Dysregulation of Plasma Growth Factors and Chemokines in Cocaine Use Disorder: Implications for Dual Diagnosis with Schizophrenia and Antisocial Personality Disorder in an Exploratory Study.

INTRODUCTION: Dual diagnosis in individuals with cocaine use disorders (CUDs) presents a mental health challenge marked by an increased susceptibility to disabling morbidities and premature mortality. Despite extensive research on depression and anxiety, other prevalent comorbidities, such as psychotic and personality disorders, have received less attention. This study explores inflammation-related mediators as potential biomarkers for CUD and dual diagnosis with schizophrenia (SCZ) or antisocial personality disorder (APD). METHODS: This exploratory study included 95 participants, comprising 40 healthy subjects and 55 abstinent patients with CUD. Lifetime CUD was diagnosed either as single diagnosis (CUD group, N = 25) or as a dual diagnosis (DD group. N = 30) with SCZ (CUD+SCZ subgroup) or APD (CUD+APD subgroup). Participants were clinically assessed, and the plasma concentrations of growth factors (i.e., G-CSF, BDNF, and VEGF-A) and chemokines (i.e., CCL11/eotaxin-1, CCL2/MCP-1, and CXCL12/SDF-1) were determined and log(10)-transformed for analysis. RESULTS: Growth factors and chemokines were dysregulated by CUD and psychiatric diagnoses. Specifically, patients in the CUD group exhibited significantly lower concentrations of G-CSF and CCL11/eotaxin-1 than the control group. In contrast, the DD group showed significantly higher concentrations of all analytes than both the CUD and control groups. Additionally, no differences in these analytes were observed between the CUD+SCZ and CUD+APD subgroups within the DD group. Regarding cocaine-related variables, significant associations were identified in the CUD group: an inverse correlation between the age at first cocaine use and the concentrations of BDNF and CCL2/MCP-1; and a positive correlation between the duration of the cocaine abstinence and the concentrations of BDNF and CCL11/eotaxin-1. Lastly, a logistic regression model incorporating all these analytes demonstrated high discriminatory power in distinguishing patients with CUD alone from those with dual diagnosis. CONCLUSIONS: Individuals with dual diagnosis of CUD exhibit elevated concentrations of growth factors and chemokines, distinguishing them from those with CUD alone. It is unclear whether the differences in these inflammatory mediators are specific to the presence of SCZ and APD. The study highlights potential biomarkers and associations, providing valuable insights into the intricate interplay of CUD and psychiatric disorders to enhance clinical diagnosis and therapeutics.

Lithium as a Neuroprotective Agent for Bipolar Disorder: An Overview.

Lithium (Li+) is a first option treatment for adult acute episodes of Bipolar Disorder (BD) and for the prophylaxis of new depressed or manic episodes. It is also the preferred choice as maintenance treatment. Numerous studies have shown morphological abnormalities in the brains of BD patients, suggesting that this highly heritable disorder may exhibit progressive and deleterious changes in brain structure. Since treatment with Li+ ameliorates these abnormalities, it has been postulated that Li+ is a neuroprotective agent in the same way atypical antipsychotics are neuroprotective in patients diagnosed with schizophrenia spectrum disorders. Li+'s neuroprotective properties are related to its modulation of nerve growth factors, inflammation, mitochondrial function, oxidative stress, and programmed cell death mechanisms such as autophagy and apoptosis. Notwithstanding, it is not known whether Li+-induced neuroprotection is related to the inhibition of its putative molecular targets in a BD episode: the enzymes inositol-monophosphatase, (IMPase), glycogen-synthase-kinase 3ß (GSK3), and Protein kinase C (PKC). Furthermore, it is uncertain whether these neuroprotective mechanisms are correlated with Li+'s clinical efficacy in maintaining mood stability. It is expected that in a nearby future, precision medicine approaches will improve diagnosis and expand treatment options. This will certainly contribute to ameliorating the medical and economic burden created by this devastating mood disorder.

Lack of cytomegalovirus detection in human glioma.

Gliomas are the most common brain tumors and include a variety of histologic types and grades of malignancy. They arise from glial cells and represent approximately 70% of the primary brain tumors. According to the criteria of the World Health Organization (WHO), the majority of gliomas can be classified into four grades of malignancy (I-IV). Virus infection, especially by DNA viruses and retroviruses, which may cause insertion of viral DNA sequences into the host genome, often triggers the host defense mechanisms. Particularly, the DNA methylation machinery can be activated to cause the methylation of foreign movable viral sequences and, therefore, silence viral gene expression. Several studies have shown the presence of Human Cytomegalovirus (HCMV) in glioblastoma, suggesting that the virus may participate in tumor pathogenesis. But this relationship is controversial because many other studies did not detect HCMV in these tumors. This study aims to detect the presence of HCMV in several samples of human glioma (94 formalin-fixed, paraffin-embedded samples and 28 snap-frozen samples) by different sensitive techniques. We have been unable to detect HCMV DNA and proteins in glioma samples. Therefore, arguments used so far to conclude that HCMV is an oncomodulator virus in gliomas must be, in our view, seriously reconsidered.

Human cytomegalovirus and Epstein-Barr virus infection impact on (18)F-FDG PET/CT SUVmax, CT volumetric and KRAS-based parameters of patients with locally advanced rectal cancer treated with neoadjuvant therapy.

PURPOSE: It has long been debated whether human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) are associated with rectal cancer. The gene products of HCMV and EBV contribute to cell-cycle progression, mutagenesis, angiogenesis and immune evasion. The aim of this prospective study was to analyse the association between infection of a tumour by HCMV and EBV and clinical, histological, metabolic ((18)F-FDG uptake), volumetric (from CT) and molecular (KRAS status) features and long-term outcomes in a homogeneously treated group of patients with locally advanced rectal cancer. METHODS: HCMV and EBV were detected in pretreatment biopsies using polymerase chain reaction (PCR). The Cox proportional hazards regression model was used to explore associations between viral infection and disease-free survival (DFS) and overall survival (OS). RESULTS: We analysed 37 patients with a median follow-up of 74 months (range 5-173 months). Locoregional control, OS and DFS at 5 years were 93%, 74% and 71%, respectively. Patients with HCMV/EBV coinfection had a significantly higher maximum standardized uptake value than patients without viral coinfection (p = 0.02). Significant differences were also observed in staging and percentage relative reduction in tumour volume between patients with and without HCMV infection (p < 0.01) and EBV infection (p < 0.01). KRAS wildtype status was significantly more frequently observed in patients with EBV infection (p <0.01) and HCMV/EBV co-infection (p = 0.04). No significant differences were observed in OS or DFS between patients with and without EBV infection (p = 0.88 and 0.73), HCMV infection (p = 0.84 and 0.79), and EBV/CMV coinfection (p = 0.24 and 0.39). CONCLUSION: This pilot study showed that viral infections were associated with metabolic staging differences, and differences in the evolution of metabolic and volumetric parameters and KRAS mutations. Further findings of specific features will help determine the best candidates for metabolic and volumetric staging and restaging. Further toxicity profile findings will help to determine the best candidates for specific supportive treatment during pelvic chemoradiotherapy in patients with locally advanced rectal cancer.

The Impact of Liquid Biopsy in Advanced Ovarian Cancer Care.

INTRODUCTION: Ovarian cancer is the third most common gynaecological cancer and has a very high mortality rate. The cornerstone of treatment is complete debulking surgery plus chemotherapy. Even with treatment, 80% of patients have a recurrence. Circulating tumour DNA (ctDNA) has been shown to be useful in the control and follow-up of some tumours. It could be an option to define complete cytoreduction and for the early diagnosis of recurrence. OBJECTIVE: We aimed to demonstrate the usefulness of ctDNA and cell-free DNA (cfDNA) as a marker of complete cytoreduction and during follow-up in patients with advanced ovarian cancer. MATERIAL AND METHODS: We selected 22 women diagnosed with advanced high-grade serous ovarian cancer, of which only 4 had complete records. We detected cfDNA by polymerase chain reaction (PCR), presented as ng/mL, and detected ctDNA with droplet digital PCR (ddPCR). We calculated Pearson correlation coefficients to evaluate correlations among cfDNA, ctDNA, and cancer antigen 125 (CA125), a biomarker. RESULTS: The results obtained in the evaluation of cfDNA and ctDNA and their correlation with tumour markers and the radiology of patients with complete follow-up show disease progression during the disease, stable disease, or signs of recurrence. cfDNA and ctDNA correlated significantly with CA125. Following cfDNA and ctDNA over time indicated a recurrence several months earlier than computed tomography and CA125 changes. CONCLUSION: An analysis of cfDNA and ctDNA offers a non-invasive clinical tool for monitoring the primary tumour to establish a complete cytoreduction and to diagnose recurrence early.

Clinical significance of VEGFR-2 and ¹8F-FDG PET/CT SUVmax pretreatment score in predicting the long-term outcome of patients with locally advanced rectal cancer treated with neoadjuvant therapy.

PURPOSE: Vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor-1 (EGFR), and cyclooxygenase-2 (COX-2) stimulate key processes involved in tumor progression and are important targets for cancer drugs. (18)F-FDG maximum standardized uptake value (SUVmax) is a marker of tumor metabolic activity. The purpose of this study was to measure SUVmax combined with VEGFR-2, EGFR and COX-2 proteins in pretreatment tumor biopsies from patients with locally advanced rectal cancer receiving intensive neoadjuvant treatment and to correlate the findings with clinical outcome. METHODS: VEGFR-2, EGFR and COX-2 were measured using the immunoreactive score (IRS). SUVmax (median 8.4) was quantified in tumors with molecular overexpression (IRS ≥3 + SUVmax ≥ 8.4 indicating active tumors; SUVmax <8.4 indicating inactive tumors). The Cox proportional hazards model was used to explore associations between tumor markers, disease-free survival (DFS) and overall survival (OS). RESULTS: The study group comprised 38 patients with a median follow-up of 69.3 months (range 4.5 - 92 months). Multivariate analysis showed that active tumors (overexpressing VEGFR-2, high SUVmax) were associated with worse DFS (HR 4.73, 95 % CI 1.18 - 22.17; p = 0.04) and OS (HR 4.28, 95 % CI 1.04 - 20.12; p = 0.05). CONCLUSION: Active tumors overexpressing VEGFR-2 are associated with a worse overall outcome in patients with rectal cancer treated with induction chemotherapy followed by pelvic chemoradiation and surgery. The optimal diagnostic cut-off level for this novel biomarker association should be investigated. Evaluation in a clinical trial is required to determine whether selected patients could benefit from a VEGFR-targeting drug.

Transcultural psychiatry made simple--asynchronous telepsychiatry as an approach to providing culturally relevant care.

OBJECTIVE: To examine the feasibility and diagnostic reliability of asynchronous telepsychiatry (ATP) consultations in Spanish and ATP consultation with Spanish-to-English translation. SUBJECTS AND METHODS: Twenty-four interviews of Spanish-speaking patients were videorecorded by a bilingual clinician who also collected patient history data and gave the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) to each patient. The ATP data (video of the interview and patient history) were forwarded for psychiatric consultation and a diagnostic assessment by the investigators. The ATP data were then examined separately by two Spanish-speaking psychiatrists, before being translated into English and then re-examined by two English-speaking psychiatrists. Agreement between the expert diagnoses of the investigators and the diagnoses from the Spanish consultations, the Spanish-to-English translated consultations, and the SCID-I results was assessed using kappa statistics. RESULTS: We found acceptable levels of agreement for major diagnostic groupings among the Spanish- and English-speaking psychiatrists. Kappa values for diagnostic agreement between the expert and the translated consultations, the original language consultations, and the SCID-I were at least 0.52 (percentage agreement, 79%) and higher. CONCLUSIONS: ATP consultations in Spanish, and those translated from Spanish to English, are feasible, and broad diagnostic reliability was achieved. The ATP process allows for rapid language translation. This approach could be useful across national boundaries and in numerous ethnic groups. Cross-language ATP may also offer significant benefits over the use of real-time interpreting services and has the potential to improve the quality of care by allowing for the addition of culturally relevant information.

Relationship of DRD5 and MAO-B VNTR polymorphisms with paranoid and antisocial personality disorders in polydrug users.

Although multiple studies have shown the role genetics plays in personality disorders and in addictions, few have studied the genetic aspects of their comorbidity. Here, we carried out a cross-sectional study in a sample comprising 303 Caucasian polydrug-consuming patients. The presence of personality disorders was evaluated using the International Personality Disorder Examination, and genes related to dopamine, serotonin and monoamine oxidase (MAO) were genotyped. A significant relationship was observed between the bp 279 DRD5 variable number of tandem repeat (VNTR) polymorphism and paranoid personality disorder OR 95 % CI = 2.186 1.074 ; 4.449 ; p = 0.006 . The bp 182 OR 95 % CI = 0.407 0.178 ; 0.931 ; p = 0.033 and bp 184 OR 95 % CI = 0.391 0.188 ; 0.813 ; p = 0.012 alleles of the MAOB VNTR were also associated with antisocial personality disorder. Among patients with addictions, paranoid personality disorder should also be considered in addition to the importance of antisocial and borderline personality disorders. The higher frequency of the bp 279 DRD5 VNTR allele found in patients with paranoid personality disorder, as well as the associations between alleles of the MAOB VNTR and antisocial personality disorder, support the monoaminergic bases of these personality disorders, especially when dealing with patients with addictions.

Evidence for classification of c.1852_1853AA>GC in MLH1 as a neutral variant for Lynch syndrome.

BACKGROUND: Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala) variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS. METHODS: The following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co-segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls). Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers. RESULTS: Twenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%), seven were suspected of having hereditary CRC (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of microsatellite instability (2/17, 11.8%) were detected in tumours from p.Lys618Ala carriers, indicating that this variant does not play a role in functional inactivation of MLH1 in CRC patients. CONCLUSIONS: The p.Lys618Ala variant should be considered a neutral variant for LS. These findings have implications for the clinical management of CRC probands and their relatives.

Malignant melanoma arising from a perianal fistula and harbouring a BRAF gene mutation: a case report.

BACKGROUND: Melanoma of the anal region is a very uncommon disease, accounting for only 0.2-0.3% of all melanoma cases. Mutations of the BRAF gene are usually absent in melanomas occurring in this region as well as in other sun-protected regions. The development of a tumour in a longstanding perianal fistula is also extremely rare. More frequent is the case of a tumour presenting as a fistula, that is, the fistula being a consequence of the cancerous process, although we have found only two cases of fistula-generating melanomas reported in the literature. CASE PRESENTATION: Here we report the case of a 38-year-old male who presented with a perianal fistula of four years of evolution. Histopathological examination of the fistulous tract confirmed the presence of malignant melanoma. Due to the small size and the central location of the melanoma inside the fistulous tract, we believe the melanoma reported here developed in the epithelium of the fistula once the latter was already formed. Resected sentinel lymph nodes were negative and the patient, after going through a wide local excision, remains disease-free nine years after diagnosis. DNA obtained from melanoma tissue was analysed by automated direct sequencing and the V600E (T1799A) mutation was detected in exon 15 of the BRAF gene. CONCLUSION: Since fistulae experience persistent inflammation, the fact that this melanoma harbours a BRAF mutation strengthens the view that oxidative stress caused by inflammatory processes plays an important role in the genesis of BRAF gene mutations.

Tumoral presentation of primary central nervous system lymphomatoid granulomatosis.

PURPOSE: Lymphomatoid granulomatosis (LYG) is an angiocentric Epstein-Barr virus (EBV) related B-cell proliferation associated with a reactive T-cell component with an uncertain malignant potential. LYG present at diagnosis as a mass lesion in the central nervous system (CNS) is rare, and only a few cases have been reported. In this article we present four cases of tumoral CNS-LYG and propose some guidelines for its management. METHODS: Clinical, pathological, imaging and laboratory information of four immunocompetent patients, all of them treated surgically, with a final diagnosis of LYG and presenting with an isolated intracranial tumoral mass is reviewed. RESULTS: Two parenchymal lesions were located in the cerebellum and temporal lobe, and the other two involved the cavernous sinus. At surgery they were avascular, hard, lard-like, necrotic and plastic well-defined lesions, with invasion of the leptomeninges and thrombosis of the small leptomeningeal arteries and veins. Intraoperative pathology excluded any tumor. Pathological studies showed a polymorphic and polyclonal infiltration around, in the wall and into the lumen of medium-sized cortical and leptomeningeal vessels causing their obstruction and tissular necrosis. EBV-infected cells were present. CONCLUSIONS: Making a preoperative diagnosis of CNS-LYG appearing initially as a tumoral mass is difficult because of the lack of pathognomonic clinical symptoms or imaging signs. Surgical management with radical resection of the mass is almost always followed by the long-term local control of the lesion, although the disease may have a disseminated, systemic or malignant evolution.

Prepulse Inhibition in Cocaine Addiction and Dual Pathologies.

Cocaine addiction is frequently associated with different psychiatric disorders, especially schizophrenia and antisocial personality disorder. A small number of studies have used prepulse inhibition (PPI) as a discriminating factor between these disorders. This work evaluated PPI and the phenotype of patients with cocaine-related disorder (CRD) who presented a dual diagnosis of schizophrenia or antisocial personality disorder. A total of 74 men aged 18-60 years were recruited for this research. The sample was divided into four groups: CRD (n = 14), CRD and schizophrenia (n = 21), CRD and antisocial personality disorder (n = 16), and a control group (n = 23). We evaluated the PPI and other possible vulnerability factors in these patients by using different assessment scales. PPI was higher in the CRD group at 30 ms (F(3, 64) = 2.972, p = 0.038). Three discriminant functions were obtained which allowed us to use the overall Hare Psychopathy Checklist Revised score, reward sensitivity, and PPI at 30 ms to predict inclusion of these patients in the different groups with a success rate of 79.7% (42.9% for CRD, 76.2% for CRD and schizophrenia, 100% for CRD and antisocial personality disorder, and 91.3% in the control group). Despite the differences we observed in PPI, this factor is of little use for discriminating between the different diagnostic groups and it acts more as a non-specific endophenotype in certain mental disorders, such as in patients with a dual diagnosis.

The role of nicotinic cholinergic neurotransmission in delusional thinking.

Delusions are a difficult-to-treat and intellectually fascinating aspect of many psychiatric illnesses. Although scientific progress on this complex topic has been challenging, some recent advances focus on dysfunction in neural circuits, specifically in those involving dopaminergic and glutamatergic neurotransmission. Here we review the role of cholinergic neurotransmission in delusions, with a focus on nicotinic receptors, which are known to play a part in some illnesses where these symptoms appear, including delirium, schizophrenia spectrum disorders, bipolar disorder, Parkinson, Huntington, and Alzheimer diseases. Beginning with what we know about the emergence of delusions in these illnesses, we advance a hypothesis of cholinergic disturbance in the dorsal striatum where nicotinic receptors are operative. Striosomes are proposed to play a central role in the formation of delusions. This hypothesis is consistent with our current knowledge about the mechanism of action of cholinergic drugs and with our abstract models of basic cognitive mechanisms at the molecular and circuit levels. We conclude by pointing out the need for further research both at the clinical and translational levels.

The Int7G24A variant of transforming growth factor-beta receptor type I is a risk factor for colorectal cancer in the male Spanish population: a case-control study.

BACKGROUND: The Int7G24A variant of transforming growth factor-beta receptor type I (TGFBR1) has been shown to increase the risk for kidney, ovarian, bladder, lung and breast cancers. Its role in colorectal cancer (CRC) has not been established. The aims of this study were to assess the association of TGFBR1*Int7G24A variant with CRC occurrence, patient age, gender, tumour location and stage. METHODS: We performed a case-control study with 504 cases of sporadic CRC; and 504 non-cancerous age, gender and ethnically matched controls. Genotyping analysis was performed using allelic discrimination assay by real time PCR. RESULTS: The Int7G24A variant was associated with increased CRC incidence in an additive model of inheritance (P for trend = 0.005). No significant differences were found between Int7G24A genotypes and tumour location or stage. Interestingly, the association of the Int7G24A variant with CRC risk was significant in men (odds ratio 4.10 with 95% confidence intervals 1.41-11.85 for homozygous individuals; P for trend = 0.00023), but not in women. We also observed an increase in susceptibility to CRC for individuals aged less than 70 years. CONCLUSION: Our data suggest that the Int7G24A variant represents a risk factor for CRC in the male Spanish population.

The TGFBR1*6A allele is not associated with susceptibility to colorectal cancer in a Spanish population: a case-control study.

BACKGROUND: TGF-beta receptor type I is a mediator of growth inhibitory signals. TGFBR1*6A (rs11466445) is a common polymorphic variant of the TGF-beta receptor I gene and has been associated with tumour susceptibility. Nevertheless, the role of this polymorphism as a risk factor for colorectal cancer is controversial. The aim of this study was to assess the association between TGFBR1*6A and colorectal cancer, age, sex, tumour location and tumour stage in a Spanish population. METHODS: The case-control study involved 800 Spanish subjects: 400 sporadic colorectal cancer patients and 400 age-, sex-, and ethnic-matched controls. The odds ratio (OR) and 95% confidence interval (95% CI) for the TGFBR1*6A polymorphism were calculated using unconditional logistic regression adjusted for age and sex. Analysis of somatic mutations at the GCG repeat of TGFBR1 exon 1 and germline allele-specific expression were also conducted to obtain further information on the contribution of the TGFBR1*6A allele to CRC susceptibility. RESULTS: There was no statistically significant association between the TGFBR1*6A allele and CRC (p > 0.05). The OR was 1.147 (95% CI: 0.799-1.647) for carriers of the TGFBR1*6A allele and 0.878 (95% CI: 0.306-2.520) for homozygous TGFBR1*6A individuals compared with the reference. The frequency of the polymorphism was not affected by age, sex or tumour stage. The TGFBR1*6A allele was more prevalent among colon tumour patients than among rectal tumour patients. Tumour somatic mutations were found in only two of 69 cases (2.9%). Both cases involved a GCG deletion that changed genotype 9A/9A in normal DNA to genotype 9A/8A. Interestingly, these two tumours were positive for microsatellite instability, suggesting that these mutations originated because of a deficient DNA mismatch repair system.Allele-specific expression of the 9A allele was detected in seven of the 14 heterozygous 9A/6A tumour cases. This could have been caused by linkage disequilibrium of the TGFBR1*6A allele with mutations that cause allele-specific expression, as was recently suggested. CONCLUSION: Our results suggest that the TGFBR1*6A allele does not confer an increased risk of colorectal cancer in the Spanish population.

Cyborg mini-trainer.

We present the smallest surgical trainer with a total weight of 400 gr, built in aluminum of 25 cm large and 24 cm wide, and 23 cm high. It's a system integrated by a small and open module, a lamp and a microcamera connected to a Head Mounted display. It holds two endoscopic instruments, and items to make knots or sutures and enhance visual-motor coordination. The vision we got is by a small microcamera displayed to a Head Mounted Display HMD. This surgical trainer is the smallest in the worldwide, easy to install, and easy to carry.

Streptococcus gallolyticus infection in colorectal cancer and association with biological and clinical factors.

There is an unambiguous association of Streptococcus gallolyticus infection with colorectal cancer, although there is limited information about epidemiology or interaction between molecular and environmental factors. We performed an original quantitative analysis of S. gallolyticus in unselected colorectal cancer patients (n = 190) and their association with clinical, pathological tumor molecular profiles (microsatellite instability, hypermethylator phenotype and chromosomal instability pathways), and other biological factors in colorectal tumor and normal tissues (cytomegalovirus and Epstein-Barr virus infection). We developed a new quantitative method to assess bacterial load. Analytical validation was reached with a very high sensitivity and specificity. Our results showed a 3.2% prevalence of S. gallolyticus infection in our unselected cohort of colorectal cancer cases (6/190). The average S. gallolyticus copy number was 7,018 (range 44-34,585). No previous reports relating to S. gallolyticus infection have been published for unselected cohorts of patients. Finally, and despite a low prevalence of S. gallolyticus in this study, we were able to define a specific association with tumor tissue (p = 0.03) and with coinfection with Epstein-Barr virus (p = 0.042; OR: 9.49; 95% IC: 1.1-82.9). The prevalence data provided will be very useful in the design of future studies, and will make it possible to estimate the sample size needed to assess precise objectives. In conclusion, our results show a low prevalence of S. gallolyticus infection in unselected colorectal cancer patients and an association of positive S. gallolyticus infection with tumor tissue and Epstein-Barr virus coinfection. Further studies will be needed to definitively assess the prevalence of S. gallolyticus in colorectal cancer and the associated clinicopathological and molecular profiles.

Comportamiento de la mortalidad por cáncer cervicouterino en el municipio de Rafael Freyre: 1997-2014 / Behavior of Mortality from Cervical Cancer in the Municipality of Rafael Freyre: 1997-2014

Introducción: el cáncer cervicouterino persiste como un problema de salud no resuelto a nivel mundial; después del cáncer de mama, es el más frecuente en el sexo femenino y ocupa el séptimo lugar entre todas las neoplasias malignas que afectan a ambos sexos. Objetivo: describir el comportamiento de la mortalidad por cáncer cervicouterino en el municipio de Rafael Freyre entre 1997 y 2014. Método: se realizó un estudio de mortalidad con las 56 fallecidas reportadas por esa causa en el municipio y períodos referidos. Como fuente de datos se utilizó el reporte mensual computarizado que envía el Departamento de Estadísticas provincial de los fallecidos a cada municipio. Resultados: la tasa media anual de mortalidad en el municipio fue de 12,3 x 100 000 mujeres; los grupos de edades más afectados son los de 70-74 y 80 y más, con tasas de 62,5 y 60,0, respectivamente. Las áreas geográficas de mayor riesgo epidemiológico de fallecer las mujeres por esta causa fueron el Área de Salud de Santa Lucía y los consejos populares de "Carlos Noris", Dagame y Santa Lucía, con tasas de mortalidad de 23,5; 21,5 y 19,5, respectivamente. Conclusiones: este problema de salud tiene una tendencia descendente en el municipio, pero la tasa de mortalidad media anual supera la tasa provincial y la nacional.

Introduction: cervical cancer persists as an unresolved health problem worldwide; after breast cancer, it is the most frequent in females and ranks seventh among all malignant neoplasms affecting both sexes. Objective: to describe the behavior of cervical cancer mortality in the municipality of Rafael Freyre among the years 1997-2014. Methods: a mortality study was carried out, as universe was chosen the 56 deceaseds reported by that cause in the municipality at referred periods, as a source of data was used the monthly report of death on-line that sends the provincial department of health in Holguin. Results: the annual half rate of mortality in the Municipality was 12.3 x 100 000 women, the groups of ages more affected were 70-74 years and 80 and but, with rates of 62.5 and 60.0 respectively. The geographical areas of more epidemic risk of dying the women for this cause were, the Area of Health of "Santa Lucía" and popular Council of "Carlos Noris", "Dagame" and "Santa Lucía" with rates of mortality of 23.5, 21.5 and 19.5 respectively. Conclusions: this problem of health has a descending tendency in the municipality, but the rate half annual of mortality overcomes the provincial and national rate.

TGFBR1 intralocus epistatic interaction as a risk factor for colorectal cancer.

In colorectal cancer (CRC), an inherited susceptibility risk affects about 35% of patients, whereas high-penetrance germline mutations account for <6% of cases. A considerable proportion of sporadic tumors could be explained by the coinheritance of multiple low-penetrance variants, some of which are common. We assessed the susceptibility to CRC conferred by genetic variants at the TGFBR1 locus. We analyzed 14 polymorphisms and the allele-specific expression (ASE) of TGFBR1 in 1025 individuals from the Spanish population. A case-control study was undertaken with 504 controls and 521 patients with sporadic CRC. Fourteen polymorphisms located at the TGFBR1 locus were genotyped with the iPLEX Gold (MassARRAY-Sequenom) technology. Descriptive analyses of the polymorphisms and haplotypes and association studies were performed with the SNPator workpackage. No relevant associations were detected between individual polymorphisms or haplotypes and the risk of CRC. The TGFBR1*9A/6A polymorphism was used for the ASE analysis. Heterozygous individuals were analyzed for ASE by fragment analysis using cDNA from normal tissue. The relative level of allelic expression was extrapolated from a standard curve. The cutoff value was calculated with Youden's index. ASE was found in 25.4% of patients and 16.4% of controls. Considering both bimodal and continuous types of distribution, no significant differences between the ASE values of patients and controls were identified. Interestingly, a combined analysis of the polymorphisms and ASE for the association with CRC occurrence revealed that ASE-positive individuals carrying one of the most common haplotypes (H2: 20.7%) showed remarkable susceptibility to CRC (RR: 5.25; 95% CI: 2.547-5.250; p<0.001) with a synergy factor of 3.7. In our study, 54.1% of sporadic CRC cases were attributable to the coinheritance of the H2 haplotype and TGFBR1 ASE. These results support the hypothesis that the allelic architecture of cancer genes, rather than individual polymorphisms, more accurately defines the CRC risk.