Enapotamab Vedotin,an AXL-Specific Antibody-Drug Conjugate,Demonstrates Antitumor Efficacy in Patient-Derived Xenograft Models of Soft Tissue Sarcoma

Doxorubicin (doxo) remains the standard of care for patients with advanced soft tissue sarcoma (STS), even though response rates to doxo are only around 14% to 18%. We evaluated enapotamab vedotin (EnaV), an AXL-specific antibody-drug conjugate (ADC), in a panel of STS patient-derived xenografts (PDX). Eight models representing multiple STS subtypes were selected from our STS PDX platform (n = 45) by AXL immunostaining on archived passages. Models were expanded by unilateral transplantation of tumor tissue into the left flank of 20 NMRI nu/nu mice. Once tumors were established, mice were randomized into an EnaV treatment group, or a group treated with isotype control ADC. Treatment efficacy was assessed by tumor volume evaluation, survival analysis, and histological evaluation of tumors, and associated with AXL expression. EnaV demonstrated significant tumor growth delay, regression, and/or prolonged survival compared to isotype control ADC in 5/8 STS PDX models investigated. Experimental passages of responding models were all found positive for AXL at varying levels, but no linear relationship could be identified between the level of expression and level of response to EnaV. One model was found negative for AXL on experimental passage and did not respond to EnaV. This study provides a preclinical rationale for the evaluation of AXL-targeting ADCs in the treatment of AXL-expressing sarcomas.     

Nutritional Calcium Supply Dependent Calcium Balance,Bone Calcification and Calcium Isotope Ratios in Rats

Serum calcium isotopes (δ^44/42Ca) have been suggested as a non-invasive and sensitive Ca balance marker. Quantitative δ^44/42Ca changes associated with Ca flux across body compartment barriers relative to the dietary Ca and the correlation of δ^44/42Ca_Serum with bone histology are unknown. We analyzed Ca and δ^44/42Ca by mass-spectrometry in rats after two weeks of standard-Ca-diet (0.5%) and after four subsequent weeks of standard- and of low-Ca-diet (0.25%). In animals on a low-Ca-diet net Ca gain was 61 ± 3% and femur Ca content 68 ± 41% of standard-Ca-diet, bone mineralized area per section area was 68 ± 15% compared to standard-Ca-diet. δ^44/42Ca was similar in the diets, and decreased in feces and urine and increased in serum in animals on low-Ca-diet. δ^44/42Ca_Bone was higher in animals on low-Ca-diet, lower in the diaphysis than the metaphysis and epiphysis, and unaffected by gender. Independent of diet, δ^44/42Ca_Bone was similar in the femora and ribs. At the time of sacrifice, δ^44/42Ca_Serum inversely correlated with intestinal Ca uptake and histological bone mineralization markers, but not with Ca content and bone mineral density by µCT. In conclusion, δ^44/42Ca_Bone was bone site specific, but mechanical stress and gender independent. Low-Ca-diet induced marked changes in feces, serum and urine δ^44/42Ca in growing rats. δ^44/42Ca_Serum inversely correlated with markers of bone mineralization.     

DOT1L Methyltransferase Regulates Calcium Influx in Erythroid Progenitor Cells in Response to Erythropoietin

Erythropoietin (EPO) signaling plays a vital role in erythropoiesis by regulating proliferation and lineage-specific differentiation of murine hematopoietic progenitor cells (HPCs). An important downstream response of EPO signaling is calcium (Ca²⁺) influx, which is regulated by transient receptor potential channel (TRPC) proteins, particularly TRPC2 and TRPC6. While EPO induces Ca²⁺ influx through TRPC2, TRPC6 inhibits the function of TRPC2. Thus, interactions between TRPC2 and TRPC6 regulate the rate of Ca²⁺ influx in EPO-induced erythropoiesis. In this study, we observed that the expression of TRPC6 in KIT-positive erythroid progenitor cells was regulated by DOT1L. DOT1L is a methyltransferase that plays an important role in many biological processes during embryonic development including early erythropoiesis. We previously reported that Dot1l knockout (Dot1l^KO) HPCs in the yolk sac failed to develop properly, which resulted in lethal anemia. In this study, we detected a marked downregulation of Trpc6 gene expression in Dot1l^KO progenitor cells in the yolk sac compared to the wild type (WT). The promoter and the proximal regions of the Trpc6 gene locus exhibited an enrichment of H3K79 methylation, which is mediated solely by DOT1L. However, the expression of Trpc2, the positive regulator of Ca²⁺ influx, remained unchanged, resulting in an increased TRPC2/TRPC6 ratio. As the loss of DOT1L decreased TRPC6, which inhibited Ca²⁺ influx by TRPC2, Dot1l^KO HPCs in the yolk sac exhibited accelerated and sustained elevated levels of Ca²⁺ influx. Such heightened Ca²⁺ levels might have detrimental effects on the growth and proliferation of HPCs in response to EPO.     

On the reliability of electrostatic NEMS/MEMS devices: Review of present knowledge on the dielectric charging and stiction failure mechanisms and novel characterization methodologies

This paper reviews the state of the art knowledge related to critical failure mechanisms in electrostatic micro- and nano-electromechanical systems (MEMS and NEMS) which are the dielectric charging and stiction. It describes also the recent employed nanoscale characterization techniques for these phenomena based on Kelvin probe force microscopy (KPFM) and force–distance curve measurements. The influence of relative humidity and dielectric deposition conditions on the charging/discharging processes is discussed. Moreover, different stiction mechanisms induced by electrostatic force and/or meniscus formation are analyzed. Finally, novel characterization methods are presented and used to correlate between the results from MEMS devices and metal–insulator–metal (MIM) capacitors. These methods are employed in view of application in electrostatic capacitive MEMS switches and could be easily extended to explore other NEMS/MEMS devices. The study provides an accurate understanding of the charging and stiction related failure mechanisms, presents guidelines for a proper packaging environment, and reveals precise explanations for the literature reported device level measurements of electrostatic MEMS devices.     

Variational density matrix optimization using semidefinite programming

We discuss how semidefinite programming can be used to determine the second-order density matrix directly through a variational optimization. We show how the problem of characterizing a physical or N-representable density matrix leads to matrix-positivity constraints on the density matrix. We then formulate this in a standard semidefinite programming form, after which two interior point methods are discussed to solve the SDP. As an example we show the results of an application of the method on the isoelectronic series of Beryllium.     

复合材料为模具制造商创造机遇

在这个高科技操作运行的时代,先进的金属加工技术将能满足复合材料的生产需要。航宇工业和国防工业的业务正在迅猛发展,以及重塑军事能力在武器系统的发展,这为飞机制造业开创了有利局面。对这两个行业起着重要发展作用的一项技术就是复合材料,这一般是指碳纤维材料或玻璃纤维热固性和热塑性多材料层压板。这     

A dynamical model for generating synthetic electrocardiogram signals

A dynamical model based on three coupled ordinary differential equations is introduced which is capable of generating realistic synthetic electrocardiogram (ECG) signals. The operator can specify the mean and standard deviation of the heart rate, the morphology of the PQRST cycle, and the power spectrum of the RR tachogram. In particular, both respiratory sinus arrhythmia at the high frequencies (HFs) and Mayer waves at the low frequencies (LFs) together with the LF/HF ratio are incorporated in the model. Much of the beat-to-beat variation in morphology and timing of the human ECG, including QT dispersion and R-peak amplitude modulation are shown to result. This model may be employed to assess biomedical signal processing techniques which are used to compute clinical statistics from the ECG.     

Hardware Implementation of a Fixed-Point Decoder for Low-Density Lattice Codes

Journal of Signal Processing Systems - This paper describes a field-programmable gate array (FPGA) implementation of a fixed-point low-density lattice code (LDLC) decoder where the Gaussian mixture...     

Modeling and Simulation for Transient Thermal Analyses Using a Voltage-in-Current Latency Insertion Method

This article presents a modeling and simulation method for transient thermal analyses of integrated circuits(ICs) using the original and voltage-in-current(VinC) latency insertion method(LIM). LIM-based algorithms are a set of fast transient simulation methods that solve electrical circuits in a leapfrog updating manner without relying on large matrix operations used in conventional Simulation Program with Integrated Circuit Emphasis(SPICE)-based methods which can significantly slow down the sol...     

A comparison of MOSFETs aging under d.c., a.c. and alternating stress conditions

The effects of static, alternating and dynamic stress conditions on the degradation rate of 0.8μm n- and p-channel LDD MOS transistors have systematically been investigated and compared. The shifts of the threshold voltage, transconductance, linear drain current and charge pumping current were used to monitor the transistor degradation. The results suggest that the aging induced by a dynamic stress cannot be directly explained with static stress models, essentially because it is highly dependent on a larger number of parameters (biases and durations of the top and bottom levels of the pulses, transient times). The correlation of static and dynamic stresses also clarifies the degradation mechanisms, in particular the role of hot holes in the generation of interface states.