Identification of Novel Candidate Oncogenes in Chromosome Region 17p11.2-p12 in Human Osteosarcoma

Osteosarcoma is the most common primary malignancy of bone. The tumours are characterized by high genomic instability, including the occurrence of multiple regions of amplifications and deletions. Chromosome region 17p11.2–p12 is amplified in about 25% of cases. In previous studies, COPS3 and PMP22 have been identified as candidate oncogenes in this region. Considering the complexity and variation of the amplification profiles for this segment, the involvement of additional causative oncogenes is to be expected. The aim of the present investigation is to identify novel candidate oncogenes in 17p11.2–p12. We selected 26 of in total 85 osteosarcoma samples (31%) with amplification events in 17p11.2–p12, using quantitative PCR for 8 marker genes. These were subjected to high-resolution SNP array analysis and subsequent GISTIC analysis to identify the most significantly amplified regions. Two major amplification peaks were found in the 17p11.2–p12 region. Overexpression as a consequence of gene amplification is a major mechanism for oncogene activation in tumours. Therefore, to identify the causative oncogenes, we next determined expression levels of all genes within the two segments using expression array data that could be generated for 20 of the selected samples. We identified 11 genes that were overexpressed through amplification in at least 50% of cases. Nine of these, c17orf39, RICH2, c17orf45, TOP3A, COPS3, SHMT1, PRPSAP2, PMP22, and RASD1, demonstrated a significant association between copy number and expression level. We conclude that these genes, including COPS3 and PMP22, are candidate oncogenes in 17p11.2–p12 of importance in osteosarcoma tumourigenesis

Effect of tofacitinib on patient-reported outcomes in patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors in the phase III, randomised controlled trial: OPAL Beyond.

Objectives: Tofacitinib is an oral Janus kinase inhibitor for treatment of psoriatic arthritis (PsA). Patient-reported outcomes (PROs) were evaluated in patients with PsA with inadequate responses to tumour necrosis factor inhibitors (TNFi-IR) in a 6-month, phase III randomised controlled trial (OPAL Beyond [NCT01882439]). Methods: Patients (N=394) received tofacitinib 5 or 10 mg twice daily or placebo (advancing to tofacitinib 5 or 10 mg twice daily at month 3). Least squares mean changes from baseline and percentages of patients reporting improvements ≥minimum clinically important differences and scores ≥normative values were determined in Patient Global Assessment of disease activity (PtGA), Pain, Patient Global Joint and Skin Assessment (PGJS), Short Form-36 Health Survey version 2 (SF-36v2), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), EuroQol 5-Dimensions-3-level (EQ-5D-3L), EQ-VAS and Ankylosing Spondylitis Quality of Life (ASQoL). Nominal p values are without multiple comparison adjustments. Results: At month 3, PtGA, Pain, PGJS, SF-36v2 Physical Component Summary (PCS), physical functioning (PF), bodily pain (BP), vitality and social functioning (SF) domains, FACIT-Fatigue Total score, EQ-5D-3L pain/discomfort, EQ-VAS and ASQoL scores exceeded placebo with both tofacitinib doses (role physical [RP] with 10 mg twice daily only; p≤0.05). Patients reporting improvements ≥MCID (%) in PtGA, PGJS, Pain, ASQoL and SF-36v2 PCS, PF, RP, BP, SF (both tofacitinib doses) exceeded placebo (p≤0.05). Conclusion: TNFi-IR patients with PsA receiving tofacitinib reported statistically and clinically meaningful improvements in PROs versus placebo over 3 months, which were maintained to month 6. Despite lower baseline scores, these improvements were similar to the csDMARD-IR TNFi-naive OPAL Broaden trial

A Bayesian sensitivity model for intention-to-treat analysis on binary outcomes with dropouts

Intention-to-treat (ITT) analysis is commonly used in randomized clinical trials. However, the use of ITT analysis presents a challenge: how to deal with subjects who drop out. Here we focus on randomized trials where the primary outcome is a binary endpoint. Several approaches are available for including the dropout subject in the ITT analysis, mainly chosen prior to unblinding the study. These approaches reduce the potential bias due to breaking the randomization code. However, the validity of the results will highly depend on untestable assumptions about the dropout mechanism. Thus, it is important to evaluate the sensitivity of the results across different missing-data mechanisms. We propose here a Bayesian pattern-mixture model for ITT analysis of binary outcomes with dropouts that applies over different types of missing-data mechanisms. We introduce a new parameterization to identify the model, which is then used for sensitivity analysis. The parameterization is defined as the odds ratio of having an endpoint between the subjects who dropped out and those who completed the study. Such parameterization is intuitive and easy to use in sensitivity analysis; it also incorporates most of the available methods as special cases. The model is applied to TRial Of Preventing HYpertension. Copyright © 2008 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/61532/1/3494_ftp.pd

The effect of proprioceptive knee bracing on knee stability during three different sport related movement tasks in healthy subjects and the implications to the management of Anterior Cruciate Ligament (ACL) injuries

Abstract Introduction: Proprioceptive knee braces have been shown to improve knee mechanics, however much of the work to date has focused on tasks such as slow step down tasks rather than more dynamic sporting tasks. Objective: This study aimed to explore if such improvements in stability may be seen during faster sports specific tasks as well as slower tasks. Method: Twelve subjects performed a slow step down, single leg drop jump and pivot turn jump with and without a silicone web brace. 3D kinematics of the knee were collected using a ten camera Qualisys motion analysis system. Reflective markers were placed on the foot, shank, thigh and pelvis using the Calibrated Anatomical Systems Technique. A two way ANOVA with repeated measures was performed with post-hoc pairwise comparison to explore the differences between the two conditions and three tasks. Results: Significant differences were seen in the knee joint angles and angular velocities in the sagittal, coronal and transverse planes between the tasks. The brace showed a reduction in knee valgum and internal rotation across all tasks, with the most notable effect during the single leg drop jump and pivot turn jump. The transverse plane also showed a significant reduction in the external rotation knee angular velocity when wearing the brace. Discussion: The brace influenced the knee joint kinematics in coronal and transverse planes which confirms that such braces can have a significant effect on knee control during dynamic tasks. Further studies are required exploring the efficacy of proprioceptive braces in athletic patient cohort. Acknowledgements This study is partly founded by Erasmus+ program who have sponsored two masters students. The braces were supplied by DJO Global, Inc. The suppliers played no role in the design, execution, analysis and interpretation of the data or writing of this study

Novel avian-origin influenza A (H7N9) virus attaches to epithelium in both upper and lower respiratory tract of humans

Influenza A viruses from animal reservoirs have the capacity to adapt to humans and cause influenza pandemics. The occurrence of an influenza pandemic requires efficient virus transmission among humans, which is associated with virus attachment to the upper respiratory tract. Pandemic severity depends on virus ability to cause pneumonia, which is associated with virus attachment to the lower respiratory tract. Recently, a novel avian-origin H7N9 influenza A virus with unknown pandemic potential emerged in humans. We determined the pattern of attachment of two genetically engineered viruses containing the hemagglutinin of either influenza virus A/Shanghai/1/13 or A/Anhui/1/13 to formalin-fixed human respiratory tract tissues using histochemical analysis. Our results show that the emerging H7N9 virus attached moderately or abundantly to both upper and lower respiratory tract, a pattern not seen before for avian influenza A viruses. With the caveat that virus attachment is only the first step in the virus replication cycle, these results suggest that the emerging H7N9 virus has the potential both to transmit efficiently among humans and to cause severe pneumonia

Severity of systemic inflammatory response syndrome (SIRS) affects the blood levels of circulating inflammatory-relevant miRNAs

The systemic inflammatory response syndrome (SIRS) is a potentially lethal response triggered by diverse forms of tissue injury and infection. When systemic inflammation is triggered by infection the term sepsis is used. Understanding how inflammation is mediated and regulated is of enormous medical importance. We previously demonstrated that circulating inflammatory-relevant micro-RNAs (CIR-miRNAs) are candidate biomarkers for differentiating sepsis from SIRS. Here we set out to determine how CIR-miRNA levels reflect SIRS severity and whether they derive from activated immune cells. Clinical disease severity scores and markers of red blood cell (RBC) damage or immune cell activation were correlated with CIR-miRNA levels in patients with SIRS and sepsis. The release of CIR-miRNAs modulated during SIRS was assessed in immune cell cultures. We show that severity of non-infective SIRS, but not sepsis is reflected in the levels of miR-378a-3p, miR-30a-5p, miR-30d-5p, and miR-192-5p. These CIR-miRNA levels positively correlate with levels of the redox biomarker, peroxiredoxin-1 (Prdx-1), which has previously been shown to be released by immune cells during inflammation. Furthermore, in vitro activated immune cells produce SIRS-associated miR-378a-3p, miR-30a-5p, miR-30d-5p, and miR-192-5p. Our study furthers the understanding of the origin, role and trafficking of CIR-miRNAs as potential regulators of inflammation

Improving economic evaluations in stroke : A report from the ESO Health Economics Working Group

Introduction Approaches to economic evaluations of stroke therapies are varied and inconsistently described. An objective of the European Stroke Organisation (ESO) Health Economics Working Group is to standardise and improve the economic evaluations of interventions for stroke. Methods The ESO Health Economics Working Group and additional experts were contacted to develop a protocol and a guidance document for data collection for economic evaluations of stroke therapies. A modified Delphi approach, including a survey and consensus processes, was used to agree on content. We also asked the participants about resources that could be shared to improve economic evaluations of interventions for stroke. Results Of 28 experts invited, 16 (57%) completed the initial survey, with representation from universities, government, and industry. More than half of the survey respondents endorsed 13 specific items to include in a standard resource use questionnaire. Preferred functional/quality of life outcome measures to use for economic evaluations were the modified Rankin Scale (14 respondents, 88%) and the EQ-5D instrument (11 respondents, 69%). Of the 12 respondents who had access to data used in economic evaluations, 10 (83%) indicated a willingness to share data. A protocol template and a guidance document for data collection were developed and are presented in this article. Conclusion The protocol template and guidance document for data collection will support a more standardised and transparent approach for economic evaluations of stroke care.Peer reviewe