Adverse Effect of the Duration of Antibiotic Use Prior to Immune Checkpoint Inhibitors on the Overall Survival of Patients with Recurrent Gynecologic Malignancies.

PURPOSE: Antibiotic use preceding immune checkpoint inhibitor (ICI) treatment has been associated with a decreased efficacy of ICI in solid tumors. In this study, we evaluated the effect of antibiotic use before ICI therapy on oncological outcomes. METHODS: We examined patients with recurrent gynecologic malignancies at two academic institutions. The clinical data, including antibiotic use within 60 days of ICI initiation, type of antibiotics, reasons for antibiotic use, body mass index, tumor site, chemotherapy-free interval, prior history of radiotherapy, disease control rate (DCR), and overall survival (OS), were assessed. RESULTS: Of 215 patients, 22.9% (n = 47) received antibiotics before ICI treatment. The most common cancer was ovarian (52.1%, n = 112), followed by cervical (24.7%, n = 53) and endometrial (16.7%, n = 36). When we divided the cohort based on antibiotic use before ICIs, there were no significant differences in the DCR and baseline characteristics between the two groups. On multivariate analyses, the variables associated with poor OS were previous use of antibiotics for a cumulative duration of >14 days (HR 2.286, 95% CI 1.210-4.318; p = 0.011); Eastern Cooperative Oncology Group 2 or 3 (HR 4.677, 95% CI 2.497-8.762; p < 0.001); and chemotherapy-free interval of <6 months (HR 2.007, 95% CI 1.055-3.819; p = 0.034). CONCLUSION: Prior use of antibiotics for a cumulative duration of >14 days was associated with reduced survival in recurrent gynecologic malignancies.

IQSEC3 Deletion Impairs Fear Memory Through Upregulation of Ribosomal S6K1 Signaling in the Hippocampus.

BACKGROUND: IQSEC3, a gephyrin-binding GABAergic (gamma-aminobutyric acidergic) synapse-specific guanine nucleotide exchange factor, was recently reported to regulate activity-dependent GABAergic synapse maturation, but the underlying signaling mechanisms remain incompletely understood. METHODS: We generated mice with conditional knockout (cKO) of Iqsec3 to examine whether altered synaptic inhibition influences hippocampus-dependent fear memory formation. In addition, electrophysiological recordings, immunohistochemistry, and behavioral assays were used to address our question. RESULTS: We found that Iqsec3-cKO induces a specific reduction in GABAergic synapse density, GABAergic synaptic transmission, and maintenance of long-term potentiation in the hippocampal CA1 region. In addition, Iqsec3-cKO mice exhibited impaired fear memory formation. Strikingly, Iqsec3-cKO caused abnormally enhanced activation of ribosomal P70-S6K1-mediated signaling in the hippocampus but not in the cortex. Furthermore, inhibiting upregulated S6K1 signaling by expressing dominant-negative S6K1 in the hippocampal CA1 of Iqsec3-cKO mice completely rescued impaired fear learning and inhibitory synapse density but not deficits in long-term potentiation maintenance. Finally, upregulated S6K1 signaling was rescued by IQSEC3 wild-type, but not by an ARF-GEF (adenosine diphosphate ribosylation factor-guanine nucleotide exchange factor) inactive IQSEC3 mutant. CONCLUSIONS: Our results suggest that IQSEC3-mediated balanced synaptic inhibition in hippocampal CA1 is critical for the proper formation of hippocampus-dependent fear memory.

Youth Suicide in Korea Across the Educational Stages.

Background: Youth suicides have diverse characteristics according to the young people's developmental stages. Warning signs and communication of suicidal intent can be vague among early adolescents, while mental health problems may be more evidently related to suicidal ideation in older adolescents. Understanding the developmental characteristics of youth suicide is necessary for effective suicide prevention. Aims: We explored the differences between children and adolescents who died by suicide and the characteristics of these young people as observed by their school teachers. Method: We analyzed teachers' mandatory postmortem reports of suicides among 308 Korean students. We compared: suicide-related information including personal, familial, and school factors; stressful life events; and participation in interventions among elementary, middle, and high school students who died by suicide. We also assessed the distribution of student suicides per month. Results: Suicide among elementary school students increased during school vacations, and suicide among middle and high school students increased during the school semester. According to the teachers' reports, elementary school students who died by suicide were more extroverted and had better academic achievements than their high school peers, and had significantly lower levels of substance/tobacco use. Elementary school students who died by suicide showed significantly less academic stress and use of external professional help than did other groups. Limitations: Because this research is based on mandatory teacher reports, the subjective opinions of teachers may have affected the reliability of the data. Suicide by out-of-school youth was not included. Conclusion: School-based suicide prevention should be implemented in accordance with young people's developmental characteristics.