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Zhao-Ting Gong,1 Yu-Yan Xiong,1,2 Yu Ning,1 Rui-Jie Tang,1 Jun-Yan Xu,3 Wen-Yang Jiang,1 Xiao-Song Li,1 Li-Li Zhang,1 Cheng Chen,1 Qi Pan,1 Meng-Jin Hu,1 Jing Xu,1 Yue-Jin Yang1 1State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, People’s Republic of China; 2Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 3Department of Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of ChinaCorrespondence: Yue-Jin Yang, Email yangyjfw@126.comBackground: Exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) have been considered as a promising cell-free therapeutic strategy for ischemic heart disease. Cardioprotective drug pretreatment could be an effective approach to improve the efficacy of MSC-exo. Nicorandil has long been used in clinical practice for cardioprotection. This study aimed to investigate whether the effects of exosomes derived from nicorandil pretreated MSC (MSCNIC-exo) could be enhanced in facilitating cardiac repair after acute myocardial infarction (AMI).Methods: MSCNIC-exo and MSC-exo were collected and injected into the border zone of infarcted hearts 30 minutes after coronary ligation in rats. Macrophage polarization was detected 3 days post-infarction, cardiac function as well as histological pathology were measured on the 28th day after AMI. Macrophages were separated from the bone marrow of rats for in vitro model. Exosomal miRNA sequencing was conducted to identify differentially expressed miRNAs between MSCNIC-exo and MSC-exo. MiRNA mimics and inhibitors were transfected to MSCs or macrop

Mantle peridotites of ophiolites have traditionally been interpreted as fragments of residual oceanic lithospheric mantle depleted by partial melting. However, recent petrological, geochemical and isotopic data suggest that this hypothesis needs to be reconsidered. Spinel grains in ophiolitic mantle peridotites, previously believed to record melt extraction, exhibit significant compositional variations that are incompatible with partial melting. These grains occur mostly as interstitial, anhedral crystals associated with clinopyroxene or as inclusions in silicates; they commonly also contain a variety of inclusions. Their elemental compositions are highly variable at both intra- and inter-grain, as well as intra- and inter-sample scales. In addition to association with spinel, interstitial clinopyroxene is also widespread in ophiolitic mantle peridotites. Individual clinopyroxene grains show positive correlations between Al2O3 and Cr2O3 contents, akin to those observed in orthopyroxene, which deviate from partial melting trends. Reactive and replacive features are well-developed in orthopyroxene grains. Olivine has anomalously variable Li isotope compositions and generally heavier Fe and Cr isotope compositions than coexisting spinel, contrary to theoretical predictions and results from mantle peridotite xenoliths. Additionally, aggregates of olivine, orthopyroxene, clinopyroxene, spinel and amphibole are also commonly observed in many samples. All of these characteristics suggest significant post-crystallization modifications of the constituent minerals in the mantle peridotites of ophiolites. Amphibole, a widespread hydrous mineral in mantle peridotites of ophiolites, serves as robust evidence of the past presence of hydrous melts/fluids. It typically exhibits variable compositions that can be distinguished from grains in other lithologies or different tectonic settings. These melts/fluids are most likely related to t

The role of BACH1 in the process of vascular smooth muscle cell (VSMC) differentiation from human embryonic stem cells (hESCs) remains unknown. Here, we find that the loss of BACH1 in hESCs attenuates the expression of VSMC marker genes, whereas overexpression of BACH1 after mesoderm induction increases the expression of VSMC markers during in vitro hESC-VSMC differentiation. Mechanistically, BACH1 binds directly to coactivator-associated arginine methyltransferase 1 (CARM1) during in vitro hESC-VSMC differentiation, and this interaction is mediated by the BACH1 bZIP domain. BACH1 recruits CARM1 to VSMC marker gene promoters and promotes VSMC marker expression by increasing H3R17me2 modification, thus facilitating in vitro VSMC differentiation from hESCs after the mesoderm induction. The increased expression of VSMC marker genes by BACH1 overexpression is partially abolished by inhibition of CARM1 or the H3R17me2 inhibitor TBBD in hESC-derived cells. These findings highlight the critical role of BACH1 in hESC differentiation into VSMCs by CARM1-mediated methylation of H3R17.

The transcription factor BTB and CNC homology 1(BACH1) has been linked to coronary artery disease risk by human genome-wide association studies, but little is known about the role of BACH1 in vascular smooth muscle cell (VSMC) phenotype switching and neointima formation following vascular injury. Therefore, this study aims to explore the role of BACH1 in vascular remodeling and its underlying mechanisms. BACH1 was highly expressed in human atherosclerotic plaques and has high transcriptional factor activity in VSMCs of human atherosclerotic arteries. VSMC-specific loss of Bach1 in mice inhibited the transformation of VSMC from contractile to synthetic phenotype and VSMC proliferation and attenuated the neointimal hyperplasia induced by wire injury. Mechanistically, BACH1 suppressed chromatin accessibility at the promoters of VSMC marker genes via recruiting histone methyltransferase G9a and cofactor YAP and maintaining the H3K9me2 state, thereby repressing VSMC marker genes expression in human aortic smooth muscle cells (HASMCs). BACH1-induced repression of VSMC marker genes was abolished by the silencing of G9a or YAP. Thus, these findings demonstrate a crucial regulatory role of BACH1 in VSMC phenotypic transition and vascular homeostasis and shed light on potential future protective vascular disease intervention via manipulation of BACH1.

Autonomous driving systems (ADSs) must be sufficiently tested to ensure their safety. Though various ADS testing methods have shown promising results, they are limited to a fixed set of vehicle characteristics settings (VCSs). The impact of variations in vehicle characteristics (e.g., mass, tire friction) on the safety of ADSs has not been sufficiently and systematically studied.Such variations are often due to wear and tear, production errors, etc., which may lead to unexpected driving behaviours of ADSs. To this end, in this paper, we propose a method, named SAFEVAR, to systematically find minimum variations to the original vehicle characteristics setting, which affect the safety of the ADS deployed on the vehicle. To evaluate the effectiveness of SAFEVAR, we employed two ADSs and conducted experiments with two driving simulators. Results show that SAFEVAR, equipped with NSGA-II, generates more critical VCSs that put the vehicle into unsafe situations, as compared with two baseline algorithms: Random Search and a mutation-based fuzzer. We also identified critical vehicle characteristics and reported to which extent varying their settings put the ADS vehicles in unsafe situations.

On many e-commerce platforms such as Airbnb, StubHub and TURO, where each seller sells a fixed inventory over a finite horizon, the pricing problems are intrinsically dynamic. However, many sellers on these platforms do not update prices frequently. In markets where sellers have fixed inventories and limited selling time, optimal prices respond to both the remaining inventory and time (Gallego and van Ryzin 1994). Empirical studies (Williams 2018; Cho et al. 2018) examining pricing problems in these environments also support Gallego and van Ryzin’s (1994) theoretical prediction. However, on many e-commerce platforms where small sellers are facing a fixed inventory and limited selling time problem, we commonly observe price rigidity, which seems to contradict Gallego and Ryzin’s theory. Automated pricing, which uses machine learning algorithms to automatically price products, is becoming a standard feature on some of these platforms. One key feature of automated pricing is that it reduces the seller’s burden; the seller does not need to carry out a price-optimization problem every day. This paper develops a dynamic pricing model to study the revenue and welfare implication of automated pricing, which allows sellers to update their prices without manual interference. The model focuses on three factors through which automated pricing influences sellers: price adjustment cost, buyer’s varying willingness to pay and inventory structure. In the model, we also take into account competition among sellers. Utilizing a unique data set of detailed Airbnb rental history and price trajectory in New York City, we find that the price rigidity observed in the data can be rationalized by a price adjustment cost ranging from 0:9% to 2:2% of the listed price. Moreover, automated pricing can increase the platform’s revenue by 4.8% and the hosts’ (sellers’) by 3.9%. The renters (buyers) could be either better off or worse off depending on the length of their stays. © 2022, The Author(s)

Xiaoye Duan,1,2 Qi Pan,1 Lixin Guo1,2 1Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Lixin Guo, Email glx1218@163.comBackground: This study aimed to assess the effects of chronic sleep deprivation (CSD) on bone metabolism in growing rats and the likely underlying mechanism.Methods: Twenty 5-week-old male Wistar rats and randomly divided into the CSD and normal control (NC) groups after one-week acclimatization. After a 6-week intervention of sleep deprivation, the distal femurs of both groups were harvested for micro-computed tomography scans and histological analysis. Meanwhile, the femur tissues were measured the mRNA and protein expression via RNA sequencing and immunohistochemical analysis. Serum bone turnover markers were evaluated at 0, 2, 4, and 6 weeks.Results: CSD impaired the bone growth, showing an imbalance of bone turnover status, dysphasia in the metaphysis growth plate, and deterioration of bone microarchitecture. Further, CSD suppressed bone formation, showing that the expression of osteogenesis-related proteins (col1α 1 and osteocalcin) and mRNA (igf1, bglap, runx2, col1α 1, pth1r) are down-regulated. Differentially expressed genes were detected, and functional enrichment analyses revealed that the PI3K/AKT pathway was significantly down-regulated in the CSD group.Conclusion: These results suggest that CSD can significantly impaire bone health, and it may exert these effects in part by suppressing bone formation and osteoblast differentiation, and inactivating the PI3K/AKT signaling pathway.Keywords: chronic sleep deprivation, sleep loss, growth, bone formation, RNA sequencing, PI3K/AKT pathway

Qi Pan,1 Jing Xu,1 Cen-Jin Wen,2 Yu-Yan Xiong,1 Zhao-Ting Gong,1 Yue-Jin Yang1 1State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Yue-Jin YangState Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaEmail yangyjfw@126.comAbstract: Despite several recent advances, current therapy and prevention strategies for myocardial infarction are far from satisfactory, owing to limitations in their applicability and treatment effects. Nanoparticles (NPs) enable the targeted and stable delivery of therapeutic compounds, enhance tissue engineering processes, and regulate the behaviour of transplants such as stem cells. Thus, NPs may be more effective than other mechanisms, and may minimize potential adverse effects. This review provides evidence for the view that function-oriented systems are more practical than traditional material-based systems; it also summarizes the latest advances in NP-based strategies for the treatment and prevention of myocardial infarction.Keywords: nanoparticles, myocardial infarction, treatment, prevention

Organisms have developed common behavioral and physiological adaptations to the influence of the day/night cycle. The CLOCK system forms an internal circadian rhythm in the suprachiasmatic nucleus (SCN) during light/dark input. The SCN may synchronize the growth hormone (GH) secretion rhythm with the dimming cycle through somatostatin neurons, and the change of the clock system may be related to the pulsatile release of GH. The GH—insulin-like growth factor 1 (IGF-1) axis and clock system may interact further on the metabolism through regulatory pathways in peripheral organs. We have summarized the current clinical and animal evidence on the interaction of clock systems with the GH—IGF-1 axis and discussed their effects on metabolism.

Vascular aging is a potent driver of cardiovascular and cerebrovascular diseases. Vascular aging features cellular and functional changes, while its molecular mechanisms and the cell heterogeneity are poorly understood. This study aims to 1) explore the cellular and molecular properties of aged cardiac vasculature in monkey and mouse and 2) demonstrate the role of transcription factor BACH1 in the regulation of endothelial cell (EC) senescence and its mechanisms. Here we analyzed published single-cell RNA sequencing (scRNA-seq) data from monkey coronary arteries and aortic arches and mouse hearts. We revealed that the gene expression of YAP1, insulin receptor, and VEGF receptor 2 was downregulated in both aged ECs of coronary arteries’ of monkey and aged cardiac capillary ECs of mouse, and proliferation-related cardiac capillary ECs were significantly decreased in aged mouse. Increased interaction of ECs and immunocytes was observed in aged vasculature of both monkey and mouse. Gene regulatory network analysis identified BACH1 as a master regulator of aging-related genes in both coronary and aorta ECs of monkey and cardiac ECs of mouse. The expression of BACH1 was upregulated in aged cardiac ECs and aortas of mouse. BACH1 aggravated endothelial cell senescence under oxidative stress. Mechanistically, BACH1 occupied at regions of open chromatin and bound to CDKN1A (encoding for P21) gene enhancers, activating its transcription in senescent human umbilical vein endothelial cells (HUVECs). Thus, these findings demonstrate that BACH1 plays an important role in endothelial cell senescence and vascular aging.

This dissertation is an empirical study of a peer-to-peer market, Airbnb. Chapter 2 examines the impact of Airbnb on the rental housing market. Airbnb can potentially cannibalize long-term rental and affects rental housing supply and affordability. However, Airbnb also provides extra income for long-term renters. Existing regulations try to improve rental supply, either by prohibiting certain types of apartments from operating on Airbnb or by controlling the maximum nights a listing can be rented. It remains unclear whether these regulations can achieve their goals. Using Airbnb listings data and a novel dataset that allows me to trace the moving history of long-term renters, I build a structural model and simulate the effectiveness of these policies. I find that Airbnb does cannibalize the long-term rental supply market. Airbnb also has a greater negative impact on long-term renters with higher income. The counterfactual results suggest that the first policy is better in improving the welfare of long-term renters than the second policy. Chapter 3 turns from the impact of Airbnb on the long-term rental market to the pricing on the platform. On many e-commerce platforms such as Airbnb, the pricing problems are intrinsically dynamic. However, many sellers on these platforms do not update prices frequently. In this chapter, I develop a dynamic pricing model to study the revenue and welfare implication of automated pricing, which allows sellers to update their prices without manual interference. The model focuses on three factors through which automated pricing influences sellers: price adjustment cost, buyer’s varying willingness to pay and inventory structure. In the model, I also take into account competition among sellers. Utilizing a unique data set of detailed Airbnb rental history and price trajectory in New York City, I find that the price rigidity observed in the data can be rationalized by a price adjustment cost ranging from 0.9% to 2.2% of the listed price.

Duwu Liao,1,* Guang Yang,2,* Yuan Yang,3,* Xueyong Tang,4,* Haixia Huang,5 Jichun Shao,1 Qi Pan4 1Department of Urology Surgery, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, People’s Republic of China; 2Department of Urology Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 4Department of Dermatology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, People’s Republic of China; 5Department of Critical Care Medicine, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jichun ShaoDepartment of Urology Surgery, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation, 416 Hospital, 4# Second Ring Road, North Fourth Section, Chengdu, Sichuan 610057, People’s Republic of ChinaEmail shaoji93@163.comQi PanDepartment of Dermatology, Chongqing Traditional Chinese Medicine Hospital, 40# Daomenkou, Yuzhong District, Chongqing 400011, People’s Republic of ChinaEmail qi_pan@vip.sina.comPurpose: Prostate cancer (PCa) is a widespread urinary neoplasm and one of the most prevalent and second most frequent malignancies diagnosed in males worldwide. This study aimed to identify a candidate marker and explore its molecular mechanism in PCa.Methods: Gene expression datasets, GSE55945 (n=21) and GSE46602 (n=50), were downloaded from the Gene Expression Omnibus database. Bioinformatic approaches were applied to identify potential markers. Effect

Cisplatin-based chemotherapy has been deployed as the first-line therapy for advanced bladder cancer for over 30 years. However, even after the chemotherapy, the disease specific survival of patients with regional lymph node invasion or distant metastasis is still quite poor. Target therapy, which is designed to selectively inhibit the cellular molecular pathways necessary for cancer viability and progression, has been deployed as a novel therapeutic strategy in a wide range of cancer since 1990s. Unfortunately, though targeting the immune checkpoint could be a promising therapy in a small ratio of advanced BCs, so far no other target therapy has been approved by FDA or evaluated in phase III clinical trial for BC therapy. The CDK4/6-RB1-E2F pathway, which regulates the transition of cell cycle from G1 phase to S phase, is frequently disrupted in 93% of advanced bladder cancer. Our previous work has characterized the CDK4/6-RB1 pathway as a potential therapy target in BC testing the effects of CDK4/6 inhibitors in vitro and in vivo. In this project, we further studied molecular mechanisms induced by CDK4/6 inhibitor PD-0332991 and analyzed the roles of these molecules in therapy response. A prerequisite for response to CDK4/6 inhibitors was the expression of RB1, since RB1-negative cells, which were either RB1 mutant or established via RB1 knockdown, were resistant to CDK4/6 inhibition. We also observed that the therapy response of RB1-positive cell lines, T24 and RT112, to PD-0332991 correlated with a synchronous robust reduction in protein level of both total and phosphorylated RB1. The mechanism underlying the down-regulation on RB1 upon CDK4/6 inhibition was characterized next. First, we revealed a transcriptional repression on RB1 upon the treatment by RT-qPCR. Second, we observed that proteasome inhibition partially rescue the down-regulation of RB1, indicating a proteasomal degradation of RB1 upon the treatment. MDM2 was identified as a mediator that promoted, Cisplatin basierte Chemotherapie wird seit mehr als 30 Jahren als first-line Therapie für das fortgeschrittene Blasenkarzinom angewandt. Doch trotz Chemotherapie ist das krankheitsspezifische Überleben von Patienten mit regionalem Lymphknotenbefall oder entfernten Metastasen sehr gering. Targettherapien wurden designt um spezifisch zelluläre Signalwege zu inhibieren, welche für das Überleben und die Progression eines Tumors essenziell sind. Diese Targettherapien werden seit den 1990er Jahren für verschiedene Tumorentitäten angewandt. Die Immuncheckpoint Blockade stellt einen viel versprechenden Therapieansatz für einen kleinen Anteil der Patienten mit fortgeschrittenem Blasenkarzinom dar. Jedoch wurden bisher keine weiteren Targettherapien für das Blasenkarzinom von der FDA zugelassen oder in einer klinischen Phase III Studie getestet. Der CDK4/6-RB1-E2F Signalweg, welcher den Übergang des Zellzykluses von der G1- zur S-Phase reguliert, ist in 93% der fortgeschrittenen Blasenkarzinome mutiert. In früheren Arbeiten unserer Gruppe wurde die Inhibierung des CDK4/6-RB1 Signalwegs als potentielle Therapieoption für das Blasenkarzinom identifiziert und die Effekte von CDK4/6 Inhibitoren in vitro und in vivo untersucht. In diesem Projekt wurden die molekularen Mechanismen des CDK4/6 Inhibitors PD-0332991 weiter untersucht und die Rolle dieser Moleküle auf das Therapieansprechen analysiert. Eine Voraussetzung für das Ansprechen auf CDK4/6 Inhibitoren war die Expression von RB1, da RB1 negative Zellen, welche entweder RB1 Mutationen aufwiesen oder in denen RB1 ausgeschaltet wurde, resistent gegenüber CDK4/6 Inhibitoren waren. Des Weiteren wurde gezeigt, dass das Ansprechen der RB1 positiven Zellen T24 und RT112 auf PD-0332991 mit einer robusten Reduktion der Proteinexpression von RB1 und Phospho-RB1 korrelierte. Im Weiteren wurde der Mechanismus, der dieser Herunterregulation von RB1 unter CDK4/6 Inhibition zugrunde liegt, charakterisiert. Zuerst wurde mittels RT-qPCR eine t

BackgroundThe aim of this study was to compare intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI) parameters such as standard apparent diffusion coefficient (ADCstandard), pure diffusion coefficient (Dslow), pseudodiffusion coefficient (Dfast) and perfusion fraction (ƒ) for differentiating pancreatic ductal adenocarcinoma (PDAC) with different pathological grades.MethodsInstitutional Review Board of our hospital approved this study protocol. Subjects comprised 38 PDACs confirmed by pathology. Pancreatic multiple b values DWI with 15 b values of 0, 10, 20, 40, 60, 80, 100, 150, 200, 400, 800, 1,000, 1200, 1,500, and 2,000 s/mm2 was performed using GE Discovery MR750 3.0T scanner. ADCstandard, Dslow, Dfast and ƒ values of all PDACs were calculated using mono- and bi-exponential models. Parameters of well/moderately differentiated and poorly differentiated PDAC were compared using Independent Sample t-test. P values <0.05 were considered significant.ResultsMean Dslow value of well/moderately differentiated PDAC was significantly lower than that of poorly differentiated PDAC (0.540×10-3vs. 0.676×10-3 mm2/s, P<0.001). Mean ƒ value of well/moderately differentiated PDAC was significantly higher than that of poorly differentiated PDAC (60.3% vs. 38.4%, P<0.001). The area under curve value of ƒ in differentiating well/moderately differentiated PDAC from poorly differentiated PDAC was slightly higher than that of Dslow (0.894>0.865). When the Dslow value was less than or equal to 0.599×10-3 mm2/s, the sensitivity and specificity were 100% and 84.6% respectively. When ƒ value was greater than 49.6%, the sensitivity and specificity were 92.0% and 84.6% respectively.ConclusionsDslow and ƒ derived from IVIM-DWI model can be used to distinguish well/moderately differentiated PDAC from poorly differentiated PDAC. And to serve this purpose, Dslow and ƒ have high diagnostic performance. IVIM-DWI is a promising and non-invasive tool for predicting patholog

Cisplatin-based chemotherapy has been deployed as the first-line therapy for advanced bladder cancer for over 30 years. However, even after the chemotherapy, the disease specific survival of patients with regional lymph node invasion or distant metastasis is still quite poor. Target therapy, which is designed to selectively inhibit the cellular molecular pathways necessary for cancer viability and progression, has been deployed as a novel therapeutic strategy in a wide range of cancer since 1990s. Unfortunately, though targeting the immune checkpoint could be a promising therapy in a small ratio of advanced BCs, so far no other target therapy has been approved by FDA or evaluated in phase III clinical trial for BC therapy. The CDK4/6-RB1-E2F pathway, which regulates the transition of cell cycle from G1 phase to S phase, is frequently disrupted in 93% of advanced bladder cancer. Our previous work has characterized the CDK4/6-RB1 pathway as a potential therapy target in BC testing the effects of CDK4/6 inhibitors in vitro and in vivo. In this project, we further studied molecular mechanisms induced by CDK4/6 inhibitor PD-0332991 and analyzed the roles of these molecules in therapy response. A prerequisite for response to CDK4/6 inhibitors was the expression of RB1, since RB1-negative cells, which were either RB1 mutant or established via RB1 knockdown, were resistant to CDK4/6 inhibition. We also observed that the therapy response of RB1-positive cell lines, T24 and RT112, to PD-0332991 correlated with a synchronous robust reduction in protein level of both total and phosphorylated RB1. The mechanism underlying the down-regulation on RB1 upon CDK4/6 inhibition was characterized next. First, we revealed a transcriptional repression on RB1 upon the treatment by RT-qPCR. Second, we observed that proteasome inhibition partially rescue the down-regulation of RB1, indicating a proteasomal degradation of RB1 upon the treatment. MDM2 was identified as a mediator that promoted, Cisplatin basierte Chemotherapie wird seit mehr als 30 Jahren als first-line Therapie für das fortgeschrittene Blasenkarzinom angewandt. Doch trotz Chemotherapie ist das krankheitsspezifische Überleben von Patienten mit regionalem Lymphknotenbefall oder entfernten Metastasen sehr gering. Targettherapien wurden designt um spezifisch zelluläre Signalwege zu inhibieren, welche für das Überleben und die Progression eines Tumors essenziell sind. Diese Targettherapien werden seit den 1990er Jahren für verschiedene Tumorentitäten angewandt. Die Immuncheckpoint Blockade stellt einen viel versprechenden Therapieansatz für einen kleinen Anteil der Patienten mit fortgeschrittenem Blasenkarzinom dar. Jedoch wurden bisher keine weiteren Targettherapien für das Blasenkarzinom von der FDA zugelassen oder in einer klinischen Phase III Studie getestet. Der CDK4/6-RB1-E2F Signalweg, welcher den Übergang des Zellzykluses von der G1- zur S-Phase reguliert, ist in 93% der fortgeschrittenen Blasenkarzinome mutiert. In früheren Arbeiten unserer Gruppe wurde die Inhibierung des CDK4/6-RB1 Signalwegs als potentielle Therapieoption für das Blasenkarzinom identifiziert und die Effekte von CDK4/6 Inhibitoren in vitro und in vivo untersucht. In diesem Projekt wurden die molekularen Mechanismen des CDK4/6 Inhibitors PD-0332991 weiter untersucht und die Rolle dieser Moleküle auf das Therapieansprechen analysiert. Eine Voraussetzung für das Ansprechen auf CDK4/6 Inhibitoren war die Expression von RB1, da RB1 negative Zellen, welche entweder RB1 Mutationen aufwiesen oder in denen RB1 ausgeschaltet wurde, resistent gegenüber CDK4/6 Inhibitoren waren. Des Weiteren wurde gezeigt, dass das Ansprechen der RB1 positiven Zellen T24 und RT112 auf PD-0332991 mit einer robusten Reduktion der Proteinexpression von RB1 und Phospho-RB1 korrelierte. Im Weiteren wurde der Mechanismus, der dieser Herunterregulation von RB1 unter CDK4/6 Inhibition zugrunde liegt, charakterisiert. Zuerst wurde mittels RT-qPCR eine t

Pin Fu,1 Fuchun Chen,2 Qi Pan,2 Xianda Zhao,1 Chen Zhao,1 William Chi-Shing Cho,3 Honglei Chen1,4 1Department of Pathology, School of Basic Medical Science, Wuhan University, Wuhan, 2Department of Thoracosurgery, Traditional Chinese Medical Hospital of Wenling, Wenling, Zhejiang, 3Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong, 4Department of Pathology, Maternal and Child Health Hospital of Hubei, Wuhan, People’s Republic of China Abstract: Caveolin-1 (Cav-1), a major structural protein of caveolae, is an integral membrane protein which plays an important role in the progression of carcinoma. However, whether Cav-1 acts as a tumor promoter or a tumor suppressor still remains controversial. For example, the tumor-promoting function of Cav-1 has been found in renal cancer, prostate cancer, tongue squamous cell carcinoma (SCC), lung SCC and bladder SCC. In contrast, Cav-1 also plays an inhibitory role in esophagus adenocarcinoma, lung adenocarcinoma and cutaneous SCC. The role of Cav-1 is still controversial in thyroid cancer, hepatocellular carcinoma, gastric adenocarcinoma, colon adenocarcinoma, breast cancer, pancreas cancer, oral SCC, laryngeal SCC, head and neck SCC, esophageal SCC and cervical SCC. Besides, it has been reported that the loss of stromal Cav-1 might predict poor prognosis in breast cancer, gastric cancer, pancreas cancer, prostate cancer, oral SCC and esophageal SCC. However, the accumulation of stromal Cav-1 has been found to be promoted by the progression of tongue SCC. Taken together, Cav-1 seems playing a different role in different cancer subtypes even of the same organ, as well as acting differently in the same cancer subtype of different organs. Thus, we hereby explore the functions of Cav-1 in human adenocarcinoma and SCC from the perspective of clinical significances and pathogenesis. We envision that novel targets may come with the further investigation of Cav-1 in carcinogenesis. Keywords: caveoli

We present a class of charged black hole solutions in an ($n+2)$-dimensional massive gravity with a negative cosmological constant, and study thermodynamics and phase structure of the black hole solutions both in grand canonical ensemble and canonical ensemble. The black hole horizon can have a positive, zero or negative constant curvature characterized by constant $k$. By using Hamiltonian approach, we obtain conserved charges of the solutions and find black hole entropy still obeys the area formula and the gravitational field equation at the black hole horizon can be cast into the first law form of black hole thermodynamics. In grand canonical ensemble, we find that thermodynamics and phase structure depends on the combination $k -\mu^2/4 +c_2 m^2$ in the four dimensional case, where $\mu$ is the chemical potential and $c_2m^2$ is the coefficient of the second term in the potential associated with graviton mass. When it is positive, the Hawking-Page phase transition can happen, while as it is negative, the black hole is always thermodynamically stable with a positive capacity. In canonical ensemble, the combination turns out to be $k+c_2m^2$ in the four dimensional case. When it is positive, a first order phase transition can happen between small and large black holes if the charge is less than its critical one. In higher dimensional ($n+2 \ge 5$) case, even when the charge is absent, the small/large black hole phase transition can also appear, the coefficients for the third ($c_3m^2$) and/or the fourth ($c_4m^2$) terms in the potential associated with graviton mass in the massive gravity can play the same role as the charge does in the four dimensional case., Comment: Latex 19 pages with 8 figures

Yan-Gang Qu,1 Qian Zhang,2 Qi Pan,3 Xian-Da Zhao,4 Yan-Hua Huang,2 Fu-Chun Chen,3 Hong-Lei Chen41Department of Pathology, The Central Hospital of Enshi Autonomous Prefecture, Enshi, 2Department of Molecular Pathology, Wuhan Nano Tumor Diagnosis Engineering Research Center, Wuhan, Hubei, People’s Republic of China; 3Department of Thoracosurgery, Traditional Chinese Medical Hospital of Wenling, Wenling, Zhejiang, People’s Republic of China; 4Department of Pathology, School of Basic Medical Science, Wuhan University, Wuhan, Hubei, People’s Republic of ChinaBackground: Epidermal growth factor receptor (EGFR) mutation status plays an important role in therapeutic decision making for non-small cell lung cancer (NSCLC) patients. Since EGFR mutation-specific antibodies (E746-A750del and L858R) have been developed, EGFR mutation detection by immunohistochemistry (IHC) is a suitable screening test. On this basis, we want to establish a new screening test, quantum dots immunofluorescence histochemistry (QDs-IHC), to assess EGFR gene mutation in NSCLC tissues, and we compared it to traditional IHC and amplification refractory mutation system (ARMS).Materials and methods: EGFR gene mutations were detected by QDs-IHC, IHC, and ADx-ARMS in 65 cases of NSCLC composed of 55 formalin-fixed, paraffin-embedded specimens and ten pleural effusion cell blocks, including 13 squamous cell carcinomas, two adenosquamous carcinomas, and 50 adenocarcinomas.Results: Positive rates of EGFR gene mutations detected by QDs-IHC, IHC, and ADx-ARMS were 40.0%, 36.9%, and 46.2%, respectively, in 65 cases of NSCLC patients. The sensitivity of QDs-IHC when detecting EGFR mutations, as compared to ADx-ARMS, was 86.7% (26/30); the specificity for both antibodies was 100.0% (26/26). IHC sensitivity was 80.0% (24/30) and the specificity was 92.31% (24/26). When detecting EGFR mutations, QDs-IHC and ADx-ARMS had perfect consistency (κ=

Knowledge matching is an important problem for many emerging applications in many areas including scientific knowledge management, ontology matching, e-commerce, and enterprise application integration. Matching the concepts of heterogeneous knowledge representations is very challenging due to the difficulty of taking contextual information into account and detecting complex matches. In this chapter, we describe a knowledge matching approach that uses subtree patterns to utilize structural information for matching at the conceptual and structural level. Initially, the algorithm does not take any syntactic information into account, but rather forms candidate mappings according to their structural/contextual relationships in the knowledge structures, which are then validated using online dictionaries and string similarity measures. The approach will then automatically extract the knowledge structure that is shared among all the matched knowledge representations. Experimental evaluation is performed on a number of real world XML schemas, which demonstrates the effectiveness of the proposed approach.

Concept matching is important when heterogeneous data sources are to be merged for the purpose of knowledge sharing. It has many useful applications in areas such as schema matching, ontology matching, scientific knowledge management, e-commerce, enterprise application integration, etc. With the desire of knowledge sharing and reuse in these fields, merging commonly occurs among different organizations where the knowledge describing the same domain is to be matched. Due to the different naming conventions, granularity and the use of concepts in different contexts, a semantic approach to this problem is preferred in comparison to syntactic approach that performs matches based upon the labels only. We propose a concept matching method that initially does not consider labels when forming candidate matches, but rather utilizes structural information to take the context into account and detect complex matches. Real world knowledge representations (schemas) are used to evaluate the method.

Pan, Qi., Thesis (M.Phil.)--Chinese University of Hong Kong, 2009., Includes bibliographical references (leaves 70-73)., also in Chinese., p.i, Acknowledgement --- p.iii, Chapter 1 --- Introduction --- p.1, Chapter 1.1 --- Main Contributions --- p.5, Chapter 1.2 --- Structure of Thesis --- p.6, Chapter 2 --- Related Works --- p.7, Chapter 2.1 --- Literature Review --- p.7, Chapter 2.1.1 --- Existing Works on Bursty Feature Idenfication --- p.9, Chapter 2.2 --- Classification --- p.9, Chapter 2.2.1 --- Support Vector Machine --- p.9, Chapter 2.2.2 --- Decision Tree and C4.5 Algorithm --- p.10, Chapter 2.3 --- PageRank and HITS Algorithm --- p.10, Chapter 2.3.1 --- PageRank --- p.11, Chapter 2.3.2 --- HITS --- p.11, Chapter 2.4 --- Efficient Market Hypothesis --- p.12, Chapter 3 --- Problem Statement --- p.14, Chapter 3.1 --- Volatility --- p.14, Chapter 3.2 --- Financial Model --- p.15, Chapter 3.3 --- Problem Statement --- p.16, Chapter 4 --- Volatility V.S. Trend Prediction --- p.18, Chapter 5 --- Bursty Volatility Features --- p.22, Chapter 5.1 --- ADFIDF Measure --- p.24, Chapter 5.2 --- Bursty Volatility Features --- p.28, Chapter 5.3 --- Bursty Volatility Features Selection --- p.29, Chapter 6 --- Volatility Ranking --- p.32, Chapter 6.1 --- Graph Construction --- p.32, Chapter 6.2 --- Volatility Ranking By News --- p.35, Chapter 7 --- Volatility Index for Stock Volatility --- p.37, Chapter 8 --- Experiments --- p.41, Chapter 8.1 --- Experiments for Volatility Index --- p.41, Chapter 8.1.1 --- Effectiveness of Volatility Index --- p.42, Chapter 8.1.2 --- Information from News --- p.42, Chapter 8.1.3 --- Information from Market --- p.45, Chapter 8.1.4 --- Correlation Value --- p.46, Chapter 8.1.5 --- Bursty Feature selection --- p.47, Chapter 8.2 --- Experiments for Ranking --- p.48, Chapter 8.2.1 --- Ranking Quality Comparison --- p.49, Chapter 8.2.2 --- Capturing Bursty Features --- p.51, Chapter 8.2.3 --- The Effectiveness of Feature Rank --- p.52, Chapter 8.2.4 --- The Effectiveness of Random Walk --- p.53, Chapter 8.2.5 --- Combination of VbN and GARCH --- p.54, Chapter 8.2.6 --- Ranking Result Sample --- p.56, Chapter 9 --- Conclusion --- p.58, Chapter A --- Most Important Features for Stocks --- p.60, Chapter B --- Correlation Matrix of Stocks --- p.63, Chapter C --- News Index Evaluation Result Table --- p.65, Chapter D --- Stock Data in Experiments --- p.67, Chapter E --- Constructed Graph --- p.68, Bibliograph --- p.70, http://library.cuhk.edu.hk/record=b5894204, Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/)

With the knowledge management requirement growing, enterprises are becoming increasingly aware of the significance of interlinking business information across structured and semi-structured data sources. This problem has become more important with the growing amount of semi-structured data often found in XML repositories, web logs, biological databases, etc. Effectively creating links between semi-structured and structured data is a challenging and unresolved problem. Once an optimized method has been formulated, the process of data mining can be implemented in a conjoint manner. This paper investigates a way in which this challenging problem can be tackled. The proposed method is experimentally evaluated using a real world database and the effectiveness and the potential in discovering collective information is demonstrated.

In this thesis, dewetting of polymer/polymer bilayers and phase separation in polymer blend thin films are investigated to understand the effects of film thickness and substrate type on the film stability. The kinetics of dewetting a polycarbonate (PC) film from a poly(styrene-co-acrylonitrile) (SAN) film deposited on a silicon substrate is studied at 180$\sp\circ$C. Using video-optical microscopy (OM), the hole velocity, V, is constant for a PC thickness, H, of 200 nm but increases with time for H = 310 nm. In both cases, V increases linearly with SAN thickness, L, then becomes constant for L $>$ 1000 nm. In contrast to liquid/liquid theories, detailed morphology analysis by atomic force microscopy (AFM) finds the hole rim to be asymmetric and the resulting rim velocity field to be non-uniform. The SAN thickness within the hole is found to be lower than the original SAN thickness, in agreement with the equilibration of hydrostatic and dynamic pressures. Phase separation in rigidly confined polymer films of polystyrene (PS) and poly(vinyl methyl ether) (PVME) with 0.30 volume fraction of PS is also studied. Using OM to monitor morphology, the PS-rich minority phase is observed to grow anisotropically under confinement. The phase separation displays evolution and pseudo-equilibrium stages. With decreasing film thickness, phase evolution becomes faster because of the preferential wetting of the PVME-rich phase at the substrate. Also, the pseudo-equilibrium area fraction of the PS-rich phase, A$\rm \sb{p},$ decreases linearly due to spatial confinement. When compared with the results in glass-confined films, phase separation in gold-confined films evolves faster and reaches a larger A$\rm \sb{p}.$ Films of deuterated polystyrene (DPS) and PVME with 0.30 volume fraction of DPS deposited on silicon are also studied. Because of the deformable air/film interface a slower phase evolution and larger pseudo-equilibrium phase size are observed. In contrast to the confined film

A mathematical model of the production system was established to reduce occurrences of equipment breakdown and their influence on phosphate ore output at Chinese mines. The model was used to study the availability and reliability of the production system, the average normal operating time, average repair times, the average production cycle and numbers of breakdowns per unit time under stable conditions. The conclusions of the study can be used to determine precautions to be taken at individual mines., A mathematical model of the production system was established to reduce occurrences of equipment breakdown and their influence on phosphate ore output at Chinese mines. The model was used to study the availability and reliability of the production system, the average normal operating time, average repair times, the average production cycle and numbers of breakdowns per unit time under stable conditions. The conclusions of the study can be used to determine precautions to be taken at individual mines.