Combination treatment of inflammatory bowel disease:Present status and future perspectives

The treatment of patients with inflammatory bowel disease(IBD),especially those with severe or refractory disease,represents an important challenge for the clinical gastroenterologist.It seems to be no exaggeration to say that in these patients,not only the scientific background of the gastroenterologist is tested,but also the abundance of“gifts”that he should possess(insight,intuition,determ-ination,ability to take initiative,etc.)for the successful outcome of the treatment.In daily clinical practice,depending on the severity of the attack,IBD is treated with one or a combination of two or more pharmaceutical agents.These combin-ations include not only the first-line drugs(e.g.,mesalazine,corticosteroids,antibiotics,etc)but also second-and third-line drugs(immunosuppressants and biologic agents).It is a fact that despite the significant therapeutic advances there is still a significant percentage of patients who do not satisfactorily respond to the treatment applied.Therefore,a part of these patients are going to surgery.In recent years,several small-size clinical studies,reviews,and case reports have been published combining not only biological agents with other drugs(e.g.,immunosuppressants or corticosteroids)but also the combination of two biologi-cal agents simultaneously,especially in severe cases.In our opinion,it is at least a strange(and largely unexplained)fact that we often use combinations of drugs in a given patient although studies comparing the simultaneous administration of two or more drugs with monotherapy are very few.As mentioned above,there is a timid tendency in the literature to combine two biological agents in severe cases unresponsive to the applied treatment or patients with severe extraintestinal manifestations.The appropriate dosage,the duration of the administration,the suitable timing for checking the clinical and laboratory outcome,as well as the treatment side-effects,should be the subject of intense clinical research shortly.In this editorial,we attempt to summarize the existing data regarding the already applied combination therapies and to humbly formulate thoughts and suggestions for the future application of the combination treatment of biological agents in a well-defined category of patients.We suggest that the application of biomarkers and artificial intelligence could help in establishing new forms of treatment using the available modern drugs in patients with IBD resistant to treatment.

Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival

BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths.Increased activity of the epidermal growth factor receptor(EGFR)is often observed in pancreatic cancer,and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration.Nevertheless,erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes.We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential(Δψm),facilitate tumor cell uptake ofΔψm-sensitive agents,disrupt mitochondrial homeostasis,and subsequently trigger tumor cell death.Erlotinib has not been tested for this effect.AIM To determine whether erlotinib can elevateΔψm and increase tumor cell uptake ofΔψm-sensitive agents,subsequently triggering tumor cell death.METHODSΔψm-sensitive fluorescent dye was used to determine how erlotinib affectsΔψm in pancreatic adenocarcinoma(PDAC)cell lines.The viability of conventional and patient-derived primary PDAC cell lines in 2D-and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone(MitoQ),aΔψm-sensitive MitoQ.The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0.The preclinical efficacy of the twodrug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts.RESULTS Erlotinib elevatedΔψm in PDAC cells,facilitating tumor cell uptake and mitochondrial enrichment ofΔψm-sensitive agents.MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses,while erlotinib pretreatment potentiated low doses of MitoQ.SynergyFinder suggested that these drugs synergistically induced tumor cell lethality.Consistent with in vitro data,erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent.CONCLUSION Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.

Adaptive H_(∞)Filtering Algorithm for Train Positioning Based on Prior Combination Constraints

To solve the problem of data fusion for prior information such as track information and train status in train positioning,an adaptive H∞filtering algorithm with combination constraint is proposed,which fuses prior information with other sensor information in the form of constraints.Firstly,the train precise track constraint method of the train is proposed,and the plane position constraint and train motion state constraints are analysed.A model for combining prior information with constraints is established.Then an adaptive H∞filter with combination constraints is derived based on the adaptive adjustment method of the robustness factor.Finally,the positioning effect of the proposed algorithm is simulated and analysed under the conditions of a straight track and a curved track.The results show that the positioning accuracy of the algorithm with constrained filtering is significantly better than that of the algorithm without constrained filtering and that the algorithm with constrained filtering can achieve better performance when combined with track and condition information,which can significantly reduce the train positioning error.The effectiveness of the proposed algorithm is verified.

Combinational therapy with Myc decoy oligodeoxynucleotides encapsulated in nanocarrier and X-irradiation on breast cancer cells

The Myc gene is the essential oncogene in triple-negative breast cancer(TNBC).This study investigates the synergistic effects of combining Myc decoy oligodeoxynucleotides-encapsulated niosomes-selenium hybrid nanocarriers with X-irradiation exposure on the MDA-MB-468 cell line.Decoy and scramble ODNs for Myc transcription factor were designed and synthesized based on promoter sequences of the Bcl2 gene.The nanocarriers were synthesized by loading Myc ODNs and selenium into chitosan(Chi-Se-DEC),which was then encapsulated in niosome-nanocarriers(NISM@Chi-Se-DEC).FT-IR,DLS,FESEM,and hemolysis tests were applied to confirm its characterization and physicochemical properties.Moreover,cellular uptake,cellular toxicity,apoptosis,cell cycle,and scratch repair assays were performed to evaluate its anticancer effects on cancer cells.All anticancer assessments were repeated under X-ray irradiation conditions(fractionated 2Gy).Physicochemical characteristics of niosomes containing SeNPs and ODNs showed that it is synthesized appropriately.It revealed that the anticancer effect of NISM@Chi-Se-DEC can be significantly improved in combination with X-ray irradiation treatment.It can be concluded that NISM@Chi-Se-DEC nanocarriers have the potential as a therapeutic agent for cancer treatment,particularly in combination with radiation therapy and in-vivo experiments are necessary to confirm the efficacy of this nano-drug.

LociScan,a tool for screening genetic marker combinations for plant variety discrimination

To reduce the cost and increase the efficiency of plant genetic marker fingerprinting for variety discrimination,it is desirable to identify the optimal marker combinations.We describe a marker combination screening model based on the genetic algorithm(GA)and implemented in a software tool,Loci Scan.Ratio-based variety discrimination power provided the largest optimization space among multiple fitness functions.Among GA parameters,an increase in population size and generation number enlarged optimization depth but also calculation workload.Exhaustive algorithm afforded the same optimization depth as GA but vastly increased calculation time.In comparison with two other software tools,Loci Scan accommodated missing data,reduced calculation time,and offered more fitness functions.In large datasets,the sample size of training data exerted the strongest influence on calculation time,whereas the marker size of training data showed no effect,and target marker number had limited effect on analysis speed.

A Clinical Study to Assess the Effectiveness of Oral Combination Kit Therapy in Syndromic Management of Abnormal Vaginal Discharge (FEMINE Study) in Kinshasa, Democratic Republic of Congo

Background: Vaginal discharge is one of most common and nagging problems that women face. About 20% - 25% of women who visit gynecology department complain of vaginal discharge and leucorrhoea. An orally administered combination kit, containing 2 g secnidazole, 1 g azithromycin and 150 mg fluconazole (Azimyn FS Kit), has been successfully evaluated in clinical trials and used in several countries for management syndromic vaginal discharge due to infections. Methods: This is a longitudinal study which aimed to verify the clinical efficacy of the combined oral kit containing secnidazole, azithromycin and fluconazole (Azimyn FS Kit®) in the syndromic treatment of abnormal vaginal discharge in patients received in outpatient consultations in Kinshasa/DR Congo from March to September 2023. Results: Majority of patients had whitish vaginal discharge (51.6%) of average abundance (56.2%), accompanied by pruritus in 72.1% of cases, and dyspareunia in 23.5% of cases and hypogastralgia in 40.2% of cases. One week after treatment with the Azimyn FS® combined kit, at the greatest majority of patients (97.3%), abnormal vaginal discharge had decreased by more than 50% (84.1%). Two weeks after treatment with the Azimyn FS® combined kit, almost all patients (97.3%) no longer had abnormal vaginal discharge which had completely disappeared. Conclusion: A single dose of secnidazole, azithromycin and fluconazole in the form of an oral combi-kit (Azimyn FS Kit) has shown excellent therapeutic effectiveness in the syndromic treatment of abnormal vaginal discharge wherein patients were treated without diagnostic confirmation.

Approximate solution of Volterra-Fredholm integral equations using generalized barycentric rational interpolant

It is well-known that interpolation by rational functions results in a more accurate approximation than the polynomials interpolation.However,classical rational interpolation has some deficiencies such as uncontrollable poles and low convergence order.In contrast with the classical rational interpolants,the generalized barycentric rational interpolants which depend linearly on the interpolated values,yield infinite smooth approximation with no poles in real numbers.In this paper,a numerical collocation approach,based on the generalized barycentric rational interpolation and Gaussian quadrature formula,was introduced to approximate the solution of Volterra-Fredholm integral equations.Three types of points in the solution domain are used as interpolation nodes.The obtained numerical results confirm that the barycentric rational interpolants are efficient tools for solving Volterra-Fredholm integral equations.Moreover,integral equations with Runge’s function as an exact solution,no oscillation occurrs in the obtained approximate solutions so that the Runge’s phenomenon is avoided.

Legendre-Jacobi’s Elliptic Integrals Shed Light on the Luminosity Distance in Cosmology

This article concerns the integral related to the transverse comoving distance and, in turn, to the luminosity distance both in the standard non-flat and flat cosmology. The purpose is to determine a straightforward mathematical formulation for the luminosity distance as function of the transverse comoving distance for all cosmology cases with a non-zero cosmological constant by adopting a different mindset. The applied method deals with incomplete elliptical integrals of the first kind associated with the polynomial roots admitted in the comoving distance integral according to the scientific literature. The outcome shows that the luminosity distance can be obtained by the combination of an analytical solution followed by a numerical integration in order to account for the redshift. This solution is solely compared to the current Gaussian quadrature method used as basic recognized algorithm in standard cosmology.

Advances in extracellular vesicle-based combination therapies for spinal cord injury

Spinal cord injury is a severe insult to the central nervous system that causes persisting neurological deficits.The currently available treatments involve surgical,medical,and rehabilitative strategies.However,none of these techniques can markedly reverse neurological deficits.Recently,extracellular vesicles from various cell sources have been applied to different models of spinal cord injury,thereby generating new cell-free therapies for the treatment of spinal cord injury.However,the use of extracellular vesicles alone is still associated with some notable shortcomings,such as their uncertainty in targeting damaged spinal cord tissues and inability to provide structural support to damaged axons.Therefore,this paper reviews the latest combined strategies for the use of extracellular vesicle-based technology for spinal cord injury,including the combination of extracellular vesicles with nanoparticles,exogenous drugs and/or biological scaffold materials,which facilitate the targeting ability of extracellular vesicles and the combinatorial effects with extracellular vesicles.We also highlight issues relating to the clinical transformation of these extracellular vesicle-based combination strategies for the treatment of spinal cord injury.

Heterogeneous information phase space reconstruction and stability prediction of filling body–surrounding rock combination

Traditional research believes that the filling body can effectively control stress concentration while ignoring the problems of unknown stability and the complex and changeable stress distribution of the filling body–surrounding rock combination under high-stress conditions.Current monitoring data processing methods cannot fully consider the complexity of monitoring objects,the diversity of monitoring methods,and the dynamics of monitoring data.To solve this problem,this paper proposes a phase space reconstruction and stability prediction method to process heterogeneous information of backfill–surrounding rock combinations.The three-dimensional monitoring system of a large-area filling body–surrounding rock combination in Longshou Mine was constructed by using drilling stress,multipoint displacement meter,and inclinometer.Varied information,such as the stress and displacement of the filling body–surrounding rock combination,was continuously obtained.Combined with the average mutual information method and the false nearest neighbor point method,the phase space of the heterogeneous information of the filling body–surrounding rock combination was then constructed.In this paper,the distance between the phase point and its nearest point was used as the index evaluation distance to evaluate the stability of the filling body–surrounding rock combination.The evaluated distances(ED)revealed a high sensitivity to the stability of the filling body–surrounding rock combination.The new method was then applied to calculate the time series of historically ED for 12 measuring points located at Longshou Mine.The moments of mutation in these time series were at least 3 months ahead of the roadway return dates.In the ED prediction experiments,the autoregressive integrated moving average model showed a higher prediction accuracy than the deep learning models(long short-term memory and Transformer).Furthermore,the root-mean-square error distribution of the prediction results peaked at 0.26,thus outperforming the no-prediction method in 70%of the cases.

Feynman Path Integral Using Operator Integration in Banach Space

Feynman-Path Integral in Banach Space: In 1940, R.P. Feynman attempted to find a mathematical representation to express quantum dynamics of the general form for a double-slit experiment. His intuition on several slits with several walls in terms of Lagrangian instead of Hamiltonian resulted in a magnificent work. It was known as Feynman Path Integrals in quantum physics, and a large part of the scientific community still considers them a heuristic tool that lacks a sound mathematical definition. This paper aims to refute this prejudice, by providing an extensive and self-contained description of the mathematical theory of Feynman Path Integration, from the earlier attempts to the latest developments, as well as its applications to quantum mechanics. About a hundred years after the beginning of modern physics, it was realized that light could in fact show behavioral characteristics of both waves and particles. In 1927, Davisson and Germer demonstrated that electrons show the same dual behavior, which was later extended to atoms and molecules. We shall follow the method of integration with some modifications to construct a generalized Lebesgue-Bochner-Stieltjes (LBS) integral of the form , where u is a bilinear operator acting in the product of Banach spaces, f is a Bochner summable function, and μ is a vector-valued measure. We will demonstrate that the Feynman Path Integral is consistent and can be justified mathematically with LBS integration approach.

CAUCHY TYPE INTEGRALS AND A BOUNDARY VALUE PROBLEM IN A COMPLEX CLIFFORD ANALYSIS

Clifford analysis is an important branch of modern analysis;it has a very important theoretical significance and application value,and its conclusions can be applied to the Maxwell equation,Yang-Mill field theory,quantum mechanics and value problems.In this paper,we first give the definition of a quasi-Cauchy type integral in complex Clifford analysis,and get the Plemelj formula for it.Second,we discuss the H?lder continuity for the Cauchy-type integral operators with values in a complex Clifford algebra.Finally,we prove the existence of solutions for a class of linear boundary value problems and give the integral representation for the solution.

Design of integral sliding mode guidance law based on disturbance observer

With the increasing precision of guidance,the impact of autopilot dynamic characteristics and target maneuvering abilities on precision guidance is becoming more and more significant.In order to reduce or even eliminate the autopilot dynamic operation and the target maneuvering influence,this paper suggests a guidance system model involving a novel integral sliding mode guidance law(ISMGL).The method utilizes the dynamic characteristics and the impact angle,combined with a sliding mode surface scheme that includes the desired line-ofsight angle,line-of-sight angular rate,and second-order differential of the angular line-of-sight.At the same time,the evaluation scenario considere the target maneuvering in the system as the external disturbance,and the non-homogeneous disturbance observer estimate the target maneuvering as a compensation of the guidance command.The proposed system’s stability is proven based on the Lyapunov stability criterion.The simulations reveale that ISMGL effectively intercepted large maneuvering targets and present a smaller miss-distance compared with traditional linear sliding mode guidance laws and trajectory shaping guidance laws.Furthermore,ISMGL has a more accurate impact angle and fast convergence speed.

Results Involving Partial Differential Equations and Their Solution by Certain Integral Transform

In this study,we aimto investigate certain triple integral transformand its application to a class of partial differentialequations.We discuss various properties of the new transformincluding inversion, linearity, existence, scaling andshifting, etc. Then,we derive several results enfolding partial derivatives and establish amulti-convolution theorem.Further, we apply the aforementioned transform to some classical functions and many types of partial differentialequations involving heat equations,wave equations, Laplace equations, and Poisson equations aswell.Moreover,wedraw some figures to illustrate 3-D contour plots for exact solutions of some selected examples involving differentvalues in their variables.

Wave propagation of a functionally graded plate via integral variables with a hyperbolic arcsine function

Several studies on functionally graded materials(FGMs)have been done by researchers,but few studies have dealt with the impact of the modification of the properties of materials with regard to the functional propagation of the waves in plates.This work aims to explore the effects of changing compositional characteristics and the volume fraction of the constituent of plate materials regarding the wave propagation response of thick plates of FGM.This model is based on a higher-order theory and a new displacement field with four unknowns that introduce indeterminate integral variables with a hyperbolic arcsine function.The FGM plate is assumed to consist of a mixture of metal and ceramic,and its properties change depending on the power functions of the thickness of the plate,such as linear,quadratic,cubic,and inverse quadratic.By utilizing Hamilton’s principle,general formulae of the wave propagation were obtained to establish wave modes and phase velocity curves of the wave propagation in a functionally graded plate,including the effects of changing compositional characteristics of materials.

The tangential k-Cauchy-Fueter type operator and Penrose type integral formula on the generalized complex Heisenberg group

The tangential k-Cauchy-Fueter operator and k-CF functions are counterparts of the tangential Cauchy–Riemann operator and CR functions on the Heisenberg group in the theory of several complex variables,respectively.In this paper,we introduce a Lie group that the Heisenberg group can be imbedded into and call it generalized complex Heisenberg.We investigate quaternionic analysis on the generalized complex Heisenberg.We also give the Penrose integral formula for k-CF functions and construct the tangential k-Cauchy-Fueter complex.

Existence of Solutions of a Convolution Integral Equation

In this study, we prove the of existence of solutions of a convolution Volterra integral equation in the space of the Lebesgue integrable function on the set of positive real numbers and with the standard norm defined on it. An operator P was assigned to the convolution integral operator which was later expressed in terms of the superposition operator and the nonlinear operator. Given a ball Br belonging to the space L it was established that the operator P maps the ball into itself. The Hausdorff measure of noncompactness was then applied by first proving that given a set M∈ B r the set is bounded, closed, convex and nondecreasing. Finally, the Darbo fixed point theorem was applied on the measure obtained from the set E belonging to M. From this application, it was observed that the conditions for the Darbo fixed point theorem was satisfied. This indicated the presence of at least a fixed point for the integral equation which thereby implying the existence of solutions for the integral equation.

Solvability and Construction of a Solution to the Fredholm Integral Equation of the First Kind

The issues of solvability and construction of a solution of the Fredholm integral equation of the first kind are considered. It is done by immersing the original problem into solving an extremal problem in Hilbert space. Necessary and sufficient conditions for the existence of a solution are obtained. A method of constructing a solution of the Fredholm integral equation of the first kind is developed. A constructive theory of solvability and construction of a solution to a boundary value problem of a linear integrodifferential equation with a distributed delay in control, generated by the Fredholm integral equation of the first kind, has been created.

Fuzzy Henstock-Kurzweil Triple Integral on a Type 1 Quasi-Fuzzy Parallelepipedal Domain

In this article, we propose by using the Hausdorff distance Simpson’s rule for the triple integral of a fuzzy-valued function and the error bound of this method, one of the variables of which is fuzzy. In addition, thin δ-fine partitions are introduced. The integration domain is a quasi-fuzzy parallelipiped. A numerical example is presented in order to show the application and the significance of the method.

Trajectory tracking guidance of interceptor via prescribed performance integral sliding mode with neural network disturbance observer

This paper investigates interception missiles’trajectory tracking guidance problem under wind field and external disturbances in the boost phase.Indeed,the velocity control in such trajectory tracking guidance systems of missiles is challenging.As our contribution,the velocity control channel is designed to deal with the intractable velocity problem and improve tracking accuracy.The global prescribed performance function,which guarantees the tracking error within the set range and the global convergence of the tracking guidance system,is first proposed based on the traditional PPF.Then,a tracking guidance strategy is derived using the integral sliding mode control techniques to make the sliding manifold and tracking errors converge to zero and avoid singularities.Meanwhile,an improved switching control law is introduced into the designed tracking guidance algorithm to deal with the chattering problem.A back propagation neural network(BPNN)extended state observer(BPNNESO)is employed in the inner loop to identify disturbances.The obtained results indicate that the proposed tracking guidance approach achieves the trajectory tracking guidance objective without and with disturbances and outperforms the existing tracking guidance schemes with the lowest tracking errors,convergence times,and overshoots.