Oxygen in health and disease: regulation of oxygen homeostasis--clinical implications

Oxygen is critical for multicellular existence. Its reduction to water by the mitochondrial electron transport chain helps supply the metabolic demands of human life. The incompletely reduced, reactive oxygen byproducts of this reaction, however, can be quite toxic. In this review, we explore the mechanisms responsible for maintaining oxygen homeostasis and the consequences of their dysfunction. With an eye toward defining clinical care guidelines for the management of critically ill neonates, we present evidence describing the role of physiologic hypoxia during development and the adverse consequences of hyperoxia in-term as well as preterm infants.     

Matrix metalloproteinase-21 expression is associated with keratinocyte differentiation and upregulated by retinoic acid in HaCaT cells

In the skin, expression of several matrix metalloproteinases (MMPs) occurs in response to tissue injury, tumorigenesis, angiogenesis, apoptosis, and inflammation. The recently cloned MMP-21 has been implicated in skin development and various epithelial cancers. In this study, we found that it is also expressed by differentiated keratinocytes (KCs) in various benign skin disorders, in which it was not associated with KC apoptosis or proliferation, and in organotypic cultures. Furthermore, MMP-21 was induced in keratinocytes in association with increased calcium and presence of the differentiation marker filaggrin. In stably transfected A431 and HEK293 cell lines, MMP-21 increased invasion of cells but did not associate with increased apoptosis, proliferation, or epithelial-to-mesenchymal transition. Of various agents tested in HaCaT cell cultures, only retinoic acid (10(-6) M) and staurosporine (2.5 x 10(-8) M) upregulated MMP-21 mRNA and protein expression, whereas tumor promoters, hormones, or dexamethasone were without effect. Our results suggest that MMP-21 may be an important protease in the terminal differentiation of keratinocytes.     

Retrospective Study of the Effect of Statins on the Outcome of Lung Cancer Patients,University of Cincinnati Experience

Objectives: Numerous studies addressed the effect of statin on cancer patients. The aim of this study is to define theeffect of statin administration with chemotherapy on the patients’ outcomes. Methods: We retrospectively researchedthe database of the University of Cincinnati cancer to identify lung cancer patients who received statins (S+, n=41)during their treatment in our institute. We also, retrieved data for contemporaneously treated patients who did notreceive statins (S-, n=159) as a control arm. Clinico-demographical data and overall survival (OS) were analyzed usingPearson’s Chi-square (χ2) test and Kaplan-Meier survival curves with Log-rank test. Adjustment using Cox proportionalhazard ratios (HR) were done based on (age, gender, race and stage) to identify effect of statins on their outcomes.Results: The median age for S+ was 64y (IQR; 55-69) and 71.2% of the patients were white. Histopathology was55.4% and 31.7% for adenocarcinoma and squamous cell carcinoma, respectively. Fifty-six percent were stage IV ineach study arm and the median OS was14.9 m. Median OS was insignificantly lower in S–ve arm (13.7 vs 15.6 months;P=0.652, HR=0.91, 95%CI 0.52-1.57). Our results show that after different types of adjustments, S+ did not showsurvival advantage (P>0.05) compared to the control arm. Conclusion: While showing an increase in overall survivalin patients with advanced lung cancer, the results of this study did not reach statistical significance. This could be duefor the small sample size of this retrospective study.     

The synthetic retinoid ST1926 attenuates prostate cancer growth and potentially targets prostate cancer stem‐like cells

Retinoids are vitamin A derivatives that regulate crucial biological processes such as cellular proliferation, apoptosis, and differentiation. The use of natural retinoids in cancer therapy is limited due to their toxicity and the acquired resistance by cancer cells. Therefore, synthetic retinoids were developed, such as the atypical adamantyl retinoid ST1926 that provides enhanced bioavailability and reduced toxicity. We have assessed the in vitro and in vivo antitumor properties and mechanism of action of ST1926 in targeting cancer stem‐like cells population of human prostate cancer (PCa) cell lines, DU145 and PC3, and mouse PCa cell lines, PLum‐AD and PLum‐AI. We demonstrated that ST1926 substantially reduced proliferation of PCa cells and induced cell cycle arrest, p53‐independent apoptosis, and early DNA damage. It also decreased migration and invasion of PCa cells and significantly reduced prostate spheres formation ability in vitro denoting sufficient eradication of the self‐renewal ability of the highly androgen‐resistant cancer stem cells. Importantly, ST1926 potently inhibited PCa tumor growth and progression in vivo. Our results highlight the potential of ST1926 in PCa therapy and warrant its clinical development.     

Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma

Polycomb repressive complex 2 (PRC2) components, EZH2 and its homolog EZH1, and PI3K/Akt signaling pathway are focal points as therapeutic targets for multiple myeloma. However, the exact crosstalk between their downstream targets remains unclear. We herein elucidated some epigenetic interactions following Akt inhibition and demonstrated the efficacy of the combined inhibition of Akt and PRC2. We found that TAS‐117, a potent and selective Akt inhibitor, downregulated EZH2 expression at the mRNA and protein levels via interference with the Rb‐E2F pathway, while EZH1 was compensatively upregulated to maintain H3K27me3 modifications. Consistent with these results, the dual EZH2/EZH1 inhibitor, UNC1999, but not the selective EZH2 inhibitor, GSK126, synergistically enhanced TAS‐117‐induced cytotoxicity and provoked myeloma cell apoptosis. RNA‐seq analysis revealed the activation of the FOXO signaling pathway after TAS‐117 treatment. FOXO3/4 mRNA and their downstream targets were upregulated with the enhanced nuclear localization of FOXO3 protein after TAS‐117 treatment. ChIP assays confirmed the direct binding of FOXO3 to EZH1 promoter, which was enhanced by TAS‐117 treatment. Moreover, FOXO3 knockdown repressed EZH1 expression. Collectively, the present results reveal some molecular interactions between Akt signaling and epigenetic modulators, which emphasize the benefits of targeting PRC2 full activity and the Akt pathway as a therapeutic option for multiple myeloma.     

Socio-economic inequality in the self-reported number of natural teeth among Norwegian adults--an analytical study

Abstract – Objective: To assess inequality in dental status associated with educational level, gross personal and family income among Norwegian adults. Methods: Data were collected by Norway's Central Bureau of Statistics in November–December 2003. A two‐stage, proportional random sample comprising 2000 persons aged 16–79 years was drawn from the national population register. Information became available for 1309 subjects by interview. The present analyses pertain to 1092 subjects aged 25–79 years (response rate 66%, mean age 47.9 years). Results: Of the respondents, 3% were edentulous and 9% had fewer than 20 teeth. The mean number of teeth was 27.1 (SD 7.0). In multiple logistic regression analysis, low gross personal and adjusted family income were associated with increased likelihood of having fewer than 20 natural teeth (OR = 2.84, 95% CI 1.58, 5.10; OR = 3.63, 95% CI 1.99, 6.62, respectively). Educational level was significantly associated with dental status in bivariate but not in multivariate analyses, except once among males. The predictors of socio‐economic inequality in dental status accounted for a limited proportion of explained variance (Nagelkerke's R²) when controlling for age, place of residence, perceived oral health compared with others, perceived importance of oral health, dental attendance and smoking. Conclusion: Socio‐economic inequality in dental status persists among Norwegians aged 25–79 years but absolute differences have decreased during the last 30 years. The findings are encouraging but challenging as far as choice of strategy for further reduction of differences in tooth loss.     

Effect of early treatment with disease-modifying anti-rheumatic drugs and treatment adherence on disease outcome in rheumatoid arthritis patients

Aim of the work

To evaluate the effects of early and regular treatment with Disease Modifying Anti-Rheumatic Drugs (DMARDs) on disease outcome in rheumatoid arthritis (RA) patients and factors affecting adherence to treatment.

The role of magnetic resonance imaging in early detection of recurrent breast cancer

Purpose

The purpose of this work was the evaluation of new advances of magnetic resonance imaging (MRI) in diagnosis of recurrent breast cancer after conservative surgery, chemotherapy and radiotherapy.

Tonsil surgery in Sweden 2013–2015. Indications,surgical methods and patient-reported outcomes from the National Tonsil Surgery Register

Aim: To describes how tonsil surgery was performed in Sweden from 2013 to 2015 with data from the National Tonsil Surgery Registry in Sweden (NTSRS).

Method: The registry collects data from both professionals and patients through questionnaires. A total of 33,870 tonsil surgeries were analysed, comprising approximately 80% of all tonsil surgeries in Sweden from 2013 to 2015.

Results: The two most common procedures were tonsillectomy (41%) and tonsillotomy with adenoidectomy (38%). Tonsillectomy was most commonly performed to treat frequent tonsillitis, while the main indication for tonsil surgery with combined adenoidectomy and for tonsillotomy alone was upper airway obstruction. The most commonly used techniques were cold steel (70%) for tonsillectomy/adenotonsillectomy and radiofrequency (79%) for tonsillotomy/adenotonsillotomy. Ninety-five percent of patients reported symptom relief after 180 d. Day surgery was utilised in 70% of the surgeries. The rate of readmission due to post-tonsillectomy haemorrhage was 5.1%. Male patients more often underwent tonsil surgery at preschool ages due to upper airway obstruction; in comparison, female patients to a larger extent underwent surgery in their early teens because of previous infections.

Conclusions: The NTSRS provides an opportunity to survey tonsil surgery in Sweden and to launch and follow up improvement programmes as desired.