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Objective Cardiovascular complications are the leading cause of morbidity and mortality in patients with myeloproliferative neoplasms (MPNs). The acquired kinase mutation JAK2V617F plays a central role in these disorders. Mechanisms responsible for cardiovascular dysfunction in MPNs are not fully understood, limiting the effectiveness of current treatment. Vascular endothelial cells (ECs) carrying the JAK2V617F mutation can be detected in patients with MPNs. The goal of this study was to test the hypothesis that the JAK2V617F mutation alters endothelial function to promote cardiovascular complications in patients with MPNs. Approach and Results We employed murine models of MPN in which the JAK2V617F mutation is expressed in specific cell lineages. When JAK2V617F is expressed in both blood cells and vascular ECs, the mice developed MPN and spontaneous, age‐related dilated cardiomyopathy with an increased risk of sudden death as well as a prothrombotic and vasculopathy phenotype on histology evaluation. In contrast, despite having significantly higher leukocyte and platelet counts than controls, mice with JAK2V617F‐mutant blood cells alone did not demonstrate any cardiac dysfunction, suggesting that JAK2V617F‐mutant ECs are required for this cardiovascular disease phenotype. Furthermore, we demonstrated that the JAK2V617F mutation promotes a pro‐adhesive, pro‐inflammatory, and vasculopathy EC phenotype, and mutant ECs respond to flow shear differently than wild‐type ECs. Conclusions These findings suggest that the JAK2V617F mutation can alter vascular endothelial function to promote cardiovascular complications in MPNs. Therefore, targeting the MPN vasculature represents a promising new therapeutic strategy for patients with MPNs.

Fatty acid synthase (FASN) has been shown to be selectively up‐regulated in cancer cells to drive the development of cancer. However, the role and associated mechanism of FASN in regulating the malignant progression of salivary adenoid cystic carcinoma (SACC) still remains unclear. In this study, we demonstrated that FASN inhibition attenuated invasion, metastasis and EMT of SACC cells as well as the expression ofPRRX1, ZEB1, Twist, Slug and Snail, among which the level of PRRX1 changed the most obviously. Overexpression of PRRX1 restored migration and invasion in FASN knockdown cells, indicating that PRRX1 is an important downstream target of FASN signalling. Levels of cyclin D1 and c‐Myc, targets of Wnt/β‐catenin pathway, were significantly decreased by FASN silencing and restored by PRRX1 overexpression. In addition, FASN expression was positively associated with metastasis and poor prognosis of SACC patients as well as with the expression of PRRX1, cyclin D1 and c‐Myc in SACC tissues. Our findings revealed that FASN in SACC progression may induce EMT in a PRRX1/Wnt/β‐catenin dependent manner.

With advances in the fields of regenerative medicine, cell-free therapy has received increased attention. Exosomes have a variety of endogenous properties that provide stability for molecular transport across biological barriers to cells, as a form of cell-to-cell communication that regulates function and phenotype. In addition, exosomes are an important component of paracrine signaling in stem-cell-based therapy and can be used as a stand-alone therapy or as a drug delivery system. The remarkable potential of exosomes has paved the pathway for cell-free treatment in bone regeneration. Exosomes are enriched in distinct noncoding RNAs (ncRNAs), including microRNAs, long ncRNAs and circular RNAs. Different ncRNAs have multiple functions. Altered expression of ncRNA in exosomes is associated with the regenerative potential and development of various diseases, such as femoral head osteonecrosis, myocardial infarction, and cancer. Although there is increasing evidence that exosome-derived ncRNAs (exo-ncRNAs) have the potential for bone regeneration, the detailed mechanisms are not fully understood. Here, we review the biogenesis of exo-ncRNA and the effects of ncRNAs on angiogenesis and osteoblast- and osteoclast-related pathways in different diseases. However, there are still many unsolved problems and challenges in the clinical application of ncRNA; for instance, production, storage, targeted delivery and therapeutic potency assessment. Advancements in exo-ncRNA methods and design will promote the development of therapeutics, revolutionizing the present landscape.

To investigate the effect of paired related homeobox1 (PRRX1) on autophagy of salivary adenoidcystic carcinoma (SACC) cells.PRRX1-overexpressed lentiviral vectors and their negative control lentiviral vectors were used to transfect SACC cells. The transfection effect was detected by Western blot. Autophagosome was observed under transmission electron microscopy(TEM). The level of autophagy markers (LC3-II/Beclin1) was detected by immunofluorescence and Western blot. Statistical analysis was performed with SPSS 17.0 software package.PRRX1 protein level increased, autophagosome number decreased, and autophagy marker level decreased in the PRRX1 overexpressed group, compared to the control (P0.05).PRRX1 inhibits the autophagy of SACC cells.

Cell migration-inducing protein (CEMIP) and binding immunoglobulin protein (BiP) are upregulated in human cancers, where they drive cancer progression and metastasis. It has been shown that CEMIP resides in the endoplasmic reticulum (ER) where it interacts with BiP to induce cell migration, but the relationship between the two proteins was previously unknown. Here we show that CEMIP mediates activation of the BiP promoter and upregulates BiP transcript and protein levels in breast cancer cell lines. Moreover, CEMIP overexpression confers protective adaptations to cancer cells under hypoxic conditions, by decreasing apoptosis, activating autophagy, and increasing glucose uptake, to facilitate tumor growth. We demonstrate that BiP signals downstream of CEMIP, modulating cellular resistance to hypoxia. Reducing BiP in CEMIP-expressing cells sensitized cells to hypoxia treatment, decreased glucose uptake, and resulted in tumor regression in vivo. Our study provides insights into the link between CEMIP and BiP expression and the pro-survival role they play in hypoxia. Better understanding of the mechanisms behind cancer cell adaptations to harsh tumor environments could lead to development of improved cancer treatments.

The presence of tumor-infiltrating T cells is associated with favorable patient outcomes, yet most pancreatic cancers are immunologically silent and resistant to currently available immunotherapies. Here we show using a syngeneic orthotopic implantation model of pancreatic cancer that Pik3ca regulates tumor immunogenicity. Genetic silencing of Pik3ca in KrasG12D/Trp53R172H-driven pancreatic tumors resulted in infiltration of T cells, complete tumor regression, and 100% survival of immunocompetent host mice. By contrast, Pik3ca-null tumors implanted in T cell-deficient mice progressed and killed all of the animals. Adoptive transfer of tumor antigen-experienced T cells eliminated Pik3ca-null tumors in immunodeficient mice. Loss of PIK3CA or inhibition of its effector, AKT, increased the expression of MHC Class I and CD80 on tumor cells. These changes contributed to the increased susceptibility of Pik3ca-null tumors to T cell surveillance. Our results indicate that tumor cell PIK3CA-AKT signaling limits T cell recognition and clearance of pancreatic cancer cells. Strategies that target this pathway may yield an effective immunotherapy for this cancer.

Background Doxorubicin, an anthracycline chemotherapeutic agent, is widely used in the treatment of many cancers. However, doxorubicin posts a great risk of adverse cardiovascular events, which are thought to be caused by oxidative stress. We recently reported that the ubiquitin E3 ligase TRIM21 interacts and ubiquitylates p62 and negatively regulates the p62-Keap1-Nrf2 antioxidant pathway. Therefore, we sought to determine the role TRIM21 in cardiotoxicity induced by oxidative damage. Methods Using TRIM21 knockout mice, we examined the effects of TRIM21 on cardiotoxicity induced by two oxidative damage models: the doxorubicin treatment model and the Left Anterior Descending (LAD) model. We also explored the underlying mechanism by RNA-sequencing of the heart tissues, and by treating the mouse embryonic fibroblasts (MEFs), immortalized rat cardiomyocyte line H9c2, and immortalized human cardiomyocyte line AC16 with doxorubicin. Findings TRIM21 knockout mice are protected from heart failure and fatality in both the doxorubicin and LAD models. Hearts of doxorubicin-treated wild-type mice exhibit deformed mitochondria and elevated level of lipid peroxidation reminiscent of ferroptosis, which is alleviated in TRIM21 knockout hearts. Mechanistically, TRIM21-deficient heart tissues and cultured MEFs and H9c2 cells display enhanced p62 sequestration of Keap1 and are protected from doxorubicin-induced ferroptosis. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient TRIM21 mutants impedes the protection from doxorubicin-induced cell death. Interpretation Our study demonstrates that TRIM21 ablation protects doxorubicin-induced cardiotoxicity and illustrates a new function of TRIM21 in ferroptosis, and suggests TRIM21 as a therapeutic target for reducing chemotherapy-related cardiotoxicity. Funding NIH (CA129536; DK108989): data collection, analysis. Shanghai Pujiang Program (19PJ1401900): data collection. National Natural Science Foundation (31971161): data collection. Department of Veteran Affairs (BX004083): data collection. Tianjin Science and Technology Plan Project (17ZXMFSY00020): data collection.

Diabetes-associated sexual dysfunction and fertility impairments are major secondary complications in diabetic patients and animal models. Natural herbs are important sources of therapeutic agents for diabetic complications. This study investigated the effect of vitexin on male sexual dysfunction and fertility impairments in streptozotocin (STZ)-induced diabetic mice. Diabetes was induced by intraperitoneal injection of 45 mg/kg STZ for 5 consecutive days in mice. Vitexin (10, 20 or 40 mg/kg) and Sildenafil citrate (SC, 5 mg/kg) were administered daily for 62 days after the induction of diabetes. The parameters of sexual behavior and fertility were analyzed. The reproductive organ weight, sperm motility, and viability of the treated mice were examined. Testicular histopathological alterations were detected by hematoxylin and eosin (H&E) staining. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate serum hormonal levels. Results showed that 40 mg/kg vitexin significantly improved the sexual behavior and fertility levels compared with the diabetic group. Moreover, vitexin (20 or 40 mg/kg) significantly increased reproductive organ weight and improved testicular pathological structure damage. Meanwhile, sperm analysis demonstrated that vitexin significantly restored sperm quality in a dose-dependent manner. Furthermore, ELISA data showed that vitexin significantly increased the serum testosterone (T), follicular-stimulating hormone (FSH), and luteinizing hormone (LH) levels but decreased the gonadotropin-releasing hormone (GnRH) level to different degrees. These findings suggest that vitexin ameliorates sexual dysfunction and fertility impairments in male diabetic mice possibly by modulating the hypothalamus–pituitary–gonadal axis.

Testicular dysfunction is one of the serious secondary complications in diabetes. Lycium barbarum polysaccharide (LBP) has long been considered to possess a wide range of beneficial properties including antiaging, anticancer and reproductive-enhancing. Abnormal autophagy was reported to play a significant role in accelerating diabetic reproductive injury. However, the autophagy regulation mechanism of LBP on diabetic testicular dysfunction is incompletely understood. We investigate the protective effects of LBP on diabetic testicular dysfunction and its underlying mechanism with different approaches. Protective effects of LBP (40 mg/kg) on testicular functions were assessed through the use of sperm parameters, testosterone levels and hematoxylin and eosin staining. Antioxidant capacity and serum malondialdehyde levels were determined using assay kits. Immune intensity of Beclin-1 and LC3I in testes was detected by immunofluorescence staining. Western blot analysis was used to detect expressions of p-PI3K, Akt, p-Akt, Beclin-1, LC3I and LC3II proteins. Q-PCR was used to evaluate Beclin-1 and LC3I mRNA expressions in testis. Administration of LBP (40 mg/kg) considerably recovered testicular function, obviously improved testicular histopathologic structure and significantly increased antioxidant enzyme activities. Immunofluorescence staining showed that immune intensity of Beclin-1 and LC3I significantly decreased in the LBP 40 mg/kg group. The results of Q-PCR and western blot analysis showed that LBP 40 mg/kg significantly downregulated Beclin-1 and LC3I protein expressions upregulated p-PI3K and p-Akt protein expressions and decreased Beclin-1 and LC3I mRNA expressions compared with diabetic mice. In conclusion, inhibition of PI3K/Akt pathway-mediated testicular excessive autophagy may be a target for protective effects of LBP on diabetic testicular dysfunction.

Receptors that activate the heterotrimeric G protein Gαq are thought to play a role in the development of heart failure. Dysregulation of autophagy occurs in some pathological cardiac conditions including heart failure, but whether Gαq is involved in this process is unknown. We used a cardiomyocyte-specific transgenic mouse model of inducible Gαq activation (termed GαqQ209L) to address this question. After 7 days of Gαq activation, GαqQ209L hearts contained more autophagic vacuoles than wild type hearts. Increased levels of proteins involved in autophagy, especially p62 and LC3-II, were also seen. LysoTracker staining and western blotting showed that the number and size of lysosomes and lysosomal protein levels were increased in GαqQ209L hearts, indicating enhanced lysosomal degradation activity. Importantly, an autophagic flux assay measuring LC3-II turnover in isolated adult cardiomyocytes indicated that autophagic activity is enhanced in GαqQ209L hearts. GαqQ209L hearts exhibited elevated levels of the autophagy initiation complex, which contains the Class III phosphoinositide 3-kinase Vps34. As a consequence, Vps34 activity and phosphatidylinositol 3-phosphate levels were higher in GαqQ209L hearts than wild type hearts, thus accounting for the higher abundance of autophagic vacuoles. These results indicate that an increase in autophagy is an early response to Gαq activation in the heart.

RationalThe myeloproliferative neoplasms (MPNs) are clonal hematological malignancies characterized by hematopoietic stem cell expansion and overproduction of mature blood cells. Cardiovascular complications are the leading cause of morbidity and mortality in patients with MPNs. The acquired kinase mutation JAK2V617F plays a central role in these disorders. Mechanisms responsible for cardiovascular dysfunction in MPNs are not fully understood, limiting the effectiveness of current treatment.ObjectiveVascular endothelial cells (ECs) play critical roles in the regulation of hemostasis and thrombosis. ECs carrying the JAK2V617F mutation can be detected in patients with MPNs. The goal of this study was to test the hypothesis that the JAK2V617F mutation alters endothelial function to promote cardiovascular complications in patients with MPNs.Methods and ResultsWe employed murine models of MPN in which the JAK2V617F mutation is expressed in specific cell lineages. When JAK2V617F is expressed in both blood cells and vascular ECs, the mice developed MPN and spontaneous, age-related dilated cardiomyopathy with an increased risk of sudden death as well as a prothrombotic and vasculopathy phenotype on histology evaluation. We showed that JAK2V617F-mutant ECs are required for this cardiovascular disease phenotype and the mutation can alter endothelial cell function. Finally, in a more therapeutically oriented approach, we demonstrated that transplantation with wild-type donor marrow cells can improve cardiac function by reversing the left ventricle remodeling process in this JAK2V617F-positive MPN murine model.ConclusionsThese findings suggest that the JAK2V617F mutation alters vascular endothelial function to promote cardiovascular complications in MPNs. Therefore, targeting the MPN vasculature represents a promising new therapeutic strategy for patients with MPNs.

Background Blood-testis barrier (BTB) impairments is one of the major secondary complications of diabetes. Betaine (BET) is the important active ingredients isolated from Lycium barbarum, which exhibits numerous pharmacological activities such as antioxidant, anti-diabetic, and anti-inflammatory effects. This study aimed to establish whether BET contributes to the recovery from BTB dysfunction in streptozotocin (STZ) induced diabetic mice. Methods BET (200, 400, 800 mg/kg) was orally administered to diabetic mice for 8 weeks. Testis tissues were collected for histopathological and biochemical analysis, the reproductive organ weight was estimated. Antioxidant enzyme activity and BTB associated protein expressions were determined with their corresponding assay kits and western blot analysis. The results revealed that BET significantly improved the weight of the reproductive organs and testicular morphology in diabetic mice. Furthermore, reactive oxygen species (ROS) and malondialdehyde (MDA) levels were significantly reduced, and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), markedly increased in the testicular tissue after SAL treatment. In addition, our data also showed a marked down-regulated the expressions of p38 MAPK phosphorylation and up-regulation the protein expressions of ZO-1, Occludin, Claudin-11, N-cadherin, and Connexin-43 after BET administration compared with the diabetic group. In conclusion, these results demonstrated that BET exerts protective effects on diabetes-induced BTB dysfunction, which may be through regulating oxidative stress-mediated p38 MAPK pathways.

Objectives Increasing evidences demonstrate a close correlation between epithelial‐to‐mesenchymal transition (EMT) induction and cancer lipid metabolism. However, the molecular mechanisms have not been clarified. Materials and methods In our study, the relative expression level of PRRX1 was detected, its relationship with free fatty acid (FFA) and PPARG2 was analysed in 85 SACC tissues and 15 salivary glands from the benign salivary tumours. We also compared the FFAs composition and levels in these SACC cells. PPARG2 was detected in PRRX1‐induced FFAs treatment as well as Src and MMP‐9 were detected in FFAs treatment–induced invasion and migration of SACC cells, and ChIP test was performed to identify the target interactions. Results Our data showed that overexpression of PRRX1 induced EMT and facilitated the invasion and migration of SACC cells, and PRRX1 expression was closely associated with high FFAs level and poor prognosis of SACC patients. Furthermore, PRRX1 silence led to the increase of PPARG2 and the reduction of FFAs level and the migration and invasion of SACC cells. And inhibition of PPARG2 rescued FFAs level and migration and invasion capabilities of SACC cells. Free fatty acids treatment induced an increase of Stat5‐DNA binding activity via Src‐ and MMP‐9‐dependent pathway. Conclusions Collectively, our findings showed that the PRRX1/PPARG2/FFAs signalling in SACC was important for accelerating tumour metastasis through the induction of EMT and the metabolic reprogramming of FFAs.

Spermatogenic dysfunction is one of the major secondary complications of male diabetes. Salidroside (SAL) is the important active ingredients isolated from Herba Cistanche, which exhibits numerous pharmacological activities such as antioxidant, anti-diabetic, and anti-inflammatory effects. The present study was designed to determine whether SAL contributes to the recovery from spermatogenic dysfunction in streptozotocin (STZ) induced type-1 diabetic mice. SAL (25, 50, or 100 mg/kg) and Clomiphene citrate (CC, 5 mg/kg) were orally administered to male type-1 diabetic mice for 10 weeks. Testis tissues were collected for histopathological and biochemical analysis. Moreover, reproductive organ weight, sperm parameters, and testicular cell DNA damage were estimated. The results revealed that SAL significantly improved the weight of the reproductive organs, sperm parameters and testicular morphology to different degrees in type-1 diabetic mice. Furthermore, reactive oxygen species (ROS) and malondialdehyde (MDA) levels were significantly reduced, and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), markedly increased in the testicular tissue after SAL treatment. In addition, our data also showed a marked downregulation the fluorescence expressions of p38 MAPK phosphorylation and upregulation the protein expressions of ZO-1, Occludin, Claudin-11 and N-cadherin after SAL administration (100 mg/kg) compared with the type-1 diabetic group. In conclusion, these results demonstrated that SAL exerts protective effects on type-1 diabetes-induced male spermatogenic dysfunction, which is likely mediated by inhibiting oxidative stress-mediated blood testis barrier damage.

// Xiangrui Ma 1, 2, * , Surui Sheng 1, * , Jingbiao Wu 1, * , Yaping Jiang 1, 3 , Xiaolei Gao 1 , Xiao Cen 1 , Jiashun Wu 1 , Shasha Wang 1 , Yajie Tang 4 , Yaling Tang 1, 5 and Xinhua Liang 1, 6 1 State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, Sichuan 610041, China 2 Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Binzhou Medical College, Binzhou, Shandong 256600, China 3 Department of Implant, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, China 4 Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, Hubei 430068, China 5 Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), Chengdu, Sichuan 610041, China 6 Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), Chengdu, Sichuan 610041, China * These authors have contributed equally to this work Correspondence to: Yaling Tang, email: tangyaling@scu.edu.cn Xinhua Liang, email: lxh88866@scu.edu.cn Keywords: head and neck squamous cell carcinomas (HNSCC), human papillomavirus (HPV), the non-coding RNA (lncRNA), myeloid-derived suppressor cells (MDSCs) Received: November 08, 2016 Accepted: December 27, 2016 Published: February 01, 2017 ABSTRACT The emerging evidence showed that long noncoding RNAs (lncRNAs) are involved in cell growth and apoptosis as well as cancer progression and metastasis of malignant tumor, however, limited data are available on the role of lncRNAs in human papillomavirus (HPV)-associated Head and neck squamous cell carcinomas (HNSCC). Here, we demonstrated that 23.98% of 196 HNSCC cases in Southwest China could be classified as HPV16 infection. The number of MDSCs in HPV-positive HNSCC was significantly higher than normal control, indicating that HPV infection may promote MDSCs aggregation. Then, we applied an array-based approach to monitor the lncRNA expression between HPV-positive HNSCC, HPV-negative HNSCC and normal oral mucous, and obtained 132 different lncRNAs in different HPV infected states of HNSCC. HOTAIR, PROM1, CCAT1, and MUC19 mRNA levels, determined by qRT-PCR were inversely correlated with MDSCs collection of HPV-associated HNSCC in 2 independent patient cohorts. The results may provide a rationale for the further evaluation of lncRNAs as a molecular target to elucidate the molecular mechanism of HPV promoting MDSCs collection of HNSCC.

This study aimed to conduct measurement uncertainty assessment of a new method for determination of Sudan colorants (Sudan I, II, III and IV) in food by high performance liquid chromatography (HPLC). Samples were extracted with organic solvents (hexane, 20% acetone) and first purified by magnesium trisilicate (2MgO·3SiO2). The Sudan colorants (Sudan I-IV) were also initially separated on C8 by gradient elution using acetonitrile and 0.1% (v/v) formic acid aqueous solution as the mobile phases and detected with diode-array detector (DAD). The uncertainty of mathematical model of Sudan I, II, III and IV is based on EURACHEM guidelines. The sources and components of uncertainty were calculated. The experiment gave a good linear relationship over the concentration from 0.4 to 4.0 μg/mL and spiked recoveries were from 74.0% to 97.5%. The limits of determination (LOD) were 48, 61, 36, 58 μg/kg for the four analytes, respectively. The total uncertainty of Sudan colorants (Sudan I, II, III and IV) was 810±30.8, 790±28.4, 750±27.0, 730±50.0 μg/kg, respectively. The recovery uncertainty was the most significant factor contributing to the total uncertainty. The developed method is simple, rapid, and highly sensitive. It can be used for the determination of trace Sudan dyes in food samples. The sources of uncertainty have been identified and uncertainty components have been simplified and considered.

Cancer stem cells (CSCs) have gained much attention due to their roles in the invasion and metastasis of numerous kinds of human cancers. Here, we showed that the positive expression of CD133, the stemness marker, was positively associated with vasculogenic mimicry (VM) formation, local regional recurrence, distant metastasis and poorer prognosis in salivary adenoid cystic carcinoma (ACC) specimens. Compared with CD133- ACC cells, CD133+ cancer stem-like cells had more migration and invasion capabilities, as well as more VM formation. The levels of endothelial cell marker VE-cadherin, MMP-2 and MMP-9 expression in CD133+ cancer stem-like cells and xenograft tumors of nude mice injected with CD133+ cells were significantly higher than those with CD133- cells. The data indicated that CD133+ cancer stem-like cells might contribute to the migration and invasion of ACC through inducing VM formation.

The presence of tumor-infiltrating T cells is associated with favorable patient outcomes, yet most pancreatic cancers are immunologically silent and resistant to currently available immunotherapies. Here we show using a syngeneic orthotopic implantation model of pancreatic cancer thatPik3caregulates tumor immunogenicity. Genetic silencing ofPik3cainKrasG12D/Trp53R172H-driven pancreatic tumors leads to infiltration of T cells, complete tumor regression, and 100% survival of immunocompetent host mice. By contrast,Pik3ca-null tumors implanted in T cell-deficient mice progress and kill all of the animals. Adoptive transfer of tumor antigen-experienced T cells eliminatesPik3ca-null tumors in immunodeficient mice. Loss of PIK3CA or inhibition of its effector, AKT, increases the expression of MHC Class I and CD80 on tumor cells. These changes contribute to the increased susceptibility ofPik3ca-null tumors to T cell surveillance. These results indicate that tumor cell PIK3CA-AKT signaling limits T cell recognition and clearance of pancreatic cancer cells. Strategies that target this pathway may yield an effective immunotherapy for this cancer.SIGNIFICANCEPIK3CA-AKT signaling in pancreatic cancer cells limits T cell infiltration and clearance of tumors by suppressing the surface expression of MHC Class I and CD80. Targeting the PIK3CA-AKT pathway in tumor cells provides a new avenue for discovery of novel pancreatic cancer immunotherapies.

Heart rate in physiological conditions is set by the sinoatrial node (SN), the primary cardiac pacing tissue. Phosphoinositide 3-kinase (PI3K) signaling is a major regulatory pathway in all normal cells, and its dysregulation is prominent in diabetes, cancer, and heart failure. Here, we show that inhibition of PI3K slows the pacing rate of the SN in situ and in vitro and reduces the early slope of diastolic depolarization. Furthermore, inhibition of PI3K causes a negative shift in the voltage dependence of activation of the pacemaker current, IF, while addition of its second messenger, phosphatidylinositol 3,4,5-trisphosphate, induces a positive shift. These shifts in the activation of IF are independent of, and larger than, those induced by the autonomic nervous system. These results suggest that PI3K is an important regulator of heart rate, and perturbations in this signaling pathway may contribute to the development of arrhythmias.

This article selects the data of Chinese Total Retail Sales of Consumer Goods from 1952 to 2016 and then established ARIMA (2,1,2) model after the comparative test. It is found that the relative error between actual numbers and predictive numbers from 2011 to 2016 is smaller than 3%. Therefore, it is feasible to use the ARIMA (2,1,2) model to predict the short-term data of Chinese Total Retail Sales of Consumer Goods. The prediction is that consumer markets will increase by more than 10% with little volatility.

There are three viewpoints towards the relationship between fiscal expenditure and economic growth. The first type is that fiscal expenditure improves the economic growth, the second is that fiscal expenditure holds up the economic growth. While the last type of viewpoint is that fiscal expenditure makes no difference on the economic growth. The paper will do the empirical study on the relationship between fiscal expenditure and economic growth of Shanghai by VAR model. The result shows that fiscal expenditure is not the Granger Cause of economic growth. While under the 1% significance level, the economic growth is regarded to be the Granger Cause of fiscal expenditure. It means that the increase of Shanghai fiscal expenditure decreases consumer expenditure and investment, which makes fiscal expenditure have no effect on the output. To avoid the crowding-out effect, the government needs to get the optimum fiscal expenditure and consider to limit the financing activity of private departments so that private investment will not be crowded out.

Traditional therapy for cancer is subject to some evident obstacles, including low effectiveness, resistance, systemic complication, etc. Gold nanostructures responsive to near-infrared (NIR) light are attractive for non-invasive and targeted therapy because of their unique physical properties especially strong absorption and scattering, and high surface area-to-volume ratio as well as the ease of which their surface chemistry can be manipulated to enhance biocompatibility surface modification and functionalization. In this Review, the progress of photothermal therapy (PTT) as well as the targeted delivery of anticancer agents as the predominant applications of gold nanostructures is detailed, with a focus on imaging-guided therapy and optimizing operational parameters. The NIR light-controlled targeted delivery and/or photothermal ablation of gold nanostructures in the treatment of metastasis are also briefly discussed. These gold nanostructures pave the way for developing better therapeutic strategies of cancer.

// Ya-ling Tang 1, 2 , Xin Liu 2 , Shi-yu Gao 2 , Hao Feng 2 , Ya-ping Jiang 2 , Sha-sha Wang 2 , Jing Yang 2 , Jian Jiang 2 , Xiang-rui Ma 2 , Ya-jie Tang 3 , Yu Chen 1 , Xin-hua Liang 2, 4 1 Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan 610041, People’s Republic of China 2 State Key Laboratory of Oral Diseases West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan 610041, People’s Republic of China 3 Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, People’s Republic of China 4 Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan 610041, People’s Republic of China Correspondence to: Xin-hua Liang, e-mail: lxh88866@scu.edu.cn , drliangxinhua@aliyun.com Keywords: wild-type p53 induced phosphatase 1 (WIP1), adenoid cystic carcinoma (ACC), salivary gland, invasion, metastasis Received: January 09, 2015 Accepted: February 23, 2015 Published: March 06, 2015 ABSTRACT The wild-type p53 induced phosphatase 1 (WIP1) is an oncogene overexpressed in a variety of human cancers. Here, we demonstrated that WIP1 silencing reduced MMP-9 and VEGF-C expression as well as migration and invasion of salivary adenoid cystic carcinoma (ACC) cells. Overexpression of MMP-9 or VEGF-C restored migration and invasion in WIP1 knockdown cells, indicating that MMP-9 and VEGF-C are downstream targets of WIP1 signaling. Levels of cyclin D1 and c-Myc, targets of Wnt/β-catenin pathway, were significantly decreased by WIP1 silencing. In addition, WIP1 expression was positively associated with metastasis and prognosis of ACC patients as well as with MMP-9 or VEGF-C in ACC tissues.

TRIM21 is a RING finger domain-containing ubiquitin E3 ligase whose expression is elevated in autoimmune disease. While TRIM21 plays an important role in immune activation during pathogen infection, little is known about its inherent cellular function. Here we show that TRIM21 plays an essential role in redox regulation by directly interacting with SQSTM1/p62 and ubiquitylating p62 at lysine 7 (K7) via K63-linkage. As p62 oligomerizes and sequesters client proteins in inclusions, the TRIM21-mediated p62 ubiquitylation abrogates p62 oligomerization and sequestration of proteins including Keap1, a negative regulator of antioxidant response. TRIM21-deficient cells display an enhanced antioxidant response and reduced cell death in response to oxidative stress. Genetic ablation of TRIM21 in mice confers protection from oxidative damages caused by arsenic-induced liver insult and pressure overload heart injury. Therefore, TRIM21 plays an essential role in p62-regulated redox homeostasis and may be a viable target for treating pathological conditions resulting from oxidative damage.

Chemotherapy could be used as an effective therapeutic treatment for ovarian cancer and subsequent peritoneal metastasis. However, the occurrence of drug resistance reduced the treatment effect originated from cancer chemotherapy. Accumulating evidences indicated the significant role of autophagy in tumor cell resistance to chemotherapy. Thus, inhibition of autophagy using natural compounds could be a promising candidate to overcome multidrug resistance in human ovarian cancer cells. Nobiletin (NOB), a polymethoxyflavonoid found in citrus fruits such as Citrus depressa and Citrus reticulate, exhibits a number of bioactivities. In the present study, NOB selectively suppressed the growth and proliferation of human SKOV3/TAX cells, inducing G0/G1 phase arrest and reducing G2/M phase, along with the increase of p53 and p21. In addition, NOB induced significant apoptosis in SKOV3/TAX cells through the intrinsic apoptosis pathway, as evidenced by the up-regulation of cleaved Caspase-9/-3 and PARP. Further, NOB impaired the autophagic degradation in SKOV3/TAX cells, resulting in autophagic flux inhibition. Moreover, the impaired autophagic flux enhanced NOB-induced apoptosis in SKOV3/TAX cells. Importantly, AKT signaling was activated by NOB, which was involved in autophagic degradation and apoptotic cell death. In conclusion, the findings here supplied the illustration that NOB could overcome multidrug resistance in human ovarian cancer cells through AKT-regulated suppression of autophagic degradation.

// Min Zheng 1, 2, * , Ya-ping Jiang 1, * , Wei Chen 1, 3, * , Kai-de Li 1 , Xin Liu 1 , Shi-yu Gao 1 , Hao Feng 1 , Sha-sha Wang 1 , Jian Jiang 1 , Xiang-rui Ma 1 , Xiao Cen 1 , Ya-jie Tang 4 , Yu Chen 1 , Yun-feng Lin 1 , Ya-ling Tang 1, 5 , Xin-hua Liang 1, 6 1 State Key Laboratory of Oral Diseases West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan 610041, People's Republic of China 2 Department of Stomatology, Zhoushan Hospital, Zhoushan, Zhejiang 316000, People's Republic of China 3 Department of Oral and Maxillofacial Surgery, Tianjin Stomatological Hospital, Tianjin 300041, People's Republic of China 4 Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, People's Republic of China 5 Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan 610041, People's Republic of China 6 Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan 610041, People's Republic of China * These authors have contributed equally to this work Correspondence to: Ya-ling Tang, e-mail: tangyaling@scu.edu.cn Xin-hua Liang, e-mail: lxh88866@scu.edu.cn ; drliangxinhua@aliyun.com Keywords: Oral tongue squamous cell carcinoma (OTSCC), Epithelial-mesenchymal transition (EMT), miR-101, Snail, Slug Received: November 03, 2014 Accepted: January 25, 2015 Published: February 09, 2015 ABSTRACT microRNAs(miRNAs) can regulate epithelial-mesenchymal transition (EMT) through transcription factors, however, little is known whether EMT transcription factors can modulate miRNAs and further induce EMT and cancer metastasis. Here we show that overexpression of Snail and Slug leads to a mesenchymal phenotype and morphology and enhances cell invasion along with stem cell properties in squamous cell carcinoma of oral tongue (OTSCC) cells. Repression of miR-101 expression by Snail and Slug is essential for Snail/Slug-induced malignant phenotypes. The suppression of miR-101 subsequently activates EZH2, the sole histone methyltransferase, inducing EMT, migration and invasion of OTSCC cells. Importantly, co-overexpression of Slug and Snail correlates with poor survival and elevated EZH2 expression in two independent patient cohorts of OTSCC specimens. These findings defined a Snail and Slug/miR-101/EZH2 pathway as a novel regulatory axis of EMT-mediated-microRNA signaling.

Diabetes mellitus (DM) is a major endocrine metabolic disease and is marked by a lack of insulin. The complication of DM is one of the most difficult problems in medicine. The initial translational studies revealed that growth factors have a major role in integrating tissue physiology and in embryology as well as in growth, maturation and tissue repair. In some tissues affected by diabetes, growth factors are induced by a relative deficit or excess. Fibroblast growth factor 21 (FGF21) is a promising regulator of glucose and lipid metabolism with multiple beneficial effects including hypoglycemic and lipid-lowering. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor and is implicated in both of these complications in diabetes. Increase or decrease in the production of transforming growth factor-β1 (TGF-β1) has been associated with diabetic nephropathy and retinopathy. The insulin-like growth factor-I (IGF-I) is a naturally-occurring single chain polypeptide which has been widely used in the treatment of diabetic glomerular and renal tubular injuries. This review summarizes the recent evidences for an involvement of growth factors in diabetic complications, focusing on their emergence in sequence of events leading to vascular complications or their potential therapeutic role in these diseases. Growth factor therapy in diabetic foot ulcers is already a clinical reality. As methods to finely regulate growth factors in a tissue and time-specific manner are further developed and tested, regulation of the growth factor to normal level in vivo may well become a therapy to prevent and treat diabetic complications.

This paper analyzes the limitation about the Basic model, with the correction of negative factor, and the parameter estimation from nonlinear least squares method, propose a new product diffusion model which could be applied to the instant-messaging market. In addition, the further diffusion of the model is studied at the end of the paper.

Nano-titanium dioxide was prepared in a microemulsion system by solvothermal method. The microemulsion system is composed of ammonium hexafluorotitanate((NH4)2TiF6) used as titanium source, water, cetyl trimethyl ammonium bromide (CTAB), n-butanol, and cyclohexane. The influences of reaction time, amount of urea added and the mole ratio of water to CTAB (ω) on particle size, and photocatalytic activity were investigated by photocatalytic degrading methyl orange and X-ray diffraction (XRD) characterization. The results show that the optimum preparation conditions are that reaction time 12 h, the amount of urea added 1.5 g, and the ratio of water to CTAB ratio (ω) 18:1.

The traditional reservoir water level monitoring system utilizes the sensors placed in the water has drawbacks of: 1) high possibility of water seepage; 2) short life cycle; 3) difficulty to achieve real-time monitoring; and 4) not easy to maintain. This paper presents a design of water level measurement sensor which relies on mechanical transmission tracking method. Since there is no need to place the sensor into the water, the life cycle is improved. Furthermore, by remote data transmission over the internet network, A real-time monitoring of the water level can be achieved, and thus significantly improve the overall management efficiency of reservoir resource utilization.

Pattern matching algorithm is widely used. It plays an important role in information retrieval, data mining, intrusion detection and other fields. Among them, the BM algorithm is the most common. A new improved algorithm-BMQ algorithm is proposed on the basis of BM and related algorithms. The improved algorithm makes use of uniqueness and combination of the last character and next character of string, to increase the probability of the maximum right shift. Theoretical analysis and experimental comparison shows that the BMQ is better than BM algorithms in the process of string matching and string searching; in order to further verify its effectiveness, the improved algorithm is introduced to intrusion detection system, the experimental results show that BMQ algorithm improves the efficiency of intrusion detection.

Adipose tissue is a highly insulin-responsive organ that contributes to metabolic regulation. Insulin resistance in the adipose tissue affects systemic lipid and glucose homeostasis. Phosphoinositide 3-kinase (PI3K) mediates downstream insulin signaling in adipose tissue, but its physiological role in vivo remains unclear. Using Cre recombinase driven by the aP2 promoter, we created mice that lack the class 1A PI3K catalytic subunit p110α or p110β specifically in the white and brown adipose tissue. The loss of p110α, not p110β, resulted in increased adiposity, glucose intolerance and liver steatosis. Mice lacking p110α in adipose tissue exhibited a decrease in energy expenditure but no change in food intake or activity compared with control animals. This low energy expenditure is a consequence of low cellular respiration in the brown adipocytes caused by a decrease in expression of key mitochondrial genes including uncoupling protein-1. These results illustrate a critical role of p110α in the regulation of energy expenditure through modulation of cellular respiration in the brown adipose tissue and suggest that compromised insulin signaling in adipose tissue might be involved in the onset of obesity.

Introduction Cardiovascular complications are the leading cause of morbidity and mortality in patients with myeloproliferative neoplasms (MPNs). The acquired kinase mutation JAK2V617F plays a central role in these disorders. Many studies have established that a significant number of vascular endothelial cells (ECs) in MPN patients carry the mutation.In this study, we tested the hypothesis that the JAK2V617F mutation alters vascular endothelial function to promote cardiovascular complications in patients with MPNs. Methods JAK2V617F Flip-Flop (FF1) mice and Tie2-Cre mice were crossed to generate the Tie2FF1 mice, in which human JAK2V617F is expressed specifically in hematopoietic cells and vascular ECs, so as to model the human diseases in which both the hematopoietic stem cells and ECs harbor the mutation. All mice were fed a standard chow diet. Results As we previously reported, Tie2FF1 mice develop a myeloproliferative phenotype with leukocytosis, thrombocytosis, significant splenomegaly, and greatly increased numbers of hematopoietic stem cells by 8 wk of age. We observed an increased incidence of sudden death during performance of minor procedures (e.g. submandibular bleeding) in Tie2FF1 mice, especially after 20 wk of age. Transthoracic echocardiography revealed significant decreases in left ventricular ejection fraction and fractional shortening, and increases in left ventricular end-diastolic volume and end-systolic volume in 20-22 wk old Tie2FF1 mice compared to age-matched Tie2-Cre controls, indicative of cardiac dysfunction. Pathological evaluation revealed increased heart size and heart weight, and evidence of pulmonary congestion in Tie2FF1 mice compared to controls, consistent with the diagnosis of congestive heart failure. No atherosclerotic lesions or myocardium infarctions were observed in Tie2FF1 mice. (Figure 1) No significant cardiac dysfunction was observed in Tie2FF1 mice at 10-12 wk of age, suggesting that the heart failure is apparently not present from birth. Next,we generated a chimeric murine model with JAK2V617F-mutant blood cells and wild-type vascular ECs by transplanting Tie2FF1 marrow cells into wild-type recipients. The transplantation of wild-type marrow cells into wild-type recipients served as a control. Recipients of Tie2FF1 marrow developed myeloproliferation and there was no difference in blood cell counts between these mice and the primary Tie2FF1 mice. However, serial echocardiography evaluation did not reveal any evidence of cardiac dysfunction in recipients of Tie2FF1 marrow. In addition, Ly-6Chighmonocytes, which are important participant at various stages of cardiovascular disease development, were significantly increased in primary Tie2FF1 micecompared to Tie2-Cre controls, but not in wild-type recipients of Tie2FF1 marrow. These observations suggest that JAK2V617F-mutant blood cells alone are not sufficient to generate the spontaneous heart failure phenotype we have observed in Tie2FF1 mice; JAK2V617F-mutant ECs are required, as cardiac dysfunction and inflammatory monocytes are only generated when the ECs bear the JAK2V617F mutation. (Figure 2) To begin to understand the roles of JAK2V617F-mutant ECs in the development of cardiovascular dysfunction in Tie2FF1 mice, we found that the expression levels of Kruppel-like factors 2 (KLF2) and 4 (KLF4), two important regulators of vascular homeostasis that contribute to an anti-adhesive, anti-thrombotic, and anti-inflammatory endothelial phenotype, as well as thrombomodulin and eNOS, two downstream targets of KLF2/4 signaling, were significantly down-regulated in JAK2V617F-mutant ECs compared to wild-type ECs. In addition, cell surface adhesion molecules PECAM and E-selection were significantly up-regulated in JAK2V617F-mutant ECs compared to wild-type ECs. Both PECAM and E-selectin were further up-regulated in flow sheared (60dyn/cm2) JAK2V617F-mutant ECs compared to un-sheared ECs, while their levels did not change in wild-type ECs. These results indicate that JAK2V617F-mutant ECs display a pro-adhesive phenotype that can contribute to the cardiovascular dysfunction we observed in Tie2FF1 mice. (Figure 3) Conclusions In summary, our findings indicate that the JAK2V617F mutation can alter vascular endothelial function to promote cardiovascular complications in a murine model of MPN. Disclosures No relevant conflicts of interest to declare.

The presence of tumor-infiltrating T cells is associated with favorable patient outcomes, yet most pancreatic cancers are immunologically silent and resistant to currently available immunotherapy. In this study, a syngeneic orthotopic implantation model of pancreatic cancer was used to show that PI3K/Akt signaling in tumor cells down-regulate immunogenicity to evade T cell surveillance. Genetic silencing of PI3K catalytic isoform Pik3ca in KrasG12D/Trp53R172H-driven pancreatic tumors leads to infiltration of T cells, complete tumor regression, and 100% survival of immunocompetent host mice. By contrast, Pik3ca-null tumors implanted in T cell-deficient mice progress and kill 100% of the animals. Adoptive transfer of tumor antigen-experienced T cells eliminates Pik3ca-null tumors in immunodeficient mice. Pik3ca silencing or inhibition of its effector, Akt, increases the expression of MHC Class I and CD80 on the surface of murine and human pancreatic cancer cells. Down-regulating MHC Class I and CD80 expression, or increasing Akt activity, in Pik3ca-null tumors increases their susceptibility to T cell-mediated regression in vivo. These results indicate that PI3K/Akt signaling in tumor cells limits T cell recognition and clearance of pancreatic cancer. Strategies that selectively target the PI3K/Akt signaling pathway in tumor cells may improve immunotherapy for pancreatic cancer. Citation Format: Nithya Sivaram, Patrick McLaughlin, Ya-Ping Jiang, Lisa Ballou, Kien Pham, Chen Liu, Adrianus van der Velden, Richard Lin. PI3K/Akt signaling in tumor cells promotes immune evasion by limiting infiltration, recognition and killing by T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 522.

Diabetes is an independent risk factor for sudden cardiac death and ventricular arrhythmia complications of acute coronary syndrome. Prolongation of the QT interval on the electrocardiogram is also a risk factor for arrhythmias and sudden death, and the increased prevalence of QT prolongation is an independent risk factor for cardiovascular death in diabetic patients. The pathophysiological mechanisms responsible for this lethal complication are poorly understood. Diabetes is associated with a reduction in phosphoinositide 3-kinase (PI3K) signaling, which regulates the action potential duration (APD) of individual myocytes and thus the QT interval by altering multiple ion currents, including the persistent sodium current INaP. Here, we report a mechanism for diabetes-induced QT prolongation that involves an increase in INaP caused by defective PI3K signaling. Cardiac myocytes of mice with type 1 or type 2 diabetes exhibited an increase in APD that was reversed by expression of constitutively active PI3K or intracellular infusion of phosphatidylinositol 3,4,5-trisphosphate (PIP3), the second messenger produced by PI3K. The diabetic myocytes also showed an increase in INaP that was reversed by activated PI3K or PIP3. The increases in APD and INaP in myocytes translated into QT interval prolongation for both types of diabetic mice. The long QT interval of type 1 diabetic hearts was shortened by insulin treatment ex vivo, and this effect was blocked by a PI3K inhibitor. Treatment of both types of diabetic mouse hearts with an INaP blocker also shortened the QT interval. These results indicate that downregulation of cardiac PI3K signaling in diabetes prolongs the QT interval at least in part by causing an increase in INaP. This mechanism may explain why the diabetic population has an increased risk of life-threatening arrhythmias.

This paper evaluates the adaptability of the water-source heat pumps (WSHP) in urban Guilin. Volume data of all assessed water areas are obtained from decades-long observations by Guilin hydrological station and government reports. Judging from data from the same sources and fresh samples, water quality in assessed areas generally meets the requirement in Technical Code for Ground-Source Heat Pumps System (GB 50366-2009). According to continuous measurement of temperature change in separate years, water temperature is basically suitable for demands in Water-Source Heat Pumps (GB/T 19409-2003). By assuming the assessed water areas as flowing waters, the maximum instantaneous heat capacity of each water area in each month is calculated. By setting the energy per square meter of building area needs as standard values, the maximum serviceable building area each water area can offer in each month is calculated. This paper can serve as guidance in adaptability evaluation on WSHP projects in hydrological-alike environment.

The theory of modern immunology provides a novel idea to study network intrusion detection and defense system. With the concepts of self, nonself, close degree and membership in an intrusion detection and prevention system presented in this paper, a model of detector generation based on immune recognition and redundancy optimization is proposed, in which detectors are generated by clone selection, genetic variation and evolutionary algorithm, as well as the improved redundancy optimization algorithm. The simulation experiments show that the model has higher detection rate and lower false detection rate.

A new uranium-containing silicotungstate A-β-Na14[Na2(UO2)2(SiW9O34)2]·43H2O (1) was synthesized in an aqueous solution. The compound was characterized by elemental analysis and infrared spectra analysis. A single-crystal X-ray analysis was carried out on crystal (1) which crystallizes in triclinic system, space group p ī, with a = 13.386 Å, b = 13.506 Å, c = 16.183 Å, α = 85.337o, β = 73.608o γ = 64.833o and Z = 1. Polyanion (1) consists of two A-β-SiW9 units which sandwich two uranium and two sodium ions, leading to a Keggin-type sandwich structure. The photoluminescent spectrum of (1) shows typical emission features of uranyl compounds.

Collective invasion of cells plays a fundamental role in tissue growth, wound healing, immune response and cancer metastasis. This paper aimed to investigate cytokeratin-14 (CK14) expression and analyze its association with collective invasion in the invasive front of salivary adenoid cystic carcinoma (SACC) to uncover the role of collective invasion in SACC. Here, in the clinical data of 121 patients with SACC, the positive expression of CK14 was observed in 35/121(28.93%) of the invasive front of SACC. CK14 expression in the invasive front, local regional recurrence and distant metastasis were independent and significant prognostic factors in SACC patients. Then, we found that in an ex vivo 3D culture assay, CK14 siRNA receded the collective invasion, and in 2D monolayer culture, CK14 overexpression induced a collective SACC cell migration. These data indicated that the presence of characterized CK14+ cells in the invasive front of SACC promoted collective cell invasion of SACC and may be a biomarker of SACC with a worse prognosis.

// Ming-xin Cao 1,2 , Ya-ping Jiang 3 , Ya-ling Tang 1,4 and Xin-hua Liang 1,2 1 State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan, People’s Republic of China 2 Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan, People’s Republic of China 3 Department of Implant, The Affiliated Hospital of Qingdao University, Qingdao,Shandong, People’s Republic of China 4 Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan, People’s Republic of China Correspondence to: Xin-hua Liang, email: // Ya-ling Tang, email: // Keywords : lncRNA, microRNA, epithelial-mesenchymal plasticity, cancer metastasis Received : October 15, 2016 Accepted : December 12, 2016 Published : December 15, 2016 Abstract Noncoding RNAs (ncRNAs) have been demonstrated to closely associate with gene regulation and encompass the well-known microRNAs (miRNAs), as well as the most recently acknowledged long noncoding RNAs (lncRNAs). Current evidence indicates that lncRNAs can interact with miRNAs and these interactions play crucial roles in cancer metastasis, through regulating critical events especially the epithelial-mesenchymal transition (EMT). This review summarizes the types of lncRNA-miRNA crosstalk identified to-date and discusses their influence on the epithelial-mesenchymal plasticity and clinical metastatic implication.

Background— Drugs are screened for delayed rectifier potassium current ( I Kr ) blockade to predict long QT syndrome prolongation and arrhythmogenesis. However, single-cell studies have shown that chronic (hours) exposure to some I Kr blockers (eg, dofetilide) prolongs repolarization additionally by increasing late sodium current ( I Na-L ) via inhibition of phosphoinositide 3-kinase. We hypothesized that chronic dofetilide administration to intact dogs prolongs repolarization by blocking I Kr and increasing I Na-L . Methods and Results— We continuously infused dofetilide (6–9 μg/kg bolus+6–9 μg/kg per hour IV infusion) into anesthetized dogs for 7 hours, maintaining plasma levels within the therapeutic range. In separate experiments, myocardial biopsies were taken before and during 6-hour intravenous dofetide infusion, and the level of phospho-Akt was determined. Acute and chronic dofetilide effects on action potential duration (APD) were studied in canine left ventricular subendocardial slabs using microelectrode techniques. Dofetilide monotonically increased QTc and APD throughout 6.5-hour exposure. Dofetilide infusion during ≥210 minutes inhibited Akt phosphorylation. I Na-L block with lidocaine shortened QTc and APD more at 6.5 hours than at 50 minutes (QTc) or 30 minutes (APD) dofetilide administration. In comparison, moxifloxacin, an I Kr blocker with no effects on phosphoinositide 3-kinase and I Na-L prolonged APD acutely but no additional prolongation occurred on chronic superfusion. Lidocaine shortened APD equally during acute and chronic moxifloxacin superfusion. Conclusions— Increased I Na-L contributes to chronic dofetilide effects in vivo. These data emphasize the need to include time and I Na-L in evaluating the phosphoinositide 3-kinase inhibition–derived proarrhythmic potential of drugs and provide a mechanism for benefit from lidocaine administration in clinical acquired long QT syndrome.

A critical regulator of autophagy is the Class III PI3K Vps34 (also called PIK3C3). Although Vps34 is known to play an essential role in autophagy in yeast, its role in mammals remains elusive. To elucidate the physiological function of Vps34 and to determine its precise role in autophagy, we have generated Vps34 f/f mice, in which expression of Cre recombinase results in a deletion of exon 4 of Vps34 and a frame shift causing a deletion of 755 of the 887 amino acids of Vps34. Acute ablation of Vps34 in MEFs upon adenoviral Cre infection results in a diminishment of localized generation of phosphatidylinositol 3-phosphate and blockade of both endocytic and autophagic degradation. Starvation-induced autophagosome formation is blocked in both Vps34-null MEFs and liver. Liver-specific Albumin-Cre;Vps34 f/f mice developed hepatomegaly and hepatic steatosis, and impaired protein turnover. Ablation of Vps34 in the heart of muscle creatine kinase-Cre;Vps34 f/f mice led to cardiomegaly and decreased contractility. In addition, while amino acid-stimulated mTOR activation was suppressed in the absence of Vps34, the steady-state level of mTOR signaling was not affected in Vps34-null MEFs, liver, or cardiomyocytes. Taken together, our results indicate that Vps34 plays an essential role in regulating functional autophagy and is indispensable for normal liver and heart function.