Comparison of CD3 and CD8 immunoscoring with histological grade of the tumor in urothelial carcinoma of bladder

Background: Inflammatory response within transitional cell carcinoma (TCC) bladder is known to be predictive of tumor prognosis. Lower scores are associated with worser outcome and vice versa. Simpler and cost-effective methods of immunoscoring using immunohistochemistry (IHC) have been described. This study uses two easily available T-cell markers CD3 and CD8 and compares their immunoscore with tumor grade and understands the association. Aims and Objectives: The aims of this study were as follows: (1) To perform immunoscoring for cytotoxic T lymphocytes -CD3+ and CD8+ lymphocytes in urothelial carcinoma and (2) to correlate the immunoscore with tumor grade and calculate its significance in predicting prognosis. Materials and Methods: A prospective cross-sectional study of 2 years duration from October 2018 to October 2020 was conducted at a tertiary level super specialty government institution. All the transurethral resection of bladder tissue biopsies reported as urothelial malignancies during the study period were included in the research. The tumors were graded histologically into high grade and low grade on histology based on the World Health Organization 2016 classification of Urothelial Carcinomas/International Society of Urological Pathology grading system. They were then subject to IHC with two T-cell markers CD3 and CD8 and immunoscoring was done using the method described by Galon. Results: A total of 42 cases of urothelial malignancies were diagnosed during the study period. Cases with higher tumor grade were 25 and lower tumor grade were 17. The association between the lower immunoscore and higher tumor grade was statistically significant. Conclusion: Immunoscoring is a useful adjunct to the routine histological evaluation of TCC. Easily available T-cell markers can be used as simple easy and cost-effective method for immunoscoring

An optimized TOPS+ comparison method for enhanced TOPS models

This article has been made available through the Brunel Open Access Publishing Fund.Background Although methods based on highly abstract descriptions of protein structures, such as VAST and TOPS, can perform very fast protein structure comparison, the results can lack a high degree of biological significance. Previously we have discussed the basic mechanisms of our novel method for structure comparison based on our TOPS+ model (Topological descriptions of Protein Structures Enhanced with Ligand Information). In this paper we show how these results can be significantly improved using parameter optimization, and we call the resulting optimised TOPS+ method as advanced TOPS+ comparison method i.e. advTOPS+. Results We have developed a TOPS+ string model as an improvement to the TOPS [1-3] graph model by considering loops as secondary structure elements (SSEs) in addition to helices and strands, representing ligands as first class objects, and describing interactions between SSEs, and SSEs and ligands, by incoming and outgoing arcs, annotating SSEs with the interaction direction and type. Benchmarking results of an all-against-all pairwise comparison using a large dataset of 2,620 non-redundant structures from the PDB40 dataset [4] demonstrate the biological significance, in terms of SCOP classification at the superfamily level, of our TOPS+ comparison method. Conclusions Our advanced TOPS+ comparison shows better performance on the PDB40 dataset [4] compared to our basic TOPS+ method, giving 90 percent accuracy for SCOP alpha+beta; a 6 percent increase in accuracy compared to the TOPS and basic TOPS+ methods. It also outperforms the TOPS, basic TOPS+ and SSAP comparison methods on the Chew-Kedem dataset [5], achieving 98 percent accuracy. Software Availability: The TOPS+ comparison server is available at http://balabio.dcs.gla.ac.uk/mallika/WebTOPS/.This article is available through the Brunel Open Access Publishing Fun

Lessons from the Pacific programme to eliminate lymphatic filariasis: a case study of 5 countries

Lymphatic Filariasis (LF) is an important Neglected Tropical Disease, being a major cause of disability worldwide. The Global Programme to Eliminate Lymphatic Filariasis aims to eliminate LF as a public health problem by the year 2020, primarily through repeated Mass Drug Administration (MDA). The Pacific region programme commenced in 1999. By June 2007, five of the eleven countries classified as endemic had completed five MDA campaigns and post-MDA prevalence surveys to assess their progress. We review available programme data and discuss their implications for other LF elimination programs in developing countries. Reported MDA coverage and results from initial surveys and post-MDA surveys of LF using the immunochromatographic test (ICT) from these five Pacific Island countries (Tonga, Niue, Vanuatu, Samoa and Cook Islands) were analysed to provide an understanding of their quality and programme progress towards LF elimination. Denominator data reported by each country programme for 2001 was compared to official sources to assess the accuracy of MDA coverage data. Initial survey results from these five countries revealed an ICT prevalence of between 2.7 and 8.6 percent in individuals tested prior to commencement of the programme. Country MDA coverage results varied depending on the source of denominator data. Of the five countries in this case study, three countries (Tonga, Niue and Vanuatu) reached the target prevalence of <1% antigenaemia following five rounds of MDA. However, endpoint data could not be reliably compared to baseline data as survey methodology varied. It was concluded that accurate and representative baseline and post-campaign prevalence data is crucial for determining program effectiveness and the factors contributing to effectiveness. This is emphasised by the findings of this case study. While three of the five Pacific countries reported achieving the target prevalence of <1% antigenaemia, limitations in the data preclude identification of key determinants of this achievement

Diverging Mechanisms of Activation of Chemokine Receptors Revealed by Novel Chemokine Agonists

CXCL8/interleukin-8 is a pro-inflammatory chemokine that triggers pleiotropic responses, including inflammation, angiogenesis, wound healing and tumorigenesis. We engineered the first selective CXCR1 agonists on the basis of residue substitutions in the conserved ELR triad and CXC motif of CXCL8. Our data reveal that the molecular mechanisms of activation of CXCR1 and CXCR2 are distinct: the N-loop of CXCL8 is the major determinant for CXCR1 activation, whereas the N-terminus of CXCL8 (ELR and CXC) is essential for CXCR2 activation. We also found that activation of CXCR1 cross-desensitized CXCR2 responses in human neutrophils co-expressing both receptors, indicating that these novel CXCR1 agonists represent a new class of anti-inflammatory agents. Further, these selective CXCR1 agonists will aid at elucidating the functional significance of CXCR1 in vivo under pathophysiological conditions

Investigation and Mechanical Modelling of Pure Molybdenum at High Strain-Rate and Temperature

This work shows the results obtained from the investigation of the mechanical behavior of two batches of pure molybdenum specimens (≥99.97 % Mo, Mo1 supplied by Plansee and Mo2 supplied by AT&M) under static and dynamic loading conditions at different temperatures, both under tensile and compressive loading conditions. Due to its properties molybdenum has applications in several fields including nuclear. At this moment, it is a good candidate for structural material application for Beam Intercepting Devices of the Large Hadron Collider at CERN, Geneva. The experimental tests in tensile loading condition were performed on small dog-bone specimens. A series of tests at room temperature and a range of strain-rates was performed in order to obtain information about the strain-rate sensitivity of the material. A series of tests at different temperatures in both static and high dynamic loading conditions was performed in order to obtain information about the thermal softening of the material. The dynamic tests were performed using the Hopkinson Bar technique, and the heating of the specimen was performed using an induction coil system. The experimental tests in compression were carried out on cylindrical specimens at room temperature and a range of strain-rates. The experimental data were analyzed via a numerical inverse method based on Finite Element numerical simulations. This approach allows to obtain the effective stress versus strain curves, which cannot be derived by using standard relations since instability and necking were present. Moreover, it also allows the non-uniform distribution of strain-rate and temperature inside the specimen to be accounted for. The results obtained from compression tests confirm the data obtained in tension in terms of strain-hardening and strain-rate sensitivity, even if the material exhibits a tension–compression asymmetry of the behavior. The analysis of the hardening, temperature and strain-rate sensitivities reveals that a unique standard visco-plastic model could not be defined to reproduce the material strength behavior under different loading conditions, especially over wide range of variation of the variables of interest

Multi-agent modeling of the South Korean avian influenza epidemic

<p>Abstract</p> <p>Background</p> <p>Several highly pathogenic avian influenza (AI) outbreaks have been reported over the past decade. South Korea recently faced AI outbreaks whose economic impact was estimated to be 6.3 billion dollars, equivalent to nearly 50% of the profit generated by the poultry-related industries in 2008. In addition, AI is threatening to cause a human pandemic of potentially devastating proportions. Several studies show that a stochastic simulation model can be used to plan an efficient containment strategy on an emerging influenza. Efficient control of AI outbreaks based on such simulation studies could be an important strategy in minimizing its adverse economic and public health impacts.</p> <p>Methods</p> <p>We constructed a spatio-temporal multi-agent model of chickens and ducks in poultry farms in South Korea. The spatial domain, comprised of 76 (37.5 km × 37.5 km) unit squares, approximated the size and scale of South Korea. In this spatial domain, we introduced 3,039 poultry flocks (corresponding to 2,231 flocks of chickens and 808 flocks of ducks) whose spatial distribution was proportional to the number of birds in each province. The model parameterizes the properties and dynamic behaviors of birds in poultry farms and quarantine plans and included infection probability, incubation period, interactions among birds, and quarantine region.</p> <p>Results</p> <p>We conducted sensitivity analysis for the different parameters in the model. Our study shows that the quarantine plan with well-chosen values of parameters is critical for minimize loss of poultry flocks in an AI outbreak. Specifically, the aggressive culling plan of infected poultry farms over 18.75 km radius range is unlikely to be effective, resulting in higher fractions of unnecessarily culled poultry flocks and the weak culling plan is also unlikely to be effective, resulting in higher fractions of infected poultry flocks.</p> <p>Conclusions</p> <p>Our results show that a prepared response with targeted quarantine protocols would have a high probability of containing the disease. The containment plan with an aggressive culling plan is not necessarily efficient, causing a higher fraction of unnecessarily culled poultry farms. Instead, it is necessary to balance culling with other important factors involved in AI spreading. Better estimations for the containment of AI spreading with this model offer the potential to reduce the loss of poultry and minimize economic impact on the poultry industry.</p

Representing and comparing protein structures as paths in three-dimensional space

BACKGROUND: Most existing formulations of protein structure comparison are based on detailed atomic level descriptions of protein structures and bypass potential insights that arise from a higher-level abstraction. RESULTS: We propose a structure comparison approach based on a simplified representation of proteins that describes its three-dimensional path by local curvature along the generalized backbone of the polypeptide. We have implemented a dynamic programming procedure that aligns curvatures of proteins by optimizing a defined sum turning angle deviation measure. CONCLUSION: Although our procedure does not directly optimize global structural similarity as measured by RMSD, our benchmarking results indicate that it can surprisingly well recover the structural similarity defined by structure classification databases and traditional structure alignment programs. In addition, our program can recognize similarities between structures with extensive conformation changes that are beyond the ability of traditional structure alignment programs. We demonstrate the applications of procedure to several contexts of structure comparison. An implementation of our procedure, CURVE, is available as a public webserver

Doxorubicin loaded Polymeric Nanoparticulate Delivery System to overcome drug resistance in osteosarcoma

<p>Abstract</p> <p>Background</p> <p>Drug resistance is a primary hindrance for the efficiency of chemotherapy against osteosarcoma. Although chemotherapy has improved the prognosis of osteosarcoma patients dramatically after introduction of neo-adjuvant therapy in the early 1980's, the outcome has since reached plateau at approximately 70% for 5 year survival. The remaining 30% of the patients eventually develop resistance to multiple types of chemotherapy. In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) tumor cells, we explored the possibility of loading doxorubicin onto biocompatible, lipid-modified dextran-based polymeric nanoparticles and evaluated the efficacy.</p> <p>Methods</p> <p>Doxorubicin was loaded onto a lipid-modified dextran based polymeric nano-system. The effect of various concentrations of doxorubicin alone or nanoparticle loaded doxorubicin on KHOS, KHOS_R2, U-2OS, and U-2OS_R2cells was analyzed. Effects on drug retention, immunofluorescence, Pgp expression, and induction of apoptosis were also analyzed.</p> <p>Results</p> <p>Dextran nanoparticles loaded with doxorubicin had a curative effect on multidrug resistant osteosarcoma cell lines by increasing the amount of drug accumulation in the nucleus via Pgp independent pathway. Nanoparticles loaded with doxorubicin also showed increased apoptosis in osteosarcoma cells as compared with doxorubicin alone.</p> <p>Conclusion</p> <p>Lipid-modified dextran nanoparticles loaded with doxorubicin showed pronounced anti-proliferative effects against osteosarcoma cell lines. These findings may lead to new treatment options for MDR osteosarcoma.</p

A human in vitro model system for investigating genome-wide host responses to SARS coronavirus infection

10.1186/1471-2334-4-34BMC Infectious Diseases4-BIDM