Therapeutic limitations in tumor-specific CD8+ memory T cell engraftment

BACKGROUND: Adoptive immunotherapy with cytotoxic T lymphocytes (CTL) represents an alternative approach to treating solid tumors. Ideally, this would confer long-term protection against tumor. We previously demonstrated that in vitro-generated tumor-specific CTL from the ovalbumin (OVA)-specific OT-I T cell receptor transgenic mouse persisted long after adoptive transfer as memory T cells. When recipient mice were challenged with the OVA-expressing E.G7 thymoma, tumor growth was delayed and sometimes prevented. The reasons for therapeutic failures were not clear. METHODS: OT-I CTL were adoptively transferred to C57BL/6 mice 21 – 28 days prior to tumor challenge. At this time, the donor cells had the phenotypical and functional characteristics of memory CD8+ T cells. Recipients which developed tumor despite adoptive immunotherapy were analyzed to evaluate the reason(s) for therapeutic failure. RESULTS: Dose-response studies demonstrated that the degree of tumor protection was directly proportional to the number of OT-I CTL adoptively transferred. At a low dose of OT-I CTL, therapeutic failure was attributed to insufficient numbers of OT-I T cells that persisted in vivo, rather than mechanisms that actively suppressed or anergized the OT-I T cells. In recipients of high numbers of OT-I CTL, the E.G7 tumor that developed was shown to be resistant to fresh OT-I CTL when examined ex vivo. Furthermore, these same tumor cells no longer secreted a detectable level of OVA. In this case, resistance to immunotherapy was secondary to selection of clones of E.G7 that expressed a lower level of tumor antigen. CONCLUSIONS: Memory engraftment with tumor-specific CTL provides long-term protection against tumor. However, there are several limitations to this immunotherapeutic strategy, especially when targeting a single antigen. This study illustrates the importance of administering large numbers of effectors to engraft sufficiently efficacious immunologic memory. It also demonstrates the importance of targeting several antigens when developing vaccine strategies for cancer

Neither MRI, CT nor US is superior to diagnose tumors in the salivary glands – an extended case study

OBJECTIVES: Ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI) are the most common radiological procedures for the diagnosis of tumor-like lesions of the salivary glands. The aim of the present study was to determine whether MRI or CT provide additional information besides that delivered by US. STUDY DESIGN/METHODS: 109 patients with a tumor-like lesion of the salivary glands underwent surgery. MRI and CT were arranged in 73 and in 40 patients respectively, whereas all 109 patients were prospectively diagnosed by US. The results of CT, MRI and US were compared with the histological outcome. Furthermore, the recent rise in the number of CT and MRI studies was investigated. RESULTS: On CT and MRI, there was no rise in the percentage of malignant tumors or advanced surgical procedures. In respect of the radiological assessment of the lesion (benign/malignant) and the correct diagnosis, CT, MRI and US were comparable in terms of sensitivity, specificity and accuracy. No significant difference was found in the Chi-square test (p > 0.05). CONCLUSION: The evaluation of the preoperative results of CT, MRI and US revealed no advantage for CT or MRI; these procedures are only required in specific cases. An update or revision of the current preoperative diagnostic management is deemed necessary

Resident interest and factors involved in entering a pediatric pulmonary fellowship

BACKGROUND: Relatively little is known about interest in pediatric pulmonology among pediatric residents. The purpose of this study, therefore, was to determine at this institution: 1) the level of pediatric resident interest in pursuing a pulmonary fellowship, 2) potential factors involved in development of such interest, 3) whether the presence of a pulmonary fellowship program affects such interest. METHODS: A questionnaire was distributed to all 52 pediatric residents at this institution in 1992 and to all 59 pediatric residents and 14 combined internal medicine/pediatrics residents in 2002, following development of a pulmonary fellowship program. RESULTS: Response rates were 79% in 1992 and 86% in 2002. Eight of the 43 responders in 1992 (19%) had considered doing a pulmonary fellowship compared to 7 of 63 (11%) in 2002. The highest ranked factors given by the residents who had considered a fellowship included wanting to continue one's education after residency, enjoying caring for pulmonary patients, and liking pulmonary physiology and the pulmonary faculty. Major factors listed by residents who had not considered a pulmonary fellowship included not enjoying the tracheostomy/ventilator population and chronic pulmonary patients in general, and a desire to enter general pediatrics or another fellowship. Most residents during both survey periods believed that they would be in non-academic or academic general pediatrics in 5 years. Only 1 of the 106 responding residents (~1%) anticipated becoming a pediatric pulmonologist. CONCLUSIONS: Although many pediatric residents consider enrolling in a pulmonary fellowship (~10–20% here), few (~1% here) will actually pursue a career in pediatric pulmonology. The presence of a pulmonary fellowship program did not significantly alter resident interest, though other confounding factors may be involved

Role of endogenous and exogenous female sex hormones in arthritis and osteoporosis development in B10.Q-ncf1*/* mice with collagen-induced chronic arthritis

<p>Abstract</p> <p>Background</p> <p>Collagen-induced arthritis (CIA) is an often-used murine model for human rheumatoid arthritis (RA). Earlier studies have shown potent anti-arthritic effects with the female sex hormone estradiol and the selective estrogen receptor modulator (SERM) raloxifene in CIA in DBA/1-mice. B10.Q-ncf1^*/*mice are B10.Q mice with a mutated Ncf1 gene. In B10.Q-ncf1^*/*mice, CIA develops as a chronic relapsing disease, which more accurately mimics human RA. We investigated the role of endogenous and exogenous sex steroids and raloxifene in the course of this model of chronic arthritis. We also examined whether treatment would prevent the development of inflammation-triggered generalized osteoporosis.</p> <p>Methods</p> <p>Female B10.Q-ncf1^*/*mice were sham-operated or ovariectomized, and CIA was induced. 22 days later, when 30% of the mice had developed arthritis, treatment with raloxifene, estradiol or vehicle was started, and the clinical disease was evaluated continuously. Treatment was continued until day 56 after immunization. At termination of the experiment (day 73), bone mineral density (BMD) was analyzed, paws were collected for histological examination, and sera were analyzed for markers of cartilage turnover and pro-inflammatory cytokines.</p> <p>Results</p> <p>Raloxifene and estradiol treatment, as well as endogenous estrogen, decreased the frequency of arthritis, prevented joint destruction and countered generalized osteoporosis. These effects were associated with lower serum levels of the pro-inflammatory cytokine IL-6.</p> <p>Conclusions</p> <p>This is the first study to show that raloxifene and estradiol can ameliorate established erosive arthritis and inflammation-triggered osteoporosis in this chronic arthritis model. We propose that treatment with raloxifene could be a beneficial addition to the treatment of postmenopausal RA.</p

The perception of disability by community groups: Stories of local understanding, beliefs and challenges in a rural part of Kenya

Cultural narratives on disability have received much attention over the past few decades. In contexts of poverty, limited information and everyday challenges associated with having, or caring for someone with a disability, different understandings have emerged. A project was set up to promote disability awareness in neighborhood communities in a rural part of Kenya, using a process of reflection and education. This paper reports on the first aspect–reflection. The aim was to investigate local understanding of disability as a co-constructed concept. The research questions were: 1. What cultural beliefs shape local understanding of disability? 2. What challenges are perceived to be associated with disability? A phenomenological approach was adopted. Focus group discussions were conducted with twenty-one community groups involving 263 participants and audio-recorded. The data were transcribed and thematic analysis was carried out. Visual maps were created to illustrate any interconnections, before establishing the final conclusions. Local beliefs attributed disability to: human transgression of social conventions, particularly concerning inappropriate family relations, which invoked a curse; supernatural forces affecting the child; the will of God; unexplained events; and biomedical factors. Challenges associated with disability related to the burden of caregiving and perceived barriers to inclusion, with stress as a shared bi-product. Local understanding of disability in this rural part of Kenya demonstrated overlapping explanations and plurality of beliefs. Two possible interpretations are offered. Firstly, oscillation between explanatory lines demonstrated instability, affecting broader acceptance of disability. Secondly, and more positively, in the face of challenges, the desire to make sense of the existing situation, reflected a healthy pluralism

A pharmacy too far? Equity and spatial distribution of outcomes in the delivery of subsidized artemisinin-based combination therapies through private drug shops

BACKGROUND: Millions of individuals with malaria-like fevers purchase drugs from private retailers, but artemisinin-based combination therapies (ACTs), the only effective treatment in regions with high levels of resistance to older drugs, are rarely obtained through these outlets due to their relatively high cost. To encourage scale up of ACTs, the Affordable Medicines Facility--malaria is being launched to subsidize their price. The Government of Tanzania and the Clinton Foundation piloted this subsidized distribution model in two Tanzanian districts to examine concerns about whether the intervention will successfully reach poor, rural communities. METHODS: Stocking of ACTs and other antimalarial drugs in all retail shops was observed at baseline and in four subsequent surveys over 15 months. Exit interviews were conducted with antimalarial drug customers during each survey period. All shops and facilities were georeferenced, and variables related to population density and proximity to distribution hubs, roads, and other facilities were calculated. To understand the equity of impact, shops stocking ACTs and consumers buying them were compared to those that did not, according to geographic and socioeconomic variables. Patterning in ACT stocking and sales was evaluated against that of other common antimalarials to identify factors that may have impacted access. Qualitative data were used to assess motivations underlying stocking, distribution, and buying disparities. RESULTS: Results indicated that although total ACT purchases rose from negligible levels to nearly half of total antimalarial sales over the course of the pilot, considerable geographic variation in stocking and sales persisted and was related to a variety of socio-spatial factors; ACTs were stocked more often in shops located closer to district towns (p<0.01) and major roads (p<0.01) and frequented by individuals of higher socioeconomic status (p<0.01). However, other antimalarial drugs displayed similar patterning, indicating the existence of underlying disparities in access to antimalarial drugs in general in these districts. CONCLUSIONS: As this subsidy model is scaled up across multiple countries, these results confirm the potential for increased ACT usage but suggest that additional efforts to increase access in remote areas will be needed for the scale-up to have equitable impact. TRIAL REGISTRATION: Current Controlled Trials ISRCTN39125414

Soil Contamination Interpretation by the Use of Monitoring Data Analysis

The presented study deals with the interpretation of soil quality monitoring data using hierarchical cluster analysis (HCA) and principal components analysis (PCA). Both statistical methods contributed to the correct data classification and projection of the surface (0–20 cm) and subsurface (20–40 cm) soil layers of 36 sampling sites in the region of Burgas, Bulgaria. Clustering of the variables led to formation of four significant clusters corresponding to possible sources defining the soil quality like agricultural activity, industrial impact, fertilizing, etc. Two major clusters were found to explain the sampling site locations according to soil composition—one cluster for coastal and mountain sites and another—for typical rural and industrial sites. Analogous results were obtained by the use of PCA. The advantage of the latter was the opportunity to offer more quantitative interpretation of the role of identified soil quality sources by the level of explained total variance. The score plots and the dendrogram of the sampling sites indicated a relative spatial homogeneity according to geographical location and soil layer depth. The high-risk areas and pollution profiles were detected and visualized using surface maps based on Kriging algorithm

Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review.

PURPOSE.—:Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from the American Society of Clinical Oncology and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research. METHODS.—:An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including preanalytical variables, analytical validity, interpretation and reporting, and clinical validity and utility. RESULTS.—:The literature search identified 1338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion. CONCLUSIONS.—:The evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer. Evidence shows discordance between the results of ctDNA assays and genotyping tumor specimens, and supports tumor tissue genotyping to confirm undetected results from ctDNA tests. There is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection. There is no evidence of clinical validity or clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial. Given the rapid pace of research, reevaluation of the literature will shortly be required, along with the development of tools and guidance for clinical practice

The role of insulin therapy and glucose normalisation in patients with acute coronary syndrome

Patients with acute myocardial infarction (AMI) and diabetes mellitus, as well as patients admitted with elevated blood glucose without known diabetes, have impaired outcome. Therefore intensive glucose-lowering therapy with insulin (IGL) has been proposed in diabetic or hyperglycaemic patients and has been shown to improve survival and reduce incidence of adverse events. The current manuscript provides an overview of randomised controlled trials investigating the effect of IGL. Furthermore, systematic glucose–insulin–potassium infusion (GIK) has been studied to improve outcome after AMI. In spite of positive findings in some early studies, GIK did not show any beneficial effects in recent clinical trials and thus this concept has been abandoned. While IGL targeted to achieve normoglycaemia improves outcome in patients with AMI, achievement of glucose regulation is difficult and carries the risk of hypoglycaemia. More research is needed to determine the optimal glucose target levels in AMI and to investigate whether computerised glucose protocols and continuous glucose sensors can improve safety and efficacy of IGL

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal