Characteristics and outcome of patients with core-binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study

The aim of this study was to evaluate the prognostic impact of FLT3-ITD in core-binding factor acute myeloid leukemia (CBFAML) in an international, multicenter survey of 97 patients of whom 52% had t(8;21)(q22;q22) and 48% had inv(16)(p13q22)/t(16;16)(p13;q22). The median age of the patients was 53 years (range, 19-81). Complete remission after anthracycline-based induction (n=86) and non-intensive therapy (n=11) was achieved in 97% and 36% of the patients, respectively. The median follow-up was 4.43 years (95% confidence interval [95% CI]: 3.35-7.39 years). The median survival after intensive and non-intensive treatment was not reached and 0.96 years, respectively. Among intensively treated patients, inv(16) with trisomy 22 (n=11) was associated with a favorable 4-year relapse-free survival rate of 80% (95% CI: 59-100%) as compared to 38% (95% CI: 27-54%; P=0.02) in all other patients with CBFAML/ FLT3-ITD (n=75). Overall, 24 patients underwent allogeneic hematopoietic cell transplantation (HCT), 12 in first complete remission and 12 after relapse. Allogeneic HCT in first complete remission was not beneficial (P=0.60); however, allogeneic HCT seemed to improve median survival in relapsed patients compared to that of patients treated with chemotherapy (not reached vs. 0.6 years, respectively; P=0.002). Excluding patients with inv(16) with trisomy 22, our data indicate that the outcome of CBF-AML patients with FLT3-ITD may be inferior to that of patients without FLT3-ITD (based on previously published data), suggesting that prognostically CBF-AML patients with FLT3-ITD should not be classified as favorable-risk. FLT3-inhibitors may improve the outcome of these patients.     

Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohn's disease

BACKGROUND: The human anti-tumour necrosis factor (TNF) antibody infliximab binds to the membrane TNF and subsequently induces apoptosis of activated lamina propria T lymphocytes in patients with Crohn's disease in vitro. AIM: To test whether the ability of rapid anti-TNF-induced apoptosis in the gut predicts the efficacy of anti-TNF treatment in inflammatory bowel disease. METHODS: (99m)Technetium-annexin V single-photon emission computer tomography (SPECT) was performed in 2 models of murine experimental colitis and in 14 patients with active Crohn's disease as assessed by the Crohńs Disease Activity Index (CDAI) to study the effect of anti-TNF treatment on apoptosis in the intestine during active colitis. Disease activity was evaluated 2 weeks after infliximab infusion using the CDAI (definition response: drop of >100 points). RESULTS: Colonic uptake of (99m)Tc-annexin V significantly increased in 2,4,6-trinitrobenzene sulphonate-induced colitis as well as in transfer colitis on administration of anti-TNF antibodies compared with a control antibody as determined with dedicated animal pinhole SPECT. In addition, uptake of (99m)Tc-annexin V significantly increased in patients with active Crohn's disease responding to infliximab treatment. Colonic (99m)Tc-annexin V uptake ratio (mean (SEM)) increased from 0.24 (0.03) to 0.41(0.07) (p<0.01), 24 h after infliximab infusion (5 mg/kg). A mean increase of 98.7% in colonic uptake of (99m)Tc-annexin V could be detected in 10 of the 14 responding patients (CDAI >100 points at week 2) compared with 15.2% in non-responding patients (p = 0.03). Analysis of the mucosal biopsy specimens identified lamina propria T cells as target cells undergoing apoptosis. CONCLUSIONS: These in vivo observations support the notion that colonic uptake of (99m)Tc-annexin V correlates with clinical benefit of anti-TNF treatment and might be predictive of therapeutic success.     

Rotational Stiffness and Carrying Capacity of Timber Frame Corners with Dowel Type Connections

With the development of wooden structures and buildings, there is a need to research physical and numerical tests of wood-based structures. The presented research is focused on construction and computational approaches for new types of joints to use in wooden structures, particularly glued lamella elements made of wood and wood-based composites. This article focuses on improving the frame connection of a wooden post and a beam with the use of fasteners to ensure better load-bearing capacity and stiffness of the structure. In common practice, bolts or a combination of bolts and pins are used for this type of connection. The aim is to replace these commonly used fasteners with modern ones, namely full thread screws. The aim is also to shorten and simplify the assembly time in order to improve the load-bearing capacity and rigidity of this type of frame connection. Two variations of the experimental test were tested in this research. The first contained bolts and pins as connecting means and the second contained the connecting means of a full threaded screw. Each experiment contained a total of two tests. For a detailed study of the problem, we used a 2D or 3D computational model that models individual components, including fasteners.     

Corrosion Behavior of an Mg2Sn Alloy

In the present work, the corrosion behavior of the Mg₂Sn alloy (Mg_66.7Sn_33.3, concentration in at.%) has been studied. The alloy was prepared from high purity Sn and Mg lumps by induction melting in argon. The alloy was composed of intermetallic Mg₂Sn with a small amount of Mg₂Sn + (Sn) eutectic. The corrosion behavior was studied by hydrogen evolution, immersion, and potentiodynamic experiments. Three aqueous solutions of NaCl (3.5 wt.%), NaOH (0.1 wt.%) and HCl (0.1 wt.%) were chosen as corrosion media. The alloy was found to be cathodic with respect to metallic Mg and anodic with respect to Sn. The corrosion potentials of the Mg₂Sn alloy were −1380, −1498 and −1361 mV vs. sat. Ag/AgCl in HCl, NaCl and NaOH solutions, respectively. The highest corrosion rate of the alloy, 92 mmpy, was found in aqueous HCl. The high corrosion rate was accompanied by massive hydrogen evolution on the alloy’s surface. The corrosion rate was found to decrease sharply with increasing pH of the electrolyte. In the NaOH electrolyte, a passivation of the alloy was observed. The corrosion of the alloy involved a simultaneous oxidation of Mg and Sn. The main corrosion products on the alloy surface were MgSn(OH)₆ and Mg(OH)₂. The corrosion mechanism is discussed and implications for practical applications of the alloy are provided.     

Differential gene expression in cisplatin-resistant and -sensitive testicular germ cell tumor cell lines

Testicular germ cell tumors (TGCTs) represent a well curable malignity due to their exceptional response to cisplatin (CDDP). Despite remarkable treatment results, approximately 5% of TGCT patients develop CDDP resistance and die. Exceptional curability makes TGCTs a highly valuable model system for studying the molecular mechanisms of CDDP sensitivity. Our study was aimed at revealing difference in gene expression between the CDDP-resistant and -sensitive TGCT cell lines, and hence at identifying candidate genes that could serve as potential biomarkers of CDDP response. Using gene expression array, we identified 281 genes that are differentially expressed in CDDP-resistant compared to -sensitive TGCT cell lines. The expression of 25 genes with the highest fold change was validated by RT-qPCR. Of them, DNMT3L, GAL, IGFBP2, IGFBP7, L1TD1, NANOG, NTF3, POU5F1, SOX2, WNT6, ZFP42, ID2, PCP4, SLC40A1 and TRIB3, displayed comparable expression change in gene expression array and RT-qPCR, when all CDDP-resistant TGCT cell lines were pairwise combined with all -sensitive ones. Products of the identified genes are pluripotency factors, or are involved in processes, such as cell metabolism, proliferation or migration. We propose that, after clinical validation, these genes could serve as prognostic biomarkers for early detection of CDDP response in TGCT patients.