A phase Ⅰ study of Hemay022, an irreversible dual EGFR/HER2 tyrosine kinase inhibitor in Chinese patients with HER2-positive advanced breast cancer

Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).

Open-Source Software Defined Networking Controllers:State-of-the-Art,Challenges and Solutions for Future Network Providers

Software Defined Networking(SDN)is programmable by separation of forwarding control through the centralization of the controller.The controller plays the role of the‘brain’that dictates the intelligent part of SDN technology.Various versions of SDN controllers exist as a response to the diverse demands and functions expected of them.There are several SDN controllers available in the open market besides a large number of commercial controllers;some are developed tomeet carrier-grade service levels and one of the recent trends in open-source SDN controllers is the Open Network Operating System(ONOS).This paper presents a comparative study between open source SDN controllers,which are known as Network Controller Platform(NOX),Python-based Network Controller(POX),component-based SDN framework(Ryu),Java-based OpenFlow controller(Floodlight),OpenDayLight(ODL)and ONOS.The discussion is further extended into ONOS architecture,as well as,the evolution of ONOS controllers.This article will review use cases based on ONOS controllers in several application deployments.Moreover,the opportunities and challenges of open source SDN controllers will be discussed,exploring carriergrade ONOS for future real-world deployments,ONOS unique features and identifying the suitable choice of SDN controller for service providers.In addition,we attempt to provide answers to several critical questions relating to the implications of the open-source nature of SDN controllers regarding vendor lock-in,interoperability,and standards compliance,Similarly,real-world use cases of organizations using open-source SDN are highlighted and how the open-source community contributes to the development of SDN controllers.Furthermore,challenges faced by open-source projects,and considerations when choosing an open-source SDN controller are underscored.Then the role of Artificial Intelligence(AI)and Machine Learning(ML)in the evolution of open-source SDN controllers in light of recent research is indicated.In addition,the challenges and limitations associated with deploying open-source SDN controllers in production networks,how can they be mitigated,and finally how opensource SDN controllers handle network security and ensure that network configurations and policies are robust and resilient are presented.Potential opportunities and challenges for future Open SDN deployment are outlined to conclude the article.

Inetetamab combined with S-1 and oxaliplatin as first-line treatment for human epidermal growth factor receptor 2-positive gastric cancer

BACKGROUND Patients with human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer have poor outcomes.Trastuzumab combined with chemotherapy is the first-line standard treatment for HER2-positive advanced gastric cancer.Inetetamab is a novel anti-HER2 drug,and its efficacy and safety in gastric cancer have not yet been reported.AIM To evaluate the efficacy and safety of the S-1 plus oxaliplatin(SOX)regimen combined with inetetamab as a first-line treatment for HER2-positive advanced gastric cancer.METHODS Thirty-eight patients with HER2-positive advanced gastric cancer or gastroeso-phageal junction adenocarcinoma were randomly divided into two groups:One group received inetetamab combined with the SOX regimen,and the other group received trastuzumab combined with the SOX regimen.After 4-6 cycles,patients with stable disease received maintenance therapy.The primary endpoints were progression-free survival(PFS)and overall survival(OS),and the secondary endpoints were the objective response rate,disease control rate,and adverse events(AEs).RESULTS Thirty-seven patients completed the trial,with 18 patients in the inetetamab group and 19 patients in the trastuzumab group.In the inetetamab group,the median PFS was 8.5 months,whereas it was 7.3 months in the trastuzumab group(P=0.046);this difference was significant.The median OS in the inetetamab group vs the trastuzumab group was 15.4 months vs 14.3 months(P=0.33),and the objective response rate was 50%vs 42%(P=0.63),respectively;these differences were not significant.Common AEs included leukopenia,thrombocytopenia,nausea,and vomiting.The incidence rates of grade≥3 AEs were 56%in the inetetamab group and 47%in the trastuzumab group(P=0.63),with no significant difference.CONCLUSION In the first-line treatment of HER2-positive advanced gastric cancer,inetetamab and trastuzumab showed comparable efficacy.The inetetamab group showed superior PFS,and both groups had good safety.

Sequential neoadjuvant chemotherapy using pegylated liposomal doxorubicin and cyclophosphamide followed by taxanes with complete trastuzumab and pertuzumab treatment for HER2-positive breast cancer: A phase Ⅱ single-arm study

Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin(PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2(HER2)-positive early breast cancer(BC).Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD(30-35 mg/m^(2)) and cyclophosphamide(600 mg/m^(2)), followed by four cycles of taxanes(docetaxel,90-100 mg/m^(2) or nab-paclitaxel, 260 mg/m^(2)), concomitant with eight cycles of trastuzumab(8 mg/kg loading dose,then 6 mg/kg) and pertuzumab(840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response(tp CR, yp T0/is yp N0). Secondary endpoints included breast p CR(bp CR),objective response rate(ORR), disease control rate, rate of breast-conserving surgery(BCS), and safety(with a focus on cardiotoxicity).Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42(53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval(95% CI), 48.5%-71.2%] patients achieved tp CR, and 49(62.8%) achieved bp CR. ORRs were 76.9%(95% CI, 66.0%-85.7%) and 93.6%(95% CI,85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine(11.5%) patients experienced asymptomatic left ventricular ejection fraction(LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP(NT-pro BNP), troponin I, or high-sensitivity troponin.Conclusions: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile,especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.

Threshold-Based Software-Defined Networking(SDN)Solution for Healthcare Systems against Intrusion Attacks

The healthcare sector holds valuable and sensitive data.The amount of this data and the need to handle,exchange,and protect it,has been increasing at a fast pace.Due to their nature,software-defined networks(SDNs)are widely used in healthcare systems,as they ensure effective resource utilization,safety,great network management,and monitoring.In this sector,due to the value of thedata,SDNs faceamajor challengeposed byawide range of attacks,such as distributed denial of service(DDoS)and probe attacks.These attacks reduce network performance,causing the degradation of different key performance indicators(KPIs)or,in the worst cases,a network failure which can threaten human lives.This can be significant,especially with the current expansion of portable healthcare that supports mobile and wireless devices for what is called mobile health,or m-health.In this study,we examine the effectiveness of using SDNs for defense against DDoS,as well as their effects on different network KPIs under various scenarios.We propose a threshold-based DDoS classifier(TBDC)technique to classify DDoS attacks in healthcare SDNs,aiming to block traffic considered a hazard in the form of a DDoS attack.We then evaluate the accuracy and performance of the proposed TBDC approach.Our technique shows outstanding performance,increasing the mean throughput by 190.3%,reducing the mean delay by 95%,and reducing packet loss by 99.7%relative to normal,with DDoS attack traffic.

Quercetin inhibits truncated isoform of dopamine-and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer

Trastuzumab resistance is one of the causes of poor prognosis in patients with human epidermal growth factor receptor 2(HER2)-positive(HER2+)breast cancer(BC).The truncated isoform of dopamine-and cAMPregulated phosphoprotein(t-DARPP)has been reported to be involved in trastuzumab therapy resistance and promoting tumor progression.To evaluate the t-DARPP expression in BC,paired tumors and surrounding normal tissues were analyzed by real-time polymerase chain reaction and confirmed higher DARPP-32 kDa family mRNA expression in HER2+BC tumor tissues.We established 2 patient-derived xenografts(PDX)mice models to test the efficacy of trastuzumab,named model 1(non-responder)and model 2(responder).t-DARPP and p95-HER2 protein-protein interactions were detected in PDX tumor tissue from non-responders using Förster resonance energy transfer assays.Instead,there is no response from the responder.Furthermore,mechanistic studies using transwell and western blot assays demonstrated that t-DARPP could upregulate epithelial-mesenchymal transition signaling proteins,enhance p95-HER2 expression and promote cell migration.We found that quercetin effectively reduced t-DARPP expression in HER2+BC cells.In t-DARPP ShRNA-suppressed cells,quercetin synergistically enhanced trastuzumab-induced apoptotic cell death and G2/M phase arrest.In conclusion,the combination of quercetin and trastuzumab treatment by targeting t-DARPP in HER2+BC patients has the potential as a biomarker for mitigating drug resistance.

Non-AIDS definings malignancies among human immunodeficiency virus-positive subjects: Epidemiology and outcome after two decades of HAART era

Highly active antiretroviral therapy(HAART) for humanimmunodeficiency virus(HIV) infection has been widely available in industrialized countries since 1996; its widespread use determined a dramatic decline in acquired immunodeficiency syndrome(AIDS)-related mortality, and consequently, a significant decrease of AIDS-defining cancers. However the increased mean age of HIV-infected patients, prolonged exposure to environmental and lifestyle cancer risk factors, and coinfection with oncogenic viruses contributed to the emergence of other malignancies that are considered non-AIDS-defining cancers(NADCs) as a relevant fraction of morbidity and mortality among HIV-infected people twenty years after HAART introduction. The role of immunosuppression in the pathogenesis of NADCs is not well defined, and future researches should investigate the etiology of NADCs. In the last years there is a growing evidence that intensive chemotherapy regimens and radiotherapy could be safely administrated to HIV-positive patients while continuing HAART. This requires a multidisciplinary approach and a close cooperation of oncologists and HIV-physicians in order to best manage compliance of patients to treatment and to face drug-related side effects. Here we review the main epidemiological features, risk factors and clinical behavior of the more common NADCs, such as lung cancer, hepatocellular carcinoma, colorectal cancer and anal cancer, Hodgkin's lymphoma and some cutaneous malignancies, focusing also on the current therapeutic approaches and preventive screening strategies.

机械产品6σ设计IDDOV中的Define方案实现研究

将产品全寿命周期六西格玛解决方案(Production Life Cycle Six Sigma Solution,LCSS)的六西格玛设计(Design For Six Sigma,DFSS)理论用于机械产品设计研究,在简要介绍IDDOV(Identify,Define,Develop,Optimize,Verify)流程的基础上,分析了顾客需求转换的系统规范,建立了机械产品Define阶段设计的技术体系和数学模型,总结了Define方案实现步骤和评估算法,为机械产品多样化、低成本、高质量和高稳健性设计提供了一种新的解决途径。

基于Define-Use图的MPI通信求解算法

针对分布存储计算机系统并行编译过程中,为维持数据一致性而产生冗余通信的问题,提出一种优化的通信求解算法。该算法基于依赖关系分析和过程间数据流分析,通过遍历Define-Use图,获得更精确的通信数据,消除过程调用时产生的冗余通信。实验结果表明,将算法所得结果作为后端生成MPI通信代码的依据,可以有效减少通信量,加速比接近手工MPI并行程序。

Cryopreservation of cynomolgus monkey (Macacafascicularis)spermatozoa in a chemically defined extender

Aim:To establish a method for cynomolgus monkey sperm cryopreservation in a chemically defined extender. Methods:Semen samples were collected by electro-ejaculation from four sexually mature male cynomolgus monkeys. The spermatozoa were frozen in straws by liquid nitrogen vapor using egg-yolk-free Tes-Tris (mTTE) synthetic extender and glycerol as cryoprotectant.The effects of glycerol concentration (1%,3 %,5 %,10 % and 15 % [v/v]) and its equilibration time (10 min,30 min,60 min and 90 min) on post-thaw spermatozoa were examined by sperm motility and sperm head membrane integrity.Results:The post-thaw motility and head membrane integrity of spermatozoa were significantly higher (P<0.05) for 5 % glycerol (42.95±2.55 and 50.39±2.42,respectively) than those of the other groups (1%:19.19±3.22 and 24.84±3.64;3 %:34.23±3.43 and 41.37±3.42;10 %: 15.68±2.36 and 21.39±3.14;15 %:7.47±1.44 and 12.90±2.18).The parameters for 30 min equilibration (42.95±2.55 and 50.39±2.42) were better (P<0.05) than those of the other groups (10 min:31.33±3.06 and 38. 98±3.31;60 min:32.49±3.86 and 40.01±4.18;90 min:31.16±3.66 and 38.30±3.78).Five percent glycerol and 30 min equilibration yielded the highest post-thaw sperm motility and head membrane integrity.Conclusion: Cynomolgus monkey spermatozoa can be successfully cryopreserved in a chemically defined extender,which is related to the concentration and the equilibration time of glycerol.

A Novel Load Balancing Strategy of Software-Defined Cloud/Fog Networking in the Internet of Vehicles

The Internet of Vehicles(IoV)has been widely researched in recent years,and cloud computing has been one of the key technologies in the IoV.Although cloud computing provides high performance compute,storage and networking services,the IoV still suffers with high processing latency,less mobility support and location awareness.In this paper,we integrate fog computing and software defined networking(SDN) to address those problems.Fog computing extends computing and storing to the edge of the network,which could decrease latency remarkably in addition to enable mobility support and location awareness.Meanwhile,SDN provides flexible centralized control and global knowledge to the network.In order to apply the software defined cloud/fog networking(SDCFN) architecture in the IoV effectively,we propose a novel SDN-based modified constrained optimization particle swarm optimization(MPSO-CO) algorithm which uses the reverse of the flight of mutation particles and linear decrease inertia weight to enhance the performance of constrained optimization particle swarm optimization(PSO-CO).The simulation results indicate that the SDN-based MPSO-CO algorithm could effectively decrease the latency and improve the quality of service(QoS) in the SDCFN architecture.

Blockchain-Based Secure Distributed Control for Software Defined Optical Networking

Software defined optical networking(SDON)is a critical technology for the next generation network with the advantages of programmable control and etc.As one of the key issues of SDON,the security of control plane has also received extensive attention,especially in certain network scenarios with high security requirement.Due to the existence of vulnerabilities and heavy overhead,the existing firewalls and distributed control technologies cannot solve the control plane security problem well.In this paper,we propose a distributed control architecture for SDON using the blockchain technique(BlockCtrl).The proposed BlockCtrl model introduces the advantages of blockchain into SDON to achieve a high-efficiency fault tolerant control.We have evaluated the performance of our proposed architecture and compared it to the existing models with respect to various metrics including processing rate,recovery latency and etc.The numerical results show that the BlockCtrl is capable of attacks detection and fault tolerant control in SDON with high performance on resource utilization and service correlation.

A Methodology for Reliability of WSN Based on Software Defined Network in Adaptive Industrial Environment

As communication technology and smart manufacturing have developed, the industrial internet of things(IIo T)has gained considerable attention from academia and industry.Wireless sensor networks(WSNs) have many advantages with broad applications in many areas including environmental monitoring, which makes it a very important part of IIo T. However,energy depletion and hardware malfunctions can lead to node failures in WSNs. The industrial environment can also impact the wireless channel transmission, leading to network reliability problems, even with tightly coupled control and data planes in traditional networks, which obviously also enhances network management cost and complexity. In this paper, we introduce a new software defined network(SDN), and modify this network to propose a framework called the improved software defined wireless sensor network(improved SD-WSN). This proposed framework can address the following issues. 1) For a large scale heterogeneous network, it solves the problem of network management and smooth merging of a WSN into IIo T. 2) The network coverage problem is solved which improves the network reliability. 3) The framework addresses node failure due to various problems, particularly related to energy consumption.Therefore, it is necessary to improve the reliability of wireless sensor networks, by developing certain schemes to reduce energy consumption and the delay time of network nodes under IIo T conditions. Experiments have shown that the improved approach significantly reduces the energy consumption of nodes and the delay time, thus improving the reliability of WSN.

Optimal investment for the defined-contribution pension with stochastic salary under a CEV model

In this paper, we study the optimal investment strategy of defined-contribution pension with the stochastic salary. The investor is allowed to invest in a risk-free asset and a risky asset whose price process follows a constant elasticity of variance model. The stochastic salary follows a stochastic differential equation, whose instantaneous volatility changes with the risky asset price all the time. The HJB equation associated with the optimal investment problem is established, and the explicit solution of the corresponding optimization problem for the CARA utility function is obtained by applying power transform and variable change technique. Finally, we present a numerical analysis.

A Dormant Multi-Controller Model for Software Defined Networking

In order to improve the scalability and reliability of Software Defined Networking(SDN),many studies use multiple controllers to constitute logically centralized control plane to provide load balancing and fail over.In this paper,we develop a flexible dormant multi-controller model based on the centralized multi-controller architecture.The dormant multi-controller model allows part of controllers to enter the dormant state under light traffic condition for saving system cost.Meanwhile,through queueing analysis,various performance measures of the system can be obtained.Moreover,we analyze the real traffic of China Education Network and use the results as the parameters of computer simulation and verify the effects of parameters on the system characteristics.Finally,a total expected cost function is established,and genetic algorithm is employed to find the optimal values of various parameters to minimize system cost for the deployment decision making.

The Impact of Delay in Software-Defined Integrated Terrestrial-Satellite Networks

Satellite communication networks have been evolving from standalone networks with ad-hoc infrastructures to possibly interconnected portions of a wider Future Internet architecture. Experts belonging to the fifth-generation(5 G) standardization committees are considering satellites as a technology to integrate in the 5 G environment. Software Defined Networking(SDN) is one of the paradigms of the next generation of mobile and fixed communications. It can be employed to perform different control functionalities, such as routing, because it allows traffic flow identification based on different parameters and traffic flow management in a centralized way. A centralized set of controllers makes the decisions and sends the corresponding forwarding rules for each traffic flow to the involved intermediate nodes that practically forward data up to the destination. The time to perform this process in integrated terrestrial-satellite networks could be not negligible due to satellite link delays. The aim of this paper is to introduce an SDN-based terrestrial satellite network architecture and to estimate the mean time to deliver the data of a new traffic flow from the source to the destination including the time required to transfer SDN control actions. The practical effect is to identify the maximum performance than can be expected.

Domain-Oriented Software Defined Computing Architecture

With the introduction of software defined hardware by DARPA Electronics Resurgence Initiative,software definition will be the basic attribute of information system.Benefiting from boundary certainty and algorithm aggregation of domain applications,domain-oriented computing architecture has become the technical direction that considers the high flexibility and efficiency of information system.Aiming at the characteristics of data-intensive computing in different scenarios such as Internet of Things(IoT),big data,artificial intelligence(AI),this paper presents a domain-oriented software defined computing architecture,discusses the hierarchical interconnection structure,hybrid granularity computing element and its computational kernel extraction method,finally proves the flexibility and high efficiency of this architecture by experimental comparison.

Design of BPS digital frontend for software defined radio receiver

In radio receivers,complete implementation of the software defined radio(SDR) concept is mainly limited by frontend.Based on bandpass sampling(BPS) theory,a flexible digital frontend(DFE) platform for SDR receiver is designed.In order to increase the processing speed,Gigabit Ethernet was applied in the platform at speed of 5×10~8 bit/s.By appropriate design of interpolant according to the position of input RF signals,multi-band receiving can be realized in the platform with suppression more than 35 d B without changing hardware.

Autoimmune pancreatitis with IgG4-positive plasma cell infiltration in salivary glands and biliary tract

A 62-year-old male was referred to our hospital because of liver dysfunction, diffuse pancreatic swelling, and trachelophyma. At admission, the patient was free of pain. Physical examination showed enlarged and palpable bilateral submandibular masses, but no palpable mass or organomegaly in the abdomen. Laboratory findings were as follows： total protein 90 g/L with γ-globulin of 37.3% （33 g/L）, total bilirubin 4 mg/L, aspartate aminotransferase 39 IU/L, alanine aminotransferase 67 IU/L,γ-glutamyl transpeptidase 1 647 IU/L, and amylase 135 IU/L. Autoantibodies were negative, and tumor markers were within the normal range. Serum IgG4 level was markedly elevated （18 900 rag/L）. Computed tomography （CT） showed diffuse swelling of the pancreas and dilatation of both common and intra-hepatic bile ducts. Endoscopic retrograde pancreatography （ERP） revealed diffuse irregular and narrow main pancreatic duct and stenosis of the lower common bile duct. Biopsy specimens from the pancreas, salivary gland and liver showed marked periductal IgG4-positive plasma cell infiltration with fibrosis. We considered this patient to be autoimmune pancreatitis （AIP） with fibrosclerosis of the salivary gland and biliary tract, prescribed prednisolone at an initial dose of 40 mg/d. Three months later, the laboratory data improved almost to normal. Abdominal CT reflected prominent improvement in the pancreatic lesion. Swelling of the salivary gland also improved. At present, the patient is on 10 mg/d of prednisolone without recurrence of the pancreatitis. We present here a case of AIP with fibrosclerosis of salivary gland and biliary tract.

The efficacy of tucatinib-based therapeutic approaches for HER2-positive breast cancer

Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in approximately 15–20% of breast cancer cases. HER2 is a member of the epidermal growth factor receptor (EGFR) family with tyrosinase kinase activity, and its overexpression is linked to poor prognosis and shorter progression-free survival (PFS) and overall survival (OS). Among various treatment options, HER2-targeting monoclonal antibodies and tyrosine kinase inhibitors (TKIs) have mostly been applied in recent decades to treat HER2-positive (HER2^(+)) breast cancer patients. Although positive clinical outcomes were documented in both advanced disease and neoadjuvant settings, the development of resistance mechanisms to such approaches has been one of the major challenges with the continuous usage of these drugs. In addition, patients who experience disease progression after treatment with multiple HER2-targeted therapies often have limited treatment options. The Food and Drug Administration (FDA) has recently approved a new TKI (i.e., tucatinib) for use in combination with immunotherapy and/or chemotherapeutic agents for the treatment of advanced-stage/metastatic HER2^(+) breast cancer. This review highlights recent updates on the efficacy of tucatinib-based therapeutic approaches in experimental models as well as in the clinical settings of HER2^(+) breast cancer.