Tumor immune escape by the loss of homeostatic chemokine expression

The novel keratinocyte-specific chemokine CCL27 plays a critical role in the organization of skin-associated immune responses by regulating T cell homing under homeostatic and inflammatory conditions. Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPK-signaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas. In vivo, precancerous skin lesions as well as cutaneous carcinomas showed significantly elevated levels of phosphorylated ERK compared with normal skin, suggesting the activation of EGFR-Ras signaling pathways in keratinocyte-derived malignancies. In vitro, exogenous stimulation of the EGFR-Ras signaling pathway through EGF or transfection of the dominant-active form of the Ras oncogene (H-RasV12) suppressed whereas an EGFR tyrosine kinase inhibitor increased CCL27 mRNA and protein production in keratinocytes. In mice, neutralization of CCL27 led to decreased leukocyte recruitment to cutaneous tumor sites and significantly enhanced primary tumor growth. Collectively, our data identify a mechanism of skin tumors to evade host antitumor immune responses.     

Deficient associative learning in drug-naive first-episode schizophrenia: results obtained using a new visual within-subjects learned irrelevance paradigm

One of the key features of schizophrenia is the inability to filter out irrelevant stimuli which consequently leads to stimulus overload. There are different methods which aim at investigating these deficient filter mechanisms; one of these is the learned irrelevance (LIrr) paradigm. LIrr refers to the retardation of associative learning that occurs if the conditioned stimulus (CS) and the unconditioned stimulus (US) are preexposed in an explicitly unpaired manner prior to the establishment of the association between the stimuli. In the present study we used a recently developed computerized within-subject visual LIrr test. We measured 11 drug-naive first-episode schizophrenia patients and compared their performance to that of 17 healthy control subjects. LIrr was observed to be intact in normal individuals but disrupted in drug-naive first-episode schizophrenia patients. After one month elapsed, 5 of the 11 patients and 16 of the 17 control subjects were retested in a follow-up study. By this time, patients had been medicated with antipsychotic drugs for at least 3 weeks. While healthy controls exhibited a robust LIrr effect, patients still failed to show LIrr. Correlations were found between the performance of unmedicated patients and the depression component of the PANSS psychopathology scale.     

A 10-year follow-up of ischemic heart disease risk factors in military pilots

INTRODUCTION: Cardiovascular diseases (CVDs) represent the reason for approximately 10% of all groundings among military pilots. After their first screening examination, which decides their fitness for flight, pilots are required to appear for screening examinations yearly, which makes it possible to monitor the changes in the risk factors of ischemic heart disease (IHD) from their candidate days until their retirement or final grounding. SUBJECTS AND METHODS: During regular fitness screenings, we determined the individual and common occurrence and changes of recorded or measured IHD risk factors on the basis of 10- (baseline), 5-, and 0-year (current) data in the cases of 250 active male military pilots, broken down into 5-year age groups. In addition, by the help of complex risk calculation methods, we calculated the 5- and 10-year risk of coronary artery disease and CVDs, respectively. RESULTS: In the first year of the examinations, the following risk factors appeared: positive family history (25.0%), obesity (40.8%), smoking (31.7%), physical inactivity (23.9%), high blood pressure (14.7%), hypercholesterolemia (53.9%), pathological electrocardiogram deviations (1.3%). By aging, the occurrence of each risk factor remained unchanged or increased and their cumulative occurrence became more frequent, except for those above 45 to 50 yrs, who seldom had four or more risk factors at the same time. The cardiovascular risk calculated by the Futrex program was elevated in 40% of the study population (levels 3 and 4). By aging, the indices received by complex risk calculation methods deteriorated in the age group 25 to 45 years, while they improved in the age group of >45 years. The 5-year risk of CVDs was below 2.5% in half of the study population and it did not exceed 15 to 20% even in the age group with the highest risk. DISCUSSION: Based on reference data, pilots usually represent a healthier population in those countries where coronary artery diseases are leading health problems. In Hungary, many young pilots leave the army due to its currently ongoing transformation, while the elder are less motivated to change careers. It is probably the role of the stricter physical fitness test and screening examinations, and the effect of military propaganda targeting health conservation, that is in the background of the elder pilots' value improvements. It is also an influencing factor that by administering antilipid and antihypertensive medication based on NATO recommendations in the cases of those with increased risk, the probability of the development of IHD decreases and the affected pilots can be kept longer in service.     

A simple method for sampling murine pulmonary and cardiac tissues for analysis of cyclic nucleotide levels

Summary A simple method for the rapid removal and freezing of mouse cardiac and pulmonary tissues is described. Samples thus obtained were judged to be suitable for valid estimation of in vivo levels of cyclic AMP and cyclic GMP based on the following findings: (a) the samples could be obtained and frozen in the very short time period of a few seconds; (b) no indication of adverse effects of the collection procedure was found upon examination of chemical indicators of energy metabolism; (c) the apparent rates of change of cyclic AMP and cyclic GMP levels during the first seconds after tissue isolation could produce small, but acceptable errors; and (d) dose-dependent elevations of pulmonary cAMP levels consistent with known effects in vitro were found after in vivo administration of isoproterenol.Abbreviations cAMP adenosine-3,5-cyclic monophosphate - cGMP guanosine-3,5-cyclic monophosphate     

Genetic polymorphisms altering microRNA activity in psoriasis – a key to solve the puzzle of missing heritability?

Psoriasis is a chronic immune‐mediated skin disease in which the balance in the interplay of immune cells and keratinocytes is disturbed. MicroRNAs (miRNAs) are endogenous small regulatory RNAs that stabilize cellular phenotypes and fine‐tune signal transduction feedback loops through the regulation of gene networks. Through the regulation of their multiple target genes, miRNAs regulate the development of inflammatory cell subsets and have a significant impact on the magnitude of inflammatory responses. Since the discovery of deregulated miRNA expression in psoriasis, we have learned that they can regulate differentiation, proliferation and cytokine response of keratinocytes, activation and survival of T cells and the crosstalk between immunocytes and keratinocytes through the regulation of chemokine production. In recent years, it became apparent that genetic polymorphisms in miRNA genes and/or in miRNA binding sites of target genes can affect miRNA activity and contribute to disease susceptibility. Psoriasis has a strong genetic background; however, the contribution of genetic variants involving miRNAs is largely unexplored in psoriasis. We propose that changes in miRNA‐mediated gene regulation may be a major contributor to the disturbed balance in immune regulation that results in chronic skin inflammation. In this viewpoint essay, we focus on the emerging new aspects of the role of miRNAs in psoriasis and propose that genetic polymorphisms that affect miRNA activity might be important in the pathogenesis of psoriasis.