Oxidative stress as a result of cigarette smoking is an important etiologic factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), a chronic steroid-insensitive inflammatory disease of the airways. Histone deacetylase-2 (HDAC2), a critical component of the corticosteroid anti-inflammatory action, is impaired in lungs of patients with COPD and correlates with disease severity. We demonstrate here that curcumin (diferuloylmethane), a dietary polyphenol, at nanomolar concentrations specifically restores cigarette smoke extract (CSE)-or oxidative stress-impaired HDAC2 activity and corticosteroid efficacy in vitro with an EC 50 of approximately 30 nM and 200 nM, respectively. CSE caused a reduction in HDAC2 protein expression that was restored by curcumin. This decrease in HDAC2 protein expression was reversed by curcumin even in the presence of cycloheximide, a protein synthesis inhibitor. The proteasomal inhibitor, MG132, also blocked CSE-induced HDAC2 degradation, increasing the levels of ubiquitinated HDAC2. Biochemical and gene chip analysis indicated that curcumin at concentrations up to 1 mM propagates its effect via antioxidant-independent mechanisms associated with the phosphorylation-ubiquitin-proteasome pathway. Thus curcumin acts at a post-translational level by maintaining both HDAC2 activity and expression, thereby reversing steroid insensitivity induced by either CSE or oxidative stress in monocytes. Curcumin may therefore have potential to reverse steroid resistance, which is common in patients with COPD and asthma.

The ATM/p53-dependent DNA damage response pathway plays an important role in the progression of lymphoid tumors. Inactivation of the ATM or TP53 gene is frequent in B-cell lymphocytic leukemia (B-CLL) and leads to aggressive disease. Although the ATM and p53 pathways overlap, they are not congruent, and it is unclear how the mechanism of tumor progression differs between ATM-and p53-deficient tumors. Using microarray analysis of ATM-mutant, TP53-mutant, and ATM/TP53 wild-type B-CLLs, we show that after exposure to DNA damage transcriptional responses are entirely dependent on ATM function. The p53 proapoptotic responses comprise only a part of ATMregulated transcription; additionally, ATM regulates prosurvival responses independently of p53. Consequently, the greater severity of the TP53-mutant B-CLLs compared with ATM-mutant B-CLLs is consistent with the additive effect of defective apoptotic and elevated survival responses after DNA damage in these tumors. We also show that transcription expression profiles of ATM-deficient, TP53-deficient, and wild-type B-CLLs are indistinguishable before irradiation. Therefore, damage-induced transcriptional fingerprinting can be used to stratify tumors according to their biologic differences and simultaneously identify potential targets for treating refractory tumors. IntroductionChronic B-cell lymphocytic leukemia (B-CLL) is the most common leukemia in western countries and is characterized by the proliferation of mature B cells. 1 Considerable clinical heterogeneity exists among patients with B-CLL. Some patients have stable disease for many years, whereas others have rapidly progressing disease and short life expectancy. Recently, a number of genetic markers have been identified that directly influence the progression of disease. The mutational status of the immunoglobulin heavy chain (V H ) gene distinguishes biologically distinct B-CLL subtypes, 2,3 and B-CLL tumors with unmutated V H genes are generally associated with rapid clinical progression, whereas those that have accumulated somatic mutations in the V H gene characteristically have a more indolent outcome. However, it is now clear that this simple subdivision does not always adequately predict clinical behavior, and the mutational state of genes associated with the DNA damage response pathway has been shown to provide more powerful predictive information. 4 The DNA damage response pathway plays a crucial role in the etiology and clinical behavior of malignant cells. Inducing tumor cell death by ionizing radiation (IR) and many cytotoxic drugs causes DNA double-strand breaks (DSBs), 5 and the inactivation of genes that regulate the response to DSBs is commonly found in human cancer. The ATM protein is the principal integrator of the various cellular responses to DSBs. 6 Critically, ATM is responsible for activating the p53 tumor-suppressor protein, leading to the up-regulation of p53-responsive genes that promote cell-cycle arrest and apoptosis. Outcomes of p53 activation, however, depend on the cellular contex...

Key Points• We develop and validate Karyogene, a comprehensive one-stop diagnostic platform for the genomic analysis of myeloid malignancies.• Karyogene simultaneously detects substitutions, insertions/deletions, translocations, copy number and zygosity changes in a single assay.The diagnosis of hematologic malignancies relies on multidisciplinary workflows involving morphology, flow cytometry, cytogenetic, and molecular genetic analyses. Advances in cancer genomics have identified numerous recurrent mutations with clear prognostic and/or therapeutic significance to different cancers. In myeloid malignancies, there is a clinical imperative to test for such mutations in mainstream diagnosis; however, progress toward this has been slow and piecemeal. Here we describe Karyogene, an integrated targeted resequencing/analytical platform that detects nucleotide substitutions, insertions/deletions, chromosomal translocations, copy number abnormalities, and zygosity changes in a single assay. We validate the approach against 62 acute myeloid leukemia, 50 myelodysplastic syndrome, and 40 blood DNA samples from individuals without evidence of clonal blood disorders. We demonstrate robust detection of sequence changes in 49 genes, including difficult-to-detect mutations such as FLT3 internal-tandem and mixed-lineage leukemia (MLL) partial-tandem duplications, and clinically significant chromosomal rearrangements including MLL translocations to known and unknown partners, identifying the novel fusion gene MLL-DIAPH2 in the process. Additionally, we identify most significant chromosomal gains and losses, and several copy neutral loss-of-heterozygosity mutations at a genome-wide level, including previously unreported changes such as homozygosity for DNMT3A R882 mutations. Karyogene represents a dependable genomic diagnosis platform for translational research and for the clinical management of myeloid malignancies, which can be readily adapted for use in other cancers. (Blood. 2016;128(1):e1-e9)

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This paper presents results of testing carried out to assess the wear and RCF performance of laser clad rail. Stronger and harder materials can be laser clad on top of the working surfaces of standard (e.g. 260 grade) rail in order to improve wear and RCF life. A twin-disc method has been used to assess the suitability of various candidate cladding materials. The materials were clad on top of 260 grade rail discs and were tested against a disc of standard wheel material. Wear was measured by weighing the discs before and after each test. An Ellotest B1 differential eddy current crack detector was used to detect RCF cracks in the rail disc. Four clad materials were used namely, Hadfield, Stellite 6, Maraging and 316 Stainless Steels. In the tests carried out, wear was not always reduced with the cladding. The tests carried out were not long enough for some of the materials to fully work harden and therefore some would improve with a greater number of cycles. However, all but the Stainless Steel showed that they did not deform under the cyclic loading applied and would offer a greatly enhanced RCF life.

A simple method has been developed for the calculation of stress intensity factors for cracks growing by a shear mechanism under contact loading (typical of rolling contacts) which includes the consideration of friction between the crack faces. The results compare well with the existing data from more complex models.

In the mid-2000s, a new rail defect that was initially classified as a squat became increasingly common on London Underground's track. By 2006, there were about 600 of these and they had become the Underground's single most common rail defect. This defect occurred almost exclusively on lines carrying relatively new rolling stock. The work reported here was undertaken initially to characterize this defect, advise as to whether it was indeed a squat, and propose a hypothesis that explained its mechanism of formation. This paper includes observations and track measurements made in the field and initial results of a metallurgical analysis. The hypothesis for formation of the defects is presented, and both similarities and differences are discussed between these defects and the classical 'squat'. The defect on London Underground appears to be the same as that described by Marich and his colleagues in Australia and by Li and his colleagues in the Netherlands. It is evidently not a conventional rolling contact fatigue defect. In order to avoid confusion arising from simple misuse of an established term, it is proposed that these defects be given a different name, for which 'stud' is proposed. Evidence to date is that the 'stud' is a significantly more benign defect than the 'squat'.

To combat adhesion loss, sand is fired into the wheel/rail contact via a hose using compressed air typically from a storage hopper mounted to the under frame of the train. Many passenger trains in the UK are fitted with stepped braking controllers which range from 1 to 3 with a 4 th 1]. According to GM/RT2461, [2], from brake step level 2 upwards, sand is fired automatically if wheel-slip is detected. Sand is automatically fired when the emergency brakes are applied irrespective of whether low adhesion/wheel slip has been detected [2]. For adhesion loss in traction, sand can be Current railway standards [2] govern the maximum permissible sand flow rate to protect against impact wheel/rail isolation on track circuits, but do not address the hose position. This results in a range of hose setups across different train types, some of which may not be effective at delivering sand. The work here was carried out using a full-scale laboratory rail-wheel test machine to find the position for the hose and sand flow rates that give optimum sand entrainment to the contact. It was found that ideally the hose should be aimed at the rail or nip and be as close to that contact as safely possible. The use of a 20mm bore nozzle on the end of a 25mm bore hose increased sand passing through the contact by up to 70% relative to widely used 25mm bore hoses without a nozzle. Reduction in sand flow rate below the 2 kg/min threshold significantly reduced the amount of sand entering the contact. It was also shown that relatively small movements in the hose/nozzle from its ideal position and cross winds significantly reduced sand entrainment.