Emerging therapies in systemic lupus erythematous: from clinical trial to the real life.

Systemic lupus erythematous (SLE) is a chronic autoimmune disease characterised by multisystem involvement and a relapsing remitting course. SLE is a highly heterogeneous condition, with wide variations in both the presentation and severity of disease and the biological markers identified. The use of biologics in SLE has lagged behind that of other rheumatological conditions such as rheumatoid arthritis, in part due to the diverse clinical manifestations of SLE, making it difficult to design appropriate trials for novel treatments.

Chronic exposure to stress hormones promotes transformation and tumorigenicity of 3T3 mouse fibroblasts.

Epinephrine and norepinephrine are produced during psychological stress and can directly bind to cells to induce DNA damage. These effects may have more long-lasting consequences such as DNA mutations resulting in an increased potential for cellular transformation and/or tumor progression. This study examined the molecular effects of a chronic (24 h) in vitro exposure to these stress hormones on murine 3T3 cells.

Pain relief in palliative care: a focus on interventional pain management.

Pharmacological treatment forms the foundation of the management of pain in patients with advanced cancer. Although the majority of patients in the realm of palliative care can be provided with acceptable pain relief using the three-step WHO cancer pain guidelines, a significant minority still have pain that is not adequately controlled by conventional pharmacological management. Development of pain management strategies using a multidisciplinary input with appropriate and timely use of interventional pain management techniques can provide satisfactory pain relief for these patients, helping to reduce distress in the patient and their relatives during this difficult period.

V-Y advancement flap as first-line treatment for all chronic anal fissures.

Introduction: It was suggested that anal advancement flap be used to treat patients with chronic anal fissures that have failed medical management and have a low-pressure sphincter complex. We wished to assess anal advancement flap as a treatment for all chronic anal fissures.

Methods: All patients with chronic anal fissures regardless of their previous management underwent V-Y advancement flap.

Prevention of mammary carcinogenesis in MMTV-neu mice by cruciferous vegetable constituent benzyl isothiocyanate.

Benzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables, inhibits growth of human breast cancer cells in culture. The present study provides in vivo evidence for efficacy of BITC for prevention of mammary cancer in MMTV-neu mice. Administration of BITC at 1 and 3 mmol/kg diet for 25 weeks markedly suppressed the incidence and/or burden of mammary hyperplasia and carcinoma in female MMTV-neu mice without causing weight loss or affecting neu protein level.

Magnetic resonance imaging-guided adoptive cellular immunotherapy of central nervous system tumors with a T1 contrast agent.

Dendritic cells (DCs) are the most effective antigen-presenting cells (APCs) and are used in a variety of immunotherapeutic approaches. Adoptive cellular immunotherapy (ACI) of cancer using DCs has attracted much interest due to their capacity to promote immunity in prophylactic and therapeutic protocols. As one approach, DCs are injected into patients or tumor-bearing animals, to trigger specific antitumor immunity.

Sulforaphane inhibits prostate carcinogenesis and pulmonary metastasis in TRAMP mice in association with increased cytotoxicity of natural killer cells.

The present study shows that oral gavage of 6 mumol d,l-sulforaphane (SFN), a synthetic analogue of cruciferous vegetable-derived L isomer, thrice per week beginning at 6 weeks of age, significantly inhibits prostate carcinogenesis and pulmonary metastasis in TRAMP mice without causing any side effects. The incidence of the prostatic intraepithelial neoplasia and well-differentiated (WD) carcinoma were approximately 23% to 28% lower (P < 0.05 compared with control by Mann-Whitney test) in the dorsolateral prostate (DLP) of SFN-treated mice compared with controls, which was not due to the suppression of T-antigen expression.

Gaining experience with military medical situational awareness and geographic information systems in a simulated influenza epidemic.

The purpose of medical situational awareness is to provide useful and actionable information for preparing and employing medical assets in support of a wide variety of operational missions around the world, and monitoring and protecting the health of the force in the face of rapidly changing health threats. Since 2005, the Medical Situational Awareness in the Theater Advanced Concept Technology Demonstration has exploited advances in information technology, geographic information systems, and open systems architecture to produce a functioning prototype of a medical situational enhancement capability. In May 2006, this prototype supported the medical staff of a combined/joint task force in a realistic command postexercise featuring a simulated outbreak of influenza during Exercise COBRA GOLD in Thailand.

Induction of DNA damage, alteration of DNA repair and transcriptional activation by stress hormones.

Stress is associated with increased production of sympathetic and other adrenal hormones. Epinephrine (E), norepinephrine (NE) and cortisol are produced during psychological stress and may affect many cells directly. These effects may be transient (e.

CD161B:ClrB interactions mediate activation of enhanced lysis of tumor target cells following NK cell:DC co-culture.

Co-culture of natural killer (NK) cells and dendritic cells (DCs) results in their reciprocal co-activation, and an enhancement of lysis of tumor target cells. The receptor:ligand pairings mediating this enhancement are unknown. Therefore, we investigated whether interactions of CD161, on NK cells, with Clrs, on DCs, might have a role in this effect.

CDC4 mutations occur in a subset of colorectal cancers but are not predicted to cause loss of function and are not associated with chromosomal instability.

CDC4/FBXW7 is part of a ubiquitin ligase complex which targets molecules such as cyclin E, c-myc, and c-jun for destruction. CDC4 mutations occur in several cancer types and are best described in colorectal tumors. Knockout of CDC4 in vitro in colorectal cancer cells causes changes suggestive of chromosomal instability (CIN).

Genomic profiling of restraint stress-induced alterations in mouse T lymphocytes.

DNA damage-, DNA repair-, and apoptosis-related gene expression in CD3(+) T lymphocytes of BALB/c mice subjected to 2-h restraint stress were compared to that in CD3(+)T lymphocytes from control mice. Using targeted cDNA arrays, significant increases in expression of genes serving as sensors of DNA damage, including MSH genes and RAD53, were observed. GADD45g, a gene responsible for regulating cell cycle arrest and apoptosis, was significantly induced; as was Pura, a gene involved in cell proliferation.

The characterization of tumor apoptosis after experimental radiosurgery.

We sought to evaluate whether radiosurgery induces apoptosis in an experimental glioma model and to elucidate the time course of this radiobiologic phenomenon. Fischer 344 rats harboring established intracranial 9L gliosarcomas underwent radiosurgery (n = 42) or no radiosurgery (n = 45). Animals were sacrificed at 3, 6, 12, 24, 48, 72 h, and 1 or 2 weeks after treatment and in situ tumor apoptosis was assessed by specific staining.

A collaborative approach to the development of psychiatric rehabilitation services in a public behavioral health managed care environment.

This article summarizes the collaborative effort that took place between providers, managed care administrators, and state and county officials in Pennsylvania to create a fluid system in the development of psychiatric rehabilitation services. The stakeholders involved solved the numerous logistical problems that are inherent in the start-up of new services and were able to cooperatively create procedures for service delivery, service coordination, and reimbursement across systems and funding mechanisms. The article reviews that process and highlights the services of Welcome House, a psychiatric rehabilitation program exemplifying the products of their collaboration.

A novel epitope of N-CAM defines precursors of human adherent NK cells.

Activated, adherent natural killer (A-NK) cells represent a distinct subpopulation of interleukin (IL)-2-stimulated NK cells, which are selectively endowed with the increased expression of integrins and ability to adhere to solid surfaces, migrate into, infiltrate, and destroy cancerous tissues. The present study defines the phenotype and functions of precursors of A-NK (pre-A-NK) cells in humans. Peripheral blood pre-A-NK cells, in contrast to the rest of NK cells, express a novel epitope of CD56 neuronal cell adhesion molecule, termed ANK-1, and increased cell-surface levels of integrins.

Delivery of interferon-alpha transfected dendritic cells into central nervous system tumors enhances the antitumor efficacy of peripheral peptide-based vaccines.

We evaluated the effects, on immunity and survival, of injection of interferon (IFN)-alpha-transfected dendritic cells (DC-IFN-alpha) into intracranial tumors in mice immunized previously with syngeneic dendritic cells (DCs) pulsed either with ovalbumin-derived CTL or T helper epitopes. These immunizations protected animals from s.c.

Expression of a soluble transforming growth factor-beta (TGFbeta) receptor reduces tumorigenicity by regulating natural killer (NK) cell activity against 9L gliosarcoma in vivo.

Immunotherapy of gliomas has been forwarded as an attractive alternative to standard therapeutic modalities. Numerous observations indicate some therapeutic efficacy with this approach, but it is not curative in most reports. It is well established that gliomas suppress immune reactivity via a number of mechanisms, including expression CD95 ligand (CD95L), which induces apoptosis of immune effector cells, and secretion of immunosuppressive factors such as transforming growth factor-beta (TGFbeta).

Stability of individual differences in cellular immune responses to two different laboratory tasks.

To explore the stability of immune reactivity across laboratory tasks, we correlated enumerative and functional lymphocyte responses to a speech task and a mental arithmetic task, delivered on the same occasion of testing in 31 healthy undergraduates. Both tasks were associated with an increase in peripheral CD8+ and CD56+ cell populations, and a decrease in proliferative response to phytohemagglutinin (PHA) and ratio of CD4:CD8 cells. Intertask correlations were significant for the magnitude of change in proliferative responses at two different concentrations of PHA, r = 0.

Identification of a novel HLA-A*0201-restricted, cytotoxic T lymphocyte epitope in a human glioma-associated antigen, interleukin 13 receptor alpha2 chain.

Purpose: Interleukin 13 receptor alpha2-chain (IL-13Ralpha2) has been reported to be abundantly and specifically overexpressed in glioblastoma multiforme. Here we report the identification of a CTL epitope derived from the IL-13Ralpha2.

Experimental Design: Mature dendritic cells (DCs) were pulsed with each of the synthetic peptides that were designed, based on a binding affinity-based prediction and a proteosomal cleavage site prediction system, and used to stimulate autologous CD8+ T cells from an HLA-A2+ healthy donor.

Flt-3 ligand (FL) drives differentiation of rat bone marrow-derived dendritic cells expressing OX62 and/or CD161 (NKR-P1).

Bone marrow-derived dendritic cells (DC) of the rat have not been as well characterized as those from the mouse. Here, large quantities of bone marrow-derived rat DC were generated when Flt-3 ligand (FL) was used as an adjunct to granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4). These cells displayed a typical DC phenotype, expressing MHC class II, CD54, CD80, CD86, and CD11b/c.

7-Hydroxystaurosporine-induced apoptosis in 9L glioma cells provides an effective antigen source for dendritic cells and yields a potent vaccine strategy in an intracranial glioma model.

Objective: On the basis of recent studies indicating that tumoral apoptotic bodies may provide a potent source of antigen for delivery to antigen-presenting cells, as well as observations that signal transduction modulation may constitute a promising approach for inducing glioma cell apoptosis, we explored the efficacy of vaccination with glioma apoptotic body-pulsed dendritic cells (DCs) for inhibiting tumor growth in the syngeneic 9L glioma/Fischer rat model.

Methods: For induction of apoptosis, 7-hydroxystaurosporine (UCN-01) (200-300 ng/ml), a selective protein kinase C inhibitor, was co-incubated with 9L cells in vitro for 72 or 96 hours. After this pretreatment period, glioma cells and DCs were mixed, and the interaction between DCs and apoptotic 9L tumor cells was assessed using two-color flow cytometry.

Glioma-associated hyaluronan induces apoptosis in dendritic cells via inducible nitric oxide synthase: implications for the use of dendritic cells for therapy of gliomas.

As a means of enhancing immunity to gliomas, we investigated local delivery of rat, bone marrow-derived dendritic cells (DCs) into rat 9L gliosarcoma tumors and into 9L tumors induced to undergo apoptosis by gamma knife radiosurgery. Contrary to other tumors, local delivery of DCs had no therapeutic effect on 9L gliomas, even when tumor apoptosis was induced via radiosurgery, which leads to efficient "loading" of the DCs with tumor antigen. To determine whether antigen-presenting cells, such as DCs, were viable in tumors, we carried out multiparametric staining of 9L tumors, using phycoerythrin-conjugated OX6 (MHC class II) or OX62 (DC specific) and FITC-labeled Val-Ala-Asp-fluoromethyl ketone (FITC-VAD-FMK; activated caspases).