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Low-dose aspirin and metformin have been individually associated with a reduced risk of cancer. Whether their concurrent use in adults with type 2 diabetes mellitus (T2DM) is associated with a reduced risk of colorectal cancer (CRC) is unclear.Among individuals with T2DM taking metformin, we sought to evaluate the association between low-dose aspirin versus no aspirin and the risk of CRC.A multiple-database new-user cohort study of patients with T2DM taking metformin was conducted between 2007-2010 (Clinical Data Analysis and Reporting System [CDARS], Hong Kong) and 2007-2016 (The Health Improvement Network [THIN], UK). The primary outcome was incident CRC. Patients were followed from index date of prescription until the earliest occurrence of an outcome of interest, an incident diagnosis of any cancer, death, or until December 31, 2019. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Estimates were pooled using an inverse variance random effects model, and heterogeneity was assessed using IAfter one-to-one propensity-score matching, 57,534 patients were included (CDARS = 16,276; THIN = 41,258). The median (IQR) follow-up was 9.3 (6.5-10.7) years in CDARS and 3.2 (1.1-5.8) years in THIN. The concurrent use of low-dose aspirin and metformin was not associated with a lower risk of CRC compared to metformin only (HR = 0.89, 95% CI 0.75-1.05, ILow-dose aspirin was not associated with a lower risk of CRC in patients with T2DM taking metformin. Our study does not support the routine use of low-dose aspirin in this population. This article is protected by copyright. All rights reserved.

Burkitt lymphoma (BL) is a malignant disease, which is frequently found in areas with holoendemic Plasmodium falciparum malaria. We have previously found that the VAR2CSA protein is present on malaria-infected erythrocytes and facilitates a highly specific binding to the placenta. ofCS is absent in other non-malignant tissues and thus VAR2CSA generally facilitates parasite sequestration and accumulation in pregnant women. In this study, we show that the specific receptor for VAR2CSA, the oncofetal chondroitin sulfate (ofCS), is likewise present in BL tissue and cell lines. We therefore explored whether ofCS in BL could act as anchor site for VAR2CSA-expressing infected erythrocytes. In contrast to the placenta, we found no evidence of in vivo sequestering of infected erythrocytes in the BL tissue. Furthermore, we found VAR2CSA-specific antibody titers in children with endemic BL to be lower than in control children from the same malaria endemic region. The abundant presence of ofCS in BL tissue and the absence of ofCS in non-malignant tissue encouraged us to examine whether recombinant VAR2CSA could be used to target BL. We confirmed the binding of VAR2CSA to BL-derived cells and showed that a VAR2CSA drug conjugate efficiently killed the BL-derived cell lines in vitro. These results identify ofCS as a novel therapeutic BL target and highlight how VAR2CSA could be used as a tool for the discovery of novel approaches for directing BL therapy.

This work explores the application of a new one-dimensional carbon nanomaterial, the diamond nanothread (DNT), as a reinforcement for nanocomposites. Owing to the existence of Stone-Wales transformation defects, the DNT intrinsically possesses irregular surfaces, which is expected to enhance the non-covalent interfacial load transfer. Through a series of in silico pull-out studies of the DNT in polyethylene (PE) matrix, we found that the load transfer between DNT and PE matrix is dominated by the non-covalent interactions, in particular the van der Waals interactions. Although the hydrogenated surface of the DNT reduces the strength of the van der Waals interactions at the interface, the irregular surface of the DNT can compensate for the weak bonds. These factors lead to an interfacial shear strength of the DNT/PE interface comparable with that of the carbon nanotube (CNT)/PE interface. Our results show that the DNT/PE interfacial shear strength remains high even as the number of Stone-Wales transformation defects decreases. It can be enhanced further by increasing the PE density or introduction of functional groups to the DNT, both of which greatly increase the non-covalent interactions., in press, early view online in Advanced Functional Materials, 2016

Head injuries due to complex blasts are not well examined due to limited published articles on the subject. Previous studies have analyzed head injuries due to impact from a single planar blast wave. Complex or concomitant blasts refer to impacts usually caused by more than a single blast source, whereby the blast waves may impact the head simultaneously or consecutively, depending on the locations and distances of the blast sources from the subject, their blast intensities, the sequence of detonations, as well as the effect of blast wave reflections from rigid walls. It is expected that such scenarios will result in more serious head injuries as compared to impact from a single blast wave, due to the larger effective duration of the blast. In this paper, the utilization of a head-helmet model for blast impact analyses in Abaqus™ is demonstrated. The model is validated against studies published in literature. RESULTS show that the skull is capable of transmitting the blast impact to cause high intracranial pressures. In addition, the pressure wave from a frontal blast may enter through the sides of the helmet and wrap around the head to result in a second impact at the rear. This study recommended better protection at the sides and rear of the helmet through the use of foam pads so as to reduce wave entry into the helmet. The consecutive frontal blasts scenario resulted in higher intracranial pressures (ICPs) compared to impact from a single frontal blast. This implied that blast impingement from an immediate subsequent pressure wave would increase severity of brain injury. For the unhelmeted head case, a peak ICP of 330 kPa is registered at the parietal lobe which exceeds the 235 kPa threshold for serious head injuries [9]. The concurrent front and side blasts scenario yielded lower ICPs and skull stresses than the consecutive frontal blasts case. It is also revealed that the additional side blast would only significantly affect ICPs at the temporal and parietal lobes when compared to results from the single frontal blast case. By analyzing the pressure wave flow surrounding the head and correlating them with the consequential evolution of ICP and skull stress, the paper provides insights into the interaction mechanics between the concomitant blast waves and the biological head model. This article is protected by copyright. All rights reserved. Language: en

International audience; The protein kinase CDK5 (cyclin-dependent kinase 5) is activated through its association with a cyclin-like protein p35 or p39. In pathological conditions (such as Alzheimer's disease and various other neuropathies), truncation of p35 leads to the appearance of the p25 protein. The interaction of p25 with CDK5 up-regulates the kinase activity and modifies the substrate specificity. ATP-mimetic inhibitors of CDK5 have already been developed. However, the lack of selectivity of such inhibitors is often a matter of concern. An alternative approach can be used to identify highly specific inhibitors that disrupt protein interactions involving protein kinases. We have developed a bioluminescence resonance energy transfer (BRET)-based screening assay in yeast to discover protein-protein interaction inhibitors (P2I2). Here, we present the first use of BRET in yeast for the screening of small molecule libraries. This screening campaign led to the discovery of one molecule that prevents the interaction between CDK5 and p25, thus inhibiting the protein kinase activity. This molecule may give rise to high-specificity drug candidates.

The crystal structures of two active forms of dissimilatory sulphite reductase (Dsr) from Desulfovibrio gigas, Dsr-I and Dsr-II, are compared at 1.76 and 2.05 A resolution respectively. The dimeric α_2β_2γ_2 structure of Dsr-I contains eight [4Fe–4S] clusters, two saddle-shaped sirohaems and two flat sirohydrochlorins. In Dsr-II, the [4Fe–4S] cluster associated with the sirohaem in Dsr-I is replaced by a [3Fe–4S] cluster. Electron paramagnetic resonance (EPR) of the active Dsr-I and Dsr-II confirm the co-factor structures, whereas EPR of a third but inactive form, Dsr-III, suggests that the sirohaem has been demetallated in addition to its associated [4Fe–4S] cluster replaced by a [3Fe–4S] centre. In Dsr-I and Dsr-II, the sirohydrochlorin is located in a putative substrate channel connected to the sirohaem. The γ-subunit C-terminus is inserted into a positively charged channel formed between the α- and β-subunits, with its conserved terminal Cysγ104 side-chain covalently linked to the CHA atom of the sirohaem in Dsr-I. In Dsr-II, the thioether bond is broken, and the Cysγ104 side-chain moves closer to the bound sulphite at the sirohaem pocket. These different forms of Dsr offer structural insights into a mechanism of sulphite reduction that can lead to S_3O_6^(2−), S_2O_3^(2−) and S^(2−).

This paper develops an enriched element-failure method for delamination analysis of composite structures. This method combines discontinuous enrichments in the extended finite element method and element-failure concepts in the element-failure method within the finite element framework. An improved discontinuous enrichment function is presented to effectively model the kinked discontinuities; and, based on fracture mechanics, a general near-tip enrichment function is also derived from the asymptotic displacement fields to represent the discontinuity and local stress intensification around the crack-tip. The delamination is treated as a crack problem that is represented by the discontinuous enrichment functions and then the enrichments are transformed to external nodal forces applied to nodes around the crack. The crack and its propagation are modeled by the ‘failed elements’ that are applied to the external nodal forces. Delamination and crack kinking problems can be solved simultaneously without remeshing the model or re-assembling the stiffness matrix with this method. Examples are used to demonstrate the application of the proposed method to delamination analysis. The validity of the proposed method is verified and the simulation results show that both interlaminar delamination and crack kinking (intralaminar crack) occur in the cross-ply laminated plate, which is observed in the experiment. Copyright © 2009 John Wiley & Sons, Ltd.

We report an efficient method to synthesize vertically aligned Co3O4 nanostructures on the surface of cobalt foils. This synthesis is accomplished by simply heating the cobalt foils in the presence of oxygen gas. The resultant morphologies of the nanostructures can be tailored to be either one-dimensional nanowires or two-dimensional nanowalls by controlling the reactivity and the diffusion rate of the oxygen species during the growth process. A possible growth mechanism governing the formation of such nanostructures is discussed. The field-emission properties of the as-synthesized nanostructures are investigated in detail. The turn-on field was determined to be 6.4 and 7.7 V μm–1 for nanowires and nanowalls, respectively. The nanowire samples show superior field-emission characteristics with a lower turn-on field and higher current density because of their sharp tip geometry and high aspect ratio.

The effects of inter-yarn friction on the ballistic performance of woven fabric armour are investigated in this paper. Frictional sliding between yarns is implemented in a computational model of the fabric that takes the form of a network. Yarn crimp and its viscoelastic properties are taken into account. Ballistic experiments are performed to verify the predictions of the model. Parametric studies show that the ballistic response of woven fabric is very sensitive to yarn friction when the friction coefficient is low but insensitive beyond a certain level. The results also show that very high inter-yarn friction can lead to premature yarn rupture, thus reducing the ability of the fabric to absorb impact energy.

BACKGROUND Few cancer specific quality-of-life (QoL) measures from the West have been translated for use with Chinese-speaking patients, and no substantial validation of these translations with adequately large cohorts has been published previously, to the authors' knowledge. The Functional Assessment of Cancer Therapy–General (FACT-G) is a well-validated QoL instrument that is specific to cancer patients. The scale was translated into Chinese and the psychometric properties of this translated scale (FACT-G [Ch]) were tested with a Chinese sample in Hong Kong, China. METHODS A total of 1262 Chinese cancer patients were selected in 3 samples from 5 Hong Kong regional hospitals. Quantitative and qualitative data were used to assess the cultural equivalence, factor structure, reliability, and validity of the FACT-G (Ch). RESULTS Focus group discussions indicated that the FACT-G was seen as covering QoL domains identified as important and relevant to Chinese cancer patients, though in some respects it was seen as having limited scope in this sample. Psychometrically, the factor structure of the FACT-G deviated from that of the original work. The FACT-G (Ch) had acceptable reliability (Cronbach alpha 0.85). The convergent validity of the FACT-G (Ch) with a generic QoL measure (WHOQOL-BREF[HK]) was 0.72 (P < 0.001), and divergent validity showed low correlations of less than 0.15 (P < 0.05) with non-QoL measures. CONCLUSIONS Focus group data indicated that the FACT-G translation into Chinese was seen as a conceptually relevant and moderately sufficient QoL measure. Psychometrically, the instrument had acceptable properties, but conceptual differences from the original version were suggested. Although more work is needed to increase its adequacy, the translated scale has reasonable utility for use with Chinese populations in clinical settings. Cancer 2000;88:1715–27. © 2000 American Cancer Society.