Oncofertility as an Essential Part of Comprehensive Cancer Treatment in Patients of Reproductive Age, Adolescents and Children.

The number of children, adolescents and young adults diagnosed with cancer has been rising recently. Various oncological treatments have a detrimental effect on female fertility, and childbearing becomes a major issue during surveillance after recovery. This review discusses the impact of oncological treatments on the ovarian reserve with a thorough explanation of oncologic treatments' effects and modes of oncofertility procedures. The aim of this review is to help clinicians in making an informed decision about post-treatment fertility in their patients. Ultimately, it may lead to improved overall long-term outcomes among young populations suffering from cancer.

Targeting yeast topoisomerase II by imidazo and triazoloacridinone derivatives resulting in their antifungal activity.

Fungal pathogens are considered as serious factors for deadly diseases and are a case of medical concern. Invasive fungal infections also complicate the clinical course of COVID-19, leading to a significant increase in mortality. Furthermore, fungal strains' multidrug resistance has increased the demand for antifungals with a different mechanism of action. The present study aimed to identify antifungal compounds targeting yeast topoisomerase II (yTOPOII) derived from well-known human topoisomerase II (hTOPOII) poisons C-1305 and C-1311. Two sets of derivatives: triazoloacridinones (IKE1-8) and imidazoacridinones (IKE9-14) were synthetized and evaluated with a specific emphasis on the molecular mechanism of action. Our results indicated that their effectiveness as enzyme inhibitors was not solely due to intercalation ability but also as a result of influence on catalytic activity by the formation of covalent complexes between plasmid DNA and yTOPOII. Lysine conjunction increased the strength of the compound's interaction with DNA and improved penetration into the fungal cells. Triazoloacridinone derivatives in contrast to starting compound C-1305 exhibited moderate antifungal activity and at least twice lower cytotoxicity. Importantly, compounds (IKE5-8) were not substrates for multidrug ABC transporters whereas a derivative conjugated with lysine (IKE7), showed the ability to overcome C. glabrata fluconazole-resistance (MIC 32-64 µg mL-1).

Collagen and elastin differences in vulvar tissue of women with lichen planus, lichen sclerosus and healthy women.

OBJECTIVES: Lichen sclerosus and lichen planus are two debilitating dermatoses. Their etiology remains unknown. Skin changes resulting from these disorders are important to understand, so we can provide targeted treatment to patients. We examined the differences in collagen (COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, COL5A3) and elastin (ELN) expression between vulvar tissue of women with lichen planus, lichen sclerosus and healthy women. MATERIAL AND METHODS: Vulvar tissue was taken from areas affected by lichen planus or lichen sclerosus. In healthy controls, we biopsied vulva at five and eight o'clock in a standardized manner. The tissue was simultaneously sent for pathological and genetic analysis. When either lichen planus or sclerosus or healthy tissue was confirmed by pathologist, we processed the genetic sample. RNA was isolated, transcribed and gene expression was analyzed using Real Time Custom Panel 96-16 and LightCycler 480 Probe Master. Kolmogorov-Smirnov test was employed to determine if the data on the population show normal distribution. For genes with normal distribution, t-Test was employed and for those lacking normality, we used Mann-Whitney 1-tail test. The threshold for p-value was set less than 0.05. RESULTS: Thirty-nine vulvar samples were examined. The mean expression of COL1A1 was 11.13, COL1A2 was 6.72, COL3A1 was 8.43, COL5A1 was 11.91, COL5A2 was 10.62 and COL5A3 was 12.79. The mean expression of elastin (ELN) was 13,13. We found statistically significant difference in expression of collagen (COL1A2) and elastin (ELN) between healthy controls and patients with lichen planus (p = 0.4). We did not find differences for other genes (p < 0.05). CONCLUSIONS: Collagen and elastin are differentially expressed between patients with lichen planus and healthy controls.

Impact of microbiota and host immunologic response on the efficacy of anticholinergic treatment for urgency urinary incontinence.

INTRODUCTION AND HYPOTHESIS: Studies within the past decade have suggested associations among composition of the urinary microbiota, local immune responses, and urinary incontinence symptoms. To investigate these relationships, we evaluated the structure of the urinary microbiome, local inflammatory markers, and patient responses prior to and at 6-weeks after treatment with anticholinergic medication for urgency urinary incontinence (UUI). METHODS: Using a prospective pilot study, we enrolled women who presented with UUI symptoms and were prescribed treatment with anticholinergics. Catheterized urine samples were collected from participants at their baseline and 6-week follow-up visits for microbiological (standard and 16S rRNA gene phylotyping analyses) and cytokine analysis along with the UDI-6 questionnaire and 2-day bladder diary. RESULTS: Patients were Caucasian, post- menopausal, with a median age of 64 and median BMI of 30.1 kg/m2. Among the patients, 75% had UUI symptoms for less than 2 years, but with a frequency of at least a few times a week or every day. Most women were prescribed 10 mg oxybutynin ER daily at enrollment. Patients had varied urinary microbiota by culture and 16S phylotyping, with species of Lactobacillus being the most common, in six samples, in addition to taxa associated with Enterococcus, Staphylococcus, and mixed flora. Cytokine levels showed no differences before and after treatment with anticholinergics, nor correlation with urinary bacteria or microbiome composition. CONCLUSIONS: Our pilot study suggests factors in addition to the urinary microbiome and local immune responses may be involved in patients' response to anticholinergics for UUI.

Xanthone synthetic derivatives with high anticandidal activity and positive mycostatic selectivity index values.

With the current massive increases in drug-resistant microbial infection as well as the significant role of fungal infections in the death toll of COVID-19, discovering new antifungals is extremely important. Natural and synthetic xanthones are promising derivatives, although only few reports have demonstrated their antifungal mechanism of action in detail. Newly synthetized by us xanthone derivative 44 exhibited strong antifungal activity against reference and fluconazole resistant C. albicans strains. Our results indicate that the most active compounds 42 and 44 are not substrates for fungal ABC transporters (Cdr1p and Cdr2p) and Mdr1p, the main representative of the major facilitator superfamily efflux pumps, membrane proteins that are responsible for the development of resistance. Moreover, fungicidal mode of action reduces the probability of persistent or recurrent infections and resistance development. In this light, the demonstrated killing activity of the examined derivatives is their undoubted advantage. Novel synthesized compounds exhibited moderate cytotoxicity against human cell lines, although the selectivity index value for human pathogenic strains remained favourable. Our results also indicate that novel synthetized compounds 42 and 44 with antifungal activity target yeast topoisomerase II activity. In summary, further validation of xanthones applicability as antifungals is highly valuable.

Contained specimen morcellation during robotics-assisted laparoscopic supracervical hysterectomy for pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: Robotics-assisted laparoscopic supracervical hysterectomy (RALSH) with concomitant apical robotics-assisted POP repair provides advantages of minimally invasive procedures; however specimen removal without intraperitoneal spillage of potential pathology remains challenging. The primary aim of our study is to determine the factors affecting contained manual morcellation (CMM) of specimens during RALSH for POP surgery. The secondary aim of the study is to report complications associated with CMM and on specimen pathology. METHODS: A total of 67 sequential patients underwent RALSH with concomitant robotics-assisted sacrocolpopexy or uterosacral vaginal suspension. Factors analyzed to affect CMM were specimen weight, length of skin and fascia incisions, patient age, body mass index (BMI), and estimated blood loss (EBL). RESULTS: Median CMM time was 11 min (1 to 46) and specimen weight 62 g (19 to 711). Median patient age was 56 years (36 to 83), and patient BMI was 28 (18 to 44). Median EBL was 50 ml (10 to 150). Median skin and fascial incision lengths were 3 cm (1.5 to 7), and 3.5 cm (1.5 to 8). CMM time was significantly dependent on specimen weight (p < 0.0001) and length of rectus fascia incision (p < 0.0126). There was no gross tissue spillage or bag ruptures. Uterine pathology revealed normal tissue (26%), leiomyoma (47%), adenomyosis (49%), and endometriosis (14%). 4.5% of specimens had evidence of microscopic neoplasm, and 5 years after surgery patients were cancer free. CONCLUSION: Contained manual extraction of the uterus and/or adnexae at the time of RALSH for POP surgery is a viable, safe, and efficient method of specimen removal.

The use of CO2 laser in vulvar lichen sclerosus treatment - molecular evidence.

Vulvar lichen sclerosus is chronic and difficult to treat disorder, which offer is recurrent and leads to multiple complications. The limited efficacy of pharmacologic treatment directed the search for new therapies including use of CO2 laser. In our study we focused on collagen and elastin gene expression as well as heat shock proteins and p53 expression in two patients with vulvar lichen sclerosus who underwent CO2 laser therapy. In both patients we observed decreased clinical symptoms observed by an experienced gynecologist as well as significant changes in gene expression before and after laser treatment.

Expression of heat shock proteins HSPA1A, HSPA1B and TP53 in vulval lichen planus and vulval lichen sclerosus.

OBJECTIVES: Heat shock proteins (HSPs) are proteins involved in protein folding and maturation. HSP expression is induced by heat shock or other stressors including cellular damage and hypoxia. The major groups, which are classified based on their molecular weight, include HSP27, HSP40, HSP60, HSP70, HSP90, and large HSP (HSP110 and glucose-regulated protein 170). The comparison of heat shock proteins and TP53 expression is yet not well studied in both vulval lichen sclerosus and lichen planus. Our aim was to assess the HSP and TP53 gene expression in women suffering from LS or LP and compare it within these groups and also healthy controls. MATERIAL AND METHODS: The inclusion criteria were willingness to donate vulval biopsies, not currently or in the prior two weeks received any local nor systemic treatment for vulval disorder, age > 18 years old. The exclusion criteria were lack of consent, current vaginal infection confirmed with microbiological studies, current local or systemic treatment for vulval disease. 45 consecutive women were recruited into the study. All appropriate vulval samples were process by genetic analysis. RESULTS: The mean expression (± SD) of HPSA1A for controls was 5.52 ± 3.18, for LS was 7.44 ± 2.16 and for LP was 7.89 ± 2.48. The mean expression (± SD) of HPSA1B for controls was 6.54 ± 3.41, for LS was 9.94 ± 6.88 and for LP was 9.43 ± 2.31. The mean expression (± SD) of TP53 for controls was 9.11 ± 1.14, for LS was 9.94 ± 1.27 and for LP was 10.41 ± 2.00. HSPA1A expression was 3,8 higher in women with lichen sclerosus than in control group. CONCLUSIONS: Heat shock protein-70 is more often expressed in LS than in healthy controls. HSP-70 not only supports tumor growth and metastasis, but on the other hand mat help to develop immune-driven treatment strategies.

Targeting DNA Topoisomerase II in Antifungal Chemotherapy.

Topoisomerase inhibitors have been in use clinically for the treatment of several diseases for decades. Although those enzymes are significant molecular targets in antibacterial and anticancer chemotherapy very little is known about the possibilities to target fungal topoisomerase II (topo II). Raising concern for the fungal infections, lack of effective drugs and a phenomenon of multidrug resistance underlie a strong need to expand the range of therapeutic options. In this review paper, we discussed the usefulness of fungal topo II as a molecular target for new drug discovery. On the basis of previously published data, we described structural and biochemical differences between fungal and human enzymes as well as a molecular basis of differential sensitivity to known anticancer drugs targeting the latter. This review focuses especially on highlighting the differences that may underlie the selectivity of action of new inhibitors. Distinct sites within fungal topo II in comparison with human counterparts are observed and should be further studied to understand the significance of those sites and their possible usage in design of new drugs.

Antifungal Effect of Penicillamine Due to the Selective Targeting of L-Homoserine O-Acetyltransferase.

Due to the apparent similarity of fungal and mammalian metabolic pathways, the number of established antifungal targets is low, and the identification of novel ones is highly desirable. The results of our studies, presented in this work, indicate that the fungal biosynthetic pathway of L-methionine, an amino acid essential for humans, seems to be an attractive perspective. The MET2 gene from Candida albicans encoding L-homoserine O-acetyltransferase (CaMet2p), an enzyme catalyzing the first step in that pathway, was cloned and expressed as the native or the oligo-His-tagged fusion protein in Escherichia coli. The recombinant enzymes were purified and characterized for their basic molecular properties and substrate specificities. The purified MET2 gene product revealed the appropriate activity, catalyzed the conversion of L-homoserine (L-Hom) to O-acetyl-L-homoserine (OALH), and exhibited differential sensitivity to several L-Hom or OALH analogues, including penicillamine. Surprisingly, both penicillamine enantiomers (L- and D-Pen) displayed comparable inhibitory effects. The results of the docking of L- and D-Pen to the model of CaMet2p confirmed that both enantiomeric forms of the inhibitor are able to bind to the catalytic site of the enzyme with similar affinities and a similar binding mode. The sensitivity of some fungal cells to L-Pen, depending on the presence or absence of L-Met in the medium, clearly indicate Met2p targeting. Moreover, C. glabrata clinical strains that are resistant to fluconazole displayed a similar susceptibility to L-Pen as the wild-type strains. Our results prove the potential usefulness of Met2p as a molecular target for antifungal chemotherapy.

A Novel Method of Endotoxins Removal from Chitosan Hydrogel as a Potential Bioink Component Obtained by CO2 Saturation.

The article presents a new approach in the purification of chitosan (CS) hydrogel in order to remove a significant amount of endotoxins without changing its molecular weight and viscosity. Two variants of the method used to purify CS hydrogels from endotoxins were investigated using the PyroGene rFC Enzymatic Cascade assay kit. The effect of the CS purification method was assessed in terms of changes in the dynamic viscosity of its hydrogels, the molecular weight of the polymer, microbiological purity after refrigerated storage and cytotoxicity against L929 cells based on the ISO 10993-5:2009(E) standard. The proposed purification method 1 (M1) allows for the removal of significant amounts of endotoxins: 87.9-97.6% in relation to their initial concentration in the CS hydrogel without affecting the solution viscosity. Moreover, the final solutions were sterile and microbiologically stable during storage. The M1 purification method did not change the morphology of the L929 cells.

Association between endometriosis and lower urinary tract symptoms.

OBJECTIVE: To determine if women with endometriosis experience lower urinary tract symptoms (LUTSs) more often than those without. DESIGN: Cross-sectional analysis at enrollment in a longitudinal cohort. SETTING: Enrollment at 2 academic hospitals and from the local community. PATIENT(S): This analysis included 1,161 women with (n = 520) and without (n = 641) surgically confirmed endometriosis who were enrolled in the Women's Health Study: from Adolescence to Adulthood between 2012 and 2018. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Prevalence of LUTSs, including stress incontinence, urgency and frequency, straining with urination, incomplete bladder emptying, hematuria, dysuria, and bladder pain using standardized questionnaires. RESULT(S): The primary outcomes were that women with endometriosis reported the following more often than those without: difficulty passing urine (7.9% vs. 2%; crude odds ratio [OR], 4.14 [95% confidence interval {CI}, 2.19-7.80]; adjusted OR [aOR], 4.31 [95% CI, 2.07-8.95]); still feeling full after urination (18.8% vs. 4.7%; crude OR, 4.73 [95% CI, 3.08-7.25]; aOR, 4.67 [95% CI, 2.88-7.56]); having to urinate again within minutes of urinating (33.1% vs. 17.0%; crude OR, 2.41 [95% CI, 1.83-3.18]; aOR, 2.49 [95% CI, 1.81-3.43]), dysuria (11.7% vs. 4.9%; crude OR, 2.55 [95% CI, 1.62-4.01]; aOR, 2.38 [95% CI, 1.40-4.02]); and pain when the bladder is full (23.0% vs. 4.9%; crude OR, 5.79 [95% CI, 3.82-8.78]; aOR, 6.04 [95% CI, 3.74-9.76]). For the secondary outcomes, among female participants with endometriosis, we observed that the odds of LUTS did not differ by the revised American Society for Reproductive Medicine stage (I/II vs. III/IV) or duration of endometriosis-associated symptoms. CONCLUSION(S): Women with surgically confirmed endometriosis were more likely to report LUTS than those without.

Perioperative use of pain medications in vaginal versus laparoscopic pelvic organ prolapse surgery.

INTRODUCTION AND HYPOTHESIS: There has been renewed interest in the management of postoperative pain after benign gynecological surgery. The purpose of the study was to determine if the use of intraoperative and immediate postoperative pain medication differs between vaginal and laparoscopic surgery in women with pelvic organ prolapse. METHODS: The study included women who had undergone pelvic organ prolapse repair between 2014 and 2019 in two tertiary care hospitals. We collected demographic data and pain medication used during and after surgery, including opioids, local anesthetics, gabapentin, ketorolac, ibuprofen, and acetaminophen. Data analyses were performed using STATA Version 16.1. A p value <0.05 was considered to indicate statistical significance. RESULTS: A total of 195 women were included in the study, with 98 in the vaginal and 97 in the laparoscopic group. Intraoperative opioid use in the two groups was similar (25 morphine milligram equivalent [MME], p = 0.34). However, women in the laparoscopic group received significantly more intravenous and local anesthesia (lidocaine: 60 vs 40 mg; bupivacaine 49.6 vs 20 ml, p < 0.001). Postoperatively, although women in the vaginal group required almost twice as many narcotics as those in the laparoscopy group (MME = 28 vs 15, p < 0.001), after controlling for confounders in the multivariate analysis, there were no differences in postoperative pain requirements between the two groups. Recovery time had a significant impact on opioid and acetaminophen use (p < 0.05). CONCLUSION: Use of pain medication was similar in the intraoperative and immediate postoperative period after pelvic organ prolapse surgery when comparing the vaginal and laparoscopic approaches after controlling for potential confounding factors.

Oxycodone Use During the Postoperative Period After Hysterectomy for Benign Indications.

OBJECTIVES: The objective of this study was to estimate the amount of oxycodone tablets required for pain control in the 2-week postoperative period after laparoscopic hysterectomy (LH) and vaginal hysterectomy (VH) for benign disease. METHODS: We conducted a prospective cohort study of English-speaking women 18 years or older undergoing hysterectomy for benign indications. Participants completed a pain survey at baseline and daily for 2 weeks postoperatively. In addition, they recorded the number of oxycodone tablets and other pain medications taken daily for 2 weeks. The primary outcome was the median number of oxycodone tablets (5 mg) consumed after LH or VH during 2 weeks postoperative. RESULTS: Eighty-one women underwent VH and 82 underwent LH. Women who underwent VH were older (mean ± SD, 64.2 ± 10.3 years vs 47.5 ± 7.7 years), more parous (2 [interquartile range (IQR), 2-3] vs 2 [IQR, 1-2]), and less likely to be sexually active (51.9% vs 79.3%, P < 0.02). Women in the VH group also had significantly lower baseline pain levels (0 [IQR, 0-1] vs 1 [IQR, 0-4], P < 0.001). All VH participants had surgery for prolapse, whereas only 12.2% in the LH group had surgery for this indication (P < 0.001). Most in the LH group had surgery for fibroids (61%) or abnormal uterine bleeding (15.9%). Women in the VH group consumed significantly less oxycodone tablets postoperatively (median, 4.5 [IQR, 1-9] vs 7 [IQR, 2-18]; P = 0.047) and took oxycodone for less days after discharge (median, 1 [IQR, 0-3] vs 3 [IQR, 1-6]; P < 0.001). CONCLUSIONS: Women consume less oxycodone after minimally invasive hysterectomy than previously thought. Those who undergo VH may consume less oxycodone than those who undergo LH.

The Effect of Conjugation with Octaarginine, a Cell-Penetrating Peptide on Antifungal Activity of Imidazoacridinone Derivative.

Acridine cell-penetrating peptide conjugates are an extremely important family of compounds in antitumor chemotherapy. These conjugates are not so widely analysed in antimicrobial therapy, although bioactive peptides could be used as nanocarriers to smuggle antimicrobial compounds. An octaarginine conjugate of an imidazoacridinone derivative (Compound 1-R8) synthetized by us exhibited high antifungal activity against reference and fluconazole-resistant clinical strains (MICs ≤ 4 µg mL-1). Our results clearly demonstrate the qualitative difference in accumulation of the mother compound and Compound 1-R8 conjugate into fungal cells. Only the latter was transported and accumulated effectively. Microscopic and flow cytometry analysis provide some evidence that the killing activity of Compound 1-R8 may be associated with a change in the permeability of the fungal cell membrane. The conjugate exhibited low cytotoxicity against human embryonic kidney (HEK-293) and human liver (HEPG2) cancer cell lines. Nevertheless, the selectivity index value of the conjugate for human pathogenic strains remained favourable and no hemolytic activity was observed. The inhibitory effect of the analysed compound on yeast topoisomerase II activity suggested its molecular target. In summary, conjugation with R8 effectively increased imidazoacridinone derivative ability to enter the fungal cell and achieve a concentration inside the cell that resulted in a high antifungal effect.

Quest for the Molecular Basis of Improved Selective Toxicity of All-Trans Isomers of Aromatic Heptaene Macrolide Antifungal Antibiotics.

Three aromatic heptaene macrolide antifungal antibiotics, Candicidin D, Partricin A (Gedamycin) and Partricin B (Vacidin) were subjected to controlled cis-trans→ all trans photochemical isomerization. The obtained all-trans isomers demonstrated substantially improved in vitro selective toxicity in the Candida albicans cells: human erythrocytes model. This effect was mainly due to the diminished hemotoxicity. The molecular modeling studies on interactions between original antibiotics and their photoisomers with ergosterol and cholesterol revealed some difference in free energy profiles of formation of binary antibiotic/sterol complexes in respective membrane environments. Moreover, different geometries of heptaene: sterol complexes and variations in polyene macrolide molecule alignment in cholesterol-and ergosterol-containing membranes were found. None of these effects are of the crucial importance for the observed improvement of selective toxicity of aromatic heptaene antifungals but each seems to provide a partial contribution.

Antifungal Activity of Capridine ß as a Consequence of Its Biotransformation into Metabolite Affecting Yeast Topoisomerase II Activity.

In the last few years, increasing importance is attached to problems caused by fungal pathogens. Current methods of preventing fungal infections remain unsatisfactory. There are several antifungal compounds which are highly effective in some cases, however, they have limitations in usage: Nephrotoxicity and other adverse effects. In addition, the frequent use of available fungistatic drugs promotes drug resistance. Therefore, there is an urgent need for the development of a novel antifungal drug with a different mechanism of action, blocking of the fungal DNA topoisomerases activity appear to be a promising idea. According to previous studies on the m-AMSA moderate inhibitory effect on fungal topoisomerase II, we have decided to study Capridine ß (also acridine derivative) antifungal activity, as well as its inhibitory potential on yeast topoisomerase II (yTOPOII). Results indicated that Capridine ß antifungal activity depends on the kind of strains analyzed (MICs range 0.5-64 µg mL-1) and is related to its biotransformation in the cells. An investigation of metabolite formation, identified as Capridine ß reduction product (IE1) by the fungus Candida albicans was performed. IE1 exhibited no activity against fungal cells due to an inability to enter the cells. Although no antifungal activity was observed, in contrast to Capridine ß, biotransformation metabolite totally inhibited the yTOPOII-mediated relaxation at concentrations lower than detected for m-AMSA. The closely related Capridine ß only slightly diminished the catalytic activity of yTOPOII.

A new 1-nitro-9-aminoacridine derivative targeting yeast topoisomerase II able to overcome fluconazole-resistance.

Fungal resistance remains a significant threat and a leading cause of death worldwide. Thus, overcoming microbial infections have again become a serious clinical problem. Although acridine derivatives are widely analyzed as anticancer agents, only a few reports have demonstrated their antifungal activity. In an effort to develop biologically active antifungals, twelve novel C-857 (9-(2'-hydroxyethylamino)-1-nitroacridine) and C-1748 (9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine) derivatives were synthesized. The evaluation of biological properties suggests that starting compounds: C-1748, C-857 and IE3 (2-[(4-methyl-1-nitroacridin-9-yl)amino]ethyl lysinate), IE4 (2-[(1-nitroacridin-9-yl)amino]ethyl lysinate) antifungal mode of action differ from that determined for IE5 (N'-{3-[(4-methyl-1-nitroacridin-9-yl)amino]propyl}lysinamide), IE6 (N'-{3-[(1-nitroacridin-9-yl)amino]propyl}lysinamide) and IE10 (3,3'-Bis-(1-nitroacridin-9-ylamino)-aminoethylaminoethylaminoethylamine). Although MIC values determined for the latter were higher, in contrast to C-857 and C-1748, newly synthesized IE5, IE6 and IE10 reduced C. albicans hyphal growth in different inducing media. Those compounds also exhibited antibiofilm activity, whereas IE10 was the most effective. Moreover, only IE6 exhibited antifungal activity against fluconazole resistant C. albicans strains with MICs values in the range of 16-64 µg mL-1. Our results also indicate that, in contrast to other analyzed derivatives, novel synthetized compounds IE6 and IE10 with antifungal activity target yeast topoisomerase II activity.

Analysis of microRNA regulating cell cycle-related tumor suppressor genes in endometrial cancer patients.

Endometrial cancer remains the most common malignancy of the female genital system in developed countries. Tumor suppressor genes are responsible for controlling the cells fate in the cell cycle and preventing cancerogenesis. Gene expression affects cancer progression and is modulated by microRNAs defined as both tumor suppressors and oncogenes. These molecules indirectly regulate multiple processes like cell proliferation, differentiation and apoptosis. The aim of this study was to analyze miRNAs expression that can regulate the activity of tumor suppressor genes related to the cell cycle in patients with endometrioid endometrial cancer. The study group consisted of 12 samples that met the inclusion criteria from a total of 48 obtained. The 12 samples were used to analyze microRNA expression. Complementary miRNAs were identified using TargetScan Database and statistical analysis. MicroRNAs were determined for the tumor suppressor genes: CYR61, WT1, TSPYL5, HNRNPA0, BCL2L1 and BAK1. All the miRNAs were complementary to the described target genes based on TargetScan Database. There were five miRNAs differentially expressed that can regulate tumor suppressor genes related to the cell cycle. The distinguished miRNAs: mir-340-3p, mir-1236-5p, mir-874-3p, mir-873-5p.2 and mir-548-5p were differentially expressed in endometrial cancer in comparison to the control. Among the distinguished miRNAs, the most promising is mir-874-3p, which may have an important role in endometrial adenocarcinoma proliferation.

Pelvic organ prolapse after 3 modes of hysterectomy: long-term follow-up.

BACKGROUND: There are various indications and approaches for hysterectomy; yet, the difference in long-term risk of subsequent prolapse after surgery is not well studied. OBJECTIVE: To assess the risk of prolapse after abdominal, vaginal, and laparoscopic or robotic hysterectomy for up to 17 years from surgery. STUDY DESIGN: A retrospective chart review study of women undergoing hysterectomy across all indications (benign and malignant) between 2001 and 2008 was conducted. An equivalent random sample of hysterectomy patients was selected each year. We compared demographic and other surgical characteristics data including age, race, parity, body mass index, indication and year of hysterectomy, blood loss, cervix removal, cuff suspension, and complications using chi-square, Kruskal-Wallis test, and Fisher's exact across the 3 groups. Presence and treatment of subsequent prolapse (based on patient symptoms, pelvic exam, International Classification of Diseases, Ninth Revision diagnosis, and current procedural terminology pessary or surgical codes) were compared with Kaplan-Meier survival analysis and Cox proportional hazards regression. RESULTS: Of the 2158 patients, 1459, 375, and 324 underwent open, vaginal, and laparoscopic or robotic hysterectomy, respectively. The vaginal group (56) was older than the abdominal (52) or laparoscopic or robotic (49) groups, with a P value of <.05. Most patients were White with a mean body mass index of 30 kg/m2. The main indication was cancer for abdominal (33%) and laparoscopic or robotic hysterectomy (25%) and prolapse for vaginal hysterectomy (60%). Time to prolapse was shortest after vaginal surgery (27 months) and longest after laparoscopic or robotic surgery (71 months). After controlling for confounders, including surgery indication, the hazard ratio for subsequent prolapse was no different among vaginal (hazard ratio=1.36 [0.77-2.45]), laparoscopic or robotic (hazard ratio=1.47 [0.80-2.69]), or open (reference) hysterectomy. Prolapse grade was similar across the 3 groups. About 50% of women with recurrent prolapse received physical therapy, pessary, or surgical treatment. CONCLUSION: At the 17-year follow-up, the route of hysterectomy is not associated with a difference in recurrence, grade, or subsequent treatment of prolapse when the indication for hysterectomy is considered. Prolapse, as an indication for hysterectomy, increases risk for recurrence. Women planning a hysterectomy should be counseled appropriately about the risk of subsequent prolapse.