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Aspergillus versicolor, a widely distributed fungus, is associated with pollution and carcinogenic hazards. This study aimed to examine the functions of the A. versicolor exudate and laid a scientific foundation for improving our understanding, utilization, and control of A. versicolor. The A. versicolor exudate proteome, ion content, and amino acid components were determined using label-free quantitation, atomic absorption spectrophotometry, and high-performance liquid chromatography, respectively. In total, 502 proteins were identified in the A. versicolor exudate. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and cluster of orthologous group analyses were used to annotate the functional classification and pathways of the aligned proteins. Proteins identified in the exudate were mainly enriched in carbohydrate metabolic process, translation, oxidoreductase activity, oxidoreductase activity, hydrolase activity, cell wall-related processes, catalytic activity, and unknown functions. The exudate comprised Na, K, Ca, Fe, and Mg cations. Among the 17 types of amino acids detected in the exudate, 7 were essential and 10 were nonessential. The exudate may be involved in the vital processes of A. versicolor. Additionally, the exudate may play an important role in the growth, development, reproduction, homeostasis, nutrient supply for regrowth, and virulence of A. versicolor.

Supplementary Figures S1-S5 from Survival Signaling by Notch1: Mammalian Target of Rapamycin (mTOR)–Dependent Inhibition of p53

Supplementary Materials, Figure Legends 1-3 from Heterotrimerization of the Growth Factor Receptors erbB2, erbB3, and Insulin-like Growth Factor-I Receptor in Breast Cancer Cells Resistant to Herceptin

Supplementary Figure 1 from Heterotrimerization of the Growth Factor Receptors erbB2, erbB3, and Insulin-like Growth Factor-I Receptor in Breast Cancer Cells Resistant to Herceptin

Notch signaling is believed to promote cell survival in general. However, the mechanism is not clearly understood. Here, we show that cells expressing intracellular domain of human Notch1 (NIC-1) are chemoresistant in a wild-type p53-dependent manner. NIC-1 inhibited p53 by inhibiting its activating phosphorylations at Ser15, Ser20, and Ser392 as well as nuclear localization. In addition, we found that inhibition of p53 by NIC-1 mainly occurs through mammalian target of rapamycin (mTOR) using phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) pathway as the mTOR inhibitor, rapamycin treatment abrogated NIC-1 inhibition of p53 and reversed the chemoresistance. Consistent with this, rapamycin failed to reverse NIC-1-induced chemoresistance in cells expressing rapamycin-resistant mTOR. Further, ectopic expression of eukaryotic initiation factor 4E (eIF4E), a translational regulator that acts downstream of mTOR, inhibited p53-induced apoptosis and conferred protection against p53-mediated cytotoxicity to similar extent as that of NIC-1 overexpression but was not reversed by rapamycin, which indicates that eIF4E is the major target of mTOR in Notch1-mediated survival signaling. Finally, we show that MCF7 (breast cancer) and MOLT4 (T-cell acute lymphoblastic leukemia) cells having aberrant Notch1 signaling are chemoresistant, which can be reversed by both PI3K and mTOR inhibitors. These results establish that Notch1 signaling confers chemoresistance by inhibiting p53 pathway through mTOR-dependent PI3K-Akt/PKB pathway and imply that p53 status perhaps is an important determinant in combination therapeutic strategies, which use mTOR inhibitors and chemotherapy. (Cancer Res 2006; 66(9): 4715-24)

Supplementary Figure 2 from Heterotrimerization of the Growth Factor Receptors erbB2, erbB3, and Insulin-like Growth Factor-I Receptor in Breast Cancer Cells Resistant to Herceptin

In this paper, tube-model predictive control based on the sum of squares technique is developed for hypersonic vehicles with state-dependent input constraints. Firstly, the longitudinal non-linear model in the presence of uncertain parameters is transformed into the polytopic linear parameter varying model with bounded disturbance by feedback linearization. Then the actual input constraints are converted to the virtual state-dependent input constraints in linear multivariable polynomial. A composite feedback control law based on tube-model predictive control is designed into a convex combination of unconstrained and constrained control. The real control law can be obtained by inversion. The sum of squares technique is used to transform the polynomial constraints into the convex matrix sum of squares condition via linear matrix inequality. Finally, simulation results verify the effectiveness of the proposed controller.

Ethylene is positively correlated with the anthocyanin accumulation in postharvest plum fruit, but the regulation mechanism has not been fully clarified. In this work, the ‘Friar’ plum fruit under different storage temperatures (0, 10 and 25 °C) and treatments (100.0 μL L−1 ethylene and 1.0 μL L−1 1-MCP) were applied to study the relationship between anthocyanin accumulation and ethylene signal pathway. The fruits stored at 10 °C had higher ethylene production rate and more anthocyanin in flesh than those stored at 0 °C and 25 °C. Ten ethylene biosynthesis associated genes and forty-one ethylene signal transduction related genes were obtained from the previous transcriptome data. Among them, the expression levels of ethylene biosynthesis associated genes (PsACS1, PsACS4 and PsACO1), and ethylene signal transduction related genes (PsERS1s, PsETR2, PsERF1a, and PsERF12) were markedly higher in the fruits stored at 10 °C than those at 0 °C and 25 °C. Exogenous ethylene treatment enhanced while 1-MCP treatment inhibited the anthocyanin accumulation in the flesh under storage at 10 °C. In addition, exogenous ethylene treatment markedly increased the expression levels of PsACS1, PsACS4, PsACO1, PsETR2, PsERF1a, and PsERF12 in the flesh once it turning red, as well as the anthocyanin biosynthesis related genes (PsPAL, PsCHS, PsF3H, PsDRF, PsANS, PsUFGT and PsMYB10), whereas 1-MCP treatment manifested the contrary effects. Correlation analysis indicated that there was a significant positive correlation between genes expression related to ethylene signal pathway and anthocyanin biosynthesis, except for PsERF11. In conclusion, ethylene signal pathway is involved in the flesh reddening by up-regulating the anthocyanin biosynthesis related genes.

Background Rice sheath blight, caused by Rhizoctonia solani Kühn (teleomorph: Thanatephorus cucumeris), is one of the most severe diseases in rice (Oryza sativa L.) worldwide. Studies on resistance genes and resistance mechanisms of rice sheath blight have mainly focused on indica rice. Rice sheath blight is a growing threat to rice production with the increasing planting area of japonica rice in Northeast China, and it is therefore essential to explore the mechanism of sheath blight resistance in this rice subspecies. Results In this study, RNA-seq technology was used to analyse the gene expression changes of leaf sheath at 12, 24, 36, 48, and 72 h after inoculation of the resistant cultivar ‘Shennong 9819’ and susceptible cultivar ‘Koshihikari’ with R. solani. In the early stage of R. solani infection of rice leaf sheaths, the number of differentially expressed genes (DEGs) in the inoculated leaf sheaths of resistant and susceptible cultivars showed different regularity. After inoculation, the number of DEGs in the resistant cultivar fluctuated, while the number of DEGs in the susceptible cultivar increased first and then decreased. In addition, the number of DEGs in the susceptible cultivar was always higher than that in the resistant cultivar. After inoculation with R. solani, the overall transcriptome changes corresponding to multiple biological processes, molecular functions, and cell components were observed in both resistant and susceptible cultivars. These included metabolic process, stimulus response, biological regulation, catalytic activity, binding and membrane, and they were differentially regulated. The phenylalanine metabolic pathway; tropane, piperidine, and pyridine alkaloid biosynthesis pathways; and plant hormone signal transduction were significantly enriched in the early stage of inoculation of the resistant cultivar Shennong 9819, but not in the susceptible cultivar Koshihikari. This indicates that the response of the resistant cultivar Shennong 9819 to pathogen stress was faster than that of the susceptible cultivar. The expression of plant defense response marker PR1b gene, transcription factor OsWRKY30 and OsPAL1 and OsPAL6 genes that induce plant resistance were upregulated in the resistant cultivar. These data suggest that in the early stage of rice infection by R. solani, there is a pathogen-induced defence system in resistant rice cultivars, involving the expression of PR genes, key transcription factors, PAL genes, and the enrichment of defence-related pathways. Conclusion The transcriptome data revealed the molecular and biochemical differences between resistant and susceptible cultivars of rice after inoculation with R. solani, indicating that resistant cultivars have an immune response mechanism in the early stage of pathogen infection. Disease resistance is related to the overexpression of PR genes, key transcriptome factors, and PAL genes, which are potential targets for crop improvement.

Resistance to CDK4/6 inhibitors (CDKis) is emerging as a clinical challenge. Identification of the factors contributing to CDKi resistance, with mechanistic insight, is of pivotal significance. Recent studies linked aberrant FGFR signaling to CDKi resistance. However, detailed mechanisms are less clear. Based on control and FGFR1 overexpressing luminal A cell line models, we demonstrated that FGFR1 overexpression rendered the cells resistant to palbociclib. FGFR1 overexpression abolished palbociclib-mediated cell cycle arrest, as well as the attenuated palbociclib-induced inhibition of G1/S transition regulators (pRb, E2F1, and cyclin D3) and factors that promote G2/M transition (cyclin B1, cdc2/CDK1, and cdc25). Importantly, FGFR1-induced palbociclib resistance was associated with promotion of cancer cell stemness and the upregulation of Wnt/β-catenin signaling. We found that palbociclib may function as an ER agonist in MCF-7/FGFR1 cells. Upregulation of the ER-mediated transcription in MCF-7/FGFR1 cells was associated with ERα phosphorylation and enhanced receptor tyrosine kinase signaling. The combination of palbociclib with FGFR-targeting AZD4547 resulted in remarkable synergistic effects on MCF-7/FGFR1 cells, especially for the inhibition of cancer cell stemness. Our findings of FGFR1-induced palbociclib resistance, promotion of cancer stem cells and associated molecular changes advance our mechanistic understanding of CDKi resistance, which will facilitate the development of strategies targeting CDKi resistance in breast cancer treatment.

In this paper, a robust model predictive controller based on sum of squares (SOS-RMPC) is proposed to realize the trajectory tracking control of hypersonic vehicle with actuator fault. Firstly, the polytopic feedback linearization error model of hypersonic vehicle with actuator fault is derived. The integration of altitude and velocity are introduced to eliminate the steady state error. The lose efficiency fault of actuator is separated from control input and the additional bounded disturbance term is formed. Secondly, the real input constraint is converted to virtual state-dependent input constraint in polynomial. Finally, a composite control law with and without virtual state-dependent constraint is proposed, and the SOS-RMPC fault-tolerant controller is designed. By SOS technology, the virtual state-dependent input constraint in polynomial is transformed into convex optimization problem of linear matrix inequality (LMI). The norm-bounded theory is applied to suppress the disturbance. The simulations show that the designed controller can realize trajectory tracking control of hypersonic vehicle with actuator fault.

Background: Frogeye leaf spot (FLS) is a destructive fungal disease in soybean production. The most economical and effective strategy to control FLS is to use resistant cultivars. However, the use of a limited number of resistant loci in FLS management will be countered by the emergence of new, and more virulent, Cercospora sojina races. Thus, we identified quantitative trait loci (QTL) that control resistance to FLS and identified novel resistant genes using a genome-wide association study (GWAS) on 234 Chinese soybean cultivars.Results: A total of 30,890 single nucleotide polymorphism (SNP) markers were used to estimate linkage disequilibrium (LD) and population structure. The GWAS results identified six loci (pGlyma20g31630 encoding pyruvate dehydrogenase (PDH), Glyma05g28980 encoding mitogen-activated protein kinase 7 (MPK7), and Glyma20g31510, Glyma20g31520 encoding the calcium-dependent protein kinase 4(CDPK4) in the haplotype blocks were found to be associated with FLS resistance.Conclusions: The proteins encoded by these four genes directly, or indirectly participate in the biological pathway of salicylic acid (SA) and jasmonic acid (JA). These two plant hormones can induce the expression of disease resistance related genes and are essential for plant systemic acquired resistance (SAR). Therefore, the novel loci and candidate genes provide genomic location information for further advances in FLS resistance gene cloning and molecular breeding.

Background Frogeye leaf spot (FLS) is a destructive fungal disease that affects soybean production. The most economical and effective strategy to control FLS is the use of resistant cultivars. However, the use of a limited number of resistant loci in FLS management will be countered by the emergence of new high-virulence Cercospora sojina races. Therefore, we identified quantitative trait loci (QTL) that control resistance to FLS and identified novel resistant genes using a genome-wide association study (GWAS) on 234 Chinese soybean cultivars. Results A total of 30,890 single nucleotide polymorphism (SNP) markers were used to estimate linkage disequilibrium (LD) and population structure. The GWAS results showed four loci (p Glyma20g31630 encoding pyruvate dehydrogenase (PDH), Glyma05g28980, which encodes mitogen-activated protein kinase 7 (MPK7), and Glyma20g31510, Glyma20g31520 encoding calcium-dependent protein kinase 4 (CDPK4) in the haplotype blocks deserves special attention. Conclusions This study showed that GWAS can be employed as an effective strategy for identifying disease resistance traits in soybean and narrowing SNPs and candidate genes. The prediction of candidate genes in the haplotype blocks identified by disease resistance loci can provide a useful reference to study systemic disease resistance.

In this paper, a robust fault-tolerant controller is designed for flexible air-breathing hypersonic vehicle (HSV) with actuator fault and external disturbance. Firstly, the polytopic linear parameter variable (LPV) model of flexible HSV is established through Jacobian linearization and tensor product (TP) method. The integral terms of height error and velocity error are introduced to eliminate the steady state error, and the extended system is constructed. The actuator loss of effectiveness fault is separated from the control input and lumped into disturbance term together with the external disturbance. And the extended polytopic LPV faulty system is obtained. Secondly, the fault-tolerant controller is designed based on robust model predictive control (RMPC). The state feedback control law is obtained by solving the linear matrix inequality (LMI) optimization problem. Norm bounded theory is introduced to suppress the lumped disturbance term of the real system. The disturbed and undisturbed state are guaranteed to be in the same invariant set. Finally, numerical simulations have demonstrated the fault-tolerant performance of the developed controller.

Triple negative breast cancer (TNBC) is the breast cancer subtype that is most refractory to treatment. Thus, identification of novel molecular targets and drug treatments are needed to improve prognosis for patients. The widely used anti-diabetic drug Metformin has been reported to possess anti-cancer properties. Although it is believed that Metformin may exert its anti-cancer effects through indirect reduction of glucose and insulin levels, and directly activating the AMPK kinase and inhibiting downstream cancer-related pathways, the molecular mechanisms underlying its anti-cancer function in TNBC have yet to be fully elucidated. In this study, we investigated the role and mechanism of Metformin-mediated downregulation of oncogenic c-Met in MDA-MB-468 TNBC cells. Our results demonstrated greater sensitivity of MDA-MB-468 cells to Metformin compared to other breast cancer cell lines. Metformin-induced inhibition of MDA-MB-468 cell proliferation was correlated with the downregulation of c-Met at both protein and mRNA levels. Overexpression of c-Met in MDA-MB-468 cells using a lentiviral vector system rendered the cells resistant to Metformin, which was accompanied by the promotion of cancer stem cell stemness. Functionally, we demonstrated that c-Met induced activation of receptor tyrosine kinase (RTK) signaling pathways play a critical role in c-Met-modulated Metformin responsiveness. These novel findings highlight c-Met as a key regulator of Metformin-mediated inhibition of TNBC cell growth, suggesting that c-Met overexpression may be a critical factor contributing to metformin resistance. To this end, combination of Metformin with c-Met inhibitors could be a useful strategy to improve Metformin-mediated anti-cancer efficacies in TNBC. Citation Format: Dana M. Gant, Zhikun Ma, Amanda B. Parris, Xiaohe Yang. c-Met downregulation contributes to Metformin-induced inhibition of MDA-MB-468 triple negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1123.

Rice false smut (RFS) disease, which is caused by Ustilaginoidea virens, has been widespread all over the world in recent years, causing irreversible losses. Under artificial culture conditions, exudates will appear on colonies of U. virens during the growth of the hyphae. Exudation of droplets is a common feature in many fungi, but the functions of exudates are undetermined. As the executors of life functions, proteins can intuitively reflect the functions of exudates. Shotgun proteomics were used in this study. A total of 650 proteins were identified in the exudate of U. virens, and the raw data were made available via ProteomeXchange with the identifier PXD019861. There were 57 subcategories and 167 pathways annotated with Gene Ontology (GO) classification and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, respectively. Through protein–protein interaction (PPI) network analysis, it was found that 20 proteins participated in the biosynthesis of secondary metabolites. Two separate PPI analyses were performed for carbon metabolism and microbial metabolism in diverse environments. After comparing and annotating the functions of proteins of the exudate, it was speculated that the exudate was involved in the construction and remodeling of the fungal cell wall. Pathogenicity, sporulation, and antioxidant effects might all be affected by the exudate.

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One of the most current concerns in the field of information system is whether cloud computing technology can deliver the desired improvement of capability and value to enterprises. This paper studied the enterprise technology development capability of the enterprises in Beijing Zhongguancun Technology Park, the first national high-tech industrial development zone in China, from the perspective of the breadth and depth of the alignment of cloud computing and enterprise. It proposed a theoretical model to study how the breadth and depth of alignment affects the enterprise technology development capability in a turbulent environment and considers the intermediary role of the enterprise technology absorption capability and the moderation role of environmental turbulence in it. The model was tested empirically by questionnaires and structural equation model (SEM). Empirical results showed that both the deep and wide alignment of cloud computing can enhance the enterprise technology development capability by improving the enterprise technology absorption capability.

From the perspective of technical review, this paper made statistics on the supplement contents of

With the change of lifestyle and the acceleration of aging process, inflammatory diseases have increasingly become one of the most vital threats to global human health. SHP2 protein is a non-receptor tyrosine phosphatase encoded by PTPN11 gene, and it is widely expressed in various tissues and cells. Numerous studies have shown that SHP2 plays important roles in the regulation of inflammatory diseases, including cancer-related inflammation, neurodegenerative diseases and metabolic diseases. In this paper, the roles of SHP2 in inflammatory diseases of various physiological systems were reviewed. At the same time, the latest SHP2 inhibitors were summarized, which will hold a promise for the therapeutic potential in future.

This paper adopts Tube robust model predictive control (RMPC) approach to achieve the trajectory tracking control for flexible air-breathing hypersonic vehicle (FAHV) with lose efficiency fault of actuator. First of all, Jacobian linearization and tensor-product transformation are used to build the polytopic linear parameter varying (LPV) model for FAHV. Then, the FAHV faulty model is obtained by transforming lose efficiency fault of actuator into the additional disturbance term. Thirdly, fault-tolerant control is realized by composite control law. The error system is obtained by the difference between the actual and the nominal system. By designing the minimum robust positive invariant set (mRPI), the error system state is limited to the mRPI set. The additional disturbance term in mRPI set is suppressed by the auxiliary robust feedback control law. The nominal control law provides a reasonable trajectory for the actual system. And it is calculated by the convex optimization problem, which is constrained by linear matrix inequality (LMI). The fault-tolerant controller guarantees that the actual trajectory is located in the mRPI set all the time and centered on the nominal trajectory. Finally, the designed Tube RMPC controller is validated by simulation.

Crop productivity in Albic soil is poor, owing to poor soil physicochemical properties. Mixing of Aw layers, representing Albic soil, with B layers, could improve the physicochemical properties of Albic soil, which is characterized by poor humus on the topsoil and high penetration resistance. The objective of the present study conducted in 2015-2016 in an Albic soil region in Heilongjiang province, China, was to explore the effects of different soil mixing strategies on the physicochemical properties of Albic soil and crop yield. There were four soil mixing treatments: conventional subsoiler (CS), three-stage subsoil mixing plough (TSMP), four-stage subsoil mixing plough (FSMP), and three-stage subsoil interval mixing plough (TSIMP). Our results demonstrated that the Aw layer bulk density of Albic soil under TSMP, FSMP, and TSIMP decreased significantly compared to that under CS. In addition, the total porosity of the soil under these treatments increased significantly in 2 years. Compared to the water holding capacity under the CS treatment, other treatments increased significantly in the Aw layer. Furthermore, soil penetration resistance of the Aw layer decreased following Aw and B layer mixing. All three soil mixing treatments also increased soil aggregate stability and cation exchange capacity but reduced soil organic carbon content in the Aw layer. Soil mixing increased soybean and maize seed yield. Overall, Aw and B layer mixing improved Albic soil structure and physiochemical properties and increased crop yield; thus, this mixing is a feasible approach for Albic soil improvement, with optimal improvements observed under the FMSP strategy, which also added organic substances to the Aw layer.

Background Cercospora armoraciae causes leaf spot disease on Armoracia rusticana. Exudation of droplets, when grown on PDA, distinguishes this fungi from other members of the genus Cercospora. The role this exudate plays in the virulence of this pathogen has not been elucidated. To explore this, we characterized the transcriptome of C. armoraciae and the proteome of exudate associated with this plant pathogen. Methods Virulence of three strains of C. armoraciae was evaluated in greenhouse assays. De novo sequencing was applied to assemble transcriptome from these strains. Nano-HPLC-MS/MS analysis was used to identify proteins in the pathogen exudate. Identified proteins were functionally classified and annotated using GO, KEGG, and COG/KOG bioinformatics analysis methods. Results When treated with the exudate of C. armoraciae strain SCa-01, leaves of A. rusticana showed yellowing and necrosis of the leaves and similar symptoms to plants inoculated with this fungi. A total of 14,937 unigenes were assembled from C. armoraciae, and 576 proteins comprising 1,538 peptides, 1,524 unique peptide, were identified from the exudate. GO annotation classified 411 proteins (71%) into 27 functional categories, namely, 12, seven and eight biological process, cellular component, and molecular function subcategories, respectively. KEGG analysis assigned 314 proteins to 84 signaling/metabolic pathways, and 450 proteins were annotated against the COG/KOG database. Discussion Transcriptome and GO analysis of C. armoraciae found most proteins in the exudate. GO analysis suggested that a considerable proportion of proteins were involved in cellular process and metabolic process, which suggests exudates maintain the metabolic balance of this fungi. Some proteins annotated to the phenylalanine metabolism, which suggests that the exudates may enhance the virulence of this pathogen. Some proteins annotated to the phenylalanine metabolism, which suggests that the exudates may enhance the pathogenicity of the pathogen. Also some proteins were annotated to the peroxisome metabolic pathway and the fatty acid biosynthesis pathways. These pathways may confer antifungal, antioxidant and antimicrobial activity on the exudates.

Additional file 4: Table S4. Gene annotation/prediction statistics for Race15.

Additional file 2: Table S2. Coding gene prediction results from Race15.

The estimation of glaucoma progression is a challenging task as the rate of disease progression varies among individuals in addition to other factors such as measurement variability and the lack of standardization in defining progression. Structural tests, such as thickness measurements of the retinal nerve fiber layer or the macula with optical coherence tomography (OCT), are able to detect anatomical changes in glaucomatous eyes. Such changes may be observed before any functional damage. In this work, we built a generative deep learning model using the conditional GAN architecture to predict glaucoma progression over time. The patient’s OCT scan is predicted from three or two prior measurements. The predicted images demonstrate high similarity with the ground truth images. In addition, our results suggest that OCT scans obtained from only two prior visits may actually be sufficient to predict the next OCT scan of the patient after six months.

Additional file 7: Table S7. Statistics of corepan genes between Race15 and Race1.

Additional file 4: Table S4. Gene annotation/prediction statistics for Race15.

Additional file 6: Table S6. Statistical of colinearity and coverage between Race15 and Race1.

Additional file 9: Table S9. General mapping information for the 30 C. sojina isolates.

Additional file 9: Table S9. General mapping information for the 30 C. sojina isolates.

Additional file 1: Table S1. Sequencing quality control results from Race15.

Additional file 2: Table S2. Coding gene prediction results from Race15.

Additional file 7: Table S7. Statistics of corepan genes between Race15 and Race1.

Additional file 3: Table S3. Repeat sequence predictive statistical results.

Additional file 3: Table S3. Repeat sequence predictive statistical results.

Additional file 6: Table S6. Statistical of colinearity and coverage between Race15 and Race1.

Although ErbB2-targeted therapeutics have significantly improved ErbB2+ breast cancer patient outcomes, therapeutic resistance remains a significant challenge. Therefore, the development of novel ErbB2-targeting strategies is necessary. Importantly, ErbB2 is a sensitive client protein of heat shock protein 90 (HSP90), which regulates client protein folding, maturation, and stabilization. HSP90 inhibition provides an alternative therapeutic strategy for ErbB2-targeted degradation. In particular, ganetespib, a novel HSP90 inhibitor, is a promising agent for ErbB2+ cancers. Nevertheless, the anti-cancer efficacy and clinical application of ganetespib for ErbB2+ breast cancer is largely unknown. In our study, we examined the anti-cancer effects of ganetespib on ErbB2+ BT474 and SKBR3 breast cancer cells, and isogenic paired cancer cell lines with lentivirus-mediated ErbB2 overexpression. Ganetespib potently inhibited cell proliferation, cell cycle progression, survival, and activation/phosphorylation of ErbB2 and key downstream effectors in ErbB2+ breast cancer cells. Moreover, ganetespib decreased the total protein levels of HSP90 client proteins and reduced ErbB2 protein half-life. ErbB2-overexpressing cancer cells were also more sensitive to ganetespib-mediated growth inhibition than parental cells. Ganetespib also strikingly potentiated the inhibitory effects of lapatinib in BT474 and SKBR3 cells. Ultimately, our results support the application of ganetespib-mediated HSP90 inhibition as a promising therapeutic strategy for ErbB2+ breast cancer.

Metformin, a first line medication for type II diabetes, initially entered the spotlight as a promising anti-cancer agent due to epidemiologic reports that found reduced cancer risk and improved clinical outcomes in diabetic patients taking metformin. To uncover the anti-cancer mechanisms of metformin, preclinical studies determined that metformin impairs cellular metabolism and suppresses oncogenic signaling pathways, including receptor tyrosine kinase, PI3K/Akt, and mTOR pathways. Recently, the anti-cancer potential of metformin has gained increasing interest due to its inhibitory effects on cancer stem cells (CSCs), which are associated with tumor metastasis, drug resistance, and relapse. Studies using various cancer models, including breast, pancreatic, prostate, and colon, have demonstrated the potency of metformin in attenuating CSCs through the targeting of specific pathways involved in cell differentiation, renewal, metastasis, and metabolism. In this review, we provide a comprehensive overview of the anti-cancer actions and mechanisms of metformin, including the regulation of CSCs and related pathways. We also discuss the potential anti-cancer applications of metformin as mono- or combination therapies.

// Zhiying Guo 1 , Ming Zhao 1 , Erin W. Howard 1 , Qingxia Zhao 1 , Amanda B. Parris 1 , Zhikun Ma 1 and Xiaohe Yang 1 1 Julius L. Chambers Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, Kannapolis, North Carolina, USA Correspondence to: Xiaohe Yang, email: xyang@nccu.edu Keywords: phenformin, breast cancer, epithelial-mesenchymal transition, insulin-like growth factor 1 receptor, MMTV-ErbB2 transgenic mice Received: November 04, 2016 Accepted: June 19, 2017 Published: July 22, 2017 ABSTRACT Reports suggest that metformin, a popular anti-diabetes drug, prevents breast cancer through various systemic effects, including insulin-like growth factor receptor (IGFR) regulation. Although the anti-cancer properties of metformin have been well-studied, reports on a more bioavailable/potent biguanide, phenformin, remain sparse. Phenformin exerts similar functional activity to metformin and has been reported to impede mammary carcinogenesis in rats. Since the effects of phenformin on specific breast cancer subtypes have not been fully explored, we used ErbB2-overexpressing breast cancer cell and animal models to test the anti-cancer potential of phenformin. We report that phenformin (25–75 μM) decreased cell proliferation and impaired cell cycle progression in SKBR3 and 78617 breast cancer cells. Reduced tumor size after phenformin treatment (30 mg/kg/day) was demonstrated in an MMTV-ErbB2 transgenic mouse syngeneic tumor model. Phenformin also blocked epithelial-mesenchymal transition, decreased the invasive phenotype, and suppressed receptor tyrosine kinase signaling, including insulin receptor substrate 1 and IGF1R, in ErbB2-overexpressing breast cancer cells and mouse mammary tumor-derived tissues. Moreover, phenformin suppressed IGF1-stimulated proliferation, receptor tyrosine kinase signaling, and epithelial-mesenchymal transition markers in vitro . Together, our study implicates phenformin-mediated IGF1/IGF1R regulation as a potential anti-cancer mechanism and supports the development of phenformin and other biguanides as breast cancer therapeutics.

// Ming Zhao 1 , Erin W. Howard 1 , Amanda B. Parris 1 , Zhiying Guo 1 , Qingxia Zhao 1, 2 , Zhikun Ma 1 , Ying Xing 2 , Bolin Liu 3 , Susan M. Edgerton 3 , Ann D. Thor 3 and Xiaohe Yang 1, 4 1 Julius L. Chambers Biomedical/Biotechnology Research Institute and Department of Biological and Biomedical Sciences, North Carolina Central University, Kannapolis, North Carolina, USA 2 Basic Medical College of Zhengzhou University, Zhengzhou, Henan, P.R. China 3 Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA 4 College of Medicine, Henan University of Sciences and Technology, Luoyang, Henan, P.R. China Correspondence to: Xiaohe Yang, email: xyang@nccu.edu Keywords: CIP2A, lapatinib resistance, ErbB2, breast cancer, PP2A Received: November 05, 2016 Accepted: July 11, 2017 Published: July 19, 2017 ABSTRACT Lapatinib, a small molecule ErbB2/EGFR inhibitor, is FDA-approved for the treatment of metastatic ErbB2-overexpressing breast cancer; however, lapatinib resistance is an emerging clinical challenge. Understanding the molecular mechanisms of lapatinib-mediated anti-cancer activities and identifying relevant resistance factors are of pivotal significance. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that is overexpressed in breast cancer. Our study investigated the role of CIP2A in the anti-cancer efficacy of lapatinib in ErbB2-overexpressing breast cancer cells. We found that lapatinib concurrently downregulated CIP2A and receptor tyrosine kinase signaling in ErbB2-overexpressing SKBR3 and 78617 cells; however, these effects were attenuated in lapatinib-resistant (LR) cells. CIP2A overexpression rendered SKBR3 and 78617 cells resistant to lapatinib-induced apoptosis and growth inhibition. Conversely, CIP2A knockdown via lentiviral shRNA enhanced cell sensitivity to lapatinib-induced growth inhibition and apoptosis. Results also suggested that lapatinib downregulated CIP2A through regulation of protein stability. We further demonstrated that lapatinib-induced CIP2A downregulation can be recapitulated by LY294002, suggesting that Akt mediates CIP2A upregulation. Importantly, lapatinib induced differential CIP2A downregulation between parental BT474 and BT474/LR cell lines. Moreover, CIP2A shRNA knockdown significantly sensitized the BT474/LR cells to lapatinib. Collectively, our results demonstrate that CIP2A is a molecular target and resistance factor of lapatinib with a critical role in lapatinib-induced cellular responses, including the inhibition of the CIP2A-Akt feedback loop. Further investigation of lapatinib-mediated CIP2A regulation will advance our understanding of lapatinib-associated anti-tumor activities and drug resistance.

Heat shock protein 90 (HSP90) regulates several important cellular processes via its repertoire of 'client proteins'. These client proteins have been found to play fundamental roles in signal transduction, cell proliferation, cell cycle progression and survival, as well as other features of malignant cells, such as invasion, tumor angiogenesis and metastasis. Thus, HSP90 is an emerging target for cancer therapy. To this end, we evaluated ganetespib (STA-9090), a novel and potent HSP90 inhibitor, for its activity in gastric cancer cell lines. Ganetespib significantly inhibited the proliferation of AGS and N87 human gastric cancer cell lines and potently induced G2/M cell cycle arrest and apoptosis. Upregulation of cleaved poly(ADP-ribose) polymerase (c-PARP), c-caspase-3, c-caspase-8 and c-caspase-9 and suppression of gastric cancer‑associated HSP90 client proteins, including ErbB2, Erk, Akt, mTOR, GSK3 and Src, were observed in ganetespib-treated cells. These findings demonstrate that the ganetespib-induced mechanism of cell growth inhibition involves the activation of death receptor and mitochondrial pathways and the inhibition of receptor tyrosine kinase signaling pathways. Our study implicates ganetespib as a potential strategy for gastric cancer treatment, which warrants further preclinical and clinical investigation.

A fault-tolerant controller based on robust model predictive control (RMPC) is proposed for hypersonic vehicle with external disturbances and actuator loss of effectiveness faults. Firstly, the polytopic linear parameter-varying (LPV) model is established by Jacobian linearization and tensor-product method. Secondly, considering actuator loss of effectiveness faults and outputs static errors, the augmented faulty model is established. Thirdly, the external disturbances and the faults are transformed into lumped bounded disturbance item. The norm bounded theorem is used to deal with the disturbances. Finally, the fault-tolerant controller is obtained by solving the convex optimization problem under linear matrix inequality (LMI) constraints. Simulation results show that the designed fault-tolerant controller is feasible and effective.