Prospective study of a molecular selection profile for RAS wild type colorectal cancer patients receiving irinotecan-cetuximab

Background: The aim of our study was to evaluate whether a panel of biomarkers, prospectively analysed might be able to predict patients' clinical outcome more accurately than RAS status alone. Methods: K-RAS (exons 2, 3, 4) wild type colorectal cancer patients, candidates to second/third-line cetuximab with chemotherapy were prospectively allocated into 2 groups on the basis of their profile: favourable (BRAF and PIK3CA exon 20 wild type, EGFR GCN ≥ 2.6, HER-3 Rajkumar score ≤ 8, IGF-1 immunostaining < 2) or unfavourable (any of the previous markers altered or mutated). After the introduction of N-RAS status (exons 2, 3, 4) only RAS wild type patients were considered eligible. Results: Forty-six patients were enrolled. Seventeen patients (37%) were allocated to the favourable and 29 patients (63%) to the unfavourable profile. RR in the favourable and unfavourable group was 11/17 (65%) and 2/29 (7%) (p = 0.007) respectively. The favourable group also showed an improved PFS (8months vs. 3months, p < 0.0001) and OS (15months vs. 6months, p < 0.0001). Conclusions: Our results suggest that prospective selection of optimal candidates for cetuximab treatment is feasible and may be able to improve clinical outcom

Intrauterine Undernourishment Alters TH1/TH2 Cytokine Balance and Attenuates Lung Allergic Inflammation in Wistar Rats

IL-4 produced by Th2 cells can block cytokine production by Th1 cells, and Th1 IFN-gamma is known to counterregulate Th2 immune response, inhibiting allergic eosinophilia. As intrauterine undernutrition can attenuate lung inflammation, we investigated the influence of intrauterine undernourishment on the Th1/Th2 cytokine balance and allergic lung inflammation. Intrauterine undernourished offspring were obtained from dams fed 50% of the nourished diet of their counterparts and were immunized at 9 weeks of age. We evaluated the cell counts and cytokine protein expression in the bronchoalveolar lavage, mucus production and collagen deposition, and cytokine gene expression and transcription factors in lung tissue 21 days after ovalbumin immunization. Intrauterine undernourishment significantly reduced inflammatory cell airway infiltration, mucus secretion and collagen deposition, in rats immunized and challenged. Intrauterine undernourished rats also exhibited an altered cytokine expression profile, including higher TNF-alpha and IL-1 beta expression and lower IL-6 expression than well-nourished rats following immunization and challenge. Furthermore, the intrauterine undernourished group showed reduced ratios of the IL-4/IFN-gamma and the transcription factors GATA-3/T-Bet after immunization and challenge. We suggest that the attenuated allergic lung inflammation observed in intrauterine undernourished rats is related to an altered Th1/Th2 cytokine balance resulting from a reduced GATA-3/T-bet ratio. Copyright (C) 2012 S. Karger AG, BaselConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundo de Auxilio aos Docentes e Alunos (FADA-UNIFESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Inst Ciencias Ambientais Quim & Farmaceut, BR-09972270 São Paulo, BrazilUniv São Paulo, Inst Ciencias Biomed, Dept Imunol, Lab Imunol Transplantes, BR-05508 São Paulo, BrazilUniversidade Federal de São Paulo, Div Nefrol, Lab Imunol Clin & Expt, BR-09972270 São Paulo, BrazilUniv São Paulo, Inst Ciencias Biomed, Dept Farmacol, BR-05508 São Paulo, BrazilUniversidade Federal de São Paulo, Inst Ciencias Ambientais Quim & Farmaceut, BR-09972270 São Paulo, BrazilUniversidade Federal de São Paulo, Div Nefrol, Lab Imunol Clin & Expt, BR-09972270 São Paulo, BrazilFAPESP: 07/07139-3FAPESP: 09/09849-3FAPESP: 09/52119-6FAPESP: 10/01404-0FAPESP: 12/02270-2Web of Scienc

Prevalence of latent tuberculosis, syphilis, hepatitis B and C among asylum seekers in Malta

Background: In the last few years, Malta has witnessed increasing immigration flows from the Libyan coasts. Public health policies are focused on screening migrants for tuberculosis, whereas no systematic actions against STIs are implemented. The aim of this study is to define the epidemiological profile of asylum seekers in Malta as regards syphilis, hepatitis B, C and latent tuberculosis, thus supporting screening policies. Methods: Five hundred migrants living in open centres were screened between December 2010 and June 2011. Results: 83.2% of people was from Somalia, 81.2% males, average age 26.5 years. The tuberculin skin test (TST) was positive in 225 migrants (45%). Latent syphilis was diagnosed in 11 migrants, hepatitis C in 3 and 31 migrants were HBsAg positive. Conclusion: Systematic screening for asymptomatic migrants in Malta is not recommended for hepatitis C and syphilis, given the low prevalence observed. On the contrary, it should be considered for hepatitis B. TST could be indicated as the first step of a two step screening for migrants from countries with high TB incidence. Efficacy and cost-effectiveness could be achieved by further targeting screening to specific subgroups at higher risk of reactivation, such as people living with HIV and subjects affected by chronic diseases.peer-reviewe

Modulation of pain perception by transcranial magnetic stimulation of left prefrontal cortex

Evidence by functional imaging studies suggests the role of left dorsolateral prefrontal cortex (DLPFC) in the inhibitory control of nociceptive transmission system. Repetitive transcranial magnetic stimulation (rTMS) is able to modulate pain response to capsaicin. In the present study, we evaluated the effect of DLPFC activation (through rTMS) on nociceptive control in a model of capsaicin-induced pain. The study was performed on healthy subjects that underwent capsaicin application on right or left hand. Subjects judged the pain induced by capsaicin through a 0–100 VAS scale before and after 5 Hz rTMS over left and right DLPFC at 10 or 20 min after capsaicin application in two separate groups (8 subjects each). Left DLPFC-rTMS delivered either at 10 and 20 min after capsaicin application significantly decreased spontaneous pain in both hands. Right DLPFC rTMS showed no significant effect on pain measures. According to these results, stimulation of left DLPFC seems able to exert a bilateral control on pain system, supporting the critical antinociceptive role of such area. This could open new perspectives to non-invasive brain stimulation protocols of alternative target area for pain treatment

A Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex Regulation

Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals—5 of which were identified only with the custom arrays—and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10−29); for ESR, at the HBB (rs4910472, p = 2.31×10−11) and UCN119B/SPPL3 (rs11829037, p = 8.91×10−10) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10−13) and in CADM3 (rs3026968, p = 7.63×10−13); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10−21), near DARC (rs3845624, p = 1.43×10−10), UNC119B/SPPL3 (rs11829037, p = 1.50×10−14), and ICOSLG/AIRE (rs113459440, p = 1.54×10−08) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process

Genetic loci linked to Type 1 Diabetes and Multiple Sclerosis families in Sardinia

<p>Abstract</p> <p>Background</p> <p>The Mediterranean island of Sardinia has a strikingly high incidence of the autoimmune disorders Type 1 Diabetes (T1D) and Multiple Sclerosis (MS). Furthermore, the two diseases tend to be co-inherited in the same individuals and in the same families. These observations suggest that some unknown autoimmunity variant with relevant effect size could be fairly common in this founder population and could be detected using linkage analysis.</p> <p>Methods</p> <p>To search for T1D and MS loci as well as any that predispose to both diseases, we performed a whole genome linkage scan, sequentially genotyping 593 microsatellite marker loci in 954 individuals distributed in 175 Sardinian families. In total, 413 patients were studied; 285 with T1D, 116 with MS and 12 with both disorders. Model-free linkage analysis was performed on the genotyped samples using the Kong and Cox logarithm of odds (LOD) score statistic.</p> <p>Results</p> <p>In T1D, aside from the HLA locus, we found four regions showing a lod-score ≥1; 1p31.1, 6q26, 10q21.2 and 22q11.22. In MS we found three regions showing a lod-score ≥1; 1q42.2, 18p11.21 and 20p12.3. In the combined T1D-MS scan for shared autoimmunity loci, four regions showed a LOD >1, including 6q26, 10q21.2, 20p12.3 and 22q11.22. When we typed more markers in these intervals we obtained suggestive evidence of linkage in the T1D scan at 10q21.2 (LOD = 2.1), in the MS scan at 1q42.2 (LOD = 2.5) and at 18p11.22 (LOD = 2.6). When all T1D and MS families were analysed jointly we obtained suggestive evidence in two regions: at 10q21.1 (LOD score = 2.3) and at 20p12.3 (LOD score = 2.5).</p> <p>Conclusion</p> <p>This suggestive evidence of linkage with T1D, MS and both diseases indicates critical chromosome intervals to be followed up in downstream association studies.</p

Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis.

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease

Integrated genomic study of quadruple-WT GIST (KIT/PDGFRA/SDH/RAS pathway wild-type GIST)

BACKGROUND: About 10-15% of adult gastrointestinal stromal tumors (GIST) and the vast majority of pediatric GIST do not harbour KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations (J Clin Oncol 22:3813-3825, 2004; Hematol Oncol Clin North Am 23:15-34, 2009). The molecular biology of these GIST, originally defined as KIT/PDGFRA wild-type (WT), is complex due to the existence of different subgroups with distinct molecular hallmarks, including defects in the succinate dehydrogenase (SDH) complex and mutations of neurofibromatosis type 1 (NF1), BRAF, or KRAS genes (RAS-pathway or RAS-P).In this extremely heterogeneous landscape, the clinical profile and molecular abnormalities of the small subgroup of WT GIST suitably referred to as quadruple wild-type GIST (quadrupleWT or KITWT/PDGFRAWT/SDHWT/RAS-PWT) remains undefined. The aim of this study is to investigate the genomic profile of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, by using a massively parallel sequencing and microarray approach, and compare it with the genomic profile of other GIST subtypes. METHODS: We performed a whole genome analysis using a massively parallel sequencing approach on a total of 16 GIST cases (2 KITWT/PDGFRAWT/SDHWT and SDHBIHC+/SDHAIHC+, 2 KITWT/PDGFRAWT/SDHAmut and SDHBIHC-/SDHAIHC- and 12 cases of KITmut or PDGFRAmut GIST). To confirm and extend the results, whole-genome gene expression analysis by microarray was performed on 9 out 16 patients analyzed by RNAseq and an additional 20 GIST patients (1 KITWT/PDGFRAWTSDHAmut GIST and 19 KITmut or PDGFRAmut GIST). The most impressive data were validated by quantitave PCR and Western Blot analysis. RESULTS: We found that both cases of quadrupleWT GIST had a genomic profile profoundly different from both either KIT/PDGFRA mutated or SDHA-mutated GIST. In particular, the quadrupleWT GIST tumors are characterized by the overexpression of molecular markers (CALCRL and COL22A1) and of specific oncogenes including tyrosine and cyclin- dependent kinases (NTRK2 and CDK6) and one member of the ETS-transcription factor family (ERG). CONCLUSION: We report for the first time an integrated genomic picture of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, using massively parallel sequencing and gene expression analyses, and found that quadrupleWT GIST have an expression signature that is distinct from SDH-mutant GIST as well as GIST harbouring mutations in KIT or PDGFRA. Our findings suggest that quadrupleWT GIST represent another unique group within the family of gastrointestintal stromal tumors