DNA oxidative damage in oral cancer: 8-hydroxy-2´-deoxyguanosine immunoexpression assessment.

BACKGROUND: The development and establishment of oral squamous cell carcinoma are confined to carcinogenesis, which involves oxidative stress via oxygen-free radical production as a hydroxyl radical (HO•), considered the most important cause of oxidative damage to basic biomolecules since it targets DNA strands. 8-Hydroxy-2´-deoxyguanosine (8-OHdG) is considered a free radical with a promutagenic capacity due to its ability to pair with adenosine instead of cytosine during replication. MATERIAL AND METHODS: We collected 30 paraffin-embedded tissue samples of OSCC from patients treated between 2013 and 2018. We recorded risk habits, disease stage, disease free survival and death with at least 3 years of follow-up. 8-Hydroxyguanosine was evaluated by immunohistochemistry and subsequently classified as weak-moderate or strong positive expression. Additionally, we noted whether it was expressed in the cytoplasm and/or nucleus. RESULTS: Most of the cases expressed 8-OHdG with a strong intensity (80%). All neoplastic cells were preferentially stained in only the cytoplasm (70.0%), but nuclear positivity was found in 30%, independent of the intensity. Based on the location in the cytoplasm and/or nucleus, tumors >4 cm showed a high frequency (95.5%) of 8-OHdG expression in only the cytoplasm, with a significant difference (p value 0.001). Additionally, overall survival was affected when immunoexpression was present in the cytoplasm and nucleus because all deaths were in this group were statistically significant (p value = 0.001). CONCLUSIONS: All tumors showed DNA oxidative damage, and 8-OHdG was preferentially expressed in the cytoplasm. This finding was associated with tumor size and, when present in the nucleus, might also be related to death.

Potential effect of chloroquine and propranolol combination to treat colorectal and triple-negative breast cancers.

Drug repositioning explores the reuse of non-cancer drugs to treat tumors. In this work, we evaluated the effect of the combination of chloroquine and propranolol on colorectal and triple-negative breast cancers. Using as in vitro models the colorectal cancer cell lines HCT116, HT29, and CT26, and as triple-negative breast cancer models the 4T1, M-406, and MDA-MB-231 cell lines, we evaluated the effect of the drugs combination on the viability, apoptosis, clonogenicity, and cellular migratory capacity. To explore the in vivo effects of the combination on tumor growth and metastasis development we employed graft models in BALB/c, nude, and CBi mice. In vitro studies showed that combined treatment decreased cell viability in a dose-dependent manner and increased apoptosis. Also, we demonstrated that these drugs act synergically and that it affects clonogenicity and migration. In vivo studies indicated that this drug combination was effective on colorectal models but only partially on breast cancer. These results contributed to the search for new and safe treatments for colorectal and triple-negative carcinomas.

Statins inhibit protein kinase D (PKD) activation in intestinal cells and prevent PKD1-induced growth of murine enteroids.

We examined the impact of statins on protein kinase D (PKD) activation by G protein-coupled receptor (GPCR) agonists. Treatment of intestinal IEC-18 cells with cerivastatin inhibited PKD autophosphorylation at Ser916 induced by angiotensin II (ANG II) or vasopressin in a dose-dependent manner with half-maximal inhibition at 0.2 µM. Cerivastatin treatment inhibited PKD activation stimulated by these agonists for different times (5-60 min) and blunted HDAC5 phosphorylation, a substrate of PKD. Other lipophilic statins, including simvastatin, atorvastatin, and fluvastatin also prevented PKD activation in a dose-dependent manner. Using IEC-18 cell lines expressing PKD1 tagged with EGFP (enhanced green fluorescent protein), cerivastatin or simvastatin blocked GPCR-mediated PKD1-EGFP translocation to the plasma membrane and its subsequent nuclear accumulation. Similar results were obtained in IEC-18 cells expressing PKD3-EGFP. Mechanistically, statins inhibited agonist-dependent PKD activation rather than acting directly on PKD catalytic activity since exposure to cerivastatin or simvastatin did not impair PKD autophosphorylation or PKD1-EGFP membrane translocation in response to phorbol dibutyrate, which bypasses GPCRs and directly stimulates PKC and PKD. Furthermore, cerivastatin did not inhibit recombinant PKD activity determined via an in vitro kinase assay. Using enteroids generated from intestinal crypt-derived epithelial cells from PKD1 transgenic mice as a model of intestinal regeneration, we show that statins oppose PKD1-mediated increase in enteroid area, complexity (number of crypt-like buds), and DNA synthesis. Our results revealed a previously unappreciated inhibitory effect of statins on receptor-mediated PKD activation and in opposing the growth-promoting effects of PKD1 on intestinal epithelial cells.

Italian translation, cultural adaptation, and validation of the Intermittent Catheterization Acceptance Test (I-CAT).

Aims: The purpose of the present study was to translate and culturally adapt the Intermittent Catheterization Acceptance Test (I-CAT) for Italian individuals with spinal cord injury and spina bifida and to measure its psychometric properties. Methods: Consent from the authors of I-CAT was received, and then, following international guidelines, it was culturally adapted to Italian. The included participants adults who practice self-catheteri-zation. In order to evaluate criterion validity, the Qualiveen-30, Spinal Cord Independence Measure (SCIM-self reported), and the Moorong self-efficacy scale (MSES) were administered together. Test-retest reliability was assessed administering the I-CAT a second time within a week. Following the COSMIN checklist, psychometric properties were evaluated. Results: All translated items resulted identical or similar to the original versions. Internal consistency, evaluated on 34 individuals, showed values of Cronbach's alpha of 0.889, test-retest reliability was evaluated through the intraclass correlation coefficient with values of 0.96. Statistically significant correlation between the I-ICAT and Qualiveen were found through Pearson's correlation coefficient and Spearman's Correlation Coefficient for criterion validity. Conclusions: The Italian validation of I-CAT allows Italian professionals to investigate psychological barriers linked with self-catheterization in people with urinary tract dysfunction before learning about aseptic Intermittent Self Catheterization (IC) and improving patients' acceptance of it. This tool can also be used as follow-up after the training of intermittent self-catheterization techniques. Finally, it is an important tool for medical research.

PLGA-TiO2 as a Carrier System for Drug Release.

This paper reports the results of the PLGA-TiO2 nanocomposite regarding the green synthesis of titanium dioxide nanoparticles using a natural extract, its characterization, and encapsulation with poly(lactic-co-glycolic acid) (PLGA). UV-visible spectrometry was used for the identification of terpenes present in the extracts. The morphology of the nanoparticles was determined by scanning electron microscopy. Infrared spectroscopy was used for the determination of functional groups, while X-ray diffraction was used to determine the crystal structure. The analysis of the extended release of the encapsulated extract in the matrix of the nanomaterial resulted in a maximum visible UV absorbance at approximately 260 nm and confirmed the synthesis of titanium dioxide nanoparticles. Moreover, terpenes enhance synthesis and stabilize titanium dioxide nanoparticles. The synthesized structures are spherical and amorphous, 44 nm in size, and encapsulated at 65 nm.

Obstetric comorbidity index and the odds of general vs. neuraxial anesthesia in women undergoing cesarean delivery: a retrospective cohort study.

BACKGROUND: Maternal and fetal concerns have prompted a significant reduction in general anesthesia (GA) use for cesarean delivery (CD). The obstetric comorbidity index (OB-CMI) is a validated, dynamic composite score of comorbidities encountered in an obstetric patient. We sought to estimate the association between OB-CMI and odds of GA vs. neuraxial anesthesia (NA) use for CD. METHODS: In this single-center, retrospective cohort study conducted at a large academic hospital in the United States of America, OB-CMI was calculated on admission and every 12 h for women undergoing CD at ≥23 weeks' gestation (n=928). The CD urgency, anesthesia type, and most recent OB-CMI were extracted from the medical record. The association between OB-CMI and GA use was estimated by logistic regression, with and without adjustment for CD urgency, parity and race. RESULTS: Each one-point increase in OB-CMI was associated with a 32% (95% confidence interval [CI] 17% to 48%) increase in the odds of GA use (Model 1, area under the receiver operating characteristic curve [AUC] 0.708, 95% CI 0.610 to 0.805). The AUC improved to 0.876 (95% CI 0.815 to 0.937) with the addition of emergent CD (Model 2, P <0.001 vs. Model 1), but not parity and race (Model 3, AUC 0.880, 95% CI 0.824 to 0.935; P=0.616 vs. Model 2). CONCLUSIONS: The OB-CMI is associated with increased odds of GA vs. NA use for CD, particularly when emergent. Collected in real time, the OB-CMI may enable prophylaxis (e.g. comorbidity modification, earlier epidural catheter placement, elective CD) or preparation for GA use.

Gallbladder disease and pancreatic cancer risk: a multicentric case-control European study.

BACKGROUND AND AIMS: The overall evidence on the association between gallbladder conditions (GBC: gallstones and cholecystectomy) and pancreatic cancer (PC) is inconsistent. To our knowledge, no previous investigations considered the role of tumour characteristics on this association. Thus, we aimed to assess the association between self-reported GBC and PC risk, by focussing on timing to PC diagnosis and tumour features (stage, location, and resection). METHODS: Data derived from a European case-control study conducted between 2009 and 2014 including 1431 PC cases and 1090 controls. We used unconditional logistic regression models to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) adjusted for recognized confounders. RESULTS: Overall, 298 (20.8%) cases and 127 (11.6%) controls reported to have had GBC, corresponding to an OR of 1.70 (95% CI 1.33-2.16). The ORs were 4.84 (95% CI 2.96-7.89) for GBC diagnosed <3 years before PC and 1.06 (95% CI 0.79-1.41) for ≥3 years. The risk was slightly higher for stage I/II (OR = 1.71, 95% CI 1.15-2.55) vs. stage III/IV tumours (OR = 1.23, 95% CI 0.87-1.76); for tumours sited in the head of the pancreas (OR = 1.59, 95% CI 1.13-2.24) vs. tumours located at the body/tail (OR = 1.02, 95% CI 0.62-1.68); and for tumours surgically resected (OR = 1.69, 95% CI 1.14-2.51) vs. non-resected tumours (OR = 1.25, 95% CI 0.88-1.78). The corresponding ORs for GBC diagnosed ≥3 years prior PC were close to unity. CONCLUSION: Our study supports the association between GBC and PC. Given the time-risk pattern observed, however, this relationship may be non-causal and, partly or largely, due to diagnostic attention and/or reverse causation.

Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment.

Drug repositioning refers to new uses for existing drugs outside the scope of the original medical indications. This approach fastens the process of drug development allowing finding effective drugs with reduced side effects and lower costs. Colorectal cancer (CRC) is often diagnosed at advanced stages, when the probability of chemotherapy resistance is higher. Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, highly metastatic and difficult to treat. For both tumor types, available treatments are generally associated to severe side effects. In our work, we explored the effect of combining metformin and propranolol, two repositioned drugs, in both tumor types. We demonstrate that treatment affects viability, epithelial-mesenchymal transition and migratory potential of CRC cells as we described before for TNBC. We show that combined treatment affects different steps leading to metastasis in TNBC. Moreover, combined treatment is also effective preventing the development of 5-FU resistant CRC. Our data suggest that combination of metformin and propranolol could be useful as a putative adjuvant treatment for both TNBC and CRC and an alternative for chemo-resistant CRC, providing a low-cost alternative therapy without associated toxicity.

[Failure mode effect analysis for safety improvement in the automatic drug dispensing systems]. / Aplicación de un análisis modal de fallos y efectos para la mejora de la seguridad en la utilización de los sistemas automatizados de dispensación de medicamentos.

OBJECTIVE: To identify the risks in automated dispensing cabinet use in order to improve routine procedure safety. METHODS: We used the Failure Mode Effect Analysis (FMEA) methodology. A multidisciplinary team identified potential failure modes of the procedure through a brainstorming session. We assessed the impact associated with each failure mode with the Risk Priority Number (RPN), which involves three variables: occurrence, severity, and detectability. Improvement measures were established for failure modes with RPN>100 considered critical. The final RPN (theoretical) that would result from the proposed measures was also calculated. RESULTS: The process was divided into five sub-processes: automatic delivery of order replacement, to prepare order in a pyramidal cart, transport of the pyramidal cart from the pharmacy service to the automated dispensing cabinet, replacement of the automated dispensing cabinet by the pharmacy technician and dispensing/returning by nursing staff. Twenty-two failure modes, with 25 cases and with varying effects (severity 2-8) were evaluated. The sub-process with more failure modes with NPR>100 was dispensing/returning by nursing staff. CONCLUSIONS: The FMEA methodology was a useful tool when applied to automated dispensing cabinet system use. The implementation of improvement actions significantly reduced the risk.

A cluster quasi-randomized controlled trial of an interactive, monthly obstetric anesthesiology curriculum: impact on resident satisfaction and knowledge retention.

BACKGROUND: Increasingly, evidence supports the use of educational paradigms that focus on teacher-learner interaction and learner engagement. We redesigned our monthly obstetric anesthesia resident didactics from a lecture-based curriculum to an interactive format including problem-based learning, case discussion, question/answer sessions, and simulation. We hypothesized that the new curriculum would improve resident satisfaction with the educational experience, satisfaction with the rotation, and knowledge retention. METHODS: Fifty-three anesthesiology residents were prospectively recruited and quasi-randomized through an alternating-month pattern to attend either interactive sessions or traditional lectures. Residents completed a daily satisfaction survey about quality of teaching sessions and a comprehensive satisfaction survey at the conclusion of the rotation. Knowledge retention was assessed with a knowledge test completed on the final day. The primary outcome was daily satisfaction with the curriculum, and secondary outcomes included overall satisfaction with the curriculum, overall rotation satisfaction, and within-resident difference between pre- and post-knowledge test scores. RESULTS: No differences were observed in daily resident satisfaction after interactive sessions vs traditional lectures. Furthermore, no differences were observed between the interactive sessions and traditional lecture groups in overall satisfaction with the curriculum, overall satisfaction with the entire rotation or within-resident difference between pre- and post-knowledge test scores. CONCLUSIONS: Our study failed to demonstrate improvement in resident satisfaction or knowledge retention following implementation of an interactive curriculum on a month-long obstetric anesthesia rotation. Reasons may include misalignment of the intervention with measured study outcomes, lack of sensitivity of the survey tools, and inadequate training of faculty presenters.

Nanostructured lipid carriers loaded with curcuminoids: Physicochemical characterization, in vitro release, ex vivo skin penetration, stability and antioxidant activity.

Four formulations of nanostructured lipid carriers (NLC) loaded with curcuminoids where prepared, testing two types of solid lipids (Compritol® 888 ATO and Precirol® ATO 5) and two kinds of stabilizers (poloxamer 407 and polysorbate 80). Particle size values between 111 and 214 nm and polydispersity indices < 0.3 were registered, with low Z potential values due to the nonionic character of the stabilizers. The results showed that the type of surfactant had an impact on the in vitro release rate and on the ex vivo skin permeation capability of curcuminoids. Polysorbate 80 delayed the release, but favors the transport of a higher amount of curcuminoids to the receptor solution during the ex vivo permeation studies than the systems with poloxamer 407. Confocal microscopy confirmed that all systems favored the penetration of curcuminoids to deeper layers of the skin and in a greater amount than curcuminoids in solution. Exposure of the systems to intense radiation caused the degradation of curcuminoids, without loss of antioxidant activity, confirming that the degradation products also function as antioxidants. The NLC prepared can be valuable carriers to enhance the penetration of curcuminoids into the skin, to treat different disorders and skin diseases.