BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma.

Purpose: NRAS mutations in malignant melanoma are associated with aggressive disease requiring rapid antitumor intervention, but there is no approved targeted therapy for this subset of patients. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF-MEK-ERK (MAPK) pathway amplified its proapoptotic activity in BRAF-mutant melanoma. The present study investigated whether this effect might extent to NRAS-mutant melanoma, in which MAPK activation would be expected.Experimental Design and Results: BRAFi increased pERK, but also significantly increased growth inhibition and apoptosis induced by the MEKi in monolayer, spheroids, organotypic, and patient-derived tissue slice cultures of NRAS-mutant melanoma. BRAFi such as encorafenib induced an ER stress response via the PERK pathway, as detected by phosphorylation of eIF2α and upregulation of the ER stress-related factors ATF4, CHOP, and NUPR1 and the proapoptotic protein PUMA. MEKi such as binimetinib induced the expression of the proapoptotic protein BIM and activation of the mitochondrial pathway of apoptosis, the latter of which was enhanced by combination with encorafenib. The increased apoptotic rates caused by the combination treatment were significantly reduced through siRNA knockdown of ATF4 and BIM, confirming its critical roles in this process.Conclusions: The data presented herein encourage further advanced in vivo and clinical studies to evaluate MEKi in combination with ER stress inducing BRAFi as a strategy to treat rapidly progressing NRAS-mutant melanoma. Clin Cancer Res; 23(20); 6203-14. ©2017 AACR.

PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain Metastases In Vitro and In Vivo.

PURPOSE: Great advances have recently been made in treating patients with metastatic melanoma. However, existing therapies are less effective on cerebral than extracerebral metastases. This highlights the potential role of the brain environment on tumor progression and drug resistance and underlines the need for "brain-specific" therapies. We previously showed that the PI3K-AKT survival pathway is hyperactivated in brain but not extracerebral melanoma metastases and that astrocyte-conditioned medium activates AKT in melanoma cells in vitro We therefore tested the PI3K inhibitor buparlisib as an antitumor agent for melanoma brain metastases. EXPERIMENTAL DESIGN AND RESULTS: Buparlisib inhibited AKT activity, decreased proliferation, and induced apoptosis in metastatic melanoma cell lines and short-term brain melanoma cells, irrespective of their BRAF and NRAS mutation status. In addition, buparlisib inhibited hyperactivated AKT and induced apoptosis in melanoma cells that were stimulated with astrocyte-conditioned medium. The growth of tumors induced by injecting human BRAF- and NRAS-mutant metastatic melanoma cells into the brain of mice was significantly inhibited by buparlisib. CONCLUSIONS: These results emphasize the value of targeting the PI3K pathway as a strategy to develop drugs for melanoma brain metastases. Clin Cancer Res; 22(23); 5818-28. ©2016 AACR.

A combined intrauterine and cervical pregnancy diagnosed in the 13th gestational week: which type of management is more feasible and successful?

OBJECTIVE: To present a case of a simultaneous nonviable cervical pregnancy and viable intrauterine pregnancy diagnosed in the 13th gestational week and to discuss the possible therapeutic options. DESIGN: Case report. SETTING: University hospital of Münster, Germany. PATIENT(S): A 40-year-old woman who had undergone IVF-embryo transfer because of previous surgical sterilization. INTERVENTION(S): Hospitalization with observation, expecting spontaneous expulsion of the nonviable cervical pregnancy. MAIN OUTCOME MEASURE(S): Intrauterine pregnancy preservation; maternal morbidity and mortality. RESULT(S): Three weeks after diagnosis, the expulsion of a nonviable cervical pregnancy occurred. It was accompanied by pronounced cervical hemorrhage, conservatively managed with cervical curettage and stitches under general anesthesia. Unfortunately, a few hours later, spontaneous abortion of the intrauterine pregnancy occurred. Blood transfusion was postoperatively avoided, although pronounced anemia was detected (7.3 g/dL). The patient was than discharged 3 days later. CONCLUSION(S): Combined intrauterine and cervical pregnancy is a remote but possible event, particularly after assisted reproductive technology (ART) procedures. Its management should be carefully evaluated, according to the clinical situation and patient's desire. In case of nonviable cervical pregnancy, if a noninterventional approach is chosen, and especially when gestational age is advanced, hospitalization should be recommended in an attempt to prevent possible critical hemorrhagic complications due to cervical pregnancy expulsion.

Mutational analysis of the connexin 36 gene (CX36) and exclusion of the coding sequence as a candidate region for catatonic schizophrenia in a large pedigree.

The murine connexin 36 gene (Cx36) encodes a gap-junction channel protein which is preferentially expressed in brain and retina. The human orthologue CX36 is located on chromosome 15q14, a region recently shown to contain a susceptibility gene for hereditary catatonic schizophrenia. Therefore, CX36 was considered as a positional candidate for mutational analysis. Three polymorphic sites within CX36 were found by sequencing the two exons, the intron-exon boundaries and the putative promoter region of the gene derived from patients and control subjects. No variant exclusively cosegregates with the disease in a large pedigree that mainly supports the chromosome 15q14 locus, providing evidence that CX36 is not causative for the pathogenesis of catatonic schizophrenia in this family.