Correlation between AAV and HPV infection in normal, dysplastic and neoplastic cervical smears

The aim of this study was to investigate if AAV infections can be associated with a reduced risk for HPV-related cervical neoplasia. The study population consisted of 654 women, aged 19-65 years old. All women, after cytologic and colposcopic evaluation were categorized in 3 groups: A. control group, B. with present cervical pathology and C. with past, treated cervical pathology. Groups B and C were further divided in subgroups according to the severity of the lesions (WNL, LGGIN, HGGIN, CA). AAV and HPV detection were performed by nested-PRC and RFLP-PCR, respectively. AAV was detected in 17,8% of the control group, and there was no statistical difference regarding the different disease and patients groups. The HPV prevalence was, as expected, significantly different between the control group (8,9%) and each of the disease groups (p<0,001). The association between HPV/AAV in B and C patients groups confirmed that the absence of AAVDNA in HPV infected women was correlated with the development of cervical lesions (p<0,001, p=0,008 and p=0,002 for LGGIN, HGGN and CA, respectively). Consequently, AAV probably demonstrates a protective role against the pathologic effects of HPV infections.Σκοπός της παρούσας διατριβής ήταν η διερεύνηση του ρόλου των AAV στην εξέλιξη της HPV-επαγόμενης τραχηλικής καρκινογένεσης. Ελέγχθησαν 654 γυναίκες, ηλικίας 19-65 ετών. Μετά από κολποσκοπικό και κυτταρολογικό έλεγχο, οι γυναίκες κατανεμήθηκαν σε 3 ομάδες: Α. ομάδα ελέγχου, Β. με παρούσα νόσο και Γ. γυναίκες υπό παρακολούθηση έπειτα από θεραπεία για τραχηλικές ενδοεπιθηλιακές αλλοιώσεις. Σύμφωνα με τη σοβαρότητα των βλαβών, οι Β. και Γ., χωρίστηκαν σε ομάδες 4 ομάδες ασθενών: WNL (παθολογικά ευρήματα εντός φυσιολογικών ορίων), LGCIN (χαμηλού βαθμού αλλοιώσεις) και CA (καρκίνος). Η ανίχνευση των ΑΑV έγινε με τη μέθοδο της φωλιασμένης PCR, ενώ η τυποποίηση των HPV με RFLP-PCR. Το ποσοστό των AAV ανέρχεται στο 17,8% για την ομάδα ελέγχου, ενώ δεν υπήρχαν σημαντικές διαφορές ανάμεσα στις διάφορες ομάδες ασθενών. Οι HPV ανιχνεύθηκαν στο 8,9% των γυναικών της ομάδας ελέγχου, και όπως ήταν αναμενόμενο σε στατιστικά υψηλότερα ποσοστά στις άλλες ομάδες γυναικών (p<0,001). Από την περαιτέρω ανάλυση των αποτελεσμάτων προκύπτει ότι η απουσία των ΑΑV στις HPV μολυσμένες γυναίκες αποτελεί παράγοντα κινδύνου, καθώς ο συνδυασμός HPV+/AAV- συναντάται πολύ συχνότερα στις γυναίκες με παθολογικά ευρήματα ποικίλης σοβαρότητας (p<0,001, p=0,008 και p=0,002 για τις LGGN, HGGN και CA ομάδες, αντίστοιχα). Τα αποτελέσματα της παρούσας διατριβής είναι ενδεικτικά της προστατευτικής δράσης των AAV έναντι της HPV-επαγόμενης τραχηλικής νεοπλασίας

Screening for adeno-associated viruses and human papillomaviruses in greek women with no cervical lesion

In order to investigate the correlation between human papillomaviruses (HPV), causative agents of cervical cancer, and adeno-associated viruses (AAV), possible protective factor from this disease, we evaluated first the prevalence of cervical infection by these two viruses in asymptomatic Greek females (i.e. with normal cervices and no pathologic history). Our data indicates relatively low prevalence for both viruses (8.8% for HPV and 17.7% for AAV), compared to studies from other countries. This report is the first concerning prevalence of cervical AAV infection in Greece

Evaluation of Current Prognostic and Predictive Markers in Breast Cancer: A Validation Study of Tissue Microarrays

Background: Tissue microarrays (TMAs) are an attractive alternative to analysis of whole sections (WS). For breast carcinomas, the recent recommendations for cut-offs (i.e. Ki67, H-score) have necessitated the re-evaluation of TMAs. Materials and Methods: TMA results of immunohistochemistry (IHC) and Fluorescence in situ hybridization (FISH) testing for Estrogen receptors (ER), Progesterone receptors (PgR), Ki67 and HER2 were compared against the results of WS for 88 breast carcinomas. Results: We found excellent agreement between the two methods for ER and PgR IHC evaluation, using the H-score (Kappa coefficient 0.972 and 0.9, respectively). There was also excellent correlation for HER2 IHC (Kappa coefficient I) and amplification (Kappa coefficient 0.933). Furthermore, scoring of Ki67 was highly-correlated between TMAs and WS (Kappa coefficient 0.954). The latter excellent correlation has not, to our knowledge, been previously reported. Conclusion: For breast cancer, TMAs are an efficient and reliable alternative to the use of WS, using the currently recommended markers, evaluation protocols and cut-off values

Prognostic Biomarkers in Early-stage Gastric Adenocarcinoma Treated with Adjuvant Chemoradiotherapy

Background/Aim: Early-stage gastric cancer has a high risk of recurrence, despite trimodality therapy with surgery, chemotherapy and radiation. To improve patient selection for adjuvant chemoradiotherapy, we evaluated the prognostic significance of immunohistochemical and genetic biomarkers in patients with resected gastric adenocarcinoma. Patients and Methods: Tumors from 119 patients were subjected to immunohistochemistry for 12 protein biomarkers, as well as next-generation sequencing. Clinical and biomarker data were available for 91 patients. Results: EBV-positive tumors and tumors with mutations had higher intratumoral CD8 tumor-infiltrating lymphocyte density (p=0.009 and p=0.017, respectively). PIK3CA mutations were correlated with VEGFA overexpression (p=0.042), while KRAS mutations and HER2 expression were mutually exclusive (p=0.036). PTEN expression univariately confirmed longer overall survival (HR=0.27; p=0.046), while there was a trend between the presence of KRAS mutations and inferior disease-free and overall survival. Conclusion: PTEN protein expression and KRAS mutations may predict disease outcome in early-stage gastric cancer. These results need to be further validated in larger cohorts. © 2020 International Institute of Anticancer Research. All rights reserved

A Role for Circular Non-Coding RNAs in the Pathogenesis of Sporadic Parathyroid Adenomas and the Impact of Gender-Specific Epigenetic Regulation

Epigenetic changes, including altered small non-coding RNAs, appear to be implicated in the pathogenesis of sporadic parathyroid adenomas (PAs). In this study, we investigated the circular RNAs (circRNAs) expression profile in sporadic PAs. Sixteen tissue samples of sporadic PAs, and four samples of normal parathyroid tissue (NPT) were investigated. Sample preparation and microarray hybridization were performed based on the Arraystar&rsquo;s standard protocols, and circRNAs sequences were predicted by bioinformatics tools. We identified 35 circRNAs that were differentially expressed in sporadic PAs compared to NPT; 22 were upregulated, and 13 were downregulated, according to the pre-defined thresholds of fold-change &gt; 2.0 and p &lt; 0.05. In the subgroup analysis of PAs from male patients (n = 7) compared to PAs from female patients (n = 9), we also find a different expression profile. In particular, 19 circRNAs were significantly upregulated, and four circRNAs were significantly downregulated in male patients, compared to female counterparts. We show here for the first time a differential circRNA expression pattern in sporadic PAs compared to NPT, and a different expression profile in PA samples from male compared to female patients, suggesting an epigenetic role in the PA pathogenesis, and also an effect of gender in the epigenetic regulation of PAs

Circulating and Tissue Expression Profile of MicroRNAs in Primary Hyperparathyroidism Caused by Sporadic Parathyroid Adenomas

We investigated the expression profile of selected microRNAs (miRs) in serum and tissue samples from patients with sporadic parathyroid adenomas (sPAs). This was a prospective, controlled cohort study. Forty patients with sPAs who had undergone parathyroidectomy (PTX) were included. MiR extraction was performed from (i) 40 formalin-fixed paraffin-embedded samples (FFPEs) of sPAs, (ii) 10 FFPEs of normal parathyroid tissue (NPT), (iii) serum samples of the 40 patients with sPAs (t1 = baseline; t2 = 2months post-PTX), and (vi) serum samples of 10 healthy individuals (controls; t1 = baseline and t2 = 2months later). Ten miRs were selected based on their interaction with genes related to parathyroid tumorigenesis (miR-17-5p, miR-24-3p, miR-29b-3p, miR-31-5p, miR-135b-5p, miR-186-5p, miR-195-5p, miR-330-3p, miR-483-3p, and miR-877-5p). At tissue level, the relative expression of miR-17-5p, miR-31-5p, miR-135b-5p, miR-186-5p, and miR-330-3p was significantly decreased (fold change [FC]: 0.17, FC: 0.03, FC: 0.01, FC: 0.10, FC: 0.10, respectively; all p values &lt;0.001), and the expression of miR-24-3p and miR-29b-3p was significantly increased (FC: 12.4, p&lt;0.001; FC: 18.5, p = 0.011, respectively) in sPA compared with NPT samples. The relative expression of miR-135b-5p was also significantly decreased in the serum samples of patients compared with controls (FC: 0.7, p = 0.035). No significant differences were found in the serum samples of patients before and after PTX. MiRs that regulate genes linked to parathyroid tumors such as menin 1 (miR-24-3p, miR-29b-3p), cyclin D1 (miR-17-5p), calcium sensing receptor (miR-31-5p, miR-135b-5p), cyclin-dependent kinase inhibitors (miR-186-5p), and beta -catenin (miR-330-3p) were significantly deregulated in sPAs compared with NPT samples, suggesting a role for epigenetic changes in parathyroid tumorigenesis. (c) 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research

The androgen receptor as a surrogate marker for molecular apocrine breast cancer subtyping

The Androgen Receptor (AR) is a potential prognostic marker and therapeutic target in breast cancer. We evaluated AR protein expression in high-risk breast cancer treated in the adjuvant setting. Tumors were subtyped into luminal (ER+/PgR +/-/AR +/-), molecular apocrine (MAC, [ER-/PgR-/AR+]) and hormone receptor negative carcinomas (HR-negative, [ER-/PgR-/AR-]). Subtyping was evaluated with respect to prognosis and to taxane therapy. High histologic grade (p &lt; 0.001) and increased proliferation (p = 0.001) more often appeared in MAC and HR-negative than in luminal tumors. Patients with MAC had outcome comparable to the luminal group, while patients with HR-negative disease had increased risk for relapse and death. MAC outcome was favorable upon taxane-containing treatment; this remained significant upon multivariate analysis for overall survival (HR 0.31, 95% CI 0.13-0.74, interaction p = 0.035) and as a trend for time to relapse (p = 0.15). In conclusion, AR-related subtyping of breast cancer may be prognostic and serve for selecting optimal treatment combinations. (C) 2014 Elsevier Ltd. All rights reserved

A Role for Circular Non-Coding RNAs in the Pathogenesis of Sporadic Parathyroid Adenomas and the Impact of Gender-Specific Epigenetic Regulation

Epigenetic changes, including altered small non-coding RNAs, appear to be implicated in the pathogenesis of sporadic parathyroid adenomas (PAs). In this study, we investigated the circular RNAs (circRNAs) expression profile in sporadic PAs. Sixteen tissue samples of sporadic PAs, and four samples of normal parathyroid tissue (NPT) were investigated. Sample preparation and microarray hybridization were performed based on the Arraystar&apos;s standard protocols, and circRNAs sequences were predicted by bioinformatics tools. We identified 35 circRNAs that were differentially expressed in sporadic PAs compared to NPT; 22 were upregulated, and 13 were downregulated, according to the pre-defined thresholds of fold-change &gt; 2.0 and p &lt; 0.05. In the subgroup analysis of PAs from male patients (n = 7) compared to PAs from female patients (n = 9), we also find a different expression profile. In particular, 19 circRNAs were significantly upregulated, and four circRNAs were significantly downregulated in male patients, compared to female counterparts. We show here for the first time a differential circRNA expression pattern in sporadic PAs compared to NPT, and a different expression profile in PA samples from male compared to female patients, suggesting an epigenetic role in the PA pathogenesis, and also an effect of gender in the epigenetic regulation of PAs

Mismatch repair deficiency and aberrations in the Notch and Hedgehog pathways are of prognostic value in patients with endometrial cancer.

The aim of this study was to investigate the prognostic value of the Hedgehog (Gli, Patched-1, Shh, Smo) and Notch (Jag1, Notch2, Notch3) pathway members, in comparison to a panel of proteins (ER, PgR, HER2/neu, Ki67, p53, p16, PTEN and MMR) previously suggested to be involved in the pathogenesis of endometrial cancer, in association with clinical outcome and standard clinicopathological characteristics. A total of 204 patients with histological diagnosis of endometrial cancer treated from 2004 to 2013 were included. The evaluation of protein expression was assessed by immunohistochemistry. Univariate analysis showed that higher Ki67 labeling, expression of PTEN, p16, Notch2 and Notch3 proteins, as well as MMR proficiency were associated with increased relapse and mortality rate. Additionally, Patched-1 protein expression was associated with worse DFS, while p53 overexpression was associated with worse OS. In multivariate analyses, patients with MMR proficient tumors had more than double risk for death than patients with MMR deficient (MMRd) tumors (adjusted HR = 2.19, 95% CI 1.05-4.58, p = 0.036). Jag1 positivity conferred reduced mortality risk (HR = 0.48, 95% CI 0.23-0.97, p = 0.042). However, as shown by hierarchical clustering, patients fared better when their tumors expressed high Jag1 protein in the absence of Notch2 and Notch3, while they fared worse when all three proteins were highly expressed. Patched-1 positivity conferred higher risk for relapse (HR = 2.04, 95% CI 1.05-3.96, p = 0.036). Aberrant expression of key components of the Notch and Hedgehog signaling pathways, as well as MMRd may serve as independent prognostic factors for recurrence and survival in patients with endometrial cancer