Programmed cell death-1 and its ligands: Current knowledge and possibilities in immunotherapy

Programmed Cell Death-1 (PCD-1) is a key immune checkpoint receptor, which mainly expresses on activated T, B, Dendritic (DC), Natural Killer (NK), and Treg cells. On the surface of activated T-cells, PCD-1 expression is upregulated after the recognition of peripherals antigens by T cells; subsequently, the elevated binding of PD-1 to Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2) becomes a key step for downstream inhibitory signaling. Although the role of PD-L1 has been evaluated more thoroughly by clinical research, and PD-L1 has also been used more widely in the clinical setting, PD-L2 also plays an important role in the negative regulation of T-cells, one of the necessary conditions that lead to immune tolerance. Expression of PD-L1 either in tumors or in infiltrating immune cells has been verified predominantly by Immunohistochemistry (IHC) in a variety of tumors, suggesting a role for the PD-1/PD-L1 axis as a prognostic trait and therapeutic target across multiple histotypes. The complex interplay between these factors plays a major role in the diffusion and clinical application of PD-L1 IHC assays as predictive biomarkers of response to PD-1/PD-L1 inhibitors. Checkpoint blockades are registered for the treatment of various cancers, including gynecological malignancies

Preliminary outcomes of five-year survival for ovarian malignancies in profiled Serbian Oncology Centre

Objective: The present study purposed to determine characteristics of ovarian carcinoma and to analyze predictors of survival in patients with ovarian carcinoma. Method: A retrospective cohort study was conducted including the patients with diagnosed ovarian carcinoma treated at the Clinic for Operative Oncology, Oncology Institute of Vojvodina in the period from January 2012 to December 2016. Seventy-two women with ovarian carcinoma were included in the analysis. The data about the histological type of tumor, disease stage, treatment, lymphatic infiltration, and surgical procedure were collected retrospectively, using the database of the institution where the research was conducted (BirPis 21 SRC Infonet DOO ‒ Information System Oncology Institute of Vojvodina). Descriptive statistics and multivariate analysis using Cox proportional hazards model were performed. Results: The univariate Cox regression analysis identified histology, tumor grade, FIGO (International Federation of Gynecology and Obstetrics) stage, NACT (Neoadjuvant Chemotherapy), number of therapy cycles, type of surgery, and chemotherapy response as independent predictors of mortality. Finally, the type of tumor and chemotherapy response had an increased hazard ratio for mortality in the multivariate Cox regression model. Herewith, the percentage of high-grade, advanced-stage ovarian cancer patients with complete response to chemotherapy, absence of recurrent disease, and lymphovascular space invasion were significant predictors of survival in patients with ovarian carcinoma. Conclusions: Herein, emerging data regarding precision medicine and molecular-based personalized treatments are promising and will likely modify the way the authors provide multiple lines of treatments in the near future

Factors Associated with the Leisure-Time Physical Activity (LTPA) during the First Trimester of the Pregnancy: The Cross-Sectional Study among Pregnant Women in Serbia

Background: The benefits of physical activity during pregnancy include lower maternal weight gain, a lower likelihood of gestational diabetes, low back pain, preeclampsia, preterm delivery, caesarian delivery, and macrosomia. This study aimed to examine the factors associated with insufficient leisure-time physical activity (LTPA) during the first trimester. Methods: A cross-sectional study was conducted at the Clinic for Obstetrics and Gynecology of Clinical Center of Serbia, Belgrade, between January and June of 2018. The final analyses included 162/175 pregnant women. The questionnaire was used to obtain social characteristics, pregnancy, and lifestyle characteristics (Pregnancy Risk Assessment Monitoring System—PRAMS), pre-pregnancy LTPA (International Physical Activity Questionnaire—IPAQ), and LTPA during the first trimester (Pregnancy Physical Activity Questionnaire—PPAQ). Women were classified into two groups of sufficient and insufficient LTPA during the first trimester based on the recommendations of the World Health Organization. Multivariate logistic regression analysis was applied. Results: A total of 27.2% of the women had insufficient LTPA during pregnancy. Insufficient LTPA during pregnancy was associated with <12 years of education (OR: 2.3, 95% CI: 1.05–5.04), self-rated financial status as poor (OR: 0.34, 95% CI: 0.14–0.79), and hours spent walking before pregnancy (OR: 0.87, 95% CI: 0.77–0.99). Conclusions: Our results can help direct health care professionals advice for women who are planning pregnancy towards walking as it seems to be sustained during pregnancy

Prenatal monitoring of pregnancies complicated by diabetes mellitus

Preconception and prenatal monitoring evaluate the condition of the mother's underlying disease and possible complications during pregnancy. Before conception, patients with diabetes should be informed that suboptimal glycoregulation is associated with reduced fertility and pregnancy losses. The task of the perinatologist in pregnancies affected by diabetes mellitus is to prevent complications of the underlying disease, such as hypoglycemic crises. Another important component of prenatal care in diabetic pregnancies is the recognition and prevention of pregnancy complications such as preeclampsia, polyhydramnios, congenital malformations, fetal macrosomia, and infections

Doppler Indices of the Uterine, Umbilical and Fetal Middle Cerebral Artery in Diabetic versus Non-Diabetic Pregnancy: Systematic Review and Meta-Analysis

Background and Objectives: The aim of this study was to assess the differences in Doppler indices of the uterine (Ut), umbilical (UA), and middle cerebral artery (MCA) in diabetic versus non-diabetic pregnancies by conducting a comprehensive systematic review of the literature with a meta-analysis. Materials and Methods: PubMed, Web of Science, and SCOPUS were searched for studies that measured the pulsatility index (PI), resistance index (RI), and systolic/diastolic ratio index (S/D ratio) of the umbilical artery, middle cerebral artery, and uterine artery in diabetic versus non-diabetic pregnancies. Two reviewers independently evaluated the eligibility of studies, abstracted data, and performed quality assessments according to standardized protocols. The standardized mean difference (SMD) was used as a measure of effect size. Heterogeneity was assessed using the I2 statistic. Publication bias was evaluated by means of funnel plots. Results: A total of 62 publications were included in the qualitative and 43 in quantitative analysis. The UA-RI, UtA-PI, and UtA-S/D ratios were increased in diabetic compared with non-diabetic pregnancies. Subgroup analysis showed that levels of UtA-PI were significantly higher during the third, but not during the first trimester of pregnancy in diabetic versus non-diabetic pregnancies. No differences were found for the UA-PI, UA-S/D ratio, MCA-PI, MCA-RI, MCA-S/D ratio, or UtA-RI between diabetic and non-diabetic pregnancies. Conclusions: This meta-analysis revealed the presence of hemodynamic changes in uterine and umbilical arteries, but not in the middle cerebral artery in pregnancies complicated by diabetes

Pregnancy complicated with deficiency of antithrombin: Review of current literature

Antithrombin deficiency, although the rarest thrombophilia, carries the highest risk of thromboembolism. This risk is increased especially for pregnant women due to physiological coagulation changes in pregnancy. Therefore, in cases of positive personal and/or family history of thromboembolic events as well as recurrent pregnancy loss women should be tested for antithrombin deficiency. Antithrombin deficiency is caused by numerous mutations of serpin peptidase inhibitor clade C 1 gene (SERPINC) and is classified according to antithrombin plasma activity and antigen levels into Type I (quantitative defect) and Type II (qualitative defect). Complications during pregnancy can be divided into those regarding the mother and those concerning the fetus. The main clinical manifestation of antithrombin deficiency regarding the mother is thromboembolism occurring spontaneously or recurrently during pregnancy. Numerous major gestational complications such as miscarriage, intrauterine growth restriction or fetal death, placental abruption, preeclampsia and hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome can be linked to antithrombin deficiency. Close monitoring with early and adequate prophylaxis and treatment nowadays can mostly assure the positive pregnancy outcome for both mother and child. Prophylaxis/therapy with both low molecular weight heparin and antithrombin concentrate should start as soon as pregnancy is planned or at least as early as possible in pregnancy and continue until the end of the puerperium

Nutrition in pregnancy with diabetes mellitus

The nutritional needs of diabetic pregnancies are different from normal pregnancies. Differences in nutritional recommendations can also be seen between pregnant women who are using and who are not using insulin therapy. In this literature review, recommendations for different meal proportions of carbohydrates, proteins, and fats in the diets of pregnant women with diabetes mellitus are listed. Different meal plans were also addressed in this group of patients. The role of exercise in the management of diabetes in pregnancy is undeniable and different approaches found in the literature are presented

Theoretical basis of perinatology therapy in pregnant women with diabetes mellitus

Diabetes mellitus is a metabolic disorder that can occur before pregnancy, be detected during pregnancy, or develop during pregnancy. Therapeutic modalities available today significantly facilitate glycoregulation during pregnancy and childbirth. This review presents different insulin regimens, as well as the advantages and disadvantages of oral antidiabetic agents use with a special focus on hypoglycemia. The importance of maintaining optimal glycemic levels and educating patients in blood glucose self-measurement is explained

Trends of the Prevalence of Pre-gestational Diabetes in 2030 and 2050 in Belgrade Cohort

The aim of this study was to analyze the trends in diabetes in pregnancy in Belgrade, Serbia for the period of the past decade and forecast the number of women with pre-gestational diabetes for the years 2030 and 2050. The study included the data on all pregnant women with diabetes from the registry of the deliveries in Belgrade, by the City Institute of Public Health of Belgrade, Serbia for the period between 2010 and 2020 and the published data on the deliveries on the territory of Belgrade. During the examined period the total number of live births in Belgrade was 196,987, and the prevalence of diabetes in pregnancy was 3.4%, with the total prevalence of pre-gestational diabetes of 0.7% and overall prevalence of GDM of 2.7%. The average age of women in our study was significantly lower in 2010 compared to 2020. The forecasted prevalence of pre-gestational diabetes among all pregnant women for 2030 is 2% and 4% for 2050 in our cohort. Our study showed that the prevalence of pre-gestational diabetes has increased both among all pregnant women and among women with diabetes in pregnancy in the past decade in Belgrade, Serbia and that it is expected to increase further in the next decades and to further double by 2050

Role of A Novel Angiogenesis FKBPL-CD44 Pathway in Preeclampsia Risk Stratification and Mesenchymal Stem Cell Treatment

Context: Preeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies.Objective: To investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44.Design and intervention: FKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preeclampsia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling.Settings and participants: Human samples prediagnosis (15 and 20 weeks of gestation; n ≥ 57), or postdiagnosis (n = 18 for plasma; n = 4 for placenta) of preeclampsia were used to determine FKBPL and CD44 levels, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid.Main outcome measures: Preeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed.Results: The CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preeclampsia. At 20 weeks of gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.3-fold increased risk of preeclampsia (odds ratio = 2.3, 95% confidence interval [CI] 1.03-5.23, P = 0.04). In combination with high mean arterial blood pressure (>82.5 mmHg), the risk further increased to 3.9-fold (95% CI 1.30-11.84, P = 0.016). Both hypoxia and MSC-based therapy inhibited FKBPL-CD44 signaling, enhancing cell angiogenesis.Conclusions: The FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preeclampsia, showing promising utilities for early diagnostic and therapeutic purposes.</p