Pivotal role of long non-coding ribonucleic acid-X-inactive specific transcript in regulating immune checkpoint programmed death ligand 1 through a shared pathway between miR-194-5p and miR-155-5p in hepatocellular carcinoma

BACKGROUND Anti-programmed death therapy has thrust immunotherapy into the spotlight.However,such therapy has a modest response in hepatocellular carcinoma(HCC).Epigenetic immunomodulation is a suggestive combinatorial therapy with immune checkpoint blockade.Non-coding ribonucleic acid(ncRNA)driven regulation is a major mechanism of epigenetic modulation.Given the wide range of ncRNAs that co-opt in programmed cell-death protein 1(PD-1)/programmed death ligand 1(PD-L1)regulation,and based on the literature,we hypothesized that miR-155-5p,miR-194-5p and long non-coding RNAs(lncRNAs)X-inactive specific transcript(XIST)and MALAT-1 are involved in a regulatory upstream pathway for PD-1/PD-L1.Recently,nutraceutical therapeutics in cancers have received increasing attention.Thus,it is interesting to study the impact of oleuropein on the respective study key players.AIM To explore potential upstream regulatory ncRNAs for the immune checkpoint PD-1/PD-L1.METHODS Bioinformatics tools including microrna.org and lnCeDB software were adopted to detect targeting of miR-155-5p,miR-194-5p and lncRNAs XIST and MALAT-1 to PD-L1 mRNA,respectively.In addition,Diana tool was used to predict targeting of both aforementioned miRNAs to lncRNAs XIST and MALAT-1.HCC and normal tissue samples were collected for scanning of PD-L1,XIST and MALAT-1 expression.To study the interaction among miR-155-5p,miR-194-5p,lncRNAs XIST and MALAT-1,as well as PD-L1 mRNA,a series of transfections of the Huh-7 cell line was carried out.RESULTS Bioinformatics software predicted that miR-155-5p and miR-194-5p can target PDL1,MALAT-1 and XIST.MALAT-1 and XIST were predicted to target PD-L1 mRNA.PD-L1 and XIST were significantly upregulated in 23 HCC biopsies compared to healthy controls;however,MALAT-1 was barely detected.MiR-194 induced expression elevated the expression of PD-L1,XIST and MALAT-1.However,overexpression of miR-155-5p induced the upregulation of PD-L1 and XIST,while it had a negative impact on MALAT-1 expression.Knockdown of XIST did have an impact on PD-L1 expression;however,following knockdown of the negative regulator of X-inactive specific transcript(TSIX),PD-L1 expression was elevated,and abolished MALAT-1 activity.Upon co-transfection of miR-194-5p with siMALAT-1,PD-L1 expression was elevated.Co-transfection of miR-194-5p with siXIST did not have an impact on PD-L1 expression.Upon co-transfection of miR-194 with siTSIX,PD-L1 expression was upregulated.Interestingly,the same PD-L1 expression pattern was observed following miR-155-5p cotransfections.Oleuropein treatment of Huh-7 cells reduced the expression profile of PD-L1,XIST,and miR-155-5p,upregulated the expression of miR-194-5p and had no significant impact on the MALAT-1 expression profile.CONCLUSION This study reported a novel finding revealing that opposing acting miRNAs in HCC,have the same impact on PD-1/PD-L1 immune checkpoint by sharing a common signaling pathway.

A Tabu Search Algorithm for Quadratic 0-1 Programming Problem

In this paper,quadratic 0-1 programming problem (I) is considered, in terms of its features quadratic 0-1 programming problem is solved by linear approxity heurstic algrothm and a developed tabu search ahgrothm .

Global optimality conditions for quadratic 0-1 programming with inequality constraints

Quadratic 0-1 problems with linear inequality constraints are briefly considered in this paper.Global optimality conditions for these problems,including a necessary condition and some sufficient conditions,are presented.The necessary condition is expressed without dual variables.The relations between the global optimal solutions of nonconvex quadratic 0-1 problems and the associated relaxed convex problems are also studied.

Effects of aerobic training on serum paraoxonase activity and its relationship with PON1-192 phenotypes in women

Background：Paraoxonase 1（PON1） is an antioxidant enzyme that protects high-density lipoprotein（HDL） and low-density lipoprotein against oxidation.Limited studies have addressed the influenc of exercise on PON1 activity and its relationship with PON1 phenotypes.We investigated relationships between PON1-192 phenotypes,PON1 activity,aerobic exercise,and blood lipid and lipoprotein concentrations in middle-aged women.Methods：An exercise group（n=50） engaging in regular aerobic exercise and a control group（n=41） were selected from a subset of 300 Caucasian women that met the inclusion criteria.Serum PON1,salt-stimulated PON1（SSPON1）,and arylesterase（ARE） activities;cholesterol levels and ARE activities of total HDL and HDL subgroups（HDLs）（supernatants obtained by polyethylene glycol）;and blood lipid and lipoprotein concentrations were determined by standardized enzymatic methods.PON1-192 QQ（low activity）,QR（moderate activity）,and RR（high activity） phenotype groups were define using serum SSPON1/ARE activity ratios.The R-carries（RC） phenotype group consisted of the QR and RR groups combined.Results：All lipid and lipoprotein concentrations were greater in the exercise group than in the control group.Regardless of phenotype,no significan differences were observed between the exercise and control groups in terms of serum PON1,SSPON1,or ARE activity associated with HDLs（p〉 0.05）,whereas PON1 activities in QQ-phenotyped women in the exercise group were significant y higher than those in the control group（p〈0.01）,but not the RC group.A statistically significan interaction between PON1 phenotypes（QQ and RC groups） and exercise（exercise and control groups） on PON1 activity was found.Conclusion：These results showed that a regular aerobic exercise program can improve PON1 activity depending on PON1-192 phenotype,but not on lipid and lipoprotein levels,in middle-aged Turkish women.

Expression and significance of B7-H1 in peripheral blood dendritic cells from patients with bladder cancer

Objective： The aim of this study was to study the expression and the clinical significance of B7-H1 on dendritic cells （DCs） in peripheral blood from patients with bladder cancer. Methods： Peripheral blood mononuclear cell were disparted from 30 bladder cancer patients and 7 healthy controls by density gradient centfifugation and then co-cultured. The expres- sion of B7-H1 on DCs were analyzed by flow cytometry. Results： Expression of BT-H1 on DCs in bladder cancer was higher than healthy controls （P 〈 0.01）. And the expression were strongly associated with the pathological grade and clinical stage of bladder cancer （P 〈 0,05）. Conclusion： The up-regulation of B7-H1 on DCs was strongly associated with neoplastic progres-sion of bladder cancer. B7-H1/programmed death （PD）-1 signal pathway may also play an important role in immune escape of bladder cancer during initial phase of T cell immune response.

Compact Model for the Obnoxious <i>p</i>-Median Problem

Obnoxious facilities are those crucial to human living, yet antagonistic to the public or environment. However, the interactions between obnoxious facilities and their clients have been less frequently investigated. A state-of-the-art model for this problem involves numerous 0 - 1 variables, rendering it difficult to solve. This study aims at removing most of these 0 - 1 variables to enhanced model efficiency. A compact model is presented in this study, with the equivalence between the new and original models proved. Additionally, numerical tests were conducted to show that the proposed compact model is more efficient than the original one.

A Hybrid Dynamic Programming Method for Concave Resource Allocation Problems

Concave resource allocation problem is an integer programming problem of minimizing a nonincreasing concave function subject to a convex nondecreasing constraint and bounded integer variables. This class of problems are encountered in optimization models involving economies of scale. In this paper, a new hybrid dynamic programming method was proposed for solving concave resource allocation problems. A convex underestimating function was used to approximate the objective function and the resulting convex subproblem was solved with dynamic programming technique after transforming it into a 0-1 linear knapsack problem. To ensure the convergence, monotonicity and domain cut technique was employed to remove certain integer boxes and partition the revised domain into a union of integer boxes. Computational results were given to show the efficiency of the algorithm.

Nonconvex Quadratic Programming Method for k－Coloring Problem：Algorithm and Computation

In this paper, we consider the socalled k-coloring problem in general case.Firstly, a special quadratic 0-1 programming is constructed to formulate k-coloring problem. Secondly, by use of the equivalence between above quadratic0-1 programming and its relaxed problem, k-coloring problem is converted intoa class of (continuous) nonconvex quadratic programs, and several theoreticresults are also introduced. Thirdly, linear programming approximate algorithmis quoted and verified for this class of nonconvex quadratic programs. Finally,examining problems which are used to test the algorithm are constructed andsufficient computation experiments are reported.

A NEW ALGORITHM FOR PURX O-1 LINEAR PROGRAMS WITH INEQUALITY CONSTRAINTS

ＡＮＥＷＡＬＧＯＲＩＴＨＭＦＯＲＰＵＲＸＯ－１ＬＩＮＥＡＲＰＲＯＧＲＡＭＳＷＩＴＨＩＮＥＱＵＡＬＩＴＹＣＯＮＳＴＲＡＩＮＴＳ￥ＣＨＥＮＪｉａｎｆｅｉ（ＢｉｏｃｈｅｍｉｃａｌＥｎｇｉｎｅｅｒｉｎｇＳｔａｔｅＫｅｙＬａｂｏｒａｔｏｒｙ，Ｂｅｉｊｉｎｇ１０...

A class of polynomially solvable 0-1 programming problems and an application

It is well known that general 0-1 programming problems are NP-Complete and their optimal solutions cannot be found with polynomial-time algorithms unless P=NP. In this paper, we identify a specific class of 0-1 programming problems that is polynomially solvable, and propose two polynomial-time algorithms to find its optimal solutions. This class of 0-1 programming problems commits to a wide range of real-world industrial applications. We provide an instance of representative in the field of supply chain management.

Understanding the function and dysfunction of the immune system in lung cancer: the role of immune checkpoints

Survival rates for metastatic lung cancer, including non-small cell lung cancer （NSCLC） and small cell lung cancer （SCLC）, are poor with S-year survivals of less than 5%. The immune system has an intricate and complex relationship with tumorigenesis; a groundswell of research on the immune system is leading to greater understanding of how cancer progresses and presenting new ways to halt disease progress. Due to the extraordinary power of the immune system-- with its capacity for memory, exquisite specificity and central and universal role in human biology--immunotherapy has the potential to achieve complete, long-lasting remissions and cures, with few side effects for any cancer patient, regardless of cancer type. As a result, a range of cancer therapies are under development that work by turning our own immune cells against tumors. However deeper understanding of the complexity of immunomodulation by tumors is key to the development of effective immunotherapies, especially in lung cancer.

Frequency ofT-cell FoxP3＋ Treg and CD4＋/CD8＋ PD-1 expression is related to HBeAg seroconversion in hepatitis B patients on pegylated interferon

Background Host immune responses against hepatitis B virus （HBV） induced by antiviral therapy play a crucial role in viral clearance. To further investigate the immune mechanisms underlying the differences between respondents and non-respondents, we analyzed myeloid dendritic cells （mDCs）, plasmacytoid dendritic cells （pDCs）, FoxP3＋ regulatory T cells （FoxP3＋ Treg） and programmed death 1 （PD-1） expression in CD4＋/CD8＋ T cells in chronic hepatitis B patients undergoing pegylated interferon （PeglFN）α-2b treatment. Methods Patients received PeglFNα-2b for 24 or 48 weeks, with follow-up at 24 weeks. The frequencies of mDCs, pDCs, FoxP3＋ Treg, and PD-1 expression by CD4＋/CD8＋ T cells were evaluated by flow cytometry at baseline, weeks 4 and 12, end of treatment, and follow-up （12/24 weeks）. Results In HBeAg seroconverters （respondents）, the mDC relative frequency decreased at week 4 and then rebounded at week 12. The pDC relative frequency decreased consistently. In non-HBeAg seroconverters （non-respondents）, both mDC and pDC frequencies decreased slightly. The FoxP3＋ Treg relative frequency decreased during treatment and remained low during follow-up in respondents, while in non-respondents it decreased slightly during therapy but rebounded after discontinuation. In patients with HBeAg 〈17.55 PEI-U/ml at week 12 and 〈8.52 PEI-U/ml at week 24, the FoxP3＋ Treg frequency decreased during treatment and at follow-up. In respondents, CD4~PD-1 and CD8＋PD-1 levels decreased at week 4 and remained low at week 12. In non-respondents, PD-1 expression decreased at week 4 but rebounded at week 12. Conclusions The results indicate that the dynamic changes in DCs, FoxP3＋ Treg frequency, and PD-1 expression by CD4＋ and CD8＋ T cells exhibit different trends in HBeAg and non-HBeAg seroconversion patients. During PeglFNa-2b treatment of chronic hepatitis B patients, these changes may be of predictive value for HBeAg seroconversion. HBsAg and HBeAg levels are related to FoxP3＋ Treg frequency.

Recent Advances in Mathematical Programming with Semi-continuous Variables and Cardinality Constraint

Mathematical programming problems with semi-continuous variables and cardinality constraint have many applications,including production planning,portfolio selection,compressed sensing and subset selection in regression.This class of problems can be modeled as mixed-integer programs with special structures and are in general NP-hard.In the past few years,based on new reformulations,approximation and relaxation techniques,promising exact and approximate methods have been developed.We survey in this paper these recent developments for this challenging class of mathematical programming problems.

Weekly Fleet Assignment Model and Algorithm

A 0-1 integer programming model for weekly fleet assignment was put forward based on linear network and weekly flight scheduling in China. In this model, the objective function is to maximize the total profit of fleet assignment, subject to the constraints of coverage, aircraft flow balance, fleet size, aircraft availability, aircraft usage, flight restriction, aircraft seat capacity, and stopover. Then the branch-and-bound algorithm based on special ordered set was applied to solve the model. At last, a real- wofld case study on an airline with 5 fleets, 48 aircrafts and 1 786 flight legs indicated that the profit increase was ￥ 1 591276 one week and the running time was no more than 4 rain, which shows that the model and algorithm are fairly good for domestic airline.

Economical Analysis and Optimization of Recovery Processing Policies about Discarded Product

On the foundation of analyzing the closed loop logistics chain of product with multi-lifecycle, the connotation of environmental value is set forth, recurring to such conceptions as supply chain and value chain. The plotting rules about disassembly tree are discussed in detail. The reachable matrix R of components’ disas- sembly is introduced into distinguishing if disassembly is needed, in combination with disassembly-deciding vector X. Furthermore, the arithmetic of disassembly cost is put forward. And the cost-benefits of components’ reusing, materials’ recycling, safety disposing are dissertated based on the activity-based costing. Then the 0-1 goal-programming model on product recovery processing is established, with components’ demotion calculated. In addition, taking the PC’s recovery processing for example, we put it into application.

Robust Optimization of Performance Scheduling Problem under Accepting Strategy

In this paper, the problem of program performance scheduling with accepting strategy is studied. Considering the uncertainty of actual situation, the duration of a program is expressed as a bounded interval. Firstly, we decide which programs are accepted. Secondly, the risk preference coefficient of the decision maker is introduced. Thirdly, the min-max robust optimization model of the uncertain program show scheduling is built to minimize the performance cost and determine the sequence of these programs. Based on the above model, an effective algorithm for the original problem is proposed. The computational experiment shows that the performance’s cost (revenue) will increase (decrease) with decision maker’s risk aversion.

A Simulated Annealing Approach tothe Train Routing and Makeup

This paper presents the formulation and solution of a train routing and makeupmodel.This formulation results in a large scale 0-1 integer programmingproblem with nonlinear objective function, and linear and nonlinearcoastraints. We know this problem is NP-complete;hence,it is diffieult to solvefor a globelly optimal solution. In this paper we propose a simulated annealingalgorithm for the train routing and makeup problem. This method avoidsentrapment in the local minima of the objective function. The effectiveness ofthis approach has been demonstrasted by results from test casee,

Optimized Three-Stage Strategy of Orderly Management of File Stream in Network Printing Workflow

This paper proposed the optimized three-stage strategy of orderly management of file stream in network printing workflow. In first stage the customer preflight was added to the conventional prepress preflight, which set quick-type, general-type, stable-type and comprehensive-type preflight scheme for customers by investigating the possibility of occurrence of errors of various preflight entries and customer relevancy. Based on four types of preflight schemes, four customer preflight applications were created by using Pitstop Pro and Connector You. Customers can select one of the appropriate applications for quick preflight before delivering to reduce the probability of returning the files back for correction when errors occur in preflight. Second stage is printing enterprise prepress preflight,which proposed the concept of the prepress preflight tolerance. In addition, according to the different requirements of printing technology and quality, this paper established the prepress preflight scheme based on the printing enterprises’ tolerance for preflight error. Third stage is to manage the optimized sorting of prepress file stream. To achieve it, the SPT rule and the 0-1 programming model were adopted, time spend of preflight, printing process and post-press finishing was also taken into account.Moreover, Enfocus Switch software was applied to establish automated network printing workflow and complete the file stream sorting. Finally, the result of simulation analysis of the optimized strategy shows that the optimized three-stage strategy can effectively shorten the file processing time.

Logistics Network Design for Manufacturing Enterprises with Component Processing Workshops

Logistics network design influences the efficiency and cost of Logistics directly.Some manufacturing enterprises not only have warehouse hubs,but also build component processing workshops which are usually located in those places where the costs of materials and workforce are lower.This paper establishes a logistics network design model for the manufacturing enterprises with component processing workshops based on 0-1 mixture integer programming.The model optimizes the logistics network in an integrated view,by which the selection of the nodes,the manufacturing plan,and transportation plan can be obtained.An example is given to verify its feasibility.The approach is helpful for designing of the logistics network in manufacturing enterprises.