Delivery of the newborn occurs either vaginally or via caesarean section. It is not known whether the mode of delivery and exposure to labor affects early autonomic nervous system (ANS) function, as measured by heart rate variability (HRV), or cortical electroencephalogram (EEG) activity. The objective of the study was to determine if autonomic function in newborns differs by mode of delivery. Simultaneous recording of EEG and electrocardiogram were collected in low-risk term newborns at <72 hours of age to measure HRV, the asymmetry index, and EEG power. Newborns were compared by delivery type: vaginal delivery (VD), cesarean section (CS) after labor (L-CS), or elective CS (E-CS). Quantile Regression controlled for gestational age, postnatal age, and percent active states. One hundred and eighteen newborns were studied at 25.2 (11.4) hours of age. Sixty-two (52.5%) were born by VD, 22 by L-CS (18.6%), and 34 by E-CS (28.8%). HRV metrics didn't differ by delivery mode. Asymmetry index was higher in L-CS compared to VD and E-CS (P = 0.03). On EEG, L-CS newborns showed lower relative gamma power compared to VD and E-CS (P = 0.005). The study found that overall ANS tone is not altered by mode of delivery in low-risk term newborns.

Although 70-80% of newly diagnosed ovarian cancer patients respond to first-line therapy, almost all relapse and five-year survival remains below 50%. One strategy to increase five-year survival is prolonging time to relapse by improving first-line therapy response. However, no biomarker today can accurately predict individual response to therapy. In this study, we present analytical and prospective clinical validation of a new test that utilizes primary patient tissue in 3D cell culture to make patient-specific response predictions prior to initiation of treatment in the clinic. Test results were generated within seven days of tissue receipt from newly diagnosed ovarian cancer patients obtained at standard surgical debulking or laparoscopic biopsy. Patients were followed for clinical response to chemotherapy. In a study population of 44, the 32 test-predicted Responders had a clinical response rate of 100% across both adjuvant and neoadjuvant treated populations with an overall prediction accuracy of 89% (39 of 44, p < 0.0001). The test also functioned as a prognostic readout with test-predicted Responders having a significantly increased progression-free survival compared to test-predicted Non-Responders, p = 0.01. This correlative accuracy establishes the test's potential to benefit ovarian cancer patients through accurate prediction of patient-specific response before treatment.

Cesarean section (CS) is recognized as being a shared environmental risk factor associated with chronic immune disease. A study of maternal gene expression changes between different delivery modes can add to our understanding of how CS contributes to disease patterns later in life. We evaluated the association of delivery mode with postpartum gene expression using a cross-sectional study of 324 mothers who delivered full-term (≥ 37 weeks) singletons. Of these, 181 mothers had a vaginal delivery and 143 had a CS delivery (60 with and 83 without labor). Antimicrobial peptides (AMP) were upregulated in vaginal delivery compared to CS with or without labor. Peptidase inhibitor 3 (PI3), a gene in the antimicrobial peptide pathway and known to be involved in antimicrobial and anti-inflammatory activities, showed a twofold increase in vaginal delivery compared to CS with or without labor (adjusted p-value 1.57 × 10-11 and 3.70 × 10-13, respectively). This study evaluates differences in gene expression by delivery mode and provides evidence of antimicrobial peptide upregulation in vaginal delivery compared to CS with or without labor. Further exploration is needed to determine if AMP upregulation provides protection against CS-associated diseases later in life.

Pathogenic mutations in fumarate hydratase (FH) drive hereditary leiomyomatosis and renal cell cancer (HLRCC) and increase the risk of developing uterine leiomyomas (ULMs). An integrated proteogenomic analysis of ULMs from HLRCC (n = 16; FH-mutation confirmed) and non-syndromic (NS) patients (n = 12) identified a significantly higher protein:transcript correlation in HLRCC (R = 0.35) vs. NS ULMs (R = 0.242, MWU p = 0.0015). Co-altered proteins and transcripts (228) included antioxidant response element (ARE) target genes, such as thioredoxin reductase 1 (TXNRD1), and correlated with activation of NRF2-mediated oxidative stress response signaling in HLRCC ULMs. We confirm 185 transcripts previously described as altered between HLRCC and NS ULMs, 51 co-altered at the protein level and several elevated in HLRCC ULMs are involved in regulating cellular metabolism and glycolysis signaling. Furthermore, 367 S-(2-succino)cysteine peptides were identified in HLRCC ULMs, of which sixty were significantly elevated in HLRCC vs. NS ULMs (LogFC = 1.86, MWU p < 0.0001). These results confirm and define novel proteogenomic alterations in uterine leiomyoma tissues collected from HLRCC patients and underscore conserved molecular alterations correlating with inactivation of the FH tumor suppressor gene.

It is well-established that women are disproportionately affected by Alzheimer's disease. The mechanisms underlying this sex-specific disparity are not fully understood, but several factors that are often associated-including interactions of sex hormones, genetic factors, and the gut microbiome-likely contribute to the disease's etiology. Here, we have examined the role of sex hormones and the gut microbiome in mediating Aβ amyloidosis and neuroinflammation in APPPS1-21 mice. We report that postnatal gut microbiome perturbation in female APPPS1-21 mice leads to an elevation in levels of circulating estradiol. Early stage ovariectomy (OVX) leads to a reduction of plasma estradiol that is correlated with a significant alteration of gut microbiome composition and reduction in Aβ pathology. On the other hand, supplementation of OVX-treated animals with estradiol restores Aβ burden and influences gut microbiome composition. The reduction of Aβ pathology with OVX is paralleled by diminished levels of plaque-associated microglia that acquire a neurodegenerative phenotype (MGnD-type) while estradiol supplementation of OVX-treated animals leads to a restoration of activated microglia around plaques. In summary, our investigation elucidates the complex interplay between sex-specific hormonal modulations, gut microbiome dynamics, metabolic perturbations, and microglial functionality in the pathogenesis of Alzheimer's disease.

As patient derived xenograft (PDX) models are increasingly used for preclinical drug development, strategies to account for the nonhuman component of PDX RNA expression data are critical to its interpretation. A bioinformatics pipeline to separate donor tumor and mouse stroma transcriptome profiles was devised and tested. To examine the molecular fidelity of PDX versus donor tumors, we compared mRNA differences between paired PDX-donor tumors from nine ovarian cancer patients. 1,935 differentially expressed genes were identified between PDX and donor tumors. Over 90% (n = 1767) of these genes were down-regulated in PDX models and enriched in stroma-specific functions. Several protein kinases were also differentially expressed in PDX tumors, e.g. PDGFRA, PDGFRB and CSF1R. Upon in silico removal of these PDX-donor tumor differentially expressed genes, a stronger transcriptional resemblance between PDX-donor tumor pairs was seen (average correlation coefficient increases from 0.91 to 0.95). We devised and validated an effective bioinformatics strategy to separate mouse stroma expression from human tumor expression for PDX RNAseq. In addition, we showed most of the PDX-donor differentially expressed genes were implicated in stromal components. The molecular similarities and differences between PDX and donor tumors have implications in future therapeutic trial designs and treatment response evaluations using PDX models.

Primary ovarian insufficiency (POI) is defined as the loss of ovarian function before 40 years of age. It clinically manifests as amenorrhea, infertility, and signs of estrogen insufficiency. POI is frequently induced by chemotherapy. Gonadotoxic chemotherapy reagents damage granulosa cells, which are essential for follicular function and development. Our recently published studies demonstrated that intraovarian transplantation of human mesenchymal stem cells (hMSCs) can restore fertility in a chemotherapy-induced POI mouse model. However, the regenerative mechanism underlying the hMSC effect in POI mice is not fully understood. Here, we report that the hMSC secretome increased the proliferation of human granulosa cells (HGrC1). We showed by FACS analysis that treatment of HGrC1 cells with hMSC-conditioned media (hMSC CM) stimulates cellular proliferation. We also demonstrated that the expression of steroidogenic enzymes involved in the production of estrogen, CYP19A1 and StAR, are significantly elevated in hMSC CM-treated HGrC1 cells. Our data suggest that hMSC CM stimulates granulosa cell proliferation and function, which may explain the therapeutic effect of hMSCs in our chemotherapy-induced POI animal model. Our findings indicate that the hMSC secretome may be a novel treatment approach for restoring granulosa cell and ovarian function in patients with POI.