TYMSTR, a putative chemokine receptor selectively expressed in activated T cells, exhibits HIV-1 coreceptor function

AbstractBackground: Chemokines bind to specific receptors and mediate leukocyte migration to sites of inflammation. Recently, some chemokine receptors, notably CXCR4 and CCR5, have been shown to be essential fusion factors on target cells for infection by human immunodeficiency virus (HIV); the chemokines bound by these receptors have also been shown to act as potent inhibitors of HIV infection. Here, we describe the isolation of a novel, putative chemokine receptor.Results: We have isolated the cDNA for a putative human chemokine receptor, which we have termed TYMSTR (T-lymphocyte-expressed seven-transmembrane domain receptor). The TYMSTR gene is localized to human chromosome 3 and encodes a protein that has a high level of identity with chemokine receptors. TYMSTR mRNA was selectively expressed in interleukin-2-stimulated T lymphocytes but not in freshly isolated lymphocytes and leukocytes or related cell lines. The natural ligand for TYMSTR was not identified among 32 human chemokines and other potential ligands. Cells co-expressing TYMSTR and human CD4 fused with cells expressing envelope glycoproteins of macrophage (M)-tropic HIV-1 as well as T-cell line (T)-tropic HIV-1 isolates. Addition of infectious, T-tropic HIV-1 particles to TYMSTR/CD4-expressing cells resulted in viral entry and proviral DNA formation.Conclusions: Our findings demonstrate that TYMSTR, in combination with CD4, mediates HIV-1 fusion and entry. The high-level expression of TYMSTR in CD4+ T lymphocytes and the selectivity of this receptor for T-tropic and M-tropic HIV-1 strains indicates that TYMSTR might function as HIV coreceptor at both early and late stages of infection

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

A unified approach for the prediction of vibration induced by underground metro

In this paper a methodological approach employing a mathematical model to evaluate the vibration level transmitted by railway traffic is proposed. The originality of the approach is related to the explicit coupling of a vibration generation model which is based on the dynamic interaction between the railway vehicle and the superstructure with a vibration propagation model that analyses the dynamic interaction between the railway superstructure and the underlying soil/structures. The vibration level provided by the prediction model has been compared with vibration measurements carried out on a test site located along Turin underground lin

Validity and Repeatability of the Sizestream 3D Scanner and Poikos Modeling System

Three-dimensional (3D) body scanning becomes increasingly important in the medical, ergonomical and apparel industry. The SizeStream 3D body scanner is a 3D body scanner in the shape of a fitting room that can generate a 3D copy of the human body in a few seconds. The Poikos modeling system generates a 3D image of a person using a front- and side photo. This study evaluates the repeatability and validity of both systems with human subjects. Hundred fifty-six participants were included in this study, of whom 85 were scanned twice by the SizeStream Scanner and 139 by the Poikos modeling system. The repeatability is assessed by calculating the intra-class correlation coefficients (ICC) and standard error of measurement (SEM), and the validity of 6 Sizestream and 4 Poikos measurements is evaluated by comparing these measurements with collected tape measurements. The ICC and the SEM results indicate that 79 of the 163 SizeStream measurements are repeatable enough to use for fashion purposes, since they had an ICC above 0.80 and a SEM below 10mm. Fifty-one measurements give a good indication but are not accurate enough for pattern making. The waist, chest and hip circumferences are valid after a correction of the over- or underestimation of the measurements. The Poikos modeling system is a promising, but is as expected, less repeatable and valid than the SizeStream scanner. Although the Poikos modeling system can give a good estimation of the body shape, the measurements are not accurate enough (SEM > 10mm) to use in the fashion industry. Future studies have to be performed to validate more Poikos and SizeStream measurements and to assess the usability of these measurements for the fashion industry

Increased Morbidity With Diagnosis and Treatment of Pulmonary Embolism After Total Joint Arthroplasty: A Matched Control Analysis of 30,000 Patients

Currently, the risks associated with the diagnosis of pulmonary embolism (PE) and subsequent treatment are not well known. The purpose of our study is to quantify the specific in-hospital complications and resource utilization of patients with PE following total joint arthroplasty when compared to a matched cohort. The Nationwide Inpatient Sample database was used to identify patients undergoing primary hip and knee arthroplasty from January 1993 to December 2008. PE was determined using International Classification of Diseases, Ninth Revision, Clinical Modification codes. In-hospital complications, costs, and length of stay for patients with PE were compared to patients without PE, matched on the basis of age, gender, procedure (total hip arthroplasty vs total knee arthroplasty), year of surgery, morbid obesity, and all 28 comorbid-defined elements of the Elixhauser Comorbidity Index. Of 8,634,038 procedures, 30,281 (0.4%) patients had a PE after total joint arthroplasty. In total, 29,917 (98%) were matched one-to-one with patients without PE. Patients with PE had a substantially higher risk of all postoperative in-hospital complications: deep vein thrombosis (odds ratio [OR] 17), peripheral vascular (OR 34), hematoma (OR 3.7), and gastrointestinal bleeding (OR 7.0) (all P < .001). Mortality was significantly higher in patients with PE compared to patients without PE (3.4% vs 0.1%, OR 30), along with total hospital costs, lengths of stay, and rates of discharge to rehabilitation facilities. After controlling for comorbidities patients with PE have a significantly higher risk for complications including in-hospital mortality and higher hospital costs when compared to patient without PE