Postmenopausal women often suffer from vaginal symptoms associated with atrophic vaginitis. Additionally, gynecologic cancer survivors may live for decades with additional, clinically significant, persistent vaginal toxicities caused by cancer therapies, including pain, dyspareunia, and sexual dysfunction. The vaginal microbiome (VM) has been previously linked with vaginal symptoms related to menopause ( i.e. dryness). Our previous work showed that gynecologic cancer patients exhibit distinct VM profiles from healthy women, with low abundance of lactobacilli and prevalence of multiple opportunistic pathogenic bacteria. Here we explore the association between the dynamics and structure of the vaginal microbiome with the manifestation and persistence of vaginal symptoms, during one year after completion of cancer therapies, while controlling for clinical and sociodemographic factors. We compared cross-sectionally the vaginal microbiome in 134 women, 64 gynecologic patients treated with radiotherapy and 68 healthy controls, and we longitudinally followed a subset of 52 women quarterly (4 times in a year: pre-radiation therapy, 2, 6 and 12 months post-therapy). Differences among the VM profiles of cancer and healthy women were more pronounced with the progression of time. Cancer patients had higher diversity VMs and a variety of vaginal community types (CTs) that are not dominated by Lactobacilli , with extensive VM variation between individuals. Additionally, cancer patients exhibit highly unstable VMs (based on Bray-Curtis distances) compared to healthy controls. Vaginal symptoms prevalent in cancer patients included vaginal pain (40%), hemorrhage (35%), vaginismus (28%) and inflammation (20%), while symptoms such as dryness (45%), lack of lubrication (33%) and dyspareunia (32%) were equally or more prominent in healthy women at baseline. However, 24% of cancer patients experienced persistent symptoms at all time points, as opposed to 12% of healthy women. Symptom persistence was strongly inversely correlated with VM stability; for example, patients with persistent dryness or abnormally high pH have the most unstable microbiomes. Associations were identified between vaginal symptoms and individual bacterial taxa, including: Prevotella with vaginal dryness, Delftia with pain following vaginal intercourse, and Gemillaceaea with low levels of lubrication during intercourse. Taken together our results indicate that gynecologic cancer therapy is associated with reduced vaginal microbiome stability and vaginal symptom persistence.
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Enhanced drug delivery to the reproductive tract using nanomedicine reveals therapeutic options for prevention of preterm birth
Inflammation contributes to nearly 4 million global premature births annually. Here, we used a mouse model of intrauterine inflammation to test clinically used formulations, as well as engineered nanoformulations, for the prevention of preterm birth (PTB). We observed that neither systemic 17a-hydroxyprogesterone caproate (Makena) nor vaginal progesterone gel (Crinone) was sufficient to prevent inflammation-induced PTB, consistent with recent clinical trial failures. However, we found that vaginal delivery of mucoinert nanosuspensions of histone deacetylase (HDAC) inhibitors, in some cases with the addition of progesterone, prevented PTB and resulted in delivery of live pups exhibiting neurotypical development. In human myometrial cells in vitro, the P4/HDAC inhibitor combination both inhibited cell contractility and promoted the anti-inflammatory action of P4 by increasing progesterone receptor B stability. Here, we demonstrate the use of vaginally delivered drugs to prevent intrauterine inflammation–induced PTB resulting in the birth of live offspring in a preclinical animal model.
more » « less- NSF-PAR ID:
- 10209801
- Publisher / Repository:
- American Association for the Advancement of Science (AAAS)
- Date Published:
- Journal Name:
- Science Translational Medicine
- Volume:
- 13
- Issue:
- 576
- ISSN:
- 1946-6234
- Page Range / eLocation ID:
- Article No. eabc6245
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Introduction The Robson 10‐group classification system stratifies cesarean birth rates using maternal characteristics. Our aim was to compare cesarean birth utilization in US centers with and without midwifery care using the Robson classification.
Methods We used National Institute of Child and Human Development Consortium on Safe Labor data from 2002 to 2008. Births to women in centers with interprofessional care that included midwives (n = 48,857) were compared with births in non‐interprofessional centers (n = 47,935). To compare cesarean utilization, births were classified into the Robson categories. Cesarean birth rates within each category and the contribution to the overall rate were calculated. Maternal demographics, labor and birth outcomes, and neonatal outcomes were described. Logistic regression was used to adjust for maternal comorbidities.
Results Women were less likely to have a cesarean birth (26.1% vs 33.5%,
P < .001) in centers with interprofessional care. Nulliparous women with singleton, cephalic, term fetuses (category 2) were less likely to have labor induced (11.1% vs 23.4%,P < .001), and women with a prior uterine scar (category 5) had lower cesarean birth rates (73.8% vs 85.1%,P < .001) in centers with midwives. In centers without midwives, nulliparous women with singleton, cephalic, term fetuses with induction of labor (category 2a) were less likely to have a cesarean birth compared with those in interprofessional care centers in unadjusted comparison (30.3% vs 35.8%,P < .001), but this was reversed after adjustment for maternal comorbidities (adjusted odds ratio, 1.21; 95% CI, 1.12‐1.32;P < .001). Cesarean birth rates among women at risk for complications (eg, breech) were similar between groups.Discussion Interprofessional care teams were associated with lower rates of labor induction and overall cesarean utilization as well as higher rates of vaginal birth after cesarean. There was consistency in cesarean rates among women with higher risk for complications.
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Abstract Stem cell therapies have made strides toward the efficacious treatment of injured endometrium and the prevention of intrauterine adhesions, or Asherman's syndrome (AS). Despite this progress, they are limited by their risk of tumor formation, low engraftment rates, as well as storage and transportation logistics. While attempts have been made to curb these issues, there remains a need for simple and effective solutions. A growing body of evidence supports the theory that delivering media, conditioned with mesenchymal stem cells, might be a promising alternative to live cell therapy. Mesenchymal stem cell‐secretome (MSC‐Sec) has a superior safety profile and can be stored without losing its regenerative properties. It is versatile enough to be added to a number of delivery vehicles that improve engraftment and control the release of the therapeutic. Thus, it holds great potential for the treatment of AS. Here, a new strategy for loading crosslinked hyaluronic acid gel (HA gel) with MSC‐Sec is reported. The HA gel/MSC‐Sec treatment paradigm creates a sustained release system that repairs endometrial injury in rats and promotes viable pregnancy.
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Diabetes is a major risk factor for cardiovascular diseases, especially cardiomyopathy, a condition in which the smooth muscles of the heart become thick and rigid, affecting the functioning of cardiomyocytes, the contractile cells of the heart. Uncontrolled elevated glucose levels over time can result in oxidative stress, which could lead to inflammation and altered epigenetic mechanisms. In the current study, we investigated whether hyperglycemia can modify cardiac function by directly affecting these changes in cardiomyocytes. To evaluate the adverse effect of high glucose, we measured the levels of gap junction protein, connexin 43, which is responsible for modulating cardiac electric activities and Troponin I, a part of the troponin complex in the heart muscles, commonly used as cardiac markers of ischemic heart disease. AC16 human cardiomyocyte cells were used in this study. Under hyperglycemic conditions, these cells demonstrated altered levels of connexin 43 and Troponin-I after 24 h of exposure. We also examined hyperglycemia induced changes in epigenetic markers: H3K9me1, Sirtuin-1 (SIRT1), and histone deacetylase (HDAC)-2 as well as in inflammatory and stress-related mediators, such as heat shock protein (HSP)-60, receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)-4, high mobility group box (HMGB)-1 and CXC chemokine receptor (CXCR)-4. Cardiomyocytes exposed to 25mM glucose resulted in the downregulation of HSP60 and SIRT1 after 48 h. We further examined that hyperglycemia mediated the decrease in the gap junction protein CX43, as well as CXC chemokine receptor CXCR4 which may affect the physiological functions of the cardiomyocytes when exposed to high glucose for 24 and 48 h. Upregulated expression of DNA-binding nuclear protein HMGB1, along with changes in histone methylation marker H3K9me1 have demonstrated hyperglycemia-induced damage to cardiomyocyte at 24 h of exposure. Our study established that 24 to 48 h of hyperglycemic exposure could stimulate stress-mediated inflammatory mediators in cardiomyocytes in vitro. These stress-related changes in hyperglycemia-induced cardiomyocytes may further initiate an increase in injury markers which eventually could alter the epigenetic processes. Therefore, epigenetic and inflammatory mechanisms in conjunction with alterations in a downstream signaling pathway could have a direct effect on the functionality of the cardiomyocytes exposed to high glucose during short and long-term exposures.more » « less
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Abstract Maternal effects often provide a mechanism for adaptive transgenerational phenotypic plasticity. The maternal phenotype can profoundly influence the potential for such environmentally induced adjustments of the offspring phenotype, causing correlations between offspring and maternal traits. Here, we study potential effects of the maternal phenotype on offspring provisioning prior to and during gestation in the matrotrophic live‐bearing fish species
Poeciliopsis retropinna . Specifically, we examine how maternal traits such as body fat, lean mass, and length relate to pre‐ (i.e., allocation to the egg prior to fertilization) and post‐fertilization (i.e., allocation to the embryo during pregnancy) maternal provisioning and how this ultimately affects offspring size and body composition at birth. We show that pre‐ and post‐fertilization maternal provisioning is associated with maternal length and body fat, but not with maternal lean mass. Maternal length is proportionally associated with egg mass at fertilization and offspring mass at birth, notably without changing the ratio of pre‐ to post‐fertilization maternal provisioning. This ratio, referred to as the matrotrophy index (MI), is often used to quantify the level of matrotrophy. By contrast, the proportion of maternal body fat is positively associated with post‐fertilization, but not pre‐fertilization, maternal provisioning and consequently is strongly positively correlated with the MI. We furthermore found that the composition of embryos changes throughout pregnancy. Females invest first in embryo lean mass, and then allocate fat reserves to embryos very late in pregnancy. We argue that this delay in fat allocation may be adaptive, because it delays an unnecessary high reproductive burden to the mother during earlier stages of pregnancy, potentially leading to a more slender body shape and improved locomotor performance. In conclusion, our study suggests that (a) offspring size at birth is a plastic trait that is predicted by both maternal length and body fat, and (b) the MI is a plastic trait that is predicted solely by the proportion of maternal body fat. It herewith provides new insights into the potential maternal causes and consequences of embryo provisioning during pregnancy in matrotrophic live‐bearing species.
