ARIA 2016: Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle

The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma a

Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas

Precision oncology uses genomic evidence to match patients with treatment but often fails to identify all patients who may respond. The transcriptome of these \u201chidden responders\u201d may reveal responsive molecular states. We describe and evaluate a machine-learning approach to classify aberrant pathway activity in tumors, which may aid in hidden responder identification. The algorithm integrates RNA-seq, copy number, and mutations from 33 different cancer types across The Cancer Genome Atlas (TCGA) PanCanAtlas project to predict aberrant molecular states in tumors. Applied to the Ras pathway, the method detects Ras activation across cancer types and identifies phenocopying variants. The model, trained on human tumors, can predict response to MEK inhibitors in wild-type Ras cell lines. We also present data that suggest that multiple hits in the Ras pathway confer increased Ras activity. The transcriptome is underused in precision oncology and, combined with machine learning, can aid in the identification of hidden responders. Way et al. develop a machine-learning approach using PanCanAtlas data to detect Ras activation in cancer. Integrating mutation, copy number, and expression data, the authors show that their method detects Ras-activating variants in tumors and sensitivity to MEK inhibitors in cell lines

Oncogenic Signaling Pathways in The Cancer Genome Atlas

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFb signaling, p53 and beta-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy

Biomechanical Testing of the Intact and Surgically Treated Pelvis

© 2017 Elsevier Inc. All rights reserved. Pelvic fractures account for over one-tenth of all human bone fractures, but acetabular fractures account for about half of all pelvic fractures. Acetabular fractures can be simple (or elementary) and complex (or associated), being caused by a low-energy fall in the elderly and high-energy impact in the young. No gold standard exists for surgical repair of these injuries; however, surgeons most often use plate-and-screw fixation, although cable fixation may be used when osteoporosis prevents good screw fixation into bone. Acetabular fracture repair is often accompanied by simultaneous total hip arthroplasty for elderly patients who eventually require a hip prosthesis due to osteoarthritis. The goal of surgical repair is perfect anatomical reduction of the hip to minimize pain, improve strength, and restore function. A key element is the biomechanical stability provided by various acetabular fracture fixation methods. Therefore, this chapter shows how to surgically repair a pelvic acetabular fracture and perform biomechanical testing, as well as how to analyze, report, and interpret data

The biomechanical effect of anteversion and modular neck offset on stress shielding for short-stem versus conventional long-stem hip implants

© 2015 IPEM. Short-stem hip implants are increasingly common since they preserve host bone stock and presumably reduce stress shielding by improving load distribution in the proximal femur. Stress shielding may lead to decreased bone density, implant loosening, and fracture. However, few biomechanical studies have examined short-stem hip implants. The purpose of this study was to compare short-stem vs. standard length stemmed implants for stress shielding effects due to anteversion-retroversion, anterior-posterior position, and modular neck offset. Twelve artificial femurs were implanted with either a short-stem modular-neck implant or a conventional length monolithic implant in 0° or 15° of anteversion. Three modular neck options were tested in the short-stem implants. Three control femurs remained intact. Femurs were mounted in adduction and subjected to axial loading. Strain gauge values were collected to validate a Finite Element (FE) model, which was used to simulate the full range of physiologically possible anteversion and anterior-posterior combinations (n = 25 combinations per implant). Calcar stress was compared between implants and across each implant\u27s range of anteversion using one and two-way ANOVA. Stress shielding was defined as the overall change in stress compared to an intact femur.The FE model compared well with experimental strains (intact: slope = 0.898, R = 0.943; short-stem: slope = 0.731, R = 0.948; standard-stem: slope = 0.743, R = 0.859); correction factors were used to adjust slopes to unity. No implant anteversion showed significant reduction in stress shielding (α = 0.05, p \u3e 0.05). Stress shielding was significantly higher in the standard-stem implant (63% change from intact femur, p \u3c 0.001) than in short-stem implants (29-39% change, p \u3c 0.001).Short-stem implants reduce stress shielding compared to standard length stemmed implants, while implant anteversion and anterior-posterior position had no effect. Therefore, short-stem implants have a greater likelihood of maintaining calcar bone strength in the long term

Biomechanical optimization of the angle and position for surgical implantation of a straight short stem hip implant

© 2016 IPEM Conservative hip implants preserve healthy bone for revision surgeries and improve physiological loading; however, they have little supporting biomechanical data with respect to their 3D orientation during implantation. This study endeavored to determine the optimal 3D orientation of a straight short stem hip implant within the proximal femur that would yield a stress distribution most similar to an intact femur. Synthetic femurs were implanted with a stem in one of seven maximum angles or positions and axially loaded, with resultant strain values used to validate a finite element model. Design of experiments was used to analyze the range of potential implant orientations under three gait cycle loading conditions. A global optimal orientation of 9.14 ° valgus, 2.49 ° anteversion, 0.48 mm posterior position, and 0.23 mm inferior position was found to yield stress distributions most similar to the intact femur across the gait cycle range. In general, it was determined that the valgus orientation was optimal throughout the gait cycle, consistently exhibiting a stress distribution more similar to that of the intact femur. Minimal levels of anterior/posterior and inferior positioning were seen to be beneficial in achieving more physiological stresses in specific regions of interest within the proximal femur, while the anteverted orientation was only beneficial in loading under flexion. Overall, orthopaedic surgeons should aim to implant straight short stem hip implants in valgus up to 10 °, with an otherwise neutral position and version, unless some degree of deviation would be beneficial for a patient-specific reason. This work has implications for the best surgical placement of straight short stem hip implants to yield maximal biomechanical stability

Oncogenic Signaling Pathways in The Cancer Genome Atlas

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGF\u3b2 signaling, p53 and \u3b2-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy. An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies