Surface Modification by Means of Laser Melting Combined with Shot Peening:A Novel Approach

Among the available laser applications laser surface melting has turned out to be a powerful technique for the production of wear-resistant layers. Despite the advantages of this process, laser surface melting results in tensile stresses which may assist crack propagation. In this paper it will be shown that shot peening can overcome this drawback effectively. It turned out that a preceding laser treatment of an euteetic aluminium-silicon alloy is able to amplify considerably the effectiveness of the shot peening treatment. In particular the maximum attainable hardness and compressive stress increase upon increasing the quench rate, i.e. upon increasing the laser scan velocity. The high concentration of silicon in solid solution turned out to be the main reason for the enhanced mechanical performance, not only directly through solid solution hardening, but also by precipitation hardening and by a higher dislocation density. The latter contribution is affected indirectly by a changed cross slip behaviour

Reduction of the Tensile Stress State in Laser Treated Materials

It is well known that by laser melting the wear performance of metals can be improved [ 1]. After laser treatment the surface may consist of a dendritic structure consisting of tiny cells (order of ~tm). Carbide particles may also become homogeneously dispersed. Despite these advantages, the laser treatment often results in a tensile stress in the surface layer which in the case of RCC steel (2.05 wt. % C, 11.05 wt. % Cr, 0.62 wt. % W, an

Axion Clouds around Neutron Stars

Recent work has shown that axions can be efficiently produced via non-stationary pair plasma discharges in the polar cap region of pulsars. Here, we point out that for axion masses $10^{-9} \, {\rm eV} \lesssim m_a \lesssim 10^{-4} \, \rm eV$, a sizable fraction of the sourced axion population will be gravitationally confined to the neutron star. These axions accumulate over astrophysical timescales, thereby forming a dense `axion cloud' around the star. We argue that the existence of such a cloud, with densities reaching and potentially exceeding $\mathcal{O}(10^{22}) \, {\rm GeV \, cm^{-3}}$, is a generic expectation across a wide range of parameter space. For axion masses $m_a \gtrsim 10^{-7} \, \rm eV$, energy is primarily radiated from the axion cloud via resonant axion-photon mixing, generating a number of distinctive signatures that include: a sharp line in the radio spectrum of each pulsar (located at the axion mass, and with a percent-level width), and transient events arising from the reconfiguration of charge densities in the magnetosphere. While a deeper understanding of the systematic uncertainties in these systems is required, our current estimates suggest that existing radio telescopes could improve sensitivity to the axion-photon coupling by more than an order of magnitude.Comment: 17 pages, 14 figure

Novel Constraints on Axions Produced in Pulsar Polar-Cap Cascades

Axions can be copiously produced in localized regions of neutron star magnetospheres where the ambient plasma is unable to efficiently screen the induced electric field. As these axions stream away from the neutron star they can resonantly transition into photons, generating a large broadband contribution to the neutron star's intrinsic radio flux. In this work, we develop a comprehensive end-to-end framework to model this process from the initial production of axions to the final detection of radio photons, and derive constraints on the axion-photon coupling, $g_{a\gamma\gamma}$, using observations of 27 nearby pulsars. We study the modeling uncertainty in the sourced axion spectrum by comparing predictions from 2.5 dimensional particle-in-cell simulations with those derived using a semi-analytic model; these results show remarkable agreement, leading to constraints on the axion-photon coupling that typically differ by a factor of no more than $\sim 2$. The limits presented here are the strongest to date for axion masses $10^{-8} \, {\rm eV} \lesssim m_a \lesssim 10^{-5} \, {\rm eV}$, and crucially do not rely on the assumption that axions are dark matter.Comment: v2: Updated to match published version. Added new SM sections on analysis and uncertainties, updated plots, and corrected minor bugs and typos. v1: 5 pages, 2 figures + Supplementary Materia

Antiproliferative activity, mechanism of action and oral antitumor activity of CP-4126, a fatty acid derivative of gemcitabine, in in vitro and in vivo tumor models

Gemcitabine is a deoxycytidine (dCyd) analog with activity in leukemia and solid tumors, which requires phosphorylation by deoxycytidine kinase (dCK). Decreased membrane transport is a mechanism of resistance to gemcitabine. In order to facilitate gemcitabine uptake and prolong retention in the cell, a lipophilic pro-drug was synthesized (CP-4126), with an elaidic fatty acid esterified at the 5'position. CP-4126 was tested in cell lines resistant to cytarabine, another dCyd analog or gemcitabine. Activity of gemcitabine and the derivative was comparable in the parent cell lines, while in dCK deficient cells all compounds were inactive. However, inhibition of nucleoside transport increased the IC(50) for gemcitabine up to 200-fold, but not for CP-4126, underlining the independence of a nucleoside transporter. For in vivo evaluation, nude mice bearing a human xenograft were treated intraperitoneally every third day for five doses at the maximal tolerated dose. In melanoma, sarcoma, lung, prostate, pancreatic and breast cancer xenografts, gemcitabine and CP-4126 were equally and highly effective; in four other xenografts moderately but equally active. In contrast to gemcitabine, CP-4126 could be administered orally, with a schedule and dose dependent toxicity and antitumor activity. In a colon cancer xenograft, antitumor activity of orally administered CP-4126 was equal to the intraperitoneally administered drug. In conclusion, CP-4126 is membrane transporter independent. Intraperitoneally administered CP-4126 was as effective as gemcitabine in several xenografts and CP-4126 is tolerated when orally administered. CP-4126 seems to be a promising new anticancer drug

The role of ATM and 53BP1 as predictive markers in cervical cancer

Treatment of advanced-stage cervical cancers with (chemo)radiation causes cytotoxicity through induction of high levels of DNA damage. Tumour cells respond to DNA damage by activation of the DNA damage response (DDR), which induces DNA repair and may counteract chemoradiation efficacy. Here, we investigated DDR components as potential therapeutic targets and verified the predictive and prognostic value of DDR activation in patients with cervical cancer treated with (chemo)radiation. In a panel of cervical cancer cell lines, inactivation of ataxia telangiectasia mutated (ATM) or its substrate p53-binding protein-1 (53BP1) clearly gave rise to cell cycle defects in response to irradiation. Concordantly, clonogenic survival analysis revealed that ATM inhibition, but not 53BP1 depletion, strongly radiosensitised cervical cancer cells. In contrast, ATM inhibition did not radiosensitise non-transformed epithelial cells or non-transformed BJ fibroblasts. Interestingly, high levels of active ATM prior to irradiation were related with increased radioresistance. To test whether active ATM in tumours prior to treatment also resulted in resistance to therapy, immunohistochemistry was performed on tumour material of patients with advanced-stage cervical cancer (n = 375) treated with (chemo)radiation. High levels of phosphorylated (p-)ATM [p = 0.006, hazard ratio (HR) = 1.817] were related to poor locoregional disease-free survival. Furthermore, high levels of p-ATM predicted shorter disease-specific survival (p = 0.038, HR = 1.418). The presence of phosphorylated 53BP1 was associated with p-ATM (p = 0.001, odds ratio = 2.206) but was not related to any clinicopathological features or survival. In conclusion, both our in vitro and patient-related findings indicate a protective role for ATM in response to (chemo)radiation in cervical cancer and point at ATM inhibition as a possible means to improve the efficacy of (chemo)radiation

Inhibition of radiation induced migration of human head and neck squamous cell carcinoma cells by blocking of EGF receptor pathways

<p>Abstract</p> <p>Background</p> <p>Recently it has been shown that radiation induces migration of glioma cells and facilitates a further spread of tumor cells locally and systemically. The aim of this study was to evaluate whether radiotherapy induces migration in head and neck squamous cell carcinoma (HNSCC). A further aim was to investigate the effects of blocking the epidermal growth factor receptor (EGFR) and its downstream pathways (Raf/MEK/ERK, PI3K/Akt) on tumor cell migration in vitro.</p> <p>Methods</p> <p>Migration of tumor cells was assessed via a wound healing assay and proliferation by a MTT colorimeritric assay using 3 HNSCC cell lines (BHY, CAL-27, HN). The cells were treated with increasing doses of irradiation (2 Gy, 5 Gy, 8 Gy) in the presence or absence of EGF, EGFR-antagonist (AG1478) or inhibitors of the downstream pathways PI3K (LY294002), mTOR (rapamycin) and MEK1 (PD98059). Biochemical activation of EGFR and the downstream markers Akt and ERK were examined by Western blot analysis.</p> <p>Results</p> <p>In absence of stimulation or inhibition, increasing doses of irradiation induced a dose-dependent enhancement of migrating cells (p < 0.05 for the 3 HNSCC cell lines) and a decrease of cell proliferation (p < 0.05 for the 3 HNSCC cell lines). The inhibition of EGFR or the downstream pathways reduced cell migration significantly (almost all p < 0.05 for the 3 HNSCC cell lines). Stimulation of HNSCC cells with EGF caused a significant increase in migration (p < 0.05 for the 3 HNSCC cell lines). After irradiation alone a pronounced activation of EGFR was observed by Western blot analysis.</p> <p>Conclusion</p> <p>Our results demonstrate that the EGFR is involved in radiation induced migration of HNSCC cells. Therefore EGFR or the downstream pathways might be a target for the treatment of HNSCC to improve the efficacy of radiotherapy.</p

MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines

<p>Abstract</p> <p>Background</p> <p>Frequent failure and severe side effects of current sarcoma therapy warrants new therapeutic approaches. The small-molecule MDM2 antagonist Nutlin-3a activates the p53 pathway and efficiently induces apoptosis in tumours with amplified <it>MDM2 </it>gene and overexpression of MDM2 protein. However, the majority of human sarcomas have normal level of MDM2 and the therapeutic potential of MDM2 antagonists in this group is still unclear. We have investigated if Nutlin-3a could be employed to augment the response to traditional therapy and/or reduce the genotoxic burden of chemotherapy.</p> <p>Methods</p> <p>A panel of sarcoma cell lines with different <it>TP53 </it>and <it>MDM2 </it>status were treated with Nutlin-3a combined with Doxorubicin, Methotrexate or Cisplatin, and their combination index determined.</p> <p>Results</p> <p>Clear synergism was observed when Doxorubicin and Nutlin-3a were combined in cell lines with wild-type <it>TP53 </it>and amplified <it>MDM2</it>, or with Methotrexate in both <it>MDM2 </it>normal and amplified sarcoma cell lines, allowing for up to tenfold reduction of cytotoxic drug dose. Interestingly, Nutlin-3a seemed to potentiate the effect of classical drugs as Doxorubicin and Cisplatin in cell lines with mutated <it>TP53</it>, but inhibited the effect of Methotrexate.</p> <p>Conclusion</p> <p>The use of Nutlin in combination with classical sarcoma chemotherapy shows promising preclinical potential, but since clear biomarkers are still lacking, clinical trials should be followed up with detailed tumour profiling.</p