Ten-year immune persistence and safety of the HPV-16/18 AS04-adjuvanted vaccine in females vaccinated at 15–55 years of age

Women remain at risk of human papillomavirus (HPV) infection for most of their lives. The duration of protection against HPV-16/18 from prophylactic vaccination remains unknown. We investigated the 10-year immune response and long-term safety profile of the HPV-16/18 AS04-adjuvanted vaccine (AS04-HPV-16/18 vaccine) in females aged between 15 and 55 years at first vaccination. Females who received primary vaccination with three doses of AS04-HPV-16/18 vaccine in the primary phase-III study (NCT00196937) were invited to attend annual evaluations for long-term immunogenicity and safety. Anti-HPV-16/18 antibodies in serum and cervico-vaginal secretions (CVS) were measured using enzyme-linked immunosorbent assay (ELISA). Serious adverse events (SAEs) were recorded throughout the follow-up period. Seropositivity rates for anti-HPV-16 remained high (≥96.3%) in all age groups 10 years after first vaccination. It was found that 99.2% of 15–25-year olds remained seropositive for anti-HPV-18 compared to 93.7% and 83.8% of 26–45-year olds and 45–55-year olds, respectively. Geometric mean titers (GMT) remained above natural infection levels in all age groups. Anti-HPV-16 and anti-HPV-18 titers were at least 5.3-fold and 3.1-fold higher than titers observed after natural infection, respectively, and were predicted to persist above natural infection levels for ≥30 years in all age groups. At Year 10, anti-HPV-16/18 antibody titers in subjects aged 15–25 years remained above plateau levels observed in previous studies. Correlation coefficients for antibody titers in serum and CVS were 0.64 (anti-HPV-16) and 0.38 (anti-HPV-18). This study concluded that vaccinated females aged 15–55 years elicited sustained immunogenicity with an acceptable safety profile up to 10 years after primary vaccination, suggesting long-term protection against HPV

Loss of estrogen receptor beta expression correlates with shorter overall survival and lack of clinical response to chemotherapy in ovarian cancer patients

Background: Estrogen receptor beta (ERβ) belongs to a large family of nuclear receptors. Recent studies have suggested that ERβ in contrast to ERα might act as a tumour suppressor in ovarian cancer (OVCA). Materials and Methods: Expression of ERβ was detected by immunocytochemistry in 11 OVCA cell lines and by immunohistochemistry in 43 (41 FIGO stage III) OVCA specimens prepared before chemotherapy and 30 specimens from the same group after chemotherapy. Cisplatin sensitivity in the 11 cell lines was also analysed. Results: No significant correlations between cisplatin-sensitivity and expression of ERβ was found in the cell lines. In the cases which responded well to chemotherapy (complete response) ERβ expression at preliminary laparotomy (PL) was significantly higher (p=0.0004) than in those with progressive disease. Kaplan-Meier analysis revealed that the patients with higher ERβ expression (>30% of cells) at PL had an increased overall survival time and progression-free time (p=0.00161 and p=0.03255, respectively) than the patients with lower ERβ espression. Significantly shorter overall survival time characterized the cases with lower immunoreactivity score of ERβ expression at secondary cytoreduction (SCR) (p=0.00346). Conclusion: The loss of ERβ expression in ovarian tumours may be a feature of malignant transformation

Weekly AUC2 carboplatin is inactive in acquired platinum resistant ovarian cancer with or without phenoxodiol, a sensitiser of platinum cytotoxicity: the phase III OVATURE multicenter randomized study

Background Platinum-resistant ovarian cancer (PROC) constitutes a therapeutic dilemma with limited efficacy from traditional cytotoxic agents. Based on prior data suggesting that scheduling alterations of platinum would increase activity, the aim of the present study was to assess the potential therapeutic benefit of phenoxodiol (PXD), a novel biomodulator shown to have chemoresistance reversing potential, when combined with weekly AUC2-carboplatin in PROC patients. Patients and methods A multicenter randomized double-blind placebo controlled phase-III-study was conducted to compare oral PXD plus AUC2-carboplatin (group 1) versus placebo plus AUC2-carboplatin (group 2) weekly in PROC patients. The primary end point was progression-free-survival (PFS). Secondary objectives included overall survival (OS), response rates, duration of response and quality of life. Results The study was terminated early 14 April 2009, after recruitment of 142 patients due to feasibility and recruitment challenges. A total of 142 patients were randomized. The groups were well balanced in terms of important baseline characteristics. The median PFS for group 1 was 15.4 weeks [95% confidence interval (CI) 11.1–21.0] versus 20.1 weeks for group 2 (95% CI = 13.1–33.4); P = 0.3. The objective response rate and median survival in group 1 versus group 2 was 0% versus 1% and 38.3 weeks (95% CI 32.0–45.3) versus 45.7 weeks (95% CI 35.6–58.0), respectively. PXD appeared to be well tolerated. The main reason for dose modification in both groups was hematologic toxicity. Conclusions Orally delivered PXD showed no evidence of clinical activity, when combined with weekly AUC2-carboplatin in PROC. In addition, single-agent weekly AUC2-carboplatin appeared to be inactive by response criteria in a homogenously defined population of PROC. This has implications for the design of future studies

Estrogen Receptor Alpha Expression in Ovarian Cancer Predicts Longer Overall Survival

Estrogen as a potential factor of ovarian carcinogenesis, acts via two nuclear receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), but the cellular signal pathways involved are not completely clear so far. In this study we have described the expression of ERα, detected by immunocytochemistry in 11 ovarian carcinoma cell lines and by immunohistochemistry in 43 Federation Internationale des Gyneacologistes et Obstetristes stage III ovarian carcinoma specimens prepared before and after treatment with cisplatin-based schemes. For cisplatin resistance is a major obstacle in the treatment of ovarian carcinoma, analysis of cisplatin sensitivity in 11 ovarian carcinoma cell line was also performed. The strong nuclear ERα expression was only shown in the single A2780P cell line. Expression of ERα in tissue specimens did not reveal any correlations between histopathological parameters (histologic type and grading). We demonstrated a significant association with ERα expression in specimens from primary laparotomies (PL) and cause–specific survival. In the cases terminated by death of the patient, overall immunoreactivity score of ERα expression at PL was significantly lower than in surviving patients. In addition, Kaplan-Meier analysis revealed significantly shorter overall survival time and progression-free time in cases with lower immunoreactivity score of ERα expression at PL. Our findings support the hypothesis that aberrant hormone activity, by way of altered receptor expression, might be an important factor in the malignant transformation of ovarian cancer

Fitodegradacja I biodegradacja e ryzosferze jako skuteczne metody rekultywacji gruntów skażonych związkami organicznymi (artykuł przeglądowy)

Technical methods of purification of large areas of low and medium pollution are powerful, but extremely difficult to apply on a wide scale. This is due to high costs and the need to have specialised equipment during remediation. Phytoremediation is a much less complicated method. This environment cleaning technology uses the above-average capacity of some plant species to accumulate (socalled hyper-accumulation) or metabolise toxic chemicals. Soil microorganisms living in the rhizosphere also play an invaluable role in the degradation of harm-ful organic compounds; they are often much more involved in the mineralisation of xenobiotics than plants. Since plants provide favourable conditions for soil microorganisms to live – specific cooperation between them is possible. This kind of relationship can be useful in very effective removal of many toxic organic compounds, such as pesticides, polychlorinated biphenyls, polycyclic aromatic hydrocarbons and other petroleum compounds, from the soil. Although this process is relatively slow compared to other methods, its low invasiveness and economic considerations make it worthwhile. Currently, attempts at improvement of the natural process of phytoremediation using genetic engineering are undertaken more and more often. Among other things, genes encoding cytochromes from other organisms are implanted into the plant genome. This idea is constantly being developed and the results of research that is more and more widely conducted in this are promising.Techniczne metody oczyszczania rozległych terenów o niskim i średnim stopniu zanieczyszczenia są wprawdzie wydajne, ale jednocześnie niezwykle trudno je zastosować na szerszą skalę. Związane jest to z wysokimi kosztami, oraz potrzebą dysponowania wyspecjalizowanym sprzętem podczas remediacji. Znacznie mniej skomplikowaną metodą jest fitoremediacja. Jest to technologia oczyszczania środowiska, która wykorzystuje ponadprzeciętne zdolności niektórych gatunków roślin do akumulacji (tzw. hiperakumulacji) lub metabolizowania trujących substancji chemicznych. Nieocenioną rolę przy degradacji szkodliwych związków organicznych pełnią także mikroorganizmy glebowe, które bytując w strefie przykorzeniowej często w znacznie większym stopniu niż rośliny uczestniczą w mineralizacji ksenobiotyków. Poprzez to, iż rośliny stwarza-ją mikroorganizmom glebowym dogodne warunki do życia – dochodzi tutaj do swoistej współpracy między nimi. Wykorzystując tę współpracę można również w sposób bardzo efektywny usuwać z gleby wiele toksycznych związków organicznych takich jak pestycydy, polichlorowane bifenyle, wielopierścieniowe węglowodory aromatyczne oraz inne związki ropopochodne. Chociaż jest to proces stosunkowo powolny w porównaniu z innymi metodami, niska inwazyjność oraz względy ekonomiczne przemawiają na jego korzyść. Obecnie coraz częściej obserwuje się próby usprawnienia naturalnego procesu fitoremediacji przez wykorzystanie metod inżynierii genetycznej. Między innymi wszczepia się do genomu roślinnego geny kodujące cytochromy z innych organizmów. Pomysł ten jest stale rozwijany, a wyniki coraz śmielej prowadzonych w tym zakresie prac badawczych są obiecujące

Topoisomerase 1A, HER,2neu and Ki67 expression in paired primary and relapse ovarian cancer tissue samples

In the present study we examined prognostic value of immunohistochemical estimation of topoisomerase 1A (TOP 1A) and HER-2/neu expression in ovarian cancers treated with platinum-based drugs but not with topotecan and the relation between expression of these proteins on the one hand and intensity of proliferation (Ki67) on the other. The analyses were performed on 73 samples of ovarian carcinoma originating from 43 first-look laparotomies (FLL) and, in 30 cases, from secondary cytoreductions (SCR)(after chemotherapy) from the same patients. In paraffin sections immunohistochemical reactions were performed using antibodies directed to HER-2/neu, TOP 1A and Ki67. Kaplan-Meier’s analysis disclosed a shorter overall survival time in cases with augmented expression of TOP 1A at FLL and with higher expression of Ki67 at SCR. A shorter progression-free time was detected in cases with higher proportion of Ki67 positive cells at FLL. No relationship could be disclosed between HER- 2/neu expression and the studied clinicopathological parameters. The studies confirmed high value of Ki67 estimation. The augmented expression of TOP 1A was demonstrated to represent an unfavourable prognostic factor. Thus, in cases with elevated expression of TOP 1A application of topotecan-based therapeutic schemes should be considered

Expression and signaling of Toll-like receptor 4 (TLR4) and MyD88 in ovarian carcinoma cells

e16508 Background: TLR4, expressed by the cells of the immune system play a role in the protection of the host against pathogens. TLRs are also expressed on human cancer cells, but their role in tumor growth is unknown. The aim of this study was to correlate the presence of TLR4 and MyD88 expression with clinicopathologic outcome in patients with ovarian cancer and to analyze the consequences of signaling via the TLR4/MyD88 pathway in ovarian cancer cell lines. Methods: Tumor specimens from 41 patients with ovarian carcinoma were evaluated for TLR4 and MyD88 by immunohistochemistry and correlated with clinical and pathologic disease features. TLR4/MyD88 expression in OVCAR3, SKOV3, and A2780 was determined using RT-PCR, WB, and immunohistochemistry. NF-kB translocation to nucleus was measured by confocal microscopy. Culture supernatants were tested for levels of cytokines in Luminex-based assays. Proliferation of cancer cells was measured in the CFSE assays. Their sensitivity to paclitaxel (PLX) was measured by Annexin V binding. Western Blot analysis was used to measure activation of the PI3K/Akt, IRAK 1, IRAK 4, and TRIF. Results: In ovarian cancer patients TLR4 and MyD88 expression by the tumor was observed in 100% and 83% of tissues, respectively. The expression of MyD88 was associated with shorter progression-free survival (42 vs 31 months, p &lt; 0.05). Ex vivo studies showed that TLR4 was expressed on OVCAR3, SKOV3, and A2780 cell lines, while A2780 did not expressed MyD88. In MyD88+ tumor cells, LPS increased proliferation (PI 17 vs 8, p &lt; 0.05), activated NF-kB pathway and promoted cytokine production (IL-8, IL-6, RANTES, VEGF and MCP-1). LPS and PLX binding to TLR4 on MyD88+ cells induced activation of PI3K/Akt, IRAK4, and IRAK1, but decreased expression of pro-apoptotic TRIF. In contrast, in MyD88(-) cells LPS did not induce proliferation and neither LPS nor PLX induced secretion of pro-inflammatory cytokines. Further, no changes were noted in IRAK1 expression, but strong signal was observed for TRIF. TLR4+/MyD88+ tumor cells showed grater resistance to PLX. Conclusions: Our ex vivo studies elucidate the molecular mechanisms involved in TLR4/MyD88 signaling. Ligation via TLR4 leads to tumor growth, release of proinflammatory cytokines and induction of resistance to PLX-induced apoptosis. No significant financial relationships to disclose. </jats:p