Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease.

BackgroundThere are no effective treatments or validated clinical response markers in systemic sclerosis (SSc). We assessed imaging biomarkers and performed gene expression profiling in a single-arm open-label clinical trial of tyrosine kinase inhibitor dasatinib in patients with SSc-associated interstitial lung disease (SSc-ILD).MethodsPrimary objectives were safety and pharmacokinetics. Secondary outcomes included clinical assessments, quantitative high-resolution computed tomography (HRCT) of the chest, serum biomarker assays and skin biopsy-based gene expression subset assignments. Clinical response was defined as decrease of >5 or >20% from baseline in the modified Rodnan Skin Score (MRSS). Pulmonary function was assessed at baseline and day 169.ResultsDasatinib was well-tolerated in 31 patients receiving drug for a median of nine months. No significant changes in clinical assessments or serum biomarkers were seen at six months. By quantitative HRCT, 65% of patients showed no progression of lung fibrosis, and 39% showed no progression of total ILD. Among 12 subjects with available baseline and post-treatment skin biopsies, three were improvers and nine were non-improvers. Improvers mapped to the fibroproliferative or normal-like subsets, while seven out of nine non-improvers were in the inflammatory subset (p = 0.0455). Improvers showed stability in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), while both measures showed a decline in non-improvers (p = 0.1289 and p = 0.0195, respectively). Inflammatory gene expression subset was associated with higher baseline HRCT score (p = 0.0556). Non-improvers showed significant increase in lung fibrosis (p = 0.0313).ConclusionsIn patients with SSc-ILD dasatinib treatment was associated with acceptable safety profile but no significant clinical efficacy. Patients in the inflammatory gene expression subset showed increase in skin fibrosis, decreasing pulmonary function and worsening lung fibrosis during the study. These findings suggest that target tissue-specific gene expression analyses can help match patients and therapeutic interventions in heterogeneous diseases such as SSc, and quantitative HRCT is useful for assessing clinical outcomes.Trial registrationClinicaltrials.gov NCT00764309

Effects of natural covers on soil evaporation of the shelterbelt along the Tarim Desert Highway

The control of soil evaporation is one of important approaches to save water. The artificially simulated evaporation experiments have been conducted in the hinterland of the Taklimakan Desert to reveal the effects of the natural covers on the soil evaporation of the Tarim Desert Highway shelterbelt as well as provide some insights in the efficient utilization of water resources and optimization of irrigation systems. The results showed that (1) All the covers, including the sand deposit, the salt crust, the litter, the sand-litter mixed layer and so on, can significantly inhibit the soil water evaporation. Specifically, the daily evaporation, the total evaporation, and the evaporation rate in covered sands were much smaller than that of sands without cover. The cover inhibition effects increased with the cover thickness. Particularly, the soil evaporation of the covered sands was less affected by external and internal factors than that of the bare sands. Moreover, the variation of daily evaporation of covered sands was smaller than that of bare sands. The cumulative evaporation varied linearly with time in the covered sands whereas it varied logarithmically in the bare sands. In addition, the soil evaporation in the bare sands showed significantly different characteristics in the early and late stages of the evaporation. (2) All the covers exhibited the significant inhibiting effect on the soil evaporation, and the inhibition efficiency increased logarithmically with the cover thickness. However, as the cover thickness was above a certain value, the increase in the inhibition efficiency was slow. Particularly, at a cover thickness of 2 cm, there was no obvious difference in the inhibition efficiency among all kinds of covers. The maximum inhibition efficiency as calculated from the daily evaporation on the first day of irrigation was: sand-litter mixed layer (79.92%) > litter layer (78.96%) > salt crust (75.58%) > sand bed (74.11%), whereas the average inhibiting efficiency as calculated from the cumulative soil evaporation at the end of an irrigation cycle (the fourth day) was: salt crust (67.78%) > sand-litter mixed layer (66.72%) > sand deposit (63.28%) > litter layer (61.74%)

Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end joining (NHEJ) pathway required for the repair of DNA double strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. Methods: We evaluated clinicopathological significance of DNA-PKcs protein expression in 1161 tumours and DNA-PKcs mRNA expression in 1950 tumours. We correlated DNA-PKcs to other markers of aggressive phenotypes, DNA repair, apoptosis and cell cycle regulation. Results: Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps<0.05). Absence of BRCA1, low XRCC1/SMUG1/APE1/Polβ were also more likely in low DNA-PKcs expressing tumours (ps<0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer specific survival (BCCS) in univariate and multivariate analysis (ps<0.01). At the mRNA level, low DNA-PKcs was associated with PAM50.Her2 and PAM50.LumA molecular phenotypes (ps<0.01) and poor BCSS. In patients with ER positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Conclusions: Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers

Counter-current chromatography for the separation of terpenoids: A comprehensive review with respect to the solvent systems employed

Copyright @ 2014 The Authors.This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.Natural products extracts are commonly highly complex mixtures of active compounds and consequently their purification becomes a particularly challenging task. The development of a purification protocol to extract a single active component from the many hundreds that are often present in the mixture is something that can take months or even years to achieve, thus it is important for the natural product chemist to have, at their disposal, a broad range of diverse purification techniques. Counter-current chromatography (CCC) is one such separation technique utilising two immiscible phases, one as the stationary phase (retained in a spinning coil by centrifugal forces) and the second as the mobile phase. The method benefits from a number of advantages when compared with the more traditional liquid-solid separation methods, such as no irreversible adsorption, total recovery of the injected sample, minimal tailing of peaks, low risk of sample denaturation, the ability to accept particulates, and a low solvent consumption. The selection of an appropriate two-phase solvent system is critical to the running of CCC since this is both the mobile and the stationary phase of the system. However, this is also by far the most time consuming aspect of the technique and the one that most inhibits its general take-up. In recent years, numerous natural product purifications have been published using CCC from almost every country across the globe. Many of these papers are devoted to terpenoids-one of the most diverse groups. Naturally occurring terpenoids provide opportunities to discover new drugs but many of them are available at very low levels in nature and a huge number of them still remain unexplored. The collective knowledge on performing successful CCC separations of terpenoids has been gathered and reviewed by the authors, in order to create a comprehensive document that will be of great assistance in performing future purifications. © 2014 The Author(s)

Classification and regionalization of the forming environment of windblown sand disasters along the Tarim Desert Highway

Through the systematic field survey and observations, the factor quantification as well as setting the criteria, the sand disaster-forming environment along the Tarim Desert Highway can be divided into four grades by the classification and regionalization based on fuzzy mathematics. The length of the regions with significant sand disaster accounted for 37.1% of the total highway length. Particularly, the area along the Tarim Desert Highway, based on the sand disaster-forming environment classification as well as the difference in the five basic landform units along the highway, combined with the difference of wind regime, can be divided into five regions, in which the length of the regions suffering severe sand damage occupied 64.3% of the total highway length. In addition, the index of disaster formation grade along the highway decreased from north to south, showing a repeated spatial pattern in small length scales

In silico analysis and verification of S100 gene expression in gastric cancer

<p>Abstract</p> <p>Background</p> <p>The S100 protein family comprises 22 members whose protein sequences encompass at least one EF-hand Ca²⁺binding motif. They were involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. However, the expression status of S100 family members in gastric cancer was not known yet.</p> <p>Methods</p> <p>Combined with analysis of series analysis of gene expression, virtual Northern blot and microarray data, the expression levels of S100 family members in normal and malignant stomach tissues were systematically investigated. The expression of S100A3 was further evaluated by quantitative RT-PCR.</p> <p>Results</p> <p>At least 5 S100 genes were found to be upregulated in gastric cance by in silico analysis. Among them, four genes, including S100A2, S100A4, S100A7 and S100A10, were reported to overexpressed in gastric cancer previously. The expression of S100A3 in eighty patients of gastric cancer was further examined. The results showed that the mean expression levels of S100A3 in gastric cancer tissues were 2.5 times as high as in adjacent non-tumorous tissues. S100A3 expression was correlated with tumor differentiation and TNM (Tumor-Node-Metastasis) stage of gastric cancer, which was relatively highly expressed in poorly differentiated and advanced gastric cancer tissues (<it>P </it>< 0.05).</p> <p>Conclusion</p> <p>To our knowledge this is the first report of systematic evaluation of S100 gene expressions in gastric cancers by multiple in silico analysis. The results indicated that overexpression of S100 gene family members were characteristics of gastric cancers and S100A3 might play important roles in differentiation and progression of gastric cancer.</p

Magnetic Catalysis and Quantum Hall Ferromagnetism in Weakly Coupled Graphene

We study the realization in a model of graphene of the phenomenon whereby the tendency of gauge-field mediated interactions to break chiral symmetry spontaneously is greatly enhanced in an external magnetic field. We prove that, in the weak coupling limit, and where the electron-electron interaction satisfies certain mild conditions, the ground state of charge neutral graphene in an external magnetic field is a quantum Hall ferromagnet which spontaneously breaks the emergent U(4) symmetry to U(2)XU(2). We argue that, due to a residual CP symmetry, the quantum Hall ferromagnet order parameter is given exactly by the leading order in perturbation theory. On the other hand, the chiral condensate which is the order parameter for chiral symmetry breaking generically obtains contributions at all orders. We compute the leading correction to the chiral condensate. We argue that the ensuing fermion spectrum resembles that of massive fermions with a vanishing U(4)-valued chemical potential. We discuss the realization of parity and charge conjugation symmetries and argue that, in the context of our model, the charge neutral quantum Hall state in graphene is a bulk insulator, with vanishing longitudinal conductivity due to a charge gap and Hall conductivity vanishing due to a residual discrete particle-hole symmetry.Comment: 35 page