Predisposition for borderline personality disorder with comorbid major depression is associated with that for polycystic ovary syndrome in female Japanese population

Polycystic ovary syndrome (PCOS) is a common lifestyle-related endocrinopathy in women of reproductive age and is associated with several mental health problems. We examined the genotypic distributions of IRS-1 Gly972Arg and CYP11B2 -344T/C, which were previously described as influencing PCOS, and assayed the serum levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in a set of female patients with borderline personality disorder (BPD) with comorbid major depressive disorder (MDD) (n = 50) and age-matched control subjects (n = 100), to investigate the predisposition for BPD with MDD. The results showed that the patients were more frequently IRS-1 972Arg variant allele carriers (P = 0.013; OR 6.68; 95% CI = 1.30–34.43) and homozygous for the CYP11B2 −344C variant allele (P = 0.022; OR = 3.32; 95% CI = 1.18–9.35) than the control subjects. The IL-6 level was significantly higher in the patients than in the controls (P < 0.0001). There was no significant difference in the serum TNF-α level between patients with BPD with MDD and the healthy comparison group (P = 0.5273). In conclusion, the predisposition for BPD with MDD is associated with that for PCOS, in the female Japanese population. An elevated serum IL-6 level is considered to be a possible biomarker of BPD with MDD

Paclitaxel-induced aberrant mitosis and mitotic slippage efficiently lead to proliferative death irrespective of canonical apoptosis and p53.

Spindle poisons elicit various cellular responses following metaphase arrest, but how they relate to long-term clonogenicity has remained unclear. We prepared several HeLa lines in which the canonical apoptosis pathway was attenuated, and compared their acute responses to paclitaxel, as well as long-term fate, with the parental line. Three-nanomolar paclitaxel induced brief metaphase arrest (<5 h) often followed by aberrant mitosis, and about 90% of the cells of each line had lost their clonogenicity after 48 h of the treatment. A combination of the same concentration of paclitaxel with the kinesin-5 inhibitor, S-trityl-L-cysteine (STLC), at 1 µM led to much longer arrest (∼20 h) and predominance of subsequent line-specific responses: mitochondrial outer membrane permeabilization (MOMP) in the apoptosis-prone line, or mitotic slippage without obvious MOMP in the apoptosis-reluctant lines. In spite of this, combination with STLC did not lead to a marked difference in clonogenicity between the apoptosis-prone and -reluctant lines, and intriguingly resulted in slightly better clonogenicity than that of cells treated with 3 nM paclitaxel alone. This indicates that changes in the short-term response within 3 possible scenarios — acute MOMP, mitotic slippage or aberrant mitosis ― has only a weak impact on clonogenicity. Our results suggest that once cells have committed to slippage or aberrant mitosis they eventually undergo proliferative death irrespective of canonical apoptosis or p53 function. Consistent with this, cells with irregular DNA contents originating from mitotic slippage or aberrant mitosis were mostly eliminated from the population within several rounds of division after the drug treatment

Paclitaxel-induced aberrant mitosis and mitotic slippage efficiently lead to proliferative death irrespective of canonical apoptosis and p53

<p>Spindle poisons elicit various cellular responses following metaphase arrest, but how they relate to long-term clonogenicity has remained unclear. We prepared several HeLa lines in which the canonical apoptosis pathway was attenuated, and compared their acute responses to paclitaxel, as well as long-term fate, with the parental line. Three-nanomolar paclitaxel induced brief metaphase arrest (<5 h) often followed by aberrant mitosis, and about 90% of the cells of each line had lost their clonogenicity after 48 h of the treatment. A combination of the same concentration of paclitaxel with the kinesin-5 inhibitor, <i>S</i>-trityl-L-cysteine (STLC), at 1 µM led to much longer arrest (∼20 h) and predominance of subsequent line-specific responses: mitochondrial outer membrane permeabilization (MOMP) in the apoptosis-prone line, or mitotic slippage without obvious MOMP in the apoptosis-reluctant lines. In spite of this, combination with STLC did not lead to a marked difference in clonogenicity between the apoptosis-prone and -reluctant lines, and intriguingly resulted in slightly better clonogenicity than that of cells treated with 3 nM paclitaxel alone. This indicates that changes in the short-term response within 3 possible scenarios — acute MOMP, mitotic slippage or aberrant mitosis ― has only a weak impact on clonogenicity. Our results suggest that once cells have committed to slippage or aberrant mitosis they eventually undergo proliferative death irrespective of canonical apoptosis or p53 function. Consistent with this, cells with irregular DNA contents originating from mitotic slippage or aberrant mitosis were mostly eliminated from the population within several rounds of division after the drug treatment.</p

Characterization of PAX9 variant P20L identified in a Japanese family with tooth agenesis.

Transcription factors PAX9 and MSX1 play crucial roles in the development of permanent teeth at the bud stage, and their loss-of-function variants have been associated with congenital tooth agenesis. We sequenced the coding regions of the PAX9 and MSX1 genes from nine patients with non-syndromic tooth agenesis, and identified a missense mutation, P20L, of PAX9 in a single familial case involving three patients in two generations. Identical mutation was previously reported by other authors, but has not been characterized in detail. The mutation was located in a highly conserved N-terminal subdomain of the paired domain and co-segregated as a heterozygote with tooth agenesis. The patients showed defects primarily in the first and second molars, which is typical for cases attributable to PAX9 mutation. Luciferase reporter assay using the 2.3-kb promoter region of BMP4 and electrophoretic mobility shift assay using the CD19-2(A-ins) sequence revealed that P20L substitution eliminated most of the transactivation activity and specific DNA binding activity of PAX9 under the experimental conditions we employed, while some residual activity of the mutant was evident in the former assay. The hypomorphic nature of the variant may explain the relatively mild phenotype in this case, as compared with other PAX9 pathogenic variants such as R26W

Involvement of C-terminal truncation mutation of kinesin-5 in resistance to kinesin-5 inhibitor.

Cultured cells easily develop resistance to kinesin-5 inhibitors (K5Is) often by overexpressing a related motor protein, kinesin-12/KIF15, or by acquiring mutations in the N-terminal motor domain of kinesin-5/KIF11 itself. We aimed to identify novel mechanisms responsible for resistance to S-trityl L-cysteine (STLC), one of the K5Is, using human osteosarcoma cell lines. Among six lines examined, U-2OS and HOS survived chronic STLC treatment and gave rise to resistant cells with IC50s at least 10-fold higher than those of the respective parental lines. Depletion of KIF15 largely eliminated the acquired K5I resistance in both cases, consistent with the proposed notion that KIF15 is indispensable for it. In contrast to the KIF11-independent property of the cells derived from HOS, those derived from U-2OS still required KIF11 for their growth and, intriguingly, expressed a C-terminal truncated variant of KIF11 resulting from a frame shift mutation (S1017fs). All of the isolated clones harbored the same mutation, suggesting its clonal expansion in the cell population due to the growth advantage during chronic STLC treatment. Transgenic expression of KIF11S1017fs in the parental U-2OS cells, as well as in HeLa cells, conferred a moderate but reproducible STLC resistance, probably owing to STLC-resistant localization of the mutant KIF11 on mitotic spindle. Our observations indicate that both KIF15 and the C-terminal-truncated KIF11 contributes to the STLC resistance of the U-2OS derived cells