No association between the sigma receptor type 1 gene and schizophrenia: results of analysis and meta-analysis of case-control studies

BACKGROUND: Several lines of evidence have supported possible roles of the sigma receptors in the etiology of schizophrenia and mechanisms of antipsychotic efficacy. An association study provided genetic evidence that the sigma receptor type 1 gene (SIGMAR1) was a possible susceptibility factor for schizophrenia, however, it was not replicated by a subsequent study. It is necessary to evaluate further the possibility that the SIGMAR1 gene is associated with susceptibility to schizophrenia. METHODS: A case-control association study between two polymorphisms of the SIGMAR1 gene, G-241T/C-240T and Gln2Pro, and schizophrenia in Japanese population, and meta-analysis including present and previous studies. RESULTS: There was no significant association of any allele or genotype of the polymorphisms with schizophrenia. Neither significant association was observed with hebephrenic or paranoid subtype of schizophrenia. Furthermore, a meta-analysis including the present and previous studies comprising 779 controls and 636 schizophrenics also revealed no significant association between the SIGMAR1 gene and schizophrenia. CONCLUSION: In view of this evidence, it is likely that the SIGMAR1 gene does not confer susceptibility to schizophrenia

Ruptured dermoid cyst consisting of two adjacent masses with different components in the middle and posterior cranial fossa

Background: Intracranial dermoid cysts are among the rarest tumors, and cases of rupture are even rarer. Dermoid cysts present great variety of radiographic features depending on their origin, which may make the diagnosis difficult. Case description: A 17-year-old female complained of headache and nausea. Magnetic resonance imaging (MRI) showed two masses in the right middle cranial fossa and in the posterior fossa, which had different components according to their locations. Additionally, we observed fatty droplets in the subarachnoid space on MRI. We resected the tumor, and the postoperative diagnosis was ruptured dermoid cyst. There was continuity between both masses, indicating these were from the same tumor. Conclusion: We experienced a rare case of ruptured dermoid cyst which presented as two adjacent lesions in the middle cranial fossa and posterior cranial fossa. The main components of the tumor were significantly heterogeneous depending on the lesion site. Keywords: Dermoid cyst, Fat droplets, Ruptured, Middle cranial fossa, Posterior cranial foss

Diverse Mechanisms of Resistance against Osimertinib, a Third-Generation EGFR-TKI, in Lung Adenocarcinoma Cells with an EGFR-Activating Mutation

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is used as a first-line treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, the mechanisms underlying its anticancer activity, particularly the subsequent development of acquired resistance, are unclear. Herein, we investigated the mechanisms underlying the development of osimertinib resistance by treating NSCLC PC-9 cells (harboring an EGFR-activating mutation) with osimertinib, thereby developing five resistant cell lines, i.e., AZDR3, AZDR6, AZDR9, AZDR11, and AZDR14. The amplification of wild-type EGFR in AZDR3 cells and wild-type EGFR and KRAS in AZDR6 cells was also studied. AZDR3 cells showed dependence on EGFR signaling, in addition to afatinib sensitivity. AZDR9 cells harboring KRASG13D showed sensitivity to MEK inhibitors. Furthermore, combination treatment with EGFR and IGF1R inhibitors resulted in attenuated cell proliferation and enhanced apoptosis. In AZDR11 cells, increased Bim expression could not induce apoptosis, but Bid cleavage was found to be essential for the same. A SHP2/T507K mutation was also identified in AZDR14 cells, and, when associated with GAB1, SHP2 could activate ERK1/2, whereas a SHP2 inhibitor, TNO155, disrupted this association, thereby inhibiting GAB1 activation. Thus, diverse osimertinib resistance mechanisms were identified, providing insights for developing novel therapeutic strategies for NSCLC

Mechanisms of EGFR-TKI-Induced Apoptosis and Strategies Targeting Apoptosis in EGFR-Mutated Non-Small Cell Lung Cancer

Homeostasis is achieved by balancing cell survival and death. In cancer cells, especially those carrying driver mutations, the processes and signals that promote apoptosis are inhibited, facilitating the survival and proliferation of these dysregulated cells. Apoptosis induction is an important mechanism underlying the therapeutic efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-small cell lung cancer (NSCLC). However, the mechanisms by which EGFR-TKIs induce apoptosis have not been fully elucidated. A deeper understanding of the apoptotic pathways induced by EGFR-TKIs is essential for the developing novel strategies to overcome resistance to EGFR-TKIs or to enhance the initial efficacy through therapeutic synergistic combinations. Recently, therapeutic strategies targeting apoptosis have been developed for cancer. Here, we review the state of knowledge on EGFR-TKI-induced apoptotic pathways and discuss the therapeutic strategies for enhancing EGFR-TKI efficiency. We highlight the great progress achieved with third-generation EGFR-TKIs. In particular, combination therapies of EGFR-TKIs with anti-vascular endothelial growth factor/receptor inhibitors or chemotherapy have emerged as promising therapeutic strategies for patients with EGFR-mutated NSCLC. Nevertheless, further breakthroughs are needed to yield an appropriate standard care for patients with EGFR-mutated NSCLC, which requires gaining a deeper understanding of cancer cell dynamics in response to EGFR-TKIs