On the statistical mechanics of prion diseases

We simulate a two-dimensional, lattice based, protein-level statistical mechanical model for prion diseases (e.g., Mad Cow disease) with concommitant prion protein misfolding and aggregation. Our simulations lead us to the hypothesis that the observed broad incubation time distribution in epidemiological data reflect fluctuation dominated growth seeded by a few nanometer scale aggregates, while much narrower incubation time distributions for innoculated lab animals arise from statistical self averaging. We model `species barriers' to prion infection and assess a related treatment protocol.Comment: 5 Pages, 3 eps figures (submitted to Physical Review Letters

Digital Quantification of Gene Expression in Sequential Breast Cancer Biopsies Reveals Activation of an Immune Response

Advancements in molecular biology have unveiled multiple breast cancer promoting pathways and potential therapeutic targets. Large randomized clinical trials remain the ultimate means of validating therapeutic efficacy, but they require large cohorts of patients and are lengthy and costly. A useful approach is to conduct a window of opportunity study in which patients are exposed to a drug pre-surgically during the interval between the core needle biopsy and the definitive surgery. These are non-therapeutic studies and the end point is not clinical or pathological response but rather evaluation of molecular changes in the tumor specimens that can predict response. However, since the end points of the non-therapeutic studies are biologic, it is critical to first define the biologic changes that occur in the absence of treatment. In this study, we compared the molecular profiles of breast cancer tumors at the time of the diagnostic biopsy versus the definitive surgery in the absence of any intervention using the Nanostring nCounter platform. We found that while the majority of the transcripts did not vary between the two biopsies, there was evidence of activation of immune related genes in response to the first biopsy and further investigations of the immune changes after a biopsy in early breast cancer seem warranted

Diagnosis of obstructive coronary artery disease using computed tomography angiography in patients with stable chest pain depending on clinical probability and in clinically important subgroups: meta-analysis of individual patient data

OBJECTIVE: To determine whether coronary computed tomography angiography (CTA) should be performed in patients with any clinical probability of coronary artery disease (CAD), and whether the diagnostic performance differs between subgroups of patients. DESIGN: Prospectively designed meta-analysis of individual patient data from prospective diagnostic accuracy studies. DATA SOURCES: Medline, Embase, and Web of Science for published studies. Unpublished studies were identified via direct contact with participating investigators. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective diagnostic accuracy studies that compared coronary CTA with coronary angiography as the reference standard, using at least a 50% diameter reduction as a cutoff value for obstructive CAD. All patients needed to have a clinical indication for coronary angiography due to suspected CAD, and both tests had to be performed in all patients. Results had to be provided using 2×2 or 3×2 cross tabulations for the comparison of CTA with coronary angiography. Primary outcomes were the positive and negative predictive values of CTA as a function of clinical pretest probability of obstructive CAD, analysed by a generalised linear mixed model; calculations were performed including and excluding non-diagnostic CTA results. The no-treat/treat threshold model was used to determine the range of appropriate pretest probabilities for CTA. The threshold model was based on obtained post-test probabilities of less than 15% in case of negative CTA and above 50% in case of positive CTA. Sex, angina pectoris type, age, and number of computed tomography detector rows were used as clinical variables to analyse the diagnostic performance in relevant subgroups. RESULTS: Individual patient data from 5332 patients from 65 prospective diagnostic accuracy studies were retrieved. For a pretest probability range of 7-67%, the treat threshold of more than 50% and the no-treat threshold of less than 15% post-test probability were obtained using CTA. At a pretest probability of 7%, the positive predictive value of CTA was 50.9% (95% confidence interval 43.3% to 57.7%) and the negative predictive value of CTA was 97.8% (96.4% to 98.7%); corresponding values at a pretest probability of 67% were 82.7% (78.3% to 86.2%) and 85.0% (80.2% to 88.9%), respectively. The overall sensitivity of CTA was 95.2% (92.6% to 96.9%) and the specificity was 79.2% (74.9% to 82.9%). CTA using more than 64 detector rows was associated with a higher empirical sensitivity than CTA using up to 64 rows (93.4% v 86.5%, P=0.002) and specificity (84.4% v 72.6%, P<0.001). The area under the receiver-operating-characteristic curve for CTA was 0.897 (0.889 to 0.906), and the diagnostic performance of CTA was slightly lower in women than in with men (area under the curve 0.874 (0.858 to 0.890) v 0.907 (0.897 to 0.916), P<0.001). The diagnostic performance of CTA was slightly lower in patients older than 75 (0.864 (0.834 to 0.894), P=0.018 v all other age groups) and was not significantly influenced by angina pectoris type (typical angina 0.895 (0.873 to 0.917), atypical angina 0.898 (0.884 to 0.913), non-anginal chest pain 0.884 (0.870 to 0.899), other chest discomfort 0.915 (0.897 to 0.934)). CONCLUSIONS: In a no-treat/treat threshold model, the diagnosis of obstructive CAD using coronary CTA in patients with stable chest pain was most accurate when the clinical pretest probability was between 7% and 67%. Performance of CTA was not influenced by the angina pectoris type and was slightly higher in men and lower in older patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42012002780

Risk factors for oesophageal squamous cell carcinoma in Mozambique

Studies evaluating risk factors for the occurrence of oesophageal squamous cell carcinoma (ESCC) in high-risk regions might contribute to a better understanding of the oesophageal cancer aetiology and incidence variation worldwide. We aimed to quantify the association between alcohol, tobacco and dietary history, and the occurrence of ESCC in Mozambique. A case–control study was conducted at Maputo Central Hospital. Cases (n = 143) were patients with newly diagnosed oesophageal cancer recruited in the Gastroenterology Service. Controls (n = 212) were selected in the Orthopaedic Ward among subjects with pathologies related to trauma. Crude and adjusted odds ratios (ORs), and the corresponding 95% confidence intervals (CI) were computed using non-conditional logistic regression. The risk of ESCC was higher in older participants and lower in those with higher household income. Alcohol drinking (lifetime consumption ≥ 55.1 versus 0 kg ethanol: OR = 5.56; 95% CI: 2.43–12.73) and tobacco smoking (lifetime consumption ≥ 20 versus 0 pack/years: OR=7.26; 95% CI: 1.42–37.17) were associated with increased risk of ESCC. Tea (at least twice daily versus less than daily: OR = 5.09; 95% CI: 2.45–10.58) was also associated with the occurrence of ESCC. No significant differences were observed for fruit and vegetable and for smoked meat or fish consumption. Findings from this study show that in our sample, the occurrence of ESCC is strongly influenced by lifetime consumption of tobacco and alcohol, and with tea drinking. This highlights the importance of preventive measures based on the promotion of healthier lifestyles. Copyright: © the authors; licensee ecancermedicalscience

CIP2A expression predicts recurrences of tamoxifen-treated breast cancer

CIP2A is emerging as an oncoprotein overexpressed commonly across many tumours and generally correlated with higher tumour grade and therapeutic resistance. CIP2A drives an oncogenic potential through inhibiting protein phosphatase 2A, stabilizing MYC, and promoting epithelial-to-mesenchymal transition, although further biological mechanisms for CIP2A are yet to be defined. CIP2A protein expression was studied by immunohistochemistry in oestrogen receptor–positive primary breast cancers (n = 250) obtained from the Leeds Tissue Bank. In total, 51 cases presented with a relapse or metastasis during adjuvant treatment with tamoxifen and were regarded as tamoxifen resistant. CIP2A expression was scored separately for cytoplasmic, nuclear, or membranous staining, and scores were tested for statistically significant relationships with clinicopathological features. Membranous CIP2A was preferentially expressed in cases who experienced a recurrence during tamoxifen treatment thus predicting a worse overall survival (log rank = 8.357, p = 0.004) and disease-free survival (log rank = 21.766, p < 0.001). Cox multivariate analysis indicates that it is an independent prognostic indicator for overall survival (hazard ratio = 4.310, p = 0.013) and disease-free survival (hazard ratio = 5.449, p = 0.002). In this study, we propose the assessment of membranous CIP2A expression as a potential novel prognostic and predictive indicator for tamoxifen resistance and recurrence within oestrogen receptor–positive breast cancer

ANANALYTICAL STUDY OF MARBLE CONSOLIDATION BY OXALATE PRECIPITATION USING DENSITY, FTIR AND POWDER-XRD MEASUREMENTS

oai:ojs2.www.jepm.rs.ba:article/28Our recent study on consolidation of marble samples with the purpose of culture heritage protection occurred by periodical calcium oxalate precipitation on top of quasi parallelepipedic samples. The overall process consisting of three stages of treatment, starting with 5 % calcium acetate solution for 60 minutes at 20°C, a draining step at 70°C for 30 min, followed by a treatment with 5 % ammonium sulfate solution, it followed with the third stage which includes the treatment with 5% ammonium oxalate solution revealed a continuous density increace, determined using ethanol. As the natural samples had an initial density of 2.5871 g/cm3 , it increased up to 2.6980 g/cm3 for 50 times treatments. The precipitation of oxalate on top of calcium carbonate substrate, in form of calcite, revealed two distinguished infra-red bands, at 1316 cm-1 and 1624 cm-1 unsymmetrically located around the carbonate one at 1426 cm-1 .The intensity of the bands was proportional to the number of treatments. The continuous surface coverage investigated in parallel by powder XRD evidenced the presence of whewellite crystallites deposited on top of calcite, and their intensity increasing as well with the number of treatments. This method exhibits a reliable oxalate coverage of marble sample surfaces which doesn’t influence considerably their water solubility

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies : an international multicenter retrospective study

Background: Immunodysregulation polyendocrinopathy enteropathy x-linked(IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n 5 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term.disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen

Physico-Chemical Characteristics and In Vitro Rumen Degradability of Insect Frass as NPN Source for Mineral Blocks in Goats

The study was conducted to determine the potential of superworm (Zophobas morio) larvae (SWL) and black soldier fly (Hermetia illucens) larvae (BSFL) frass at 10% inclusion as non-protein nitrogen (NPN) source in formulating mineral blocks for goats, with emphasis on the physico-chemical properties of the mineral blocks, and to assess the extent of feed degradation in goats supplemented with insect frass-based mineral block through an in vitro degradability trial. A total of 16 post-weaned goats were used to determine the effects of supplementing insect frass-based mineral blocks on the feed degradation in goats. The goats were arranged in a randomized complete block design (RCBD) with four (4) treatments and four (4) blocks with initial body weight (BW) as the blocking factor. Treatment A (control), Treatment B (urea molasses mineral block) (UMMB), Treatment C (superworm larvae frass mineral block) (SWLFMB), and Treatment D (black soldier fly larvae frass mineral block) (BSFLFMB) served as treatments. Based on the results, insect frass-based mineral blocks showed potential as a good nutritional supplement for goats. These mineral blocks offer valuable sources of protein, non-protein nitrogen (NPN), and minerals. Evaluation of hardness and solubility indicated that the SWLFMB showed better hardness and compactness, but demonstrated the highest solubility among formulations. In contrast, the UMMB displayed relatively low hardness and compactness, yet was the least soluble of all the mineral block variants. Moreover, in vitro studies showed no significant difference among treatments. Therefore, insect frass-based mineral blocks are a viable alternative source of minerals and NPN for goats, which can be utilized to optimize ruminant feed resources

Cinnamides Target Leishmania amazonensis Arginase Selectively

Caffeic acid and related natural compounds were previously described as Leishmania amazonensis arginase (L-ARG) inhibitors, and against the whole parasite in vitro. In this study, we tested cinnamides that were previously synthesized to target human arginase. The compound caffeic acid phenethyl amide (CAPA), a weak inhibitor of human arginase (IC50 = 60.3 ± 7.8 μM) was found to have 9-fold more potency against L-ARG (IC50 = 6.9 ± 0.7 μM). The other compounds that did not inhibit human arginase were characterized as L-ARG, showing an IC50 between 1.3-17.8 μM, and where the most active was compound 15 (IC50 = 1.3 ± 0.1 μM). All compounds were also tested against L. amazonensis promastigotes, and only the compound CAPA showed an inhibitory activity (IC50 = 80 μM). In addition, in an attempt to gain an insight into the mechanism of competitive L-ARG inhibitors, and their selectivity over mammalian enzymes, we performed an extensive computational investigation, to provide the basis for the selective inhibition of L-ARG for this series of compounds. In conclusion, our results indicated that the compounds based on cinnamoyl or 3,4-hydroxy cinnamoyl moiety could be a promising starting point for the design of potential antileishmanial drugs based on selective L-ARG inhibitors