Genes associated with metabolic syndrome predict disease-free survival in stage II colorectal cancer patients. A novel link between metabolic dysregulation and colorectal cancer

Producción CientíficaStudies have recently suggested that metabolic syndrome and its components increase the risk of colorectal cancer. Both diseases are increasing in most countries, and the genetic association between them has not been fully elucidated. The objective of this study was to assess the association between genetic risk factors of metabolic syndrome or related conditions (obesity, hyperlipidaemia, diabetes mellitus type 2) and clinical outcome in stage II colorectal cancer patients. Expression levels of several genes related to metabolic syndrome and associated alterations were analysed by real-time qPCR in two equivalent but independent sets of stage II colorectal cancer patients. Using logistic regression models and cross-validation analysis with all tumour samples, we developed a metabolic syndrome-related gene expression profile to predict clinical outcome in stage II colorectal cancer patients. The results showed that a gene expression profile constituted by genes previously related to metabolic syndrome was significantly associated with clinical outcome of stage II colorectal cancer patients. This metabolic profile was able to identify patients with a low risk and high risk of relapse. Its predictive value was validated using an independent set of stage II colorectal cancer patients. The identification of a set of genes related to metabolic syndrome that predict survival in intermediate-stage colorectal cancer patients allows delineation of a high-risk group that may benefit from adjuvant therapy and avoid the toxic and unnecessary chemotherapy in patients classified as low risk. Our results also confirm the linkage between.Ministerio de Ciencia, Innovación y Universidades (AGL2010-21565, RyC 2008-03734, IPT-2011-1248-060000),y la Comunidad de Madrid (ALIBIRD, S2009/AGR-1469

The polymyxin B-induced transcriptomic response of a clinical, multidrug-resistant Klebsiella pneumoniae involves multiple regulatory elements and intracellular targets

Background: The emergence of multidrug-resistant Klebsiella pneumoniae is a major public health concern. Many K. pneumoniae infections can only be treated when resorting to last-line drugs such as polymyxin B (PB). However, resistance to this antibiotic is also observed, although insufficient information is described on its mode of action as well as the mechanisms used by resistant bacteria to evade its effects. We aimed to study PB resistance and the influence of abiotic stresses in a clinical K. pneumoniae strain using whole transcriptome profiling. Results: We sequenced 12 cDNA libraries of K. pneumoniae Kp13 bacteria, from two biological replicates of the original strain Kp13 (Kp13) and five derivative strains: induced high-level PB resistance in acidic pH (Kp13(pH)), magnesium deprivation (Kp13(Mg)), high concentrations of calcium (Kp13(Ca)) and iron (Kp13(Fe)), and a control condition with PB (Kp13(PolB)). Our results show the involvement of multiple regulatory loci that differentially respond to each condition as well as a shared gene expression response elicited by PB treatment, and indicate the participation of two-regulatory components such as ArcA-ArcB, which could be involved in re-routing the K. pneumoniae metabolism following PB treatment. Modules of co-expressed genes could be determined, which correlated to growth in acid stress and PB exposure. We hypothesize that polymyxin B induces metabolic shifts in K. pneumoniae that could relate to surviving against the action of this antibiotic. Conclusions: We obtained whole transcriptome data for K. pneumoniae under different environmental conditions and PB treatment. Our results supports the notion that the K. pneumoniae response to PB exposure goes beyond damaged membrane reconstruction and involves recruitment of multiple gene modules and intracellular targets.Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Lab Nacl Comp Cient, Petropolis, RJ, BrazilFiocruz MS, Ctr Pesquisas Goncalo Moniz, Salvador, BA, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Dept Internal Med, Lab Alerta,Div Infect Dis, Sao Paulo, SP, BrazilUniv Catolica Cordoba, Fac Ingn, CONICET, Cordoba, ArgentinaUniv Fed Sao Paulo, Escola Paulista Med, Dept Internal Med, Lab Alerta,Div Infect Dis, Sao Paulo, SP, BrazilFAPERJ: E-26/110.315/2014FAPESP: 2010/12891-9CAPES: 23038.010041/2013-13Web of Scienc

ColoLipidGene: Signature of lipid metabolism-related genes to predict prognosis in stage-II colon cancer patients

Lipid metabolism plays an essential role in carcinogenesis due to the requirements of tumoral cells to sustain increased structural, energetic and biosynthetic precursor demands for cell proliferation. We investigated the association between expression of lipid metabolism-related genes and clinical outcome in intermediate-stage colon cancer patients with the aim of identifying a metabolic profile associated with greater malignancy and increased risk of relapse. Expression profile of 70 lipid metabolismrelated genes was determined in 77 patients with stage II colon cancer. Cox regression analyses using c-index methodology was applied to identify a metabolic-related signature associated to prognosis. The metabolic signature was further confirmed in two independent validation sets of 120 patients and additionally, in a group of 264 patients from a public database. The combined analysis of these 4 genes, ABCA1, ACSL1, AGPAT1 and SCD, constitutes a metabolic-signature (ColoLipidGene) able to accurately stratify stage II colon cancer patients with 5-fold higher risk of relapse with strong statistical power in the four independent groups of patients. The identification of a group of 4 genes that predict survival in intermediate-stage colon cancer patients allows delineation of a high-risk group that may benefit from adjuvant therapy, and avoids the toxic and unnecessary chemotherapy in patients classified as low-risk groupThis work was supported by Ministerio de Ciencia e Innovación del Gobierno de España (Plan Nacional I + D + i AGL2013–48943-C2–2-R and IPT-2011–1248-060000), Comunidad de Madrid (P2013/ABI-2728. ALIBIRDCM) and European Union Structural Funds. CIBEREHD is funded by the Instituto de Salud Carlos III. This is a collaborative study between the Molecular Oncology Unit of The Institute of Advanced Studies of Madrid IMDEA Food and the Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD

Teste rápido para o HIV como estratégia de prevenção da transmissão vertical no Brasil

OBJECTIVE: To assess the feasibility of HIV rapid testing for pregnant women at maternity hospital admission and of subsequent interventions to reduce perinatal HIV transmission. METHODS: Study based on a convenience sample of women unaware of their HIV serostatus when they were admitted to delivery in public maternity hospitals in Rio de Janeiro and Porto Alegre, Brazil, between March 2000 and April 2002. Women were counseled and tested using the Determine HIV1/2 Rapid Test. HIV infection was confirmed using the Brazilian algorithm for HIV infection diagnosis. In utero transmission of HIV was determined using HIV-DNA-PCR. There were performed descriptive analyses of sociodemographic data, number of previous pregnancies and abortions, number of prenatal care visits, timing of HIV testing, HIV rapid test result, neonatal and mother-to-child transmission interventions, by city studied. RESULTS: HIV prevalence in women was 6.5% (N=1,439) in Porto Alegre and 1.3% (N=3.778) in Rio de Janeiro. In Porto Alegre most of women were tested during labor (88.7%), while in Rio de Janeiro most were tested in the postpartum (67.5%). One hundred and forty-four infants were born to 143 HIV-infected women. All newborns but one in each city received at least prophylaxis with oral zidovudine. It was possible to completely avoid newborn exposure to breast milk in 96.8% and 51.1% of the cases in Porto Alegre and Rio de Janeiro, respectively. Injectable intravenous zidovudine was administered during labor to 68.8% and 27.7% newborns in Porto Alegre and Rio de Janeiro, respectively. Among those from whom blood samples were collected within 48 hours of birth, in utero transmission of HIV was confirmed in 4 cases in Rio de Janeiro (4/47) and 6 cases in Porto Alegre (6/79). CONCLUSIONS: The strategy proved feasible in maternity hospitals in Rio de Janeiro and Porto Alegre. Efforts must be taken to maximize HIV testing during labor. There is a need of strong social support to provide this population access to health care services after hospital discharge.OBJETIVO: Analizar la viabilidad de evaluación rápida del HIV entre gestantes en la admisión en la maternidad y de intervenciones para reducir la transmisión perinatal del HIV. MÉTODOS: Muestra de conveniencia de mujeres que desconocían su situación serológica para el HIV al ser admitidas para el parto en maternidades públicas de Rio de Janeiro (Sureste) y de Porto alegre (Sur de Brasil), entre marzo de 2000 y abril de 2002. Las mujeres fueron aconsejadas y evaluadas con prueba rápida Determine HIV1/2 en la maternidad. Infección por el HIV fue confirmada por el algoritmo brasilero para el diagnóstico de la infección por el HIV. La transmisión intra- útero fue determinada por el PCR-DNA-HIV. Fueron realizados análisis descriptivos de los datos sociodemográficos, número de gestaciones y de abortos previos, número de visitas de prenatal, momento de la evaluación para el HIV, resultado de la prueba rápida para el HIV, intervenciones recibidas por los recién nacidos y de transmisión vertical del HIV, de acuerdo con cada ciudad. RESULTADOS: La prevalencia de HIV entre las mujeres fue de 6,5% (N=1.439) en Porto Alegre y 1,3% (N=3,778) en Rio de Janeiro. La mayoría fue evaluada durante el trabajo de parto en Porto Alegre y en el postparto, en Rio de Janeiro. Ciento y cuarenta y cuatro niños nacieron de 143 mujeres infectadas por el HIV. Todos los recién nacidos recibieron al menos la profilaxia con zidovudina oral, excepto uno en cada ciudad. Fue posible evitar cualquier exposición a la leche materna en 96,8% y 51,1% de los recién nacidos en Porto Alegre y en Rio de Janeiro, respectivamente. La zidovudina inyectable fue administrada durante el trabajo de parto a 68,8% de los recién nacidos en Porto Alegre y 27,7% en Rio de Janeiro. Entre aquellos con muestras de sangre colectadas hasta 48 horas de nacimiento, la transmisión intra-útero fue confirmada en cuatro casos en Rio de Janeiro (4/47) y en seis casos en Porto Alegre (6/79). CONCLUSIONES: La estrategia se mostró factible en las maternidades de Rio de Janeiro y de Porto Alegre. Esfuerzos deben ser emprendidos para maximizar la evaluación durante el trabajo de parto. Fuerte soporte social precisa ser acoplado a esa estrategia para garantizar el acceso de dicha población al sistema de salud posterior a ser dado de alta de la maternidad.OBJETIVO: Analisar a viabilidade da testagem rápida para o HIV entre gestantes na admissão à maternidade e de intervenções para reduzir a transmissão perinatal do HIV. MÉTODOS: Amostra de conveniência de mulheres que desconheciam sua situação sorológica para o HIV quando admitidas para o parto em maternidades públicas do Rio de Janeiro, RJ, e de Porto Alegre, RS, entre março de 2000 e abril de 2002. As mulheres foram aconselhadas e testadas com teste rápido Determine HIV1/2 na maternidade. Infecção pelo HIV foi confirmada pelo algoritmo brasileiro para o diagnóstico da infecção pelo HIV. A transmissão intra-útero foi determinada pelo PCR-DNA-HIV. Foram realizadas análises descritivas dos dados sociodemográficos, número de gestações e de abortos prévios, número de visitas de pré-natal, momento da testagem para o HIV, resultado do teste rápido para o HIV, intervenções recebidas pelos recém-natos e de transmissão vertical do HIV, de acordo com cada cidade. RESULTADOS: A prevalência de HIV entre as mulheres foi 6,5% (N=1.439) em Porto Alegre e 1,3% (N=3.778) no Rio de Janeiro. A maioria foi testada durante o trabalho de parto em Porto Alegre e no pós-parto, no Rio de Janeiro. Cento e quarenta e quatro crianças nasceram de 143 mulheres infectadas pelo HIV. Todos os recém-natos receberam ao menos a profilaxia com zidovudina oral, exceto um em cada cidade. Foi possível evitar qualquer exposição ao leite materno em 96,8% e 51,1% dos recém-natos em Porto Alegre e no Rio de Janeiro, respectivamente. A zidovudina injetável foi administrada durante o trabalho de parto para 68,8% dos recém-natos em Porto Alegre e 27,7% no Rio de Janeiro. Entre aqueles com amostras de sangue coletadas até 48 horas do nascimento, a transmissão intra-útero foi confirmada em quatro casos no Rio de Janeiro (4/47) e em seis casos em Porto Alegre (6/79). CONCLUSÕES: A estratégia mostrou-se factível nas maternidades do Rio de Janeiro e de Porto Alegre. Esforços devem ser empreendidos para maximizar a testagem durante o trabalho de parto. Forte suporte social precisa ser acoplado a essa estratégia para garantir o acesso dessa população ao sistema de saúde após a alta da maternidade

Soybean Date of Planting and Maturity in Northern Iowa

Inevitably, every year soybean planting gets delayed or needs to be replanted because of weather somewhere in Iowa. Even if soybean planting starts and progresses in a timely manner, there always is the question of what maturity group should be planted. This trial was setup to determine what maturities are well suited for a given geographic location, but also how maturity selection should be adjusted as planting dates get pushed into late spring

Widespread genomic influences on phenotype in Dravet syndrome, a ‘monogenic’ condition

Dravet syndrome is an archetypal rare severe epilepsy, considered “monogenic”, typically caused by loss-of-function SCN1A variants. Despite a recognisable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A-related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as a set and examples of blended phenotypes, including one individual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. Polygenic risk scores for intelligence are lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors

3'UTR Polymorphism in ACSL1 Gene Correlates with Expression Levels and Poor Clinical Outcome in Colon Cancer Patients.

Strong evidence suggests that lipid metabolism (LM) has an essential role in tumor growth to support special energetic and structural requirements of tumor cells. Recently, overexpression of LM-related genes, apolipoproteins related to metabolic syndrome, and ACSL/SCD network involved in fatty acid activation have been proposed as prognostic markers of colon cancer (CC). Furthermore, activation of this latter lipid network has been recently demonstrated to confer invasive and stem cell properties to tumor cells promoting tumor aggressiveness and patient relapse. With the aim of elucidating whether any genetic variation within these genes could influence basal expression levels and consequent susceptibility to relapse, we genotype, in 284 CC patients, 57 polymorphisms located in the 7 genes of these lipid networks previously associated with worse clinical outcome of CC patients (ABCA1, ACSL1, AGPAT1, APOA2, APOC1, APOC2 and SCD), some of them related to CC aggressiveness. After adjusting with clinical confounding factors and multiple comparisons, an association between genotype and disease-free survival (DFS) was shown for rs8086 in 3'-UTR of ACSL1 gene (HR 3.08; 95% CI 1.69-5.63; adjusted p = 0.046). Furthermore, the risk T/T genotype had significantly higher ACSL1 gene expression levels than patients carrying C/T or C/C genotype (means = 5.34; 3.73; 2.37 respectively; p-value (ANOVA) = 0.019), suggesting a functional role of this variant. Thus, we have identified a "risk genotype" of ACSL1 gene that confers constitutive high levels of the enzyme, which is involved in the activation of fatty acids through conversion to acyl-CoA and has been recently related to increased invasiveness of tumor cells. These results suggest that rs8086 of ACSL1 could be a promising prognostic marker in CC patients, reinforcing the relevance of LM in the progression of CC

SEOM clinical guideline for the diagnosis and treatment of gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJA) (2019).

Gastric cancer (GC) is the fifth most common cancer worldwide with a varied geographic distribution and an aggressive behavior. In Spain, it represents the sixth cause of cancer death. In Western countries, the incidence is decreasing slightly, with an increase in gastroesophageal junction adenocarcinoma (GEJA), a different entity that we separate specifically in the guideline. Molecular biology advances have been done recently, but do not yet lead to the choice in treatment approach except in advanced disease with overexpression of HER2. Endoscopic resection in very early stage, perioperative chemotherapy in locally advanced tumors and preliminary immune therapy resulting in advanced disease are the main treatment innovations in the GC/GEJA treatment. We describe the different evidences and recommendations following the statements of the American College of Physicians

Correlation of hypertension and proteinuria with outcome in elderly bevacizumab-treated patients with metastatic colorectal cancer.

BACKGROUND:Studies suggest a relationship between hypertension and outcome in bevacizumab-treated patients with metastatic colorectal cancer (mCRC). We performed a retrospective analysis of two phase II studies (BECA and BECOX) to determine if hypertension and proteinuria predict outcome in elderly patients with mCRC treated with bevacizumab. PATIENTS AND METHODS:Patients ≥ 70 years of age received either capecitabine 1250 mg/m(2) bid days 1-14 + bevacizumab 7.5 mg/kg day 1 every 21 days (BECA study) or capecitabine 1000 mg/m(2) bid days 1-14 with bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m(2) day 1 (BECOX study). The primary objective was to correlate hypertension and proteinuria with overall response rate (ORR), time to progression (TTP) and overall survival (OS). Secondary objectives included identification of risk factors associated with the development of hypertension and proteinuria and determining whether development of hypertension or proteinuria in the first 2 cycles was related to ORR, disease-control rate (DCR), TTP or OS. RESULTS:In total, 127 patients (median age 75.5 years) were included in the study. Hypertension correlated with DCR and OS; proteinuria correlated with ORR and DCR. Proteinuria or hypertension in the first 2 cycles did not correlate with efficacy. Risk factors for hypertension were female gender (odds ratio [OR] 0.241; P = 0.011) and more bevacizumab cycles (OR 1.112; P = 0.002); risk factors for proteinuria were diabetes (OR 3.869; P = 0.006) and more bevacizumab cycles (OR 1.181; P<0.0001). Multivariate analysis identified as having prognostic value: baseline lactate dehydrogenase, haemoglobin, number of metastatic lesions and DCR. CONCLUSION:This analysis of two phase II studies suggests that hypertension is significantly correlated with OS but not with ORR and TTP, whereas proteinuria is correlated with ORR but not with OS and TTP. Both hypertension and proteinuria are associated with the duration of bevacizumab treatment and do not represent an independent prognostic factor