Low-interference sensing electronics for high-resolution error-correcting biomechanical ground reaction sensor cluster

Journal ArticleAbstract- This paper presents a low-interference and low -power sensing electronics design for a high-resolution errorcorrecting biomechanical ground reaction sensor cluster (GRSC) developed for improving inertial measurement unit (IMU) positioning resolution and accuracy. The GRSC is composed of 13 x 13 sensing nodes, which can measure dynamic ground forces, shear strains, and sole deformation associated with a ground locomotion gait. The integrated sensing electronics consist of a front-end multiplexer that can sequentially connect individual sensing nodes in a GRSC to a capacitance-to-voltage converter followed by an ADC, digital control unit, and driving circuitry to interrogate the GRSC. The sensing electronics are designed in a 0.15 μm CMOS process and occupy an area of approximately 3 mm2 with an expected resolution of 10-bits and 14-bits for the z-axis pressure sensing and the x and y-axes shear strain sensing, respectively, while dissipating a DC power less than 2 mW from a 3V supply

Lymph node ratio is an important and independent prognostic factor for patients with stage III melanoma

INTRODUCTION: The incidence of melanoma is dramatically increasing worldwide. We hypothesized that the ratio of metastatic to examined lymph node ratio (LNR) would be the most important prognostic factor for stage III patients. METHODS: We retrospectively reviewed our institutional database of melanoma patients and identified 168 patients who underwent lymph node dissection (LND) for stage III disease between 1993 and 2007. Patients were divided into three groups based on LNR (≤10%, n = 93; 10-≤25%, n = 45; and \u3e25%, n = 30). Univariate and multivariate analysis was performed using Cox proportional hazards model. RESULTS: The median survival time of the entire group of patients was 34 months. The median number of positive nodes was 2 (range = 1, 55), and the median number of examined nodes was 22 (range = 5-123). Tumor characteristics of the primary melanoma (such as thickness, ulceration, and primary site) were not significant predictors of survival in this analysis. By univariate analysis, LNR was an important prognostic factor. Patients with LNR 10-25% and \u3e25% had decreased survival compared to those patients with LNR ≤10% (HR = hazard ratio = 2.0 and 3.1, respectively; P ≤ 0.005). The number of positive lymph nodes also impacted on survival (P = 0.001). In multivariate analysis, LNR of 10-25% and \u3e25% predicted survival (HR = 2.5 and 4.0, respectively). CONCLUSION: LNR is an important prognostic factor in patients undergoing LND for stage III melanoma. It can be used to stratify patients being considered for adjuvant therapy trials and should be evaluated using a larger prospective database

SIRT6 protects against endothelial dysfunction and atherosclerosis in mice

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In vitro migration of cytotoxic T lymphocyte derived from a colon carcinoma patient is dependent on CCL2 and CCR2

BACKGROUND: Infiltration of colorectal carcinomas (CRC) with T-cells has been associated with good prognosis. There are some indications that chemokines could be involved in T-cell infiltration of tumors. Selective modulation of chemokine activity at the tumor site could attract immune cells resulting in tumor growth inhibition. In mouse tumor model systems, gene therapy with chemokines or administration of antibody (Ab)-chemokine fusion proteins have provided potent immune mediated tumor rejection which was mediated by infiltrating T cells at the tumor site. To develop such immunotherapeutic strategies for cancer patients, one must identify chemokines and their receptors involved in T-cell migration toward tumor cells. METHODS: To identify chemokine and chemokine receptors involved in T-cell migration toward CRC cells, we have used our previously published three-dimensional organotypic CRC culture system. Organotypic culture was initiated with a layer of fetal fibroblast cells mixed with collagen matrix in a 24 well tissue culture plate. A layer of CRC cells was placed on top of the fibroblast-collagen layer which was followed by a separating layer of fibroblasts in collagen matrix. Anti-CRC specific cytotoxic T lymphocytes (CTLs) mixed with fibroblasts in collagen matrix were placed on top of the separating layer. Excess chemokine ligand (CCL) or Abs to chemokine or chemokine receptor (CCR) were used in migration inhibition assays to identify the chemokine and the receptor involved in CTL migration. RESULTS: Inclusion of excess CCL2 in T-cell layer or Ab to CCL2 in separating layer of collagen fibroblasts blocked the migration of CTLs toward tumor cells and in turn significantly inhibited tumor cell apoptosis. Also, Ab to CCR2 in the separating layer of collagen and fibroblasts blocked the migration of CTLs toward tumor cells and subsequently inhibited tumor cell apoptosis. Expression of CCR2 in four additional CRC patients\u27 lymphocytes isolated from infiltrating tumor tissues suggests their role in migration in other CRC patients. CONCLUSIONS: Our data suggest that CCL2 secreted by tumor cells and CCR2 receptors on CTLs are involved in migration of CTLs towards tumor. Gene therapy of tumor cells with CCL2 or CCL2/anti-tumor Ab fusion proteins may attract CTLs that potentially could inhibit tumor growth

Personal Navigation via High-Resolution Gait-Corrected Inertial Measurement Units

In this paper, a personal micronavigation system that uses high-resolution gait-corrected inertial measurement units is presented. The goal of this paper is to develop a navigation system that uses secondary inertial variables, such as velocity, to enable long-term precise navigation in the absence of Global Positioning System (GPS) and beacon signals. In this scheme, measured zerovelocity duration from the ground reaction sensors is used to reset the accumulated integration errors from accelerometers and gyroscopes in position calculation. With the described system, an average position error of 4 m is achieved at the end of half-hour walks

Personal Navigation via High-Resolution Gait-Corrected Inertial Measurement Units

In this paper, a personal micronavigation system that uses high-resolution gait-corrected inertial measurement units is presented. The goal of this paper is to develop a navigation system that uses secondary inertial variables, such as velocity, to enable long-term precise navigation in the absence of Global Positioning System (GPS) and beacon signals. In this scheme, measured zerovelocity duration from the ground reaction sensors is used to reset the accumulated integration errors from accelerometers and gyroscopes in position calculation. With the described system, an average position error of 4 m is achieved at the end of half-hour walks

Tumor-derived interleukin-10 as a prognostic factor in stage III patients undergoing adjuvant treatment with an autologous melanoma cell vaccine.

OBJECTIVES: Interleukin-10 (IL-10) downregulates T-cell-mediated immune responses. We studied the association between IL-10 production by freshly isolated melanoma cell suspensions in vitro and overall survival in patients undergoing adjuvant treatment with a vaccine prepared from the same autologous melanoma cells modified with a hapten, dinitrophenyl (DNP). METHODS: Forty-four patients with cutaneous melanoma (29 stage III and 15 stage IV) were prospectively evaluated. Tumor cells were extracted from metastatic deposits for production of DNP-modified autologous melanoma cell vaccine. Small aliquots of the melanoma cell suspensions were separated prior to vaccine processing and cultured overnight for IL-10 production. Based on a blind assessment of the distribution of IL-10 levels in the culture supernatants, a cutoff of 200 pg/ml was used to define high versus low IL-10 producers. Cox regression model was used for multivariate analysis. Overall survival was calculated using the Kaplan-Meier method, and survival curves were compared with the log-rank test. RESULTS: Out of 44 patients, 29 were low and 15 were high IL-10 producers. The median OS was significantly worse for high compared with low IL-10 producers (10.5 months vs. 42 months; P = 0.022). In stage III patients, the multivariate hazard ratio for high versus low IL-10 producers was 2.92 (95% CI, 1.04-8.20; P = 0.041). The corresponding hazard ratio in stage IV patients was 0.92 (95% CI, 1.04-8.20; P = 0.888). CONCLUSIONS: High IL-10 production in the tumor microenvironment could be a determinant of clinical outcomes in stage III melanoma patients receiving autologous melanoma cell vaccine

A Phase I Study of Ad5-GUCY2C-PADRE in Stage I and II Colon Cancer Patients

Background Ad5-GUCY2C-PADRE is a replication-deficient human type 5 recombinant adenovirus (Ad5) vaccine encoding guanylyl cyclase C (GUCY2C) fused to the PAn DR Epitope (PADRE). GUCY2C, a paracrine hormone receptor producing the second messenger cyclic GMP (cGMP), is selectively expressed by intestinal epithelial cells and a subset of hypothalamic neurons, but not other tissues. Importantly, GUCY2C is over-expressed in nearly all primary and metastatic human colorectal tumors. Preclinical studies in mice demonstrated selective tolerance of GUCY2C-specific CD4+ T cells, but not CD8+ T or B cells, necessitating inclusion of the exogenous CD4+ T helper cell epitope PADRE to maximize GUCY2C-specific CD8+ T-cell and antibody responses and antitumor efficacy, without autoimmunity. Patients and Methods This is an open-label, single arm “proof-of-concept” study evaluating a single dose level of Ad5-GUCY2C-PADRE as a vaccine for surgically-treated, node-negative colon cancer subjects (NCT01972737). Patients received a single intramuscular administration of 1011 Ad5-GUCY2C-PADRE viral particles. Safety and immunomonitoring were examined at 30, 90 and 180 days following vaccination. Primary objectives were to determine the safety, tolerability, and toxicity of Ad5-GUCY2C-PADRE and to determine whether Ad5- GUCY2C-PADRE induces GUCY2C-specific immune responses. The study employed a joint efficacy-toxicity design and included stopping rules for either efficacy or toxicity.Results here were obtained during the planned interim analysis following accrual of 10 subjects. Results The vaccine was well tolerated, producing only mild adverse events (AEs). Short-lived injection site pain/swelling, body aches, and chills were the most commonly observed AEs and occurred in 30-40% of subjects. GUCY2C-specific antibody and T-cell responses were observed in a subset of subjects. Consistent with preclinical mouse data, T-cell responses were composed of CD8+, but not CD4+, T cells. Importantly, GUCY2C-specific responses occurred only in subjects with low Ad5 neutralizing antibody (NAb) titers at the time of vaccination, suggesting that pre-existing Ad5 immunity limits Ad5-GUCY2C-PADRE immunogenicity. Conclusions Interim analysis of 10 subjects receiving Ad5-GUCY2C-PADRE demonstrates proof-of-concept that GUCY2C is immunogenic in humans and that GUCY2C-directed vaccination is safe. Moreover, the presence of GUCY2C-specific antibody and CD8+ T-cell, but not CD4+ T-cell, responses is consistent with selective CD4+ T-cell tolerance observed in mouse models. These data establish GUCY2C as a safe and immunogenic target for immunotherapy in cancer patients. Poster presented at: Immunotherapy of Cancer (SITC) 30th Annual Meeting in National Harbor Maryland.https://jdc.jefferson.edu/petposters/1001/thumbnail.jp