The lincRNA MIRAT binds to IQGAP1 and modulates the MAPK pathway in NRAS mutant melanoma.

Despite major advances in targeted melanoma therapies, drug resistance limits their efficacy. Long noncoding RNAs (lncRNAs) are transcriptome elements that do not encode proteins but are important regulatory molecules. LncRNAs have been implicated in cancer development and response to different therapeutics and are thus potential treatment targets; however, the majority of their functions and molecular interactions remain unexplored. In this study, we identify a novel cytoplasmic intergenic lincRNA (MIRAT), which is upregulated following prolonged MAPK inhibition in NRAS mutant melanoma and modulates MAPK signaling by binding to the MEK scaffold protein IQGAP1. Collectively, our results present MIRAT's direct modulatory effect on the MAPK pathway and highlight the relevance of cytoplasmic lncRNAs as potential targets in drug resistant cancer

A Novel Approach of Determining the Risks for the Development of Hyperinsulinemia in the Children and Adolescent Population Using Radial Basis Function and Support Vector Machine Learning Algorithm

Hyperinsulinemia is a condition with extremely high levels of insulin in the blood. Various factors can lead to hyperinsulinemia in children and adolescents. Puberty is a period of significant change in children and adolescents. They do not have to have explicit symptoms for prediabetes, and certain health indicators may indicate a risk of developing this problem. The scientific study is designed as a cross-sectional study. In total, 674 children and adolescents of school age from 12 to 17 years old participated in the research. They received a recommendation from a pediatrician to do an OGTT (Oral Glucose Tolerance test) with insulinemia at a regular systematic examination. In addition to factor analysis, the study of the influence of individual factors was tested using RBF (Radial Basis Function) and SVM (Support Vector Machine) algorithm. The obtained results indicated statistically significant differences in the values of the monitored variables between the experimental and control groups. The obtained results showed that the number of adolescents at risk is increasing, and, in the presented research, it was 17.4%. Factor analysis and verification of the SVM algorithm changed the percentage of each risk factor. In addition, unlike previous research, three groups of children and adolescents at low, medium, and high risk were identified. The degree of risk can be of great diagnostic value for adopting corrective measures to prevent this problem and developing potential complications, primarily type 2 diabetes mellitus, cardiovascular disease, and other mass non-communicable diseases. The SVM algorithm is expected to determine the most accurate and reliable influence of risk factors. Using factor analysis and verification using the SVM algorithm, they significantly indicate an accurate, precise, and timely identification of children and adolescents at risk of hyperinsulinemia, which is of great importance for improving their health potential, and the health of society as a whole

Recent efforts toward the establishment of the Lonjsko Polje Geomagnetic Observatory

More than ten years ago, the Geophysical Institute initiated the installation of a geomagnetic observatory in Croatia. Over the past decade, extensive surveys and studies have been conducted in order to determine the proper location for the observatory. Finally, in 2012, the observatory was established in Lonjsko Polje. This paper presents the first data recorded in the period 2012.5-2015.0. Also presented are the technical aspects and data processing techniques of this remotely operated observatory. Analysis of data quality and comparison with data from the surrounding INTERMAGNET observatories is discussed in detail. Although remote observatories cannot provide the ideal environment for magnetometers, the obtained results accentuate the potential of the new observatory to provide high-quality data. The establishment of this observatory paves the way for scientific and professional development of geomagnetism in Croatia

S2k guidelines on the management of paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND Paraneoplastic pemphigus (PNP), also called paraneoplastic autoimmune multiorgan syndrome (PAMS), is a rare autoimmune disease with mucocutaneous and multi-organ involvement. PNP/PAMS is typically associated with lymphoproliferative or haematological malignancies, and less frequently with solid malignancies. The mortality rate of PNP/PAMS is elevated owing to the increased risk of severe infections and disease-associated complications, such as bronchiolitis obliterans. OBJECTIVES These guidelines summarize evidence-based and expert-based recommendations (S2k level) for the clinical characterization, diagnosis and management of PNP/PAMS. They have been initiated by the Task Force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology with the contribution of physicians from all relevant disciplines. The degree of consent among all task force members was included. RESULTS Chronic severe mucositis and polymorphic skin lesions are clue clinical characteristics of PNP/PAMS. A complete assessment of the patient with suspected PNP/PAMS, requiring histopathological study and immunopathological investigations, including direct and indirect immunofluorescence, ELISA and, where available, immunoblotting/immunoprecipitation, is recommended to achieve a diagnosis of PNP/PAMS. Detection of anti-envoplakin antibodies and/or circulating antibodies binding to the rat bladder epithelium at indirect immunofluorescence is the most specific tool for the diagnosis of PNP/PAMS in a patient with compatible clinical and anamnestic features. Treatment of PNP/PAMS is highly challenging. Systemic steroids up to 1.5 mg/kg/day are recommended as first-line option. Rituximab is also recommended in patients with PNP/PAMS secondary to lymphoproliferative conditions but might also be considered in cases of PNP/PAMS associated with solid tumours. A multidisciplinary approach involving pneumologists, ophthalmologists and onco-haematologists is recommended for optimal management of the patients. CONCLUSIONS These are the first European guidelines for the diagnosis and management of PNP/PAMS. Diagnostic criteria and therapeutic recommendations will require further validation by prospective studies

A Novel Approach of Determining the Risks for the Development of Hyperinsulinemia in the Children and Adolescent Population Using Radial Basis Function and Support Vector Machine Learning Algorithm

Hyperinsulinemia is a condition with extremely high levels of insulin in the blood. Various factors can lead to hyperinsulinemia in children and adolescents. Puberty is a period of significant change in children and adolescents. They do not have to have explicit symptoms for prediabetes, and certain health indicators may indicate a risk of developing this problem. The scientific study is designed as a cross-sectional study. In total, 674 children and adolescents of school age from 12 to 17 years old participated in the research. They received a recommendation from a pediatrician to do an OGTT (Oral Glucose Tolerance test) with insulinemia at a regular systematic examination. In addition to factor analysis, the study of the influence of individual factors was tested using RBF (Radial Basis Function) and SVM (Support Vector Machine) algorithm. The obtained results indicated statistically significant differences in the values of the monitored variables between the experimental and control groups. The obtained results showed that the number of adolescents at risk is increasing, and, in the presented research, it was 17.4%. Factor analysis and verification of the SVM algorithm changed the percentage of each risk factor. In addition, unlike previous research, three groups of children and adolescents at low, medium, and high risk were identified. The degree of risk can be of great diagnostic value for adopting corrective measures to prevent this problem and developing potential complications, primarily type 2 diabetes mellitus, cardiovascular disease, and other mass non-communicable diseases. The SVM algorithm is expected to determine the most accurate and reliable influence of risk factors. Using factor analysis and verification using the SVM algorithm, they significantly indicate an accurate, precise, and timely identification of children and adolescents at risk of hyperinsulinemia, which is of great importance for improving their health potential, and the health of society as a whole

Acyl protein thioesterase 1 and 2 (APT-1, APT-2) inhibitors palmostatin B, ML348 and ML349 have different effects on NRAS mutant melanoma cells

Oncogenic NRAS mutations are frequent in melanoma and lead to increased downstream signaling and uncontrolled cell proliferation. Since the direct inhibition of NRAS is not possible yet, modulators of NRAS posttranslational modifications have become an area of interest. Specifically, interfering with NRAS posttranslational palmitoylation/depalmitoylation cycle could disturb proper NRAS localization, and therefore decrease cell proliferation and downstream signaling. Here, we investigate the expression and function of NRAS depalmitoylating acyl protein thioesterases 1 and 2 (APT-1, APT-2) in a panel of NRAS mutant melanoma cells. First, we show that all melanoma cell lines examined express APT-1 and APT-2. Next, we show that siRNA mediated APT-1 and APT-2 knock down and that the specific APT-1 and -2 inhibitors ML348 and ML349 have no biologically significant effects in NRAS mutant melanoma cells. Finally, we test the dual APT-1 and APT-2 inhibitor palmostatin B and conclude that palmostatin B has effects on NRAS downstream signaling and cell viability in NRAS mutant melanoma cells, offering an interesting starting point for future studies

Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.

PURPOSE:Genetically-targeted therapies are both promising and costly advances in the field of oncology. Several treatments for metastatic melanoma with a mutation in the BRAF gene have been approved. They extend life but are more expensive than the previous standard of care (dacarbazine). Vemurafenib, the first drug in this class, costs $13,000 per month ($207,000 for a patient with median survival). Patients failing vemurafenib are often given ipilimumab, an immunomodulator, at $150,000 per course. Assessment of cost-effectiveness is a valuable tool to help navigate the transition toward targeted cancer therapy. METHODS:We performed a cost-utility analysis to compare three strategies for patients with BRAF+ metastatic melanoma using a deterministic expected-value decision tree model to calculate the present value of lifetime costs and quality-adjusted life years (QALYs) for each strategy. We performed sensitivity analyses on all variables. RESULTS:In the base case, the incremental cost-effectiveness ratio (ICER) for vemurafenib compared with dacarbazine was$353,993 per QALY gained (0.42 QALYs added, $156,831 added). The ICER for vemurafenib followed by ipilimumab compared with vemurafenib alone was$158,139. In sensitivity analysis, treatment cost had the largest influence on results: the ICER for vemurafenib versus dacarbazine dropped to $100,000 per QALY gained with a treatment cost of$3600 per month. CONCLUSION:The cost per QALY gained for treatment of BRAF+ metastatic melanoma with vemurafenib alone or in combination exceeds widely-cited thresholds for cost-effectiveness. These strategies may become cost-effective with lower drug prices or confirmation of a durable response without continued treatment

Measurements of the Total Charge-Changing Cross Sections for Collisions of Fast Ions with Target Gas Using High Current Experiment

The sum of ionization and charge-exchange cross sections of several gas targets (H2, N2, He, Ne, Kr, Xe, Ar, and water vapor) impacted by 1MeV K+ beam are measured. In a high current ion beam, the self-electric field of the beam is high enough that ions produced from the gas ionization or charge exchange by the ion beam are quickly swept to the sides of accelerator. The flux of the expelled ions is measured by a retarding field analyzer. This allows accurate measuring of the total charge-changing cross sections (ionization plus charge exchange) of the beam interaction with gas. Cross sections for H2, He, and N2 are simulated using classical trajectory Monte Carlo (CTMC) method and compared with the experimental results, showing good agreement