Abstract Patients diagnosed with advanced gastrointestinal stromal tumours (GISTs) who are resistant or intolerant to both imatinib and second-line sunitinib have a poor prognosis and few therapeutic ...options. We evaluated the efficacy of nilotinib, a novel tyrosine kinase inhibitor (TKI) in patients pretreated with imatinib and sunitinib. Fifty-two consecutive patients treated with oral nilotinib, 400 mg twice daily, within the nilotinib compassionate use programme in 12 European cancer centres, were included in this retrospective analysis. Median age was 59 years (range 24–80), and all patients had WHO performance score better than 3. All patients had failed both imatinib and sunitinib pretreatment, either due to progressing GIST (96%) or intolerance (4%). Five patients (10%; 95% confidence interval (CI) 2–18) responded to nilotinib and 19 patients (37%; 95% CI 24–50) achieved a disease stabilisation. Nilotinib was generally well tolerated, but six patients (12%) discontinued treatment due to intolerance. Median progression-free survival of nilotinib treatment was 12 weeks (95% CI 9–15; range 0–104) and median overall survival was 34 weeks (95% CI 3–65; range 2–135). Nilotinib is active in GIST resistant to both imatinib and sunitinib. These results warrant further investigation of nilotinib in GIST.
Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting ...histone deacetylases to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1 expression (GFI1-KD). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients.
Abstract Background Tyrosine kinase inhibitors (TKI) improve the outcome of patients with advanced gastrointestinal stromal tumour (GIST), but treatment failure is frequent, and prognosis then bleak. ...Smaller trials in this setting suggested activity for sorafenib, a multikinase inhibitor of receptor tyrosine kinases and RAF serine/threonine kinases. Patients and methods We retrospectively evaluated the efficacy of sorafenib, starting dose 400 mg twice daily, in a large community-based cohort of 124 patients treated in 12 European and one United States (U.S.) cancer centre. All but one patient had a WHO performance score 0–2. All had failed both imatinib and sunitinib, 68 patients nilotinib and 26 had failed investigational therapy, too. Results Twelve (10%) patients responded to sorafenib and 70 (57%) patients achieved disease stabilisation. Sorafenib was moderately tolerated, and toxicity reported in 56% of the patients. Rash, hand-foot-syndrome and diarrhea occurred frequently. Sorafenib dosage was reduced in a third of patients, but this did not have an impact on progression-free survival (PFS) ( p = 0.15). Median PFS was 6.4 months (95% confidence interval CI, 4.6–8.0 months) and median overall survival (OS) 13.5 months (95% CI, 10.0–21.0 months). Patients with a good performance status and those who responded to sorafenib had a significant better PFS. Conclusion We conclude that sorafenib is active in GIST resistant to imatinib, sunitinib and nilotinib. These results warrant further investigation of sorafenib or similar molecules in GIST.
The growth modulation index (GMI) is the ratio of time to progression with the nth line (TTPn) of therapy to the TTPn-1 with the n-1th line. GMI >1.33 is considered as a sign of activity in phase II ...trials.
This retrospective analysis evaluated the concordance between the GMI and the efficacy outcomes in 279 patients with advanced soft tissue sarcoma (ASTS) treated with trabectedin 1.5 mg/m² (24-h infusion every 3 weeks) in four phase II trials.
One hundred and forty-two (51%) patients received one prior line and 137 ≥2 lines. The median TTPn was 2.8 months (range 0.2–26.8), whereas the median TTPn-1 was 4.0 months (0.3–79.5). The median GMI was 0.6 (0.0–14.4). Overall, 177 patients (63%) had a GMI <1; 21 (8%) a GMI equal to 1–1.33 and 81 (29%) a GMI >1.33, which correlated with the median overall survival in those patients (9.1, 13.9 and 23.8 months, respectively, P = 0.0005). A high concordance rate between the GMI and response rate (P < 0.0001) and progression-free survival (PFS, P < 0.0001) was observed. Good performance status (PS) was the only factor associated with GMI >1.33 (PS = 0; P < 0.04).
A high GMI was associated with favorable efficacy outcomes in patients treated with trabectedin. Further research is needed to assess GMI as an indicator in this setting.
Joints are cost-intensive and have a great influence on the properties of a joined assembly. There is a wide variety of research on optimizing the joint distribution in an assembly. These ...optimizations are performed with joint models, which are rotational symmetrical and thus have transversely isotropic properties. The potential of joints with direction-dependent stiffness is not exploited in those studies. Joints with different shear stiffness can be oriented concerning the local planar force distribution. In this way, individual joints can be designed regarding the local force distribution and the overall properties of the assembly.
This paper presents a method to identify these joints based on numerical simulations. For this purpose, a multibody full vehicle model is created, and various steady state driving simulations are carried out. Within these simulations, both the forces at the suspension struts and the connections between subframe and body are determined. Subsequently, these forces are defined as input of an implicit finite element model of the vehicle body, where the joint forces are calculated. Finally, the joint forces of various driving maneuvers and static load cases are superposed and evaluated.
With the presented methodology the joints which are suitable for a load adapted shape are successfully determined. The results show great potential for the use of joints with fully anisotropic properties in a vehicle body, which is currently not realized. Joints with three different stiffness could enhance the stiffness properties of a vehicle body.
Abstract The thermal plasma filling the early universe generated a stochastic gravitational wave background that peaks in the microwave frequency range today. If the graviton production rate is ...expressed as a series in a fine-structure constant, α , and the temperature over the Planck mass, T 2 / m pl 2 , then the lowest-order contributions come from single (∼ αT 2 / m pl 2 ) and double (∼ T 4 / m pl 4 ) graviton production via 2 → 2 scatterings. We show that in the Standard Model, single-graviton production dominates if the maximal temperature is smaller than 4 × 10 18 GeV. This justifies previous calculations which relied solely on single-graviton production. We mention Beyond the Standard Model scenarios in which the single and double-graviton contributions could be of comparable magnitudes. Finally, we elaborate on what these results imply for the range of applicability of General Relativity as an effective theory.
LMO1 is a transcriptional regulator and a T-acute lymphoblastic leukaemia (T-ALL) oncogene. Although first identified in association with a chromosomal translocation in T-ALL, the ectopic expression ...of LMO1 occurs far more frequently in the absence of any known mutation involving its locus. Given that LMO1 is barely expressed in any haematopoietic lineage, and activation of transcriptional drivers in leukaemic cells is not well described, we investigated the regulation of this gene in normal haematopoietic and leukaemic cells. We show that LMO1 has two promoters that drive reporter gene expression in transgenic mice to neural tissues known to express endogenous LMO1. The LMO1 promoters display bivalent histone marks in multiple blood lineages including T-cells, and a 3' flanking region at LMO1 +57 contains a transcriptional enhancer that is active in developing blood cells in transgenic mouse embryos. The LMO1 promoters become activated in T-ALL together with the 3' enhancer, which is bound in primary T-ALL cells by SCL/TAL1 and GATA3. Taken together, our results show that LMO1 is poised for expression in normal progenitors, where activation of SCL/TAL1 together with a breakdown of epigenetic repression of LMO1 regulatory elements induces ectopic LMO1 expression that contributes to the development and maintenance of T-ALL.
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