Morphine Analgesia, Cannabinoid Receptor 2, and Opioid Growth Factor Receptor Cancer Tissue Expression Improve Survival after Pancreatic Cancer Surgery.

Pancreatic cancer (PDAC) has a poor prognosis despite surgical removal and adjuvant therapy. Additionally, the effects of postoperative analgesia with morphine and piritramide on survival among PDAC patients are unknown, as are their interactions with opioid/cannabinoid receptor gene expressions in PDAC tissue. Cancer-specific survival data for 71 PDAC patients who underwent radical surgery followed by postoperative analgesia with morphine (n = 48) or piritramide (n = 23) were therefore analyzed in conjunction with opioid/cannabinoid receptor gene expressions in the patients' tumors. Receptor gene expressions were determined using the quantitative real-time polymerase chain reaction. Patients receiving morphine had significantly longer cancer-specific survival (CSS) than those receiving piritramide postoperative analgesia (median 22.4 vs. 15 months; p = 0.038). This finding was supported by multivariate modelling (p < 0.001). The morphine and piritramide groups had similar morphine equipotent doses, receptor expression, and baseline characteristics. The opioid/cannabinoid receptor gene expression was analyzed in a group of 130 pancreatic cancer patients. Of the studied receptors, high cannabinoid receptor 2 (CB2) and opioid growth factor receptor (OGFR) gene expressions have a positive influence on the length of overall survival (OS; p = 0.029, resp. p = 0.01). Conversely, high delta opioid receptor gene expression shortened OS (p = 0.043). Multivariate modelling indicated that high CB2 and OGFR expression improved OS (HR = 0.538, p = 0.011, resp. HR = 0.435, p = 0.001), while high OPRD receptor expression shortened OS (HR = 2.264, p = 0.002). Morphine analgesia, CB2, and OGFR cancer tissue gene expression thus improved CSS resp. OS after radical PDAC surgery, whereas delta opioid receptor expression shortened OS.

Proteome Mapping of Cervical Mucus and Its Potential as a Source of Biomarkers in Female Tract Disorders.

Cervical mucus (CM) is a viscous fluid that is produced by the cervical glands and functions as a uterine cervix plug. Its viscosity decreases during ovulation, providing a window for non-invasive sampling. This study focuses on proteomic characterization of CM to evaluate its potential as a non-invasively acquired source of biomarkers and in understanding of molecular (patho)physiology of the female genital tract. The first objective of this work was to optimize experimental workflow for CM processing and the second was to assess differences in the proteomic composition of CM during natural ovulatory cycles obtained from intrauterine insemination (IUI) cycles and in vitro fertilization (IVF) cycles with controlled ovarian hyperstimulation. Proteomic analysis of CM samples revealed 4370 proteins involved in processes including neutrophil degranulation, cellular stress responses, and hemostasis. Differential expression analysis revealed 199 proteins enriched in IUI samples and 422 enriched in IVF. The proteins enriched in IUI were involved in phosphatidic acid synthesis, responses to external stimulus, and neutrophil degranulation, while those enriched in IVF samples were linked to neutrophil degranulation, formation of a cornified envelope and hemostasis. Subsequent analyses clarified the protein composition of the CM and how it is altered by hormonal stimulation of the uterus.

Cannabinoid receptor 2 expression in early-stage non-small cell lung cancers identifies patients with good prognosis and longer survival.

Background: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death with a 5-year survival of only 21%. Reliable prognostic and/or predictive biomarkers are needed to improve NSCLC patient stratification, particularly in curative disease stages. Since the endogenous cannabinoid system is involved in both carcinogenesis and anticancer immune defense, we hypothesized that tumor tissue expression of cannabinoid 1 and 2 receptors (CB1 and CB2) may affect survival. Methods: Tumor tissue samples collected from 100 NSCLC patients undergoing radical surgery were analyzed for CB1 and CB2 gene and protein expression using the quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The gene and protein expression data were correlated with disease stage, histology, tumor grading, application of chemotherapy, and survival. Additional paired tumor and normal tissue samples of 10 NSCLC patients were analyzed independently for comparative analysis of CB1 and CB2 gene expression. Results: Patients with tumors expressing the CB2 gene had significantly longer overall survival (OS) (P<0.001), cancer specific survival (CSS) (P=0.002), and disease-free survival (DFS) (P<0.001). They also presented with fewer lymph node metastases at the time of surgery (P=0.011). A multivariate analysis identified CB2 tumor tissue gene expression as a positive prognostic factor for CSS [hazard ratio (HR) =0.274; P=0.013] and DFS (HR =0.322; P=0.009), and increased CSS. High CB2 gene and protein expression were detected in 79.6% and 31.5% of the tested tumor tissue samples, respectively. Neither CB1 gene nor CB1 or CB2 protein expression affected survival. When comparing paired tumor and tumor-free lung tissue samples, we observed reduced CB1 (P=0.008) and CB1 (P=0.056) gene expression in tumor tissues. Conclusions: In NSCLC patients undergoing radical surgery, expression of the CB1 and CB2 receptor genes is significantly decreased in neoplastic versus tumor-free lung tissue. CB2 tumor tissue gene expression is strongly associated with longer survival (OS, CSS, DFS) and fewer lymph node metastases at the time of surgery. More studies are needed to evaluate its role as a biomarker in NSCLC and to investigate the potential use of CB2 modulators to treat or prevent lung cancers.

2­Cl­IB­MECA regulates the proliferative and drug resistance pathways, and facilitates chemosensitivity in pancreatic and liver cancer cell lines.

Specific A3 adenosine receptor (A3AR) agonist, 2­chloro­N6­(3­iodobenzyl)­5'­N­methylcarboxamidoadenosine (2­Cl­IB­MECA), demonstrates anti­proliferative effects on various types of tumor. In the present study, the cytotoxicity of 2­Cl­IB­MECA was analyzed in a panel of tumor and non­tumor cell lines and its anticancer mechanisms in JoPaca­1 pancreatic and Hep­3B hepatocellular carcinoma cell lines were also investigated. Initially, decreased tumor cell proliferation, cell accumulation in the G1 phase and inhibition of DNA and RNA synthesis was found. Furthermore, western blot analysis showed decreased protein expression level of ß­catenin, patched1 (Ptch1) and glioma­associated oncogene homolog zinc finger protein 1 (Gli1), which are components of the Wnt/ß­catenin and Sonic hedgehog/Ptch/Gli transduction pathways. In concordance with these findings, the protein expression levels of cyclin D1 and c­Myc were reduced. Using a luciferase assay, it was revealed for the first time a decrease in ß­catenin transcriptional activity, as an early event following 2­Cl­IB­MECA treatment. In addition, the protein expression levels of multidrug resistance­associated protein 1 and P­glycoprotein (P­gp) were reduced and the P­gp xenobiotic efflux function was also reduced. Next, the enhancing effects of 2­Cl­IB­MECA on the cytotoxicity of conventional chemotherapy was investigated. It was found that 2­Cl­IB­MECA enhanced carboplatin and doxorubicin cytotoxic effects in the JoPaca­1 and Hep­3B cell lines, and a greater synergy was found in the highly tumorigenic JoPaca­1 cell line. This provides a novel in vitro rationale for the utilization of 2­Cl­IB­MECA in combination with chemotherapeutic agents, not only for hepatocellular carcinoma, but also for pancreatic cancer. Other currently used conventional chemotherapeutics, fluorouracil and gemcitabine, showed synergy only when combined with high doses of 2­Cl­IB­MECA. Notably, experiments with A3AR­specific antagonist, N­[9­Chloro­2­(2­furanyl)(1,2,4)­triazolo(1,5­c)quinazolin­5­yl]benzene acetamide, revealed that 2­Cl­IB­MECA had antitumor effects via both A3AR­dependent and ­independent pathways. In conclusion, the present study identified novel antitumor mechanisms of 2­Cl­IB­MECA in pancreatic and hepatocellular carcinoma in vitro that further underscores the importance of A3AR agonists in cancer therapy.

Impact of human papillomavirus infection on semen parameters and reproductive outcomes.

BACKGROUND: Human papillomavirus (HPV) has been shown to adversely affect human reproduction. We aimed to evaluate the prevalence of human papillomavirus (HPV) infection in men and its correlation with semen parameters and reproductive outcomes. METHODS: Semen samples and penile swabs were collected from potential sperm donors (SD, n = 97) and male partners of infertile couples (IM, n = 328). The presence of HPV DNA in semen samples and penile swabs was analyzed. Associations between hrHPV positive status and fertility outcomes as well as socio-behavioral and health characteristics were evaluated using the R software package. RESULTS: High-risk HPV (hrHPV) genotypes were detected in 28.9% of SD and 35.1% of IM (P = 0.312). Penile swabs were more frequently positive for hrHPV genotypes than semen samples in both IM (32.3% vs. 11.9%, P < 0.001) and SD (26.8% vs. 6.2%, P = 0.006). Men with hrHPV positive semen samples had lower semen volume (median volume 2.5 ml vs. 3 ml, P = 0.009), sperm concentration (median concentration 16 × 106/ml vs. 31 × 106/ml, P = 0.009) and total sperm count (median count 46 × 106 vs. 82 × 106, P = 0.009) than men with hrHPV negative samples. No association was identified between penile hrHPV status and semen parameters. CONCLUSIONS: Our findings indicate that penile HPV infection is common in both potential sperm donors and men from infertile couples. Although HPV positivity is higher in penile swabs, only HPV infection in semen samples affects sperm parameters. However, there was no association between hrHPV positivity in semen and fertility outcomes including abortion rate.

Prevalence and genotype distribution of human papillomavirus in Czech non-vaccinated heterosexual couples.

BACKGROUND: Data about the genotype-specific human papillomavirus (HPV) prevalence in the Czech Republic is limited. We aimed to evaluate the prevalence and concordance of genotype-specific HPV infection detected in semen samples, penile swabs and cervical swabs from non-vaccinated heterosexual couples without HPV-associated disease. METHODS: Semen samples and penile swabs were collected from male partners and cervical swabs were collected from female partners of heterosexual couples treated for infertility (n = 195). Presence of HPV DNA in semen samples and cervical swabs was analyzed using the cobas® HPV Test and PapilloCheck®. Only the PapilloCheck® test was used to detect HPV in penile swabs. The genotype-specific prevalence and concordance of HPV infection not targeted by vaccine were evaluated using Fisher exact test. RESULTS: Both partners were infected with any HPV type in 13.8% (27/195) of couples and, of these couples, 55.6% (15/27) harbored at least one mutual genotype. High-risk HPV (hrHPV) genotypes were detected in 12.3% (24/195) of semen samples, 31.3% (61/195) of penile swabs, and 19.5% (38/195) of cervical swabs (P < 0.001). The most prevalent hrHPV genotype were HPV53 (2.56%; 5/195) in semen samples, HPV16 (6.67%, 13/195) in penile swabs and HPV39 (3.59%, 7/195) in cervical swabs. Low-risk (lrHPV) genotypes were detected in 5.13% (10/195) of semen samples, 15.9% (31/195) of penile swabs, and 4.10% (8/195) of cervical swabs (P < 0.001). Male sexual partners of HPV-positive women were more likely to be infected with at least one of the same HPV types than female sexual partners of HPV-positive men (34.9% vs. 17.9%, P = 0.055). CONCLUSIONS: This study showed that the detection of HPV infection differ by anatomic site and gender. Regardless the anatomic site, high prevalence of HPV genital infection was found in both Czech men and women.

Comparison of Bypass and Non-Bypass Surgical Treatments for Internal Carotid Artery Blood Blister-Like Aneurysms: A Meta-Analysis of Efficacy, Safety, and Outcomes.

BACKGROUND: The optimal surgical strategy for treating internal carotid artery (ICA) blood blister-like aneurysms (BBAs) has remained unclear. Although some have preferred bypass surgery, others have favored less-demanding surgical methods. The aim of the present meta-analysis was to assess the efficacy, safety, and outcomes of bypass and non-bypass surgical methods when intended as primary treatment of ICA BBAs. METHODS: Studies reporting data on the outcomes of interest for surgically treated patients with ICA BBAs were searched for in the PubMed/MEDLINE, Evidence-Based Medicine Reviews, Cochrane Central, ProQuest, and Scopus databases. The data were analyzed using random effects modeling. RESULTS: Seven observational studies involving 140 patients met the inclusion criteria. The patients treated with bypass surgery, compared with those treated with non-bypass techniques, had lower odds of poor outcomes (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.28-2.02; P = 0.57; I2 = 0%), postoperative vasospasm (OR, 1.73; 95% CI, 0.38-7.92; P = 0.48; I2 = 19%), intraoperative bleeding (OR, 3.37; 95% CI, 0.82-13.90; P = 0.09; I2 = 0%), postoperative bleeding (OR, 1.91; 95% CI, 0.47-7.76; P = 0.36; I2 = 0%), and postoperative recurrence of BBAs (OR, 2.16; 95% CI, 0.54-8.66; P < 0.28; I2 = 0%). No comparison, however, achieved statistical significance. CONCLUSIONS: For surgeons who use both bypass and non-bypass surgical strategies, the 2 methods seemed comparable in terms of the outcomes of interest, although the bypass technique appeared superior. However, comparisons with studies reporting bypass as the uniquely preferred technique have indicated that specialization in, and preference for, the bypass procedure has been associated with more favorable outcomes.

Recurrence of surgically treated parasagittal meningiomas: a meta-analysis of risk factors.

BACKGROUND: As the predictive role of many risk factors for parasagittal meningioma (PM) recurrence remains unclear, the objective of the meta-analysis was to make a comprehensive assessment of the predictive value of selected risk factors in these lesions. METHODS: Studies including data on selected risk factors, such as histology, tumor and sinus resection, sinus invasion, tumor localization, and immediate postoperative radiotherapy for PMs recurrence, were searched in the NCBI/NLM PubMed/MEDLINE, EBM Reviews/Cochrane Central, ProQuest, and Scopus databases, and analyzed using random effects modeling. RESULTS: Thirteen observational studies involving 1243 patients met the criteria for inclusion in the meta-analysis. WHO grading of meningiomas was identified as the most powerful risk factor for recurrence. WHO grade II meningiomas (OR 11.61; 95% CI 4.43-30.43; P < .01; I2 = 31%) or composite group of WHO grades II and III (OR 14.84; 95% CI 5.10-43.19; P < .01; I2 = 48%) had a significantly higher risk of recurrence than benign lesions. Moreover, an advanced sinus involvement (types IV-VI according to the Sindou classification) (OR 3.49; 95% CI 1.30-9.33; P = .01; I2 = 0%) and partial tumor resection (Simpson grades III-V) (OR 2.73; 95% CI 1.41-5.30; P = .03; I2 = 52%) were associated with a significantly higher risk of recurrence than their counterparts. CONCLUSION: Among the selected risk factors, high-grade WHO lesions, advanced sinus invasion, and partial tumor resection were associated with a higher risk of PM recurrence, with WHO grading system being the most powerful risk factor.