Hypoxia counteracts taxol-induced apoptosis in MDA-MB-231 breast cancer cells:Role of autophagy and JNK activation

Cancer cell resistance against chemotherapy is still a heavy burden to improve anticancer treatments. Autophagy activation and the development of hypoxic regions within the tumors are known to promote cancer cell resistance. Therefore, we sought to evaluate the role of autophagy and hypoxia on the taxol-induced apoptosis in MDA-MB-231 breast cancer cells. The results showed that taxol induced apoptosis after 16 h of incubation, and that hypoxia protected MDA-MB-231 cells from taxol-induced apoptosis. In parallel, taxol induced autophagy activation already after 2 h of incubation both under normoxia and hypoxia. Autophagy activation after taxol exposure was shown to be a protective mechanism against taxol-induced cell death both under normoxia and hypoxia. However, at longer incubation time, the autophagic process reached a saturation point under normoxia leading to cell death, whereas under hypoxia, autophagy flow still correctly took place allowing the cells to survive. Autophagy induction is induced after taxol exposure via mechanistic target of rapamycin (mTOR) inhibition, which is more important in cells exposed to hypoxia. Taxol also induced c-Jun N-terminal kinase (JNK) activation and phosphorylation of its substrates B-cell CLL/lymphoma 2 (Bcl(2)) and BCL2-like 1 (Bcl(XL)) under normoxia and hypoxia very early after taxol exposure. Bcl(2) and Bcl(XL) phosphorylation was decreased more importantly under hypoxia after long incubation time. The role of JNK in autophagy and apoptosis induction was studied using siRNAs. The results showed that JNK activation promotes resistance against taxol-induced apoptosis under normoxia and hypoxia without being involved in induction of autophagy. In conclusion, the resistance against taxol-induced cell death observed under hypoxia can be explained by a more effective autophagic flow activated via the classical mTOR pathway and by a mechanism involving JNK, which could be dependent on Bcl(2) and Bcl(XL) phosphorylation but independent of JNK-induced autophagy activation

Serum neuron-specific enolase in children's cancer.

To test its diagnostic potential and sensitivity in paediatric malignancy, serum NSE was measured at diagnosis in 191 children with solid tumours and 25 with acute leukaemia. In stages I + II, III + IV and IVs neuroblastoma median levels were 18.0, 91.0 and 24.0 ng ml-1 respectively. For Wilms' patients, median values for stages I, II, III and IV disease were 16.6, 18.0, 29.0 and 47.0 ng ml-1 respectively. High levels of NSE were also found in patients with other types of tumour. Children in clinical remission after treatment for neuroblastoma invariably had normal NSE levels (mean +/- s.d. = 9.2 +/- 3.0 ng ml-1) even though the majority had radiologically identifiable residual disease. The values rose when relapse was radiologically or clinically obvious. We conclude (a) that, though levels of greater than 100 ng ml-1 are highly suggestive of advanced neuroblastoma, caution should be exercised in using serum NSE as a diagnostic test in children with cancer and (b) that serum NSE levels are not a sensitive index of residual neuroblastoma in patients, with initially elevated levels, that are receiving treatment

Structure of 12Be: intruder d-wave strength at N=8

The breaking of the N=8 shell-model magic number in the 12Be ground state has been determined to include significant occupancy of the intruder d-wave orbital. This is in marked contrast with all other N=8 isotones, both more and less exotic than 12Be. The occupancies of the 0 hbar omega neutron p1/2-orbital and the 1 hbar omega, neutron d5/2 intruder orbital were deduced from a measurement of neutron removal from a high-energy 12Be beam leading to bound and unbound states in 11Be.Comment: 5 pages, 2 figure

Structure of 13^{13}Be probed via secondary beam reactions

The low-lying level structure of the unbound neutron-rich nucleus $^{13}$Be has been investigated via breakup on a carbon target of secondary beams of $^{14,15}$B at 35 MeV/nucleon. The coincident detection of the beam velocity $^{12}$Be fragments and neutrons permitted the invariant mass of the $^{12}$Be+$n$ and $^{12}$Be+$n$+$n$ systems to be reconstructed. In the case of the breakup of $^{15}$B, a very narrow structure at threshold was observed in the $^{12}$Be+$n$ channel. Contrary to earlier stable beam fragmentation studies which identified this as a strongly interacting $s$-wave virtual state in $^{13}$Be, analysis here of the $^{12}$Be+$n$+$n$ events demonstrated that this was an artifact resulting from the sequential-decay of the $^{14}$Be(2$^+$) state. Single-proton removal from $^{14}$B was found to populate a broad low-lying structure some 0.70 MeV above the neutron-decay threshold in addition to a less prominent feature at around 2.4 MeV. Based on the selectivity of the reaction and a comparison with (0-3)$\hbar\omega$ shell-model calculations, the low-lying structure is concluded to most probably arise from closely spaced J$^\pi$=1/2$^+$ and 5/2$^+$ resonances (E$_r$=0.40$\pm$0.03 and 0.85$^{+0.15}_{-0.11}$ MeV), whilst the broad higher-lying feature is a second 5/2$^+$ level (E$_r$=2.35$\pm$0.14 MeV). Taken in conjunction with earlier studies, it would appear that the lowest 1/2$^+$ and 1/2$^-$ levels lie relatively close together below 1 MeV.Comment: 14 pages, 13 figures, 2 tables. Accepted for publication in Physical Review

Phase III randomized trial comparing moderate-dose cisplatin to combined cisplatin and carboplatin in addition to mitomycin and ifosfamide in patients with stage IV non-small-cell lung cancer

A phase III randomized trial was conducted in patients with metastatic NSCLC, to determine if, in association with mitomycin (6 mg m–2) and ifosfamide (3 g m–2), the combination of moderate dosages of cisplatin (60 mg m–2) and carboplatin (200 mg m–2) – CarboMIP regimen – improved survival in comparison with cisplatin (50 mg m–2) alone – MIP regimen. A total of 305 patients with no prior chemotherapy were randomized, including 297 patients assessable for survival (147 in the MIP arm and 150 in the CarboMIP arm) and 268 patients assessable for response to chemotherapy. All but eight (with malignant pleural effusion) had stage IV disease. There was a 27% (95% CI, 19–34) objective response (OR) rate to MIP (25% of the eligible patients) and a 33% (95% CI, 24–41) OR rate to CarboMIP (29% of the eligible patients). This difference was not statistically significant (P = 0.34). Duration of response was not significantly different between both arms. There was also no difference (P = 0.67) in survival: median survival times were 28 weeks (95% Cl, 24–32) for MIP and 32 weeks (95% Cl, 26–35) for CarboMIP, with respectively 1-year survival rates of 24% and 23% and 2-year survival rates of 5% and 2%. The main toxicities consisted in emesis, alopecia, leucopenia and thrombocytopenia, that were, except alopecia, significantly more severe in the CarboMIP arm. Our trial failed to demonstrate a significant improvement in response or survival when patients with metastatic NSCLC were treated, in addition to ifosfamide and mitomycin, by combination of moderate dosages of cisplatin and carboplatin instead of moderate dosage of cisplatin alone. The results support the use of a moderate dose (50 mg m–2) of cisplatin in combination with ifosfamide and mitomycin for the chemotherapy of this disease. © 2000 Cancer Research Campaig

The CMS Event Builder

The data acquisition system of the CMS experiment at the Large Hadron Collider will employ an event builder which will combine data from about 500 data sources into full events at an aggregate throughput of 100 GByte/s. Several architectures and switch technologies have been evaluated for the DAQ Technical Design Report by measurements with test benches and by simulation. This paper describes studies of an EVB test-bench based on 64 PCs acting as data sources and data consumers and employing both Gigabit Ethernet and Myrinet technologies as the interconnect. In the case of Ethernet, protocols based on Layer-2 frames and on TCP/IP are evaluated. Results from ongoing studies, including measurements on throughput and scaling are presented. The architecture of the baseline CMS event builder will be outlined. The event builder is organised into two stages with intelligent buffers in between. The first stage contains 64 switches performing a first level of data concentration by building super-fragments from fragments of 8 data sources. The second stage combines the 64 super-fragments into full events. This architecture allows installation of the second stage of the event builder in steps, with the overall throughput scaling linearly with the number of switches in the second stage. Possible implementations of the components of the event builder are discussed and the expected performance of the full event builder is outlined.Comment: Conference CHEP0

A new experiment for the determination of the 18F(p,alpha) reaction rate at nova temperatures

The 18F(p,alpha) reaction was recognized as one of the most important for gamma ray astronomy in novae as it governs the early 511 keV emission. However, its rate remains largely uncertain at nova temperatures. A direct measurement of the cross section over the full range of nova energies is impossible because of its vanishing value at low energy and of the short 18F lifetime. Therefore, in order to better constrain this reaction rate, we have performed an indirect experiment taking advantage of the availability of a high purity and intense radioactive 18F beam at the Louvain La Neuve RIB facility. We present here the first results of the data analysis and discuss the consequences.Comment: Contribution to the Classical Novae Explosions conference, Sitges, Spain, 20-24 May 2002, 5 pages, 3 figure

Three-body correlations in Borromean halo nuclei

Three-body correlations in the dissociation of two-neutron halo nuclei are explored using a technique based on intensity interferometry and Dalitz plots. This provides for the combined treatment of both the n-n and core-n interactions in the exit channel. As an example, the breakup of 14Be into 12Be+n+n by Pb and C targets has been analysed and the halo n-n separation extracted. A finite delay between the emission of the neutrons in the reaction on the C target was observed and is attributed to 13Be resonances populated in sequential breakup.Comment: 5 pages, 4 figures, submitted to PR