LIN28B Underlies the Pathogenesis of a Subclass of Ewing Sarcoma

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Energetic eruptions leading to a peculiar hydrogen-rich explosion of a massive star

Every supernova so far observed has been considered to be the terminal explosion of a star. Moreover, all supernovae with absorption lines in their spectra show those lines decreasing in velocity over time, as the ejecta expand and thin, revealing slower-moving material that was previously hidden. In addition, every supernova that exhibits the absorption lines of hydrogen has one main light-curve peak, or a plateau in luminosity, lasting approximately 100 days before declining1. Here we report observations of iPTF14hls, an event that has spectra identical to a hydrogen-rich core-collapse supernova, but characteristics that differ extensively from those of known supernovae. The light curve has at least five peaks and remains bright for more than 600 days; the absorption lines show little to no decrease in velocity; and the radius of the line-forming region is more than an order of magnitude bigger than the radius of the photosphere derived from the continuum emission. These characteristics are consistent with a shell of several tens of solar masses ejected by the progenitor star at supernova-level energies a few hundred days before a terminal explosion. Another possible eruption was recorded at the same position in 1954. Multiple energetic pre-supernova eruptions are expected to occur in stars of 95 to 130 solar masses, which experience the pulsational pair instability2,3,4,5. That model, however, does not account for the continued presence of hydrogen, or the energetics observed here. Another mechanism for the violent ejection of mass in massive stars may be required

The effect of TAT-RasGAP_317-326 as a chemosensitizer of leukemia cells and non-tumor lymphocytes.

<p><b>A.</b> Two acute myeloid leukemia cell lines (THP-1 and M-07e) and one T acute lymphoblastic leukemia cell line (CCRF-CEM) were seeded in 6-well plates and directly treated with 4-HC, etoposide, vincristine or doxorubicin at the indicated concentrations in the presence or in the absence of 10 μM TAT-RasGAP_317-326. After 24 hours of drug incubation, 7-AAD or Annexin V-FITC staining was performed to evaluate cell death (last four columns). Alternatively (first column), the cells were treated with increasing concentrations of TAT or TAT-RasGAP_317-326 alone. After 24 hours, the evaluation of cell death was carried out using 7-AAD staining. <b>B.</b> Isolated lymphocytes from three distinct healthy subjects were treated as described in Fig. 2A. The dosages of chemotherapeutic agents used to treat the healthy lymphocytes from the three subjects are similar to those used to treat the T-ALL CCRF-CEM cells. Note that the graphs are derived from single experiments where lymphocytes are immediately used after their isolation (if cultured <i>in vitro</i>, they would experience high levels of spontaneous apoptosis that would prevent accurate measurement of anti-cancer drug- and peptide-induced death). T-ALL, T-acute lymphoblastic leukemia; AML, acute myeloid leukemia; 4-HC, 4-hydroperoxycyclophosphamide. * p<0.05 t-test after Bonferroni correction.</p

The RasGAP moiety carries the tumor sensitizing activity of TAT-RasGAP_317-326.

<p><b>A.</b> CCRF-CEM cells were seeded in 6-well plates and directly treated with 10 μM TAT-RasGAP_317-326, TAT, TAT-Scrambled or TAT-Mutated in the absence or in the presence of 4-HC, etoposide, vincristine or doxorubicin at the indicated concentrations. After 24 hours of drug incubation, 7-AAD or Annexin V-FITC staining was performed to evaluate cell death. <b>B-C.</b> The TC252 (B) and NB1-FBS (C) cell lines were treated similarly but in combination with 4-HC only. P10, TAT-RasGAP_317-326; TAT-S, TAT-Scrambled; TAT-M, TAT-Mutated; 4-HC, 4-hydroperoxycyclophosphamide. Means with the same letter are not significantly different.</p

Mechanism of action and clinical use of cyclophosphamide, doxorubicin, etoposide and vincristine.

<p>Only the tumor types that were analyzed in this study are mentioned here. The listing was based on the protocols of the Children’s Oncology Group and the International Society of the Pediatric Oncology (EURO-E.W.I.N.G. 99; AALL0232; HR-NBL-1.5/SIOPEN). NB, neuroblastoma; ES, Ewing sarcoma; ALL, acute lymphoblastic leukemia; AML: acute myeloid leukemia.</p><p>Mechanism of action and clinical use of cyclophosphamide, doxorubicin, etoposide and vincristine.</p

TAT-RasGAP_317-326 sensitizes neuroblastoma cells to chemotherapy and displays a direct killing effect on NB1-derived cell lines.

<p><b>A.</b> The light grey thick arrow on top of the figure represents the treatment regimen administrated to the patient from whom the three NB1-derived cell lines were established. The NB1 cells are derived from primary high risk neuroblastoma bone marrow samples. NB1-NBM and NB1-FBS were established at initial diagnosis and cultured in NBM and DMEM media, respectively. NB1-NBM-Re was established at a subsequent relapse and cultured in DMEM. The three NB1-derived cell lines were treated as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120487#pone.0120487.g003" target="_blank">Fig 3</a>. <b>B.</b> The LAN-1 cell line is derived from a high risk neuroblastoma. LAN-1 cells were treated as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120487#pone.0120487.g003" target="_blank">Fig 3</a>. M, month; BM, bone marrow; 4-HC, 4-hydroperoxycyclophosphamide. * p<0.05 t-test after Bonferroni correction.</p

Necrosis-like death induced by 4-HC in CCRF-CEM cells.

<p><b>A.</b> Three hundred thousand CCRF-CEM cells were seeded in 6-well plates and directly treated with 50 μM 4-HC. Cell death was evaluated after several time points (0, 3, 6, 12 and 24 hours) using 7-AAD and Annexin V-FITC staining. <b>B.</b> CCRF-CEM cells were seeded in 6-well plates and directly treated with the indicated doses of 4-HC, etoposide or vincristine in the presence or in the absence of 10 μM TAT-RasGAP_317-326. After 24 hours of drug incubation, 7-AAD and Annexin V-FITC staining was performed to evaluate cell death. 4-HC, 4-hydroperoxycyclophosphamide.</p

Low-carbohydrate, high-fat diets have sex-specific effects on bone health in rats

Studies in humans suggest that consumption of low-carbohydrate, high-fat diets (LC-HF) could be detrimental for growth and bone health. In young male rats, LC-HF diets negatively affect bone health by impairing the growth hormone/insulin-like growth factor axis (GH/IGF axis), while the effects in female rats remain unknown. Therefore, we investigated whether sex-specific effects of LC-HF diets on bone health exist. METHODS: Twelve-week-old male and female Wistar rats were isoenergetically pair-fed either a control diet (CD), "Atkins-style" protein-matched diet (LC-HF-1), or ketogenic low-protein diet (LC-HF-2) for 4 weeks. In females, microcomputed tomography and histomorphometry analyses were performed on the distal femur. Sex hormones were analysed with liquid chromatography-tandem mass spectrometry, and endocrine parameters including GH and IGF-I were measured by immunoassay. RESULTS: Trabecular bone volume, serum IGF-I and the bone formation marker P1NP were lower in male rats fed both LC-HF diets versus CD. LC-HF diets did not impair bone health in female rats, with no change in trabecular or cortical bone volume nor in serum markers of bone turnover between CD versus both LC-HF diet groups. Pituitary GH secretion was lower in female rats fed LC-HF diet, with no difference in circulating IGF-I. Circulating sex hormone concentrations remained unchanged in male and female rats fed LC-HF diets. CONCLUSION: A 4-week consumption of LC-HF diets has sex-specific effects on bone health-with no effects in adult female rats yet negative effects in adult male rats. This response seems to be driven by a sex-specific effect of LC-HF diets on the GH/IGF system

Additional file 1: Figure S1. of Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma

Stem cell markers are enriched during neurosphere culture. Figure S2. DEAB treatment is efficient to transitory inhibit ALDH activity. Figure S3. Illustration of the insertions/deletions in the different ALDH1A3 KO clones. Figure S4. ALDH1A3 KO has no impact on the percentage of ALDH+ cells. (ZIP 3370 kb