Gene signatures to therapeutics:Assessing the potential of ivermectin against t(4;14)multiple myeloma

BACKGROUND Multiple myeloma(MM)is a terminal differentiated B-cell tumor disease characterized by clonal proliferation of malignant plasma cells and excessive levels of monoclonal immunoglobulins in the bone marrow.The translocation,(t)(4;14),results in high-risk MM with limited treatment alternatives.Thus,there is an urgent need for identification and validation of potential treatments for this MM subtype.Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets.AIM To elucidate the molecular basis and search for potential effective drugs of t(4;14)MM subtype by employing a comprehensive approach.METHODS The transcriptional signature of t(4;14)MM was sourced from the Gene Expression Omnibus.Two datasets,GSE16558 and GSE116294,which included 17 and 15 t(4;14)MM bone marrow samples,and five and four normal bone marrow samples,respectively.After the differentially expressed genes were identified,the Cytohubba tool was used to screen for hub genes.Then,the hub genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis.Using the STRING database and Cytoscape,protein–protein interaction networks and core targets were identified.Potential small-molecule drugs were identified and validated using the Connectivity Map database and molecular docking analysis,respectively.RESULTS In this study,a total of 258 differentially expressed genes with enriched functions in cancer pathways,namely cytokine receptor interactions,nuclear factor(NF)-κB signaling pathway,lipid metabolism,atherosclerosis,and Hippo signaling pathway,were identified.Ten hub genes(cd45,vcam1,ccl3,cd56,app,cd48,btk,ccr2,cybb,and cxcl12)were identified.Nine drugs,including ivermectin,deforolimus,and isoliquiritigenin,were predicted by the Connectivity Map database to have potential therapeutic effects on t(4;14)MM.In molecular docking,ivermectin showed strong binding affinity to all 10 identified targets,especially cd45 and cybb.Ivermectin inhibited t(4;14)MM cell growth via the NF-κB pathway and induced MM cell apoptosis in vitro.Furthermore,ivermectin increased reactive oxygen species accumulation and altered the mitochondrial membrane potential in t(4;14)MM cells.CONCLUSION Collectively,the findings offer valuable molecular insights for biomarker validation and potential drug development in t(4;14)MM diagnosis and treatment,with ivermectin emerging as a potential therapeutic alternative.

Real-Time Analytical Solutions as Series Formulas and Heaviside off/on Switch Functions for Multiple Intermittent Intravenous Infusions in One- and Two-Compartment Models

Pharmacokinetic compartment models are the only models that can extract pharmacokinetic parameters from data collected in clinical studies but their estimates lack accuracy, explanations and physiological significance. The objective of this work was to develop particular solutions to drug concentration and AUC in the form of mathematical series and Heaviside functions for repetitive intermittent infusions in the one- and two-compartment models, as a function of dose number and total time using differential calculus. It was demonstrated that the central and peripheral compartment volumes determined from regression analysis of the aminoglycoside antibiotic Sisomicin concentration in plasma represent the actual physiological body fluid volumes accessible by the drug. The drug peak time and peak concentration in the peripheral compartment were also calculated as a function of dose number. It is also shown that the time of intercompartmental momentary distribution equilibrium can be used to determine the drug’s apparent volume of distribution within any dosing interval in multi-compartment models. These estimates were used to carry out simulations of plasma drug concentration with time in the one-compartment model. In conclusion, the two-compartment open mammillary pharmacokinetic model was fully explained for the aminoglycoside antibiotic sisomicin through the new concept of the apparent volume of distribution.

SPECTRAL ANALYSIS OF SOME INDEPENDENCES OF MULTIPLE-VALUED LOGICAL FUNCTIONS ON THEIR VARIABLES

There are many kinds of special relationships between multiple-valued logical func-tions and their variables, and they are difficult to be judged from their expressions. In thispaper, some sufficient and necessary conditions of the independence and statistical independenceof multiple-valued logical functions on their variables are given. Some conditions of algebraicindependence of multiple-valued logical functions on some of their variables and the way to de-generate a function to the greatest extent are proposed, and some applications of these resultsare indicated. All the results are studied by using Chrestenson spectral techniques.

Stabilization of fractional bilinear systems with multiple inputs

In this paper,we study in a constructive way the stabilization problem of fractional bilinear systems with multiple inputs.Using the quadratic Lyapunov functions and some additional hypotheses on the unit sphere,we construct stabilizing feedback laws for the considered fractional bilinear system.A numerical example is given to illustrate the efficiency of the obtained result.

Anti-BCMA CAR-T Cell Therapy in Relapsed or Refractory Multiple Myeloma Patients with Impaired Renal Function

Anti-B cell maturation antigen(BCMA)chimeric antigen receptor(CAR)T-cell therapyis effective and well-tolerated for refractory or relapsed multiple myeloma(RRMM).The purposcof the present study was to analyze efficacy in RRMM patients with renal impairment treated byanti-BCMA CAR-T cell therapy.A total of 59 RRMM patients were selected,and divided intoimpaired renal function(lRF)group[basclinc cstimated giomerular filtration rate(eSFR)<90 m/min/1.73 m^2(n=18)]and normal renal function(NRF)group(baseline eGFR≥90 mL/min/1.73 m,n=41).For patients with IRF,eGFR at the 6th month post-CAR-T cells infusion was significantlyhigher than the baseline(P<0.05).The multivariate analysis showed that light chain type and beta-2 micro-globulin(bcta-2M)were associated factors with the decrease of serum creatinine.Medianprogression-free survival(PFS)in the NRF group and IRF group was 266 days and 181 daysrespectively.Overall survival(OS)in the NRF group and lRF group was 877 days and 238 daysrespectively.There was no significant difference in the objective response rate(ORR)between thelRF group and the NRF group.It is suggested that CAR-T cells therapy could improve the renalfunction during the treatment of RRMM.The renal function could be more significantly improvedin RRMM patients with light chain type than with other types.

Multiple failure function based fragility curves for structures equipped with TMD

This paper presents a procedure to develop fragility curves of structures equipped with TMD considering multiple failure functions.The failure criteria considered are maximum inter-story drift ratio as a safety criterion,maximum absolute acceleration as a convenience criterion and TMD stroke length.The relationship between intensity measure and responses of the structure was assumed to follow the power-law model,and a regression analysis was used to estimate its properties.A nonlinear eight-story shear building subjected to near-fault earthquakes was used for the numerical studies.Fragility curves using multiple and single failure functions for an uncontrolled structure and a structure equipped with optimal TMDs were developed.Numerical analysis showed that using multiple failure functions led to increasing the fragility when compared with using the single failure function for both the uncontrolled and controlled structures.However,TMDs slightly reduced the seismic fragility and have the capability to improve the reliability of the structure.Also,it was found that the fragility was significantly influenced by the values of the capacity thresholds of both the acceleration of the structure and TMD stroke length,which should be selected by considering the target performance and application of the structure and control device.

Correlations between hippocampal functional connectivity,structural changes,and clinical data in patients with relapsing-remitting multiple sclerosis:a case-control study using multimodal magnetic resonance imaging

Multiple sclerosis is associated with structural and functional brain alterations leading to cognitive impairments across multiple domains including attention,memory,and the speed of information processing.The hippocampus,which is a brain important structure involved in memory,undergoes microstructural changes in the early stage of multiple sclerosis.In this study,we analyzed hippocampal function and structure in patients with relapsing-remitting multiple sclerosis and explored correlations between the functional connectivity of the hippocampus to the whole brain,changes in local brain function and microstructure,and cognitive function at rest.We retrospectively analyzed data from 20 relapsing-remitting multiple sclerosis patients admitted to the Department of Neurology at the China-Japan Union Hospital of Jilin University,China,from April 2015 to November 2019.Sixteen healthy volunteers were recruited as the healthy control group.All participants were evaluated using a scale of extended disability status and the Montreal cognitive assessment within 1 week before and after head diffusion tensor imaging and functional magnetic resonance imaging.Compared with the healthy control group,the patients with relapsing-remitting multiple sclerosis had lower Montreal cognitive assessment scores and regions of simultaneously enhanced and attenuated whole-brain functional connectivity and local functional connectivity in the bilateral hippocampus.Hippocampal diffusion tensor imaging data showed that,compared with the healthy control group,patients with relapsing-remitting multiple sclerosis had lower hippocampal fractional anisotropy values and higher mean diffusivity values,suggesting abnormal hippocampal structure.The left hippocampus whole-brain functional connectivity was negatively correlated with the Montreal cognitive assessment score(r=-0.698,P=0.025),and whole-brain functional connectivity of the right hippocampus was negatively correlated with extended disability status scale score(r=-0.649,P=0.042).The mean diffusivity value of the left hippocampus was negatively correlated with the Montreal cognitive assessment score(r=-0.729,P=0.017)and positively correlated with the extended disability status scale score(r=0.653,P=0.041).The right hippocampal mean diffusivity value was positively correlated with the extended disability status scale score(r=0.684,P=0.029).These data suggest that the functional connectivity and presence of structural abnormalities in the hippocampus in patients with relapse-remission multiple sclerosis are correlated with the degree of cognitive function and extent of disability.This study was approved by the Ethics Committee of China-Japan Union Hospital of Jilin University,China(approval No.201702202)on February 22,2017.

Rheological Behaviour for Polymer Melts and Concentrated Solutions Part Ⅲ: A New Multiple Entanglement Model to Predict the Dependence of Linear Viscoelastic Function (η_0, Ψ_(10)~0,η_(ext)~0) on the Ranges of Primary Molecular Weights and th

It is shown theoretically that the viscoelasticity of polymer melts is determined by three combining factorst they are the primary molecular weight and its distribution, the number of entanglement sites on polymer chain and the sequence distribution of constituent chains in entanglement spacings. A unified quantity for the three combing factors is the average constrained dimensional number of constituent chains in the long entanglement spacings (v). A new relation of v to the primary molecular weight and the number of testing polymers were derived from the multiple entanglement and reptation model, and a new method for determining v was proposed. The dependences of linear viscoelastic functions on the primary molecular weight and its distribution were derived by the statistical method. When Mn=6Me to 18 Me, the values of (v) can range from 3.33 to 3.70. Their values are in a good agreement with the experiment data, and it can slightjy vary with the different species of polymers and the different ranges of molecular weight of

GUT BARRIER FUNCTION DAMAGE FOLLOWING MULTIPLE FIREARM INJURIES IN A PORCINE MODEL

Objective. To study the characteristics and pathogenesis of gut barrier damage following multiple firearm injuries in a porcine model. Methods. Twenty four small pigs were divided into 4 groups: control group (n=6, group C), group H (n=6, gunshot induced tangential fracture of parietal bone), group L (n=6, gunshot induced comminuted fracture of bilateral femora) and group M (n=6, combined group H+L). Gastric intramucosal pH (pHi), plasma endotoxin levels in portal vein, and plasma D lactate levels were measured and blood samples were cultured at different intervals after trauma. The animals were sacrificed at 72 h following trauma and intestinal tissues were harvested for pathological examination and diamine oxidase (DAO) activity measurement. Results. In group M at 72 h, pHi was significantly lower than that of group H and L (P< 0.01), and plasma endotoxin level was significantly higher than that of group H (P< 0.01) and group L (P< 0.05). Simultaneously, in groupM, D lactate level was markedly higher than that of group H (P< 0.01), and incidence of positive blood culture was much higher than that of group H and L (P<0.05). Necrosis and exfoliation were revealed at ileum villus top in all traumagroups, especially in group M, in which ileum DAO activity declined most significantly as well. Conclusion. Multiple trauma is prone to cause gastrointestinal ischemia even without hemorrhagic shock. The damage of gut barrier in multiple trauma appears to be more severe than that in one site trauma, thereby promoting gut derived endotoxemia and bacterial translocation and contributing to the development of endogenous infection.SURGICAL TREATMENT OF MALIGNANTESOPHAGEAL TUMORS IN PUMC HOSPITAL Guo Huiqin,Li Zejian ,Zhang Fan1 ,Zhang Zhiyong,Xu Letian ,Li Weidong2,Wang Xiuqin2and Wu Min2Department of Thoracic Surgery, PUMC Hospital, CAMS &PUMC, Beijing 100730Key words malignant esophageal tumors; early diagnosis; FHIT geneTo study how to prolong the postoperative survival time of the patientswith malignant esophageal tumors. The clinical data of 1098 patients with malignant esophageal tumors from 1961 to 1992 were retrospectively analyzed. The deletion of fragile histamine triplet (FHIT) gene (a tumor suppressor gene) in 30 fresh esophageal samples obtained in 1996 was detected with PCR and RT PCR method. The resectability was raised gradually and the operative morbidity and mortality decreased year by year, but there was no significant improvement on the postoperative 5 year survival rate. Delayed diagnosis and irradical resection influenced the long term survival. The deletion of cDNA of FHIT gene was 64.2%in esophageal cancer and 20%in the resected margin of the cancer. We believe that high grade atypical hyperplasia in esophageal epithelium and deletion of FHIT gene in esophageal cancer and its resected margin are pathological and molecular markers for early diagnosis of esophageal cancer respectively, and the latter may be one of the molecular markers for the resection. Early diagnosis and treatment, radical resection, and postoperative nutritional support are very important for the improvement of the postoperative survival time of the patients.

A multiplicative Gauss-Newton minimization algorithm:Theory and application to exponential functions

Multiplicative calculus(MUC)measures the rate of change of function in terms of ratios,which makes the exponential functions significantly linear in the framework of MUC.Therefore,a generally non-linear optimization problem containing exponential functions becomes a linear problem in MUC.Taking this as motivation,this paper lays mathematical foundation of well-known classical Gauss-Newton minimization(CGNM)algorithm in the framework of MUC.This paper formulates the mathematical derivation of proposed method named as multiplicative Gauss-Newton minimization(MGNM)method along with its convergence properties.The proposed method is generalized for n number of variables,and all its theoretical concepts are authenticated by simulation results.Two case studies have been conducted incorporating multiplicatively-linear and non-linear exponential functions.From simulation results,it has been observed that proposed MGNM method converges for 12972 points,out of 19600 points considered while optimizing multiplicatively-linear exponential function,whereas CGNM and multiplicative Newton minimization methods converge for only 2111 and 9922 points,respectively.Furthermore,for a given set of initial value,the proposed MGNM converges only after 2 iterations as compared to 5 iterations taken by other methods.A similar pattern is observed for multiplicatively-non-linear exponential function.Therefore,it can be said that proposed method converges faster and for large range of initial values as compared to conventional methods.

TWO MEROMORPHIC FUNCTIONS SHARE SOME PAIRS OF SMALL FUNCTIONS WITH TRUNCATED MULTIPLICITIES

Using the techniques proposed in [3], we prove that two nonconstant meromorphic functions f and g on C must be linked by a quasi-Mbius transformation if they share some pairs of small functions with more precise truncated multiplicities, which improve and extend the results of Duc Quang Si.

Application of Multiple Sensor Data Fusion for the Analysis of Human Dynamic Behavior in Space: Assessment and Evaluation of Mobility-Related Functional Impairments

The authors have applied a systems analysis approach to describe the musculoskeletal system as consisting of a stack of superimposed kinematic hier-archical segments in which each lower segment tends to transfer its motion to the other superimposed segments. This segmental chain enables the derivation of both conscious perception and sensory control of action in space. This applied systems analysis approach involves the measurements of the complex motor behavior in order to elucidate the fusion of multiple sensor data for the reliable and efficient acquisition of the kinetic, kinematics and electromyographic data of the human spatial behavior. The acquired kinematic and related kinetic signals represent attributive features of the internal recon-struction of the physical links between the superimposed body segments. In-deed, this reconstruction of the physical links was established as a result of the fusion of the multiple sensor data. Furthermore, this acquired kinematics, kinetics and electromyographic data provided detailed means to record, annotate, process, transmit, and display pertinent information derived from the musculoskeletal system to quantify and differentiate between subjects with mobility-related disabilities and able-bodied subjects, and enabled an inference into the active neural processes underlying balance reactions. To gain insight into the basis for this long-term dependence, the authors have applied the fusion of multiple sensor data to investigate the effects of Cerebral Palsy, Multiple Sclerosis and Diabetic Neuropathy conditions, on biomechanical/neurophysiological changes that may alter the ability of the human loco-motor system to generate ambulation, balance and posture.

On Multiplicative Generators of n-Dimensional Overlap Functions

In this paper, inspired by the multiplicative generators of overlap functions, we mainly propose the concepts of multiplicative generator pairs of n-dimensional overlap functions, in order to extend the dimensionality of overlap functions from 2 to n. We present the condition under which the pair (g, h) can multiplicatively generate an n-dimensional overlap function Og,h. we focus on the homogeneity and idempotency property on multiplicatively generated n-dimensional overlap functions.

Review:Multiple Functionalities of Aqueous Zinc-Ion Batteries

Aqueous zinc-ion batteries are a kind of attractive power supply devices due to their high energy, environmental benignity, and intrinsic safety. In recent years, tremendous enthusiasm has been devoted to the functionalities of aqueous zinc-ion batteries, aiming to extend their potential applications in multiple dimensions and multiple scales. Here, the latest advances in the design, construction, and performance evaluation of aqueous zinc-ion batteries are summarized. The focus is on various functionalities such as flexibility, self-healing, self-charging, and miniaturization. We also highlight the materials and structures that have been engineered to realize these functionalities. Finally, we offer some general insights into the challenges and chances in such exciting field.

Effectiveness of Mindfulness Training in Enhancing Executive Function and Decreasing Symptoms of Depression and Anxiety in Patients with Multiple Sclerosis (MS)

The purpose of the present study was to evaluate the effectiveness of mindfulness training in enhancing executive function and decreasing symptoms of depression and anxiety in multiple sclerosis patients. The population in this study consisted of people with MS who referred to Karaj city MS society in 1394. These people didn’t experience medicinal changes during the study period and their expanded disability status score (EDSS) was between 0 and 5.5. 40 of them were randomly selected and placed into two experimental and control groups (20 for the experimental and the other for the control group). The treatment of mindfulness training was held in 8 sessions of group training, once a week and for 2 hours. The statistical method of multivariate analysis of covariance was used. The measurement tools were the State-Trait Anxiety Inventory (STAI), the Beck Depression Inventory-II (BDI-II) and the Wisconsin Card Sorting Test (WCST). After all, the results in both groups were compared and evaluated by the use of analysis of covariance. The results showed significant differences in symptoms of anxiety and depression between the two groups (p 0.05). Generally, the results of this research showed positive effects of mindfulness training on reducing anxiety and depression among patients with MS and ineffectiveness of mindfulness training on their executive function. Therefore, considering that there is no certain treatment for MS plus results of this study, the application of mindfulness training can be quite useful to reduce levels of anxiety and depression in patients with MS.

Exploring the Abnormal Brain Regions and Abnormal Functional Connections in SZ by Multiple Hypothesis Testing Technique

Schizophrenia(SZ)is one of the most common mental diseases.Its main characteristics are abnormal social behavior and inability to correctly understand real things.In recent years,the magnetic resonance imaging(MRI)technique has been popularly utilized to study SZ.However,it is still a great challenge to reveal the essential information contained in the MRI data.In this paper,we proposed a biomarker selection approach based on the multiple hypothesis testing techniques to explore the difference between SZ and healthy controls by using both functional and structural MRI data,in which biomarkers represent both abnormal brain functional connectivity and abnormal brain regions.By implementing the biomarker selection approach,six abnormal brain regions and twenty-three abnormal functional connectivity in the brains of SZ are explored.It is discovered that compared with healthy controls,the significantly reduced gray matter volumes are mainly distributed in the limbic lobe and the basal ganglia,and the significantly increased gray matter volumes are distributed in the frontal gyrus.Meanwhile,it is revealed that the significantly strengthened connections are those between the middle frontal gyrus and the superior occipital gyrus,the superior occipital gyrus and the middle occipital gyrus as well as the middle occipital gyrus and the fusiform gyrus,and the rest connections are significantly weakened.

Multiple Scattering Between Adjacent Sound Sources in Head-Related Transfer Function Measurement System

To accelerate head-related transfer functions(HRTFs)measurement,two or more independent sound sources are usually employed in the measurement system.However,the multiple scattering between adjacent sound sources may influence the accuracy of measurement.On the other hand,the directivity of sound source could induce measurement error.Therefore,a model consisting of two spherical sound sources with approximate omni-directivity and a rigid-spherical head is proposed to evaluate the errors in HRTF measurement caused by multiple scattering between sources.An example of analysis using multipole re-expansion indicates that the error of ipsilateral HRTFs are within the bound of±1.0 dB below a frequency of 20 kHz,provided that the sound source radius does not exceed 0.025 m,the source distance relative to head center is not less than 0.5 m,and the angular interval between two adjacent sources is not less than 20 degrees.Similar conclusions under different conditions can also be analyzed and discussed by using this calculation method.Furthermore,the results are verified by measurements of HRTFs for a rigid sphere and a KEMAR artificial head.

Basic solutions of multiple parallel symmetric mode-III cracks in functionally graded piezoelectric/piezomagnetic material plane

The Schmidt method is adopted to investigate the fracture problem of multiple parallel symmetric and permeable finite length mode-III cracks in a functionally graded piezoelectric/piezomagnetic material plane. This problem is formulated into dual integral equations, in which the unknown variables are the displacement jumps across the crack surfaces. In order to obtain the dual integral equations, the displacement jumps across the crack surfaces are directly expanded as a series of Jacobi polynomials. The results show that the stress, the electric displacement, and the magnetic flux intensity factors of cracks depend on the crack length, the functionally graded parameter, and the distance among the multiple parallel cracks. The crack shielding efect is also obviously presented in a functionally graded piezoelectric/piezomagnetic material plane with multiple parallel symmetric mode-III cracks.

MULTIPLICATION OF WEAK FUNCTIONS

This paper is a contionuation of [1] and is concerned with multiplication of weak functions. Here the weak functions are treated as generalized expansions in Hermite functions in [2].