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Yanwu Sun,1,* Yiyi Zhang,2,* Xuejing Wu,3,* Pan Chi1 1Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, People’s Republic of China; 2Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; 3Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pan ChiDepartment of Colorectal Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, People’s Republic of ChinaTel +86-0591-82618410Fax +86-0591-83357896Email chipan363@163.comAim: Resistance to neoadjuvant chemoradiotherapy (NCRT) and tumor recurrence presents a major clinical problem in locally advanced rectal cancer (LARC) patients. This study aimed to explore a genetic risk score related to NCRT response and tumor recurrence in rectal cancer after NCRT.Materials and Methods: Weighted gene co-expression network analysis was employed to identify hub genes associated with NCRT response from the GSE93375 dataset. Prognostic hub genes were determined using Cox regression analysis and associated with disease-free survival (DFS). A risk score system was constructed and the prognostic significance of the risk score was validated in our patient cohort. A predictive nomogram for DFS was developed and validated internally.Results: The Tan module had the highest correlations with NCRT response. Ten hub genes (COL15A1, THBS2, ITGB1, MMP2, CD34, SPARC, NOTCH3, PDGFRB, DCN, and SERPINH1) were associated with NCRT response. Immunostaining expression of four genes (NOTCH3, SPARC, DCN, and ITGB1) was found to be significantly associated with both NCRT response and DFS in our patient cohort and was selected to build a prognostic risk score for DFS as follows: risk score= (0.6188×ExpNOTCH3) + (0.6511×ExpSPARC) + (− 0.2976×ExpDCN

Podophyllotoxin-based glycosidic derivatives have seen numerous uses in cancer chemotherapy. However, these analogs are primarily derived from semisynthetic modifications of the natural product, and the inherent restriction of semisynthesis has prevented further development of new analogs. In the first chapter of this dissertation, a concise and modular total synthesis of the prototypical aryltetralin lignan, podophyllotoxin, is disclosed. Central to the overall strategy is a palladium-catalyzed C-H arylation reaction as the point of diversification. From an advanced intermediate, a two-step sequence furnished not only the natural product but also fully synthetic podophyllotoxin analogs. Moreover, this work uncovered subtle previously overlooked conformational effects governing reductive elimination from high-valent palladium centers. In the second chapter, a general strategy for the synthesis of complex meroterpene natural products is reported. First, a modular 10-step synthesis of the flagship PPAP, hyperforin, is disclosed. The synthetic approach includes two key transformations 1.) a novel annulation reaction between lithium enolates and diketene, and 2.) an oxidative ring expansion reaction mediated by hypervalent iodine. Second, the substrate scope of the diketene annulation reaction is reported. Finally, a synthesis of berkeleyone A, a complex meroterpene derived from 3,5-dimethylorsellinic acid, is reported in thirteen steps.

Podophyllotoxin-based glycosidic derivatives have seen numerous uses in cancer chemotherapy. However, these analogs are primarily derived from semisynthetic modifications of the natural product, and the inherent restriction of semisynthesis has prevented further development of new analogs. In the first chapter of this dissertation, a concise and modular total synthesis of the prototypical aryltetralin lignan, podophyllotoxin, is disclosed. Central to the overall strategy is a palladium-catalyzed C-H arylation reaction as the point of diversification. From an advanced intermediate, a two-step sequence furnished not only the natural product but also fully synthetic podophyllotoxin analogs. Moreover, this work uncovered subtle previously overlooked conformational effects governing reductive elimination from high-valent palladium centers. In the second chapter, a general strategy for the synthesis of complex meroterpene natural products is reported. First, a modular 10-step synthesis of the flagship PPAP, hyperforin, is disclosed. The synthetic approach includes two key transformations 1.) a novel annulation reaction between lithium enolates and diketene, and 2.) an oxidative ring expansion reaction mediated by hypervalent iodine. Second, the substrate scope of the diketene annulation reaction is reported. Finally, a synthesis of berkeleyone A, a complex meroterpene derived from 3,5-dimethylorsellinic acid, is reported in thirteen steps.

Zongbin Xu,1,* Yiyi Zhang,1,* Meifang Xu,2,* Xin Zheng,2 Mengxin Lin,3 Jie Pan,4 Chengwei Ye,1 Yu Deng,1 Caiyun Jiang,1 Yu Lin,1 Xingrong Lu,1 Pan Chi1 1Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China; 2Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China; 3Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China; 4Department of Emergency Surgery, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xingrong Lu; Pan ChiDepartment of Colorectal Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou City 350001, Fujian, People’s Republic of ChinaTel +86-591-83357896-8410Fax +86-591-87113828Email fjxhlxr@163.com; chipan363@163.comPurpose: This study aimed to evaluate the role of colony-stimulating factor 2 (CSF2) in chemotherapy resistance, prognosis, and immune response and to identify its possible mechanisms underlying drug resistance.Methods: Drug-resistant cell lines were obtained by successively increasing drug concentration. RNA-Seq was performed to screen hub genes. CSF2 expression was analyzed via immunohistochemistry. Moreover, The Cancer Genome Atlas (TCGA), Tumor Immune Estimation Resource (TIMER) dataset, and R2 platform were used to explore the correlations among CSF2 expression, prognosis, and immune response.Results: RNA-Seq indicated that microRNAs in cancer, P53 signaling pathway, and cell cycle were associated with FOLFOX chemotherapy resistance. Protein-protein interaction (PPI), molecular complex detection (MOCDE), and qRT-PCR analysis verified CSF2 as the hub gene in chemotherapy resistance. Moreover, CSF2 expression was lower in the normal tissue than in the cancerous tissue (P<0.05). Higher expression of CSF2 was associated with poor

Yiyi Zhang,* Zongbin Xu,* Yanwu Sun,* Pan Chi, Xingrong Lu Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China *These authors contributed equally to this work Introduction: Kallikrein 11 (KLK11) plays a crucial role in drug-resistance to oxaliplatin (L-OHP) in the treatment of metastatic colorectal cancer (mCRC). The study aimed to investigate the role of KLK11 in chemoresistance, and to clarify the mechanism underlying reverse of L-OHP resistance by knockdown of KLK11.Materials and Methods: Resistance to oxaliplatin was induced in HCT-8 (HCT-8/L-OHP) colorectal adenocarcinoma cell lines by exposing cells to increasing concentrations of L-OHP. MTT, RT-qPCR, and Western blot were used to evaluate the resistance to L-OHP. We then knocked down KLK11 in HCT-8/L-OHP cells to explore the mechanism through which KLK11 reverses L-OHP resistance. The mRNA and protein expression of KLK11 in tissues from mCRC patients were detected by RT-qPCR and immunohistochemistry.Results: The drug resistance index (RI) of HCT-8/L-OHP cell line to L-OHP, 5-Fluorouracil (5-FU), Irinotecan (CPT-11), Vincristine (VCR) and Cis-diamminedichloroplatinum (CDDP) were 10, 5.35, 3.23, 1.28, and 6.64, respectively. Increased expression of multi-drug resistant genes ABCC1, ABCB1, GSTP1 and ERCC1 were detected in HCT-8/L-OHP cell line. Moreover, the activated PI3K/AKT pathway was related to L-OHP-resistance. Knockdown of KLK11 in HCT-8/L-OHP cell reversed L-OHP-resistance by inhibiting cell growth and activating apoptosis via suppressing the PI3K/AKT signaling pathway. Moreover, high expression of KLK11 in chemoresistant-patients was associated with lymph node metastases and histopathology.Conclusion: KLK11 was highly expressed in chemoresistant-patients and L-OHP-resistant cell lines. Moreover, L-OHP resistance was associated with activated PI3K/AKT signal pathway. Knockdown of KLK11 can reverse L-OHP resistance by blocking PI3K/AKT s

Background The scale-up of tobacco control, especially after the adoption of the Framework Convention for Tobacco Control, is a major public health success story. Nonetheless, smoking remains a leading risk for early death and disability worldwide, and therefore continues to require sustained political commitment. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) offers a robust platform through which global, regional, and national progress toward achieving smoking-related targets can be assessed. Methods We synthesised 2818 data sources with spatiotemporal Gaussian process regression and produced estimates of daily smoking prevalence by sex, age group, and year for 195 countries and territories from 1990 to 2015. We analysed 38 risk-outcome pairs to generate estimates of smoking-attributable mortality and disease burden, as measured by disability-adjusted life-years (DALYs). We then performed a cohort analysis of smoking prevalence by birth-year cohort to better understand temporal age patterns in smoking. We also did a decomposition analysis, in which we parsed out changes in all-cause smoking-attributable DALYs due to changes in population growth, population ageing, smoking prevalence, and risk-deleted DALY rates. Finally, we explored results by level of development using the Socio-demographic Index (SDI). Findings Worldwide, the age-standardised prevalence of daily smoking was 25.0% (95% uncertainty interval [UI] 24.2-25.7) for men and 5.4% (5.1-5.7) for women, representing 28.4% (25.8-31.1) and 34.4% (29.4-38.6) reductions, respectively, since 1990. A greater percentage of countries and territories achieved significant annualised rates of decline in smoking prevalence from 1990 to 2005 than in between 2005 and 2015; however, only four countries had significant annualised increases in smoking prevalence between 2005 and 2015 (Congo [Brazzaville] and Azerbaijan for men and Kuwait and Timor-Leste for women). In 2015, 11.5% of global deaths (6.4

This paper investigates the many-to-one throughput capacity (and by symmetry, one-to-many throughput capacity) of IEEE 802.11 multi-hop networks. It has generally been assumed in prior studies that the many-to-one throughput capacity is upper-bounded by the link capacity L. Throughput capacity L is not achievable under 802.11. This paper introduces the notion of "canonical networks", which is a class of regularly-structured networks whose capacities can be analyzed more easily than unstructured networks. We show that the throughput capacity of canonical networks under 802.11 has an analytical upper bound of 3L/4 when the source nodes are two or more hops away from the sink; and simulated throughputs of 0.690L (0.740L) when the source nodes are many hops away. We conjecture that 3L/4 is also the upper bound for general networks. When all links have equal length, 2L/3 can be shown to be the upper bound for general networks. Our simulations show that 802.11 networks with random topologies operated with AODV routing can only achieve throughputs far below the upper bounds. Fortunately, by properly selecting routes near the gateway (or by properly positioning the relay nodes leading to the gateway) to fashion after the structure of canonical networks, the throughput can be improved significantly by more than 150%. Indeed, in a dense network, it is worthwhile to deactivate some of the relay nodes near the sink judiciously.

Distributed denial-of-service (DDoS) attacks present serious threats to servers in the Internet. They can exhaust critical resources at a target host with the help of a large number of compromised Internet hosts and hence deny services to legitimate clients. This paper studies some existing schemes for the detection and defense against TCP-based DDoS attacks. We propose a distributed scheme that can mitigate the damage caused by DDoS through a coordinated detection and response framework. This proposed scheme composes of a number of heterogeneous defense systems which cooperate with each other in protecting Internet servers. We have set up a network testbed for carrying out extensive experiments using real server machines, routers and software attack tools. Experimental results show that, compared to existing schemes, our proposed scheme can greatly improve the throughput of legitimate traffic and reduce the attack traffic during DDoS attacks. To investigate the scale-up behavior of our scheme, we have also developed a software simulator for largerscale experiments. Simulation results show that our scheme performs consistently well even in networks with more than 3000 nodes and under high traffic load. © 2006 IEEE.

Distributed denial-of-service (DDoS) attacks present serious threats to servers in the Internet. They can exhaust critical resources at a target host with the help of a large number of compromised Internet hosts and hence deny services to legitimate clients. This paper studies some existing schemes for the detection and defense against TCP-based DDoS attacks. We propose a distributed scheme that can mitigate the damage caused by DDoS through a coordinated detection and response framework. This proposed scheme composes of a number of heterogeneous defense systems which cooperate with each other in protecting Internet servers. We have set up a network testbed for carrying out extensive experiments using real server machines, routers and software attack tools. Experimental results show that, compared to existing schemes, our proposed scheme can greatly improve the throughput of legitimate traffic and reduce the attack traffic during DDoS attacks. To investigate the scale-up behavior of our scheme, we have also developed a software simulator for largerscale experiments. Simulation results show that our scheme performs consistently well even in networks with more than 3000 nodes and under high traffic load. © 2006 IEEE.

Chan Chi Pan., Thesis (M.Phil.)--Chinese University of Hong Kong, 2006., Includes bibliographical references (leaves xiv-xv)., s in English and Chinese., Chapter Chapter 1 --- Introduction --- p.1, Chapter 1.1 --- Overview --- p.1, Chapter 1.2 --- Related Works --- p.1, Chapter 1.3 --- Our Contributions --- p.2, Chapter 1.4 --- Organization of the Thesis --- p.3, Chapter Chapter 2 --- Definitions and Assumptions --- p.5, Chapter 2.1 --- Data-collection Networks --- p.5, Chapter 2.2 --- Assumptions --- p.9, Chapter Chapter 3 --- Canonical Networks --- p.13, Chapter 3.1 --- Theoretical Analysis --- p.13, Chapter 3.1.1 --- Fixed Link Distance --- p.13, Chapter 3.1.2 --- Variable Link Distance --- p.17, Chapter 3.2 --- Simulation --- p.20, Chapter Chapter 4 --- Beyond the Assumptions --- p.24, Chapter 4.1 --- Multiple Interference --- p.24, Chapter 4.2 --- HFD versus non-HFD performance --- p.27, Chapter Chapter 5 --- Perfect Scheduling and IEEE 802.11 Scheduling --- p.30, Chapter 5.1 --- Relationship between Perfect Scheduling and IEEE 802.11 Scheduling --- p.30, Chapter 5.2 --- Throughput Analysis under IEEE 802.11 scheduling --- p.33, Chapter Chapter 6 --- General Networks --- p.37, Chapter 6.1 --- Discussion of HFP --- p.37, Chapter 6.2 --- HFP Formulation --- p.39, Chapter 6.3 --- Optimization in Finding Best HFP --- p.43, Chapter 6.4 --- Experiment --- p.44, Chapter 6.5 --- NS-2 Simulation --- p.47, Chapter Chapter 7 --- Applying Canonical Network to General Networks --- p.49, Chapter 7.1 --- Direct Application --- p.49, Chapter 7.2 --- Manifold Canonical Network with Shorter Link Distance --- p.51, Chapter 7.3 --- Robustness on Node Positions in Manifold Canonical Network --- p.54, Chapter Chapter 8 --- Conclusion --- p.56, Appendix A RTS/CTS and Power Control --- p.x, References --- p.xiv, http://library.cuhk.edu.hk/record=b5892994, 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/)

Chan Chi Pan., Thesis (M.Phil.)--Chinese University of Hong Kong, 2006., Includes bibliographical references (leaves xiv-xv)., s in English and Chinese., Chapter Chapter 1 --- Introduction --- p.1, Chapter 1.1 --- Overview --- p.1, Chapter 1.2 --- Related Works --- p.1, Chapter 1.3 --- Our Contributions --- p.2, Chapter 1.4 --- Organization of the Thesis --- p.3, Chapter Chapter 2 --- Definitions and Assumptions --- p.5, Chapter 2.1 --- Data-collection Networks --- p.5, Chapter 2.2 --- Assumptions --- p.9, Chapter Chapter 3 --- Canonical Networks --- p.13, Chapter 3.1 --- Theoretical Analysis --- p.13, Chapter 3.1.1 --- Fixed Link Distance --- p.13, Chapter 3.1.2 --- Variable Link Distance --- p.17, Chapter 3.2 --- Simulation --- p.20, Chapter Chapter 4 --- Beyond the Assumptions --- p.24, Chapter 4.1 --- Multiple Interference --- p.24, Chapter 4.2 --- HFD versus non-HFD performance --- p.27, Chapter Chapter 5 --- Perfect Scheduling and IEEE 802.11 Scheduling --- p.30, Chapter 5.1 --- Relationship between Perfect Scheduling and IEEE 802.11 Scheduling --- p.30, Chapter 5.2 --- Throughput Analysis under IEEE 802.11 scheduling --- p.33, Chapter Chapter 6 --- General Networks --- p.37, Chapter 6.1 --- Discussion of HFP --- p.37, Chapter 6.2 --- HFP Formulation --- p.39, Chapter 6.3 --- Optimization in Finding Best HFP --- p.43, Chapter 6.4 --- Experiment --- p.44, Chapter 6.5 --- NS-2 Simulation --- p.47, Chapter Chapter 7 --- Applying Canonical Network to General Networks --- p.49, Chapter 7.1 --- Direct Application --- p.49, Chapter 7.2 --- Manifold Canonical Network with Shorter Link Distance --- p.51, Chapter 7.3 --- Robustness on Node Positions in Manifold Canonical Network --- p.54, Chapter Chapter 8 --- Conclusion --- p.56, Appendix A RTS/CTS and Power Control --- p.x, References --- p.xiv, http://library.cuhk.edu.hk/record=b5892994, 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/)

Distributed denial-of-service (DDoS) attacks present serious threats to servers in the Internet. They can exhaust critical resources at a target host with the help of a large number of compromised Internet hosts and hence deny services to legitimate clients. This paper studies some existing schemes for the detection and defense against TCP-based DDoS attacks. We propose a distributed scheme that can mitigate the damage caused by DDoS through a coordinated detection and response framework. This proposed scheme composes of a number of heterogeneous defense systems which cooperate with each other in protecting Internet servers. We have set up a network testbed for carrying out extensive experiments using real server machines, routers and software attack tools. Experimental results show that, compared to existing schemes, our proposed scheme can greatly improve the throughput of legitimate traffic and reduce the attack traffic during DDoS attacks. To investigate the scale-up behavior of our scheme, we have also developed a software simulator for largerscale experiments. Simulation results show that our scheme performs consistently well even in networks with more than 3000 nodes and under high traffic load. © 2006 IEEE.

Distributed denial of service (DDoS) attacks present a serious threat to the Internet. They exhaust the critical resources at a target by engaging the power of a large number of compromised Internet hosts and hence deny services to legitimate clients. The current Internet infrastructure is vulnerable to DDoS attacks since it has no built-in attack defense mechanisms. This thesis investigates effective methods that can be practically deployed in the Internet for detection and defense against DDoS attacks. We propose a distributed scheme that can mitigate the damage caused by DDoS through a coordinated detection and response framework. This proposed scheme composes of a number of heterogeneous defense systems which cooperatively protect Internet servers. To evaluate the effectiveness of the proposed scheme, a prototype has been implemented, and a large network testbed has been constructed for carrying out experimental studies using real server machines and attack tools. The performance results show that compared to three other existing schemes, the proposed scheme greatly improves the throughput of legitimate traffic during an attack while effectively suppressing the attack traffic to an insignificant level. More importantly, our scheme works reasonably well even in a partial deployment environment.

Distributed denial of service (DDoS) attacks present a serious threat to the Internet. They exhaust the critical resources at a target by engaging the power of a large number of compromised Internet hosts and hence deny services to legitimate clients. The current Internet infrastructure is vulnerable to DDoS attacks since it has no built-in attack defense mechanisms. This thesis investigates effective methods that can be practically deployed in the Internet for detection and defense against DDoS attacks. We propose a distributed scheme that can mitigate the damage caused by DDoS through a coordinated detection and response framework. This proposed scheme composes of a number of heterogeneous defense systems which cooperatively protect Internet servers. To evaluate the effectiveness of the proposed scheme, a prototype has been implemented, and a large network testbed has been constructed for carrying out experimental studies using real server machines and attack tools. The performance results show that compared to three other existing schemes, the proposed scheme greatly improves the throughput of legitimate traffic during an attack while effectively suppressing the attack traffic to an insignificant level. More importantly, our scheme works reasonably well even in a partial deployment environment.

Background The scale-up of tobacco control, especially after the adoption of the Framework Convention for Tobacco Control, is a major public health success story. Nonetheless, smoking remains a leading risk for early death and disability worldwide, and therefore continues to require sustained political commitment. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) offers a robust platform through which global, regional, and national progress toward achieving smoking-related targets can be assessed. Methods We synthesised 2818 data sources with spatiotemporal Gaussian process regression and produced estimates of daily smoking prevalence by sex, age group, and year for 195 countries and territories from 1990 to 2015. We analysed 38 risk-outcome pairs to generate estimates of smoking-attributable mortality and disease burden, as measured by disability-adjusted life-years (DALYs). We then performed a cohort analysis of smoking prevalence by birth-year cohort to better understand temporal age patterns in smoking. We also did a decomposition analysis, in which we parsed out changes in all-cause smoking-attributable DALYs due to changes in population growth, population ageing, smoking prevalence, and risk-deleted DALY rates. Finally, we explored results by level of development using the Socio-demographic Index (SDI). Findings Worldwide, the age-standardised prevalence of daily smoking was 25·0% (95% uncertainty interval [UI] 24·2–25·7) for men and 5·4% (5·1–5·7) for women, representing 28·4% (25·8–31·1) and 34·4% (29·4–38·6) reductions, respectively, since 1990. A greater percentage of countries and territories achieved significant annualised rates of decline in smoking prevalence from 1990 to 2005 than in between 2005 and 2015; however, only four countries had significant annualised increases in smoking prevalence between 2005 and 2015 (Congo [Brazzaville] and Azerbaijan for men and Kuwait and Timor-Leste for women). In 2015, 11·5% of global deaths (6·4