T. Paszkowski

Cytokines and anticytokines in psoriasis.

BACKGROUND Psoriasis is a chronic autoimmune hyperproliferative skin disease of varying severity affecting approximately 2-3% of the general population in the USA and Europe. Although the pathogenesis of psoriasis has not been fully elucidated, an immunologic-genetic relationship is likely. Cutaneous and systemic overexpression of various proinflammatory cytokines (TNF, interleukins, interferon-gamma) has been demonstrated in psoriatic patients. METHODS We reviewed the current database literature and summarized the involvement of cytokines and their receptors in the pathogenesis and treatment of psoriasis. RESULTS Although many cytokine/anti-cytokine therapies have been conducted, TNF antagonists in the treatment of both psoriasis arthropatica and vulgaris appear to be the most widely used clinically. Interestingly, the efficacy and tolerability of some cytokines (rhIL-11 or ABX-IL-8,) were found to be much lower than expected. CONCLUSIONS Preliminary results obtained with cytokine and anti-cytokine therapies appear promising and as such continued research is clearly indicated.

Diagnostic and prognostic significance of miRNA signatures in tissues and plasma of endometrioid endometrial carcinoma patients

The aim of our study was to define tissue and plasma miRNA signatures, which could potentially serve as diagnostic and prognostic markers in endometrioid endometrial cancer (EEC) and to investigate miRNA profiles in regard to clinicopathological characteristics. Tissue and plasma samples were collected from 122 women (77 EEC and 45 controls). Expression profiling of 866 human miRNAs and 89 human viral miRNAs was performed in 24 samples and was followed by qPCR validation in 104 patients. Expression of 16 miRNAs was analyzed in 48 plasma samples. Microarray study revealed regulation of 21 miRNAs in EEC tissues comparing to normal endometrium. Altered expression of 17 miRNAs was confirmed by qPCR performed in 104 tissue samples. Seven miRNAs were upregulated and two were downregulated in EEC plasma samples. Expression of a number of miRNAs was associated with International Federation of Gynecology and Obstetrics stage, grade, relapse and nodal metastases. Two miRNA signatures: miR‐92a/miR‐410 and miR‐92a/miR‐205/miR‐410 classified tumor tissues with higher accuracy in comparison to single miRNAs (AUC: 0.977, 95% CI: 0.927–0.996 and 0.984, 95% CI: 0.938–0.999, respectively). miRNA signature composed of miR‐205 and miR‐200a predicted relapse with AUC of 0.854 (95% CI: 0.691–0.951). Tissue miRNA signatures were independent prognostic markers of overall (miR‐1228/miR‐200c/miR‐429, HR: 2.98) and progression‐free survival (miR‐1228/miR‐429, HR: 2.453). Plasma miRNA signatures: miR‐9/miR‐1228 and miR‐9/miR‐92a, classified EEC plasma samples with high accuracy yielding AUCs of 0.909 (95% CI: 0.789–973) and 0.913 (95% CI: 0.794–0.976), respectively. We conclude that miRNA signatures hold a great promise to become noninvasive biomarkers for early EEC detection and prognosis.

Deregulation of miR-100, miR-99a and miR-199b in tissues and plasma coexists with increased expression of mTOR kinase in endometrioid endometrial carcinoma

BackgroundAlterations of mTOR gene expression have been implicated in the pathogenesis of endometrioid endometrial cancer however only few studies explored the cause of increased mTOR activation in this malignancy. miRNAs are small, noncoding RNAs, which were proven to regulated gene expression at the posttranscriptional level. The study aimed to explore deregulation of miRNAs targeting mTOR kinase (miR-99a, miR-100 and miR-199b) as a possible cause of its altered expression in EEC tissues. In addition expression of the three miRNAs was investigated in plasma of EEC patients and was assessed in terms of diagnostic and prognostic utility.MethodsWe investigated expression of mTOR kinase transcripts in 46 fresh tissue samples. Expression of miR-99a, miR-100 and miR-199b was investigated in the same group of fresh samples, and in additional 58 FFPE sections as well as in 48 plasma samples using qPCR. Relative quantification was performed using experimentally validated endogenous controls.ResultsmTOR kinase expression was increased in EEC tissues and was accompanied by decreased expression of all three miRNAs. Down-regulation of the investigated miRNAs was discovered in plasma of EEC patients and miRNA signatures classified EEC tissues (miR-99a/miR-100/miR-199b) and plasma (miR-99a/miR-199b) samples with higher accuracy in comparison to single miRNAs. We also revealed that miR-100 was an independent prognostic marker of overall survival.ConclusionsWe conclude that increased expression of mTOR kinase coexists with down-regulation of its targeting miRNAs, which could suggest a new mechanism of mTOR pathway alterations in EEC. In addition, our findings implicate that miRNA signatures can be considered promising biomarkers for early detection and prognosis of endometrioid endometrial carcinoma.

Selection and validation of endogenous controls for microRNA expression studies in endometrioid endometrial cancer tissues.

OBJECTIVES microRNAs comprise a family of small, non-coding RNAs, which regulate gene expression at the posttranscriptional level. Multiple studies implicated important roles of microRNAs in various malignancies including endometrioid endometrial carcinoma (EEC). qPCR is widely used in the studies investigating microRNA expression. Relative quantification of microRNA expression requires proper normalization methods and endogenous controls are widely used for this purpose. The aim of this study was experimental identification of stable endogenous controls for normalization of microRNA qPCR expression studies in EEC. METHODS Expression of twelve candidate endogenous controls (miR-16, miR-26b, miR-92a, RNU44, RNU48, U75, U54, U6, U49, RNU6B, RNU38B, U18A) was investigated in tissue samples obtained from 45 patients (30 EEC, 15 normal endometrium) using qPCR. Stability of candidate endogenous controls was evaluated using NormFinder, geNorm, BestKeeper and equivalency test. The results were then validated using larger group of samples. RESULTS RNU48, U75 and RNU44 were identified as stably and equivalently expressed between malignant and normal tissues. Both NormFinder and geNorm indicated that those three snRNAs were optimal for qPCR data normalization in EEC tissues. CONCLUSIONS In conclusion, we suggest that average expression of those snoRNAs could be used as a reliable endogenous control in microRNA qPCR studies in endometrioid endometrial cancer. In addition to identifying suitable endogenous controls in EEC, our study presents an appropriate strategy for validation of candidate reference genes for any microRNA qPCR study.

Major regulators of microRNAs biogenesis Dicer and Drosha are down-regulated in endometrial cancer

Alterations in microRNAs expression have been proposed to play role in endometrial cancer pathogenesis. Dicer and Drosha are main regulators of microRNA biogenesis and deregulation of their expression has been indicated as a possible cause of microRNAs alterations observed in various cancers. The objective of this study was to investigate Dicer and Drosha genes expression in endometrial cancer and to analyze the impact of clinicopathological characteristics on their expression. Fresh tissue samples were collected from 44 patients (26 endometroid endometrial carcinoma and 18 controls). Clinical and pathological data were acquired from medical documentation. Dicer and Drosha genes expressions were assessed by qRT-PCR using validated reference genes. Dicer and Drosha expression levels were significantly lower in endometrial cancer samples comparing to controls. Dicer was down-regulated by the factor of 1.54 (p = 0.009) and Drosha gene mean expression value was 1.4 times lower in endometrial cancer group versus control group (p = 0.008). Down-regulation of Dicer significantly correlated with decreased expression of Drosha (coefficient value 0.75). Decreased expression of Drosha correlated with higher histological grade and was influenced by BMI. Lower Dicer expression was found in nulli- and uniparous females comparing to multiparous individuals (p = 0.002). Neither the FIGO stage nor the menstrual status had significant influence on the expression of studied genes. This study revealed for the first time that expression alterations of main regulators of microRNAs biogenesis are present in endometrial cancer tissue and could be potentially responsible for altered microRNAs profiles observed in this malignancy.

Cytokine response in the postoperative period after surgical treatment of benign adnexal masses : comparison between laparoscopy and laparotomy

BackgroundCytokines are the main mediators of the inflammation and the response to trauma. The purpose of the present study was the comparative assessment in sera of patients with benign adnexal masses treated by laparoscopy or laparotomy of the following proinflammatory and anti-inflammatory cytokines: interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), and IL-10 in the early postoperative period.MethodsA total of 40 patients with benign adnexal masses were studied; 25 of whom underwent laparoscopy and 15, laparotomy. Blood serum concentration of IL-1β, IL-6, IL-8, TNF-α, and IL-10 were measured by commercially available ELISA assays before and 4 h, 24 h, and 48 h after the operation.ResultsConcentrations of IL-6 were significantly increased in both groups at 4 h, 24 h, and 48 h after the surgery; levels of IL-10 showed a significant increase 4 h and 24 h after the operation; an increase in IL-1β levels was observed only after laparotomy; no significant variations were observed in serum levels of IL-8; the postoperative increase of IL-1β, IL-6, and IL-10 levels was more pronounced in patients undergoing laparotomy than in those treated laparoscopically; length of the surgical procedure, amount of CO2 used, tumor diameter, age, and body mass index (BMI) of the patients did not influence the postoperative patterns of the studied cytokines.ConclusionsSystemic cytokine response after operations for benign adnexal masses depends on the degree of the surgical trauma, and is less pronounced in patients undergoing laparoscopy.

Highly increased maspin expression corresponds with up-regulation of miR-21 in endometrial cancer: a preliminary report.

Background: Maspin and programmed cell death 4 (Pdcd4) are tumor suppressor genes, and miR-21 is overexpressed in many solid tumors and was proven to negatively regulate a number of tumor suppressor genes including maspin and Pdcd4. The purpose of this study was to investigate the expression of maspin, Pdcd4, and miR-21 and their interrelations with clinicopathologic features in endometrial cancer using a quantitative approach. Methods: Maspin, Pdcd4, and miR-21 expressions were evaluated by a real-time polymerase chain reaction in 20 endometrial cancer and 10 normal endometrium samples. Results: Maspin showed a significantly increased expression in endometrial cancer samples compared with the control group and was up-regulated by a mean factor of 46.54 (SE range, 2.367-1160.26; 95% confidence interval, 0.515-15001, P < 0.0001). Expression of miR-21 was found significantly up-regulated in the sample group in comparison to control group by a mean factor of 2.312 (SE range, 0.741-7.778; 95% confidence interval 0.191-15.0, P = 0.028). No significant differences were present in the expression level of Pdcd4 between endometrial cancer and control groups. Comparison between IA and more advanced International Federation of Gynecology and Obstetrics stages of endometrial cancer in regard to expression levels of maspin, Pdcd4, and miR-21 did not reveal any significant differences. Similarly, no differences were encountered when histopathologic grading, myometrial invasion, age, body mass index, and parity were taken into consideration. Conclusions: Association between increased maspin expression and up-regulation of miR-21 in endometrial cancer suggests distinct and tissue-specific relationships of the 2 molecules in this type of malignancy and requires further studies that would reveal its clinical relevance.

Increased serum insulin-like growth factor-1 levels in women with gestational diabetes.

BACKGROUND Insulin-like growth factor-1 (IGF-1), which has effects similar to insulin, reduces blood glucose level, improves insulin sensitivity and may play an important role in the pathogenesis of gestational diabetes (GDM). OBJECTIVE The aim of the study was to estimate the concentration of IGF-1 in pregnant women with GDM and 3 months after delivery and find relationships between IGF-1 and clinical and biochemical parameters. MATERIALS AND METHODS 67 women between 24th - 28th week of pregnancy were enrolled in the study (46 with GDM and 21 as a control group). All women underwent clinical and biochemical examinations. Concentrations of IGF-1, adiponectin, fasting glucose, insulin, lipids, CRP, fibrinogen were measured during pregnancy, additionally IGF-1 concentration was determined 3 months after delivery. RESULTS IGF-1, glucose, insulin, CRP, fibrinogen, lipids concentrations and HOMA-IR were significantly higher in women with GDM than in the control group (p<0.05). A significant decrease in IGF-1 concentration was observed in both groups after delivery. In the GDM group significant correlations between IGF-1 and BMI (r=0.370, p<0.05), insulin (r=0.469, p<0.01) and HOMA-IR (r=0.439, p<0.01) were observed. Regression analysis with IGF-1 as a dependent parameter showed that only BMI and insulin remained as predictors, explaining 32% of plasma IGF-1 variation. Re-evaluation after delivery revealed impaired glucose tolerance in 9% of the population studied. CONCLUSIONS Increased IGF-1 concentrations in pregnancy complicated with GDM may partly reflect metabolic disturbances, especially insulin resistance and hyperinsulinemia, and may be one of possible compensatory reactions of the organism in response to these disturbances.

Influence of ulipristal acetate therapy compared with uterine artery embolization on fibroid volume and vascularity indices assessed by three‐dimensional ultrasound: prospective observational study

To compare the effects of two alternative treatment options for uterine fibroids, ulipristal acetate (UPA) and uterine artery embolization (UAE), on fibroid volume and vascularity at 3‐month follow‐up.

Supplementation during pregnancy: beliefs and science

Abstract Pregnancy represents a challenge from a nutritional perspective, because micronutrient intake during the periconceptional period and in pregnancy affects fetal organ development and the mother’s health. Inappropriate diet/nutrition in pregnancy can lead to numerous deficiencies including iron deficiency and may impair placental function and play a role in miscarriage, intrauterine growth restriction, preterm delivery, and preeclampsia. This article reviews the risks associated with nutrient deficiencies in pregnant women and presents an overview of recommendations for dietary supplementation in pregnancy, focusing on oral iron supplementation. Risk factor detection, including dietary patterns and comorbidities, is paramount in optimal pregnancy management. Dietary habits, which can lead to deficiencies (e.g., iron, folate, vitamin D, and calcium) and result in negative health consequences for the mother and fetus/newborn, need to be investigated. Prenatal care should be personalized, accounting for ethnicity, culture, education, information level about pregnancy, and dietary and physical habits. Clinicians should make a plan for appropriate supplementation and prophylaxis/treatment of nutritional and other needs, and consider adequate intake of calcium, iodine, vitamin D, folate, and iron. Among the available oral iron supplements, prolonged-released ferrous sulfate (ferrous sulfate–polymeric complex) presents the lowest incidence of overall and gastrointestinal adverse events, with positive implications for compliance.