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The ionic environment within the nucleoplasm might diverge from the conditions found in the cytoplasm, potentially playing a role in the cellular stress response. As a result, it is conceivable that interactions of nuclear actin and actin-binding proteins (ABPs) with apoptosis factors may differ in the nucleoplasm and cytoplasm. The primary intracellular stress response is Ca 2+ influx. The junctional mediating and regulating Y protein (JMY) is an actin-binding protein and has the capability to interact with the apoptosis factor p53 in a Ca 2+ -dependent manner, forming complexes that play a regulatory role in cytoskeletal remodelling and motility. JMY's presence is observed in both the cytoplasm and nucleoplasm. Here, we show that ex vivo ectocervical squamous cells subjected to electroporation with JMY protein exhibited varying morphological alterations. Specifically, the highly differentiated superficial and intermediate cells displayed reduced nuclear size. In inflamed samples, nuclear enlargement and simultaneous cytoplasmic reduction were observable and showed signs of apoptotic processes. In contrast, the less differentiated parabasal and metaplastic cells showed increased cytoplasmic activity and the formation of membrane protrusions. Surprisingly, in severe inflammation, vaginosis or ASC-US (Atypical Squamous Cells of Undetermined Significance), JMY appears to influence only the nuclear and perinuclear irregularities of differentiated cells, and cytoplasmic abnormalities still existed after the electroporation. Our observations can provide an appropriate basis for the exploration of the relationship between cytopathologically relevant morphological changes of epithelial cells and the function of ABPs. This is particularly important since ABPs are considered potential diagnostic and therapeutic biomarkers for both cancers and chronic inflammation.

Background: National, regional and global trends in prevalence of infertility indicate its public health importance, however it effects various life dimensions of individuals and couples as well. Lifestyle habits may counteract with these factors. The aim of the study was the multicausal analysis of psychosocial and lifestyle factors undergoing assisted reproductive therapy (ART) with special regard to pre-treatment habitual physical activity (PA)., Methods: In a cross-sectional, observational cohort study on ART patients (N = 60, age 34.6 ± 5.2 years, BMI 24.2 ± 4.9 kg/m 2 ) with follow up on outcome measures a detailed description was given on PA patterns (ActriGraph GT3X, GPAQ-H) and on general and infertility related distress (BDI-13, FPI)., Results: Respondents reported normal mood state (BDI-13) but moderately high infertility-related distress (FPI) in Social- and very high distress in Sexual Concern. It was revealed that time spent with recreational PA (RPA) could counteract with infertility-related distress (Social Concern R = -0.378, p = 0.013; Relationship Concern R = -0.365, p = 0.019). In the presence of clinical pregnancy GPAQ-H RPA MET was significantly higher (p = 0.048), in the non-pregnant group cumulative values and work-related PA were higher. Correlations could be found between RPA time and the number of oocytes (R = 0.315, p = 0.045), matured oocytes (R = 0.339, p = 0.030) and embryos (R = 0.294, p = 0.062) by women who reached at least 150 min RPA (GPAQ-H). Multivariate linear regression revealed that the number of oocytes was positively influenced by the GPAQ-H recreation MET (R 2  = 0.367; F = 10.994, p = 0.004; B = 0.005, p = 0.004, B Constant = 4.604). Regarding the number of embryos (R 2  = 0.757, F = 17.692, p < 0.001, B Constant = 1.342) positive relationship was found with GPAQ-H RPA MET (B = 0.004, p < 0.001) and negative with BMI (B = -0.167, p = 0.038). It was disclosed (R 2  = 0.958, F = 408.479, p < 0.001) that higher Very Vigorous Activity (ActiGraph) was accompanied with higher hCG (B = 63.703, p ≤ 0.001). However, time spent with moderate PA (GPAQ-H) (B = 0.002, SE = 0.001, Wald = 3.944, p = 0.047, OR = 1.002) was significantly associated with live births., Conclusions: Amount of PA alone did not have a positive effect on outcome of ART. Type and intensity seemed to be more significant. Existing differences in response to infertility due to recreational PA suggest the importance of the development of a specific intervention. The robust overestimation of PA in self-reports highlights the need to improve physical literacy of women undergoing ART.

Objective: This study aimed to examine the effect of interactions between serotonin (5-HT), brain-derived neurotrophic factor (BDNF), and kisspeptin on the reproductive potential in women receiving in vitro fertilization (IVF)., Methods: Paired serum and follicular fluid (FF) samples were obtained from 30 consecutive patients receiving IVF. Primary and secondary outcome measures were the rate of chemical/clinical pregnancy and the number of mature oocytes and embryos, respectively. Serum and FF 5-HT, BDNF, kisspeptin, and platelet-activating factor (PAF) levels were measured by enzyme-linked immunosorbent assay., Results: In response to ovarian hyperstimulation, serum 5-HT and kisspeptin levels significantly increased, whereas serum BDNF and PAF levels remained unchanged. These factors were detected in FF, but they were unrelated to serum levels. FF 5-HT and BDNF levels were positively correlated. Serum kisspeptin levels were negatively correlated with FF BDNF and serum and FF PAF levels. Women who were pregnant had significantly lower FF BDNF levels compared with women who were not pregnant (21.96±12.75 vs 47.63±52.90 µg/mL). Multivariate stepwise linear regression and logistic regression analyses showed that only 5-HT and kisspeptin improved IVF outcome., Conclusions: This study indicates a role of serotoninergic mechanisms in success of IVF, but the contribution of interacting neuropeptides requires additional investigation.

Aim: This study examined the fertility performance of women after combined hysterolaparoscopic surgical management of endometriosis. Design: This study is a hospital-based retrospective review., Materials and Methods: Data collected from the records of all patients presented with endometriosis-related infertility using a checklist designed for the purpose. Result: A total of 81.3% (370/455) of women who have had the desire to have children became pregnant during the study period after the surgery. Of those who became pregnant, all three-hundred-forty-seven patients were followed to the end of their pregnancies. A successful live birth occurred in 94.2% (327/347) of individuals, and pregnancy loss occurred in 5.8% (20/347). The mean patient age was 34.1 ± 4.1 years, and the average duration of infertility was 3.4 ± 3.3 years. Pregnancy occurred spontaneously in 39.5% (146/370) of patients, after artificial insemination (AIH) in 3.8% (14/370) of women, and after in vitro fertilization-embryo transfer (IVF-ET) in 56.8% (210/370) of cases. Patients aged ≤ 35 years had a higher chance of conception post-surgery-84% versus 77%, respectively ( p = 0.039). Based on the modes of pregnancy, the timely introduction of an assisted reproductive technique (ART) demonstrated a significant effect on fertility performance postsurgery. Comparatively, this effect was 91.3% vs. 74.1% among the ≤35- and >35-year-old age groups, respectively. There was no significant difference in reproductive performance based on stages of endometriosis, nor in the other parameters evaluated. Conclusion: Our data are consistent with previous clinical studies regarding the management options of endometriosis-related infertility. Overall, the combined hysterolaparoscopy treatment is a very effective and reliable procedure, and is even more effective when combined with ART. It enhances women's wellbeing and quality of life, and significantly improves reproductive performance.

Purpose: Earlier findings revealed the damaging effect of visible light on zygotes and gametes. The aim of our study is to eliminate or significantly reduce the potentially harmful effects of light exposure during in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) and to investigate the effect of light protection on embryo development and implantation., Materials and Methods: To protect sperm cells, oocytes, and embryos from the potential harmful effects of light exposure during laboratory procedures, we created a dark environment for the cells and applied red filters on laboratory lamps and UV or infrared filters in the microscopes in order to eliminate white light exposure of the cells throughout all work stages., Results: The fertilization rate was significantly (p = 0.011) higher in light-protected ICSI cycles. Blastocyst development rates (blastocyst/embryo) were significantly (p < 0.001) higher in light-protected embryos than in those manipulated in conventional light conditions both in IVF (20.9% difference) and ICSI (38.6% difference). Numbers of clinical pregnancies/transfers of ICSI fertilized day 5 blastocysts were also significantly (p = 0.040) higher in light-protected conditions., Conclusions: These data show that light protection has a positive effect on fertilization rate and increases the blastocyst development as well as the number of clinical pregnancies/transfers. Implementation of this light protection method in IVF centers may improve the success rate while maintaining maximal embryo safety., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Transient Receptor Potential Vanilloid 1 (TRPV1) and Transient Receptor Potential Ankyrin 1 (TRPA1) expressed mainly by primary sensory neurons function as major nociceptive integrators. They are also present on the rat endometrium in an oestrogen-regulated manner. TRPV1 is upregulated in peritoneal and ovarian endometriosis patients, but there is no information about TRPA1 and their pathophysiological significances. In this study, patients undergoing laparoscopic surgery were investigated: severe dysmenorrhoea due to rectosigmoid deep infiltrating endometriosis ( n = 15), uterine fibroid-induced moderate dysmenorrhoea ( n = 7) and tubal infertility with no pain ( n = 6). TRPA1 and TRPV1 mRNA and protein expressions were determined by quantitative polymerase chain reaction and semi-quantitative immunohistochemistry from the endometrium samples taken by curettage. Results were correlated with the clinical characteristics including pain intensity. TRPA1 and TRPV1 receptors were expressed in the healthy human endometrium at mRNA and protein levels. Sparse, scattered cytoplasmic TRPA1 and TRPV1 immunopositivities were found in the stroma and epithelial layers. We detected upregulated mRNA levels in deep infiltrating endometriosis lesions, and TRPV1 gene expression was also elevated in autocontrol endometrium of deep infiltrating endometriosis patients. Histological scoring revealed significant TRPA1 and TRPV1 difference between deep infiltrating endometriosis stroma and epithelium, and in deep infiltrating endometriosis epithelium compared to control samples. Besides, we measured elevated stromal TRPV1 immunopositivity in deep infiltrating endometriosis. Stromal TRPA1 and TRPV1 immunoreactivities strongly correlated with dysmenorrhoea severity, as well TRPV1 expression on ectopic epithelial cells and macrophages with dyspareunia. Epithelial TRPA1 and stromal TRPV1 immunopositivity also positively correlated with dyschezia severity. We provide the first evidence for the presence of non-neuronal TRPA1 receptor in the healthy human endometrium and confirm the expression of TRPV1 channels. Their upregulations in rectosigmoid deep infiltrating endometriosis lesions and correlations with pain intensity suggest potential roles in pathophysiological mechanisms of the disease.

Objective: To evaluate the effect of low-dose aspirin therapy on ovarian hyperstimulation syndrome (OHSS) in an unselected group of patients undergoing in vitro fertilization (IVF)., Design: Randomized clinical trial., Setting: Division of Reproductive Medicine at the Department of Obstetrics and Gynecology, University of Pécs, Faculty of Medicine, Pécs, Hungary., Patient(s): Patients who underwent IVF between 2000 and 2006., Intervention(s): Initiation of 3154 IVF cycles, for which gonadotropin-releasing hormone agonist was used in 2425 cycles; 1503 cycles randomly selected for low-dose aspirin treatment starting from the first day of controlled ovarian hyperstimulation compared with no treatment in the remaining 922 cycles., Main Outcome Measure(s): The incidence of severe or critical OHSS and the rate of clinical pregnancy., Result(s): During this time period, 45 cases of severe OHSS were detected. Only two of the OHSS patients had received aspirin previously., Conclusion(s): Based on our preliminary results, introduction of low-dose aspirin therapy during ovulation induction for the prevention of OHSS in high-risk patients should be considered., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Seasonal variations of reproductive functions in wild mammals are well known. Similar but blunted seasonal trends have also been described for humans., Methods: We performed a questionnaire-based study of 149 patients that was designed to search for environmental influence on symptom presentation among patients attending an open menopause service., Results: The evaluated data show a conspicuous seasonality in cessation of menstrual bleeding, with a higher peak after the vernal (spring) equinox and a lower one after the autumn equinox., Conclusions: Of the several environmental factors considered in this study, the sequence of seasons seems to affect most obviously the process leading to the loss of menstrual cycling. The triggering factor(s) eliciting the onset of the menopausal process and the mediators involved, however, need further analysis.

Insulin-like growth factors I and II (IGF-I and -II) are potent mitogens for various cancers, including carcinoma of the prostate. In several experimental cancers, treatment with antagonists of growth hormone-releasing hormone (GH-RH) produces a reduction in IGF-I and -II, concomitant to inhibition of tumor growth. To investigate the mechanisms involved, we treated male nude mice bearing xenografts of DU-145 human androgen-independent prostate cancer for 8 weeks with potent GH-RH antagonist MZ-5-156 at a dose of 20 microg/animal s.c. twice a day. Tumor growth, serum and tumor levels of IGF-I and -II, and the mRNA expression of IGF-I and -II in tumors were evaluated. After 8 weeks of therapy, final volume and weight of DU-145 tumors in mice treated with MZ-5-156 were significantly (P < 0.01) decreased compared with controls, and serum IGF-I showed a significant reduction. Treatment of nude mice bearing DU-145 xenografts with MZ-5-156 also significantly (P < 0.01) diminished by 77% the levels of IGF-II in tumor tissue compared with controls, but did not affect the concentration of IGF-I. Reverse transcription-PCR analyses revealed a high expression of IGF-II mRNA in DU-145 tumors. Treatment with GH-RH antagonist MZ-5-156 decreased the expression of IGF-II mRNA by 58% (P < 0.01) as compared with controls. Our work suggests that GH-RH antagonist MZ-5-156 may inhibit the growth of DU-145 human androgen-independent prostate cancers through a reduction in the production and mRNA expression of IGF-II by the tumor tissue. These findings extend our observations on the mechanism of action of GH-RH antagonists and may explain how GH-RH antagonists inhibit tumor growth.

To create cytotoxic hybrid analogs of somatostatin (SST), octapeptides RC-160 (D-Phe-Cys-Tyr-D-Trp- Lys-Val-Cys-Trp-NH2) and RC-121 (D-Phe-Cys-Tyr-D-Trp- Lys-Val-Cys-Thr-NH2) were linked to doxorubicin (DOX) or its superactive derivative, 2-pyrrolino-DOX (AN-201). The conjugation was performed by coupling N-9-fluorenylmethoxycarbonyl (N-Fmoc)-DOX-14-O-hemiglutarate or 2-pyrrolino-DOX-14-O-hemiglutarate to the amino terminus of [Lys(Fmoc)5]RC-160 yielding AN-163 and AN-258, respectively, after deprotection. The respective cytotoxic conjugates of RC-121 (AN-162 and AN-238) were prepared similarly. In vitro tests on human cancer cell lines-MKN-45 gastric cancer, MDA-MB-231 breast cancer, PC-3 prostate cancer, and MIA PaCa-2 pancreatic cancer-demonstrated that the antiproliferative activity of the cytotoxic radicals in these conjugates was virtually retained. In H-345 human small cell lung carcinoma cell line, conjugates of RC-121 preserved the cytotoxic activity of their radicals, but the hybrids with RC-160 showed approximately 10 times lower activity. The ability of the carriers and the hybrids to inhibit the binding of 125I-labeled RC-160 to receptors for SST on rat pituitary membrane preparation was also determined. The cytotoxic conjugates inhibited 50% of the specific binding of the radioligand in the nanomolar concentration range (IC50 < 80 nM). When SST-like activities of AN-238 and its carrier, RC-121, were compared in the rat pituitary superfusion system, both compounds were found to suppress a stimulated growth hormone release at nanomolar concentrations. Preliminary studies in animal models of breast and prostate cancers showed that AN-238 is less toxic than AN-201 and more potent in inhibiting tumor growth. These highly active cytotoxic analogs of SST have been designed as targeted antitumor agents for the treatment of various cancers expressing receptors for SST octapeptides.