Gut Microbiota and Oral Contraceptive Use in Women with Polycystic Ovary Syndrome: A Systematic Review.

Background: Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine syndromes affecting women at reproductive age. With increasing knowledge of the role of the microbiota in the pathogenesis of PCOS, new management strategies began to emerge. However, data on the impact of established treatment regimens, such as metformin and oral contraceptive agents, on the gut microbiota composition are scarce. This study aimed to evaluate the specificity of the gut microbiota in women with PCOS before and after treatment with oral contraceptives. Methods: We have systematically searched the following databases: PubMed/MEDLINE, Scopus, Web of Science and Google Scholar. The last search was performed on 13 May 2024. We included only full-text original research articles written in English. The risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale. Results: The above described search strategy retrieved 46 articles. Additionally, 136 articles were identified and screened through Google Scholar. After removing duplicates, we screened the titles and abstracts, resulting in three eligible articles constituting the final pool. They were published between 2020 and 2022 and are based on three ethnically distinct study populations: Turkish, Spanish and American. The studies included a total of 37 women diagnosed with PCOS and using OCs. Conclusions: OC treatment does not seem to affect the gut microbiota in a significant way in patients with PCOS in short observation. Well-designed randomized controlled studies with adequate, unified sample size are lacking.

Dysbiosis of the Upper Gastrointestinal Tract in Head-and-Neck Cancer Survivors: A Pilot Study Using the Capsule Sponge Device.

BACKGROUND: A non-endoscopic capsule-sponge device allows sampling the entire length of the esophagus. Here, we compared microbiomes of the oral cavity, esophagus, and gastric corpus collected by oral swab, capsule-sponge device, and endoscopic biopsy, respectively, in patients representing three distinct risk profiles for esophageal squamous cell carcinoma (ESCC). METHODS: The study enrolled 11 patients with esophageal squamous intraepithelial neoplasia, 21 patients after curative treatment for head and neck squamous cell cancer (HNSCC) (HNSCC survivors), and 40 patients with functional dyspeptic (FD) symptoms. Microbial genomic DNA was analyzed using 16S rRNA gene amplicon sequencing. RESULTS: The Shannon index of the capsule-sponge sample microbiota was significantly higher in FD group than in patients after treatment for HNSCC, and the Chao index of gastric samples differed between HNSCC survivors and FD patients. Analysis of the ß-diversity of FD patients, HNSCC, and esophageal squamous intraepithelial neoplasia showed that different genera formed at each location. The abundance of 205, 116, and 9 genera differed between FD patients and HNSCC survivors in the gastric, capsule-sponge, and oral samples, respectively; 33 genera differed between the FD group and patients with esophageal squamous intraepithelial neoplasia in capsule-sponge samples. CONCLUSIONS: The bacterial communities of the upper digestive tract were clustered according to the anatomic site. Despite substantial differences in gastric and esophageal microbiota samples between FD patients and HNSCC survivors, the microbial members and diversity showed small differences between FD patients and those with esophageal squamous intraepithelial neoplasia. It remains unclear whether gastric and esophageal dysbiosis is associated with or is a consequence of treatment for HNSCC.

Intrauterine Shaping of Fetal Microbiota.

Mechanisms resulting from the physiological immaturity of the digestive system in children delivered before 32 weeks of gestation and, in particular, different interactions between the microbiome and the body have not been fully elucidated yet. Next-generation sequencing methods demonstrated the presence of bacterial DNA in the placenta and amniotic fluid, which may reflect bacterial populations that initiate intestinal colonization in utero. Numerous studies confirmed the hypothesis stating that intestinal bacteria played an important role in the pathogenesis of necrotizing enterocolitis (NEC) early- and late-onset neonatal sepsis (EONS and LONS). The model and scale of disorders within the intestinal microbiome are the subject of active research in premature infants. Neonatal meconium was primarily used as an indicator defining the environment in utero, as it is formed before birth. Metagenomic results and previous data from microbiological bacterial cultures showed a correlation between the time from birth to sample collection and the detection of bacteria in the neonatal meconium. Therefore, it may be determined that the colonization of the newborn's intestines is influenced by numerous factors, which may be divided into prenatal, perinatal, and postnatal, with particular emphasis put on the mode of delivery and contact with the parent immediately after birth. Background: The aim of this review was to collect available data on the intrauterine shaping of the fetal microbiota. Methods: On 13 March 2024, the available literature in the PubMed National Library of Medicine search engine was reviewed using the following selected keywords: "placental microbiome", "intestinal bacteria in newborns and premature infants", and "intrauterine microbiota". Results: After reviewing the available articles and abstracts and an in-depth analysis of their content, over 100 articles were selected for detailed elaboration. We focused on the origin of microorganisms shaping the microbiota of newborns. We also described the types of bacteria that made up the intrauterine microbiota and the intestinal microbiota of newborns. Conclusions: The data presented in the review on the microbiome of both term newborns and those with a body weight below 1200 g indicate a possible intrauterine colonization of the fetus depending on the duration of pregnancy. The colonization occurs both via the vaginal and intestinal route (hematogenous route). However, there are differences in the demonstrated representatives of various types of bacteria, phyla Firmicutes and Actinobacteria in particular, taking account of the distribution in their abundance in the individual groups of pregnancy duration. Simultaneously, the distribution of the phyla Actinobacteria and Proteobacteria is consistent. Considering the duration of pregnancy, it may also be concluded that the bacterial flora of vaginal origin dominates in preterm newborns, while the flora of intestinal origin dominates in term newborns. This might explain the role of bacterial and infectious factors in inducing premature birth with the rupture of fetal membranes.

Microbial and Metabolic Gut Profiling across Seven Malignancies Identifies Fecal Faecalibacillus intestinalis and Formic Acid as Commonly Altered in Cancer Patients.

The key association between gut dysbiosis and cancer is already known. Here, we used whole-genome shotgun sequencing (WGS) and gas chromatography/mass spectrometry (GC/MS) to conduct metagenomic and metabolomic analyses to identify common and distinct taxonomic configurations among 40, 45, 71, 34, 50, 60, and 40 patients with colorectal cancer, stomach cancer, breast cancer, lung cancer, melanoma, lymphoid neoplasms and acute myeloid leukemia (AML), respectively, and compared the data with those from sex- and age-matched healthy controls (HC). α-diversity differed only between the lymphoid neoplasm and AML groups and their respective HC, while ß-diversity differed between all groups and their HC. Of 203 unique species, 179 and 24 were under- and over-represented, respectively, in the case groups compared with HC. Of these, Faecalibacillus intestinalis was under-represented in each of the seven groups studied, Anaerostipes hadrus was under-represented in all but the stomach cancer group, and 22 species were under-represented in the remaining five case groups. There was a marked reduction in the gut microbiome cancer index in all case groups except the AML group. Of the short-chain fatty acids and amino acids tested, the relative concentration of formic acid was significantly higher in each of the case groups than in HC, and the abundance of seven species of Faecalibacterium correlated negatively with most amino acids and formic acid, and positively with the levels of acetic, propanoic, and butanoic acid. We found more differences than similarities between the studied malignancy groups, with large variations in diversity, taxonomic/metabolomic profiles, and functional assignments. While the results obtained may demonstrate trends rather than objective differences that correlate with different types of malignancy, the newly developed gut microbiota cancer index did distinguish most of the cancer cases from HC. We believe that these data are a promising step forward in the search for new diagnostic and predictive tests to assess intestinal dysbiosis among cancer patients.

Gas Chromatography-Mass Spectrometry-Based Analyses of Fecal Short-Chain Fatty Acids (SCFAs): A Summary Review and Own Experience.

The gut microbiome, crucial to human health, changes with age and disease, and influences metabolic profiles. Gut bacteria produce short-chain fatty acids (SCFAs), essential for maintaining homeostasis and modulating inflammation. Dysbiosis, commonly due to poor diet or lifestyle, disrupts the integrity of the intestinal barrier and may contribute to conditions such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD). Analytical methods such as gas chromatography-mass spectrometry (GC/MS) are vital for SCFA analysis, with various preparation and storage techniques improving the accuracy. Advances in these methods have improved the reliability and sensitivity of SCFA quantification, which is crucial for the identification of disease biomarkers. Evidence from GC/MS-based studies has revealed that accurate SCFA quantification requires meticulous sample preparation and handling. The process begins with the extraction of SCFAs from biological samples using methods such as direct solvent extraction or solid-phase microextraction (SPME), both of which require optimization for maximum recovery. Derivatization, which chemically modifies SCFAs to enhance volatility and detectability, is a crucial step, typically involving esterification or silylation. Following this, the cleanup process removes impurities that might interfere with the analysis. Although recent advances in GC/MS technology have significantly improved SCFA-detection sensitivity and specificity, proper sample storage, with acid preservatives and the avoidance of repeated thawing, is essential for maintaining SCFA integrity.

Uterine fibroids: current research on novel drug targets and innovative therapeutic strategies.

INTRODUCTION: Uterine fibroids, the most common nonmalignant tumors affecting the female genital tract, are a significant medical challenge. This article focuses on the most recent studies that attempted to identify novel non-hormonal therapeutic targets and strategies in UF therapy. AREAS COVERED: This review covers the analysis of the pharmacological and biological mechanisms of the action of natural substances and the role of the microbiome in reference to UFs. This study aimed to determine the potential role of these compounds in UF prevention and therapy. EXPERT OPINION: While there are numerous approaches for treating UFs, available drug therapies for disease control have not been optimized yet. This review highlights the biological potential of vitamin D, EGCG and other natural compounds, as well as the microbiome, as promising alternatives in UF management and prevention. Although these substances have been quite well analyzed in this area, we still recommend conducting further studies, particularly randomized ones, in the field of therapy with these compounds or probiotics. Alternatively, as the quality of data continues to improve, we propose the consideration of their integration into clinical practice, in alignment with the patient's preferences and consent.

Microbiome Sex-Related Diversity in Non-Muscle-Invasive Urothelial Bladder Cancer.

Sex-specific discrepancies in bladder cancer (BCa) are reported, and new studies imply that microbiome may partially explain the diversity. We aim to provide characterization of the bladder microbiome in both sexes diagnosed with non-muscle-invasive BCa with specific insight into cancer grade. In our study, 16S rRNA next-generation sequencing was performed on midstream urine, bladder tumor sample, and healthy-appearing bladder mucosa. Bacterial DNA was isolated using QIAamp Viral RNA Mini Kit. Metagenomic analysis was performed using hypervariable fragments of the 16S rRNA gene on Ion Torrent Personal Genome Machine platform. Of 41 sample triplets, 2153 taxa were discovered: 1739 in tumor samples, 1801 in healthy-appearing bladder mucosa and 1370 in midstream urine. Women were found to have smaller taxa richness in Chao1 index than men (p = 0.03). In comparison to low-grade tumors, patients with high-grade lesions had lower bacterial diversity and richness in urine. Significant differences between sexes in relative abundance of communities at family level were only observed in high-grade tumors.

Cervical microbiota dysbiosis associated with high-risk Human Papillomavirus infection.

High-risk Human Papillomavirus (HR-HPV) genotypes, specifically HPV16 and HPV18, pose a significant risk for the development of cervical intraepithelial neoplasia and cervical cancer. In the multifaceted cervical microenvironment, consisting of immune cells and diverse microbiota, Lactobacillus emerges as a pivotal factor, wielding significant influence in both stabilizing and disrupting the microbiome of the reproductive tract. To analyze the distinction between the cervical microbiota and Lactobacillus-dominant/non-dominant status of HR-HPV and non-infected healthy women, sixty-nine cervical swab samples were analyzed, included 44 with HR-HPV infection and healthy controls. All samples were recruited from Human Papillomavirus-based cervical cancer screening program and subjected to 16s rRNA sequencing analysis. Alpha and beta diversity analyses reveal no significant differences in the cervical microbiota of HR-HPV-infected women, including 16 and 18 HPV genotypes, and those with squamous intraepithelial lesion (SIL), compared to a control group. In this study we identified significantly lower abundance of Lactobacillus mucosae in women with HR-HPV infection compared to the control group. Furthermore, changes in bacterial diversity were noted in Lactobacillus non-dominant (LND) samples compared to Lactobacillus-dominant (LD) in both HR-HPV-infected and control groups. LND samples in HR-HPV-infected women exhibited a cervical dysbiotic state, characterized by Lactobacillus deficiency. In turn, the LD HR-HPV group showed an overrepresentation of Lactobacillus helveticus. In summary, our study highlighted the distinctive roles of L. mucosae and L. helveticus in HR-HPV infections, signaling a need for further research to demonstrate potential clinical implications of cervical microbiota dysbiosis.

Effects of Soluble Dextrin Fiber from Potato Starch on Body Weight and Associated Gut Dysbiosis Are Evident in Western Diet-Fed Mice but Not in Overweight/Obese Children.

BACKGROUND: The study investigated the impact of starch degradation products (SDexF) as prebiotics on obesity management in mice and overweight/obese children. METHODS: A total of 48 mice on a normal diet (ND) and 48 on a Western diet (WD) were divided into subgroups with or without 5% SDexF supplementation for 28 weeks. In a human study, 100 overweight/obese children were randomly assigned to prebiotic and control groups, consuming fruit and vegetable mousse with or without 10 g of SDexF for 24 weeks. Stool samples were analyzed for microbiota using 16S rRNA gene sequencing, and short-chain fatty acids (SCFA) and amino acids (AA) were assessed. RESULTS: Results showed SDexF slowed weight gain in female mice on both diets but only temporarily in males. It altered bacterial diversity and specific taxa abundances in mouse feces. In humans, SDexF did not influence weight loss or gut microbiota composition, showing minimal changes in individual taxa. The anti-obesity effect observed in mice with WD-induced obesity was not replicated in children undergoing a weight-loss program. CONCLUSIONS: SDexF exhibited sex-specific effects in mice but did not impact weight loss or microbiota composition in overweight/obese children.

Breast cancer but not the menopausal status is associated with small changes of the gut microbiota.

Background: Possible relationships between gut dysbiosis and breast cancer (BC) development and progression have been previously reported. However, the results of these metagenomics studies are inconsistent. Our study involved 88 patients diagnosed with breast cancer and 86 cancer-free control women. Participants were divided into groups based on their menopausal status. Fecal samples were collected from 47 and 41 pre- and postmenopausal newly diagnosed breast cancer patients and 51 and 35 pre- and postmenopausal controls, respectively. In this study, we performed shotgun metagenomic analyses to compare the gut microbial community between pre- and postmenopausal BC patients and the corresponding controls. Results: Firstly, we identified 12, 64, 158, and 455 bacterial taxa on the taxonomy level of phyla, families, genera, and species, respectively. Insignificant differences of the Shannon index and ß-diversity were found at the genus and species levels between pre- and postmenopausal controls; the differences concerned only the Chao index at the species level. No differences in α-diversity indexes were found between pre- and postmenopausal BC patients, although ß-diversity differed these subgroups at the genus and species levels. Consistently, only the abundance of single taxa differed between pre- and postmenopausal controls and cases, while the abundances of 14 and 23 taxa differed or tended to differ between premenopausal cases and controls, and between postmenopausal cases and controls, respectively. There were similar differences in the distribution of enterotypes. Of 460 bacterial MetaCyc pathways discovered, no pathways differentiated pre- and postmenopausal controls or BC patients, while two and one pathways differentiated cases from controls in the pre- and postmenopausal subgroups, respectively. Conclusion: While our findings did not reveal an association of changes in the overall microbiota composition and selected taxa with the menopausal status in cases and controls, they confirmed differences of the gut microbiota between pre- and postmenopausal BC patients and the corresponding controls. However, these differences were less extensive than those described previously.

Human Papillomavirus Infections and the Role Played by Cervical and Cervico-Vaginal Microbiota-Evidence from Next-Generation Sequencing Studies.

This comprehensive review encompasses studies examining changes in the cervical and cervico-vaginal microbiota (CM and CVM) in relation to human papillomavirus (HPV) using next-generation sequencing (NGS) technology. HPV infection remains a prominent global health concern, with a spectrum of manifestations, from benign lesions to life-threatening cervical cancers. The CM and CVM, a unique collection of microorganisms inhabiting the cervix/vagina, has emerged as a critical player in cervical health. Recent research has indicated that disruptions in the CM and CVM, characterized by a decrease in Lactobacillus and the overgrowth of other bacteria, might increase the risk of HPV persistence and the progression of cervical abnormalities. This alteration in the CM or CVM has been linked to a higher likelihood of HPV infection and cervical dysplasia. NGS technology has revolutionized the study of the cervical microbiome, providing insights into microbial diversity, dynamics, and taxonomic classifications. Bacterial 16S rRNA gene sequencing, has proven invaluable in characterizing the cervical microbiome, shedding light on its role in HPV infections and paving the way for more tailored strategies to combat cervical diseases. NGS-based studies offer personalized insights into an individual's cervical microbiome. This knowledge holds promise for the development of novel diagnostic tools, targeted therapies, and preventive interventions for cervix-related conditions, including cervical cancer.

Association of Mitochondrial Variants with the Joint Occurrence of Polycystic Ovary Syndrome and Hashimoto's Thyroiditis.

BACKGROUND: The prevalence of Hashimoto's thyroiditis (HT) among women with polycystic ovary syndrome (PCOS) is higher than in the general female population, but the factors predisposing to the coexistence of these disorders remain unclear. This study employed whole genome sequencing of mitochondrial DNA to identify genetic variants potentially associated with the development of PCOS and HT and predisposing to their joint occurrence. RESULTS: A total of 84 women participated, including patients with PCOS, HT, coexisting PCOS and HT (PCOS + HT) and healthy women. Both Fisher's exact and Mann-Whitney U statistical analyses were performed to compare the frequency of variants between groups. Ten differentiating variants were common to both analyses in PCOS + HT vs. PCOS, one in PCOS + HT vs. HT, and six in PCOS + HT vs. control. Several variants differentiating the PCOS + HT group from PCOS and controls were identified, located both in the mitochondrial genes (including the MT-CYB, MT-ND1, MT-ND2, MT-ND4, MT-ND6, MT-CO1, MT-CO3) and the D-loop region. Only two variants differentiated PCOS + HT and HT groups. One variant (13237a in MT-ND5) was common for all three comparisons and underrepresented in the PCOS + HT group. Functional enrichment analysis showed 10 pathways that were unique for the comparison of PCOS + HT and PCOS groups, especially related to ATP production and oxidative phosphorylation, and one pathway, the NADH-quinone oxidoreductase, chain M/4, that was unique for the comparison of PCOS + HT and control groups. Notably, nine pathways shared commonality between PCOS + HT vs. PCOS and PCOS + HT vs. control, related to the biogenesis and assembly of Complex I. CONCLUSION: This study provides novel insights into the genetic variants associated with oxidative stress in women with coexisting PCOS and HT. Mitochondrial dysfunction and oxidative stress appear to play a role in the pathogenesis of both conditions. However, more mitochondrial variants were found to differentiate women with both PCOS and HT from those with PCOS alone than from those with HT alone.

Polycystic Ovary Syndrome and Oxidative Stress-From Bench to Bedside.

Oxidative stress (OS) is a condition that occurs as a result of an imbalance between the production of reactive oxygen species (ROS) and the body's ability to detoxify and neutralize them. It can play a role in a variety of reproductive system conditions, including polycystic ovary syndrome (PCOS), endometriosis, preeclampsia, and infertility. In this review, we briefly discuss the links between oxidative stress and PCOS. Mitochondrial mutations may lead to impaired oxidative phosphorylation (OXPHOS), decreased adenosine triphosphate (ATP) production, and an increased production of ROS. These functional consequences may contribute to the metabolic and hormonal dysregulation observed in PCOS. Studies have shown that OS negatively affects ovarian follicles and disrupts normal follicular development and maturation. Excessive ROS may damage oocytes and granulosa cells within the follicles, impairing their quality and compromising fertility. Impaired OXPHOS and mitochondrial dysfunction may contribute to insulin resistance (IR) by disrupting insulin signaling pathways and impairing glucose metabolism. Due to dysfunctional OXPHOS, reduced ATP production, may hinder insulin-stimulated glucose uptake, leading to IR. Hyperandrogenism promotes inflammation and IR, both of which can increase the production of ROS and lead to OS. A detrimental feedback loop ensues as IR escalates, causing elevated insulin levels that exacerbate OS. Exploring the relations between OS and PCOS is crucial to fully understand the role of OS in the pathophysiology of PCOS and to develop effective treatment strategies to improve the quality of life of women affected by this condition. The role of antioxidants as potential therapies is also discussed.

Diarrheal-associated gut dysbiosis in cancer and inflammatory bowel disease patients is exacerbated by Clostridioides difficile infection.

Introduction: Low diversity gut dysbiosis can take different forms depending on the disease context. In this study, we used shotgun metagenomic sequencing and gas chromatography-mass spectrometry (GC-MS) to compared the metagenomic and metabolomic profiles of Clostridioides (Clostridium) difficile diarrheal cancer and inflammatory bowel disease (IBD) patients and defined the additive effect of C. difficile infection (CDI) on intestinal dysbiosis. Results: The study cohort consisted of 138 case-mix cancer patients, 43 IBD patients, and 45 healthy control individuals. Thirty-three patients were also infected with C. difficile. In the control group, three well-known enterotypes were identified, while the other groups presented with an additional Escherichia-driven enterotype. Bacterial diversity was significantly lower in all groups than in healthy controls, while the highest level of bacterial species richness was observed in cancer patients. Fifty-six bacterial species had abundance levels that differentiated diarrheal patient groups from the control group. Of these species, 52 and 4 (Bacteroides fragilis, Escherichia coli, Klebsiella pneumoniae, and Ruminococcus gnavus) were under-represented and over-represented, respectively, in all diarrheal patient groups. The relative abundances of propionate and butyrate were significantly lower in fecal samples from IBD and CDI patients than in control samples. Isobutyrate, propanate, and butyrate concentrations were lower in cancer, IBD, and CDI samples, respectively. Glycine and valine amino acids were over- represented in diarrheal patients. Conclusion: Our data indicate that different external and internal factors drive comparable profiles of low diversity dysbiosis. While diarrheal-related low diversity dysbiosis may be a consequence of systemic cancer therapy, a similar phenotype is observed in cases of moderate to severe IBD, and in both cases, dysbiosis is exacerbated by incidence of CDI.

Exome sequencing to explore the possibility of predicting genetic susceptibility to the joint occurrence of polycystic ovary syndrome and Hashimoto's thyroiditis.

A large body of evidence indicates that women with polycystic ovary syndrome (PCOS) have a higher risk of developing Hashimoto's thyroiditis (HT) than healthy individuals. Given the strong genetic impact on both diseases, common predisposing genetic factors are possibly involved but are not fully understood. Here, we performed whole-exome sequencing (WES) for 250 women with sporadic PCOS, HT, combined PCOS and HT (PCOS+HT), and healthy controls to explore the genetic background of the joint occurrence of PCOS and HT. Based on relevant comparative analyses, multivariate logistic regression prediction modeling, and the most informative feature selection using the Monte Carlo feature selection and interdependency discovery algorithm, 77 variants were selected for further validation by TaqMan genotyping in a group of 533 patients. In the allele frequency test, variants in RAB6A, GBP3, and FNDC7 genes were found to significantly (padjusted < 0.05) differentiated the PCOS+HT and PCOS groups, variant in HIF3A differentiated the PCOS+HT and HT groups, whereas variants in CDK20 and CCDC71 differentiated the PCOS+HT and both single disorder groups. TaqMan genotyping data were used to create final prediction models, which differentiated between PCOS+HT and PCOS or HT with a prediction accuracy of AUC = 0.78. Using a 70% cutoff of the prediction score improved the model parameters, increasing the AUC value to 0.87. In summary, we demonstrated the polygenic burden of both PCOS and HT, and many common and intersecting signaling pathways and biological processes whose disorders mutually predispose patients to the development of both diseases.

Resolving the role of podoplanin in the motility of papillary thyroid carcinoma-derived cells using RNA sequencing.

The intracellular level of podoplanin (PDPN), a transmembrane protein of still unclear function, is frequently altered in metastatic tumors. High expression of PDPN is frequently observed in papillary thyroid cancer (PTC) specimens. Similarly, PTC-derived cell lines (BCPAP and TPC1, harboring the BRAF V600E mutation and RET/PTC1 fusion, respectively), also present enhanced PDPN yield. We previously reported that depletion of PDPN impairs migration of TPC1 cells, but augments metastasis of BCPAP cells. Interestingly, this phenomenon stays in contrast to the migratory pattern observed for wild-type cells, where TPC1 exhibited higher motility than BCPAP cells. Here, we aimed to elucidate the potential role of PDPN in regulation of molecular mechanisms leading to the diverse metastatic features of the studied PTC-derived cells. We consider that this phenomenon may be caused by alternative regulation of signaling pathways due to the presence of the mutated BRAF allele or RET/PTC1 fusion. The high-throughput RNA sequencing (RNA-seq) technique was used to uncover the genes and signaling pathways affected in wild-type and PDPN-depleted TPC1 and BCPAP cells. We found that changes in the expression of various factors of signaling pathways, like RHOA and RAC1 GTPases and their regulators, are linked with both high PDPN levels and presence of the BRAF V600E mutation. We imply that the suppressed motility of wild-type BCPAP cells results from overactivation of RHOA through natively high PDPN expression. This process is accompanied by inhibition of the PI3K kinase and consequently RAC1, due to overactivation of RAS-mediated signaling and the PTEN regulator.

Molecular Pathways of Altered Brain Development in Fetuses Exposed to Hypoxia.

Perinatal hypoxia is a major cause of neurodevelopmental impairment and subsequent motor and cognitive dysfunctions; it is associated with fetal growth restriction and uteroplacental dysfunction during pregnancy. This review aims to present the current knowledge on brain development resulting from perinatal asphyxia, including the causes, symptoms, and means of predicting the degree of brain damage. Furthermore, this review discusses the specificity of brain development in the growth-restricted fetus and how it is replicated and studied in animal models. Finally, this review aims at identifying the least understood and missing molecular pathways of abnormal brain development, especially with respect to potential treatment intervention.

The role of microbiota in the pathophysiology of uterine fibroids - a systematic review.

For a long time, the uterus had been considered a sterile organ, meaning that under physiological conditions the uterus would not be colonized by bacteria. Based on available data, it may be concluded that the gut and uterine microbiome are related, and that the role of this microbiome is greater than expected. Despite being the most common pelvic neoplasms in women of reproductive age, uterine fibroids (UFs) are still poorly understood tumors whose etiology has not been fully determined. This systematic review presents the relationship between intestinal and uterine dysbiosis and uterine fibroids. A systematic review of three medical databases was carried out: the MEDLINE/PubMed, Scopus and Cochrane. In this study, 195 titles and abstracts were reviewed, including only original articles and clinical trials of uterine microbiome criteria. Finally, 16 studies were included to the analysis. In recent years, researchers dealing with reproduction in a broad sense have focused on the microbiome in various locations to study its role in the pathogenesis and, consequently, the prevention and treatment of diseases of the genital organ. Conventional microbial detection methods are not suitable for identifying bacteria, which are difficult to culture. Next-generation sequencing (NGS) provides an easier and faster and more informative analysis of bacterial populations. It seems that gut microbiota dysbiosis has the potential to be a risk factor for uterine fibroids or affect the disease process. Some changes were shown in many types of bacteria, such as Firmicutes, Proteobacteria, Actinobacteria and Verrucomicrobia detected in fecal samples in patients with uterine fibroids. In view of the few results on the link between the microbiome and uterine fibroids, further intensive studies in humans and animal models are necessary, including the possible use of different microbiome modulations in the prevention or treatment of uterine fibroids.

Biomarkers for Pregnancy Latency Prediction after Preterm Premature Rupture of Membranes-A Systematic Review.

Preterm premature rupture of membranes, leading to preterm birth, is associated with neonatal and maternal morbidity and mortality. The study aimed to review the existing data on the best predictive value of pregnancy latency for known biomarkers in pregnancies after preterm premature rupture of membranes. The following databases were screened for the purposes of this systematic review: Pubmed/MEDLINE, Web of Science, EMBASE, Scopus, and the Cochrane Library. The study was conducted according to the PRISMA guidelines for systematic reviews. Only a few studies assessed biomarkers predicting pregnancy duration after PPROM. IL-6, IL-8, CRP, IL1RA, s-endoglin, ßhCG, AFP, PCT, urea, creatinine, oxygen radical absorbance capacity, MDA, lipocalin-2, endotoxin activity, MMP-8, MMP-9 and S100 A8/A9 were found to have a positive predictive value for delivery timing prediction. Proinflammatory biomarkers, such as IL-6 or CRP, proved to be best correlated with delivery timing, independent of the occurrence of intrauterine infection.

The interplay between gingival crevicular fluid microbiome and metabolomic profile in intensively treated people with type 1 diabetes - a combined metagenomic/metabolomic approach cross-sectional study.

Aims: This study aimed to assess the gingival crevicular fluid (GCF) microbiome and metabolome of adults with type 1 diabetes (T1D) treated with continuous subcutaneous insulin infusion (CSII). Methods: In this cross-sectional study, the GCF of adults with T1D treated with CSII and non-diabetic controls were sampled, and metagenomic/metabolomic analyses were performed. Results: In total, 65 participants with T1D and 45 healthy controls with a mean age of 27.05 ± 5.95 years were investigated. There were 22 cases of mild gingivitis (G) in the T1D group. There were no differences considering the Shannon and Chao indices and ß-diversity between people with T1D and G, with T1D without G, and healthy controls. Differential taxa were identified, which were mainly enriched in people with T1D and G. Acetic acid concentration was higher in people with T1D, regardless of the presence of G, than in healthy controls. Propionic acid was higher in people with T1D and G than in healthy controls. Isobutyric and isovaleric acid levels were higher in individuals with T1D and G than in the other two subgroups. The concentration of valeric acid was lower and that of caproic acid was higher in people with T1D (regardless of gingival status) than in healthy controls. Conclusions: The identification of early changes in periodontal tissues by targeting the microbiome and metabolome could potentially enable effective prevention and initial treatment of periodontal disease in people with T1D.