Recruited Cells Can Become Transformed and Overtake PDGF-Induced Murine Gliomas In Vivo during Tumor Progression

Gliomas are thought to form by clonal expansion from a single cell-of-origin, and progression-associated mutations to occur in its progeny cells. Glioma progression is associated with elevated growth factor signaling and loss of function of tumor suppressors Ink4a, Arf and Pten. Yet, gliomas are cellularly heterogeneous; they recruit and trap normal cells during infiltration.We performed lineage tracing in a retrovirally mediated, molecularly and histologically accurate mouse model of hPDGFb-driven gliomagenesis. We were able to distinguish cells in the tumor that were derived from the cell-of-origin from those that were not. Phenotypic, tumorigenic and expression analyses were performed on both populations of these cells. Here we show that during progression of hPDGFb-induced murine gliomas, tumor suppressor loss can expand the recruited cell population not derived from the cell-of-origin within glioma microenvironment to dominate regions of the tumor, with essentially no contribution from the progeny of glioma cell-of-origin. Moreover, the recruited cells can give rise to gliomas upon transplantation and passaging, acquire polysomal expression profiles and genetic aberrations typically present in glioma cells rather than normal progenitors, aid progeny cells in glioma initiation upon transplantation, and become independent of PDGFR signaling.These results indicate that non-cell-of-origin derived cells within glioma environment in the mouse can be corrupted to become bona fide tumor, and deviate from the generally established view of gliomagenesis

Emergence of 3D Printed Dosage Forms: Opportunities and Challenges

The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such as extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and its potential yet to be fully explored. This paper presents various 3D printing technologies such as stereolithographic, powder based, selective laser sintering, fused deposition modelling and semi-solid extrusion 3D printing. It also provides a comprehensive review of previous attempts at using 3D printing technologies on the manufacturing dosage forms with a particular focus on oral tablets. Their advantages particularly with adaptability in the pharmaceutical field have been highlighted, including design flexibility and control and manufacture which enables the preparation of dosage forms with complex designs and geometries, multiple actives and tailored release profiles. An insight into the technical challenges facing the different 3D printing technologies such as the formulation and processing parameters is provided. Light is also shed on the different regulatory challenges that need to be overcome for 3D printing to fulfil its real potential in the pharmaceutical industry

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Therapeutic effects of lornoxicam-loaded nanomicellar formula in experimental models of rheumatoid arthritis

Hebatullah Samy Helmy,1 Ayman E El-Sahar,2 Rabab H Sayed,2 Rehab Nabil Shamma,3 Alaa Hamed Salama,4 Eman Maher Elbaz1 1Department of Biochemistry, 2Department of Pharmacology and Toxicology, 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, 4Department of Pharmaceutical Technology, National Research Center, Cairo, Egypt Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease treated by nonsteroidal anti-inflammatory drugs (NSAIDs) including lornoxicam (LX). Nanocarriers have been used to increase the efficacy and reduce the side effects of various drugs. The objective of the present study was to compare the therapeutic efficacy of systemic administration of lornoxicam-loaded nanomicellar formula (LX-NM) with that of free LX.Materials and methods: The LX-loaded mixed polymeric nanomicellar formula was prepared by direct equilibrium technique. Two rat models were used in the study: carrageenan-induced acute edema and Freund’s complete adjuvant (FCA)-induced chronic arthritis.Results: The inhibitory effect of LX-NM on carrageenan-induced edema was higher than free LX for the same dose (1.3 mg/kg, i.p.). LX-NM (0.325 mg/kg, i.p.) produced effects comparable to that of diclofenac, which served as a standard. In the FCA model, daily treatment with LX-NM (0.325 mg/kg, i.p.) starting on day 14 significantly reduced the percentage of edema and increased weight growth. However, the same dose of LX failed to confer any significant change. Additionally, LX-NM significantly attenuated the rise of tumor necrosis factor-α (TNF-α), interleukin-1β, prostaglandin E2, nuclear factor-κβ, malondialdehyde and nitric oxide serum levels. In contrast, LX failed to show any significant reduction in elevated serum biomarkers except for TNF-α.Conclusion: LX-NM is an alternative delivery system that is simply prepared at low costs. It showed a superior therapeutic efficacy against RA compared to free LX. Thus, LX-NM can be considered as a promising candidate for treatment of RA and similar inflammatory disorders. Keywords: lornoxicam, polymeric micelles, nano-carriers, rheumatoid arthritis, inflammatory mediator

Development and validation of an Arabic-language headache questionnaire for population-based surveys

Naglaa A El-Sherbiny,1 Hatem Samir Shehata,2 Hanan Amer,2 Alaa Elmazny,2 Mohamed Masoud,1 Hanan Helmy,2 Nevin M Shalaby2 1Faculty of Medicine, Fayoum University, Faiyum, Egypt; 2Faculty of Medicine, Cairo University, Cairo, Egypt Background: The reported prevalence of headache disorders in Arab regions varies considerably between countries. This may be due to a lack of standardized survey instruments that capture the prevalence. Purpose of the study: Our goal was to construct and validate a structured headache questionnaire for Arabic-speaking headache patients to be used as an epidemiological survey instrument. Methods: We developed a culturally adapted interviewer-administered questionnaire in Arabic language comprising two sets of questions. The first set included personal and sociodemographic data together with a screening question regarding the presence of headaches over the last year. The second set was designed to define the type and pattern of headaches according to the International Classification of Headache Disorders criteria (for subjects with “yes” answers on the screening question). Validation process took place in two phases through probability random sampling selected from 1,221 headache subjects collected in an epidemiological survey 3 (n=70) and 6 months (n=232) later. A detailed assessment of patients’ headaches was performed by neurologists (blinded from the questionnaire diagnosis) who clinically assessed the patients’ headache. Results: The validity of the questionnaire was tested in 232 subjects with a mean age of 41.2±10.9 years, 72.8% of whom were females. The mean time to complete the questionnaire was 8.4±1.7 minutes. The intraclass correlation coefficient was 0.903 (95% confidence interval: 0.875–0.925), the Cronbach κ coefficient was 0.775 (95% confidence interval: 0.682–0.837), and the percentage of agreement was 84.5%.Conclusion: Our results support the use of this comprehensive questionnaire as a valid tool for headache assessment among Arabic-speaking patients. Keywords: Arabic, Egypt, headache, questionnaire, validation&nbsp

Perceptions on Mentoring Concept and Mentoring Practices among Medical Mentors: A Mixed-Methods Study

Introduction: Mentoring medical students is one of the essential responsibilities or missions of a medical school faculty. Objective: This study aimed to determine the perceptions of mentorship and mentoring practices among mentors using a convergent parallel method. Method: Quantitative data was collected by using an adopted validated self-administered questionnaire and analyzed using SPSS version 20. Qualitative data was done using one-to-one interview based on semi structured interview guide and analyzed using thematic analysis. Result: A total of 61 respondents participated in the quantitative survey. Approximately 75% of the respondents had 5 to 10 mentees, with majority rated themselves as satisfactory mentor. More than 60% of them met their mentees at least once every six months. Most respondents were friendly (86.9%) and frank to their mentees (68.9%) and were interested in their mentees’ professional development (95.1%). Phone calling (93.4%) and E-mail (95.1%) were preferred as modes of contact. Mentees were allowed to call their mentors anytime of the day (74.1%). Respondents preferred to counsel their mentees (80.3%) and would refer them for professional help whenever necessary (70.5%). For qualitative data, a total of 5 participants participated with themes emerged: concepts of mentoring, factors contributing to ineffective mentoring and ways to improve mentoring practices. Conclusion: The respondents had positive perceptions regarding their mentorship and practices. A more structured approach with clear mentoring guideline and proper training should be in place