Konrad Stawiski

Diagnostic potential for a serum miRNA neural network for detection of ovarian cancer

Recent studies posit a role for non-coding RNAs in epithelial ovarian cancer (EOC). Combining small RNA sequencing from 179 human serum samples with a neural network analysis produced a miRNA algorithm for diagnosis of EOC (AUC 0.90; 95% CI: 0.81–0.99). The model significantly outperformed CA125 and functioned well regardless of patient age, histology, or stage. Among 454 patients with various diagnoses, the miRNA neural network had 100% specificity for ovarian cancer. After using 325 samples to adapt the neural network to qPCR measurements, the model was validated using 51 independent clinical samples, with a positive predictive value of 91.3% (95% CI: 73.3–97.6%) and negative predictive value of 78.6% (95% CI: 64.2–88.2%). Finally, biologic relevance was tested using in situ hybridization on 30 pre-metastatic lesions, showing intratumoral concentration of relevant miRNAs. These data suggest circulating miRNAs have potential to develop a non-invasive diagnostic test for ovarian cancer.

Maintenance therapy with everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis (the EMINENTS study)

One of the therapeutic options for patients with tuberous sclerosis (TCS) and subependymal giant cell astrocytoma (SEGA) is everolimus treatment once daily, every day, to attain trough concentrations of 5–15 ng/ml (standard treatment). The aim of this study was to evaluate the efficacy and safety of a reduced dose of everolimus (three times a week with a daily dose as in standard treatment—maintenance therapy) in a group of patients who were previously treated with standard dose for at least 12 months.

A prototypical non-malignant epithelial model to study genome dynamics and concurrently monitor micro-RNAs and proteins in situ during oncogene-induced senescence

BackgroundSenescence is a fundamental biological process implicated in various pathologies, including cancer. Regarding carcinogenesis, senescence signifies, at least in its initial phases, an anti-tumor response that needs to be circumvented for cancer to progress. Micro-RNAs, a subclass of regulatory, non-coding RNAs, participate in senescence regulation. At the subcellular level micro-RNAs, similar to proteins, have been shown to traffic between organelles influencing cellular behavior. The differential function of micro-RNAs relative to their subcellular localization and their role in senescence biology raises concurrent in situ analysis of coding and non-coding gene products in senescent cells as a necessity. However, technical challenges have rendered in situ co-detection unfeasible until now.MethodsIn the present report we describe a methodology that bypasses these technical limitations achieving for the first time simultaneous detection of both a micro-RNA and a protein in the biological context of cellular senescence, utilizing the new commercially available SenTraGorTM compound. The method was applied in a prototypical human non-malignant epithelial model of oncogene-induced senescence that we generated for the purposes of the study. For the characterization of this novel system, we applied a wide range of cellular and molecular techniques, as well as high-throughput analysis of the transcriptome and micro-RNAs.ResultsThis experimental setting has three advantages that are presented and discussed: i) it covers a “gap” in the molecular carcinogenesis field, as almost all corresponding in vitro models are fibroblast-based, even though the majority of neoplasms have epithelial origin, ii) it recapitulates the precancerous and cancerous phases of epithelial tumorigenesis within a short time frame under the light of natural selection and iii) it uses as an oncogenic signal, the replication licensing factor CDC6, implicated in both DNA replication and transcription when over-expressed, a characteristic that can be exploited to monitor RNA dynamics.ConclusionsConsequently, we demonstrate that our model is optimal for studying the molecular basis of epithelial carcinogenesis shedding light on the tumor-initiating events. The latter may reveal novel molecular targets with clinical benefit. Besides, since this method can be incorporated in a wide range of low, medium or high-throughput image-based approaches, we expect it to be broadly applicable.

Efficacy and safety of B-cell receptor signaling pathway inhibitors in relapsed/refractory chronic lymphocytic leukemia: a systematic review and meta-analysis of randomized clinical trials

Abstract Ibrutinib and idelalisib, B-cell receptor (BCR) signaling pathway inhibitors, have been recently approved for use against relapsed/refractory chronic lymphocytic leukemia (CLL). To assess the efficacy and safety of BCR pathway inhibitors in relapsed/refractory CLL, we conducted a systematic review and meta-analysis of five randomized controlled trials (1866 patients). Our study demonstrated that BCR pathway inhibitors significantly prolonged progression-free survival (PFS; pooled HR = 0.24; 95% CI: 0.19–0.30) and overall survival (HR = 0.58; 0.46–0.73) compared with control treatment. BCR pathway inhibitors increased the probability of response (RR = 3.54; 95% CI: 1.69–7.41) and decreased the risk of progression (RR = 0.21, 95% CI: 0.13–0.34). However, BCR pathway inhibitors increased the risk of grade 3 and 4 adverse events (AEs; RR = 1.25; 95% CI: 1.08–1.44) and serious AEs (RR = 1.32; 95% CI: 1.17–1.50). AEs causing discontinuation (RR = 1.26; 95% CI: 0.88–1.81) or death (RR = 1.06; 95% CI: 0.72–1.57) were not significantly increased. No statistically significant difference in any aspect of meta-analysis was noted between ibrutinib and idelalisib.

NIRCa: An artificial neural network-based insulin resistance calculator

Direct measurement of insulin sensitivity in children with type 1 diabetes is cumbersome and time consuming.

Optical coherence tomography and magnetic resonance imaging visual pathway evaluation in Wolfram syndrome

The aim of this study was to assess parameters of retinal morphology by using high‐definition optical coherence tomography (OCT) in patients with Wolfram syndrome (WFS) and their relation to optic tract atrophy in magnetic resonance imaging (MRI).

GlyCulator2: an update on a web application for calculation of glycemic variability indices

Continuous glucose monitoring (CGM) was shown to be clinically useful in improving treatment of type 1 and type 2 diabetes [1]. The clinical benefits of CGM are numerous, but in essence, the additional insight into short-term glucose fluctuations may, if properly interpreted by the patient, limit the number of hypoglycemic episodes, reduce average blood glucose concentration and lower HbA1c levels [2]. However, apart from these indices, CGM enables the patients and their doctors to evaluate glycemic variability (GV) with unprecedented detail and make clinical judgments on the characteristics of the CGM changes quantified using multiple methodologies. The debate on the feasibility of using GV indices in clinical decision making process has been ongoing [3] and was hindered by the lack of clear guidelines for the manner of reporting and interpreting GV. Prompted by the publication of the International Consensus On Use of Continuous Glucose Monitoring [4], which specified the recommended method of relaying CGM results, we decided to create and release an update and expansion of our GV indices calculator—GlyCulator2. Methods