Ring-like Oligomers of Synaptotagmins and Related C2 Domain Proteins

We recently reported that the C2AB portion of Synaptotagmin 1 (Syt1) could self-assemble into Ca2+-sensitive ring-like oligomers on membranes, which could potentially regulate neurotransmitter release. Here we report that analogous ring-like oligomers assemble from the C2AB domains of other Syt isoforms (Syt2, Syt7, Syt9) as well as related C2 domain containing protein, Doc2B and extended Synaptotagmins (E-Syts). Evidently, circular oligomerization is a general and conserved structural aspect of many C2 domain proteins, including Synaptotagmins. Further, using electron microscopy combined with targeted mutations, we show that under physiologically relevant conditions, both the Syt1 ring assembly and its rapid disruption by Ca2+ involve the well-established functional surfaces on the C2B domain that are important for synaptic transmission. Our data suggests that ring formation may be triggered at an early step in synaptic vesicle docking and positions Syt1 to synchronize neurotransmitter release to Ca2+ influx

Survival trends for small intestinal cancer in England and Wales, 1971–1990: national population-based study

This population-based study examines prognostic factors and survival trends among adults (15–99 years) diagnosed with small intestinal cancer in England and Wales during 1971–1990 and followed up to 1995. During this period, the 1- and 5-year age-standardised relative survival rates for small intestinal cancers combined were 42% and 23%, respectively. Duodenal tumours, adenocarcinomas, men, patients with advanced age and the most deprived patients had the poorest prognosis. For all small bowel tumours combined, the excess risk of death fell significantly by 6–9% every 4 years over the 20-year period (adjusted excess hazard ratio (EHR) 0.91 at 1 year after diagnosis, 0.94 at 5 years). For duodenal tumours, the EHR fell by about 14% (95% CI 5–22%) every 4 years between 1979 and 1990, and a similar trend for jejunal tumours was of borderline significance. Further population-based investigations linking survival data to individual data on diagnostic methods and types of treatment are needed

Effect of Er:YAG laser enamel conditioning and moisture on the microleakage of a hydrophilic sealant

For a given sealant, successful pit and fissure sealing is principally governed by the enamel conditioning technique and the presence of moisture contamination. A new generation of hydrophilic resin sealants is reported to tolerate moisture. This study investigates the impact of Er:YAG laser pre-conditioning and moisture contamination on the microleakage of a recent hydrophilic sealant. Occlusal surfaces of extracted human molars were either acid etched (n = 30), or successively lased and acid etched (n = 30). Ten teeth from each group were either air-dried, water-contaminated, or saliva-contaminated prior to sealing with UltraSeal XT® hydro™. Samples were inspected for penetration of fuchsin dye following 3000 thermocycles between 5 and 50 °C, and the enamel–sealant interfaces were observed by scanning electron microscopy (SEM). Significant differences in microleakage were evaluated using the Mann–Whitney U test with Bonferroni adjustment (p = 0.05). Laser pre-conditioning significantly reduced dye penetration irrespective of whether the enamel surface was moist or dry. Microleakageof water-contaminated acid etched teeth was significantly greater than that of their air-dried or saliva-contaminated counterparts. SEM analysis demonstrated good adaptation in all groups with the exception of water-contaminated acid etched teeth which exhibited relatively wide gaps. In conclusion, this hydrophilic sealant tolerates the presence of saliva, although water was found to impair its sealing ability. Laser pre-conditioning significantly decreases microleakage in all cases

Expression of Drug Targets in Patients Treated with Sorafenib, Carboplatin and Paclitaxel

Introduction: Sorafenib, a multitarget kinase inhibitor, targets members of the mitogen-activated protein kinase (MAPK) pathway and VEGFR kinases. Here we assessed the association between expression of sorafenib targets and biomarkers of taxane sensitivity and response to therapy in pre-treatment tumors from patients enrolled in ECOG 2603, a phase III comparing sorafenib, carboplatin and paclitaxel (SCP) to carboplatin, paclitaxel and placebo (CP). Methods: Using a method of automated quantitative analysis (AQUA) of in situ protein expression, we quantified expression of VEGF-R2, VEGF-R1, VEGF-R3, FGF-R1, PDGF-Rβ, c-Kit, B-Raf, C-Raf, MEK1, ERK1/2, STMN1, MAP2, EB1 and Bcl-2 in pretreatment specimens from 263 patients. Results: An association was found between high FGF-R1 and VEGF-R1 and increased progression-free survival (PFS) and overall survival (OS) in our combined cohort (SCP and CP arms). Expression of FGF-R1 and VEGF-R1 was higher in patients who responded to therapy ((CR+PR) vs. (SD+PD+ un-evaluable)). Conclusions: In light of the absence of treatment effect associated with sorafenib, the association found between FGF-R1 and VEGF-R1 expression and OS, PFS and response might reflect a predictive biomarker signature for carboplatin/paclitaxel-based therapy. Seeing that carboplatin and pacitaxel are now widely used for this disease, corroboration in another cohort might enable us to improve the therapeutic ratio of this regimen. © 2013 Jilaveanu et al

A genome-wide association study identifies multiple loci for variation in human ear morphology

Here we report a genome-wide association study for non-pathological pinna morphology in over 5,000 Latin Americans. We find genome-wide significant association at seven genomic regions affecting: lobe size and attachment, folding of antihelix, helix rolling, ear protrusion and antitragus size (linear regression P values 2 × 10−8 to 3 × 10−14). Four traits are associated with a functional variant in the Ectodysplasin A receptor (EDAR) gene, a key regulator of embryonic skin appendage development. We confirm expression of Edar in the developing mouse ear and that Edar-deficient mice have an abnormally shaped pinna. Two traits are associated with SNPs in a region overlapping the T-Box Protein 15 (TBX15) gene, a major determinant of mouse skeletal development. Strongest association in this region is observed for SNP rs17023457 located in an evolutionarily conserved binding site for the transcription factor Cartilage paired-class homeoprotein 1 (CART1), and we confirm that rs17023457 alters in vitro binding of CART1

The impact of Er:YAG laser enamel conditioning on the microleakage of a new hydrophilic sealant — UltraSeal XT® hydro™

UltraSeal XT® hydro™ is a new hydrophilic, light-cured, methacrylate-based pit and fissure sealant which has been developed by Ultradent Products, USA. The sealant is highly filled with a 53 wt.% mixture of inorganic particles which confer both thixotropy and radiopacity. The principal purpose of this study was to investigate the microleakage of UltraSeal XT® hydro™ as a function of different enamel etching techniques. The occlusal surfaces of sound, extracted human molars were either acid etched, Er:YAG laser irradiated or successively laser irradiated and acid etched. UltraSeal XT® hydro™ was applied to each group of teeth (n=10) which were subjected to a thermocycling process consisting of 2500 cycles between 5 and 50°C with a dwell time of 30s. Microleakage assessments were then carried out using 0.5 % fuchsin dye and optical microscopy. The microleakage score data were analysed using the Kruskal-Wallis, Mann–Whitney U test with Bonferroni adjustment. No significant differences in microleakage were noted between the individually acid etched and laser-irradiated groups (p>0.05); however, teeth treated with a combination of laser irradiation and acid etching demonstrated significantly lower microleakage scores (p<0.001). Electron microscopy with energy-dispersive X-ray analysis revealed that the mineral filler component of UltraSeal XT® hydro™ essentially comprises micrometre-sized particles of inorganic silicon-, aluminium- and barium-bearing phases. Laser etching increases the roughness of the enamel surface which causes a concentrated zoning of the filler particles at the enamel-sealant interface

tAnGo: a randomised phase III trial of gemcitabine in paclitaxel-containing, epirubicin/cyclophosphamide-based, adjuvant chemotherapy for early breast cancer: a prospective pulmonary, cardiac and hepatic function evaluation

tAnGo is a large randomised trial assessing the addition of gemcitabine(G) to paclitaxel(T), following epirubicin(E) and cyclophosphamide(C) in women with invasive higher risk early breast cancer. To assess the safety and tolerability of adding G, a detailed safety substudy was undertaken. A total of 135 patients had cardiac, pulmonary and hepatic function assessed at (i) randomisation, (ii) mid-chemotherapy, (iii) immediately post-chemotherapy and (iv) 6 months post-chemotherapy. Skin toxicity was assessed during radiotherapy. No differences were detected in FEV1 or FVC levels between treatment arms or time points. Diffusion capacity (TLCO) reduced during treatment (P<0.0001), with a significantly lower drop in EC-GT patients (P=0.02). Most of the reduction occurred during EC and recovered by 6-months post treatment. There was no difference in cardiac function between treatment arms. Only 11 patients had echocardiography/MUGA results change from normal to abnormal during treatment, with only five having LVEF<50%. Transient transaminitis occurred in both treatment arms with significantly more in EC-GT patients post-chemotherapy (AST P=0.03, ALT P=0.003), although the majority was low grade. There was no correlation between transaminitis and other toxicities. Both treatment regimens reported temporary reductions in pulmonary functions and transient transaminitis levels. Despite these being greater with EC-GT, both regimens appear well tolerated

Gene expression profiling may improve diagnosis in patients with carcinoma of unknown primary

Carcinomas of unknown primary (CUP) represent between 3 and 10% of malignancies. Treatment with nonspecific chemotherapy is commonly unhelpful and the median survival is between 3 and 6 months. Gene expression microarray (GEM) analysis has demonstrated that molecular signatures can aid in tumour classification and propose foster primaries. In this study, we demonstrate the clinical utility of a diagnostic gene expression profiling tool and discuss its potential implications for patient management strategies. Paraffin tumour samples from 21 cases of ‘true' CUP patients in whom standard investigation had failed to determine a primary site of malignancy were investigated using diagnostic gene profiling. The results were reviewed in the context of histology and clinical history. Classification of tumour origin using the GEM method confirmed the clinicians' suspicion in 16 out of 21 cases. There was a clinical/GEM inconsistency in 4 out of 21 patients and a pathological/GEM inconsistency in 1 patient. The improved diagnoses by the GEM method would have influenced the management in 12 out of 21 cases. Genomic profiling and cancer classification tools represent a promising analytical approach to assist with the management of CUP patients. We propose that GEM diagnosis be considered when the primary clinical algorithm has failed to provide a diagnosis

A prospective study of symptoms, function, and medication use during acute illness in nursing home residents: design, rationale and cohort description

<p>Abstract</p> <p>Background</p> <p>Nursing home residents are at high risk for developing acute illnesses. Compared with community dwelling adults, nursing home residents are often more frail, prone to multiple medical problems and symptoms, and are at higher risk for adverse outcomes from acute illnesses. In addition, because of polypharmacy and the high burden of chronic disease, nursing home residents are particularly vulnerable to disruptions in transitions of care such as medication interruptions in the setting of acute illness. In order to better estimate the effect of acute illness on nursing home residents, we have initiated a prospective cohort which will allow us to observe patterns of acute illnesses and the consequence of acute illnesses, including symptoms and function, among nursing home residents. We also aim to examine the patterns of medication interruption, and identify patient, provider and environmental factors that influence continuity of medication prescribing at different points of care transition.</p> <p>Methods</p> <p>This is a prospective cohort of nursing home residents residing in two nursing homes in a metropolitan area. Baseline characteristics including age, gender, race, and comorbid conditions are recorded. Participants are followed longitudinally for a planned period of 3 years. We record acute illness incidence and characteristics, and measure symptoms including depression, pain, withdrawal symptoms, and function using standardized scales.</p> <p>Results</p> <p>76 nursing home residents have been followed for a median of 666 days to date. At baseline, mean age of residents was 74.4 (± 11.9); 32% were female; 59% were white. The most common chronic conditions were dementia (41%), depression (38%), congestive heart failure (25%) and chronic obstructive lung disease (27%). Mean pain score was 4.7 (± 3.6) on a scale of 0 to 10; Geriatric Depression Scale (GDS-15) score was 5.2 (± 4.4). During follow up, 138 acute illness episodes were identified, for an incidence of 1.5 (SD 2.0) episodes per resident per year; 74% were managed in the nursing home and 26% managed in the acute care setting.</p> <p>Conclusion</p> <p>In this report, we describe the conceptual model and methods of designing a longitudinal cohort to measure acute illness patterns and symptoms among nursing home residents, and describe the characteristics of our cohort at baseline. In our planned analysis, we will further estimate the effect of the use and interruption of medications on withdrawal and relapse symptoms and illness outcomes.</p