A Randomized Preventive Rehabilitation Trial in Advanced Head and Neck Cancer Patients Treated with Chemoradiotherapy: Feasibility, Compliance, and Short-term Effects

The aim of this study was to assess the effect of (preventive) rehabilitation on swallowing and mouth opening after concomitant chemoradiotherapy (CCRT). Forty-nine patients with advanced oral cavity, oropharynx, hypopharynx and larynx, or nasopharynx cancer treated with CCRT were randomized into a standard (S) or an experimental (E) preventive rehabilitation arm. Structured multidimensional assessment (i.e., videofluoroscopy, mouth-opening measurement, structured questionnaires) was performed before and 10 weeks after CCRT. In both S and E arms, feasibility was good (all patients could execute the exercises within a week) and compliance was satisfactory (mean days practiced per week was 4). Nevertheless, mouth opening, oral intake, and weight decreased significantly. Compared to similar CCRT studies at our institute, however, fewer patients were still tube-dependent after CCRT. Furthermore, some functional outcomes seemed less affected than those of studies in the literature that did not incorporate rehabilitation exercises. Patients in the E arm practiced significantly fewer days in total and per week, but they obtained results comparable to the S arm patients. Preventive rehabilitation (regardless of the approach, i.e., experimental or standard) in head and neck cancer patients, despite advanced stage and burdensome treatment, is feasible, and compared with historical controls, it seems helpful in reducing the extent and/or severity of various functional short-term effects of CCRT

A cost-effectiveness analysis of a preventive exercise program for patients with advanced head and neck cancer treated with concomitant chemo-radiotherapy

In recent years, concomitant chemo-radiotherapy (CCRT) has become an indispensable organ preserving treatment modality for advanced head and neck cancer, improving local control and overall survival in several anatomical sites [1]. Unfortunately, CCRT can have a detrimental effect on many functions of the upper respiratory and digestive system. Sequellae such as pain, oedema, xerostomia and fibrosis negatively affect mouth opening (trismus), chewing, swallowing and speech [1]. Several studies investigating long-term effects of CCRT have concluded that swallowing and nutritional dysfunction tend to be persistent and can be severe [2-4]. Not surprisingly, therefore, CCRT can have a negative effect on patients‟ quality of life (QoL) [2]. Moreover, even before onset of treatment patients may already present with pain, impaired swallowing, trismus, aspiration, dietary restrictions and tube dependency, and loss of body weight, because the tumour may disrupt the normal anatomy and thus interfere with normal function [1]. Many studies refer to the importance of rehabilitation after, and even during treatment, in order to support and improve those functions [2]. However, as yet, few studies have investigated the effects of (preventive) rehabilitation exercises on the predictable and inevitable swallowing and mouth opening problems for this patient group. In addition, little is known about the costs and benefits of such exercise programs for head and neck cancer. As the clinical effectiveness is established [4], it is now relevant to embark on cost-effectiveness as a contribution to decision making on coverage. The aim of this study was to analyze the incremental cost-effectiveness for a preventive exercise program (PREP) versus usual care (UC) for patients with advanced head and neck cancer treated at the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AVL)

COMMD1-Mediated Ubiquitination Regulates CFTR Trafficking

The CFTR (cystic fibrosis transmembrane conductance regulator) protein is a large polytopic protein whose biogenesis is inefficient. To better understand the regulation of CFTR processing and trafficking, we conducted a genetic screen that identified COMMD1 as a new CFTR partner. COMMD1 is a protein associated with multiple cellular pathways, including the regulation of hepatic copper excretion, sodium uptake through interaction with ENaC (epithelial sodium channel) and NF-kappaB signaling. In this study, we show that COMMD1 interacts with CFTR in cells expressing both proteins endogenously. This interaction promotes CFTR cell surface expression as assessed by biotinylation experiments in heterologously expressing cells through regulation of CFTR ubiquitination. In summary, our data demonstrate that CFTR is protected from ubiquitination by COMMD1, which sustains CFTR expression at the plasma membrane. Thus, increasing COMMD1 expression may provide an approach to simultaneously inhibit ENaC absorption and enhance CFTR trafficking, two major issues in cystic fibrosis

Liver-Specific Commd1 Knockout Mice Are Susceptible to Hepatic Copper Accumulation

Canine copper toxicosis is an autosomal recessive disorder characterized by hepatic copper accumulation resulting in liver fibrosis and eventually cirrhosis. We have identified COMMD1 as the gene underlying copper toxicosis in Bedlington terriers. Although recent studies suggest that COMMD1 regulates hepatic copper export via an interaction with the Wilson disease protein ATP7B, its importance in hepatic copper homeostasis is ill-defined. In this study, we aimed to assess the effect of Commd1 deficiency on hepatic copper metabolism in mice. Liver-specific Commd1 knockout mice (Commd1Δhep) were generated and fed either a standard or a copper-enriched diet. Copper homeostasis and liver function were determined in Commd1Δhep mice by biochemical and histological analyses, and compared to wild-type littermates. Commd1Δhep mice were viable and did not develop an overt phenotype. At six weeks, the liver copper contents was increased up to a 3-fold upon Commd1 deficiency, but declined with age to concentrations similar to those seen in controls. Interestingly, Commd1Δhep mice fed a copper-enriched diet progressively accumulated copper in the liver up to a 20-fold increase compared to controls. These copper levels did not result in significant induction of the copper-responsive genes metallothionein I and II, neither was there evidence of biochemical liver injury nor overt liver pathology. The biosynthesis of ceruloplasmin was clearly augmented with age in Commd1Δhep mice. Although COMMD1 expression is associated with changes in ATP7B protein stability, no clear correlation between Atp7b levels and copper accumulation in Commd1Δhep mice could be detected. Despite the absence of hepatocellular toxicity in Commd1Δhep mice, the changes in liver copper displayed several parallels with copper toxicosis in Bedlington terriers. Thus, these results provide the first genetic evidence for COMMD1 to play an essential role in hepatic copper homeostasis and present a valuable mouse model for further understanding of the molecular mechanisms underlying hepatic copper homeostasis

Study protocol subacromial impingement syndrome: the identification of pathophysiologic mechanisms (SISTIM)

<p>Abstract</p> <p>Background</p> <p>The Subacromial Impingement Syndrome (SIS) is the most common diagnosed disorder of the shoulder in primary health care, but its aetiology is unclear. Conservative treatment regimes focus at reduction of subacromial inflammatory reactions or pathologic scapulohumeral motion patterns (<it>intrinsic </it>aetiology). Long-lasting symptoms are often treated with surgery, which is focused at enlarging the subacromial space by resection of the anterior part of the acromion (based on <it>extrinsic </it>aetiology). Despite that acromionplasty is in the top-10 of orthopaedic surgical procedures, there is no consensus on its indications and reported results are variable (successful in 48-90%). We hypothesize that the aetiology of SIS, i.e. an increase in subacromial pressure or decrease of subacromial space, is multi-factorial. SIS can be the consequence of pathologic scapulohumeral motion patterns leading to humerus cranialisation, anatomical variations of the scapula and the humerus (e.g. hooked acromion), a subacromial inflammatory reaction (e.g. due to overuse or micro-trauma), or adjoining pathology (e.g. osteoarthritis in the acromion-clavicular-joint with subacromial osteophytes).</p> <p>We believe patients should be treated according to their predominant etiological mechanism(s). Therefore, the objective of our study is to identify and discriminate etiological mechanisms occurring in SIS patients, in order to develop tailored diagnostic and therapeutic strategies.</p> <p>Methods</p> <p>In this cross-sectional descriptive study, applied clinical and experimental methods to identify intrinsic and extrinsic etiologic mechanisms comprise: MRI-arthrography (eligibility criteria, cuff status, 3D-segmented bony contours); 3D-motion tracking (scapulohumeral rhythm, arm range of motion, dynamic subacromial volume assessment by combining the 3D bony contours and 3D-kinematics); EMG (adductor co-activation) and dynamometry instrumented shoulder radiographs during arm tasks (force and muscle activation controlled acromiohumeral translation assessments); Clinical phenotyping (Constant Score, DASH, WORC, and SF-36 scores).</p> <p>Discussion</p> <p>By relating anatomic properties, kinematics and muscle dynamics to subacromial volume, we expect to identify one or more predominant pathophysiological mechanisms in every SIS patient. These differences in underlying mechanisms are a reflection of the variations in symptoms, clinical scores and outcomes reported in literature. More insight in these mechanisms is necessary in order to optimize future diagnostic and treatment strategies for patients with SIS symptoms.</p> <p>Trial registration</p> <p>Dutch Trial Registry (Nederlands Trial Register) <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2283">NTR2283</a>.</p

Ion homeostasis in the Chloroplast

peer reviewedThe chloroplast is an organelle of high demand for macro- and micro-nutrient ions, which are required for the maintenance of the photosynthetic process. To avoid deficiency while preventing excess, homeostasis mechanisms must be tightly regulated. Here, we describe the needs for nutrient ions in the chloroplast and briefly highlight their functions in the chloroplastidial metabolism. We further discuss the impact of nutrient deficiency on chloroplasts and the acclimation mechanisms that evolved to preserve the photosynthetic apparatus. We finally present what is known about import and export mechanisms for these ions. Whenever possible, a comparison between cyanobacteria, algae and plants is provided to add an evolutionary perspective to the description of ion homeostasis mechanisms in photosynthesis