HSP90 inhibition sensitizes head and neck cancer to platin-based chemoradiotherapy by modulation of the DNA damage response resulting in chromosomal fragmentation.

Background Concurrent cisplatin radiotherapy (CCRT) is a current standard-of-care for locally advanced head and neck squamous cell carcinoma (HNSCC). However, CCRT is frequently ineffective in patients with advanced disease. It has previously been shown that HSP90 inhibitors act as radiosensitizers, but these studies have not focused on CCRT in HNSCC. Here, we evaluated the HSP90 inhibitor, AUY922, combined with CCRT.Methods The ability of AUY922 to sensitize to CCRT was assessed in p53 mutant head and neck cell lines by clonogenic assay. Modulation of the CCRT induced DNA damage response (DDR) by AUY922 was characterized by confocal image analysis of RAD51, BRCA1, 53BP1, ATM and mutant p53 signaling. The role of FANCA depletion by AUY922 was examined using shRNA. Cell cycle checkpoint abrogation and chromosomal fragmentation was assessed by western blot, FACS and confocal. The role of ATM was also assessed by shRNA. AUY922 in combination with CCRT was assessed in vivo.Results The combination of AUY922 with cisplatin, radiation and CCRT was found to be synergistic in p53 mutant HNSCC. AUY922 leads to significant alterations to the DDR induced by CCRT. This comprises inhibition of homologous recombination through decreased RAD51 and pS1524 BRCA1 with a corresponding increase in 53BP1 foci, activation of ATM and signaling into mutant p53. A shift to more error prone repair combined with a loss of checkpoint function leads to fragmentation of chromosomal material. The degree of disruption to DDR signalling correlated to chromosomal fragmentation and loss of clonogenicity. ATM shRNA indicated a possible rationale for the combination of AUY922 and CCRT in cells lacking ATM function.Conclusions This study supports future clinical studies combining AUY922 and CCRT in p53 mutant HNSCC. Modulation of the DDR and chromosomal fragmentation are likely to be analytical points of interest in such trials

Recommendations for a core outcome set for measuring standing balance in adult populations: a consensus-based approach

Standing balance is imperative for mobility and avoiding falls. Use of an excessive number of standing balance measures has limited the synthesis of balance intervention data and hampered consistent clinical practice.To develop recommendations for a core outcome set (COS) of standing balance measures for research and practice among adults.A combination of scoping reviews, literature appraisal, anonymous voting and face-to-face meetings with fourteen invited experts from a range of disciplines with international recognition in balance measurement and falls prevention. Consensus was sought over three rounds using pre-established criteria.The scoping review identified 56 existing standing balance measures validated in adult populations with evidence of use in the past five years, and these were considered for inclusion in the COS.Fifteen measures were excluded after the first round of scoring and a further 36 after round two. Five measures were considered in round three. Two measures reached consensus for recommendation, and the expert panel recommended that at a minimum, either the Berg Balance Scale or Mini Balance Evaluation Systems Test be used when measuring standing balance in adult populations.Inclusion of two measures in the COS may increase the feasibility of potential uptake, but poses challenges for data synthesis. Adoption of the standing balance COS does not constitute a comprehensive balance assessment for any population, and users should include additional validated measures as appropriate.The absence of a gold standard for measuring standing balance has contributed to the proliferation of outcome measures. These recommendations represent an important first step towards greater standardization in the assessment and measurement of this critical skill and will inform clinical research and practice internationally

Mycobacterium tuberculosis ribosomal protein S1 (RpsA) and variants with truncated C-terminal end show absence of interaction with pyrazinoic acid.

Pyrazinamide (PZA) is an antibiotic used in first- and second-line tuberculosis treatment regimens. Approximately 50% of multidrug-resistant tuberculosis and over 90% of extensively drug-resistant tuberculosis strains are also PZA resistant. Despite the key role played by PZA, its mechanisms of action are not yet fully understood. It has been postulated that pyrazinoic acid (POA), the hydrolyzed product of PZA, could inhibit trans-translation by binding to Ribosomal protein S1 (RpsA) and competing with tmRNA, the natural cofactor of RpsA. Subsequent data, however, indicate that these early findings resulted from experimental artifact. Hence, in this study we assess the capacity of POA to compete with tmRNA for RpsA. We evaluated RpsA wild type (WT), RpsA ∆A438, and RpsA ∆A438 variants with truncations towards the carboxy terminal end. Interactions were measured using Nuclear Magnetic Resonance spectroscopy (NMR), Isothermal Titration Calorimetry (ITC), Microscale Thermophoresis (MST), and Electrophoretic Mobility Shift Assay (EMSA). We found no measurable binding between POA and RpsA (WT or variants). This suggests that RpsA may not be involved in the mechanism of action of PZA in Mycobacterium tuberculosis, as previously thought. Interactions observed between tmRNA and RpsA WT, RpsA ∆A438, and each of the truncated variants of RpsA ∆A438, are reported

Tertiary hypothyroidism in a dog

<p/> <p>A nine-year-old male entire Labrador was diagnosed with pituitary dependent hyperadrenocorticism. Following seven months of successful mitotane therapy, the dog presented with marked weight gain, seborrhoea and alopecia. Routine clinicopathological analyses revealed marked hypercholesterolaemia. Serum total and free thyroxine (T4) concentrations were below their respective reference ranges. Serum thyroid stimulating hormone (cTSH) concentration was within reference range. TSH and thyrotropin releasing hormone (TRH) response tests revealed adequate stimulation of total T4 in both, and cTSH in the latter test. Magnetic resonance imaging revealed a mass arising from the pituitary fossa, with suprasellar extension. A diagnosis of tertiary hypothyroidism was made. Following four weeks of levothyroxine therapy, circulating cholesterol concentration had declined, weight loss had ensued and dermatological abnormalities had improved. Euthanasia was performed four months later due to the development of neurological signs. A highly infiltrative pituitary adenoma, with effacement of the overlying hypothalamus was identified on post mortem examination. Tertiary hypothyroidism has not been previously reported in dogs.</p

Online clinical reasoning assessment with the Script Concordance test: a feasibility study

BACKGROUND: The script concordance (SC) test is an assessment tool that measures capacity to solve ill-defined problems, that is, reasoning in context of uncertainty. This tool has been used up to now mainly in medicine. The purpose of this pilot study is to assess the feasibility of the test delivered on the Web to French urologists. METHODS: The principle of SC test construction and the development of the Web site are described. A secure Web site was created with two sequential modules: (a) The first one for the reference panel (n = 26) with two sub-tasks: to validate the content of the test and to elaborate the scoring system; (b) The second for candidates with different levels of experience in Urology: Board certified urologists, residents, medical students (5 or 6(th )year). Minimum expected number of participants is 150 for urologists, 100 for residents and 50 for medical students. Each candidate is provided with an individual access code to this Web site. He/she may complete the Script Concordance test several times during his/her curriculum. RESULTS: The Web site has been operational since April 2004. The reference panel validated the test in June of the same year during the annual seminar of the French Society of Urology. The Web site is available for the candidates since September 2004. In six months, 80% of the target figure for the urologists, 68% of the target figure for the residents and 20% of the target figure for the student passed the test online. During these six months, no technical problem was encountered. CONCLUSION: The feasibility of the web-based SC test is successful as two-thirds of the expected number of participants was included within six months. Psychometric properties (validity, reliability) of the test will be evaluated on a large scale (N = 300). If positive, educational impact of this assessment tool will be useful to help urologists during their curriculum for the acquisition of clinical reasoning skills, which is crucial for professional competence

The Treatment In Morning versus Evening (TIME) study:Analysis of recruitment, follow-up and retention rates post-recruitment

Abstract Background The use of information technology (IT) is now the preferred method of capturing and storing clinical research data. The Treatment In Morning versus Evening (TIME) study predominantly uses electronic data capture and IT to compare morning dosing of hypertensive medication against evening dosing. Registration, consent, participant demographics and follow-up data are all captured via the study website. The aim of this article is to assess the success of the TIME methodology compared with similar studies. Methods To assess the TIME study, published literature on similar clinical trials was reviewed and compared against TIME recruitment, follow-up and email interaction data. Results The TIME website registered 31,695 individuals, 21,116 of whom were randomised. Recruitment cost per randomised participant varied by strategy: £17.40 by GP practice, £3.08 by UK Biobank and £58.82 for GoShare. Twelve-month follow-up retention rates were 96%. A total of 1089 participants have withdrawn from their assigned time of dosing, 2% of whom have declined follow-up by record linkage or further contact. When the TIME data are compared with similar study data, study recruitment is very successful. However, TIME suffers difficulties with participant follow-up and withdrawal rates similar to those of conventional studies. Conclusions The TIME study has been successful in recruitment. Follow-up, retention rates and withdrawal rates are all acceptable, but ongoing work is required to ensure participants remain engaged with the study. Various recruitment strategies are necessary, and all viable options should be encouraged to maintain participant engagement throughout the life of studies using IT

Differences in gait patterns, pain, function and quality of life between males and females with knee osteoarthritis: a clinical trial

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to gain a deeper understanding of the gender differences in knee osteoarthritis (OA) by evaluating the differences in gait spatio-temporal parameters and the differences in pain, quality of life and function between males and females suffering from knee OA.</p> <p>Methods</p> <p>49 males and 85 females suffering from bilateral medial compartment knee OA participated in this study. Each patient underwent a computerized gait test and completed the WOMAC questionnaire and the SF-36 health survey. Independent t-tests were performed to examine the differences between males and females in age, BMI, spatio-temporal parameters, the WOMAC questionnaire and the SF-36 health survey.</p> <p>Results</p> <p>Males and females had different gait patterns. Although males and females walked at the same walking speed, cadence and step length, they presented significant differences in the gait cycle phases. Males walked with a smaller stance and double limb support, and with a larger swing and single limb support compared to females. In addition, males walked with a greater toe out angle compared to females. While significant differences were not found in the WOMAC subscales, females consistently reported higher levels of pain and disability.</p> <p>Conclusion</p> <p>The spatio-temporal differences between genders may suggest underlying differences in the gait strategies adopted by males and females in order to reduce pain and cope with the loads acting on their affected joints, two key aspects of knee OA. These gender effects should therefore be taken into consideration when evaluating patients with knee OA.</p> <p>Trial Registration</p> <p>The study is registered in the NIH clinical trial registration, protocol No. NCT00599729.</p

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

InterGEO: a digital platform for university education on geomorphological heritage

The project InterGEO was carried out with the objective to disseminate knowledge on geomorphological heritage by developing a digital learning platform. It aims at improving students' autonomy by the reduction of face-to-face teaching and increasing autonomous learning as well as promoting international interactions between students interested in geomorphological heritage. A completely free-access virtual course on geomorphosites was developed with the Learning Management System Moodle. The course is divided into 24 thematic chapters, each of them containing a short description, a list of references and selected publications, as well as other educational material (videos, virtual fieldtrips, etc.). In particular, several videos allow presenting in a dynamic way concepts and examples. The paper presents the tool and its use in academic programmes in six European universities, where it was tested, in various contexts (Bachelors' and Masters' programmes; students in geography or geology; general courses in geomorphology and specific courses on geoheritage and geoconservation), before discussing the advantages and challenges the tool is facing. The InterGEO platform is an easy-to-use and friendly educational tool, which allows developing blended learning activities; it is flexible and adaptable in various learning contexts.The coordination tasks (appointment of an assistant) and two workshops in Lausanne were financed by the University of Lausanne (Teaching Innovation Fund and Investment Fund of the Faculty of Geosciences and Environment, FGSE). The videos were designed and created with support of the universities of Lausanne (TIF) and Savoie Mont Blanc (IDEFI Promising and ReflexPro; LabEx ITEM)

Differential Effect of TLR2 and TLR4 on the Immune Response after Immunization with a Vaccine against Neisseria meningitidis or Bordetella pertussis

Neisseria meningitidis and Bordetella pertussis are Gram-negative bacterial pathogens that can cause serious diseases in humans. N. meningitidis outer membrane vesicle (OMV) vaccines and whole cell pertussis vaccines have been successfully used in humans to control infections with these pathogens. The mechanisms behind their effectiveness are poorly defined. Here we investigated the role of Toll-like receptor (TLR) 2 and TLR4 in the induction of immune responses in mice after immunization with these vaccines. Innate and adaptive immune responses were compared between wild type mice and mice deficient in TLR2, TLR4, or TRIF. TRIF-deficient and TLR4-deficient mice showed impaired immunity after immunization. In contrast, immune responses were not lower in TLR2−/− mice but tended even to be higher after immunization. Together our data demonstrate that TLR4 activation contributes to the immunogenicity of the N. meningitidis OMV vaccine and the whole cell pertussis vaccine, but that TLR2 activation is not required