Escape from immunotherapy: possible mechanisms that influence tumor regression/progression

Tumor escape is one major obstacle that has to be addressed prior to designing and delivering successful immunotherapy. There is compelling evidence to support the notion that immunogenic tumors, in murine models and cancer patients, can be rejected by the immune system under optimum conditions for activating adaptive and nonadaptive antitumor immune responses. Despite this capability, a large number of tumors continue to grow and evade recognition and/or destruction by the immune system. The limited success in current immunotherapeutic strategies may be due to a variety of reasons: failure of effector cells to compete with the growing tumor burden, production of humoral factors by tumors that locally block cytotoxicity, antigen/MHC loss, T-cell dysfunction, production of suppressor T cells—to name but a few causes for therapeutic ineffectiveness for the particular malignancy being treated. To optimize immunotherapy strategies, correction of immune-activating signals, eradication of inhibitory factors, and the evasion from newly developed immunoresistant tumor phenotypes need to be simultaneously considered

Hygrothermal performance of building envelopes in the tropics under operative conditions : condensation and mould growth risk appraisal

Poor indoor hygrothermal performance increases the risk of indoor moisture problems and deterioration due to mould growth, corrosion and damage to archival materials. Hence, proper control of indoor thermohygric intensity abates indoor moisture and its associated problems. This paper presents the results of envelopes hygrothermal performance assessments in a hot and humid climate building with varying operational profile between adjacent spaces. The case-studied building runs on 24hrs cooling mode in one part against natural and/or mechanical supply-exhaust fan means on the other. In-situ experiments were combined with hygrothermal analytical methods to assess the envelope thermal quality together with the operative conditions against condensation and mould growth risks. The results show that the building is overcooled leading to poor envelope hygrothermal performance with associated condensation and mould growth problems on non-airconditioned sides of the envelopes

Effect of Substitution of Bovine Rumen Epithelial Tissue Scrapings for Fishmeal on the Growth Performance, Nutrient Utilization and Carcass Characteristics of Broiler Chickens

. An eight-week feeding trial was conducted to evaluate the performance, nutrient utilization and carcass characteristics of broiler chickens fed varied levels of bovine rumen epithelial tissue scrapings (BRETS) in replacement for fish meal at 0, 50 and 100% levels of substitution. Fifty four birds were used for the study and the birds were randomly distributed into three (3) dietary treatments which were randomly assigned to the rations. Feed and water were supplied ad libitum and data were collected on the feed intake, weight gain, feed conversion ratio and nutrient utilization. Data were also collected on the carcass characteristics after some birds had been slaughtered at the end of the experiment. Data collected were subjected to one-way analysis of variance and significant differences were indicated using Duncan multiple range test to separate the means. Results indicated that there was significant difference (P0.05) in the weight gain, heart and lung weights. It was concluded that up to 50% BRETS inclusion as substitute for fish meal protein could be employed without any adverse effect, to maintain the quality of the broiler chicken while minimizing the high cost of whole fishmeal since BRETS is an abattoir by-product that is readily available locally

Global transcript and phenotypic analysis of yeast cells expressing Ssa1, Ssa2, Ssa3 or Ssa4 as sole source of cytosolic Hsp70-Ssa chaperone activity.

BACKGROUND: Cytosolic Hsp70 is a ubiquitous molecular chaperone that is involved in responding to a variety of cellular stresses. A major function of Hsp70 is to prevent the aggregation of denatured proteins by binding to exposed hydrophobic regions and preventing the accumulation of amorphous aggregates. To gain further insight into the functional redundancy and specialisation of the highly homologous yeast Hsp70-Ssa family we expressed each of the individual Ssa proteins as the sole source of Hsp70 in the cell and assessed phenotypic differences in prion propagation and stress resistance. Additionally we also analysed the global gene expression patterns in yeast strains expressing individual Ssa proteins, using microarray and RT-qPCR analysis. RESULTS: We confirm and extend previous studies demonstrating that cells expressing different Hsp70-Ssa isoforms vary in their ability to propagate the yeast [PSI+] prion, with Ssa3 being the most proficient. Of the four Ssa family members the heat inducible isoforms are more proficient in acquiring thermotolerance and we show a greater requirement than was previously thought, for cellular processes in addition to the traditional Hsp104 protein disaggregase machinery, in acquiring such thermotolerance. Cells expressing different Hsp70-Ssa isoforms also display differences in phenotypic response to exposure to cell wall damaging and oxidative stress agents, again with the heat inducible isoforms providing better protection than constitutive isoforms. We assessed global transcriptome profiles for cells expressing individual Hsp70-Ssa isoforms as the sole source of cytosolic Hsp70, and identified a significant difference in cellular gene expression between these strains. Differences in gene expression profiles provide a rationale for some phenotypic differences we observed in this study. We also demonstrate a high degree of correlation between microarray data and RT-qPCR analysis for a selection of genes. CONCLUSIONS: The Hsp70-Ssa family provide both redundant and variant-specific functions within the yeast cell. Yeast cells expressing individual members of the Hsp70-Ssa family as the sole source of Ssa protein display differences in global gene expression profiles. These changes in global gene expression may contribute significantly to the phenotypic differences observed between the Hsp70-Ssa family members

Evaluating the design and reporting of pragmatic trials in osteoarthritis research

Objectives. Among the challenges in health research is translating interventions from controlled experimental settings to clinical and community settings where chronic disease is managed daily. Pragmatic trials offer a method for testing interventions in real-world settings but are seldom used in OA research. The aim of this study was to evaluate the literature on pragmatic trials in OA research up to August 2016 in order to identify strengths and weaknesses in the design and reporting of these trials. Methods. We used established guidelines to assess the degree to which 61 OA studies complied with pragmatic trial design and reporting. We assessed design according to the pragmatic–explanatory continuum indicator summary and reporting according to the pragmatic trials extension of the CONsolidated Standards of Reporting Trials guidelines. Results. None of the pragmatic trials met all 11 criteria evaluated and most of the trials met between 5 and 8 of the criteria. Criteria most often unmet pertained to practitioner expertise (by requiring specialists) and criteria most often met pertained to primary outcome analysis (by using intention-to-treat analysis). Conclusion. Our results suggest a lack of highly pragmatic trials in OA research. We identify this as a point of opportunity to improve research translation, since optimizing the design and reporting of pragmatic trials can facilitate implementation of evidence-based interventions for OA care

Generalized Uncertainty Principle, Modified Dispersion Relation and Barrier penetration by a Dirac particle

We have studied the energy band structure of a Dirac particle in presence of a generalised uncertainty principle (GUP). We start from defining a modified momentum operator and derive corresponding modified dispersion relation (MDR) and GUP. Apart from the forbidden band within the range $\pm m$, $m$ being the mass of the particle, we find the existence of additional forbidden bands at the both ends of the spectrum. Such band structure forbids a Dirac particle to penetrate a potential step of sufficient height ($\sim E_P$, $E_P$ being Planck energy). This is also true for massless particle. Unlike the relativistic case, a massless particle also can reflect from a barrier of sufficient height. Finally we discuss about the Klein's paradox in presence of the GUP.Comment: 10 pages, 7 figures, LaTe

Smolyak's algorithm: A powerful black box for the acceleration of scientific computations

We provide a general discussion of Smolyak's algorithm for the acceleration of scientific computations. The algorithm first appeared in Smolyak's work on multidimensional integration and interpolation. Since then, it has been generalized in multiple directions and has been associated with the keywords: sparse grids, hyperbolic cross approximation, combination technique, and multilevel methods. Variants of Smolyak's algorithm have been employed in the computation of high-dimensional integrals in finance, chemistry, and physics, in the numerical solution of partial and stochastic differential equations, and in uncertainty quantification. Motivated by this broad and ever-increasing range of applications, we describe a general framework that summarizes fundamental results and assumptions in a concise application-independent manner

Rapid diagnostic tests for molecular surveillance of Plasmodium falciparum malaria -assessment of DNA extraction methods and field applicability

Background: The need for new malaria surveillance tools and strategies is critical, given improved global malaria control and regional elimination efforts. High quality Plasmodium falciparum DNA can reliably be extracted from malaria rapid diagnostic tests (RDTs). Together with highly sensitive molecular assays, wide scale collection of used RDTs may serve as a modern tool for improved malaria case detection and drug resistance surveillance. However, comparative studies of DNA extraction efficiency from RDTs and the field applicability are lacking. The aim of this study was to compare and evaluate different methods of DNA extraction from RDTs and to test the field applicability for the purpose of molecular epidemiological investigations. Methods: DNA was extracted from two RDT devices (Paracheck-PfW and SD Bioline Malaria Pf/Pan (R)), seeded in vitro with 10-fold dilutions of cultured 3D7 P. falciparum parasites diluted in malaria negative whole blood. The level of P. falciparum detection was determined for each extraction method and RDT device with multiple nested-PCR and real-time PCR assays. The field applicability was tested on 855 paired RDT (Paracheck-Pf) and filter paper (Whatman (R) 3MM) blood samples (734 RDT negative and 121 RDT positive samples) collected from febrile patients in Zanzibar 2010. RDT positive samples were genotyped at four key single nucleotide polymorphisms (SNPs) in pfmdr1 and pfcrt as well as for pfmdr1 copy number, all associated with anti-malarial drug resistance. Results: The P. falciparum DNA detection limit varied with RDT device and extraction method. Chelex-100 extraction performed best for all extraction matrixes. There was no statistically significant difference in PCR detection rates in DNA extracted from RDTs and filter paper field samples. Similarly there were no significant differences in the PCR success rates and genotyping outcomes for the respective SNPs in the 121 RDT positive samples. Conclusions: The results support RDTs as a valuable source of parasite DNA and provide evidence for RDT-DNA extraction for improved malaria case detection, molecular drug resistance surveillance, and RDT quality control.ACT Consortium through Bill and Melinda Gates Foundation; Swedish International Development Agency (SIDA) [SWE 2009-193]; Swedish Civil Contingencies Agency (MSB) [2010-7991]; Swedish Medical Research Council (VR) [2009-3785]; Goljes Foundationinfo:eu-repo/semantics/publishedVersio

A systematic review of variables used to assess clinically acceptable alignment of unilateral transtibial amputees in the literature.

Prosthetic alignment is a subjective concept which lacks reliability. The outcome responsiveness to prosthetic alignment quality could help to improve subjective and instrument assisted prosthetic alignment. This study was aimed to review variables used to assess clinically acceptable alignment in the literature. The search was done in some databases including: Google Scholar, PubMed, EBSCO, EMBASE, ISI Web of Knowledge and Scopus. The first selection criterion was based on abstracts and titles to address the research questions of interest. The American Academy of Orthotics and Prosthetics checklists were used for paper risk of bias assessment. A total of 25 studies were included in this study. Twenty-four studies revealed the critics of standing position or walking to locate clinically acceptable alignment, only one study measured outcomes in both situations. A total of 253 adults with transtibial amputations and mean age of 48.71 years participated in included studies. The confidence level of included studies was low to moderate, and before-after trial was the most common study design (n = 19). The joint angle, load line location with respect to joints and center of pressure-related parameters were reported as sensitive outcomes to prosthetic alignment quality in standing posture. The amount of forces at various parts of gait cycle and time of events were sensitive to prosthetic alignment quality during walking. Standing balance and posture and temporal parameters of walking could help to locate clinically acceptable alignment.N/