IKKβ Suppression of TSC1 Links Inflammation and Tumor Angiogenesis via the mTOR Pathway

SummaryTNFα has recently emerged as a regulator linking inflammation to cancer pathogenesis, but the detailed cellular and molecular mechanisms underlying this link remain to be elucidated. The tuberous sclerosis 1 (TSC1)/TSC2 tumor suppressor complex serves as a repressor of the mTOR pathway, and disruption of TSC1/TSC2 complex function may contribute to tumorigenesis. Here we show that IKKβ, a major downstream kinase in the TNFα signaling pathway, physically interacts with and phosphorylates TSC1 at Ser487 and Ser511, resulting in suppression of TSC1. The IKKβ-mediated TSC1 suppression activates the mTOR pathway, enhances angiogenesis, and results in tumor development. We further find that expression of activated IKKβ is associated with TSC1 Ser511 phosphorylation and VEGF production in multiple tumor types and correlates with poor clinical outcome of breast cancer patients. Our findings identify a pathway that is critical for inflammation-mediated tumor angiogenesis and may provide a target for clinical intervention in human cancer

Cement leakage causes potential thermal injury in vertebroplasty

<p>Abstract</p> <p>Background</p> <p>Percutaneous vertebroplasty by injecting PMMA bone cement into the fractured vertebrae has been widely accepted in treatment of spinal compression fracture. However, the exothermic polymerization of bone cement may cause osseous or neural tissue injury. This study is thus designed to evaluate the potential risk of thermal damage in percutaneous vertebroplasty.</p> <p>Method</p> <p>Twelve porcine vertebrae were immersed in 37°C saline for the experiment. In the first stage of the study, vertebroplasty without cement leakage (control group, n = 6) was simulated. The anterior cortex, foramen, posterior cortex and the center of the vertebral body were selected for temperature measurement. Parameters including peak temperature and duration above 45°C were recorded. In the second stage, a model (n = 6) simulating bone cement leaking into the spinal canal was designed. The methods for temperature measurement were identical to those used in the first stage.</p> <p>Results</p> <p>In Stage 1 of the study (vertebroplasty of the porcine vertebral body in the absence of cement leakage), the average maximal temperature at the anterior cortex was 42.4 ± 2.2°C; at the neural foramen 39.5 ± 2.1°C; at the posterior cortex 40.0 ± 2.5°C and at the vertebral center, 68.1 ± 3.4°C. The average time interval above 45°C was 0 seconds at the anterior cortex; at the neural foramen, 0 seconds; at the posterior cortex, 0 seconds and at the vertebral center, 223 seconds. Thus, except at the core of the bone cement, temperatures around the vertebral body did not exceed 45°C. In Stage 2 of the study (cement leakage model), the average maximal temperature at the anterior cortex was 42.7 ± 2.4°C; at the neural foramen, 41.1 ± 0.4°C; at the posterior cortex, 59.1 ± 7.6°C and at the vertebral center, 77.3 ± 5.7°C. The average time interval above 45°C at the anterior cortex was 0 seconds; at the neural foramen, 0 seconds; at the posterior cortex, 329.3 seconds and at the vertebral center, 393.2 seconds. Based on these results, temperatures exceeded 45°C at the posterior cortex and at the vertebral center.</p> <p>Conclusions</p> <p>The results indicated that, for bone cement confined within the vertebra, curing temperatures do not directly cause thermal injury to the nearby soft tissue. If bone cement leaks into the spinal canal, the exothermic reaction at the posterior cortex might result in thermal injury to the neural tissue.</p

Clinical Efficacy and Post-Treatment Seromarkers Associated with the Risk of Hepatocellular Carcinoma among Chronic Hepatitis C Patients

This follow-up study enrolled chronic hepatitis C patients to evaluate the treatment efficacy and to identify post-treatment seromarkers associated with risk of hepatocellular carcinoma (HCC) among patients with a sustained virological response (SVR) or nonsustained virological response (NSVR). A total of 4639 patients who received pegylated interferon and ribavirin during 2004–2013 were followed until December 2014. HCC was confirmed through health examinations and data linkage with a national database. A total of 233 HCC cases were reported after 26,163 person-years of follow-up, indicating an incidence of 8.9 per 1000 person-years: 6.9 for SVR and 21.6 for NSVR per 1000 person-years. The associated risk of HCC in patients with SVR was 0.37 (0.22–0.63) for those without cirrhosis and 0.54 (0.31–0.92) for those with cirrhosis compared with their respective counterparts with NSVR. Among patients with SVR, advanced age, male gender, cirrhosis, decreased platelet count, and increased aspartate aminotransferase and α-fetoprotein levels were associated with HCC (p < 0.001). The treatment of chronic hepatitis C patients before they developed cirrhosis showed a higher efficacy than did the treatment of those who had already developed cirrhosis. Patients with SVR may still have a risk of HCC and need to be regularly monitored

Measurements of GEn/GMn from the ^2H(vec{e},e'vec{n})^1H Reaction to Q^2=1.45 (GeV/c)^2

We report new measurements of the ratio of the electric form factor to the magnetic form factor of the neutron, GEn/GMn, obtained via recoil polarimetry from the quasielastic ^2H(vec{e},e'vec{n})^1H reaction at Q^2 values of 0.45, 1.13, and 1.45 (GeV/c)^2 with relative statistical uncertainties of 7.6 and 8.4% at the two higher Q^2 points, which were not reached previously via polarization measurements. Scale and systematic uncertainties are small.Comment: 5 pages, 4 figures, 2 table

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

Advancement of Integrated CAD/CAM Software System

電腦輔助設計/製造系統可說是個複雜的產品，因為要成就一個成功的CAD/CAM系統，在軟體應用開發上涵蓋了一些最複雜困難的技術。泛用型CAD/CAM系統具備有高效能的影像顯示、複雜的計算幾何理論與進階的人機介面技術。本研究的主要目地是利用軟體工程、工業設計與CAD/CAM核心技術發展一整合型軟體系統。 系統整合是一種趨勢也是在CAD/CAM產品快速變遷下保持競爭力的重要因素。一般而言，CAD/CAM軟體提供三大類不同的功能：設計流程、加工製造規劃與數值控制程式，整合CAD與CAM模組將可幫助資訊/檔案在這三個主要功能間獲得完整的轉換。CAD/CAM設計者在一個以圖像為主的環境中工作，創新、辨識、啟發、評估與操控為工作過程中的重要內容，這些必須藉由幾何關係間的圖像來促成。通常在一般的CAD/CAM操作工作都是相類似與重複，此時，幾何操作上的自動化過程就變的相當重要，在市場上也成了必備條件。此外，一套整合完善的CAD/CAM系統不只是能提供豐富的特性資訊讓複雜的產品設計變為可能並且設計上靈活方便具彈性；而且要能夠針對不同的機械系統需求來定義加工指令，自動產生完整的加工程式來生產設計產品。 在本研究中除了對複雜人機介面的互動提出軟體開發的準則，並提出重要的核心技術作為成就CAD/CAM軟體的重要資源。藉由一些新方法與理論來提升CAD/CAM軟體的功能，例如強健的平面曲線偏置與NURBS曲線格式之應用，這些是本研究的重要技術核心。而由強健的曲線偏置發展出含島嶼之袋型銑削加工，此方法不只可應用在五面加工上亦可應用在曲面之粗銑與精修加工上。利用對NURBS曲線格式的解析，本研究對NURBS曲線的偏置與降階也作深入的討論並提出新方法，可直接利用CAD/CAM軟體輸出高速銑削所需之NURBS加工格式碼，符合各類工業加工控制器標準。最後我們將前面的研究成果應用在一個既簡單又複雜的圖形上-橢圓，看似簡單卻又難以駕駑一直以來就是工具機加工上既存的問題。本研究提出利用連續相切弧與NBRBS格式兩種方法來模擬橢圓，這兩種方法都可以取代以密集線段描繪橢圓而準確地模擬橢圓並滿足加工上所需的所有條件。 要找出製造程序規劃應用上的解決方案，直接衝擊一些演繹上的問題，本研究致力於將計算幾何的方法應用在製造程序上。所有的理論與方法已整合在CAD/CAM軟體的開發上，並且成功地應用在市場的生產使用上。CAD/CAM systems are complex products, the first and foremost reason is that they involve several of the most sophisticated technologies used in the development of software applications. General CAD/CAM systems require high performance visualization, computational geometry complex algorithms, and advanced ergonomic user interfacing techniques. In this research, an integrated software system will be developed by various methodologies including software engineering, industrial design and CAD/CAM technology. Integration is the way forward and is responsible for keeping pace with the rapidly changing CAD/CAM products. Generally speaking, CAD/CAM software systems serve three distinct functions: design process, manufacturing operation and NC programming. Integrating CAD with CAM helps streamline the transfer of information/files between these three functions. CAD/CAM designers work in a predominantly graphical environment. Creation, recognition, inspiration, evaluation and manipulation are required by graphics of geometric relationships are central to their work. Usually, the routine CAD/CAM operations are similar and reiterative. The importance of automating processes of geometric operations is conspicuous and prerequisite. A commendably-integrated design and manufacturing system should not only provide a rich set of features making it possible to design complex parts with greater flexibility, but also be able to automatically generate programs for various numerical control machines to produce the designed parts. During the research we not only proposed some principles for Human-Computer Interaction on software organization but also developed new methods and algorithms to advance CAD/CAM software such as robust curves offset and NURBS curves representation. From robust curves offset technologies, a reliable automatic tool-path generation and pocket machining with islands were developed. Such method can be applied on surface roughing and sculpture surface machining. By using NURBS curves format, we proposed optimum processes to offset NURBS curves and reduce the degrees of NURBS curves. Finally, we dealt with a simple but complex shape — Ellipse to verify our efforts. There are two ways to approximate ellipses in our study, one is tangent arcs and the other one is NURBS format. Both of these methods are all more efficient than to connect points laboriously determined in a CNC system. Applications in manufacturing process planning require solutions to challenging algorithmic problems, this thesis is devoted to the study of some problems from manufacturing to which methods of computational geometry can be successfully applied. Based on these efforts and empirical experience, a complete CAD/CAM software system has been developed for market applications.中文摘要 I ABSTRACT III ACKNOWLEDGEMENTS VI CONTENTS VII FIGURES XII TABLES XX CHAPTER 1: CAD/CAM System 1 1.1 Introduction 1 1.2 CAD 2 1.3 Advantages of CAD 3 1.4 CAM 4 1.5 Associate with CAM 4 1.6 CAD/CAM Software 6 1.7 Integrated CAD/CAM 7 1.8 An Overview 10 CHAPTER 2: Developing Strategy 12 2.1 Product Development 12 2.2 Industrial Design for Software Development 14 2.3 The CAD/CAM/CNC Interface 16 2.4 Design Models 17 2.5 Software Environment 19 2.6 Virtual Integrated CAD/CAM Architecture 22 CHAPTER 3: Robust Strategy of Planar Curves Offset 27 3.1 Introduction 27 3.2 Robust Curve Offsets Strategic Flow Chart 31 3.3 Offset Procedure and Manipulation 33 3.3.1 Progenitor curve (Original data) 33 3.3.2 Continuity check and vector establish 37 3.3.3 Identify direction automatically 38 3.3.4 Offset segments individually 38 3.3.5 Modified Voronoi Rule (medial axis) 39 3.3.6 Connection (pair-wise) 41 3.3.7 Self-loop detection (local) 42 3.3.8 Vertex corner type 43 3.3.9 Multi-loop detection (global) 46 3.4 Verification and Discussion 48 3.5 Discussions 51 CHAPTER 4: Invalid Loops Removal of Planar Curves Offset 52 4.1 Introduction 52 4.2 Related Work 54 4.3 Voronoi Diagram Rule (Medial Axis) 55 4.4 Forward Locus Tracing Method (FLTM) 57 4.5 Illustrative Implementation 62 4.6 Further Demonstration and Discussion 65 4.7 Tangential/Multiple Intersections and Collinear Segments 71 4.8 Conclusions 74 CHAPTER 5: Automatic Tool-Path Generation in Pocket with Islands 76 5.1 Introduction 76 5.2 Conventional and Climb Milling 77 5.3 Engaged Circumference 80 5.4 Pocketing Strategies 85 5.5 Practical Implementations 88 5.6 Zigzag Algorithm 92 5.7 Contour-parallel Algorithms 94 5.8 Multiple Tools for Pocket Machining 97 5.9 Discussions 98 CHAPTER 6: Optimizing Offsets of NURBS Curves by Normalization Process 101 6.1 Introduction 101 6.2 Related works 103 6.3 Build an Evaluating Bound Error (EBE) Function 105 6.4 Regularize Parameter and Normalization Process 107 6.4.1 Sampling offset points 107 6.4.2 Regularize parameters 109 6.4.3 Normalization 110 6.5 Optimum process 112 6.6 Experiment Test 116 6.6.1 Accuracy Test 116 6.6.2 Optimum Test 121 6.7 Discussions 127 CHAPTER 7: Degree Reduction of NURBS Curves 128 7.1 Introduction 128 7.2 Establishing the initial conditions 129 7.3 Build a Global Bound Error function 130 7.4 Optimum process 132 7.5 Examples and Comparisons 133 7.5.1 Comparison and verification 133 7.5.2 Full circle precision test 136 7.5.3 Optimum test 138 7.6 Summary 142 CHAPTER 8: Approximating an Ellipse by Piecewise Circular Arcs 145 8.1 Introduction 145 8.2 Establish the Initial Conditions 145 8.3 Optimum Process 150 8.4 Examples and Comparisons 151 8.5 Discussions 156 CHAPTER 9: Approximating Ellipses by NURBS Curves 159 9.1 Introduction 159 9.2 Establish the Initial Conditions 160 9.2.1 Equivalent approximating curve 160 9.2.2 Approximating offset curve 161 9.3 Build Global Bound Error Functions 161 9.3.1 Equivalent approximating curves 161 9.3.2 Approximating offset curves 162 9.4 Locations and Eights Optimization for Control Points 163 9.5 Illustration and Application 165 9.6 Discussions 171 CHAPTER 10: Conclusions and Futures 172 10.1 Conclusions 172 10.2 Trends 174 10.2.1 Making Software Compact to your Advantage 174 10.2.2 Trends of CAD/CAM 176 10.3 Futures 177 10.3.1 Future Features of CAD/CAM/NC Software 177 10.3.2 High-speed machining 179 10.3.3 Knowledge-based machining 180 10.3.4 Manufacturing Challenges 181 REFERENCES 18