Tumor-Shed PGE2 Impairs IL2Rγc-Signaling to Inhibit CD4+ T Cell Survival: Regulation by Theaflavins

BACKGROUND:Many tumors are associated with decreased cellular immunity and elevated levels of prostaglandin E2 (PGE2), a known inhibitor of CD4+ T cell activation and inducer of type-2 cytokine bias. However, the role of this immunomodulator in the survival of T helper cells remained unclear. Since CD4+ T cells play critical roles in cell-mediated immunity, detail knowledge of the effect tumor-derived PGE2 might have on CD4+ T cell survival and the underlying mechanism may, therefore, help to overcome the overall immune deviation in cancer. METHODOLOGY/PRINCIPAL FINDINGS:By culturing purified human peripheral CD4+ T cells or Jurkat cells with spent media of theaflavin- or celecoxib-pre-treated MCF-7 cells, we show that tumor-shed PGE2 severely impairs interleukin 2 receptor gammac (IL2Rgammac)-mediated survival signaling in CD4+ T cells. Indeed, tumor-shed PGE2 down-regulates IL2Rgammac expression, reduces phosphorylation as well as activation of Janus kinase 3 (Jak-3)/signal transducer and activator of transcription 5 (Stat-5) and decreases Bcl-2/Bax ratio thereby leading to activation of intrinsic apoptotic pathway. Constitutively active Stat-5A (Stat-5A1 6) over-expression efficiently elevates Bcl-2 levels in CD4+ T cells and protects them from tumor-induced death while dominant-negative Stat-5A over-expression fails to do so, indicating the importance of Stat-5A-signaling in CD4+ T cell survival. Further support towards the involvement of PGE2 comes from the results that (a) purified synthetic PGE2 induces CD4+ T cell apoptosis, and (b) when knocked out by small interfering RNA, cyclooxygenase-2 (Cox-2)-defective tumor cells fail to initiate death. Interestingly, the entire phenomena could be reverted back by theaflavins that restore cytokine-dependent IL2Rgammac/Jak-3/Stat-5A signaling in CD4+ T cells thereby protecting them from tumor-shed PGE2-induced apoptosis. CONCLUSIONS/SIGNIFICANCE:These data strongly suggest that tumor-shed PGE2 is an important factor leading to CD4+ T cell apoptosis during cancer and raise the possibility that theaflavins may have the potential as an effective immunorestorer in cancer-bearer

Solid Tumor-Targeted Infiltrating Cytotoxic T Lymphocytes Retained by a Superantigen Fusion Protein

Successful immune-mediated regression of solid tumors is difficult because of the small number of cytotoxic T lymphocytes (CTLs) that were traffic to the tumor site. Here, the targeting of tumor-specific infiltrating CTLs was dependent on a fusion protein consisting of human epidermal growth factor (EGF) and staphylococcal enterotoxin A (SEA) with the D227A mutation. EGF-SEA strongly restrained the growth of murine solid sarcoma 180 (S180) tumors (control versus EGF-SEA, mean tumor weight: 1.013 versus 0.197 g, difference  = 0.816 g). In mice treated with EGF-SEA, CD4+, CD8+ and SEA-reactive T lymphocytes were enriched around the EGFR expressing tumor cells. The EGF receptors were potentially phosphorylated by EGF-SEA stimulation and the fusion protein promoted T cells to release the tumoricidal cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Intratumoral CTLs secreted cytolytic pore-forming perforins and granzyme B proteins near the surface of carcinomas, causing the death of many tumor cells. We additionally show that labeled EGF-SEA was directly targeted to the tumor tissue after intravenous (i.v.) injection. The findings demonstrate that antibody-like EGF-SEA plays an important role in arresting CTLs in the solid tumor site and has therapeutic potential as a tumor-targeting agent

Income level and regional policies, underlying factors associated with unwarranted variations in conservative breast cancer surgery in Spain

<p>Abstract</p> <p>Background</p> <p>Geographical variations in medical practice are expected to be small when the evidence about the effectiveness and safety of a particular technology is abundant. This would be the case of the prescription of conservative surgery in breast cancer patients. In these cases, when variation is larger than expected by need, socioeconomic factors have been argued as an explanation. Objectives: Using an ecologic design, our study aims at describing the variability in the use of surgical conservative versus non-conservative treatment. Additionally, it seeks to establish whether the socioeconomic status of the healthcare area influences the use of one or the other technique.</p> <p>Methods</p> <p>81,868 mastectomies performed between 2002 and 2006 in 180 healthcare areas were studied. Standardized utilization rates of breast cancer conservative (CS) and non-conservative (NCS) procedures were estimated as well as the variation among areas, using small area statistics. Concentration curves and dominance tests were estimated to determine the impact of income and instruction levels in the healthcare area on surgery rates. Multilevel analyses were performed to determine the influence of regional policies.</p> <p>Results</p> <p>Variation in the use of CS was massive (4-fold factor between the highest and the lowest rate) and larger than in the case of NCS (2-fold), whichever the age group. Healthcare areas with higher economic and instruction levels showed highest rates of CS, regardless of the age group, while areas with lower economic and educational levels yielded higher rates of NCS interventions. Living in a particular Autonomous Community (AC), explained a substantial part of the CS residual variance (up to a 60.5% in women 50 to 70).</p> <p>Conclusion</p> <p>The place where a woman lives -income level and regional policies- explain the unexpectedly high variation found in utilization rates of conservative breast cancer surgery.</p

High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014

Interleukin-2 (IL-2) was historically one of the few treatments for adults with stage IV solid tumors that could produce complete responses (CRs) that were often durable for decades without further therapy. The majority of complete responders with metastatic renal cell carcinoma (mRCC) and metastatic melanoma (mM) could probably be classified as "cures". Recent publications have suggested improved efficacy, perhaps due to improved patient Selection based on a better understanding of clinical features predicting outcomes. Guidelines for clinical management were established from experience at the National Cancer Institute (NCI) and an affiliation of institutions known as the Cytokine Working Group (CWG), who were among the first to utilize HD IL-2 treatment outside of the NCI. As new centers have opened, further management variations have emerged based upon center-specific experience, to optimize administration of IL-2 and provide high quality care for patients at each individual site. Twenty years of evolution in differing environments has led to a plethora of clinical experience and effective management approaches. The goal of this review is to summarize the spectrum of HD IL-2 treatment approaches, describing various effective strategies that incorporate newer adjunctive treatments for managing the side effects of IL-2 in patients with mRCC and mM. The goal for IL-2 therapy is typically to administer the maximum number of doses of IL-2 without putting the patient at unacceptable risk for severe, irreversible toxicity. This review is based upon a consensus meeting and includes guidelines on pre-treatment screening, criteria for administration and withholding doses, and defines consensus criteria for safe administration and toxicity management. The somewhat heterogeneous best practices of 2014 will be compared and contrasted with the guidelines provided in 2001 and the package inserts from 1992 and 1998

Cutaneous lesions of the external ear

Skin diseases on the external aspect of the ear are seen in a variety of medical disciplines. Dermatologists, othorhinolaryngologists, general practitioners, general and plastic surgeons are regularly consulted regarding cutaneous lesions on the ear

Computed tomography in staging of patients with melanoma metastatic to the regional nodes

Background: This study addresses the yield and clinical impact of computed tomography (CT) imaging in otherwise asymptomatic patients with stage III melanoma metastatic to the regional nodes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41414/1/10434_2006_Article_BF02305552.pd