2-Deoxy-Glucose Downregulates Endothelial AKT and ERK via Interference with N-Linked Glycosylation, Induction of Endoplasmic Reticulum Stress, and GSK3ß Activation.

Interference with endothelial cell metabolism is a promising, yet unexploited strategy for angiogenesis inhibition. We reported that the glucose analogue 2-deoxy-D-glucose (2-DG) inhibits angiogenesis at significantly lower concentrations than those required for tumor cytotoxicity. Here, we found that hypersensitivity to 2-DG in endothelial cells is not associated with enhanced drug uptake compared with tumor cells, but with time-dependent, endothelial-selective inhibition of AKT and ERK phosphorylation. Downregulation of these critical survival pathways is shown to be due to 2-DG's interference with N-linked glycosylation, leading to alterations in VEGFR2 (and downstream signaling) as well as induction of endoplasmic reticulum (ER) stress, GSK3ß activation, and apoptosis. In vivo, periocular administration of 2-DG in LHBETATAG mice was associated with significant reduction of newly formed (CD105(+)) tumor capillaries, ER stress (GRP 78 expression), and endothelial apoptosis (TUNEL). These findings uniquely link N-linked glycosylation inhibition, ER stress, and ERK/AKT downregulation in endothelial cells, and provide a novel drug development strategy to overcome resistance mechanisms to currently available antiangiogenic agents.

Severe systemic inflammatory response syndrome in a patient with adult onset Still's disease treated with the anti-IL1 drug anakinra: a case report.

Interleukin 1 (IL1) plays an important role in adult onset Still's disease. Anakinra (Kineret), a recombinant IL1 Receptor Antagonist (IL 1 RA) was therefore recently proposed in adult onset Still's disease with great efficacy. Anakinra appeared to be well tolerated and safe. The case of a patient with refractory adult onset Still's disease who experienced a Systemic Inflammatory Response Syndrome and Adult Respiratory Distress Syndrome requiring intensive care unit hospitalization 10 days after the introduction of anakinra is reported.

Adoptively transferred tumor-specific T cells stimulated ex vivo using herpes simplex virus amplicons encoding 4-1BBL persist in the host and show antitumor activity in vivo.

4-1BB is a T-cell costimulatory receptor which binds its ligand 4-1BBL, resulting in prolonged T cell survival. We studied the antitumor effects of adoptively transferred tumor-specific T cells expanded ex vivo using tumors transduced with herpes simplex virus (HSV) amplicons expressing 4-1BBL as a direct source of antigen and costimulation. We constructed HSV amplicons encoding either the 4-1BBL (HSV.4-1BBL) or B7.1 (HSV.B7.1) costimulatory ligands. Lewis lung carcinoma cells expressing ovalbumin (LLC/OVA) were transduced with HSV.4-1BBL, HSV.B7.1, or control HSV amplicons and used to stimulate GFP+ OVA-specific CD8+ T cells (OT-1/GFP) ex vivo. Naive or ex vivo stimulated OT-1/GFP cells were adoptively transferred into LLC/OVA tumor-bearing mice. Higher percentages of OT-1/GFP cells were seen in the peripheral blood, spleen, and tumor bed of the HSV.4-1BBL-stimulated OT-1/GFP group compared with all other experimental groups. OT-1 cells identified within the tumor bed and draining lymph nodes of the HSV.4-1BBL-stimulated OT-1 group showed enhanced bromodeoxyuridine (BrdUrd) incorporation, suggesting ongoing expansion in vivo. Mice receiving HSV.4-1BBL-stimulated OT-1/GFP had significantly decreased tumor volumes compared with untreated mice (P<0.001) or to mice receiving naive OT-1/GFP (P<0.001). Transfer of HSV.B7.1-stimulated OT-1/GFP did not protect mice from tumor. Mice that received HSV.4-1BBL-stimulated OT-1/GFP exhibited increased cytolytic activity against LLC/OVA and higher percentages of Ly-6C+ OT-1/GFP in the spleen and tumor bed compared with controls. Tumor-specific T cells stimulated ex vivo using tumor transduced with HSV.4-1BBL expand in vivo following adoptive transfer, resulting in tumor eradication and the generation of tumor-specific CD44+Ly-6C+CD62L- effector memory T cells.

A randomized, multicenter, controlled trial using intravenous pulses of methylprednisolone in the initial treatment of simple forms of giant cell arteritis: a one year followup study of 164 patients.

OBJECTIVE: (1) To evaluate the corticosteroid sparing effect of an initial intravenous (i.v.) pulse of methylprednisolone (MP) in the treatment of simple forms of giant cell arteritis (GCA). (2) To analyze corticosteroid response, steroid related side effects, and GCA complications. METHODS: Patients received a 240 mg i.v. pulse of MP followed by 0.7 mg/kg/day oral prednisone (Group 1) or 0.7 mg/kg/day prednisone without an i.v. pulse (Group 2, controls), or a 240 mg i.v. pulse of MP followed by 0.5 mg/kg/day prednisone (Group 3). Corticosteroid dosage was reduced after normalization of 2 biological inflammatory variables to obtain half-dosage after 4 weeks in Groups 1 and 2 and 20 mg/day after 2 weeks in Group 3. Tapering was systematically attempted from the 6th month of treatment. RESULTS: One hundred sixty-four patients were included in the trial (1992-96). Cumulative doses of corticosteroids after one year were identical for all groups (p = 0.39). No significant differences were observed in the time required for normalization of C-reactive protein, corticosteroid resistance (13.5%), and corticosteroid related side effects (39% of patients; p = 0.37). Corticosteroid resistant patients received larger doses and showed a high risk of GCA related complications (p = 0.02). CONCLUSION: MP pulses have no significant longterm, corticosteroid sparing effects in the treatment of simple forms of GCA and should be limited to complicated forms. Moreover, corticosteroid resistance is a real risk factor for GCA complications.

Work and social support: a comparison of consumers who have achieved stability in ACT and clubhouse programs.

A current debate in the field is whether consumers, who have achieved stability in Assertive Community Treatment programs, can be transferred to less intensive services. To bring some data to bear on this question, this study compared consumers and members, who have achieved stability, in either an Assertive Community Treatment (ACT) or a clubhouse program, on domains of vocational activity, social relationships/loneliness and community integration. The 51 stable clients from the two programs who were interviewed, reported similar vocational activity, similar experiences with social relationships and social networks, and similar community integration. Clients in both groups were less lonely than previously reported in the literature. Study results indicate, that for those clients who have achieved stability, there are sufficient similarities between consumers in the two programs, to suggest a potential for movement from more to less intensive programs with less disruption than previously assumed possible.

Cell-free Fc-gamma receptor III in sera from patients with systemic lupus erythematosus: correlation with clinical and biological features.

Fifty patients (41 females and 9 males, ranging in age from 12 to 79 years) with systemic lupus erythematosus (SLE) and 20 normal controls were evaluated for the presence of plasma cell-free Fc gamma receptor III (Fc gamma RIII) using an ELISA based upon a sandwich of two monoclonal antibodies. The standard curve was obtained with serial dilutions of recombinant Fc gamma RIII. In the patients, the cell-free Fc gamma RIII levels ranged from to 1.76 micrograms/ml, while it did not exceed 0.21 microgram/ml in the controls. Assuming that the cutoff is 0.25 microgram/ml, 11 SLE patients and no controls had elevated cell-free Fc gamma RIII levels in the serum. Among the SLE patients, the level of cell-free Fc gamma RIII was significantly lower (p = 0.05) in 4 patients with sicca syndrome than in the remaining 46. Furthermore, cell-free Fc gamma RIII levels appeared to be lower in 11 patients with renal involvement than in those without. For the biological parameters, we observed that the 27 patients who presented lymphopenia also had a lower level of cell-free Fc gamma RIII when compared to the 23 patients without lymphopenia (0.09 +/- 0.19 versus 0.35 +/- 0.52 microgram/ml; p = 0.05). Circulating cell-free Fc gamma RIII may originate from shedding by presumably activated polymorphonuclear cells.

Relationship of interleukin-4 to isotypic distribution of anti-double-stranded DNA antibodies in systemic lupus erythematosus.

IgG subclasses of anti-double-stranded DNA antibodies were determined in 182 patients with systemic lupus erythematosus. All isotypes were detected, but IgG1 and IgG3 were predominant (62 and 51% of the cases, respectively). An average of 64 +/- 27% was IgG1, 16 +/- 22% IgG2, 16 +/- 19% IgG3 and 4 +/- 10% IgG4. The rank order or frequency was IgG1, IgG3, IgG2 and IgG4 in patients with musculoskeletal involvement; IgG1, IgG2, IgG3 and IgG4 in those with renal complications; IgG3, IgG1, IgG2 and IgG4 in those with cutaneous involvement; and IgG1, IgG3, IgG2 and IgG4 in those with hematological manifestations. Interleukin-4 (IL-4) was detectable in 17 of 36 selected patients, as opposed to 1 of 40 normal controls. The percentage of the total autoantibody contributed by IgG1 was significantly higher (p < 0.03) in these patients than in the remainder with undetectable levels of IL-4.

Hypovitaminemia A in idiopathic hemochromatosis and hepatic cirrhosis. Role of retinol-binding protein and zinc.

Serum levels of vitamin A, its specific carrier protein retinol-binding protein (RBP), and zinc were determined in 34 cases of idiopathic hemochromatosis, 33 cases of alcoholic cirrhosis, 10 cases of non-alcoholic cirrhosis, and in 35 normal controls. In both alcoholic and non-alcoholic cirrhosis, vitamin A and RBP levels were very significantly reduced, whereas a significantly low zinc was observed only in the alcoholic cirrhosis group. In idiopathic hemochromatosis, vitamin A values were significantly lower compared to normals, whereas serum RBP levels were normal and serum zinc was very close to that of the controls. A significant correlation was found between vitamin A and RBP levels in the entire group of 112 patients. These results, (1) in alcoholic and non-alcoholic cirrhosis, confirm a dramatic vitamin A deficiency and the major role played by decreased RBP, but tend to deemphasize the possible role of zinc deficiency; (2) in idiopathic hemochromatosis, affirm a significant serum vitamin A deficiency supposedly by a different mechanism from that of alcoholic cirrhosis since in idiopathic hemochromatosis plasma RBP levels are normal. The role of this vitamin A disorder should be considered in the interpretation of clinical signs of idiopathic hemochromatosis such as ichthyosis and visual disorders.