ObjectivesComplex interactions of vaginal microorganisms with the genital tract epithelium shape mucosal innate immunity, which holds the key to sexual and reproductive health. Bacterial vaginosis (BV), a microbiome-disturbance syndrome prevalent in reproductive-age women, occurs commonly in concert with trichomoniasis, and both are associated with increased risk of adverse reproductive outcomes and viral infections, largely attributable to inflammation. To investigate the causative relationships among inflammation, BV and trichomoniasis, we established a model of human cervicovaginal epithelial cells colonised by vaginal Lactobacillus isolates, dominant in healthy women, and common BV species (Atopobium vaginae, Gardnerella vaginalis and Prevotella bivia).MethodsColonised epithelia were infected with Trichomonas vaginalis (TV) or exposed to purified TV virulence factors (membrane lipophosphoglycan (LPG), its ceramide-phosphoinositol-glycan core (CPI-GC) or the endosymbiont Trichomonas vaginalis virus (TVV)), followed by assessment of bacterial colony-forming units, the mucosal anti-inflammatory microbicide secretory leucocyte protease inhibitor (SLPI), and chemokines that drive pro-inflammatory, antigen-presenting and T cells.ResultsTV reduced colonisation by Lactobacillus but not by BV species, which were found inside epithelial cells. TV increased interleukin (IL)-8 and suppressed SLPI, likely via LPG/CPI-GC, and upregulated IL-8 and RANTES, likely via TVV as suggested by use of purified pathogenic determinants. BV species A vaginae and G vaginalis induced IL-8 and RANTES, and also amplified the pro-inflammatory responses to both LPG/CPI-GC and TVV, whereas P bivia suppressed the TV/TVV-induced chemokines.ConclusionsThese molecular host–parasite–endosymbiont–bacteria interactions explain epidemiological associations and suggest a revised paradigm for restoring vaginal immunity and preventing BV/TV-attributable inflammatory sequelae in women.

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Bacterial vaginosis (BV) has been linked to an increased risk of human immunodeficiency virus (HIV) acquisition and transmission in observational studies, but the underlying biological mechanisms are unknown. We measured biomarkers of subclinical vaginal inflammation, endogenous antimicrobial activity, and vaginal flora in women with BV and repeated sampling 1 week and 1 month after completion of metronidazole therapy. We also compared this cohort of women with BV to a healthy control cohort without BV. A longitudinal, open label study of 33 women with a Nugent score of 4 or higher was conducted. All women had genital swabs, cervicovaginal lavage (CVL) fluid, and cervicovaginal biopsies obtained at enrollment and received 7 days of metronidazole treatment. Repeat sampling was performed approximately 1 week and 1 month after completion of therapy. Participant's baseline samples were compared to a healthy, racially matched control group (n=13) without BV. The CVL from women with resolved BV (Nugent 0-3) had significantly higher anti-HIV activity, secretory leukocyte protease inhibitor (SLPI), and growth-related oncogene alpha (GRO-α) levels and their ectocervical tissues had significantly more CD8 cells in the epithelium. Women with persistent BV after treatment had significantly higher levels of interleukin-1β, tumor necrosis factor alpha (TNF-α), and intercellular adhesion molecule 1 (ICAM-1) in the CVL. At study entry, participants had significantly greater numbers of CCR5(+) immune cells and a higher CD4/CD8 ratio in ectocervical tissues prior to metronidazole treatment, compared to a racially matched cohort of women with a Nugent score of 0-3. These data indicate that BV is associated with changes in select soluble immune mediators, an increase in HIV target cells, and a reduction in endogenous antimicrobial activity, which may contribute to the increased risk of HIV acquisition.

Abstract-The complement cascade is activated in normal pregnancy, and excessive complement activation propagates the systemic inflammatory response in severe preeclampsia. Consequently, biomarkers of complement dysregulation may be useful for prediction or treatment of disease. Because renal damage with proteinuria is a characteristic pathological feature of preeclampsia, we hypothesized that complement markers in urine, rather than plasma, could better reflect complement dysregulation in disease. 0001).Urinary excretion of C5b-9 was detected in 96% of cases with severe preeclampsia, 12% of controls with chronic hypertension, and 8% of healthy controls. Cases were also notable for significantly greater urinary excretion of C3a and C5a. Plasma levels of C5a and C5b-9, but not C3a, were increased in the cases with severe preeclampsia compared with healthy controls; however, they did not distinguish preeclampsia from chronic hypertension, supporting our hypothesis that complement markers in urine, rather than plasma, better reflect complement dysregulation. Complement inhibition is an intriguing treatment option for patients with severe preeclampsia. (Hypertension. 2013;62:1040-1045.)

Trichomoniasis is the most common non-viral sexually transmitted infection caused by the vaginotropic extracellular protozoan parasite Trichomonas vaginalis. The infection is recurrent, with no lasting immunity, often asymptomatic, and linked to pregnancy complications and risk of viral infection. The molecular mechanisms of immune evasion by the parasite are poorly understood. We demonstrate that galectin-1 and -3 are expressed by the human cervical and vaginal epithelial cells and act as pathogen-recognition receptors for the ceramide phosphoinositol glycan core (CPI-GC) of the dominant surface protozoan lipophosphoglycan (LPG). We used an in vitro model with siRNA galectin knockdown epithelial clones, recombinant galectins, clinical Trichomonas isolates, and mutant protozoan derivatives to dissect the function of galectin-1 and -3 in the context of Trichomonas infection. Galectin-1 suppressed chemokines that facilitate recruitment of phagocytes, which can eliminate extracellular protozoa (IL-8) or bridge innate to adaptive immunity (MIP-3α and RANTES (regulated on activation normal T cell expressed and secreted)). Silencing galectin-1 increased and adding exogenous galectin-1 suppressed chemokine responses to Trichomonas or CPI-GC/LPG. In contrast, silencing galectin-3 reduced IL-8 response to LPG. Live Trichomonas depleted the extracellular levels of galectin-3. Clinical isolates and mutant Trichomonas CPI-GC that had reduced affinity to galectin-3 but maintained affinity to galectin-1 suppressed chemokine expression. Thus via CPI-GC binding, Trichomonas is capable of regulating galectin bioavailability and function to the benefit of its parasitic survival. These findings suggest novel approaches to control trichomoniasis and warrant further studies of galectin-binding diversity among clinical isolates as a possible source for symptom disparity in parasitic infections.

BackgroundCancer subtype classification attains the great importance for accurate diagnosis and personalized treatment of cancer. Latest developments in high-throughput sequencing technologies have rapidly produced multi-omics data of the same cancer sample. Many computational methods have been proposed to classify cancer subtypes, however most of them generate the model by only employing gene expression data. It has been shown that integration of multi-omics data contributes to cancer subtype classification.ResultsA new hierarchical integration deep flexible neural forest framework is proposed to integrate multi-omics data for cancer subtype classification named as HI-DFNForest. Stacked autoencoder (SAE) is used to learn high-level representations in each omics data, then the complex representations are learned by integrating all learned representations into a layer of autoencoder. Final learned data representations (from the stacked autoencoder) are used to classify patients into different cancer subtypes using deep flexible neural forest (DFNForest) model.Cancer subtype classification is verified on BRCA, GBM and OV data sets from TCGA by integrating gene expression, miRNA expression and DNA methylation data. These results demonstrated that integrating multiple omics data improves the accuracy of cancer subtype classification than only using gene expression data and the proposed framework has achieved better performance compared with other conventional methods.ConclusionThe new hierarchical integration deep flexible neural forest framework(HI-DFNForest) is an effective method to integrate multi-omics data to classify cancer subtypes.

OBJECTIVELoss of pituitary function due to nonfunctional pituitary adenoma (NFPA) may be due to compression of the pituitary gland. It has been proposed that the size of the gland and relative perioperative gland expansion may relate to recovery of pituitary function, but the extent of this is unclear. This study aims to assess temporal changes in hormonal function after transsphenoidal resection of NFPA and the relationship between gland reexpansion and endocrine recovery.METHODSPatients who underwent endoscopic transsphenoidal surgery by a single surgeon for resection of a nonfunctional macroadenoma were selected for inclusion. Patients with prior pituitary surgery or radiosurgery were excluded. Patient characteristics and endocrine function were extracted by chart review. Volumetric segmentation of the pre- and postoperative (≥ 6 months) pituitary gland was performed using preoperative and long-term postoperative MR images. The relationship between endocrine function over time and clinical attributes, including gland volume, were examined.RESULTSOne hundred sixty eligible patients were identified, of whom 47.5% were female; 56.9% of patients had anterior pituitary hormone deficits preoperatively. The median tumor diameter and gland volume preoperatively were 22.5 mm (interquartile range [IQR] 18.0–28.8 mm) and 0.18 cm3 (IQR 0.13–0.28 cm3), respectively. In 55% of patients, endocrine function normalized or improved in their affected axes by median last clinical follow-up of 24.4 months (IQR 3.2–51.2 months). Older age, male sex, and larger tumor size were associated with likelihood of endocrine recovery. Median time to recovery of any axis was 12.2 months (IQR 2.5–23.9 months); hypothyroidism was the slowest axis to recover. Although the gland significantly reexpanded from preoperatively (0.18 cm3, IQR 0.13–0.28 cm3) to postoperatively (0.33 cm3, IQR 0.23–0.48 cm3; p < 0.001), there was no consistent association with improved endocrine function.CONCLUSIONSRecovery of endocrine function can occur several months and even years after surgery, with more than 50% of patients showing improved or normalized function. Tumor size, and not gland volume, was associated with preserved or recovered endocrine function.

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