A similarity network approach for the analysis and comparison of protein sequence/structure sets

A set of proteins is a complex system whose elements are interrelated on the concept of sequence- and structure-based similarity. Here, we applied a similarity network-based methodology for the representation and analysis of protein sequences and structures sets using a non-redundant set of 311 proteins and three different information criteria based on sequence-derived features, sequence local alignment and structural alignment. A wide set of measurements, like network degree, clustering coefficient, characteristic path length and vertex centrality were utilized to characterize the networks’ topology. Protein similarity networks were found medium or highly interconnected and the existence of both clusters and random edges classified their fully connected versions as Small World Networks (SWNs). The SWN architecture was able to host the continuous similarity transition among proteins and model the protein information flow during evolution. Recently reported ancestral elements, like the α/β class and certain folds, were remarkably found to act as hubs in the networks. Additionally, the moderate information value of sequence-derived features when used for fold and class assignment was shown on a network basis. The methodology described here can be applied for the analysis of other complex systems which consist of interrelated elements and a certain information flow.     

Overexpression of the oncostatin M receptor in cervical squamous cell carcinoma cells is associated with a pro-angiogenic phenotype and increased cell motility and invasiveness

Oncostatin M receptor (OSMR) shows frequent copy number gain and overexpression in advanced cervical squamous cell carcinoma (SCC). We used cell-based in vitro assays, RNA interference, and integrative gene expression profiling to investigate the functional significance of this observation. CaSki and SW756 were selected as representative cervical SCC cells that overexpressed OSMR, and ME180 and MS751 as cells that did not. The STAT-dependent pro-angiogenic factors VEGF-A and ID1 were rapidly induced by OSM in CaSki/SW756 but not in ME180/MS751. However, rapid induction did occur in MS751 following forced OSMR overexpression, while depleting OSMR in CaSki abrogated VEGF-A expression. Conditioned medium from both CaSki and SW756 stimulated endothelial tube formation in vitro, effects that were inhibited by depleting OSMR in the SCC cells. For both CaSki and SW756, migration in a wound healing assay and invasion through Matrigel were stimulated by OSM and consistently inhibited by OSMR depletion. The phenotype was rescued by transfection with OSMR containing a silent mutation that provided specific siRNA resistance. Overall, there was a positive correlation between OSMR levels and invasiveness. We used gene expression profiling to identify genes induced by OSM in CaSki/SW756 but not in ME180/MS751. The most prominent gene ontology category groups for the differentially expressed genes were cell motility/invasion, angiogenesis, signal transduction, and apoptosis. We also profiled 23 cervical SCC samples, identifying genes that were differentially expressed in cases with OSMR overexpression versus those without. Integration of the datasets identified 15 genes that showed consistent differential expression in association with OSMR levels in vitro and in vivo. We conclude that OSMR overexpression in cervical SCC cells provides increased sensitivity to OSM, which induces pro-malignant changes. OSMR is a potential prognostic and therapeutic target in cervical SCC. The genes that mediate OSM:OSMR effects will be valuable indicators of the effectiveness of antibody blockade in pre-clinical systems.     

Erythrokeratodermia variabilis: report of two cases and a novel missense variant in GJB4 encoding connexin 30.3

Erythrokeratodermia variabilis (EKV) is characterized by migrating red patches resembling a geographical map, and by localized or generalized hyperkeratosis with scaling of the skin. The onset is usually at birth or during infancy, and the disease persists throughout life. EKV is mainly inherited as an autosomal dominant disease, although recessive transmission has occasionally been reported. Mutations associated with EKV have been identified in the connexin (Cx) genes GJB3 (Cx31) and GJB4 (Cx30.3), however, several cases of EKV have been tested negative for mutations in these two Cx genes. Here, we report our findings of the clinical, histological, and molecular examinations performed in two unrelated sporadic cases of EKV. The molecular screening involved bidirectional sequencing of the coding regions of the GJB3 and GJB4 genes and revealed the existence of a novel c.295G>A missense variant in the GJB4 gene found in homozygosity in one case. The substitution was found to result in a p.E99K change of the Cx30.3 protein, an alteration predicted to have a benign rather than a damaging effect on the protein function.     

Knowledge of European orthodontic postgraduate students on biostatistics

The purpose of this study was to explore the level of knowledge in biostatistics of orthodontic postgraduate students. A four-section questionnaire, which included a knowledge test/quiz on biostatistics and epidemiology, was developed. This questionnaire was distributed to postgraduate programme directors of European universities to be delivered to students for completion under mock examination conditions (in-class session). The frequency distributions of demographic characteristics were examined, the percentages of participants who agreed or strongly agreed with each attitudinal statement were calculated, and the percentages of participants who felt fairly to highly confident for each statement were determined. Knowledge scores were calculated by the percentage of correct answers; missing values were counted as incorrect answers. The Student's t-test or one-way analysis of variance, where appropriate, was utilized to determine the participants' characteristics associated with mean knowledge scores. Data were further analysed with multiple linear regression modelling to determine the adjusted/unconfounded effect of possible knowledge score predictors. A two-tailed P-value of 0.05 was considered statistically significant with a 95 percent confidence interval (CI). One hundred and twenty seven from a total of 129 orthodontic students who replied completed the questionnaire. The mean correct answers of the participants were 43.8 percent with a 95 percent CI of 40.2-47.3 percent. This score was not influenced by gender, years elapsed from graduation, other advanced degree, or year of study; the sole parameter, which seemed to influence this score was attendance at a biostatistics/epidemiology course (51.9 versus 39.5 percent score of participants who had previously taken a course versus those who had not, P<0.001). A surprising finding was the inability of the responders to identify the appropriate use of the chi-square test (11.8 percent, 95 percent CI: 6.1-17.5 percent). The knowledge on biostatistics of orthodontic postgraduate students in Europe is only influenced by previous relevant education.     

The effects of age on the incidence of aneuploidy rates in spermatozoa of oligoasthenozoospermic patients and its relationship with ICSI outcome

The development of intracytoplasmic sperm injection (ICSI) for treatment of infertility as a result of severe male factor has improved the chances of achieving pregnancy in many infertile couples. However, concerns have been raised regarding the safety of this technique, because natural sperm selection is bypassed. In the present study, 25 oligoasthenozoospermic patients who were divided into two groups according to age: group A, 20-34 (n = 10) and group B, 35-50 (n = 15), were included. Pooling the data of the three semen parameters that were tested (volume, concentration and progressive motility) no statistically significant difference between the two age groups was found. A total of 50 883 decondensed spermatozoa was analysed using the dual and triple colour fluorescence in situ hybridization to estimate the rates of aneuploidy for chromosomes 13, 18, 21, X and Y in the two age groups. There was a significantly higher incidence of disomy for chromosome 21 compared to the other autosomes (chromosomes 13 and 18) in both age groups. The disomy rate of XY was significantly higher in the younger subject group (0.1%) compared to the older group (0.05%, p < 0.05). Statistically significant differences in the mean number of clinical pregnancies and abortions were not observed between the two age groups. The aneuploidy rates for all the analysed chromosomes did not differ significantly, both between and within the two age groups, and as a result there seems to be no effect of male age on chromosome numbers in the spermatozoa and on the ICSI outcome.     

Portal hypertension caused by acute cytomegalovirus infection with liver involvement in an immunocompetent patient

Primary infection by cytomegalovirus in immunocompetent patients is usually unapparent. We report a case of severe acute cytomegalovirus infection in a young immunocompetent male with pulmonary and hepatic involvement and portal hypertension who recovered without specific antiviral therapy with complete resolution of sonographic signs of portal hypertension after 6 months.     

Simultaneous expression of c-erbB-1, c-erbB-2, c-erbB-3 and c-erbB-4 receptors in non-small-cell lung carcinomas: correlation with clinical outcome

The expression of c-erbB receptors was immunohistochemically examined in paraffin embedded specimens from non-small-cell lung carcinomas. A total of 209 patients were enrolled [squamous-cell carcinomas (n=59), adenocarcinomas (n=130), large-cell carcinomas (n=15) and giant-cell carcinomas (n=5)]. The HercepTest kit scoring guidelines were used for the interpretation of positivity. C-erbB-1 was overexpressed in older patients, in squamous-cell carcinomas and in poorly-differentiated tumours, whereas c-erbB-2 overexpression with adenocarcinomas and poorly-differentiated tumours. C-erbB-4 overexpression correlated with advanced disease stage. The c-erbB-1/4 pair was the most commonly overexpressed and significantly correlated with female gender, while the c-erbB-1/2 pair with older age. Response to chemotherapy was significantly reduced in patients with tumours overexpressing c-erbB-1 receptor as well as the c-erbB-1/2 and c-erbB-3/4 receptor pairs. Patients' overall survival was significantly correlated with the co-expression of c-erbB-1 and c-erbB-4 receptors. These findings clearly suggest that specific receptors overexpression or co-overexpression is correlated with patients' disease control rate and outcome. A better understanding of the overexpression of the heterodimerized partners of c-erbB family receptors may provide a useful predictive indicator of response to molecular targeted therapies with c-erbB inhibitors.