the genomes of two traditional landraces grown in the Campania region (Southern Italy). Crovarese, belonging to the Corbarino type (COR), and Lucariello (LUC) are typically grown under low water regimes and produce highly appreciated fruits, which can be stored up to 4-8 months. We generated 65.8M and 56.4M of paired-end 30-150 bp reads with an average insert size of 380 bp (± 52bp) and 364 bp (± 49bp) for COR and LUC, respectively. A referenceguided assembly was performed using 'Heinz 1706' as a reference genome. We estimated a mean coverage depth of ~15X for COR and 13X for LUC. Comparing the genomes of COR and LUC with that of 'Heinz 1706' we found a similar distribution of SNPs (68.8% vs. 69.9%, respectively), small deletions (8.9% vs. 8.6%) and small insertions (22.1% vs. 21.3%). Through a de novo assembly of the unmapped reads we identified 29 and 36 new contigs in COR and LUC, respectively. The new contigs could be assigned to the chromosomes thanks to the use of a splitread approach. On average, the contigs inserted in COR were 654bp, whereas those inserted in LUC were 616bp. Using custom RNA-seq data, a total of 43054 and 44576 gene loci were annotated in COR and LUC, corresponding to 62369 and 65094 transcripts, respectively. Among the genes showing a similar structure in COR and LUC compared to 'Heinz 1706', we identified ~2000 and 1700 SNPs causing potentially disruptive effects on the function of 1371 and 1201 genes in COR and LUC, respectively. Interesting GO categories highly represented in genes affected by sequence changes were identified. Major variations were present in stress-responsive genes as well as in fruit quality and development-related genes. From a practical perspective, the identified SNPs and InDels are candidate polymorphisms to track DNA variations associated to key traits of economic interest

Medical treatment of renal cancer: new horizons.

Renal cell carcinoma (RCC) makes up 2-3% of adult cancers. The introduction of tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors in the mid-2000s radically changed the management of RCC. These targeted treatments superseded immunotherapy with interleukin-2 and interferon. The pendulum now appears to be shifting back towards immunotherapy, with the evidence of prolonged overall survival of patients with metastatic RCC on treatment with the anti-programmed cell death 1 ligand monoclonal antibody, nivolumab. Clinical prognostic criteria aid prediction of relapse risk for resected localised disease. Unfortunately, for patients at high risk of relapse, no adjuvant treatment has yet shown benefit, although further trials are yet to report. Clinical prognostic models also have a role in the management of advanced disease; now there is a pressing need for predictive biomarkers to direct therapy. Treatment selection for metastatic disease is currently based on histology, prognostic group and patient preference based on side effect profile. In this article, we review the current medical and surgical management of localised, oligometastatic and advanced RCC, including side effect management and the evidence base for management of poor-risk and non-clear cell disease. We discuss recent results from clinical trials and how these are likely to shape future practice and a renaissance of immunotherapy for renal cell cancer

Brugia malayi Excreted/Secreted Proteins at the Host/Parasite Interface: Stage- and Gender-Specific Proteomic Profiling

Relatively little is known about the filarial proteins that interact with the human host. Although the filarial genome has recently been completed, protein profiles have been limited to only a few recombinants or purified proteins of interest. Here, we describe a large-scale proteomic analysis using microcapillary reverse-phase liquid chromatography-tandem-mass spectrometry to identify the excretory-secretory (ES) products of the L3, L3 to L4 molting ES, adult male, adult female, and microfilarial stages of the filarial parasite Brugia malayi. The analysis of the ES products from adult male, adult female, microfilariae (Mf), L3, and molting L3 larvae identified 852 proteins. Annotation suggests that the functional and component distribution was very similar across each of the stages studied; however, the Mf contributed a higher proportion to the total number of identified proteins than the other stages. Of the 852 proteins identified in the ES, only 229 had previous confirmatory expressed sequence tags (ESTs) in the available databases. Moreover, this analysis was able to confirm the presence of 274 “hypothetical” proteins inferred from gene prediction algorithms applied to the B. malayi (Bm) genome. Not surprisingly, the majority (160/274) of these “hypothetical” proteins were predicted to be secreted by Signal IP and/or SecretomeP 2.0 analysis. Of major interest is the abundance of previously characterized immunomodulatory proteins such as ES-62 (leucyl aminopeptidase), MIF-1, SERPIN, glutathione peroxidase, and galectin in the ES of microfilariae (and Mf-containing adult females) compared to the adult males. In addition, searching the ES protein spectra against the Wolbachia database resulted in the identification of 90 Wolbachia-specific proteins, most of which were metabolic enzymes that have not been shown to be immunogenic. This proteomic analysis extends our knowledge of the ES and provides insight into the host–parasite interaction

The urokinase-type plasminogen activator polymorphism PLAU_1 is a risk factor for APOE-epsilon4 non-carriers in the Italian Alzheimer's disease population and does not affect the plasma Abeta(1-42) level

Sporadic Alzheimer's disease (AD) is the most frequent form of dementia in the elderly. A non-conservative polymorphism in the urokinase-type plasminogen activator gene (PLAU_1=RS2227564) has been analyzed, but data are conflicting on whether it is a risk factor for AD. To clarify whether this genetic variant modifies AD risk in the Italian population, we ran a case-control association study on 192 AD and 126 age-matched controls. We did not find any association between PLAU_1 genotype and AD in the whole AD population, but when we stratified our sample by APOE-epsilon4 status, we found a significant association between PLAU_1 genotype (C/T+T/T) and APOE-epsilon4 negative AD subjects (p=0.02, chi(2)-test). The PLAU_1 genotype did not appear to affect the plasma Abeta42 concentration. Our data support a role for PLAU_1 as an independent genetic risk factor for AD in the Italian population for those subjects who do not have the APOE-epsilon4 allele