Tumour immune escape via P2X7 receptor signalling.

While P2X7 receptor expression on tumour cells has been characterized as a promotor of cancer growth and metastasis, its expression by the host immune system is central for orchestration of both innate and adaptive immune responses against cancer. The role of P2X7R in anti-tumour immunity is complex and preclinical studies have described opposing roles of the P2X7R in regulating immune responses against tumours. Therefore, few P2X7R modulators have reached clinical testing in cancer patients. Here, we review the prognostic value of P2X7R in cancer, how P2X7R have been targeted to date in tumour models, and we discuss four aspects of how tumours skew immune responses to promote immune escape via the P2X7R; non-pore functional P2X7Rs, mono-ADP-ribosyltransferases, ectonucleotidases, and immunoregulatory cells. Lastly, we discuss alternative approaches to offset tumour immune escape via P2X7R to enhance immunotherapeutic strategies in cancer patients.

The ART of tumor immune escape.

We recently identified the adenosine-5'-diphosphate (ADP)-ribosyltransferase-1 (ART1) as a novel immune checkpoint expressed by cancer cells. ART1 utilizes free nicotinamide adenine dinucleotide (NAD+) in the tumor microenvironment (TME) to mono-ADP-ribosylate (MARylate) the P2X7 receptor (P2X7R) on CD8 T cells, resulting in NAD-induced cell death (NICD) and tumor immune resistance. This process is blocked by therapeutic antibody targeting of ART1.

Trends in Barrett's esophagus diagnosis in Southern Europe: implications for surveillance.

The incidence of Barrett's esophagus (BE) and esophageal adenocarcinoma has increased in Western countries in recent decades. The aim of this study is to describe the changes in incidence and prevalence of BE diagnosis, dysplasia, and adenocarcinoma development in BE patients in a South-European Mediterranean area. Retrospective population-based analyses of endoscopy and pathology reports from 1976 to 2001 was performed. Data from patients with diagnosis of BE and/or esophageal carcinoma were collected. The study period was divided in four quartiles for statistical calculations; parametric and nonparametric tests were used. A 6.9-fold increase was found in the diagnosis of long-segment BE from the first to the fourth quartile, and a 9.3-fold increase in short-segment BE from 1995 to 2000, in contrast to a much smaller increase of 1.9-fold increase in the number of upper gastrointestinal endoscopies. The adjusted incidence of BE diagnosis increased from 0.73 to 9.73 cases/100,000 (first to fourth quartile, respectively) and the adjusted prevalence from 6.51 to 76.04 cases/100,000 (1985-2001). The incidence of dysplasia was 2.13% per year (95% confidence interval: 0.05-11.3%) - 1.78% for low-grade dysplasia and 0.36% for high-grade dysplasia - giving a total incidence of 1 per 47 patient-years. The incidence of adenocarcinoma during follow-up was 0.48% per year (95% confidence interval: 0.006-2.62%), for an incidence of 1 per 210 patient-years. Nineteen patients with BE (14 long-segment BE, 5 short-segment BE) were diagnosed with esophageal adenocarcinoma, with eight being diagnosed during endoscopic surveillance. Only 14 (8%) adenocarcinoma patients diagnosed during the study period had a history of BE. BE diagnosis has dramatically increased over recent decades in our population, unrelated to an increase in endoscopies. Progression to low-grade dysplasia and adenocarcinoma is rare. Surveillance may have a low impact on the survival of adenocarcinoma patients in Southern Europe.

A dopamine D2 receptor gene-related polymorphism is associated with schizophrenia in a Spanish population isolate.

Numerous lines of evidence have highlighted the involvement of the dopamine system in the pathophysiology of schizophrenia. Association studies of dopaminergic genes such as the dopamine D2 receptor gene (DRD2), however, have produced contradictory results. To test the hypothesis that DRD2 polymorphisms are associated with schizophrenia, we investigated two DRD2-related polymorphisms (TaqI A1/A2 or rs1800497 and -141-C Ins/Del or rs1799732) in a Spanish population isolate from northern Spain consisting of 165 controls and 119 patients with schizophrenia. The TaqI A1 allele was less frequent in schizophrenic patients than in controls (P=0.002). A similar association was found for the TaqI A2/A2 genotype (P=0.0003). No association was found for the DRD2 -141-C Ins/Del polymorphism. The strong association between a potentially functional polymorphism, downstream of the DRD2 gene and schizophrenia, suggests that the direct or indirect functional effects of this polymorphism, acting on either the ANKK1 or DRD2 genes, may play a role in the pathophysiology of schizophrenia.

Association of the dysbindin gene with bipolar affective disorder.

OBJECTIVE: In the study of bipolar affective disorder and schizophrenia, there is some evidence suggesting a phenotypic and genetic overlap between the two disorders. A possible link between bipolar affective disorder and schizophrenia remains arguable, however. The authors hypothesized that dysbindin, which is a probable susceptibility gene for schizophrenia, was associated with bipolar affective disorder and tested this hypothesis using a case-control design study. METHOD: Participants included 213 patients with bipolar I disorder and 197 comparison subjects. In each subject, 10 polymorphisms in the dysbindin gene were genotyped and assessed. RESULTS: Two polymorphisms showed individual genotypic association with bipolar I disorder. Multiple marker haplotypes were more strongly associated, with the rarer of the two common haplotypes being overrepresented in the patients with bipolar affective disorder. A similar finding was reported in patients with schizophrenia in a previous study. CONCLUSIONS: Findings suggest that the human dysbindin gene may play a role in the susceptibility to bipolar affective disorder, which underscores a potentially important area of etiological overlap with schizophrenia. The existence of shared genetic risk factors will, in time, lead to changes in the current nosology of major psychoses.

CagA-positive Helicobacter pylori infection is not associated with decreased risk of Barrett's esophagus in a population with high H. pylori infection rate.

BACKGROUND & AIM: The role that H. pylori infection plays in the development of and Barrett's esophagus (BE) is uncertain. We tested the hypothesis that infection with cagA+ Helicobacter pylori strains protects against the development of BE. METHODS: We studied 104 consecutive patients, residents in an area with a high prevalence of H. pylori infection, with BE and 213 sex- and age-matched controls. H. pylori infection and CagA antibody status were determined by western blot serology. RESULTS: H. pylori prevalence was higher in patients with BE than in controls (87.5% vs. 74.6%; OR. 2.3; 95% CI: 1.23-4.59). Increasing age was associated with a higher prevalence of H. pylori (p < 0.05). The prevalence of CagA+ H. pylori serology was similar in patients with BE and controls (64.4% vs. 54.5%; NS). Type I H. pylori infection (CagA+ and VacA+) was similar in patients with BE and controls (44.2% vs. 41.3%; NS). Logistic regression analysis identified alcohol (O.R. 7.09; 95% CI 2.23-22.51), and H. pylori infection (OR: 2.41; 95%CI: 1.20-4.84) but not CagA+ serology as independent factors. CONCLUSION: Neither H. pylori infection nor H. pylori infection by CagA+ strains reduce the risk of BE in a population with high prevalence of H. pylori infection.

Risk of upper gastrointestinal bleeding associated with non-aspirin cardiovascular drugs, analgesics and nonsteroidal anti-inflammatory drugs.

OBJECTIVE: To evaluate the risk of upper gastrointestinal bleeding associated with non-aspirin cardiovascular drug therapy, common analgesics and individual nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: The case group was made up of 1122 consecutive patients admitted with bleeding from a peptic lesion. The 2231 control subjects consisted of 1109 patients hospitalized for other reasons and 1122 outpatients from the same geographical area. The relative risk was calculated by unconditional logistic regression after adjusting for confounding factors. RESULTS: The use of the antiplatelet agent triflusal, and other commonly used cardiovascular drugs, such as beta-receptor blockers and calcium channel blockers, was not associated with increased risk of upper gastrointestinal bleeding. The use of angiotensin-converting enzyme inhibitors reduced the risk of bleeding by 30% (odds ratio 0.7; 95% confidence interval 0.5-0.96). Use of ketorolac (odds ratio 59.4; 95% confidence interval 7.7-454) and piroxicam (odds ratio 19.6; 95% confidence interval 9.3-35.3) carried the highest risk. Use of paracetamol and tramadol was not associated with increased risk of bleeding, but the non-narcotic agent metamizol was associated with a small increase in risk of upper gastrointestinal bleeding (odds ratio 2.6; 95% confidence interval 1.3-5.2). CONCLUSIONS: The use of the antiplatelet agent triflusal and other cardiovascular drugs apart from low-dose aspirin was not associated with gastrointestinal bleeding. The use of either NSAIDs or aspirin increased the risk of gastrointestinal bleeding but, among the analgesics, only metamizol induced a small increase in the risk of gastrointestinal bleeding.

Metástasis linfática subcapsular paraaórtica en tumor de los cordones sexuales con diferenciación anular / Subcapsular paraaortic lymphatic metastasis in a sex cord tumor with anular tubules

Presentamos un caso de tumor ovárico de los cordones sexuales con diferenciación anular no asociado a síndrome de Peutz-Jegher, con micrometástasis en un ganglio paraaórtico. Se diagnosticó como hallazgo ecográfico en una paciente de 15 años que consultó por amenorrea primaria. Inicialmente se realizó una anexectomía unilateral, pero ante la anatomía patológica definitiva se practicó una segunda cirugía de estadificación preservando el útero y el anejo contralateral. Se decide una observación postoperatoria con controles periódicos ecográficos y de inhibina sérica. Tres años después la paciente está asintomática con ciclos menstruales regulares y libre de enfermedad

We present a case of ovarian sex cord tumor with annular tubules not associated with Peutz-Jeghers syndrome and with micrometastasis in a paraaortic node. The tumor was diagnosed as an ultrasonographic finding in a 15-year-old patient who consulted for primary amenorrhea. Unilateral annexectomy was initially performed but, in view of the definitive pathological analysis, a second surgical staging was performed with preservation of the uterus and contralateral adnexa. Postoperative follow-up consisted of periodic ultrasound examination and serum inhibin determinations. After 3 years of follow-up the patient is asymptomatic and disease free, with normal menstrual cycles

Tratamiento erradicador de Helicobacter Pylori. Recomendaciones de la Conferencia Española de Consenso / Helicobacter pylori eradication therapy. The Spanish Consensus Report

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Anticuerpos frente a las citotoxinas CagA y VacA y riesgo de úlcera péptica en pacientes con infección por Helicobacter pylori / Serum CagA and VacA antibodies and risk for peptic ulcer disease in subjects with Helicobacter pylori infection

FUNDAMENTO: La presencia de anticuerpos frente a la citotoxina CagA constituye un marcador serológico de infección por cepas de Helicobacter pylori más virulentas. El objetivo de este trabajo fue evaluar el riesgo para la aparición de úlcera péptica en pacientes con infección por H. pylori en relación con la presencia de anticuerpos frente a las citotoxinas CagA y VacA. PACIENTES Y MÉTODO: Estudio prospectivo de casos y controles en el que se incluyeron 104 pacientes con úlcera péptica con infección activa por H. pylori (test de ureasa y/o histología positiva, o test del aliento positivo), apareados por edad y sexo con 104 individuos, sin historia previa ulcerosa, con infección activa por H. pylori (test del aliento positivo). La presencia de anticuerpos frente a las citotoxinas CagA y VacA se determinó mediante Western blot. El consumo de antiinflamatorios no esteroides (AINE) se estableció mediante encuesta dirigida. Se realizó un análisis multivariable (regresión logística) para estimación de las odds ratio (OR). RESULTADOS: La presencia de anticuerpos anti-CagA fue más frecuente en los pacientes con úlcera péptica (74 por ciento) que en los controles (46,2 por ciento) (OR, 5,7; IC del 95 por ciento, 2,1-15,6), no así la presencia de anticuerpos anti-VacA (46,2 frente a 36,5 por ciento). El consumo de AINE también fue más frecuente en los pacientes (51,9 por ciento) que en los controles (21,2 por ciento) (OR, 6,5; IC del 95 por ciento, 2, 2-19,5). CONCLUSIONES: La presencia de anticuerpos frente a la citotoxina CagA y el consumo de AINE son los dos factores de riesgo más importantes para el desarrollo de úlcera péptica (AU)