B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches.

Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM

IFN-γ, IL-17 and TGF-β involvement in shaping the tumor microenvironment: The significance of modulating such cytokines in treating malignant solid tumors

Multiple innate and adaptive immune effector cells and molecules partake in the recognition and destruction of cancer cells to protect against growing tumors, a concept that is known as cancer immunosurveillance. Unfortunately, cancer cells are capable of avoiding this process by immunoselection of poorly immunogenic tumor cells variants along with subversion of the immune system and thus shaping both the tumor and its microenvironment. Cytokines represent part of the complex pattern of the immune response which can assist the development of cancer as well as to eliminate it. Simultaneously, a large number of cytokines may be involved in the complex interactions between host and tumor cells where this dynamic cross-talk, between tumors and the immune system, can either regulate tumor growth or tumor growth, invasion and metastasis take place. In this review, we are stressing on the interface between infiltrated immune cells and tumor cells with the emphasis on the bidirectional activities of specific cytokines: IFN-γ, TGF-β and IL-17 within the tumor microenvironment and their role in shaping it. In addition, the significance of modulating such cytokines in favor of anti-tumor response is discussed and merits the use of mixture of targeted modulators to overcome the network complexity of cytokines in the tumor microenvironment

Spectral Efficiency Improvements in HetNets by Exploiting Device-to-Device Communications

Next generation cellular networks require huge capacity, ubiquitous coverage and maximum energy efficiency. In order to meet these targets, Device-to-device (D2D) communication is being considered for future heterogeneous networks (HetNets). In this paper, we consider a three tier hierarchical HetNet by exploiting D2D communication in traditional HetNet. D2D communication is deployed within the HetNet where closely located mobile users are engaged in direct communication without routing the traffic through cellular access network. The proposed configuration mandates to reduce the interference offered by the resultant HetNet by reducing the transmitter-receiver distance and ensuring that the mobile users are transmitting with adaptive power subject to maintaining their desired link quality. In this context, we analyzed and compared the spectral efficiency improvements in hierarchical HetNet against traditional HetNet. Simulation results show that D2D communication offers much higher spectral efficiency as compared to traditional HetNet

Properties of Hardened Concrete Containing CBA Ash and FCS as Partial Sand Replacement

A large amount of coal bottom ash (CBA) is being discharged from thermal power plants and has been making serious environmental pollution. Meanwhile, fine coconut shell (FCS) is an agricultural waste and is available in plentiful quantities throughout tropical countries worldwide. In many countries, coconut shell is subjected to open burning which contributes significantly to CO2 and methane emissions. Both of these materials are essential to utilize the CBA and FCS to reduce environmental pollution. Therefore, this study aims to determine the properties of combination of these materials as partial sand replacement. CBA is slow in pozzolanic activity of coal bottom ash which is suitable for partial replacement sand. Meanwhile, FCS is lightweight material with high density in porous filler.  Concrete designed for 30 MPa strength at 28 days curing age and 0.50 of water-cement ratio in this study. The percentage of CBA used is 5%, 10%, 15% and 20%, while the percentage of FCS is 2%, 4%, 6% and 8% where it has been replaced by volume replacement. The specimens were cured in water for 7, 28, 56 and 90 days curing ages before compressive and splitting tensile strength test are conducted. It can be concluded that the density of the concrete decreased, compressive and splitting tensile strength show the improvement with the utilization of CBA and FCS in concrete. In addition, the percentage of water absorption increased as both of CBA and FCS absorb the water. This study shows that an optimum percentage of CBA found is 10% and FCS is 6% for this study

Iterative Residual Fitting for Spherical Harmonic Transform of Band-Limited Signals on the Sphere: Generalization and Analysis

We present the generalized iterative residual fitting (IRF) for the computation of the spherical harmonic transform (SHT) of band-limited signals on the sphere. The proposed method is based on the partitioning of the subspace of band-limited signals into orthogonal subspaces. There exist sampling schemes on the sphere which support accurate computation of SHT. However, there are applications where samples~(or measurements) are not taken over the predefined grid due to nature of the signal and/or acquisition set-up. To support such applications, the proposed IRF method enables accurate computation of SHTs of signals with randomly distributed sufficient number of samples. In order to improve the accuracy of the computation of the SHT, we also present the so-called multi-pass IRF which adds multiple iterative passes to the IRF. We analyse the multi-pass IRF for different sampling schemes and for different size partitions. Furthermore, we conduct numerical experiments to illustrate that the multi-pass IRF allows sufficiently accurate computation of SHTs

Optimal-Dimensionality Sampling on the Sphere: Improvements and Variations

For the accurate representation and reconstruction of band-limited signals on the sphere, an optimal-dimensionality sampling scheme has been recently proposed which requires the optimal number of samples equal to the number of degrees of freedom of the signal in the spectral (harmonic) domain. The computation of the spherical harmonic transform (SHT) associated with the optimal-dimensionality sampling requires the inversion of a series of linear systems in an iterative manner. The stability of the inversion depends on the placement of iso-latitude rings of samples along co-latitude. In this work, we have developed a method to place these iso-latitude rings of samples with the objective of improving the well-conditioning of the linear systems involved in the computation of the SHT. We also propose a multi-pass SHT algorithm to iteratively improve the accuracy of the SHT of band-limited signals. Furthermore, we review the changes in the computational complexity and improvement in accuracy of the SHT with the embedding of the proposed methods. Through numerical experiments, we illustrate that the proposed variations and improvements in the SHT algorithm corresponding to the optimal-dimensionality sampling scheme significantly enhance the accuracy of the SHT

Performance improvement of fractional N-PLL synthesizers for digital communication applications

Loop filter with two order was designed to improve the performance of the fractional N-phase locked loop (PLL) circuit (reference spurs noise and switching time), decreasing these two factors give good characteristic to fractional N-PLL circuit, the second order and third order loop filters are widely used in frequency synthesizer because they give good stability tolerance and for their simple architecture. They are designed at bandwidth B=125 KHz and its multipoles, at two values of the phase margin (pm)= 35°, 57°. MATLAB program was used to find the lock time, the component values for each element in the loop filter, also the filter impedance T(s), the bode plot of frequency response for close loop (CL) and open loop gain (OL). It is found by comparing the result of the frequency response for the 2nd order loop filter and 3rd order loop filter, that increasing the order of the filter will reduce the spurs noise that destroy the received signal at receiving side