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An in vitro diagnostic device (IVD) that is essential for the safe and effective use of a corresponding therapeutic product is commonly referred to as companion diagnostic device. Clinical trials using companion diagnostic devices (tests) together with therapies can yield the information necessary to address whether both products are safe and effective. A clinical trial ideally assesses safety and effectiveness of a therapy, where the clinical trial enrolls subjects based on the final market ready companion diagnostic test (CDx). However, such a requirement may be difficult to accomplish or impractical to achieve at the time of the clinical trial enrollment, due to unavailability of the CDx. Instead, clinical trial assay(s) (CTA), which are not the final marketable product, are often used in enrollment of patients in a clinical trial. When CTA is used for subject enrollment, a clinical bridging study provides a mechanism to bridge the clinical efficacy of the therapeutic product from CTA to CDx. This manuscript reviews some issues and challenges commonly associated with clinical bridging studies, including missing data, use of local tests for enrollment, prescreening before enrollment, and evaluation of CDx for low positive rate biomarkers, with particular focus on clinical trials using a binary endpoint and provide alternative statistical methodologies to assess effectiveness of CDx. [ABSTRACT FROM AUTHOR]

RNA methyltransferase DNMT2/TRDMT1 is the most conserved member of the DNMT family from bacteria to plants and mammals. In previous studies, we found some determinants for tRNA recognition of DNMT2/TRDMT1, but the preference mechanism of this enzyme for substrates tRNA and DNA remains to be explored. In the present study, CFT-containing target recognition domain (TRD) and target recognition extension domain (TRED) in DNMT2/TRDMT1 play a crucial role in the substrate DNA and RNA selection during the evolution. Moreover, the classical substrate tRNA for DNMT2/TRDMT1 had a characteristic sequence CUXXCAC in the anticodon loop. Position 35 was occupied by U, making cytosine-38 (C38) twist into the loop, whereas C, G or A was located at position 35, keeping the C38-flipping state. Hence, the substrate preference could be modulated by the easily flipped state of target cytosine in tRNA, as well as TRD and TRED. Additionally, DNMT2/TRDMT1 cancer mutant activity was collectively mediated by five enzymatic characteristics, which might impact gene expressions. Importantly, G155C, G155V and G155S mutations reduced enzymatic activities and showed significant associations with diseases using seven prediction methods. Altogether, these findings will assist in illustrating the substrate preference mechanism of DNMT2/TRDMT1 and provide a promising therapeutic strategy for cancer. [ABSTRACT FROM AUTHOR]

In the current study, efforts are being made to formulate transdermal salbutamol-cubosomal gel to manage paediatric asthma. Salbutamol-loaded cubosomal gels were prepared by melt emulsification and sonication. The cubosomal gels were characterised by morphology, particle size, zeta potential, entrapment efficacy, assay, viscosity, and texture profiles. Ex vivo permeation and pharmacokinetic studies were performed using rats. The mean cubosomal particle size (208–361 ± 12.5–32.5 nm), PDI (0.06–0.11 ± 0.01–0.02), viscosity (8527–9019 cp), and entrapment efficacy (76.3–91.0% w/w) increase with the level of monoolein. The ex vivo permeation study showed a biphasic release pattern, with salbutamol cleared from control gel within 8 h, while cubosomal gels showed sustained release up to 72 h. The pharmacokinetic profiles in the rat model showed 8.62-fold higher bioavailability with cubosomal gel. The study demonstrated the potential of cubosomal nanoparticle-laden gel to sustain the release of salbutamol to treat paediatric asthma. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β (TGF-β) plays a critical role in regulating cell growth and differentiation. Epithelial to mesenchymal transition (EMT) induced by TGF-β promotes cancer cell migration, invasion, and proliferation. Pirfenidone (5-methyl-1-phenyl-2(1 H)-pyridone, PFD), an approved drug for treating pulmonary and renal fibrosis, is a potent TGF-β inhibitor and found reduced incidence of lung cancer and alleviated renal function decline. However, whether PFD plays a role in controlling renal cancer progression is largely unknown. In the present study, we demonstrated that high TGF-β1 expression was negatively associated with ten-year overall survival of patients with renal cancer. Functionally, blockade of TGF-β signaling with PFD significantly suppressed the progression of renal cancer in a murine model. Mechanistically, we revealed that PFD significantly decreased the expression and secretion of TGF-β both in vitro and in vivo tumor mouse model, which further prevented TGF-β-induced EMT and thus cell proliferation, migration, and invasion. Importantly, the downregulation of TGF-β upon PFD treatment shaped the immunosuppressive tumor microenvironment by limiting the recruitment of tumor-infiltrating MDSCs. Therefore, our study demonstrated that PFD prevents renal cancer progression by inhibiting TGF-β production of cancer cells and downstream signaling pathway, which might be presented as a therapeutic adjuvant for renal cancer. [ABSTRACT FROM AUTHOR]

Groundwater is exploited extensively, continuously and in a disorderly way in the North China Plain (NCP), which leads to severe problems of groundwater over-exploitation, making it the largest groundwater funnel zone in the world. Based on a comprehensive treatment of over-exploited groundwater in Shandong province, this paper analyses and forecasts the water demand, supply and savings in over-exploited areas, and puts forward a method to analyse the potential for groundwater exploitation control, which provides technical support for the comprehensive analysis of exploitation control in over-exploited areas. As a result, under a 50% guaranteed rate of water supply, the potential for groundwater exploitation control in Shandong province over-exploited areas in 2020 and 2030 is 408 × 106 and 638 × 106 m3, respectively. This study can serve as a useful reference for the comprehensive management of groundwater over-exploitation in NCP and other over-exploited areas around the world. [ABSTRACT FROM AUTHOR]

In this paper, a novel membrane-assisted fermentation coupling with foam separation (M-FCFS) technology was developed to separate polymyxin E from its broth immediately. The effects of starting aeration time, membrane, volumetric airflow rate in foam column, and nitrogen source (i.e. peptone, also known as foam stabilizer) on the production of polymyxin E were studied. Under the optimal conditions, the total titer (TT) of polymyxin E reached 1.29 × 106IU, resulting in a 50.4% improvement compared with the uncoupling experiment (8.60 × 105IU). This work combined the advantages of foam separation and membrane filtration, and provided a promising technology for the production of polymyxin E. [ABSTRACT FROM PUBLISHER]

A novel protein molecularly imprinted microsphere with three-dimensionally ordered macroporous (3DOM) structure has been successfully prepared with a combination of colloidal crystal template method and molecular imprinting technique by using bovine serum albumin as template, acrylamide as functional monomer, and N,N′-methylenebisacrylamide as crosslinker, respectively. SEM shows that the polymeric microspheres have a highly ordered three-dimensional interconnected macroporous structure with typical face-centered cubic lattice. The isothermal and kinetic adsorption behaviors of the polymer were investigated. Compared with the traditional bulk polymer, the 3DOM imprinted microspheres show higher binding rate constant, adsorption capability and specificity to template molecules. [ABSTRACT FROM AUTHOR]

A hybrid method combining Tikhonov regularization and generalized singular value decomposition (TR–GSVD) was proposed to reconstruct temperature distributions in radiant enclosures. The regularization parameter, which is crucial to accurately inverse temperature distributions, could be fast updated in TR–GSVD. Numerical reconstruction of three-dimensional temperature fields in a 10 m × 10 m × 20 m furnace proved TR–GSVD possesses the same computational accuracy but higher efficiency compared with TR. Experimental reconstruction results from practical flames in the furnace also showed the regularization parameter changed significantly in some combustion conditions. It is necessary to update the regularization parameter during the reconstruction. [ABSTRACT FROM PUBLISHER]

A perovskite-type oxide La0.4Ba0.6Fe0.8Zn0.2O3−δ(LBFZ) was investigated as the cathode material for simultaneous NO reduction and electricity generation in solid oxide fuel cells (SOFCs). The microstructure of LBFZ was demonstrated by X-ray diffraction and scanning electron microscopy. The results showed that a single cubic perovskite LBFZ was formed after calcined at 1100°C. Meanwhile, the solid-state reaction between LBFZ and Ce0.8Sm0.2O1.9(SDC) at 900°C was negligible. To measure the electrochemical properties, SOFC units were constructed with Sm0.9Sr0.1Cr0.5Fe0.5O3as the anode, SDC as the electrolyte and LBFZ as the cathode. The maximum power density increased with the increasing NO concentration and temperature. The cell resistance is mainly due to the cathodic polarization resistance. [ABSTRACT FROM AUTHOR]

The complete mitogenome sequence of the spotted steed ( Hemibarbus maculatus) was determined using long PCR reactions. The genome is 16,611 bp long and consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and a control region. The gene order and composition of H. maculatus was similar to that of most other vertebrates. The base composition of H-strand in descending order is A (29.16%), C (27.41%), T (25.93%), and G (17.50%), with an AT content of 55.09%. The Kimura two-parameter distances between mitogenome sequences of H. maculatus and Hemibarbus labeo, Hemibarbus barbus, Hemibarbus longirostris, Hemibarbus mylodon were 2.09%, 2.35%, 12.77%, and 13.92%, respectively. The phylogenetic relationships among the five Hemibarbus species based on the whole mitogenome sequence data were ((( H. barbus, H. labeo), H. maculatus), ( H. longirostris, H. mylodon)). [ABSTRACT FROM AUTHOR]

The bronze gudgeon ( Coreius heterodon) and the congeneric species largemouth bronze gudgeon ( Coreius guichenoti), two endemic fish species in China, are important economic fishes in local areas. The bronze gudgeon is distributed in Yangtze River and Huanghe River basin, whereas the largemouth bronze gudgeon is distributed only in the middle and upper reaches of Yangtze River. Here, we sequenced the complete mitochondrial genomes of the two species and compared the evolutionary rate differences between the two species. The complete mitochondrial genomes of C. heterodon and C. guichenoti are 16,611 and 16,612 bp, respectively. Both of the complete mitogenome sequences contain 13 protein-coding genes, 2 rRNA subunits, 22 tRNAs and 1 non-coding control region, which are typical vertebrate mitogenomes. The relative rate test shows that the mitochondrial genome of C. heterodon evolves nearly threefold faster than that of C. guichenoti, which is mostly caused by the higher substitution rates in rRNAs and especially in tRNAs in C. heterodon. [ABSTRACT FROM AUTHOR]