Reversing Melanoma Cross-Resistance to BRAF and MEK Inhibitors by Co-Targeting the AKT/mTOR Pathway

The sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAF(V600) mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression. Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors. However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway.The sensitivity to vemurafenib or the MEK inhibitor AZD6244 was tested in sensitive and resistant human melanoma cell lines exploring differences in activation-associated phosphorylation levels of major signaling molecules, leading to the testing of co-inhibition of the AKT/mTOR pathway genetically and pharmacologically. There was a high degree of cross-resistance to vemurafenib and AZD6244, except in two vemurafenib-resistant cell lines that acquired a secondary mutation in NRAS. In other cell lines, acquired resistance to both drugs was associated with persistence or increase in activity of AKT pathway. siRNA-mediated gene silencing and combination therapy with an AKT inhibitor or rapamycin partially or completely reversed the resistance.Primary and acquired resistance to vemurafenib in these in vitro models results in frequent cross resistance to MEK inhibitors, except when the resistance is the result of a secondary NRAS mutation. Resistance to BRAF or MEK inhibitors is associated with the induction or persistence of activity within the AKT pathway in the presence of these drugs. This resistance can be potentially reversed by the combination of a RAF or MEK inhibitor with an AKT or mTOR inhibitor. These combinations should be available for clinical testing in patients progressing on BRAF inhibitors

Dental caries in primary and permanent teeth in children's worldwide, 1995 to 2019: a systematic review and meta-analysis

Background: Early childhood caries (ECC) is a type of dental caries in the teeth of infants and children that is represented as one of the most prevalent dental problems in this period. Various studies have reported different types of prevalence of dental caries in primary and permanent teeth in children worldwide. However, there has been no comprehensive study to summarize the results of these studies in general, so this study aimed to determine the prevalence of dental caries in primary and permanent teeth in children in different continents of the world during a systematic review and meta-analysis. Methods: In this review study, articles were extracted by searching in the national and international databases of SID, MagIran, IranMedex, IranDoc, Cochrane, Embase, ScienceDirect, Scopus, PubMed, and Web of Science (ISI) between 1995 and December 2019. Random effects model was used for analysis and heterogeneity of studies was evaluated by using the I2 index. Data were analyzed by using the Comprehensive Meta-Analysis (Version 2) software. Findings: In this study, a total of 164 articles (81 articles on the prevalence of dental caries in primary teeth and 83 articles on the prevalence of dental caries in permanent teeth) were entered the meta-analysis. The prevalence of dental caries in primary teeth in children in the world with a sample size of 80,405 was 46.2% (95% CI: 41.6–50.8%), and the prevalence of dental caries in permanent teeth in children in the world with a sample size of 1,454,871 was 53.8% (95% CI: 50–57.5%). Regarding the heterogeneity on the basis of meta-regression analysis, there was a significant difference in the prevalence of dental caries in primary and permanent teeth in children in different continents of the world. With increasing the sample size and the year of study, dental caries in primary teeth increased and in permanent teeth decreased. Conclusion: The results of this study showed that the prevalence of primary and permanent dental caries in children in the world was found to be high. Therefore, appropriate strategies should be implemented to improve the aforementioned situation and to troubleshoot and monitor at all levels by providing feedback to hospitals

Cervical Schwannoma

Schwannomas are solitary, slow growing benign tumors arising from the Schwann cells that form the myelin sheath around the peripheral nerves. Head and neck is the commonest site of these tumors in the body. We present a case of schwannoma in a 35 years old man who had a painless slowly growing tumor in the right side of his neck. Key Words: Schwannoma, FNAC, parapharyngeal space.

Selectivity among Anti-� Factors by Mycobacterium tuberculosis ClpX Influences Intracellular Levels of Extracytoplasmic Function � Factors

Extracytoplasmic function � factors that are stress inducible are often sequestered in an inactive complex with a membrane-associated anti-� factor. Mycobacterium tuberculosis membrane-associated anti-� factors have a small, stable RNA gene A (ssrA)-like degron for targeted proteolysis. Interaction between the unfoldase, ClpX, and a substrate with an accessible degron initiates energy-dependent proteolysis. Four anti-� factors with a mutation in the degron provided a set of natural substrates to evaluate the influence of the degron on degradation strength in ClpX-substrate processivity. We note that a point mutation in the degron (X-Ala-Ala) leads to an order-of-magnitude difference in the dwell time of the substrate on ClpX. Differences in ClpX/anti-� interactions were correlated with changes in unfoldase activities. Green fluorescent protein (GFP) chimeras or polypeptides with a length identical to that of the anti-� factor degron also demonstrate degron-dependent variation in ClpX activities. We show that degron-dependent ClpX activity leads to differences in anti-� degradation, thereby regulating the release of free � from the �/anti-� complex. M. tuberculosis ClpX activity thus influences changes in gene expression by modulating the cellular abundance of ECF � factors.IMPORTANCE The ability of Mycobacterium tuberculosis to quickly adapt to changing environmental stimuli occurs by maintaining protein homeostasis. Extracytoplasmic function (ECF) � factors play a significant role in coordinating the transcription profile to changes in environmental conditions. Release of the � factor from the anti-� is governed by the ClpXP2P1 assembly. M. tuberculosis ECF anti-� factors have an ssrA-like degron for targeted degradation. A point mutation in the degron leads to differences in ClpX-mediated proteolysis and affects the cellular abundance of ECF � factors. ClpX activity thus synchronizes changes in gene expression with environmental stimuli affecting M. tuberculosis physiology. Copyright © 2019 American Society for Microbiology