Differential microRNA Expression Analysis in Patients with HPV-Infected Ovarian Neoplasms.

This study aimed to identify microRNAs (miRNAs) whose expression levels are altered by high-risk human papillomavirus (HR-HPV) infection in women with epithelial ovarian neoplasms. MiRNA expression was quantified by real-time polymerase chain reaction, while HR-HPV DNA was quantified using digital-droplet PCR. Analysis of 11 miRNAs demonstrated significantly lower hsa-miR-25-5p expression in HPV-infected compared to uninfected ovarian tissues (p = 0.0405), while differences in miRNA expression in corresponding serum were statistically insignificant. The expression of hsa-miR-218-5p in ovarian tumors was significantly higher in high-grade serous ovarian carcinoma (HGSOC) cases than in other neoplasms (p = 0.0166). In addition, hsa-miR-218-5p was significantly upregulated, whereas hsa-miR-191-5p was significantly downregulated in tissues with stage III/IV FIGO (p = 0.0009 and p = 0.0305, respectively). Using unsupervised clustering, we identified three unique patient groups with significantly varied frequencies of HPV16/18-positive samples and varied miRNA expression profiles. In multivariate analysis, high expression of hsa-miR-16-5p was an independent prognostic factor for poor overall survival (p = 0.0068). This preliminary analysis showed the changes in miRNA expression in ovarian neoplasms during HPV infection and those collected from HGSOCs or patients with advanced disease. This prospective study can provide new insights into the pathogenesis of ovarian neoplasms and host-virus interactions.

TLR2 2029C/T and TLR3 1377C/T and -7C/A Polymorphisms Are Associated with the Occurrence of Abdominal Aortic Aneurysm.

TLRs are a family of signaling sensors that play a crucial role in the host immune response and are involved in the modulation of inflammatory processes. To study their contribution to abdominal aortic aneurysm (AAA) formation and development, we determined the frequency of TLR2, TLR3, TLR4, and TLR9 single-nucleotide polymorphisms (SNPs) and investigated the association between polymorphisms and the risk of AAA incidence. A total of 104 patients with AAAs and 112 healthy, unrelated volunteers were screened for the presence of TLR2 (2029C/T and 2258G/A), TLR3 (1377C/T, 1234C/T, and -7C/A), TLR4 (896A/G, 1196C/T, and 3266G/A), and TLR9 (-1237T/C, -1486T/C, 1174G/A, and 2848C/T) SNPs by using PCR-RFLP analysis. The heterozygous genotype of the TLR2 2029C/T SNP was more common in patients with AAA than in healthy subjects (p < 0.0001) and was associated with at least an 8-fold increased risk of AAA incidence (p < 0.001). The wild-type genotype of the TLR3 -7C/A SNP was associated with a 3-fold increased risk of hypertension (p = 0.026). The heterozygous TLR3 genotype 1377C/T and -7C/A SNPs were less common in patients with AAA than in healthy subjects (p < 0.0001 and p = 0.0004, respectively) and were associated with a decreased risk of AAA occurrence (p < 0.001 and p = 0.0012, respectively). No relation to AAA risk was found for TLR4 SNPs. Heterozygous genotypes of the TLR2 2029C/T and TLR3 1377C/T and -7C/A SNPs may serve as genetic biomarkers of AAA incidence.

Human Papillomaviruses as Infectious Agents in Gynecological Cancers. Oncogenic Properties of Viral Proteins.

Human papillomaviruses (HPVs), which belong to the Papillomaviridae family, constitute a group of small nonenveloped double-stranded DNA viruses. HPV has a small genome that only encodes a few proteins, and it is also responsible for 5% of all human cancers, including cervical, vaginal, vulvar, penile, anal, and oropharyngeal cancers. HPV types may be classified as high- and low-risk genotypes (HR-HPVs and LR-HPVs, respectively) according to their oncogenic potential. HR-HPV 16 and 18 are the most common types worldwide and are the primary types that are responsible for most HPV-related cancers. The activity of the viral E6 and E7 oncoproteins, which interfere with critical cell cycle points such as suppressive tumor protein p53 (p53) and retinoblastoma protein (pRB), is the major contributor to HPV-induced neoplastic initiation and progression of carcinogenesis. In addition, the E5 protein might also play a significant role in tumorigenesis. The role of HPV in the pathogenesis of gynecological cancers is still not fully understood, which indicates a wide spectrum of potential research areas. This review focuses on HPV biology, the distribution of HPVs in gynecological cancers, the properties of viral oncoproteins, and the molecular mechanisms of carcinogenesis.

Cancer Stem Cells in Ovarian Cancer-A Source of Tumor Success and a Challenging Target for Novel Therapies.

Ovarian cancer is the most lethal neoplasm of the female genital organs. Despite indisputable progress in the treatment of ovarian cancer, the problems of chemo-resistance and recurrent disease are the main obstacles for successful therapy. One of the main reasons for this is the presence of a specific cell population of cancer stem cells. The aim of this review is to show the most contemporary knowledge concerning the biology of ovarian cancer stem cells (OCSCs) and their impact on chemo-resistance and prognosis in ovarian cancer patients, as well as to present the treatment options targeted exclusively on the OCSCs. The review presents data concerning the role of cancer stem cells in general and then concentrates on OCSCs. The surface and intracellular OCSCs markers and their meaning both for cancer biology and clinical prognosis, signaling pathways specifically activated in OCSCs, the genetic and epigenetic regulation of OCSCs function including the recent studies on the non-coding RNA regulation, cooperation between OCSCs and the tumor microenvironment (ovarian cancer niche) including very specific environment such as ascites fluid, the role of shear stress, autophagy and metabolic changes for the function of OCSCs, and finally mechanisms of OCSCs escape from immune surveillance, are described and discussed extensively. The possibilities of anti-OCSCs therapy both in experimental settings and in clinical trials are presented, including the recent II phase clinical trials and immunotherapy. OCSCs are a unique population of cancer cells showing a great plasticity, self-renewal potential and resistance against anti-cancer treatment. They are responsible for the progression and recurrence of the tumor. Several completed and ongoing clinical trials have tested different anti-OCSCs drugs which, however, have shown unsatisfactory efficacy in most cases. We propose a novel approach to ovarian cancer diagnosis and therapy.

Abdominal aortic aneurysm and virus infection: A potential causative role for cytomegalovirus infection?

An abdominal aortic aneurysm (AAA) is a multifactorial disease with a variety of genetic and environmental risk factors, but the exact mechanism of AAA formation and progression is still not well understood. The present study investigated the frequency of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and papillomavirus types 6 and 11 (HPV6 and HPV11), their impact on clinical manifestations of cardiovascular diseases, and their possible association with inflammation in patients with AAA and healthy volunteers. Genotyping of CMV UL75, EBV LMP-1, and HPV6, and HPV11 E6 was performed by polymerase chain reaction (PCR), while the viral DNA loads were measured by quantitative real-time PCR. Cytokine levels were determined by enzyme-linked immunosorbent assays. The CMV UL75 was detected more frequently in the blood of patients with AAA than in the blood of healthy volunteers (32.7% vs. 6.3%, p < .0001). Neither EBV LMP-1 nor HPV6 E6 was found in blood and aortic wall biopsies, while the HPV11 E6 was detected in 36.4% of AAA walls. The CMV infection in patients with AAA was associated with an increased risk of hypertension and coronary artery disease (OR, 9.057; 95% CI, 1.141-71.862; p = .037; and OR, 2.575; 95% CI, 1.002-6.615; p = .049, respectively). Additionally, CMV-infected patients with AAA had higher tumor necrosis factor-α levels compared with noninfected subjects (p = .017). Our findings suggest that CMV infection can stimulate local inflammation in the aorta but is not a direct cause of most abdominal aortic aneurysms.

Lactate Suppresses Retroviral Transduction in Cervical Epithelial Cells through DNA-PKcs Modulation.

Recently, we have shown the molecular basis for lactate sensing by cervical epithelial cells resulting in enhanced DNA repair processes through DNA-PKcs regulation. Interestingly, DNA-PKcs is indispensable for proper retroviral DNA integration in the cell host genome. According to recent findings, the mucosal epithelium can be efficiently transduced by retroviruses and play a pivotal role in regulating viral release by cervical epithelial cells. This study examined the effects of lactate on lentiviral transduction in cervical cancer cells (HeLa, CaSki, and C33A) and model glioma cell lines (DNA-PKcs proficient and deficient). Our study showed that L- and D-lactate enhanced DNA-PKcs presence in nuclear compartments by between 38 and 63%, which corresponded with decreased lentiviral transduction rates by between 15 and 36%. Changes in DNA-PKcs expression or its inhibition with NU7441 also greatly affected lentiviral transduction efficacy. The stimulation of cells with either HCA1 agonist 3,5-DHBA or HDAC inhibitor sodium butyrate mimicked, in part, the effects of L-lactate. The inhibition of lactate flux by BAY-8002 enhanced DNA-PKcs nuclear localization which translated into diminished lentiviral transduction efficacy. Our study suggests that L- and D-lactate present in the uterine cervix may play a role in the mitigation of viral integration in cervical epithelium and, thus, restrict the viral oncogenic and/or cytopathic potential.

Antiviral Effect of Nonfunctionalized Gold Nanoparticles against Herpes Simplex Virus Type-1 (HSV-1) and Possible Contribution of Near-Field Interaction Mechanism.

The antiviral activity of nonfunctionalized gold nanoparticles (AuNPs) against herpes simplex virus type-1 (HSV-1) in vitro was revealed in this study. We found that AuNPs are capable of reducing the cytopathic effect (CPE) of HSV-1 in Vero cells in a dose- and time-dependent manner when used in pretreatment mode. The demonstrated antiviral activity was within the nontoxic concentration range of AuNPs. Interestingly, we noted that nanoparticles with smaller sizes reduced the CPE of HSV-1 more effectively than larger ones. The observed phenomenon can be tentatively explained by the near-field action of nanoparticles at the virus envelope. These results show that AuNPs can be considered as potential candidates for the treatment of HSV-1 infections.

Comparative study of the effects of ortho-, meta- and para-carboranes (C2B10H12) on the physicochemical properties, cytotoxicity and antiviral activity of uridine and 2'-deoxyuridine boron cluster conjugates.

In this study, a series of uridine (U) and 2'-deoxyuridine (dU) conjugates containing an isomeric ortho-, meta- or para-carborane cluster (C2B10H12) attached at C-5 through an ethynyl linker were synthesized. The effect of carborane cluster isomerism on the conjugate syn/anti conformation, molar extinction coefficient, lipophilicity, susceptibility to phosphorylation (by TK1, TK2 and dCK), cytotoxicity and antiviral activity was evaluated. A strong effect of the boron cluster modification on the syn/anti equilibrium of the modified nucleosides was observed. An increase in lipophilicity compared with unmodified U and dU, especially for conjugates bearing a para-carborane cluster, was detected. Furthermore a pronounced and differential influence of the boron cluster modification on the electronic properties of the nucleobase chromophore was observed. The obtained conjugates have low or medium toxicity toward several cell lines, are phosphorylated fairly well by TK1 and are poor or not substrates for dCK. Furthermore, the conjugates preferentially inhibit HCMV replication with an SI index as high as 22 for the ortho-carborane derivative of U and more than 180 for the para-carborane derivative of dU.

Analysis of host Toll-like receptor 3 and RIG-I-like receptor gene expression in patients with abdominal aortic aneurysm.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a vascular disease relatively common in the elderly population. Although some events that contribute to the development and progression of AAA are known, there are limited data examining the association of Toll-like receptor 3 (TLR3) and RIG-I-like receptor expression with the pathogenesis of AAAs. In this study, we investigated the gene and protein expression of TLR3 and RIG-I-like receptors (RIG-I and MDA5) in aortic wall and blood of AAA patients and examined the relationship between their expression and immune response. METHODS: Total RNA was extracted from aortic wall tissues and blood samples collected from 20 patients with AAA and blood samples of 17 healthy volunteers without aortic aneurysm. To evaluate the DDX58 (RIG-I), IFIH1 (MDA5), and TLR3 gene expression level, quantitative real-time polymerase chain reaction was used. Extracellular cytokine and pattern recognition receptor levels were quantified by enzyme-linked immunosorbent assays. RESULTS: TLR3, RIG-I, and MDA5 were constitutively expressed in both aortic tissues and blood samples from AAA patients and healthy volunteers. In patients with AAA, higher TLR3 expression in aortic tissues than in blood was found (P = .004). The DDX58 messenger RNA expression was higher in blood of patients with AAA compared with healthy subjects (P = .021). A significantly higher level of plasma interleukin 4 was noticed in patients with AAA than in healthy individuals (P = .008). CONCLUSIONS: This study suggests that RIG-I and TLR3 seem to be important factors in the pathogenesis of AAA.

The role of single nucleotide polymorphisms, contained in proinflammatory cytokine genes, in the development of congenital infection with human cytomegalovirus in fetuses and neonates.

PURPOSE: The research project targeted the distribution of genotypes, alleles and haplotypes in single nucleotide polymorphisms (SNPs) within the interleukin (IL) 1A, IL1B, IL6, IL12B and TNFA genes, in fetuses and neonates, congenitally infected with human cytomegalovirus (HCMV), and among uninfected controls. METHODS: The study included 20 fetuses and neonates with congenital HCMV infection and 31 control individuals. The genotypes in SNPs of the studied cytokine genes were identified by a self-designed nested PCR-RFLP assays. Selected genotypes, representing distinct variants in analyzed polymorphisms, were confirmed by sequencing. The relationship between the genetic status of the studied polymorphisms and congenital infection development was estimated, using a logistic regression model. RESULTS: The CT haplotype, composed of C allele determined in IL1A -889 C > T and T allele in IL1B +3954 C > T SNP, increased the risk of congenital HCMV infection, as well as the onset of disease related symptoms (P ≤ 0.0001). Considering disease outcome, the risk of development of symptoms, was increased among the CT heterozygotes in IL1A -889 C > T polymorphism (OR 2.86, 95% CI 0.24-33.90; P = 0.045). Moreover, multiple-SNP variants CCGAG in the range of all the SNPs, analyzed in the study, increased the risk of congenital infection with HCMV (OR 7.94, 95% CI 1.38-45.69; P = 0.026). CONCLUSIONS: Polymorphisms within the proinflammatory cytokine genes may contribute to the development of congenital infection with HCMV.

TLR2 2258 G>A single nucleotide polymorphism and the risk of congenital infection with human cytomegalovirus.

BACKGROUND: Human cytomegalovirus (HCMV) is responsible for the most common intrauterine infections, which may be acquired congenitally from infected pregnant woman to fetus. The research was aimed to estimate the role of three single nucleotide polymorphisms (SNPs) located in TLR2 gene, and the common contribution of TLR2, and previously studied TLR4 and TLR9 SNPs, to the occurrence of congenital HCMV infection in fetuses and newborns. METHODS: The study was performed in 20 Polish fetuses and newborns, congenitally infected with HCMV, and in 31 uninfected controls, as well as with participation of pregnant women, the mothers of 16 infected and 14 uninfected offsprings. Genotypes in TLR2 SNPs were determined, using self-designed nested PCR-RFLP assays, and confirmed by sequencing. The genotypes were tested for Hardy-Weinberg (H-W) equilibrium, and for their relationship with the development of congenital cytomegaly, using a logistic regression model. The common influence of TLR2, TLR4 and TLR9 SNPs on the occurrence of congenital disease was estimated by multiple-SNP analysis. RESULTS: Distribution of the genotypes and alleles in TLR2 1350 T>C and 2029 C>T SNPs was similar between the studied groups of fetuses and neonates. In case of 2258 G>A polymorphism, the GA heterozygotic status was significantly more frequent in the infected cases than among the uninfected individuals (25.0% vs. 3.2%, respectively), and increased the risk of HCMV infection (OR 10.00, 95% CI 1.07-93.44; P ≤ 0.050). Similarly, the A allele within 2258 G>A polymorphism was significantly more frequent among the infected offsprings than in the uninfected ones (12.5% vs. 1.6%; P ≤ 0.050). Complex AA variants for both TLR2 2258 and TLR9 2848 G>A polymorphisms, were estimated to be at increased risk of congenital HCMV infection (OR 11.58, 95% CI 1.19-112.59; P ≤ 0.050). Additionally, significant relationships were observed between the occurrence of complex AA or GA variants for both TLR2 and TLR9 SNPs and the increased viral loads, determined in fetal amniotic fluids and in maternal blood or urine specimens (P ≤ 0.050). CONCLUSIONS: Among various TLR2, TLR4 and TLR9 polymorphisms, TLR2 2258 G>A SNP seems to be an important factor associated with increased risk of congenital HCMV infection in Polish fetuses and neonates.

Toll-like receptors genes polymorphisms and the occurrence of HCMV infection among pregnant women.

BACKGROUND: Human cytomegalovirus (HCMV) is the most common cause of intrauterine infections worldwide. The toll-like receptors (TLRs) have been reported as important factors in immune response against HCMV. Particularly, TLR2, TLR4 and TLR9 have been shown to be involved in antiviral immunity. Evaluation of the role of single nucleotide polymorphisms (SNPs), located within TLR2, TLR4 and TLR9 genes, in the development of human cytomegalovirus (HCMV) infection in pregnant women and their fetuses and neonates, was performed. METHODS: The study was performed for 131 pregnant women, including 66 patients infected with HCMV during pregnancy, and 65 age-matched control pregnant individuals. The patients were selected to the study, based on serological status of anti-HCMV IgG and IgM antibodies and on the presence of viral DNA in their body fluids. Genotypes in TLR2 2258 A > G, TLR4 896 G > A and 1196 C > T and TLR9 2848 G > A SNPs were determined by self-designed nested PCR-RFLP assays. Randomly selected PCR products, representative for distinct genotypes in TLR SNPs, were confirmed by sequencing. A relationship between the genotypes, alleles, haplotypes and multiple variants in the studied polymorphisms, and the occurrence of HCMV infection in pregnant women and their offsprings, was determined, using a logistic regression model. RESULTS: Genotypes in all the analyzed polymorphisms preserved the Hardy-Weinberg equilibrium in pregnant women, both infected and uninfected with HCMV (P > 0.050). GG homozygotic and GA heterozygotic status in TLR9 2848 G > A SNP decreased significantly the occurrence of HCMV infection (OR 0.44 95% CI 0.21-0.94 in the dominant model, P ≤ 0.050). The G allele in TLR9 SNP was significantly more frequent among the uninfected pregnant women than among the infected ones (χ2 = 4.14, P ≤ 0.050). Considering other polymorphisms, similar frequencies of distinct genotypes, haplotypes and multiple-SNP variants were observed between the studied groups of patients. CONCLUSIONS: TLR9 2848 G > A SNP may be associated with HCMV infection in pregnant women.

Human cytomegalovirus UL55, UL144, and US28 genotype distribution in infants infected congenitally or postnatally.

Cytomegalovirus (CMV) is the most common cause of congenital infection. This pathogen exhibits extensive genetic variability in the genes that encode structural envelope glycoproteins, regulatory proteins, and proteins that contribute to immune evasion. However, the role of specific viral strains in the outcome of congenital CMV infection is unclear. Variation in the UL55 gene encoding glycoprotein B (gB), the UL144 gene encoding TNF α-like receptor, and the US28 gene encoding ß-chemokine receptor was determined in 60 newborn infants with congenital CMV infection and 90 infants with postnatal or undefined CMV infection. CMV polymorphisms were studied in relation to disease outcome and viral load. Genotyping was performed by a sequencing analysis of PCR-amplified fragments, and the viral load was measured by quantitative real-time PCR. The results demonstrated that (1) the UL55 and US28 genotype distributions were similar among the group of congenital and postnatal CMV infection; (2) the UL144 B1 genotype was more prevalent in congenital than in postnatal infection and was detected in 70% of newborns with asymptomatic congenital infection; and (3) none of the examined genotype was significantly linked with symptomatic CMV infection. No relationship was observed between genotype and viral load. The results revealed that UL55, UL144, and US28 polymorphisms are not associated with the outcome of CMV infection in infants, but the presence of UL144 B1 genotype might be virological marker of asymptomatic infection at birth.

Cytomegalovirus glycoprotein H genotype distribution and the relationship with hearing loss in children.

Cytomegalovirus (CMV) is a leading cause of congenital infection and a leading infectious cause of hearing loss in children. The ORF UL75 gene encodes envelope glycoprotein H (gH), which is essential for CMV entry into host cells and the target of the immune response in humans. However, the distribution of gH variants and the relationship between the viral genotype, viral load, and sequelae in children infected with CMV is debated. The UL75 genetic variation of CMV isolates from 42 newborns infected congenitally with CMV and 93 infants with postnatal or unproven congenital CMV infection was analyzed. Genotyping was performed by analysis of PCR-amplified fragments, and the viral load was measured by quantitative real-time PCR. There were no differences in the distribution of gH genotypes in the children infected congenitally and postnatally. Mixed-genotype infections with both gH1 and gH2 variants were detected in approximately 25% of the examined patients. No relationship between UL75 gene polymorphisms and the symptoms at birth was observed. The results suggest that the infection with gH2 genotype diminishes the risk of hearing loss in children (P = 0.010). In addition, sensorineural hearing loss was associated with CMV gH1 genotype infection in infants (P = 0.032) and a high viral load in urine (P = 0.005). In conclusion, it was found that the gH genotype does not predict clinical sequelae in newborn infants following congenital CMV infection. However, these results suggest that the gH genotype might be associated with hearing loss in children.

[Role of the RIG-I-like receptors in antiviral response]. / Rola receptorów RIG-I-podobnych w odpowiedzi przeciwwirusowej.

The innate nonspecific immunity is the first line of defense against viral infection. Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are two main receptor families detecting viral nucleic acid. So far, three RLR family members were characterized: RIG-I, MDA5 and LGP2. RLR constitute a family of cytoplasmic helicases, which recognized intracellular single-stranded and double-stranded RNA that is introduced to cytosol during viral infection and replication. In this work we review the current knowledge about the mechanisms of viral recognition by RIG-I-like receptors and their signaling pathways for the activation of type I interferons and pro-inflammatory cytokines synthesis.

High-Grade Serous Ovarian Cancer-A Risk Factor Puzzle and Screening Fugitive.

High-grade serous ovarian cancer (HGSOC) is the most lethal tumor of the female genital tract. Despite extensive studies and the identification of some precursor lesions like serous tubal intraepithelial cancer (STIC) or the deviated mutational status of the patients (BRCA germinal mutation), the pathophysiology of HGSOC and the existence of particular risk factors is still a puzzle. Moreover, a lack of screening programs results in delayed diagnosis, which is accompanied by a secondary chemo-resistance of the tumor and usually results in a high recurrence rate after the primary therapy. Therefore, there is an urgent need to identify the substantial risk factors for both predisposed and low-risk populations of women, as well as to create an economically and clinically justified screening program. This paper reviews the classic and novel risk factors for HGSOC and methods of diagnosis and prediction, including serum biomarkers, the liquid biopsy of circulating tumor cells or circulating tumor DNA, epigenetic markers, exosomes, and genomic and proteomic biomarkers. The novel future complex approach to ovarian cancer diagnosis should be devised based on these findings, and the general outcome of such an approach is proposed and discussed in the paper.

Modification of selected anti-HCMV drugs with lipophilic boron cluster modulator.

Methods for the modification of ganciclovir (GCV), acyclovir (ACV), cidofovir (CDV) and valganciclovir (VCDV) with boron cluster have been developed. Toxicity of the new derivatives was evaluated in adherent cells; no cytotoxicity was observed in five different cell lines up to 1000 microM with the exception of modified valganciclovir which was cytotoxic above 300 microM. The compounds were active against HCMV or HSV-1 by cytopathic effect or plaque reduction assays. None of the tested compounds had activity against HPIV-3 or VSV.

[Evaluation of the association between maternal HCMV viremia and the course of pregnancy and neonatal outcome]. / Ocena zwiqzku poziomu wiremii HCMV u matki z przebiegiem ciqzy i stanem urodzeniowym noworodków.

UNLABELLED: Congenital cytomegaly is caused by intrauterine mother-to-fetus HCMV transmission and constitutes the most common vertical infection. OBJECTIVES: The aim of the study was to analyze the viremia level in maternal blood and its influence on the course and duration of pregnancy as well as newborn condition. MATERIAL AND METHODS: The material included blood samples collected from 117 pregnant women with serological features of HCMV infection and from 29 neonates hospitalized at DFMMG in Lodz between 1999 and 2009. The presence of HCMV DNA in the maternal and fetal blood was tested using real-time PCR. RESULTS: Prevalence of maternal viremia was observed to increase the risk of viremia in neonates, as compared to children born to mothers with no viremia. However; lack of HCMV DNA in maternal blood does not exclude fetal infection in utero. Newborn condition assessed by Apgar scores was significantly lower in the group of infants born to mothers with serological features of acute cytomegaly (p < 0.05). CONCLUSION: The assessment of viremia level in maternal blood can be helpful in assessing the risk of intrauterine infection in the fetus as well as in predicting the neonatal outcome of newborn.

Personalization of Therapy in High-Grade Serous Tubo-Ovarian Cancer-The Possibility or the Necessity?

High-grade serous tubo-ovarian cancer (HGSTOC) is the most lethal tumor of the female genital tract. The foregoing therapy consists of cytoreduction followed by standard platinum/taxane chemotherapy; alternatively, for primary unresectable tumors, neo-adjuvant platinum/taxane chemotherapy followed by delayed interval cytoreduction. In patients with suboptimal surgery or advanced disease, different forms of targeted therapy have been accepted or tested in clinical trials. Studies on HGSTOC discovered its genetic and proteomic heterogeneity, epigenetic regulation, and the role of the tumor microenvironment. These findings turned attention to the fact that there are several distinct primary tumor subtypes of HGSTOC and the unique biology of primary, metastatic, and recurrent tumors may result in a differential drug response. This results in both chemo-refractoriness of some primary tumors and, what is significantly more frequent and destructive, secondary chemo-resistance of metastatic and recurrent HGSTOC tumors. Treatment possibilities for platinum-resistant disease include several chemotherapeutics with moderate activity and different targeted drugs with difficult tolerable effects. Therefore, the question appears as to why different subtypes of ovarian cancer are predominantly treated based on the same therapeutic schemes and not in an individualized way, adjusted to the biology of a specific tumor subtype and temporal moment of the disease. The paper reviews the genomic, mutational, and epigenetic signatures of HGSTOC subtypes and the tumor microenvironment. The clinical trials on personalized therapy and the overall results of a new, comprehensive approach to personalized therapy for ovarian cancer have been presented and discussed.

"DEPHENCE" system-a novel regimen of therapy that is urgently needed in the high-grade serous ovarian cancer-a focus on anti-cancer stem cell and anti-tumor microenvironment targeted therapies.

Ovarian cancer, especially high-grade serous type, is the most lethal gynecological malignancy. The lack of screening programs and the scarcity of symptomatology result in the late diagnosis in about 75% of affected women. Despite very demanding and aggressive surgical treatment, multiple-line chemotherapy regimens and both approved and clinically tested targeted therapies, the overall survival of patients is still unsatisfactory and disappointing. Research studies have recently brought some more understanding of the molecular diversity of the ovarian cancer, its unique intraperitoneal biology, the role of cancer stem cells, and the complexity of tumor microenvironment. There is a growing body of evidence that individualization of the treatment adjusted to the molecular and biochemical signature of the tumor as well as to the medical status of the patient should replace or supplement the foregoing therapy. In this review, we have proposed the principles of the novel regimen of the therapy that we called the "DEPHENCE" system, and we have extensively discussed the results of the studies focused on the ovarian cancer stem cells, other components of cancer metastatic niche, and, finally, clinical trials targeting these two environments. Through this, we have tried to present the evolving landscape of treatment options and put flesh on the experimental approach to attack the high-grade serous ovarian cancer multidirectionally, corresponding to the "DEPHENCE" system postulates.