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The corn planthopper, Peregrinus maidis, is an economically important pest of corn and sorghum. Here we report the initial steps towards developing a CRISPR-based control method, precision guided sterile insect technique (pgSIT), for this hemipteran pest. Specifically, we evaluated the potential of transformer-2 (tra-2) as a target for sterilizing insects. First, we identified tra-2 transcripts within our P. maidis transcriptome database and performed RNA interference (RNAi) to confirm functional conservation. RNAi-mediated knockdown of Pmtra-2 in nymphs transformed females into pseudomales with deformed ovipositors resembling male claspers. While males showed no overt difference in appearance, they were indeed sterile. Importantly, the results were similar to those observed in another planthopper, Nilaparvata lugens. We also used CRISPR/Cas9 genome editing to assess the impact of tra-2 knockout in injectees. CRISPR-mediated knockout of Pmtra-2 had lethal effects on embryos, and hence not many injectees reached adulthood. However, mosaic knockout of Pmtra-2 did impact female and male fertility, which supports the use of tra-2 as a target for pgSIT in this hemipteran species. [ABSTRACT FROM AUTHOR]

Simple Summary: Microbes play important roles in the biochemistry, physiology and survival of insects. An example is Arsenophonus sp. in the brown planthopper (Nilaparvata lugens), an endosymbiotic bacterium supplementing the nutritionally poor diet of its sap-feeding host. In this study, we use the genome of Nl Arsenophonus sp. as a reference to facilitate the genome assembly of a closely related Arsenophonus sp. found in the corn planthopper (Peregrinus maidis). Our assembly is one of the largest Arsenophonus genomes reported to date. We also investigated the role of Arsenophonus sp. in P. maidis, in which it appears to provide B vitamins and essential amino acids. The co-evolution between symbionts and their insect hosts has led to intricate functional interdependencies. Advances in DNA-sequencing technologies have not only reduced the cost of sequencing but, with the advent of highly accurate long-read methods, have also enabled facile genome assembly even using mixed genomic input, thereby allowing us to more easily assess the contribution of symbionts to their insect hosts. In this study, genomic data recently generated from Peregrinus maidis was used to assemble the genome of a bacterial symbiont, Pm Arsenophonus sp. This ~4.9-Mb assembly is one of the largest Arsenophonus genomes reported to date. The Benchmarking Universal Single-Copy Orthologs (BUSCO) result indicates that this Pm Arsenophonus assembly has a high degree of completeness, with 96% of the single-copy Enterobacterales orthologs found. The identity of the Pm Arsenophonus sp. was further confirmed by phylogenetic analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicates a major contribution by Pm Arsenophonus sp. to the biosynthesis of B vitamins and essential amino acids in P. maidis, where threonine and lysine production is carried out solely by Pm Arsenophonus sp. This study not only provides deeper insights into the evolutionary relationships between symbionts and their insect hosts, but also adds to our understanding of insect biology, potentially guiding the development of novel pest control methods. [ABSTRACT FROM AUTHOR]

Known for its species abundance and evolutionary status complexity, family Roseobacteraceae is an important subject of many studies on the discovery, identification, taxonomic status, and ecological properties of marine bacteria. This study compared and analyzed the phylogenetic, genomic, biochemical, and chemo taxonomical properties of seven species from three genera (Psychromarinibacter, Lutimaribacter, and Maritimibacter) of the family Roseobacteraceae. Moreover, a novel strain, named C21-152T was isolated from solar saltern sediment in Weihai, China. The values of 16S rRNA gene sequence similarity, the average nucleotide identity (ANI), the average amino acid identity (AAI), and the digital DNA–DNA hybridization (dDDH) between genomes of the novel strain and Psychromarinibacter halotolerans MCCC 1K03203T were 97.19, 78.49, 73.45, and 21.90%, respectively. Genome sequencing of strain C21-152T revealed a complete Sox enzyme system related to thiosulfate oxidization as well as a complete pathway for the final conversion of hydroxyproline to α-ketoglutarate. In addition, strain C21-152T was resistant to many antibiotics and had the ability to survive below 13% salinity. This strain had versatile survival strategies in saline environments including salt-in, compatible solute production and compatible solute transport. Some of its physiological features enriched and complemented the knowledge of the characteristics of the genus Psychromarinibacter. Optimum growth of strain C21-152T occurred at 37 ℃, with 5–6% (w/v) NaCl and at pH 7.5. According to the results of the phenotypic, chemotaxonomic characterization, phylogenetic properties and genome analysis, strain C21-152T should represent a novel specie of the genus Psychromarinibacter, for which the name Psychromarinibacter sediminicola sp. nov. is proposed. The type strain is C21-152T (= MCCC 1H00808T = KCTC 92746T = SDUM1063002T). [ABSTRACT FROM AUTHOR]

The corn planthopper, Peregrinus maidis, is an economically important pest of maize and sorghum. Its feeding behaviour and the viruses it transmits can significantly reduce crop yield. The control of P. maidis and its associated viruses relies heavily on insecticides. However, control has proven difficult due to limited direct exposure of P. maidis to insecticides and rapid development of resistance. As such, alternative control methods are needed. In the absence of a genome assembly for this species, we first developed transcriptomic resources. Then, with the goal of finding targets for RNAi‐based control, we identified members of the ATP‐binding cassette transporter family and targeted specific members via RNAi. PmABCB_160306_3, PmABCE_118332_5 and PmABCF_24241_1, whose orthologs in other insects have proven important in development, were selected for knockdown. We found that RNAi‐mediated silencing of PmABCB_160306_3 impeded ovary development; disruption of PmABCE_118332_5 resulted in localized melanization; and knockdown of PmABCE_118332_5 or PmABCF_24241_1 each led to high mortality within five days. Each phenotype is similar to that found when targeting the orthologous gene in other species and it demonstrates their potential for use in RNAi‐based P. maidis control. The transcriptomic data and RNAi results presented here will no doubt assist with the development of new control methods for this pest. [ABSTRACT FROM AUTHOR]

A highly enantioselective [3+2] annulation of isatin-derived Morita–Baylis–Hillman (MBH) carbonates and 3-nitroindoles was enabled by a chiral DMAP-thiourea bifunctional catalyst, affording the corresponding polycyclic spirooxindoles bearing three consecutive stereocenters with good to excellent yields and enantioselectivities. Transformations of the annulation product were subsequently elaborated and the preliminary biological assays demonstrated that these artificial spirooxindoles potentially inhibited pancreatic lipase in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

Direct deprotonation represents an extremely simple, straightforward, and atom‐economic strategy to activate pronucleophiles bearing an acidic proton. However, the difficulty often arises in activating pronucleophiles with high pKa values by using conventional chiral tertiary amines. To overcome this challenge, a handful of novel chiral Brønsted superbases, including amidines, guanidines, cyclopropenimines, and iminophosphoranes, have been discovered in recent years. This minireview focuses on the application of these organo‐superbases in the catalytic asymmetric reactions of weakly acidic pronucleophiles, and highlights their comparison to the conventional tertiary amines, demonstrating the highly efficient deprotonation processes and stereoselectivity controlled conversions of the superbases. The advantage of these new superbases brings a great opportunity for developing more asymmetric transformations of weakly acidic pronucleophiles. [ABSTRACT FROM AUTHOR]

Direct deprotonation represents an extremely simple, straightforward, and atom‐economic strategy to activate pronucleophiles bearing an acidic proton. However, the difficulty often arises in activating pronucleophiles with high pKa values by using conventional chiral tertiary amines. To overcome this challenge, a handful of novel chiral Brønsted superbases, including amidines, guanidines, cyclopropenimines, and iminophosphoranes, have been discovered in recent years. This minireview focuses on the application of these organo‐superbases in the catalytic asymmetric reactions of weakly acidic pronucleophiles, and highlights their comparison to the conventional tertiary amines, demonstrating the highly efficient deprotonation processes and stereoselectivity controlled conversions of the superbases. The advantage of these new superbases brings a great opportunity for developing more asymmetric transformations of weakly acidic pronucleophiles. [ABSTRACT FROM AUTHOR]

Azacycles such as indoles and tetrahydroquinolines are privileged structures in drug development. Reported here is an unprecedented regiodivergent intramolecular nucleophilic addition reaction of imines as a flexible approach to access N‐functionalized indoles and tetrahydroquinolines, by the control of reaction at the N‐terminus and C‐terminus, respectively. Using ketimines derived from 2‐(2‐nitroethyl)anilines with isatins or α‐ketoesters, the regioselective N‐attack reaction gives N‐functionalized indoles, while the catalytic enantioselective C‐attack reaction affords chiral tetrahydroquinolines featuring an α‐tetrasubstituted stereocenter. Mechanistic studies reveal that hydrogen‐bonding interactions may greatly facilitate such unusual N‐attack reactions of imines. The utility of this protocol is highlighted by the catalytic enantioselective formal synthesis of (−)‐psychotrimine, and the construction of various fused aza‐heterocycles. [ABSTRACT FROM AUTHOR]

Azacycles such as indoles and tetrahydroquinolines are privileged structures in drug development. Reported here is an unprecedented regiodivergent intramolecular nucleophilic addition reaction of imines as a flexible approach to access N‐functionalized indoles and tetrahydroquinolines, by the control of reaction at the N‐terminus and C‐terminus, respectively. Using ketimines derived from 2‐(2‐nitroethyl)anilines with isatins or α‐ketoesters, the regioselective N‐attack reaction gives N‐functionalized indoles, while the catalytic enantioselective C‐attack reaction affords chiral tetrahydroquinolines featuring an α‐tetrasubstituted stereocenter. Mechanistic studies reveal that hydrogen‐bonding interactions may greatly facilitate such unusual N‐attack reactions of imines. The utility of this protocol is highlighted by the catalytic enantioselective formal synthesis of (−)‐psychotrimine, and the construction of various fused aza‐heterocycles. [ABSTRACT FROM AUTHOR]

Background Accumulating evidence has indicated that microRNAs play important roles in the initiation and progression of digestive system tumors. However, previous studies suggest that the accuracy of miRNA detection in digestive system tumors was inconsistent. Methods The candidate miRNAs were obtained from The Cancer Genome Atlas (TCGA). Meta-analysis was performed to evaluate the diagnostic value of these miRNAs in digestive system tumors. Furthermore, the potential target genes of the miRNAs were predicted and assessed with functional analysis. Results According to TCGA data, miR-139 was a common biomarker of digestive system tumors. It was markedly reduced in tumor tissues as compared with non-cancerous tissues in digestive system tumors. In the meta-analysis, the pooled diagnostic odds ratio (DOR) and AUC was 57.51 (95% CI: 14.25–232.04) and 0.96 (95% CI: 0.94–0.97), respectively. Furthermore, the overall sensitivity and specificity was 0.89 (95% CI: 0.73–0.96) and 0.91 (95% CI: 0.75–0.97), respectively. The diagnostic value of tissue miR-139 was higher than the diagnostic value of blood miR-139. In particular, miR-139 was a superior marker for distinguishing colorectal cancer. Conclusion miR-139 could be a potential biomarker for diagnosis of digestive system tumors especially colorectal cancer. [ABSTRACT FROM AUTHOR]

Background/Aims: Exosomal circulating long non-coding RNAs (lncRNAs) in blood are emerging as clinically useful and non-invasive biomarkers for tumor diagnosis. However, normal cells can also secrete exosomes, so it is a prerequisite to obtain tumor-derived exosomes for better understanding of their diagnostic impacts in cancer. In this study, a dual-antibody-functionalized immunoaffinity system was established to isolate exosomes and investigate their lncRNAs expression pattern and clinical significance in prostate cancer (PCa). Methods: A commercially available kit was used to isolate total exosomes, which were then purified by a dual-antibody-functionalized immunoaffinity system. RT-qPCR was performed to detect the expression of exosomal lncRNAs. Receiver operating characteristic (ROC) curves were plotted to assess the diagnostic value. Results: Expression levels of two lncRNAs in tumor-derived exosomes were significantly higher than those in total exosomes. The levels of SAP30L-AS1 were upregulated in benign prostatic hyperplasia (BPH), and SChLAP1 levels were significantly higher in PCa than in BPH and healthy individuals. The area under the ROC curve indicated that SAP30L-AS1 and SChLAP1 had adequate diagnostic value to distinguish PCa from controls. Two lncRNAs separately combined with prostate specific antigen (PSA) possessed a moderate ability for discrimination. SAP30L-AS1 expression level was related to PSA values and tumor invasion. SChLAP1 expression was significantly higher in patients with higher Gleason scores, and was also effective in differentiating between BPH and PCa when the concentration of PSA was in the gray zone. Conclusion: The isolation of tumor-derived exosomes by dual-antibody-functionalized immunoaffinity systems and detection of their lncRNAs in plasma may lead to the identification of suitable biomarkers, with potential diagnostic utility. [ABSTRACT FROM AUTHOR]

The rapid evolution of new service systems raises crucial challenges for service design and requires effective methods. This study depicts a conceptual service design framework, called design-oriented systematic inventive thinking (DSIT) approach, which can be applied in different problem contexts. DSIT is presented as a new systematic and collaborative intelligence approach for creating and evaluating complex service systems using multi-criteria data analytics. DSIT synthesizes the current field of TRIZ service-design knowledge system and the emerging area of non-TRIZ service-design knowledge system. DSIT enables integrated development of service offerings at four dimensions and provides the matching integrated service design approach for each dimension. Four types of service design approaches are conceptualized as “human-independent service engineering,” “problem-clarified service engineering,” “solution-converged service engineering,” and “designing for service.” A new service computer-aided design system (service CAD) named DSIT explorer is developed consisting of customization, compatibility, and extensiveness of DSIT modules. A pervasive and smart collaborative service system (i.e., the smart MOS burger service solution) designed using DSIT explorer is illustrated. DSIT is a holistic, interdisciplinary, and collaborative service design concept, which is incorporated into a collaborative and intelligent service CAD framework to enable systematic inventive thinking throughout phases of service design lifecycle from problem definition, problem resolution, to solution evaluation. [ABSTRACT FROM AUTHOR]

This study refines a structural service design stages based on the Theory of Inventive Problem Solving (TRIZ) and the service blueprint approach. This study uses the case study of intelligent parking services with the mobile application technology and vehicle license plate recognition system in a high-end shopping mall. In the problem definition stage, the research analyzes the enterprise problem. In the service resolution stage, the TRIZ contradiction analysis and the service blueprint of the parking service as it existed is depicted from the principles of problem resolution. In the solution evaluation stage, new intelligent parking mobile applications (apps) are proposed following the principles generated in the second stage. Furthermore, the failure points and waiting points in the prior service blueprint are overcome and the new service performance is significantly improved. It contributes to enriching the service design literature, and extends the range of TRIZ applications for future parking technology. [ABSTRACT FROM AUTHOR]

The effect mechanisms of sodium chloride (NaCl) addition on the partitioning and solubility of immunoglobulin G (IgG) in polyethylene glycol (PEG)/hydroxypropyl starch (HPS) aqueous two-phase system (ATPS) were studied. The influences of NaCl on PEG/HPS phase diagram and the hydrophobicity of IgG were investigated. The results indicated that the hydrophobicity difference between two phases and the IgG hydrophobicity were both enhanced with NaCl addition, so IgG preferred to partition into the top phase with more hydrophobicity. The solubilities of IgG in PEG and HPS solutions with or without NaCl were measured. It was found that NaCl addition could significantly reduce IgG precipitation in PEG solution. The effects of NaCl on the interaction between IgG and PEG was studied by Isothermal Titration Calorimetry (ITC). It was found that the main interactions between IgG and PEG changed from electrostatic force to hydrophobic interaction with NaCl addition. IgG would be wrapped by PEG molecules due to hydrophobic interaction so that the solubility of IgG in PEG solution was enhanced. The results reveal the mechanisms of NaCl addition on the partitioning and solubility of IgG in PEG/HPS systems, and PEG/HPS ATPS might be a promising alternative for IgG separation with good purity and yield. [Display omitted] • Mechanisms of NaCl on partition and solubility of IgG in PEG/HPS system were revealed. • Hydrophobicity of IgG with NaCl addition was determined by fluorescence probe method. • Solubility of IgG in PEG solution was significantly improved with NaCl addition. • Interactions between IgG and PEG were measured by Isothermal Titration Calorimetry. [ABSTRACT FROM AUTHOR]

Abstract: The catalytic asymmetric synthesis of 3,3-disubstituted oxindoles, a big family of privileged scaffolds in natural products and drugs, is of current interest. Recently, the catalytic asymmetric functionalization of diazooxindoles emerges as a potentially general and flexible strategy for this purpose, with several notable examples coming out in 2013. In this digest, synthetic applications of diazooxindoles have been summarized and discussed, which might be helpful for readers to understand the special properties of this type of donor/acceptor cyclic diazo reagent and to develop new catalytic asymmetric reactions. [Copyright &y& Elsevier]

Dramatic changes in the social economic environment have made companies place more emphasis on integrating social media into their overall marketing strategy. Many features of social media commerce will be developed as tactics to implement social network marketing strategy. Enterprises increasingly need to develop an innovative and effective approach to social media in order to be competitive. With the right new service development phase, companies can gain competitive advantage in service-driven markets. The present study aims to refine a multi-service design for the case study company - MOS Burger. It examines the implementation of a new geo-social networking solution, and the application of the theory of inventive problem-solving (TRIZ). In the problem definition stage, the research analyzes the problems faced by the enterprise. In the service resolution stage, the contradiction analysis and 40 inventive principles are used to examine the prior process of ordering meals, to establish the principles for problem resolution. In the solution evaluation stage, new geo-social network solutions, MOS-Wish and MOS-Order mobile Apps, are proposed using the principles generated in the second stage. This study also evaluates service performance to compare the efficiency of prior model and new model of ordering and interaction with clients. [ABSTRACT FROM AUTHOR]

The wavelet analysis can he used to disclose the evolution law of drought disaster ratio time series (DDRTS), which is important to the drought disaster early warning. Based on the wavelet and fractal analysis on the 59 years time series of drought disaster ratio in China, the original time series was decomposed and reconstructed using Mallat multi-resolution wavelet algorithm. The fractal analysis results showed that the Chinese DDRTS had obvious fractal characteristics, which minimum embedding dimension is six. The multi-resolution wavelet analysis results showed that the Chinese DDRTS had obvious multi-period characteristics, which the 30-35 years change period has maximum energy density. The following conclusions can be drawn. 1) The minimum embedding dimension of fractal analysis can be served as a maximum effective decompose level for the Mallat multi-resolution wavelet analysis, which is helpful to enlarge the application field of fractal analysis. 2) The evolution of Chinese DDRTS was driven by six independent state variables, and had obvious multi-period characteristic. As a whole, the drought disaster ratio remained to be in a growth period at present. [ABSTRACT FROM AUTHOR]

• DMOG was able to inhibit the M1-like differentiation of both RAW264.7 macrophages and bone marrow macrophages. • DMOG reduced the alveolar bone resorption in mice periodontitis. • The results may be associated with HIF-1a activity related to the NF-κB inflammatory pathway. Periodontitis is initiated by serious and sustained bacterial infection and ultimately results in chronic immune-mediated inflammation, tissue destruction, and bone loss. The pathogenesis of periodontitis remains unclear. Host immunological responses to periodontal bacteria ultimately determine the severity and mechanisms governing periodontitis progression. This study aimed to clarify the effect of the hypoxia-inducible factor-1α (HIF-1α) activator dimethyloxalylglycine (DMOG) on a mouse periodontitis model and its underlying role in macrophage polarization. qRT-PCR analysis showed that DMOG inhibited the M1-like polarization of both RAW264.7 macrophages and murine bone marrow macrophages (BMMs) and downregulated TNF-α, IL-6, CD86, and MCP-1 expression in vitro. Immunofluorescence staining and flow cytometry also confirmed the less percentage of F4/80 + CD86 + cells after DMOG treatment. The phosphorylation of NF-κB pathway was also inhibited by DMOG with higher level of HIF-1α expression. Furthermore, mice treated with DMOG showed decreased alveolar bone resorption in the experimental periodontitis model, with significant increases in alveolar bone volume/tissue volume (BV/TV) and bone mineral density (BMD). DMOG treatment of mice decreased the ratio of M1/M2 (CD86+/CD206+) macrophages in periodontal tissues, resulting in the downregulation of proinflammatory cytokines such as TNF-α and IL-6 and increased levels of anti-inflammatory factors such as IL-4 and IL-10. DMOG treatment promoted the number of HIF-1α-positive cells in periodontal tissues. This study demonstrated the cell-specific roles of DMOG in macrophage polarization in vitro and provided insight into the mechanism underlying the protective effect of DMOG in a model of periodontitis. [ABSTRACT FROM AUTHOR]

The difficulty of the H-abstraction of alkyl radicals from PAHs or hetero-PAHs follows the order: S-containing heterocycles > PAHs > N-containing heterocycles. • H-abstraction of CH 3 or C 2 H 5 from PAHs or hetero-PAHs was investigated. • CH 3 instead of C 2 H 5 is responsible for aromatic C radical formation on PAHs. • Activation entropy determines the difference in k T S T of H-abstraction on PAHs. • H-abstraction difficulty: S-containing heterocycles > PAHs > N-containing heterocycles. To understand the condensation during heavy oil thermal processing, the formation of aromatic carbon radicals by H-abstraction of methyl radicals (CH 3) or ethyl radicals (C 2 H 5) from polycyclic aromatic hydrocarbons (PAHs) or heterocyclic aromatic hydrocarbons (hetero-PAHs) was studied by density functional calculation. The H-abstraction from different PAHs all has a positive standard state Gibbs free energy change, while increasing reaction temperature or radical concentration promotes the reaction to proceed spontaneously. CH 3 mainly contributes to the formation of aromatic carbon radicals on PAHs, and the activation entropy of H-abstraction determines the difference in reaction rate constants. The particularity of H-abstraction from hetero-PAHs is reflected at the α-site of heterocycles. The H-abstraction from N-containing hetero-PAHs occurs preferentially at the α-site of heterocycles, and both CH 3 and C 2 H 5 could participate in abstracting the α-H. The H-abstraction from S-containing hetero-PAHs occurs preferentially on coupled aromatic rings, showing reaction behavior similar to the H-abstraction on PAHs. [ABSTRACT FROM AUTHOR]

Rectourethral fistula is a serious complication following laparoscopic radical prostatectomy. We report our experience with a transsphincteric approach in the repair of this uncommon complication. The rectourethral fistula was repaired in a three-stage procedure comprising fecal diversion, transsphincteric repair of the fistula and, finally, closure of the stoma. Two patients with rectourethral fistulas underwent this procedure and the postoperative course was uneventful. In conclusion, a transsphincteric approach in the repair of rectourethral fistula by a three-stage procedure is safe and may be the treatment of choice. [ABSTRACT FROM AUTHOR]

Deformation induced martensitic transformation (DIMT) usually occurs in metastable austenitic stainless steels. Recent studies have shown that DIMT may occur in the austenite phase of low alloyed duplex stainless steels. The present study demonstrates that DIMT can also take place in a high alloyed Fe-23Cr-8.5Ni duplex stainless steel, which exhibits an unexpectedly rapid transformation from γ-austenite into α′-martensite. However, an inhibited martensitic transformation has been observed by varying the initial microstructure from a coarse alternating austenite and ferrite band structure to a fine equiaxed microduplex structure. [ABSTRACT FROM AUTHOR]

Background: Adaptations by arthropod pests to host plant defenses of crops determine their impacts on agricultural production. The larval host range of western corn rootworm, Diabrotica virgifera virgifera (Coleoptera: Chrysomelidae), is restricted to maize and a few grasses. Resistance of D. v. virgifera to crop rotation practices and multiple insecticides contributes to its status as the most damaging pest of cultivated maize in North America and Europe. The extent to which adaptations by this pest contributes to host plant specialization remains unknown. Results: A 2.42 Gb draft D. v. virgifera genome, Dvir_v2.0, was assembled from short shotgun reads and scaffolded using long-insert mate-pair, transcriptome and linked read data. K-mer analysis predicted a repeat content of ≥ 61.5%. Ortholog assignments for Dvir_2.0 RefSeq models predict a greater number of species-specific gene duplications, including expansions in ATP binding cassette transporter and chemosensory gene families, than in other Coleoptera. A majority of annotated D. v. virgifera cytochrome P450s belong to CYP4, 6, and 9 clades. A total of 5,404 transcripts were differentially-expressed between D. v. virgifera larvae fed maize roots compared to alternative host (Miscanthus), a marginal host (Panicum virgatum), a poor host (Sorghum bicolor) and starvation treatments; Among differentially-expressed transcripts, 1,908 were shared across treatments and the least number were between Miscanthus compared to maize. Differentially-expressed transcripts were enriched for putative spliceosome, proteosome, and intracellular transport functions. General stress pathway functions were unique and enriched among up-regulated transcripts in marginal host, poor host, and starvation responses compared to responses on primary (maize) and alternate hosts. Conclusions: Manual annotation of D. v. virgifera Dvir_2.0 RefSeq models predicted expansion of paralogs with gene families putatively involved in insecticide resistance and chemosensory perception. Our study also suggests that adaptations of D. v. virgifera larvae to feeding on an alternate host plant invoke fewer transcriptional changes compared to marginal or poor hosts. The shared up-regulation of stress response pathways between marginal host and poor host, and starvation treatments may reflect nutrient deprivation. This study provides insight into transcriptomic responses of larval feeding on different host plants and resources for genomic research on this economically significant pest of maize. [ABSTRACT FROM AUTHOR]

When patents support anti-competitive conduct, innovation can be damaged not only by lack of market access but by the prohibitive costs of litigation. The creation of patent barriers is inconsistent with IP protection and enforcement agreed upon under the World Trade Organization and trade-related aspects of intellectual property rights (‘TRIPS’). The study uses the US Apple v HTC IP legal case to investigate anti-competitive market behavior and trade barriers. The research provides a formal patent analytic methodology and the case analysis result. The research method tests whether patent conflicts and technical trade barriers are significantly encouraged by existing IP laws. [ABSTRACT FROM AUTHOR]

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The efficient preparation of the stilbenoid lusianthridin is described. This synthesis relies on a Suzuki–Miyaura coupling and an intramolecular nucleophilic substitution as key reactions to construct the 9,10-dihydrophenanthrene core. The synthesis is completed in seven steps with a 13.2% overall yield, and each step can be conducted on a >20 gram scale. The route has provided 20 grams of lusianthridin for further biological activity studies. [ABSTRACT FROM AUTHOR]

Aims Amino acid biosynthesis is one of the cardinal events of carcinogenesis that has not been investigated in urothelial carcinoma ( UC). By data-mining a published transcriptomic database of UCs of urinary bladder ( UBUCs) ( GSE31684), we identified branched-chain amino acid transaminase 1 ( BCAT1) as the most significantly stepwise up-regulated gene during tumour progression among those associated with the amino acid biosynthetic process ( GO:0008652). Accordingly, we analysed BCAT1 transcript and protein expression with their clinicopathological significance. Methods and results We used real-time reverse transcription-polymerase chain reaction ( RT- PCR) to detect BCAT1 transcript levels in 20 UCs of upper tract ( UTUCs) and 20 UBUCs, respectively. Immunohistochemical study was performed to determine BCAT1 protein expression in 340 UTUCs and 295 UBUCs. Higher BCAT1 transcript levels were associated with higher pT status in both groups ( P < 0.05). BCAT1 protein overexpression was also associated significantly with adverse clinicopathological features, e.g. advanced pT stage, nodal metastasis, high pathological grade, etc. ( P < 0.05). BCAT1 overexpression predicted worse disease-specific survival and metastasis-free survival in both univariate and multivariate analyses ( P ≤ 0.001). Conclusion BCAT1 overexpression is associated with advanced tumour status, and implies adverse clinical outcomes of UCs, suggesting that its role in tumour progression could serve as a prognostic biomarker and a novel therapeutic target in UC. [ABSTRACT FROM AUTHOR]

The present study aimed to evaluate the effects of hypercholesterolemia on cardioprotection of ischemic preconditioning and α7 nicotinic acetylcholine receptor (α7nAChR) agonist postconditioning and explore the potential mechanisms that hypercholesterolemia affected their cardioprotection. Hypercholesterolemic and normal rats were divided into the four groups that received the following treatments: i) Hypercholesterolemic control and normal control groups; ii) hypercholesterolemic ischemia/reperfusion (HI) and normal ischemia/reperfusion (NI) groups; iii) hypercholesterolemic ischemic preconditioning (HIPC) and normal ischemic preconditioning (NIPC) groups; and iv) hypercholesterolemic PNU282987 postconditioning (HPNU) and normal PNU282987 postconditioning (NPNU) groups. Serum lactate dehydrogenase (LDH), creatine kinase isoenzyme MB (CK-MB), cardiac troponin I (cTnI), tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) levels after ischemia/reperfusion were assayed. Furthermore, infarct size and expression levels of Akt, phosphorylated (p)-Akt and endothelial nitric oxide synthase (eNOS) in ischemic myocardium were assessed. Compared with the NI group, serum LDH, CK-MB, cTnI, TNF-α and IL-6 levels and infarct size were significantly decreased, and myocardial p-Akt/Akt and eNOS/GAPDH ratios were significantly increased in the NIPC and NPNU groups. Compared with the HI group, serum CK-MB, cTnI, TNF-α and IL-6 levels and infarct size were significantly decreased in the HIPC group; however, myocardial p-Akt/Akt and eNOS/GAPDH ratios did not significantly change in the HIPC group. Furthermore, there were no significant difference between the HI and HPNU groups in serum LDH, CK-MB, cTnI, TNF-α and IL-6 levels, infarct size, myocardial p-Akt/Akt and eNOS/GAPDH ratios. In conclusion, hypercholesterolemia could aggravate myocardial ischemia/reperfusion injury, attenuate cardioprotection of ischemic preconditioning and eliminate cardioprotection from α7nAChR agonist postconditioning by enhancing inflammation and inhibiting PI3K/Akt/eNOS pathway. [ABSTRACT FROM AUTHOR]

Adverse human health effects caused by fine particulate matter (PM 2.5) were reported; however, source-specific PM 2.5 and its bioreactivity need to be assessed to understand regional human impacts. The objective of this study was to investigate the contributions of PM 2.5 to particle bioreactivity in Taichung City, an urban area of west-central Taiwan. The average mass concentration of PM 2.5 was 44.4 μg m−3 from 21 March to April 22, 2018. PM 2.5 was identified from six distinct sources using a positive matrix factorization (PMF) model. Secondary aerosols were discovered to be the primary contributor to PM 2.5 (25.58%), and were primarily composed of Cl−, NO 3 −, EC, NH 4 +, and SO 4 2−. It was found that approximately 52.20% (23.2 μg m−3) of inhaled PM 2.5 was deposited in the alveolar region after inhalation in the human lungs according to the multiple-path particle dosimetry (MPPD) model. Therefore, human alveolar epithelial A549 cells were exposed to PM 2.5 , which significantly reduced lung cell viability, and increased the cytotoxic lactate dehydrogenase (LDH), reactive oxygen species (ROS), and inflammatory interleukin (IL)-6 (p < 0.05). Next, we discovered positive correlation between secondary aerosols and ROS production, which was further linked to increases in inorganic ions (Mg2+, Cl−, NO 3 −, and SO 4 2−) (p < 0.05). In conclusion, acidic ions from secondary aerosols were positively correlated with ROS production in human alveolar epithelial cells. Our results showed that secondary aerosols could be an important determinant of the deterioration of air quality and human respiratory health in urban areas. [Display omitted] • Secondary aerosol was the primary source of PM 2.5 in Taichung city. • More than half of inhaled PM 2.5 are able to deposit in the alveolar region. • PM 2.5 reduced cell viability and increased cytotoxicity, ROS and IL-6 in vitro. • Acidic ions from secondary aerosol contributed to ROS production. [ABSTRACT FROM AUTHOR]

Objective: To elucidate the relationship of oxidative stress and specificity protein 1 (Sp1) in the process of epithelial-to-mesenchymal transdifferentiation (EMT) and also to investigate the molecular mechanism of protective effect of probucol on the pathogenesis of diabetic kidney disease (DKD). Methods: Thirty male Sprague-Dawley (SD) rats were randomly divided into control group, diabetic group, and diabetic group under probucol therapy ( n = 10 per group). The biochemical indicators including 24-h urinary total protein (24-h UTP) excretion, blood glucose (BG), lipids [triglycerides (TGs), total cholesterol (TC)], serum creatinine (Scr), creatinine clearance rate (Ccr), kidney tissue malondialdehyde (MDA) level, and glutathione peroxidase (GSH-Px) activity were assessed in all groups. The renal pathological changes were evaluated by hematoxylin and eosin (HE) and Masson staining. The protein expression of Sp1, α-smooth muscle actin ( α-SMA), and E-cadherin was also measured and analyzed by immunohistochemistry and Western blotting. Results: Compared with the control group, the BG, TC, Scr, 24-h UTP, and MDA level of renal tissue increased significantly and the Ccr reduced in the rats of diabetic group (all p < 0.01). The pathological scores and the expression of Sp1 and α-SMA in renal tissue were up-regulated ( p < 0.01) and the expression of E-cadherin was down-regulated significantly in the diabetic animals ( p < 0.01). In the diabetic animals treated with probucol, the renal injuries were alleviated ( p < 0.01). Conclusions: Oxidative stress may play an important role in the EMT process of tubular epithelial cells. Probucol could ameliorate renal disease progression in this model of diabetic nephropathy, which might be due to an antioxidant action, down-regulation of Sp1 protein expression, and inhibition of renal tubular EMT. [ABSTRACT FROM AUTHOR]

Objective. A prior report suggested that individuals medicated with captopril showed a decreased incidence of prostate cancer. This study therefore investigated whether captopril given postoperatively had any preventive effect on biochemical recurrence for patients treated with radical prostatectomy. Material and methods. Data were prospectively reviewed for 62 men subjected to radical retropubic prostatectomy due to biopsy-confirmed, clinically localized prostate cancer and comparisons were made between two groups, those receiving captopril postoperatively (12.5 mg twice daily; captopril group, n=32) and those not receiving any captopril (control group, n=30). One surgeon carried out the surgery. Results. The two groups were comparable as regards age at surgery, prostate volume, preoperative prostate-specific antigen values, pathological stage, Gleason score, organ-confined disease, occurrence of positive surgical margins and extraprostatic extension. The incidence of biochemical failure was three out of 32 patients in the captopril group and 10 out of 30 in the control group (p=0.034) during a mean observational time of 29 months. Conclusions. A lower rate of biochemical recurrence was observed in men subjected to radical prostatectomy treated with captopril postoperatively than in those not receiving captopril. These results were based on only 32 observations; a larger study may show no evidence of an association. [ABSTRACT FROM AUTHOR]

[Display omitted] • Nanosheets MOR with an ultrathin thickness of 10–30 nm can be obtained by CTAOH. • Optimizing mass transfer and adjusting BAS to 8-MR can be achieved simultaneously. • The MOR with shortened 8-MR side pocket pore length exposes more BAS. • MOR with prismatic, nanosheets, and petal-like shape can be precisely tuned. • The DME conversion and STY MA of the nanosheets MOR is 2 times higher than MOR-N. Mordenite (MOR) zeolite is an efficient catalyst for dimethyl ether (DME) carbonylation, which a key step of indirect production of ethanol from syngas. Herein, a nanosheets MOR zeolite with an ultrathin thickness of 10–30 nm can be facilely synthesized by using a commercial cetyltrimethylammonium hydroxide agent. It greatly shortened the pore length of 8-membered ring (8-MR) side pocket and more amount of Brønsted acid sites (BAS) can be exposed. More importantly, the amount of BAS in 8-MR side pockets of the MOR zeolite can be significantly increased. It should be noted that the morphology of MOR zeolite with prismatic, nanosheets, and petal-like can be obtained and precisely regulated. As a result, the conversion of DME over the nanosheets MOR zeolite is increased by nearly 2 times. Our finding proposed a novel strategy for constructing tunable nanosized morphology MOR zeolite and simultaneously directional enrichment of BAS in 8-MR channels. [ABSTRACT FROM AUTHOR]

The preparation of decahydrocyclobuta[cd]indene skeleton was accomplished through rhodium(III)‐catalyzed hydroarylation and relay thiophene‐promoted intramolecular [2+2] cycloaddition. This tandem reaction exhibited broad substrate scope (24 examples) and good functional group compatibility. Control experiments revealed the important role of sulfur (S) heteroatom, thus a tentative mechanism with thiophene‐promoted double Michael additions was proposed to explain this formal [2+2] cycloaddition. Moreover, the resulting polycyclic products displayed potent anti‐cancer activities against breast cancer cell lines MDA‐MB‐468. [ABSTRACT FROM AUTHOR]

Background: Hypertriglyceridemia (HTG) is a leading cause of acute pancreatitis. HTG can be caused by either primary (genetic) or secondary etiological factors, and there is increasing appreciation of the interplay between the two kinds of factors in causing severe HTG. Objectives: The main aim of this study was to identify the genetic basis of hypertriglyceridemia-induced acute pancreatitis (HTG-AP) in a Chinese family with three affected members (the proband, his mother and older sister). Methods: The entire coding and flanking sequences of LPL, APOC2, APOA5, GPIHBP1 and LMF1 genes were analyzed by Sanger sequencing. The newly identified LPL nonsense variant was subjected to functional analysis by means of transfection into HEK-293 T cells followed by Western blot and activity assays. Previously reported pathogenic LPL nonsense variants were collated and compared with respect to genotype and phenotype relationship. Results: We identified a novel nonsense variant, p.Gln118* (c.351C > T), in the LPL gene, which co-segregated with HTG-AP in the Chinese family. We provided in vitro evidence that this variant resulted in a complete functional loss of the affected LPL allele. We highlighted a role of alcohol abuse in modifying the clinical expression of the disease in the proband. Additionally, our survey of 12 previously reported pathogenic LPL nonsense variants (in 20 carriers) revealed that neither serum triglyceride levels nor occurrence of HTG-AP was distinguishable among the three carrier groups, namely, simple homozygotes, compound heterozygotes and simple heterozygotes. Conclusions: Our findings, taken together, generated new insights into the complex etiology and expression of HTG-AP. [ABSTRACT FROM AUTHOR]

Carcinoma-associated fibroblasts (CAFs) are abundant stromal cells in tumor microenvironment that are critically involved in cancer progression. Contrasting reports have shown that CAFs can have either pro- or antitumorigenic roles, indicating that CAFs are functionally heterogeneous. Therefore, to precisely target the cancer-promoting CAF subsets, it is necessary to identify specific markers to define these subpopulations and understand their functions. We characterized two CAFs subsets from 28 non–small cell lung cancer (NSCLC) patient tumors that were scored and classified based on desmoplasia [mainly characterized by proliferating CAFs; high desmoplastic CAFs (HD-CAF; n = 15) and low desmoplastic CAFs (LD-CAF; n = 13)], which is an independent prognostic factor. Here, for the first time, we demonstrate that HD-CAFs and LD-CAFs show different tumor-promoting abilities. HD-CAFs showed higher rate of collagen matrix remodeling, invasion, and tumor growth compared to LD-CAFs. Transcriptomic analysis identified 13 genes that were differentially significant (fold ≥1.5; adjusted P value <.1) between HD-CAFs and LD-CAFs. The top upregulated differentially expressed gene, ST8SIA2 (11.3 fold; adjusted P value =.02), enhanced NSCLC tumor cell invasion in 3D culture compared to control when it was overexpressed in CAFs, suggesting an important role of ST8SIA2 in cancer cell invasion. We confirmed the protumorigenic role of ST8SIA2, showing that ST8SIA2 was significantly associated with the risk of relapse in three independent NSCLC clinical datasets. In summary, our studies show that functional heterogeneity in CAF plays key role in promoting cancer cell invasion in NSCLC. [ABSTRACT FROM AUTHOR]

The alloying of high-manganese steel with aluminum produces wear-resistant casting components with greater yield strength and significantly reduced density, which facilitates considerable energy-savings and service life extension in cement, mining, and construction operations. However, the strengthening mechanism of Al alloying responsible for the increasing yield strength, and how the fracture mechanism influences the work hardening behavior of these castings require further clarification. The present work addresses these issues by evaluating the work hardening behavior and fracture mechanisms of casting Fe–18Mn-1.3C–2Cr steels with Al alloying concentrations of 0, 4, 7, and 11 wt%. The results reveal that work hardening is facilitated by twinning-dislocation cell intersection in the absence of Al, by deformation band-planar slipping dislocation intersections et al. concentrations of 4 and 7 wt%, and by the precipitation of κ carbides at an Al concentration of 11 wt%. Furthermore, the tensile fracture mode increasingly varied from ductile fracture at 0 Al wt.% to brittle rupture at 11 Al wt.%, which was also accompanied by large voids and cleavages. [ABSTRACT FROM AUTHOR]

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Background and purpose Seipin, which regulates adipocyte differentiation and lipolysis, inducing severe lipodystrophy and metabolic syndromes, is also highly expressed in the nervous system and affects some neurological diseases. However, the impacts of seipin in stroke remain unclear. Methods and results In this study, we subjected seipin knockout mice to cerebral ischemia/reperfusion injury and found that seipin knockout mice exhibited exacerbated neurological disorder and enlarged infarct size, companied by blood–brain barrier (BBB) damages. Furthermore, we showed that seipin knockout aggravated endoplasmic reticulum (ER) stress and significantly increased glucose levels, decreased leptin and adiponectin levels in mouse plasma. Conclusions Our findings reveal that seipin knockout exacerbates cerebral I/R-induced damages by increasing BBB permeability, amplifying ER stress and increasing glucose levels, as well as decreasing leptin and adiponectin levels, indicating that seipin may be a potential therapeutic target for stroke. [ABSTRACT FROM AUTHOR]

Hypertriglyceridemia (HTG) is a weak risk factor in primary ischemic stroke prevention. However, clinical studies have found a counterintuitive association between a good prognosis after ischemic stroke and HTG. This “HTG paradox” requires confirmation and further explanation. The aim of this study was to experimentally assess this paradox relationship using the gene-modified mice model of extreme HTG. We first used the human Apolipoprotein CIII transgenic (Tg-ApoCIII) mice and non-transgenic (Non-Tg) littermates to examine the effect of HTG on stroke. To our surprise, infarct size, neurological deficits, brain edema, BBB permeability, neuron density and lipid peroxidation were the same in Tg-ApoCIII mice and Non-Tg mice after temporary middle cerebral artery occlusion (tMCAO). In the late phase (21 days after surgery), no differences were found in brain atrophy, neurological dysfunctions, weight and mortality between the two groups. To confirm the results in Tg-ApoCIII mice, Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1(GPIHBP1) knockout mice, another severe HTG mouse model, were used and yielded similar results. Our study demonstrates for the first time that extreme HTG does not affect ischemic brain injuries in the tMCAO mouse model, indicating that the association between HTG and good outcomes after ischemic stroke probably represents residual unmeasured confounding. Further clinical and prospective population-based studies are needed to explore variables that contribute to the paradox. [ABSTRACT FROM AUTHOR]

Objectives There has been limited utility for laboratory tumor models to predict clinical performance of cancer drugs. Clinical drug trials usually recruit patients that have advanced disease, therefore preclinical tumor models that closely reflect this characteristic will be more reliable to test candidate drugs. We evaluated the use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) to sample metastatic lymph nodes in patients to establish patient-derived tumorxenograft (PDX) models of advanced lung cancer. Materials and methods Cell suspensions from TBNA aspirates were implanted into the subcutaneous tissue of NSG (NOD scid) gamma) mice. The success rate of PDX establishment was associated with tumor histopathology and the cellularity and cytopathological diagnosis of the primary EBUS-TBNA samples. Results From December 2011 to June 2012, 19 patients were enrolled in this study. Successful engraftment was achieved in 8/19 cases (42.1%). The duration between inoculation and tumor formation averaged 62.4 days (13–144 days). The engrafted tumors included 3 adenocarcinomas (3/12: 25%), 2 squamous cell carcinomas (2/3: 67%), 1 large cell carcinoma (1/1: 100%), and 2 small cell carcinomas (2/3: 67%). Conclusion EBUS-TBNA samples can be used for establishment of tumor xenograft model in immunodeficient mice. [ABSTRACT FROM AUTHOR]

The objective of present study was to assess the simultaneous removal of organics and nitrogen by four lab-scale vertical subsurface flow constructed wetlands (V-SFCWs). The emergent plants employed were Canna indica . Five-month experiments showed that the planted and aerated system largely reduced the COD by 95%, NH 4 by 88% and total inorganic nitrogen (TIN) by 83%. It outperformed the unplanted or simple aerated system and was much better than non-aerated system. The study provided a strong evidence to support widespread research and application of spray aeration as a low-cost and energy-efficient aeration technology in V-SFCWs. [ABSTRACT FROM AUTHOR]

Source-apportioned particle concentrations are necessary to properly evaluate the health impacts of air pollution. In this study, a measurement station was established at an urban roadside in northern Taiwan to the investigate lung deposited surface area (LDSA) concentration, a relevant metric for the adverse health effects of aerosol exposure, along with PM 1 and equivalent black carbon (eBC) concentrations, particle number concentration (PNC), and particle size distribution (PSD). Through positive matrix factorization and multi-linear regression analysis, we attributed 57% of LDSA to traffic emissions over the entire study. During rush hour, the motorcycle fraction increased to 0.83 and LDSA (77.6 ± 9.9 µm2/cm3) and PNC (14,000 ± 2400 particles/cm3) values peaked, while 74% of LDSA was attributed to traffic. The LDSA ratio, defined as the ratio of measured LDSA to that estimated from the particle size distribution with a spherical assumption, also increased, highlighting the greater degree of fractal morphology during rush hour. The relationship between LDSA emitted by traffic and PNC yielded a higher r 2 (0.92) than the r 2 between traffic LDSA and eBC (0.82). Finally, the excess lifetime cancer risk linked with traffic emission was 1.56 × 10-4 (i.e. 15.6 excess cancer cases for a population of 100,000 people) based on the LDSA apportionment results. [Display omitted] • Analysis of PM concentrations and properties in a motorcycle dominant city. • Compared to black carbon, LDSA had a high correlation with traffic flux (r2 = 0.78). • PMF combined with multiple linear regression was used to estimate LDSA(traffic). • Fraction of LDSA(traffic) to total LDSA was 0.57 on average and 0.74 at rush hours. • The excess lifetime cancer risk induced by LDSA from traffic emission was 1.56 × 10-4. [ABSTRACT FROM AUTHOR]

Aims There are no unified criteria for diagnosing heart failure with preserved ejection fraction (HFpEF). The aim of this study was to evaluate the present main diagnostic criteria and to discover which parameters and strategies are more valuable. Methods and results Echocardiographic data and plasma N-terminal pro-brain natriuretic peptide levels were assessed in a derivation cohort (n= 236) and a validation cohort (n= 98). Both cohorts included normal controls, patients with hypertensive heart disease without heart failure and patients with HFpEF. In the derivation cohort, the ratio of early mitral inflow velocity to tissue Doppler velocity at lateral mitral annulus (lateral E/e'≥12), left atrial volume index (LAVI≥34 mL/m2), and the difference between duration of reversed pulmonary vein atrial systole flow and duration of mitral A wave flow (Ard–Ad>30 ms) had the greatest diagnostic value among all the single parameters. A brief strategy that consisted of either: (i) lateral E/e'≥12; or (ii) 12>lateral E/e'≥8, with either LAVI≥34 mL/m2 or Ard–Ad>30 ms, provided good diagnostic accuracy for identifying diastolic dysfunction in HFpEF, with a sensitivity of 77% and specificity of 81%. These observations were confirmed in the validation cohort. Conclusion Echocardiographic parameters including lateral E/e', LAVI, and Ard–Ad have the greatest value in diagnosing HFpEF. A brief strategy that included these three parameters had great diagnostic value and would be simple to use in clinic practice. [ABSTRACT FROM AUTHOR]

Background: HuR is an RNA-binding protein that post-transcriptionally modulates the expressions of various target genes implicated in carcinogenesis, such as CCNA2 encoding cyclin A. No prior study attempted to evaluate the significance of HuR expression in a large cohort with upper urinary tract urothelial carcinomas (UTUCs).Methods: In total, 340 cases of primary localized UTUC without previous or concordant bladder carcinoma were selected. All of these patients received ureterectomy or radical nephroureterectomy with curative intents. Pathological slides were reviewed, and clinical findings were collected. Immunostaining for HuR and cyclin A was performed and evaluated by using H-score. The results of cytoplasmic HuR and nuclear cyclin A expressions were correlated with disease-specific survival (DSS), metastasis-free survival (MeFS), urinary bladder recurrence-free survival (UBRFS), and various clinicopathological factors.Results: HuR cytoplasmic expression was significantly related to the pT status, lymph node metastasis, a higher histological grade, the pattern of invasion, vascular and perineurial invasion, and cyclin A expression (p = 0.005). Importantly, HuR cytoplasmic expression was strongly associated with a worse DSS (p < 0.0001), MeFS (p < 0.0001), and UBRFS (p = 0.0370) in the univariate analysis, and the first two results remained independently predictive of adverse outcomes (p = 0.038, relative risk [RR] = 1.996 for DSS; p = 0.027, RR = 1.880 for MeFS). Cyclin A nuclear expression was associated with a poor DSS (p = 0.0035) and MeFS (p = 0.0015) in the univariate analysis but was not prognosticatory in the multivariate analyses. High-risk patients (pT3 or pT4 with/without nodal metastasis) with high HuR cytoplasmic expression had better DSS if adjuvant chemotherapy was performed (p = 0.015).Conclusions: HuR cytoplasmic expression was correlated with adverse phenotypes and cyclin A overexpression and also independently predictive of worse DSS and MeFS, suggesting its roles in tumorigenesis or carcinogenesis and potentiality as a prognostic marker of UTUC. High HuR cytoplasmic expression might identify patients more likely to be beneficial for adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis. • AMPKα facilitates TCA cycle by maintaining PDH complex activity • AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex • Activation of AMPKα-PDHA axis promotes tumor lung metastasis • AMPKα-PDHA axis predicts poor metastasis-free survival in breast cancer patients Cai et al. demonstrate that phosphorylation of the catalytic subunit PDHA on Ser295 and S314 by AMPKα is essential for the maintenance of pyruvate dehydrogenase complex activity and TCA cycle. Activation of AMPKα-PDHA axis predicts poor metastasis-free survival in breast cancer patients and facilitates tumor lung metastasis. [ABSTRACT FROM AUTHOR]

Background: The advents of novel immunotherapies have revolutionized the treatment of cancer. Adoptive cellular therapies using chimeric antigen receptor T (CAR-T) cells have achieved remarkable clinical responses in B cell leukemia and lymphoma but the effect on solid tumors including lung cancer is limited. Here we present data on the therapeutic potential of allogeneic CD3+CD4−CD8− double negative T (DNT) cells as a new cellular therapy for the treatment of lung cancer and underlying mechanisms. Methods: DNTs were enriched and expanded ex vivo from healthy donors and phenotyped by flow cytometry. Functionally, their cytotoxicity was determined against primary and established non-small-cell lung cancer (NSCLC) cell lines in vitro or through in vivo adoptive transfer into xenograft models. Mechanistic analysis was performed using blocking antibodies against various cell surface and soluble markers. Furthermore, the role of IL-15 on DNT function was determined. Results: We demonstrated that ex vivo expanded DNTs can effectively lyse various human NSCLC cells in vitro and inhibit tumor growth in xenograft models. Expanded DNTs have a cytotoxic phenotype, as they express NKp30, NKG2D, DNAM-1, membrane TRAIL (mTRAIL), perforin and granzyme B, and secrete IFNγ and soluble TRAIL (sTRAIL). DNT-mediated cytotoxicity was dependent on a combination of tumor-expressed ligands for NKG2D, DNAM-1, NKp30 and/or receptors for TRAIL, which differ among different NSCLC cell lines. Furthermore, stimulation of DNTs with IL-15 increased expression of effector molecules on DNTs, their TRAIL production and cytotoxicity against NSCLC in vitro and in vivo. Conclusion: Healthy donor-derived DNTs can target NSCLC in vitro and in vivo. DNTs recognize tumors via innate receptors which can be up-regulated by IL-15. DNTs have the potential to be used as a novel adoptive cell therapy for lung cancer either alone or in combination with IL-15. [ABSTRACT FROM AUTHOR]