Southern California Reproductive Center

Many studies have examined the acute effects of chemotherapies and radiation on the ovary; however, few address the impact of long-term chemotherapeutic agents on future reproduction for cancer survivors. The purpose of our study was to determine the effect of long-term tamoxifen (TAM) treatment on follicle development, ovarian reserve, and embryogenesis in a murine model. Adult female mice were treated with TAM (250 mg/kg fed ad libitum in mouse chow) or control chow for three weeks, followed by 0-, 1-, or 3-weeks of TAM washout. Mice were then superovulated, mated, and their oviducts flushed to determine ovulation, fertilization, and in vitro embryo development rates. At specific timepoints, one ovary from each animal was harvested, sectioned, and stained with H&E, while the other ovary was evaluated for gene expression of targeted genes. Ovarian size was calculated based on average surface area over six slices. Follicles (primordial, primary, secondary, antral / pre-ovulatory), and corpora lutea (CL) were counted and averaged for each slice. All data were analyzed using mixed-effects analysis of variance (ANOVA), with treatment group as the fixed effect and ovary treated as a random effect nested within treatment. Ovaries of TAM treated mice were 36% smaller on average than control ovaries (P = 0.01). Primordial follicle counts were 35% lower than control ovaries (P = 0.007) and there were 3.4x more atretic follicles in the ovaries of TAM treated mice (P < 0.001). There were no significant differences in the number of primary, secondary, antral or pre-ovulatory follicles. The number of oocytes and embryos flushed from control mice (total ovulated) was 1.65x greater than TAM treated mice. However, fertilization rates and in vitro embryo blastulation rates were not significantly different between controls and TAM groups. In summary, for this murine model, long-term TAM negatively impacted ovarian reserve (primordial follicle number) without overtly affecting the in vitro embryo development to the blastocyst.

Ecthyma gangrenosum is a rare dermatological manifestation often linked to Pseudomonas aeruginosa bacteremia, typically occurring in immunocompromised individuals. We present a case of ecthyma gangrenosum in a 69-year-old male with diabetes mellitus, but without HIV, malignancy, or chronic immunosuppressive therapy. The patient exhibited septic shock, pyelonephritis, and pneumonia, and was eventually diagnosed with ecthyma gangrenosum due to systemic Pseudomonas aeruginosa infection. This case highlights the occurrence of ecthyma gangrenosum in an older patient with metabolic comorbidities and age-related immune dysfunction, but without classic immunosuppressive conditions. It underscores the importance of early recognition and intervention in such populations, and the need for a nuanced approach to immune status in elderly patients with diabetes.

IntroductionHDL particle functionality is influenced by its structure, including lipid composition. However, the effects of exercise training on the HDL lipidome and its relationship with HDL-related traits are largely unknown.ObjectiveTo investigate the HDL lipidome of 154 adults before and after 20 weeks of endurance exercise training in the HERITAGE Family Study.MethodsThe HDL-sized plasma fraction was isolated utilizing FPLC-SEC, followed by untargeted lipidomic analysis using LC/MS. A total of 11 HDL lipid classes were derived from the 341 identified known lipid species. Exercise response of the HDL lipidome and its associations with HDL-related traits were examined, with significance set to FDR < 0.05.ResultsThe abundance of 42 HDL lipid species at baseline and 43 at post-training were significantly different between males and females. Exercise training did not significantly alter the abundance of any HDL lipid class, although HDL phosphatidylethanolamine trended (FDR = 0.05) towards an increase. Two species of HDL diglycerides significantly decreased in the total sample. Sex-specific nominal (p < 0.05) changes in individual HDL lipid species included primarily HDL diglyceride and triglyceride species decreasing in males only, while HDL phosphatidylethanolamine species mostly increasing in females only. Higher abundance of HDL surface lipids was associated with larger size and cholesterol content of HDL particles before and in response to exercise training.ConclusionOur analysis indicates that endurance exercise may have a limited impact on the HDL lipidome in healthy adults. However, the HDL lipidome differed across sex groups, which needs further investigation to identify potential mechanisms underlying the sex differences.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11306-025-02330-3.

We carelessly arranged a liver tissue image of control Western diet (WD)-fed Notch1 FL/FL NS5A transgenic mouse of Fig. 3e with incorrect image.The error was introduced during figure prepara-tion and is not a correct representation of the data.

Vaginal mucosa undergoes physiological changes across the lifespan, such as increased pH and reduced natural lubrication which are known to impact vaginal commensal microorganisms, hence increasing the chances of vaginal infections. An improved understanding of vaginal microbiome composition in different age groups and the effect of social behaviors, such as the use of personal lubricants, could facilitate the development of new strategies to maintain good vaginal health. The objective of this study was to assess the effect of water-based lubricants on the human vaginal microbiome. Fifty females from three age groups (18-29, 30-44, and 45-65 years) with mild-to-moderate vaginal dryness were randomized to one of five lubricants (four of which were formulated to meet expert guidance on osmolality and pH). Subjects entered the study at tolerance or treatment phase (vaginal intercourse minimum once a week using assigned lubricant). Four vaginal swabs per participant were sampled during pre-("baseline"), post-first ("2 h", "24 h") and post-last ("4 weeks") lubricant application to assess bacterial and fungal diversity via amplicon sequencing. Vaginal pH and relative humidity were measured at baseline, 2 h, and 24 h post-lubricant application. Relative bacteriome abundance was statistically compared between timepoints for each lubricant group. Vaginal moisture, age, BMI, and pH were correlated with bacteriome relative abundance. Lactobacilli and Gardnerella sp. Were predominant across participants. Repeated lubricant application did not significantly alter the vaginal bacteriome during 4 weeks of product use (p > 0.05) when measured by relative abundance and alpha-diversity index. Bacteriome diversity and abundance differed significantly between age groups at baseline whereas lactobacilli relative abundance was negatively associated with age and vaginal pH.

The P53-destabilizing TBC1D15-NOTCH protein interaction promotes self-renewal of tumor-initiating stem-like cells (TICs); however, the mechanisms governing the regulation of this pathway have not been fully elucidated. Here, we show that TBC1D15 stabilizes NOTCH and c-JUN through blockade of E3 ligase and CDK8 recruitment to phosphodegron sequences. Chromatin immunoprecipitation (ChIP-seq) analysis was performed to determine whether TBC1D15-dependent NOTCH1 binding occurs in TICs or non-TICs. The TIC population was isolated to evaluate TBC1D15-dependent NOTCH1 stabilization mechanisms. The tumor incidence in hepatocyte-specific triple knockout (Alb::CreERT2;Tbc1d15Flox/Flox;Notch1Flox/Flox;Notch2Flox/Flox;HCV-NS5A) Transgenic (Tg) mice and wild-type mice was compared after being fed an alcohol-containing Western diet (WD) for 12 months. The NOTCH1-TBC1D15-FIS1 interaction resulted in recruitment of mitochondria to the perinuclear region. TBC1D15 bound to full-length NUMB and to NUMB isoform 5, which lacks three Ser phosphorylation sites, and relocalized NUMB5 to mitochondria. TBC1D15 binding to NOTCH1 blocked CDK8- and CDK19-mediated phosphorylation of the NOTCH1 PEST phosphodegron to block FBW7 recruitment to Thr-2512 of NOTCH1. ChIP-seq analysis revealed that TBC1D15 and NOTCH1 regulated the expression of genes involved in mitochondrial metabolism-related pathways required for the maintenance of TICs. TBC1D15 inhibited CDK8-mediated phosphorylation to stabilize NOTCH1 and protect it from degradation The NUMB-binding oncoprotein TBC1D15 rescued NOTCH1 from NUMB-mediated ubiquitin-dependent degradation and recruited NOTCH1 to the mitochondrial outer membrane for the generation and expansion of liver TICs. A NOTCH-TBC1D15 inhibitor was found to inhibit NOTCH-dependent pathways and exhibited potent therapeutic effects in PDX mouse models. This unique targeting of the NOTCH-TBC1D15 interaction not only normalized the perinuclear localization of mitochondria but also promoted potent cytotoxic effects against TICs to eradicate patient-derived xenografts through NOTCH-dependent pathways.