Lung epithelial stem cells and their niches : Fgf10 takes center stage

Throughout life adult animals crucially depend on stem cell populations to maintain and repair their tissues to ensure life-long organ function. Stem cells are characterized by their capacity to extensively self-renew and give rise to one or more differentiated cell types. These powerful stem cell properties are key to meet the changing demand for tissue replacement during normal lung homeostasis and regeneration after lung injury. Great strides have been made over the last few years to identify and characterize lung epithelial stem cells as well as their lineage relationships. Unfortunately, knowledge on what regulates the behavior and fate specification of lung epithelial stem cells is still limited, but involves communication with their microenvironment or niche, a local tissue environment that hosts and influences the behaviors or characteristics of stem cells and that comprises other cell types and extracellular matrix. As such, an intimate and dynamic epithelial-mesenchymal cross-talk, which is also essential during lung development, is required for normal homeostasis and to mount an appropriate regenerative response after lung injury. Fibroblast growth factor 10 (Fgf10) signaling in particular seems to be a well-conserved signaling pathway governing epithelial-mesenchymal interactions during lung development as well as between different adult lung epithelial stem cells and their niches. On the other hand, disruption of these reciprocal interactions leads to a dysfunctional epithelial stem cell-niche unit, which may culminate in chronic lung diseases such as chronic obstructive pulmonary disease (COPD), chronic asthma and idiopathic pulmonary fibrosis (IPF)

TQM and performance appraisal : complementary or incompatible?

Despite the scholarly interest in performance management as a key determinant of the effectiveness of enterprise process improvement methods such as total quality management (TQM) and its derivatives, few empirical studies have explicitly explored the practice of performance management systems in TQM‐focused organizations. In order to redress this imbalance, this study aims to describe how organizational and managerial forces led to a performance management systems failing to embrace the core principles of process improvement methods such as TQM. Using a qualitative study of six large UK‐based automobile and auto parts manufacturers, our results illustrate how manager‐controlled, individual‐focused, past‐oriented, long‐cycle, and narrowly defined performance appraisal (PA) systems can intervene to underline the ultimate potential of TQM. The paper concludes with the discussion of implications for theory and practice of TQM and human resource performance management

Stem/progenitor cell populations resident in the lung and the role of stromal support in their maintenance and differentiation

Lungs are vital organs for respiration, being enabled by their complex three-dimensional organization [1]. Airway tubes bifurcate into millions of highly vascularized alveolar sacs, the alveoli, which are responsible for gas exchange. The gas exchange surface of the lungs makes up one of the largest surface areas of the human body. The alveoli receive air from the conducting airways, starting in the trachea, bifurcating into the bronchi and bronchioles, and ending in the terminal bronchioles, which divide into the alveolar ducts from which the alveoli arise. The aim of this chapter is to provide an overview of the progenitors in adult lung tissue and the regulation of their maintenance and differentiation by the microenvironment during lung developmental as well as repair processes, when developmental pathways are often reactivated. As most work has been done in mouse studies, the current knowledge from animal studies will be summarized and translated to what is known from human lungs. In order to understand the regenerative processes in the lung, we will first provide insight into the complex three-dimensional organization and composition of the lung, its function, and the processes involved in lung development.</p

Early Weight Bearing of Calcaneal Fractures Treated by Intraoperative 3D-Fluoroscopy and Locked-Screw Plate Fixation

Operative therapy of intraarticular fractures of the calcaneus is an established surgical standard. The aim is an accurate reduction of the fracture with reconstruction of Boehler’s angle, length, axis and subtalar joint surface. Intraoperative 3D-fluoroscopy with the Siremobil Iso-C 3D® mobile C-arm system is a valuable assistant for accurate reconstruction of these anatomical structures. Remaining incongruities can be recognized and corrected intraoperatively. The achieved reduction can be fixed by the advantages of an internal fixator (locked-screw plate interface). In the period of October 2002 until April 2007 we operated 136 patients with intraarticular fractures of the calcaneus by means of anatomical reduction, and internal plate fixator under intraoperative control of 3D-fluoroscopy. All patients were supplied with an orthesis after the operation which allowed weight bearing of 10 kg for 12 weeks for the patients operated between October 2002 and October 2004 (Group A). Transient local osteoporosis was observed in all X-Rays at follow-up after an average of 8,6 months. Therefore we changed our postoperative treatment plan for the patients operated between November 2004 and April 2007 (Group B). Weight bearing started with 20 KG after 6 weeks, was increased to 40 KG after 8 weeks and full weight bearing was allowed after 10 weeks for these patients. In no case a secondary dislocation of the fracture was seen. No bone graft was used. At follow up the average American Foot and Ankle Society Score (AOFAS) were 81 for Group_A, compared to 84 for Group B, treated with earlier weight bearing. Autologous bone graft was not necessary even if weight bearing was started after a period of six weeks postoperatively. The combination of 3D-fluoroscopy with locked internal fixation showed promising results. If the rate of patients developing subtalar arthrosis will decrease by this management will have to be shown in long term follow up

Effects of the Histone Deacetylase Inhibitor Valproic Acid on Human Pericytes In Vitro

Microvascular pericytes are of key importance in neoformation of blood vessels, in stabilization of newly formed vessels as well as maintenance of angiostasis in resting tissues. Furthermore, pericytes are capable of differentiating into pro-fibrotic collagen type I producing fibroblasts. The present study investigates the effects of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) on pericyte proliferation, cell viability, migration and differentiation. The results show that HDAC inhibition through exposure of pericytes to VPA in vitro causes the inhibition of pericyte proliferation and migration with no effect on cell viability. Pericyte exposure to the potent HDAC inhibitor Trichostatin A caused similar effects on pericyte proliferation, migration and cell viability. HDAC inhibition also inhibited pericyte differentiation into collagen type I producing fibroblasts. Given the importance of pericytes in blood vessel biology a qPCR array focusing on the expression of mRNAs coding for proteins that regulate angiogenesis was performed. The results showed that HDAC inhibition promoted transcription of genes involved in vessel stabilization/maturation in human microvascular pericytes. The present in vitro study demonstrates that VPA influences several aspects of microvascular pericyte biology and suggests an alternative mechanism by which HDAC inhibition affects blood vessels. The results raise the possibility that HDAC inhibition inhibits angiogenesis partly through promoting a pericyte phenotype associated with stabilization/maturation of blood vessels

Machine Learning Applications in Head and Neck Radiation Oncology: Lessons From Open-Source Radiomics Challenges

Radiomics leverages existing image datasets to provide non-visible data extraction via image post-processing, with the aim of identifying prognostic, and predictive imaging features at a sub-region of interest level. However, the application of radiomics is hampered by several challenges such as lack of image acquisition/analysis method standardization, impeding generalizability. As of yet, radiomics remains intriguing, but not clinically validated. We aimed to test the feasibility of a non-custom-constructed platform for disseminating existing large, standardized databases across institutions for promoting radiomics studies. Hence, University of Texas MD Anderson Cancer Center organized two public radiomics challenges in head and neck radiation oncology domain. This was done in conjunction with MICCAI 2016 satellite symposium using Kaggle-in-Class, a machine-learning and predictive analytics platform. We drew on clinical data matched to radiomics data derived from diagnostic contrast-enhanced computed tomography (CECT) images in a dataset of 315 patients with oropharyngeal cancer. Contestants were tasked to develop models for (i) classifying patients according to their human papillomavirus status, or (ii) predicting local tumor recurrence, following radiotherapy. Data were split into training, and test sets. Seventeen teams from various professional domains participated in one or both of the challenges. This review paper was based on the contestants' feedback; provided by 8 contestants only (47%). Six contestants (75%) incorporated extracted radiomics features into their predictive model building, either alone (n = 5; 62.5%), as was the case with the winner of the “HPV” challenge, or in conjunction with matched clinical attributes (n = 2; 25%). Only 23% of contestants, notably, including the winner of the “local recurrence” challenge, built their model relying solely on clinical data. In addition to the value of the integration of machine learning into clinical decision-making, our experience sheds light on challenges in sharing and directing existing datasets toward clinical applications of radiomics, including hyper-dimensionality of the clinical/imaging data attributes. Our experience may help guide researchers to create a framework for sharing and reuse of already published data that we believe will ultimately accelerate the pace of clinical applications of radiomics; both in challenge or clinical settings

Prospective metrological validation of multifrequency bioelectrical impedance analysis against volumetric imaging to identify sarcopenia in head and neck cancer patients undergoing radiation therapy

AbstractImportanceDepleted skeletal muscle mass (sarcopenia) is associated with decreased survival and cancer control in head and neck cancer patients treated with radiotherapy. There is a need for validated measures of body composition that can be implemented in routine clinical workflow.ObjectiveTo validate the use of bioelectrical impedance analysis (BIA) for body composition analysis and diagnosis of sarcopenia in head and neck cancer patients.DesignIn this prospective observational cohort study, baseline 50 patients with head and neck cancer undergoing radiation therapy (RT) were enrolled between February 2016 and March 2017. Baseline BIA measures of skeletal muscle (SM) mass, fat-free mass (FMM), and fat mass (FM) were compared to CT-based estimates of body composition using linear regression. Sex-specific BIA-derived thresholds for sarcopenia were defined by the maximum Youden Index on receiver operator characteristic (ROC) curves of BIA against CT-defined sarcopenia. Changes in body composition across treatment were compared against changes in body weight using linear regression.ParticipantsIn total, 50 patients with pathologically confirmed stage I to IVB non-metastatic head and neck cancer treated with definitive radiation therapy were enrolled.SettingSingle academic referral center.Main Outcome and MeasureThe primary outcome was relative agreement between baseline lean body mass and fat body mass predicted from BIA measurement and CT imaging.ResultsOf the 48 evaluable patients 16 (33.3%) were sarcopenic at baseline based on CT analysis. BIA measures of body composition were strongly correlated with CT measures: SM mass (r = 0.97; R2 = 0.94; p &lt; 0.0001), FFM (r = 0.97; R2 = 0.94; p &lt; 0.0001) and FM (r = 0.95; R2 = 0.90; p &lt; 0.0001). Relationship with normalized indices of SM mass, FFM, and FM was similar between BIA and CT, but not BIA and body mass index (BMI). Patients lost a mean of 5.7 ± 5.8 kg during treatment, of which 1.5 ± 1.9 kg was SM, 2.6 ± 3.3 kg was FFM, and 2.2 ± 2.6 kg was FM. Eight additional patients developed sarcopenia by the end of RT.ConclusionsBIA provides accurate estimates of body composition in head and neck cancer patients. Implementation of BIA in clinical practice may identify patients with sarcopenia.Trial RegistrationClinicalTrials.gov identifier: NCT02615275</jats:sec