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AIMS: Covid-19 caused changes on the delivery of diabetes care. This study aimed to explore perceptions of healthcare providers across Europe concerning 1) the impact of covid-19 on delivery of diabetes care; 2) impact of changes in diabetes care on experienced workload; 3) experiences with video consultation in diabetes care. METHODS: Cross-sectional survey among healthcare providers in the Netherlands, United Kingdom, Turkey, Ukraine and Sweden, with a focus on primary care. RESULTS: The survey was completed by 180 healthcare providers. During the COVID-19 pandemic 57.1% of respondents provided less diabetes care and 72.8% observed a negative impact on people with diabetes. More than half of respondents (61.9%) expressed worries to some extent about getting overloaded by work. Although the vast majority considered their work meaningful (85.6%). Almost half of healthcare providers (49.4%) thought that after the pandemic video-consultation could be blended with face-to-face contact. CONCLUSIONS: Less diabetes care was delivered and a negative impact on people with diabetes was observed by healthcare providers. Despite healthcare providers' feeling overloaded, mental wellbeing seemed unaffected. Video consultations were seen as having potential. Given the remaining covid-19 risks and from the interest of proactive management of people with diabetes, these findings urge for further exploration of incorporating video consultation in diabetes care.
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COVID-19 , Diabetes Mellitus , Humanos , COVID-19/epidemiología , Pandemias , Estudios Transversales , Personal de Salud , Europa (Continente)/epidemiología , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Diabetes Mellitus/terapiaAsunto(s)
Neoplasias Óseas/secundario , Carcinoma Hepatocelular/patología , Clavícula , Neoplasias Hepáticas/patología , Adulto , Biopsia , Neoplasias Óseas/diagnóstico por imagen , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/genética , Humanos , Hígado/cirugía , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/genética , Trasplante de Hígado , Imagen por Resonancia Magnética , Masculino , UltrasonografíaRESUMEN
Large bowel adenocarcinoma is one of the most frequent human neoplasms and despite recent insights into the pathophysiology and molecular basis of this disease, mortality remains high in advanced and metastatic cases. Most guidelines recommend adjuvant chemotherapy for tumours involving lymph nodes, but not for patients with localized stage I or II disease. However, it is well known that approximately 20% of stage II colorectal carcinoma patients eventually recur, mainly with distant or peritoneal involvement and show bad prognosis. It would be important to predict which patients are at increased risk of recurrence to guide potential adjuvant therapy use in this controversial setting. In this sense, only microsatellite stability has been proposed as a predictive tool in some guidelines. The tripartite motif family protein 72 (TRIM72) is a ubiquitin ligase, involved in the cell membrane repair machinery and known to be associated to insulin resistance. Its potential role in colon cancer has recently been proposed. The aim of this study is to determine the potential predictive value of TRIM72 immunohistochemical expression in stage II colon carcinoma. We have retrospectively reviewed a series of 95 patients with stage II colon microsatellite stable carcinomas operated with a curative intent at a single large tertiary hospital in Madrid (Spain) between 2006 and 2012. None of the patients received adjuvant chemotherapy. We reviewed the histopathological slides and constructed a tissue microarray (TMA) of three representative areas to perform immunohistochemical staining for TRIM72. In our series 30 patients (31.7%) recurred after a median follow-up of 17.5 months. Lack of immunohistochemical expression of TRIM72 in the tumor was significantly and independently associated to recurrence. A recent report by Chen et al. has shown that TRIM72 can be measured in plasma for colon carcinoma detection as an alternative to CEA or CA19.9, with lower levels in patients with carcinoma. Our report is the first one to show that lower immunohistochemical expression of TRIM72 predicts recurrence in colon stage II carcinoma. We feel this predictive influence can be related to its crucial role as a central regulator in many signaling pathways (PI3K-AKT, ERK). As an ubiquitin ligase, the lack of TRIM72 could increase the levels of several potential oncogenic molecules and therefore lead to a more aggressive phenotype. It remains to be shown whether chemotherapy could change the clinical behaviour of this bad prognosis group. We propose TRIM72 immunohistochemical analysis as a potential tool to predict recurrence risk in stage II colon carcinoma patients. Our results should be confirmed in larger series, but could open the way to management strategies refinement in this early stage group of patients.
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Adenocarcinoma/patología , Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/patología , Recurrencia Local de Neoplasia/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios RetrospectivosRESUMEN
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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Cetuximab is a standard-of-care treatment for RAS wild-type metastatic colorectal cancer (mCRC) but not for those harbor a KRAS mutation since MAPK pathway is constitutively activated. Nevertheless, cetuximab also exerts its effect by its immunomodulatory activity despite the presence of RAS mutation. The aim of this study was to determine the impact of polymorphism FcγRIIIa V158F and killer immunoglobulin-like receptor (KIR) genes on the outcome of mCRC patients with KRAS mutations treated with cetuximab. This multicenter Phase II clinical trial included 70 mCRC patients with KRAS mutated. We found KIR2DS4 gene was significantly associated with OS (HR 2.27; 95% CI, 1.08-4.77; P = 0.03). In non-functional receptor homozygotes the median OS was 2.6 months longer than in carriers of one copy of full receptor. Multivariate analysis confirmed KIR2DS4 as a favorable prognostic marker for OS (HR 6.71) in mCRC patients with KRAS mutation treated with cetuximab. These data support the potential therapeutic of cetuximab in KRAS mutated mCRC carrying non-functional receptor KIR2DS4 since these patients significantly prolong their OS even after heavily treatment. KIR2DS4 typing could be used as predictive marker for identifying RAS mutated patients that could benefit from combination approaches of anti-EGFR monoclonal antibodies and other immunotherapies to overcome the resistance mediated by mutation in RAS.
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Antineoplásicos Inmunológicos/uso terapéutico , Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Resistencia a Antineoplásicos/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptores de IgG/genética , Receptores KIR/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Femenino , Genes MCC , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Limited data are available regarding the ability of biomarkers to predict complete pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Complete response translates to better patient survival. DEK is a transcription factor involved not only in development and progression of different types of cancer, but is also associated with treatment response. This study aims to analyze the role of DEK in complete pathological response following chemoradiotherapy for locally advanced rectal cancer. METHODS: Pre-treated tumour samples from 74 locally advanced rectal-cancer patients who received chemoradiation therapy prior to total mesorectal excision were recruited for construction of a tissue microarray. DEK immunoreactivity from all samples was quantified by immunohistochemistry. Then, association between positive stained tumour cells and pathologic response to neoadjuvant treatment was measured to determine optimal predictive power. RESULTS: DEK expression was limited to tumour cells located in the rectum. Interestingly, high percentage of tumour cells with DEK positiveness was statistically associated with complete pathological response to neoadjuvant treatment based on radiotherapy and fluoropyrimidine-based chemotherapy and a marked trend toward significance between DEK positiveness and absence of treatment toxicity. Further analysis revealed an association between DEK and the pro-apoptotic factor P38 in the pre-treated rectal cancer biopsies. CONCLUSIONS: These data suggest DEK as a potential biomarker of complete pathological response to treatment in locally advanced rectal cancer.
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Biomarcadores de Tumor/biosíntesis , Proteínas Cromosómicas no Histona/biosíntesis , Proteínas Oncogénicas/biosíntesis , Proteínas de Unión a Poli-ADP-Ribosa/biosíntesis , Neoplasias del Recto/metabolismo , Neoplasias del Recto/terapia , Anciano , Anciano de 80 o más Años , Quimioradioterapia , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Valor Predictivo de las Pruebas , Pronóstico , Neoplasias del Recto/patología , Resultado del TratamientoRESUMEN
Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase expressed during mitosis and overexpressed in multiple human cancers, including leukemia and also many solid tumors. PLK1 knockdown has been shown to block proliferation of leukemic cell lines and the clonogenic potential of tumor cells grown from patients with cancer. PLK1 inhibition is a promising strategy for the treatment of some tumors. We aim to analyze expression of PLK1 in metastatic colorectal carcinoma. Retrospective analysis of colorectal carcinomas with hepatic metastasis during follow-up receiving neoadjuvant chemotherapy (NAC), based on oxaliplatin. Immunohistochemistry for PLK-1 in paraffin-embedded tissue from the primary and also from the metastasis. 50 patients. 32% showed good histopathological response. 43% of the primaries were positive for PLK1, as opposed to 23.5% of the metastasis. Expression of PLK1 was significantly reduced in metastasis compared with the primaries (p = 0.05), what could be due to therapy or to a phenotypic change of the metastatic nodule. Analysis of the prognostic influence of PLK1 expression showed significant association between PLK1 expression in metastasis and lower overall survival (p = 0.000). We have also found a significant association between PLK1 expression and histopathological response (p = 0.02). All the tumors with high expression of PLK1 showed minor response (11/11). This study shows the association between survival and poor histopathological response to therapy and high expression of PLK1 in metastasis. Our results could open a new therapeutic approach through the inhibition of PLK1.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Proteínas de Ciclo Celular/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/secundario , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/metabolismo , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Quinasa Tipo Polo 1RESUMEN
Biliopancreatic cancer is one of the most aggressive solid neoplasms, and incidence is rising worldwide. It is known that ATF6α is one of the transmembrane proteins that acts crucially in endoplasmic reticulum stress response, and knockdown induces apoptosis of pancreatic cells. Apart from this, p-p38 has been previously correlated with better outcome in pancreatic cancer. Interestingly, ATF6α knockdown pancreatic cells showed increased p-p38. The aim of this study was to evaluate the expression of these 2 proteins, p-p38 and ATF6α, and their correlation with the outcome of biliopancreatic adenocarcinoma patients. Samples from patients with biliopancreatic adenocarcinoma that underwent pancreaticoduodenectomy from 2007 to 2013 were used to construct a tissue microarray to evaluate p-p38 and ATF6α proteins by immunohistochemistry. We observed that both markers showed a tendency to impact in the time to recurrence; then a combination of these 2 proteins was analyzed. Combination of ATF6α(high) and p-p38(low) was strongly associated with a higher risk of recurrence (hazard ratio 2.918, Pâ=â0.013). This 2-protein model remained significant after multivariate adjustment.We proposed a 2-protein signature based on ATF6α(high) and p-p38(low) as a potential biomarker of risk of recurrence in resected biliopancreatic adenocarcinoma patients.
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Factor de Transcripción Activador 6/metabolismo , Adenocarcinoma/metabolismo , Neoplasias del Sistema Biliar/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Biliar/diagnóstico , Neoplasias del Sistema Biliar/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidad , Fosforilación , Pronóstico , España/epidemiologíaAsunto(s)
Osteoporosis , Fracturas Osteoporóticas , Absorciometría de Fotón , Algoritmos , Conservadores de la Densidad Ósea/uso terapéutico , Toma de Decisiones Clínicas , Terapia Combinada , Técnicas de Apoyo para la Decisión , Femenino , Fijación de Fractura/métodos , Indicadores de Salud , Fracturas de Cadera/diagnóstico , Fracturas de Cadera/etiología , Fracturas de Cadera/terapia , Humanos , Masculino , Osteoporosis/complicaciones , Osteoporosis/diagnóstico , Osteoporosis/terapia , Fracturas Osteoporóticas/diagnóstico , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/etiología , Fracturas Osteoporóticas/terapia , Medición de Riesgo , Factores de Riesgo , España/epidemiología , Fracturas de la Columna Vertebral/diagnóstico , Fracturas de la Columna Vertebral/etiología , Fracturas de la Columna Vertebral/terapia , Tomografía Computarizada por Rayos X , Vitamina D/uso terapéutico , Vitaminas/uso terapéuticoRESUMEN
BACKGROUND: Protein phosphatase 2A (PP2A) is a tumour suppressor frequently inactivated in human cancer and its tyrosine-307 phosphorylation has been reported as a molecular inhibitory mechanism. METHODS: Expression of phosphorylated PP2A (p-PP2A) was evaluated in 250 metastatic colorectal cancer (CRC) patients. Chi-square, Kaplan-Meier and Cox analyses were used to determine correlations with clinical and molecular parameters and impact on clinical outcomes. RESULTS: High p-PP2A levels were found in 17.2% cases and were associated with ECOG performance status (P=0.001) and presence of synchronous metastasis at diagnosis (P=0.035). This subgroup showed substantially worse overall survival (OS) (median OS, 6.0 vs 26.2 months, P<0.001) and progression-free survival (PFS) (median PFS, 3.8 vs 13.3 months, P<0.001). The prognostic impact of p-PP2A was particularly evident in patients aged <70 years (P<0.001). Multivariate analysis revealed that p-PP2A retained its prognostic impact for OS (hazard ratio 2.7; 95% confidence interval, 1.8-4.1; P<0.001) and PFS (hazard ratio 3.0; 95% confidence interval, 1.8-5.0; P<0.001). CONCLUSIONS: Phosphorylated PP2A is an alteration that determines poor outcome in metastatic CRC and represents a novel potential therapeutic target in this disease, thus enabling to define a subgroup of patients who could benefit from future treatments based on PP2A activators.
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Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/enzimología , Neoplasias Hepáticas/enzimología , Fosfoproteínas Fosfatasas/metabolismo , Anciano , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Masculino , Análisis Multivariante , Fosfoproteínas/metabolismo , Fosforilación , Modelos de Riesgos Proporcionales , Proteína Fosfatasa 2C , Procesamiento Proteico-PostraduccionalRESUMEN
AIM: The relevance of the cytidine diphosphate-choline and Rho GTPases pathways in the pathogenesis of cancer has been previously demonstrated. We investigate by a case-control association study if genetics variants in these pathways are associated with risk of developing lung cancer. METHODS: Thirty-seven tag SNPs were evaluated as risk factor of NSCLC in 897 cases and 904 controls. RESULTS: Six SNPs were nominally associated with lung cancer risk, which were not significant after the Bonferroni correction for multiple comparisons. No association was observed with the remaining 31 analyzed SNPs, neither it was found significant in haplotype frequencies. CONCLUSIONS: Although the implication of the two pathways investigated in our study in carcinogenesis is well established, our null results suggest that common genetic variants in CDP-choline and Rho GTPases-related genes are not risk factors for lung cancer.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Predisposición Genética a la Enfermedad/genética , Neoplasias Pulmonares/genética , Fosfolípidos/metabolismo , Anciano , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Colina Quinasa/genética , Femenino , Haplotipos , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proteínas de Unión al GTP rho/genéticaRESUMEN
Endoplasmic reticulum (ER) is a central organelle in eukaryotic cells that regulates protein synthesis and maturation. Perturbation of ER functions leads to ER stress, which has been previously associated with a broad variety of diseases. ER stress is generally regarded as compensatory, but prolonged ER stress has been involved in apoptosis induced by several cytotoxic agents. Choline kinase α (ChoKα), the first enzyme in the Kennedy pathway, is responsible for the generation of phosphorylcholine (PCho) that ultimately renders phosphatidylcholine. ChoKα overexpression and high PCho levels have been detected in several cancer types. Inhibition of ChoKα has demonstrated antiproliferative and antitumor properties; however, the mechanisms underlying these activities remain poorly understood. Here, we demonstrate that ChoKα inhibitors (ChoKIs), MN58b and RSM932A, induce cell death in cancer cells (T47D, MCF7, MDA-MB231, SW620 and H460), through the prolonged activation of ER stress response. Evidence of ChoKIs-induced ER stress includes enhanced production of glucose-regulated protein, 78 kDa (GRP78), protein disulfide isomerase, IRE1α, CHOP, CCAAT/enhancer-binding protein beta (C/EBPß) and TRB3. Although partial reduction of ChoKα levels by small interfering RNA was not sufficient to increase the production of ER stress proteins, silencing of ChoKα levels also show a decrease in CHOP overproduction induced by ChoKIs, which suggests that ER stress induction is due to a change in ChoKα protein folding after binding to ChoKIs. Silencing of CHOP expression leads to a reduction in C/EBPß, ATF3 and GRP78 protein levels and abrogates apoptosis in tumor cells after treatment with ChoKIs, suggesting that CHOP maintains ER stress responses and triggers the pro-apoptotic signal. Consistent with the differential effect of ChoKIs in cancer and primary cells previously described, ChoKIs only promoted a transient and moderated ER stress response in the non-tumorogenic cells MCF10A. In conclusion, pharmacological inhibition of ChoKα induces cancer cell death through a mechanism that involves the activation of exaggerated and persistent ER stress supported by CHOP overproduction.
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Colina Quinasa/metabolismo , Estrés del Retículo Endoplásmico/fisiología , Factor de Transcripción CHOP/metabolismo , Apoptosis/genética , Apoptosis/fisiología , Línea Celular Tumoral , Supervivencia Celular/genética , Supervivencia Celular/fisiología , Colina Quinasa/genética , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/genética , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Fosforilcolina/metabolismo , Factor de Transcripción CHOP/genéticaRESUMEN
We have analyzed the response of primary cultures derived from tumor specimens of non small cell lung cancer (NSCLC) patients to choline kinase α (ChoKα) inhibitors. ChoKα inhibitors have been demonstrated to increase ceramides levels specifically in tumor cells, and this increase has been suggested as the mechanism that explain its proapoptotic effect in cancer cells. Here, we have investigated the molecular mechanism associated to the intrinsic resistance, and found that other enzyme involved in lipid metabolism, acid ceramidase (ASAH1), is specifically upregulated in resistant tumors. NSCLC cells with acquired resistance to ChoKα inhibitors also display increased levels of ASAH1. Accordingly, ASAH1 inhibition synergistically sensitizes lung cancer cells to the antiproliferative effect of ChoKα inhibitors. Thus, the determination of the levels of ASAH1 predicts sensitivity to targeted therapy based on ChoKα specific inhibition and represents a model for combinatorial treatments of ChoKα inhibitors and ASAH1 inhibitors. Considering that ChoKα inhibitors have been recently approved to enter Phase I clinical trials by the Food and Drug Administration (FDA), these findings are anticipating critical information to improve the clinical outcome of this family of novel anticancer drugs under development.
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Ceramidasa Ácida/antagonistas & inhibidores , Antineoplásicos/farmacología , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Colina Quinasa/antagonistas & inhibidores , Resistencia a Antineoplásicos , Inhibidores Enzimáticos/farmacología , Neoplasias Pulmonares/enzimología , Ceramidasa Ácida/genética , Ceramidasa Ácida/metabolismo , Apoptosis/efectos de los fármacos , Butanos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Colina Quinasa/metabolismo , Relación Dosis-Respuesta a Droga , Endocannabinoides , Etanolaminas/farmacología , Humanos , Concentración 50 Inhibidora , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Terapia Molecular Dirigida , Miristatos/farmacología , Ácidos Oléicos , Propanolaminas/farmacología , Compuestos de Piridinio/farmacología , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
OBJECTIVE: The objective of this analysis was to evaluate the cost-effectiveness of duloxetine when considered as an additional treatment option for UK-based patients suffering from diabetic peripheral neuropathic pain. RESEARCH DESIGN AND METHODS: A decision-analytic model was used to represent the sequential management of patients with diabetic peripheral neuropathic pain. The standard UK treatment strategy was defined as first-line tricyclic antidepressants (amitriptyline), second-line anticonvulsants (gabapentin) and lastly an opioid-related treatment. The cost-effectiveness of duloxetine was evaluated as an additional first, second, third or fourth-line therapy over a 6-month treatment period for a cohort of 1000 patients. Treatment response was modelled based on changes from baseline pain severity using a standard 11-point pain scale (0-10); full response (>or= 50% change), partial response (30-49%) and no response (< 30%). The model was populated with efficacy and discontinuation data using indirect comparisons of treatment efficacy based on relative effects to a common placebo comparator. RESULTS: The second-line use of duloxetine resulted in cost savings of pound 77,071 for every 1000 treated patients, with an additional 29 patients achieving a full pain response when compared to standard UK treatment. Additional quality-adjusted life years (QALYs) were achieved at 1.88 QALYs per 1000 patients. CONCLUSIONS: This UK-based economic model suggests that second-line use of duloxetine is a beneficial and cost-effective treatment strategy for diabetic peripheral neuropathic pain.
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Antidepresivos/economía , Neuropatías Diabéticas/tratamiento farmacológico , Años de Vida Ajustados por Calidad de Vida , Tiofenos/economía , Aminas/uso terapéutico , Amitriptilina/uso terapéutico , Antidepresivos/uso terapéutico , Análisis Costo-Beneficio , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Quimioterapia Combinada , Clorhidrato de Duloxetina , Gabapentina , Humanos , Modelos Econométricos , Paclitaxel/uso terapéutico , Dimensión del Dolor , Estudios Prospectivos , Perfil de Impacto de Enfermedad , Tiofenos/uso terapéutico , Resultado del Tratamiento , Reino Unido , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
The aim of the study is to examine the association between multilocus genotypes across 10 genes encoding proteins in the antioxidant defence system and breast cancer. The 10 genes are SOD1, SOD2, GPX1, GPX4, GSR, CAT, TXN, TXN2, TXNRD1 and TXNRD2. In all, 2271 cases and 2280 controls were used to examine gene-gene interactions between 52 single nucleotide polymorphisms (SNPs) that are hypothesised to tag all common variants in the 10 genes. The statistical analysis is based on three methods: unconditional logistic regression, multifactor dimensionality reduction and hierarchical cluster analysis. We examined all two- and three-way combinations with unconditional logistic regression and multifactor dimensionality reduction, and used a global approach with all SNPs in the hierarchical cluster analysis. Single-locus studies of an association of genetic variants in the antioxidant defence genes and breast cancer have been contradictory and inconclusive. It is the first time, to our knowledge, the association between multilocus genotypes across genes coding for antioxidant defence enzymes and breast cancer is investigated. We found no evidence of an association with breast cancer with our multilocus approach. The search for two-way interactions gave experiment-wise significance levels of P=0.24 (TXN [t2715c] and TXNRD2 [g23524a]) and P=0.58 (GSR [c39396t] and TXNRD2 [a442g]), for the unconditional logistic regression and multifactor dimensionality reduction, respectively. The experiment-wise significance levels for the three-way interactions were P=0.94 (GPX4 [t2572c], TXN [t2715c] and TXNRD2 [g23524a]) and P=0.29 (GSR [c39396t], TXN [t2715c] and TXNRD2 [a442g]) for the unconditional logistic regression and multifactor dimensionality reduction, respectively. In the hierarchical cluster analysis neither the average across four rounds with replacement of missing values at random (P=0.12) nor a fifth round with more balanced proportion of missing values between cases and controls (P=0.17) was significant.
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Neoplasias de la Mama/genética , Estrés Oxidativo/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Carcinoma Ductal de Mama , Carcinoma Lobular/genética , Estudios de Casos y Controles , Epistasis Genética , Femenino , Humanos , Persona de Mediana Edad , Especies Reactivas de Oxígeno/metabolismo , Factores de RiesgoRESUMEN
OBJECTIVE: The presence of painful physical symptoms may confound the diagnosis of major depressive disorder and may worsen patient prognosis. Epidemiological literature was reviewed to investigate the association between depression and painful physical symptoms. METHOD: MEDLINE and EMBASE database searches were conducted. Studies where a definable organic basis for pain was given were excluded. The search was unrestricted by language but limited to European studies and countries. After filters were applied, 70 eligible studies were reviewed. RESULTS: The majority of studies reviewed showed an association between depression and painful physical symptoms. Over 40% of all studies examining the association between pain and depression were carried out in pain clinics in secondary care. Very few studies were conducted in psychiatric settings. CONCLUSION: The findings of this review suggest that painful physical symptoms may be an important part of the depressive syndrome. Although the relationship between depression and painful physical symptoms is not yet fully understood, findings suggest that diagnosis and treatment of depression should involve investigating and treating the full spectrum of symptoms (emotional and physical). Further research in psychiatric and generalist settings is needed to elucidate the relationship between depression and painful physical symptoms as experienced by patients and at the clinical level.
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Trastorno Depresivo Mayor/epidemiología , Trastornos Somatomorfos/epidemiología , Comorbilidad , Europa (Continente)/epidemiología , Humanos , Dimensión del Dolor , Índice de Severidad de la Enfermedad , Trastornos Somatomorfos/diagnósticoRESUMEN
The implications of delta-aminolevulinic acid dehydratase (ALAD) polymorphism for lead kinetics and toxicity have been mainly studied in occupationally exposed adults. Therefore, our purpose was to evaluate the distribution of ALAD genotype and its association with biomarkers of exposure (PbB levels) and effect (Blood ZPP) among children living in a smelter community in Mexico. We recruited 569 children from nine elementary schools close to a smelter site. PbB was determined by electrothermal atomic absorption spectrometry. A polymerase chain reaction (PCR)-based protocol was used for ALAD genotyping. Zinc protoporphyrin (ZPP) in blood was measured by direct fluorometry. Most children (93.15%) were homozygous for ALAD (1-1), 6.67% were heterozygous for ALAD for (1-2), and one child was homozygous for ALAD (2-2). There was an increased proportion of ALAD (1-2/2-2) genotype with respect to PbB levels. The ZPP geometric mean was slightly higher in ALAD (1-1) genotype children (63.48 mu mol ZPP/mol Hb) than in those having the ALAD-2 genotype (58.22 mu mol ZPP/mol Hb; p = 0.051). Linear and quadratic models showed significant relationships between ZPP and PbB. A significant increase in the odds ratio (OR) for the effect of lead exposure on ZPP levels was observed for ALAD (1-1) children having PbB values above 20 mu g/dL, as compared to those having PbB levels below 10 mu g/dL (OR = 2.95, 95% CI = 1.45-5.97; p = 0.003), whereas no significant increases were observed for the ALAD (1-2/2-2) children. In summary, our results suggest that heme biosynthesis was less affected in ALAD (1-2/2-2) lead-exposed children than in those carrying the ALAD (1-1) genotype.
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The effect of mutations at codon 804 in the RET protooncogene is disputed. Some studies have suggested that the V804L mutation causes the low penetrance multiple endocrine neoplasia type 2 syndrome, with late onset and relatively indolent course, whereas others have reported that V804L and V804M have an aggressive potential. In this paper, we report three apparently unrelated medullary thyroid carcinoma cases homozygous for these mutations. To clarify the phenotypic heterogeneity associated with these mutations, we compare the clinical data and age of diagnosis among these three homozygous patients, six other heterozygous cases from the same populations, and other homozygous and heterozygous subjects reported previously. The data are consistent with a model in which codon 804 mutations have low penetrance, the developing of medullary thyroid carcinoma being associated with a second germline or somatic mutation. The activity and (in the case of somatic mutations) timing of these other genetic alterations in the RET gene may explain the wide clinical variability associated with germline mutations at codon 804.