1,050 research outputs found

    Cancer gene therapy clinical trials: lessons for the future

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    Swendsen-Wang algorithm on the mean-field Potts model

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    We study the qq-state ferromagnetic Potts model on the nn-vertex complete graph known as the mean-field (Curie-Weiss) model. We analyze the Swendsen-Wang algorithm which is a Markov chain that utilizes the random cluster representation for the ferromagnetic Potts model to recolor large sets of vertices in one step and potentially overcomes obstacles that inhibit single-site Glauber dynamics. Long et al. studied the case q=2q=2, the Swendsen-Wang algorithm for the mean-field ferromagnetic Ising model, and showed that the mixing time satisfies: (i) Θ(1)\Theta(1) for ββc,\beta\beta_c, where βc\beta_c is the critical temperature for the ordered/disordered phase transition. In contrast, for q3q\geq 3 there are two critical temperatures 0<βu<βrc0<\beta_u<\beta_{rc} that are relevant. We prove that the mixing time of the Swendsen-Wang algorithm for the ferromagnetic Potts model on the nn-vertex complete graph satisfies: (i) Θ(1)\Theta(1) forβ<βu, \beta<\beta_u, (ii) Θ(n1/3)\Theta(n^{1/3}) for β=βu,\beta=\beta_u, (iii) exp(nΩ(1))\exp(n^{\Omega(1)}) forβu<β<βrc, \beta_u<\beta<\beta_{rc}, and (iv)Θ(logn) \Theta(\log{n}) for ββrc\beta\geq\beta_{rc}. These results complement refined results of Cuff et al. on the mixing time of the Glauber dynamics for the ferromagnetic Potts model

    Translation and Validation of the Greek Version of the Antipsychotics and Sexual Functioning Questionnaire (ASFQ)

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    Introduction Sexual dysfunction in patients with psychoses may be associated with the psychiatric illness itself (negative symptoms, such as apathy, and avolition), comorbid somatic health, psychosocial factors (stigmatization, discrimination), and the use of psychotropic drugs. In Greece, research into the study of antipsychotic-induced sexual dysfunction is not sufficient. Aim This study was conducted to translate and validate the Greek version of the Antipsychotics and Sexual Functioning Questionnaire (ASFQ) in a sample of patients receiving antipsychotic treatment. Methods A “forward-backward translation” method was applied. A pilot study was conducted with 15 outpatients with schizophrenia and bipolar disorder under antipsychotics treatment. Patients also completed the “Subjects’ Response to Antipsychotics (SRA)” questionnaire in order to assess the validity of the ASFQ. The ASFQ and the SRA questionnaire were completed twice within 2 weeks. Main outcome measures Reliability (internal consistency and test-retest) and validity were assessed. Results The Greek translation of ASFQ was reliable, with excellent internal consistency (Cronbach's a = 0.90 for men and 0.95 for women in both measurements). In addition, the Spearman correlation coefficient was 1 (P< .001) in all Likert-type questions in both assessments. Finally, Spearman correlation coefficients between ASFQ and SRA were moderately positive to strongly positive (between 0.25 and 1) in both assessments, demonstrating moderate to high validity. Conclusions The Greek version of the ASFQ has proved to be a reliable and valid clinical instrument, hence it can be used in further studies in the Greek population. Angelaki M, Galanis P, Igoumenou A, et al. Translation and Validation of the Greek Version of the Antipsychotics and Sexual Functioning Questionnaire (ASFQ). J Sex Med 2021;9:100334

    Phage typing or CRISPR typing for epidemiological surveillance of Salmonella Typhimurium?

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    Objective: Salmonella Typhimurium is the most dominant Salmonella serovar around the world. It is associated with foodborne gastroenteritis outbreaks but has recently been associated with invasive illness and deaths. Characterization of S. Typhimurium is therefore very crucial for epidemiological surveillance. Phage typing has been used for decades for subtyping of S. Typhimurium to determine the epidemiological relation among isolates. Recent studies however have suggested that high throughput clustered regular interspaced short palindromic repeats (CRISPR) typing has the potential to replace phage typing. This study aimed to determine the efficacy of highthroughput CRISPR typing over conventional phage typing in epidemiological surveillance and outbreak investigation of S. Typhimurium. Results: In silico analysis of whole genome sequences (WGS) of well-documented phage types of S. Typhimurium reveals the presence of different CRISPR type among strains belong to the same phage type. Furthermore, different phage types of S. Typhimurium share identical CRISPR type. Interestingly, identical spacers were detected among outbreak and non-outbreak associated DT8 strains of S. Typhimurium. Therefore, CRISPR typing is not useful for the epidemiological surveillance and outbreak investigation of S. Typhimurium and phage typing, until it is replaced by WGS, is still the gold standard method for epidemiological surveillance of S. Typhimurium

    MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors

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    BACKGROUND MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated. METHODS Tissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets. RESULTS Widespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a "seedless" binding site within its 3'UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change. CONCLUSIONS Expression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers

    APPLICATION OF 3-D VELOCITY MODELS AND RAY TRACING IN DOUBLE DIFFERENCE EARTHQUAKE LOCATION ALGORITHMS: APPLICATION TO THE MYGDONIA BASIN (NORTHERN GREECE)

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    In the past years there has been a growing demand for precise earthquake locations for seismotectonic and seismic hazard studies. Recently this has become possible because of the development of sophisticated location algorithms, as well as hardware resources. This is expected to lead to a better insight of seismicity in the near future. A well-known technique, which has been recently used for relocating earthquake data sets is the double difference algorithm. In its original implementation it makes use of a one-dimensional ray tracing routine to calculate seismic wave travel times. We have modified the implementation of the algorithm by incorporating a three-dimensional velocity model and ray tracing in order to relocate a set of earthquakes in the area of the Mygdonia Basin (Northern Greece). This area is covered by a permanent regional network and occasionally by temporary local networks. The velocity structure is very well known, as the Mygdonia Basin has been used as an international test site for seismological studies since 1993, which makes it an appropriate location for evaluating earthquake location algorithms, with the quality of the results depending only on the quality of the data and the algorithm itself. The new earthquake locations reveal details of the area's seismotectonic structure, which are blurred, if not misleading, when resolved by standard (routine) location algorithms

    Recapitulation of tumor heterogeneity and molecular signatures in a 3D brain cancer model with decreased sensitivity to histone deacetylase inhibition

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    INTRODUCTION Physiologically relevant pre-clinical ex vivo models recapitulating CNS tumor micro-environmental complexity will aid development of biologically-targeted agents. We present comprehensive characterization of tumor aggregates generated using the 3D Rotary Cell Culture System (RCCS). METHODS CNS cancer cell lines were grown in conventional 2D cultures and the RCCS and comparison with a cohort of 53 pediatric high grade gliomas conducted by genome wide gene expression and microRNA arrays, coupled with immunohistochemistry, ex vivo magnetic resonance spectroscopy and drug sensitivity evaluation using the histone deacetylase inhibitor, Vorinostat. RESULTS Macroscopic RCCS aggregates recapitulated the heterogeneous morphology of brain tumors with a distinct proliferating rim, necrotic core and oxygen tension gradient. Gene expression and microRNA analyses revealed significant differences with 3D expression intermediate to 2D cultures and primary brain tumors. Metabolic profiling revealed differential profiles, with an increase in tumor specific metabolites in 3D. To evaluate the potential of the RCCS as a drug testing tool, we determined the efficacy of Vorinostat against aggregates of U87 and KNS42 glioblastoma cells. Both lines demonstrated markedly reduced sensitivity when assaying in 3D culture conditions compared to classical 2D drug screen approaches. CONCLUSIONS Our comprehensive characterization demonstrates that 3D RCCS culture of high grade brain tumor cells has profound effects on the genetic, epigenetic and metabolic profiles of cultured cells, with these cells residing as an intermediate phenotype between that of 2D cultures and primary tumors. There is a discrepancy between 2D culture and tumor molecular profiles, and RCCS partially re-capitulates tissue specific features, allowing drug testing in a more relevant ex vivo system
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