c-Myc acts downstream of IL-15 in the regulation of memory CD8 T-cell homeostasis.

A subset of CD8 T cells in normal mice, expressing high levels of activation markers such as CD44, shares many properties with antigen-specific memory CD8 T cells. Homeostasis of CD44(high) CD8 T cells depends upon cytokines such as interleukin-15 (IL-15); however, the downstream signaling pathways regulating IL-15-dependent homeostatic proliferation are poorly defined. Surprisingly, we show here that haploinsufficiency of the protooncogene c-myc leads to a highly selective decrease in CD44(high) CD8 T cells in mice. Although steady-state proliferation and survival of CD44(high) CD8 T cells appeared not to be dependent on c-Myc, homeostatic proliferation of c-myc(+/-) CD44(high) CD8 T cells in lymphopenic hosts was strongly reduced, and the residual homeostatic proliferation of these cells appeared to occur independently of IL-15. Moreover, c-myc(+/-) CD44(high) CD8 T cells responded very poorly to purified IL-15 in vitro. Backcrossing of c-myc(+/-) mice to IL-15(-/-) mice revealed that the number of CD44(high) CD8 T cells decreased in an additive fashion in mice heterozygous for c-myc and IL-15. Finally homeostatic proliferation of antigen-specific memory CD44(high) CD8 T cells was also impaired in c-myc(+/-) mice. Collectively, our data identify c-Myc as a novel downstream component of the IL-15-dependent pathway controlling homeostatic proliferation of memory CD44(high) CD8 T cells.

A High-Resolution 2D/3D Seismic Study of a Thrust Fault Zone in Lake Geneva, Switzerland

P130 A HIGH-RESOLUTION 2D/3D SEISMIC STUDY OF A THRUST FAULT ZONE IN LAKE GENEVA SWITZERLAND M. SCHEIDHAUER M. BERES D. DUPUY and F. MARILLIER Institute of Geophysics University of Lausanne 1015 Lausanne, Switzerland Summary A high-resolution three-dimensional (3D) seismic reflection survey has been conducted in Lake Geneva near the city of Lausanne Switzerland where the faulted molasse basement (Tertiary sandstones) is overlain by complex Quaternary sedimentary structures. Using a single 48-channel streamer an area of 1200 m x 600 m was surveyed in 10 days. With a 5-m shot spacing and a receiver spacing of 2.5 m in the inline direction and 7.5 m in the crossline direction, a 12-fold data coverage was achieved. A maximum penetration depth of ~150 m was achieved with a 15 cu. in. water gun operated at 140 bars. The multi-channel data allow the determination of an accurate velocity field for 3D processing, and they show particularly clean images of the fault zone and the overlying sediments in horizontal and vertical sections. In order to compare different sources, inline 55 was repeated with a 30/30 and a 15/15 cu. in. double-chamber air gun (Mini GI) operated at 100 and 80 bars, respectively. A maximum penetration depth of ~450 m was achieved with this source.

RNOP-09: pegylated liposomal doxorubicine and prolonged temozolomide in addition to radiotherapy in newly diagnosed glioblastoma--a phase II study.

BACKGROUND: Although Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for. METHODS: In this phase-I/II trial, pegylated liposomal doxorubicin (Caelyx, PEG-Dox) and prolonged administration of Temozolomide in addition to radiotherapy was investigated in 63 patients with newly diagnosed glioblastoma. In phase-I, PEG-Dox was administered in a 3-by-3 dose-escalation regimen. In phase-II, 20 mg/m2 PEG-Dox was given once prior to radiotherapy and on days 1 and 15 of each 28-day cycle starting 4 weeks after radiotherapy. Temozolomide was given in a dose of 75 mg/m2 daily during radiotherapy (60 Gy) and 150-200 mg/m2 on days 1-5 of each 28-day cycle for 12 cycles or until disease progression. RESULTS: The toxicity of the combination of PEG-Dox, prolonged administration of Temozolomide, and radiotherapy was tolerable. The progression free survival after 12 months (PFS-12) was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I. None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison. CONCLUSION: Together, the investigated combination is tolerable and feasible. Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data.

Effects of an interleukin-15 antagonist on systemic and skeletal alterations in mice with DSS-induced colitis.

Inflammatory bowel diseases are commonly complicated by weight and bone loss. We hypothesized that IL-15, a pro-inflammatory cytokine expressed in colitis and an osteoclastogenic factor, could play a central role in systemic and skeletal complications of inflammatory bowel diseases. We evaluated the effects of an IL-15 antagonist, CRB-15, in mice with chronic colitis induced by oral 2% dextran sulfate sodium for 1 week, followed by another 1% for 2 weeks. During the last 2 weeks, mice were treated daily with CRB-15 or an IgG2a control antibody. Intestinal inflammation, disease severity, and bone parameters were evaluated at days 14 and 21. CRB-15 improved survival, early weight loss, and colitis clinical score, although colon damage and inflammation were prevented in only half the survivors. CRB-15 also delayed loss of femur bone mineral density and trabecular microarchitecture. Bone loss was characterized by decreased bone formation, but increased bone marrow osteoclast progenitors and osteoclast numbers on bone surfaces. CRB-15 prevented the suppression of osteoblastic markers of bone formation, and reduced osteoclast progenitors at day 14, but not later. However, by day 21, CRB-15 decreased tumor necrosis factor α and increased IL-10 expression in bone, paralleling a reduction of osteoclasts. These results delineate the role of IL-15 on the systemic and skeletal manifestations of chronic colitis and provide a proof-of-concept for future therapeutic developments.

Chronic illness, life style and emotional health in adolescence: results of a cross-sectional survey on the health of 15-20-year-olds in Switzerland.

The objective was to evaluate the prevalence of chronic conditions (CC) in adolescents in Switzerland; to describe their behaviour (leisure, sexuality, risk taking behaviour) and to compare them to those in adolescents who do not have CC in order to evaluate the impact of those conditions on their well-being. The data were obtained from the Swiss Multicentre Adolescent Survey on Health, targeting a sample of 9268 in-school adolescents aged 15 to 20 years, who answered a self-administered questionnaire. Some 11.4% of girls and 9.6% of boys declared themselves carriers of a CC. Of girls suffering from a CC, 25% (versus 13% of non carriers; P=0.007) and 38% of boys (versus 25%; P=0.002) proclaimed not to wear a seatbelt whilst driving. Of CC girls, 6.3% (versus 2.7%; P=0.000) reported within the last 12 months to have driven whilst drunk. Of the girls, 43% (versus 36%; P=0.004) and 47% (versus 39%; P=0.001) were cigarette smokers. Over 32% of boys (versus 27%; P=0.02) reported having ever used cannabis and 17% of girls (versus 13%; P=0.013) and 43% of boys (versus 36%; P=0.002) admitted drinking alcohol. The burden of their illness had important psychological consequences: 7.7% of girls (versus 3.4%; P=0.000) and 4.9% of boys (versus 2.0%; P=0.000) had attempted suicide during the previous 12 months. CONCLUSION: experimental behaviours are not rarer in adolescents with a chronic condition and might be explained by a need to test their limits both in terms of consumption and behaviour. Prevention and specific attention from the health caring team is necessary.

Effect of conditioned media, nutritive elements, and mitotic synchronization on the accuracy of the cytogenetic analysis in acute nonlymphocytic leukemia patients presenting with inv(16)/t(16;16) or t(15;17).

To improve the yield of the cytogenetic analysis in patients with acute nonlymphocytic leukemia (ANLL), six culture conditions for bone marrow or peripheral blood cells were tested in parallel. Two conditioned media (CM), phytohemagglutinin leukocyte PHA-LCM and 5637 CM, nutritive elements (NE), and methotrexate (MTX) cell synchronization were investigated in 14 patients presenting with either inv(16)/ t(16;16) (group 1, n = 9 patients) or t(15;17) (group 2, n = 5). The criteria used to identify the most favorable culture conditions were the mitotic index (MI), the morphological index (MorI), and the percentage of abnormal metaphases. In the presence of PHA-LCM and 5637 CM, the MI were significantly increased in group 2, whereas in the MTX conditions, MI remained very low in both groups. The values of the MorI did not reveal any significant changes in chromosome resolution between the conditions in either group. The addition of NE did not have a positive effect in quantity or quality of metaphases. Because of the variability of the response of leukemic cells to different stimulations in vitro, several culture conditions in parallel are required to ensure a satisfactory yield of the chromosome analysis in ANLL.