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Auletta J.J.,Seidman Cancer Center | Auletta J.J.,Case Western Reserve University | Deans R.J.,Case Western Reserve University | Deans R.J.,Athersys, Inc. | Bartholomew A.M.,University of Illinois at Chicago
Blood | Year: 2012

Multipotent, bone marrow-derived stromal cells (BMSCs, also known as mesenchymal stem cells [MSCs]), are cultureexpanded, nonhematopoietic cells with immunomodulatory effects currently being investigated as novel cellular therapy to prevent and to treat clinical disease associated with aberrant immune response. Emerging preclinical studies suggest that BMSCs may protect against infectious challenge either by direct effects on the pathogen or through indirect effects on the host. BMSCs may reduce pathogen burden by inhibiting growth through soluble factors or by enhancing immune cell antimicrobial function. In the host, BMSCs may attenuate pro-inflammatory cytokine and chemokine induction, reduce pro-inflammatory cell migration into sites of injury and infection, and induce immunoregulatory soluble and cellular factors to preserve organ function. These preclinical studies provide provocative hints into the direction MSC therapeutics may take in the future. Notably, BMSCs appear to function as a critical fulcrum, providing balance by promoting pathogen clearance during the initial inflammatory response while suppressing inflammation to preserve host integrity and facilitate tissue repair. Such exquisite balance in BMSC function appears intrinsically linked to Toll-like receptor signaling and immune crosstalk. © 2012 by The American Society of Hematology. Source


Knobf M.T.,Yale University | Jeon S.,Yale University | Smith B.,Michigan State University | Harris L.,Seidman Cancer Center | And 4 more authors.
Breast Cancer Research and Treatment | Year: 2016

Bone loss is a significant clinical problem for female cancer survivors (FCS) and increases fracture risk. The aim of the Yale Fitness Intervention Trial (Yale FIT) was to determine the effects of a 12-month aerobic–resistance exercise intervention compared to a home-based physical activity group on bone outcomes [bone mineral density (BMD)] and biomarkers bone turnover). Early postmenopausal FCS (N = 154) were randomized to the exercise intervention (3 times/week) or to a home-based physical activity group. Calcium (1200 mg) and Vitamin D (400 IU) supplements were provided to both groups. BMD was measured at baseline and 12 months. No significant difference in BMD was observed for the exercise vs home-based group. However, subjects on Tamoxifen or no endocrine therapy did not significantly lose BMD, with the exception of the femoral neck (FN). In contrast subjects on aromatase inhibitors (AIs) had significant BMD loss at all sites. The majority of subjects had sufficient serum levels of Vitamin D (>20 ng/mL) but there was significantly less bone loss in subjects in the 20–29 ng/mL range at the LS (p = 0.01), hip (p = 0.03), and GT (p = 0.008) compared to lower or higher levels. Exercise stimulates bone remodeling but the intervention was not superior for BMD outcomes at one year. The dose of the osteogenic stimulus in the intervention has been effective in preserving BMD in healthy postmenopausal women but it may be inadequate for survivors with chemotherapy-induced menopause and for those on adjuvant AI therapy. © 2016, Springer Science+Business Media New York. Source


Koon H.B.,Seidman Cancer Center | Krown S.E.,Sloan Kettering Cancer Center | Ramos J.C.,Sylvester Comprehensive Cancer Center
Journal of Infectious Diseases | Year: 2012

We studied the presence of Kaposi sarcoma herpesvirus sequences in cell-free DNA (cfDNA) isolated from the blood of patients with AIDS-related Kaposi sarcoma (KS) and primary effusion lymphoma (PEL). The use of paramagnetic beads linked to methyl-CpG binding domain protein allowed separation of virion and cell-derived DNA. Only virion DNA was detected in the blood of KS patients, whereas cell-derived DNA was detected in a patient with AIDS-related PEL. The difference in the origins of cfDNA in these settings may in part reflect very different proliferative indices in KS and PEL tumor tissue. © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. Source


Varadan V.,Philips | Agrawal V.,Philips | Harris L.,Seidman Cancer Center | Dimitrova N.,Philips
2013 IEEE Global Conference on Signal and Information Processing, GlobalSIP 2013 - Proceedings | Year: 2013

Gene fusions represent a very important class of genomic aberrations playing a significant role in certain types of cancer. In this paper we provide a method for gene fusion prioritization and assessment of their functional impact in cancer. Recent discoveries of recurrent and targetable gene fusions in breast cancer suggest the need to characterize the functional significance of such genomic aberrations within larger cohorts. Beyond existing gene fusion detection algorithms, our method identifies and prioritizes high confidence fusion calls and produces full sequence of the fused genes, annotates and visualizes protein domains included in the chimeric protein. We evaluate the sensitivity of downstream interpretive algorithms such as pathway enrichment to the statistical confidence thresholds that are parameters of the gene fusion calling algorithms in a breast cancer cohort. We show that while some pathways are strongly enriched in the results across multiple confidence cutoffs, the pathway enrichment analysis is indeed sensitive to the statistical cutoffs. This suggests that the gene fusion calling algorithms should not be considered plug-and-play tools and require great care in parameter selection before down-stream analysis and interpretation is performed. © 2013 IEEE. Source


Martin M.,Complutense University of Madrid | Prat A.,Vall dHebron Institute of Oncology VHIO | Prat A.,Autonomous University of Barcelona | Rodriguez-Lescure A.,Hospital General de Elche | And 25 more authors.
Breast Cancer Research and Treatment | Year: 2013

To identify a group of patients who might benefit from the addition of weekly paclitaxel to conventional anthracycline-containing chemotherapy as adjuvant therapy of node-positive operable breast cancer. The predictive value of PAM50 subtypes and the 11-gene proliferation score contained within the PAM50 assay were evaluated in 820 patients from the GEICAM/9906 randomized phase III trial comparing adjuvant FEC to FEC followed by weekly paclitaxel (FEC-P). Multivariable Cox regression analyses of the secondary endpoint of overall survival (OS) were performed to determine the significance of the interaction between treatment and the (1) PAM50 subtypes, (2) PAM50 proliferation score, and (3) clinical and pathological variables. Similar OS analyses were performed in 222 patients treated with weekly paclitaxel versus paclitaxel every 3 weeks in the CALGB/9342 and 9840 metastatic clinical trials. In GEICAM/9906, with a median follow up of 8.7 years, OS of the FEC-P arm was significantly superior compared to the FEC arm (unadjusted HR = 0.693, p = 0.013). A benefit from paclitaxel was only observed in the group of patients with a low PAM50 proliferation score (unadjusted HR = 0.23, p < 0.001; and interaction test, p = 0.006). No significant interactions between treatment and the PAM50 subtypes or the various clinical-pathological variables, including Ki-67 and histologic grade, were identified. Finally, similar OS results were obtained in the CALGB data set, although the interaction test did not reach statistical significance (p = 0.109). The PAM50 proliferation score identifies a subset of patients with a low proliferation status that may derive a larger benefit from weekly paclitaxel. © 2013 The Author(s). Source

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