Role of gene methylation in antitumor immune response: Implication for tumor progression

Cancer immunosurveillance theory has emphasized the role of escape mechanisms in tumor growth. In this respect, a very important factor is the molecular characterization of the mechanisms by which tumor cells evade immune recognition and destruction. Among the many escape mechanisms identified, alterations in classical and non-classical HLA (Human Leucocyte Antigens) class I and class II expression by tumor cells are of particular interest. In addition to the importance of HLA molecules, tumor-associated antigens and accessory/co-stimulatory molecules are also involved in immune recognition. The loss of HLA class I antigen expression and of co-stimulatory molecules can occur at genetic, transcriptional and post-transcriptional levels. Epigenetic defects are involved in at least some mechanisms that preclude mounting a successful host-antitumor response involving the HLA system, tumor-associated antigens, and accessory/co-stimulatory molecules. This review summarizes our current understanding of the role of methylation in the regulation of molecules involved in the tumor immune response.

Measles outbreak in Andalusia, Spain, January to August 2011.

On 7 January 2011, a six year-old child living in a Roma community near Seville, southern Spain, was hospitalised with measles. Contact tracing identified a probable index case with onset of symptoms on 20 December 2011 and several unreported cases among children under the age of 15 years in the same town. The outbreak initially spread in districts in the city of Seville with a high proportion of Roma residents, and later to other cities and towns in Andalusia. While some towns experienced wide spread of the disease with significant clusters of cases, most of the affected locations saw non-clustered cases or very few secondary cases. The outbreak resulted in 1,759 confirmed or probable cases of which 393 (19%) required hospitalisation. Measles virus of genotype D4 was diagnosed in more than half of the cases. Significant differences (p<0.0001) by age group were found between clustered and non-clustered cases. The highest proportion of clustered cases occurred in the age group of 5-14 yearolds, while the highest proportion of non-clustered cases was seen in those older than 29 years. The last confirmed case related to this outbreak was reported on 20 August 2011.

Community cluster of meningococcal disease by Neisseria meningitidis serogroup C in Andalusia, Spain, March to May 2011.

Between March and May of 2011, a cluster of three fatal cases of meningococcal sepsis occurred in Andalusia, Spain, in a municipality with a population of around 20,000 inhabitants. The cases were in their mid-teens to early thirties and were notified to the epidemiological surveillance system of Andalusia (Sistema de Vigilancia Epidemiológica de Andalucía, SVEA) during a 68-day period from March through May 2011. All three were infected with the same strain of Neisseria meningitidis serogroup C genosubtype VR1:5-1;VR2:10-8. None of the cases had been previously vaccinated against N. meningitidis serogroup C. Antibiotic post-exposure chemoprophylaxis was administered to close contacts of every diagnosed case. Once the cluster was confirmed, the local population was informed through the media about the control measures taken by the health authorities. The vaccination history against N. meningitidis serogroup C of the population under 25 years-old in the municipality was checked. Vaccination was offered to unimmunised individuals younger than 25 years of age and an additional dose of vaccine was offered to those who had been vaccinated between 2000 and 2006 with a vaccination schedule of three doses before the first year of age. No further cases occurred since the beginning of these actions.

Early estimates of the effectiveness of the 2011/12 influenza vaccine in the population targeted for vaccination in Spain, 25 December 2011 to 19 February 2012.

We present early estimates of influenza vaccine effectiveness (VE) in the population targeted for vaccination, during 25 December 2011 to 19 February 2012. The adjusted VE was 55% (95% CI: 3 to 79) against any type of influenza virus and 54% (95% CI: 1 to 79) against influenza A(H3N2) virus. This suggests a moderate protective effect of the vaccine in the targeted population in a late influenza epidemic with limited match between vaccine and circulating strains.

Rabid puppy-dog imported into the Netherlands from Morocco via Spain, February 2012.

To the editor: We read with interest the article by van Rijckevorsel et al. on a rabid puppy-dog imported into the Netherlands from Morocco via Spain, recently published in Eurosurveillance [1]. We would like to complete the information on this event with actions taken by the Spanish health authorities and lessons learnt.

Análisis de la Morfología del Raquis Torácico y Lumbar en Mujeres Trabajadoras de una Cooperativa Hortofrutícola

The aim of this study was to analyze the sagittal spinal morphology of thoracic and lumbar spine in standing and sitting in women workers from a cooperative in the production, handling and marketing business of vegetable and fruit products. A total of 50 women (mean age: 43.62±8.43 years old) were evaluated. The Spinal Mouse system was used to mesasure the sagittal thoracic and lumbar curvatures in standing and relaxed sitting. The values for thoracic and lumbar curvatures were 32.74±8.76 and -21.66±19.12 in standing and 36.32±10.55 and -1.08±18.14 in sitting. A high frequency (86.0% and 68.3%) of normal thoracic kyphosis and lumbar lordosis were found in standing posture. While sitting the 74.0% and 20.0% presented thoracic hyperkyphosis and lumbar kyphosis. In conclusion, a high percentaje of women workers presented normality values in standing posture, although a high percentage of women were found with thoracic hyperkyphosis and lumbar flexed while sitting relaxed. It is recommended that these women carry out a program to improve their actitudinal postures in their work place.

Análisis de las principales variables determinantes de la evolución de la mortalidad por demencias en Andalucía.

BACKGROUND The dementias are a cause of mortality have increased over the last years. Therefore is important to analyze the variables more related to its development in Andalusia between 1999 and 2010. METHODS With the deaths of 60 and over by dementia from Andalusia Statistical Institute and the populations from corresponding years, are estimated crude mortality rates, standardized and age-specific; by joinpoint regression was calculated percentages annual change; and also, with the population estimates by marital status and deaths was calculated crude rates and standardized for age, sex and marital status. RESULTS The standardized mortality rates increased from 124.8 to 161.0 deaths per 100,000 in women and 110.3 to 147.7 in men, the annual increase was 4.2% and 3.8% in women and men. The women died more than men with a standardized rate ratio between 1.08 and 1.29. Age was the variable that determined mortality. CONCLUSIONS Mortality from dementia in Andalusia has increased over the past 12 years and will continue to increase with the consequent social and health impacts posed by these diseases, configured as a major health problem.

Influence of IL28B polymorphisms on response to a lower-than-standard dose peg-IFN-α 2a for genotype 3 chronic hepatitis C in HIV-coinfected patients.

BACKGROUND Data on which to base definitive recommendations on the doses and duration of therapy for genotype 3 HCV/HIV-coinfected patients are scarce. We evaluated the efficacy of a lower peginterferon-α 2a dose and a shorter duration of therapy than the current standard of care in genotype 3 HCV/HIV-coinfected patients. METHODS AND FINDINGS Pilot, open-label, single arm clinical trial which involved 58 Caucasian HCV/HIV-coinfected patients who received weekly 135 µg peginterferon-α 2a plus ribavirin 400 mg twice daily during 20 weeks after attaining undetectable viremia. The relationships between baseline patient-related variables, including IL28B genotype, plasma HCV-RNA, ribavirin dose/kg, peginterferon-α 2a and ribavirin levels with virological responses were analyzed. Only 4 patients showed lack of response and 5 patients dropped out due to adverse events related to the study medication. Overall, sustained virologic response (SVR) rates were 58.3% by intention-to-treat and 71.4% by per protocol analysis, respectively. Among patients with rapid virologic response (RVR), SVR and relapses rates were 92.6% and 7.4%, respectively. No relationships were observed between viral responses and ribavirin dose/kg, peginterferon-α 2a concentrations, ribavirin levels or rs129679860 genotype. CONCLUSIONS Weekly 135 µg pegIFN-α 2a could be as effective as the standard 180 µg dose, with a very low incidence of severe adverse events. A 24-week treatment duration appears to be appropriate in patients achieving RVR, but extending treatment up to just 20 weeks beyond negativization of viremia is associated with a high relapse rate in those patients not achieving RVR. There was no influence of IL28B genotype on the virological responses.

Comunicación paciente-médico y toma de decisiones en salud en Andalucía. Expectativas de pacientes crónicos del Sistema Sanitario Público Andaluz

The purpose of the study was to know about the expectations had by chronic patients within th e Public Healthcare System in Andalusi a, concerning commu nication and making deci sions with the med ical professionals who take care of them duri ng the entire treatment process. A qualitative study was carried out in Andalusia, based on 19 i n-depth interviews and 17 focus groups with 15 4 chronic patients and their relatives, suffering from seven different types of illness, of which the content was later analyzed based on the type of disease (pathologies), and the level of care (Primary, Sp eci aliz ed or Em ergen cy Ser vices). The study shows that patients i ncl uded in all healthcare processes want information about their illness. In Primary Care, they value continued attention, closeness and trust as well as being referred to a proper specialist. In Specialized Care, they expect to receive trustworthy information, proper tests and a correct diagnosis, friendly treatment and to be listened to. In the Emergency Room, lack of tim e and overcrowding d i sru pt proper communic ation. The type of chronic illne ss i nfluenc es patients’ expectations in terms of communication and decisionmaking. Communic ation between patients and medical personnel and the decision-making process related to chronic illness are crucial for the improvement of the qualit y o f healthcare. The type of chr onic disease marks diffe rent expectation s about the communication and decision-making. The communication and the decision making in the chronic assistance is a priority to improve the quality of the assistance

Sources of pre-analytical variations in yield of DNA extracted from blood samples: analysis of 50,000 DNA samples in EPIC.

The European Prospective Investigation into Cancer and nutrition (EPIC) is a long-term, multi-centric prospective study in Europe investigating the relationships between cancer and nutrition. This study has served as a basis for a number of Genome-Wide Association Studies (GWAS) and other types of genetic analyses. Over a period of 5 years, 52,256 EPIC DNA samples have been extracted using an automated DNA extraction platform. Here we have evaluated the pre-analytical factors affecting DNA yield, including anthropometric, epidemiological and technical factors such as center of subject recruitment, age, gender, body-mass index, disease case or control status, tobacco consumption, number of aliquots of buffy coat used for DNA extraction, extraction machine or procedure, DNA quantification method, degree of haemolysis and variations in the timing of sample processing. We show that the largest significant variations in DNA yield were observed with degree of haemolysis and with center of subject recruitment. Age, gender, body-mass index, cancer case or control status and tobacco consumption also significantly impacted DNA yield. Feedback from laboratories which have analyzed DNA with different SNP genotyping technologies demonstrate that the vast majority of samples (approximately 88%) performed adequately in different types of assays. To our knowledge this study is the largest to date to evaluate the sources of pre-analytical variations in DNA extracted from peripheral leucocytes. The results provide a strong evidence-based rationale for standardized recommendations on blood collection and processing protocols for large-scale genetic studies.

Determinants of non- response to a second assessment of lifestyle factors and body weight in the EPIC-PANACEA study.

BACKGROUND This paper discusses whether baseline demographic, socio-economic, health variables, length of follow-up and method of contacting the participants predict non-response to the invitation for a second assessment of lifestyle factors and body weight in the European multi-center EPIC-PANACEA study. METHODS Over 500.000 participants from several centers in ten European countries recruited between 1992 and 2000 were contacted 2-11 years later to update data on lifestyle and body weight. Length of follow-up as well as the method of approaching differed between the collaborating study centers. Non-responders were compared with responders using multivariate logistic regression analyses. RESULTS Overall response for the second assessment was high (81.6%). Compared to postal surveys, centers where the participants completed the questionnaire by phone attained a higher response. Response was also high in centers with a short follow-up period. Non-response was higher in participants who were male (odds ratio 1.09 (confidence interval 1.07; 1.11), aged under 40 years (1.96 (1.90; 2.02), living alone (1.40 (1.37; 1.43), less educated (1.35 (1.12; 1.19), of poorer health (1.33 (1.27; 1.39), reporting an unhealthy lifestyle and who had either a low (<18.5 kg/m2, 1.16 (1.09; 1.23)) or a high BMI (>25, 1.08 (1.06; 1.10); especially ≥30 kg/m2, 1.26 (1.23; 1.29)). CONCLUSIONS Cohort studies may enhance cohort maintenance by paying particular attention to the subgroups that are most unlikely to respond and by an active recruitment strategy using telephone interviews.

Cancer genes hypermethylated in human embryonic stem cells.

Developmental genes are silenced in embryonic stem cells by a bivalent histone-based chromatin mark. It has been proposed that this mark also confers a predisposition to aberrant DNA promoter hypermethylation of tumor suppressor genes (TSGs) in cancer. We report here that silencing of a significant proportion of these TSGs in human embryonic and adult stem cells is associated with promoter DNA hypermethylation. Our results indicate a role for DNA methylation in the control of gene expression in human stem cells and suggest that, for genes repressed by promoter hypermethylation in stem cells in vivo, the aberrant process in cancer could be understood as a defect in establishing an unmethylated promoter during differentiation, rather than as an anomalous process of de novo hypermethylation.

A combined approach for the assessment of cell viability and cell functionality of human fibrochondrocytes for use in tissue engineering.

Temporo-mandibular joint disc disorders are highly prevalent in adult populations. Autologous chondrocyte implantation is a well-established method for the treatment of several chondral defects. However, very few studies have been carried out using human fibrous chondrocytes from the temporo-mandibular joint (TMJ). One of the main drawbacks associated to chondrocyte cell culture is the possibility that chondrocyte cells kept in culture tend to de-differentiate and to lose cell viability under in in-vitro conditions. In this work, we have isolated human temporo-mandibular joint fibrochondrocytes (TMJF) from human disc and we have used a highly-sensitive technique to determine cell viability, cell proliferation and gene expression of nine consecutive cell passages to determine the most appropriate cell passage for use in tissue engineering and future clinical use. Our results revealed that the most potentially viable and functional cell passages were P5-P6, in which an adequate equilibrium between cell viability and the capability to synthesize all major extracellular matrix components exists. The combined action of pro-apoptotic (TRAF5, PHLDA1) and anti-apoptotic genes (SON, HTT, FAIM2) may explain the differential cell viability levels that we found in this study. These results suggest that TMJF should be used at P5-P6 for cell therapy protocols.

Lymphocytic choriomeningitis virus-associated meningitis, southern Spain.

Lymphocytic choriomeningitis virus (LCMV) was detected in 2 patients with acute meningitis in southern Spain within a 3-year period. Although the prevalence of LCMV infection was low (2 [1.3%] of 159 meningitis patients), it represents 2.9% of all pathogens detected. LCMV is a noteworthy agent of neurologic illness in immunocompetent persons.

Effectiveness of the bevacizumab-irinotecan regimen in the treatment of recurrent glioblastoma multiforme: Comparison with other second-line treatments without this regimen.

A retrospective cohort study was conducted to analyse the effectiveness of bevacizumab and irinotecan (BVZ/CPT-11) as a second-line treatment in patients with primary glioblastoma multiforme (GBM) in comparison with a control group that were not administered BVZ/CPT-11 at the first recurrence. The difference in overall survival (OS) between the two groups was used as a predictor of effectiveness. OS was calculated according to prognostic factors and gender. A total of 28 and 32 patients were enrolled in the BVZ/CPT-11 cohort and control group, respectively. The median OS was 17.94 months (95% CI, 14.91-20.96) in the BVZ/CPT-11 treatment cohort and 10.97 months (95% CI, 7.65-14.30) in the control cohort. The results obtained on the effectiveness of BVZ/CPT-11 treatment in patients with primary GBM are consistent with data from previous studies. No significant differences were identified in OS based on prognostic factors; therefore, the latter cannot be used to select patients who would incur the greatest benefits from BVZ/CPT-11 treatment.