The metastatic cascade in prostate cancer

Morbidity and mortality due to prostate cancer are mainly a result of prostate cancer metastases. After the initial neoplastic transformation of cells, the process of metastasis involves a series of sequential steps, which involve neoangiogenesis and lymphangiogenesis, loss of adhesion with migration away from the primary tumour and entry into the systemic vasculature or lymphatics. Metastatic growth in sites such as lymph nodes and bone marrow then involves the specific non-random homing of prostate cancer cells. An appreciation and understanding of this metastatic cascade in relation to prostate cancer is clinically important in order to stratify men with prostate cancer into prognostic groups. Moreover, it is crucial in the future development of therapies that can prevent metastases.     

Comparison of resting energy expenditure in bronchopulmonary dysplasia to predicted equation

OBJECTIVE: Children with bronchopulmonary dysplasia (BPD) often suffer from growth failure because of disturbances in energy balance with an increase of resting energy expenditure (REE). Evaluation of REE is a useful tool for nutritional management. Indirect calorimetry is an elective method for measuring REE, but it is time consuming and requires rigorous procedure. The objective of this study was to test accuracy of prediction equation to evaluate REE in BPD children. PATIENTS AND METHODS: Fifty-two children aged 4-10 years with BPD (30 boys and 22 girls) and 30 healthy lean children (20 boys and 10 girls) were enrolled. In this study, indirect calorimetry was compared to four prediction equations (Schoffield-W, Schoffield-HW, Harris-Benedict and Food and Agriculture Organization equation) using Bland-Altman pair wise comparison. RESULTS: The Harris-Benedict equation was the best equation to predict REE in children with BPD, and Schoffield-W was the best in healthy children. For the children with chronic lung disease of prematurity the Harris-Benedict equation showed the lowest mean predicted REE-REE measured by indirect calorimetry difference (difference = 15 kcal/day; limits of agreement -266 and 236 kcal/day; 95% confidence interval for the bias -207 to 177 kcal/day), and graphically, the best agreement. For the group of healthy children, it was the Schofield-W equation (-2.9 kcal/day; limits of agreement -275 and 269 kcal/day; 95% confidence interval for the bias -171 to 165 kcal/day), and graphically, the best agreement. CONCLUSION: Differences in prediction equation are minimal compared to calorimetry. Prediction equation could be useful in the management of children with BPD.     

S-CMC-Lys-dependent stimulation of electrogenic glutathione secretion by human respiratory epithelium

Glutathione (GSH) is one of the most important defense mechanisms against oxidative stress in the respiratory epithelial lining fluid. Considering that GSH secretion in respiratory cells has been postulated to be at least partially electrogenic, and that the mucoregulator S-carbocysteine lysine salt monohydrate (S-CMC-Lys) can cause an activation of epithelial Cl^– conductance, the purpose of this study was to verify whether S-CMC-Lys is able to stimulate GSH secretion. Experiments have been performed by patch-clamp technique, by high-performance liquid chromatography (HPLC) assay, and by Western blot analysis on cultured lines of human respiratory cells (WI-26VA4 and CFT1-C2). In whole-cell configuration, after cell exposure to 100 M S-CMC-Lys, a current due to an outward GSH flux was observed, which was inhibitable by 5-nitro-2-(3-phenylpropylamino)-benzoate and glibenclamide. This current was not observed in CFT1-C2 cells, where a functional cystic fibrosis transmembrane conductance regulator (CFTR) is lacking. Inside-out patch-clamp experiments (GSH on the cytoplasm side, Cl^– on the extracellular side) showed the activity of a channel, which was able to conduct current in both directions: the single channel conductance was 2–4 pS, and the open probability (P_o) was low and voltage-independent. After preincubation with 100 M S-CMC-Lys, there was an increase in P_o, in the number of active channels present in each patch, and in the relative permeability to GSH vs Cl^–. Outwardly directed efflux of GSH could also be increased by protein kinase A, adenosine 5-triphosphate, and cyclic adenosine monophosphate (cAMP) added to the cytoplasmic side (whole-cell configuration). The increased secretion of GSH observed in the presence of S-CMC-Lys or 8-bromoadenosine-3,5-cyclic monophosphate was also confirmed by HPLC assay of GSH on a confluent monolayer of respiratory cells. Western blot analysis confirmed the presence of CFTR in WI-26VA4 cells. This study suggests that S-CMC-Lys is able to stimulate a channel-mediated GSH secretion by human respiratory cells: electrophysiological and pharmacological characteristics of this channel are similar to those of the CFTR channel.     

The ICln interactome

The many different functional phenotypes described in mammalian cells can only be explained by an intense interaction of the underlying proteins, substantiated by the fact that the number of independently expressed proteins in living cells seems not to exceed 25 K, a number way too small to explain the >250 K different phenotypes on a one-protein-one-function base. Therefore, the study of the interactome of the different proteins is of utmost importance. Here, we describe the present knowledge of the ICln interactome. ICln is a protein, we cloned and whose function was reported to be as divers as (i) ion permeation, (ii) cytoskeletal organization, and (iii) RNA processing. The role of ICln in these different functional modules can be described best as being a 'connector hub' with 'date hub' function.     

Effectiveness of vestibular rehabilitation on concussion-induced vertigo: a systematic review

Background: Approximately 5% of all Americans have experienced a concussion sometime during their lifetime. The predominant symptoms associated with a concussion are physical issues, cognitive issues, emotional issues, and sleep disturbances; and one of the most common physical issues is vertigo.

Objectives: The purpose of this systematic review was to investigate the effectiveness of vestibular rehabilitation on concussion-induced vertigo.

Methods: Those databases that were utilized for search terms included CINAHL Complete, Proquest Medical Library, and PubMed. Each of these databases was examined from inception through the end of 2017. The search terms were ‘concussion’ OR ‘brain injury’ OR ‘head injury’ AND ‘vestibular rehabilitation’ OR ‘vestibular therapy’ AND ‘vertigo’ OR ‘dizziness’. The Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence system was used to assess the evidence level of each included study, and methodological rigor was assessed utilizing criteria set forth in a systematic review by Medlicott and Harris.

Results: Seven articles met the inclusion criteria and were included in the qualitative synthesis. Six of the seven studies had an evidence level of less than two, and four of the seven studies had weak methodological rigor. Despite these limitations, this systematic review demonstrated that vestibular rehabilitation is generally an effective intervention for individuals with concussion-induced vertigo, even in the presence of visual disorders.

Conclusions: Vestibular rehabilitation should be considered as a component of the plan of care for individuals who experience vertigo following a concussion.     

MAPPED study design: A 6 month randomised controlled study to evaluate the effect of dutasteride on prostate cancer volume using magnetic resonance imaging

ObjectiveTo evaluate the percentage change in volume of prostate cancer, as assessed by T2-weighted MRI, following exposure to dutasteride (Avodart) 0.5 mg daily for six months.Patients and methodsMRI in Primary Prostate cancer after Exposure to Dutasteride (MAPPED) is a double-blind, placebo-controlled trial, supported by GlaxoSmithKline (GSK). Men with prostate cancer suitable for active surveillance (low-intermediate risk prostate cancer on biopsy), and a visible lesion on T2-weighted MRI of at least 0.2 cc, were eligible for consideration. Forty-two men were randomised to 6 months of daily dutasteride 0.5 mg or placebo. Multi-parametric MRI (mpMRI) scans were performed at baseline, 3 and 6 months. The percentage changes in cancer volume over time will be compared between the dutasteride and placebo groups. Planned analyses will examine the association between tumour volume and characteristics (perfusion and contrast washout) as seen on mpMRI, HistoScan ultrasound and biopsy histopathology in both groups.DiscussionMAPPED is the first randomised controlled trial to use mpMRI to look at the effect of dutasteride on the volume of prostate cancer. If dutasteride is shown to reduce the volume of prostate cancer, it might be considered as an adjunct for men on active surveillance. Analysis of the placebo arm will allow us to comment on the short-term natural variability of the MR appearance in men who are not receiving any treatment.ConclusionMAPPED will evaluate the short-term effect of dutasteride on prostate cancer volume, as assessed by mpMRI, in men undergoing active surveillance for low or intermediate risk prostate cancer. The study completed recruitment in January 2012.     

Predictors of survival following surgical resection of limited-stage small cell lung cancer

BackgroundAdjuvant chemotherapy, postoperative radiation (PORT), and prophylactic cranial irradiation (PCI) have been individually examined in limited-stage small cell lung cancer (SCLC). There is a paucity of data on the effectiveness of each adjuvant treatment modality when used in combination after surgical resection of SCLC.MethodsData were collected from 5 cancer centers on all patients with limited-stage SCLC who underwent surgical resection between 1986 and 2019. Univariate and multivariable models were conducted to identify predictors of long-term outcomes, focusing on freedom from recurrence and survival benefit of adjuvant chemotherapy, PORT, and PCI.ResultsA total of 164 patients were analyzed. Multivariable Cox regression analysis did not identify any adjuvant therapies to significantly influence recurrence in this cohort. Specifically, PORT was not associated with a significant influence on locoregional recurrence and PCI was not significantly associated with intracranial outcomes. Adjuvant chemotherapy improved survival in all stage I through III disease (hazard ratio, 0.49; 95% confidence interval, 0.29-0.81; P = .005) and even in pathologically node negative patients (hazard ratio, 0.49; 95% confidence interval, 0.27-0.91; P = .024). Although PCI was found to improve survival in univariate analysis, it was not significant in a multivariable model. PORT was not found to affect survival on either univariate or multivariable analysis.ConclusionsThis is among the largest multi-institutional studies on surgically resected limited-stage SCLC. Our results highlight survival benefit of adjuvant chemotherapy, but did not identify a statistically significant influence from mediastinal PORT or PCI in our cohort. Larger prospective studies are needed to determine the benefit of PORT or PCI in a surgically resected limited-stage SCLC population.     

Prevalence of Key Forms of Violence Against Adolescents in the Arab Region: A Systematic Review

Purpose

This article presents a systematic review of the prevalence of violence against adolescents in the 22 countries of the Arab League.