Validation of SV2A-Targeted PET Imaging for Noninvasive Assessment of Neuroendocrine Differentiation in Prostate Cancer

Neuroendocrine prostate cancer (NEPC) is an aggressive and lethal variant of prostate cancer (PCa), and it remains a diagnostic challenge. Herein we report our findings of using synaptic vesicle glycoprotein 2 isoform A (SV2A) as a promising marker for positron emission tomography (PET) imaging of neuroendocrine differentiation (NED). The bioinformatic analyses revealed an amplified SV2A gene expression in clinical samples of NEPC versus castration-resistant PCa with adenocarcinoma characteristics (CRPC-Adeno). Importantly, significantly upregulated SV2A protein levels were found in both NEPC cell lines and tumor tissues. PET imaging studies were carried out in NEPC xenograft models with ¹⁸F-SynVesT-1. Although ¹⁸F-SynVesT-1 is not a cancer imaging agent, it showed a significant uptake level in the SV2A⁺ tumor (NCI-H660: 0.70 ± 0.14 %ID/g at 50–60 min p.i.). The SV2A blockade resulted in a significant reduction of tumor uptake (0.25 ± 0.03 %ID/g, p = 0.025), indicating the desired SV2A imaging specificity. Moreover, the comparative PET imaging study showed that the DU145 tumors could be clearly visualized by ¹⁸F-SynVesT-1 but not ⁶⁸Ga-PSMA-11 nor ⁶⁸Ga-DOTATATE, further validating the role of SV2A-targeted imaging for noninvasive assessment of NED in PCa. In conclusion, we demonstrated that SV2A, highly expressed in NEPC, can serve as a promising target for noninvasive imaging evaluation of NED.     

Development of Phosphodiesterase–Protein-Kinase Complexes as Novel Targets for Discovery of Inhibitors with Enhanced Specificity

Phosphodiesterases (PDEs) hydrolyze cyclic nucleotides to modulate multiple signaling events in cells. PDEs are recognized to actively associate with cyclic nucleotide receptors (protein kinases, PKs) in larger macromolecular assemblies referred to as signalosomes. Complexation of PDEs with PKs generates an expanded active site that enhances PDE activity. This facilitates signalosome-associated PDEs to preferentially catalyze active hydrolysis of cyclic nucleotides bound to PKs and aid in signal termination. PDEs are important drug targets, and current strategies for inhibitor discovery are based entirely on targeting conserved PDE catalytic domains. This often results in inhibitors with cross-reactivity amongst closely related PDEs and attendant unwanted side effects. Here, our approach targeted PDE–PK complexes as they would occur in signalosomes, thereby offering greater specificity. Our developed fluorescence polarization assay was adapted to identify inhibitors that block cyclic nucleotide pockets in PDE–PK complexes in one mode and disrupt protein-protein interactions between PDEs and PKs in a second mode. We tested this approach with three different systems—cAMP-specific PDE8–PKAR, cGMP-specific PDE5–PKG, and dual-specificity RegA–R_D complexes—and ranked inhibitors according to their inhibition potency. Targeting PDE–PK complexes offers biochemical tools for describing the exquisite specificity of cyclic nucleotide signaling networks in cells.     

Constitutive Photomorphogenic 1 Enhances ER Stress Tolerance in Arabidopsis

Interaction between light signaling and stress response has been recently reported in plants. Here, we investigated the role of CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), a key regulator of light signaling, in endoplasmic reticulum (ER) stress response in Arabidopsis. The cop1-4 mutant Arabidopsis plants were highly sensitive to ER stress induced by treatment with tunicarmycin (Tm). Interestingly, the abundance of nuclear-localized COP1 increased under ER stress conditions. Complementation of cop1-4 mutant plants with the wild-type or variant types of COP1 revealed that the nuclear localization and dimerization of COP1 are essential for its function in plant ER stress response. Moreover, the protein amount of ELONGATED HYPOCOTYL 5 (HY5), which inhibits bZIP28 to activate the unfolded protein response (UPR), decreased under ER stress conditions in a COP1-dependent manner. Accordingly, the binding of bZIP28 to the BIP3 promoter was reduced in cop1-4 plants and increased in hy5 plants compared with the wild type. Furthermore, introduction of the hy5 mutant locus into the cop1-4 mutant background rescued its ER stress-sensitive phenotype. Altogether, our results suggest that COP1, a negative regulator of light signaling, positively controls ER stress response by partially degrading HY5 in the nucleus.     

Studies on the growth and stability of silver nanoparticles synthesized by electron beam irradiation

Stable Ag nanoparticles have been synthesized by irradiating an aqueous solution of AgNO₃ and Poly-vinyl alcohol (PVA) with 8 MeV electrons from a Microtron. The rate of formation of nanoparticles could be controlled by changing either the irradiation dosage or the relative concentration of the precursors. The size, shape, and the rate of formation of the nanoparticles depend on the final dosage, as well as the weight ratio of AgNO₃ and PVA. The formation of Ag nanoparticles and their size were established through UV–Vis spectroscopy and Transmission electron microscopy (TEM) analysis, respectively. Increasing the irradiation dosage seem to favour the formation of polygonal nanostructures. Differential scanning calorimetry (DSC) measurements show that there exists a strong interaction between the PVA matrix and the Ag nanoparticles.     

Triplex formation at physiological pH by oligonucleotides incorporating 5-Me-dC-(N4-spermine)

Oligonucleotide (ODN) directed triplex formation has therapeutic importance and depends on Hoogsteen hydrogen bonds between a duplex DNA and a third strand. While T*A:T triplets are formed at neutral pH, C+*G:C are favoured at acidic pH. Herein it is shown that 18-mer ODN containing spermine conjugated to 5-Me-dC at N4 (1-5), form triplexes with complementary 24-mer duplex 8:9 at neutral pH (7.3, 100 mM NaCl). Under such conditions, control ODN's carrying dC (6) or 5-Me-dC (7) did not show any triple helix formation. Remarkably, the triplexes from spermine-conjugates (1-5) have foremost stability at neutral pH (7.1), unlike the behavior of normal ODN's where optimal stability is at acidic pH (5.5). These results have importance in designing oligonucleotides for antigene applications.     

Contribution of plasminogen activators and their inhibitors to the survival prognosis of patients with Dukes' stage B and C colorectal cancer

Despite the advances in pre-, peri- and post-operative medical care of colorectal carcinoma patients, the prognosis has improved only marginally over recent decades. Thus, additional prognostic indicators would be of great clinical value to select patients for adjuvant therapy. In previous studies we found that colorectal carcinomas have a marked increase of the urokinase-type of plasminogen activator (u-PA), and the inhibitors PAI-1 and PAI-2, whereas the tissue-type plasminogen activator (t-PA) is found to be decreased in comparison with adjacent normal mucosa. In the present study we evaluated the prognostic value of several plasminogen activation parameters, determined in both normal and carcinomatous tissue from colorectal resection specimens, for overall survival of 136 Dukes' stage B and C colorectal cancer patients, in relation to major clinicopathological parameters. Uni- and multivariate analyses indicated that a high PAI-2 antigen level in carcinoma, a low t-PA activity and antigen level and a high u-PA/t-PA antigen ratio in adjacent normal mucosa are significantly associated with a poor overall survival. A high ratio of u-PA antigen in the carcinomas and t-PA antigen in normal mucosa, i.e. u-PA(C)/t-PA(N), was found to be predictive of a poor overall survival as well. All these parameters were found to be prognostically independent of the clinicopathological parameters. Multivariate analysis of combinations of these prognostically significant plasminogen activation parameters revealed that they are important independent prognostic indicators and have in fact a better prognostic value than their separate components. Based on these combined parameters, subgroups of patients with Dukes' stage B and C colorectal cancer could be identified as having either a high or a low risk regarding overall survival. In conclusion, these findings emphasize the relevance of the intestinal plasminogen activation system for survival prognosis of patients with colorectal cancer and, in the future, might constitute a patient selection criterion for adjuvant therapy.     

Predicting the tensile behaviour of adhesively bonded sheets using equivalent geometrical heterogeneities

In the present work, the formability of adhesively bonded sandwichsteel sheets is predicted during tensile tests, with the help of equivalent geometrical heterogeneities in the base sheets, without incorporating adhesive layer and properties during modelling simulations. This will help us mainly to overcome the difficulties while incorporating adhesion/adhesive properties during formability simulation and prediction. The limit strains during the tensile test are predicted and validated with experiments. The effect of hardener to resin (H/R) ratios of adhesive on the forming limit strains has been predicted with a set of thickness heterogeneity factor ‘f’ and size (w) of the defect, located in the base material. In other words, a relationship between defect morphology (f, w) and adhesive properties has been evaluated. For example, in the case of rectangular-infinite groove of width, w?=?0.5 mm, the limit strains of DDQ steel evaluated during tensile tests at f?=?0.912, f?=?0.9137, f?=?0.924, f?=?0.927, and f?=?0.95 are equivalent to the H/R ratios of 0.6:1, 0.7:1, 0.8:1, 0.9:1, and 1:1 of adhesive, respectively. The limit strains are predicted in the same manner with a square hole and finite square defect in the base material. It is suggested that the overall forming (tensile) behaviour of adhesively bonded blanks (ABB) can be predicted with the help of a thickness heterogeneity factor (or similar geometrical heterogeneities) that is equivalent to all the geometrical and structural heterogeneities in the whole bonded sheets.     

Data aggregation in wireless sensor network using SVM-based failure detection and loss recovery

Abstract

In wireless sensor network, data aggregation can cause increased transmission overhead, failures, data loss and security-related issues. Earlier works did not concentrate on both fault management and loss recovery issues. In order to overcome these drawbacks, in this paper, a reliable data aggregation scheme is proposed that uses support vector machine (SVM) for performing failure detection and loss recovery. Initially, a group head, selected based on node connectivity, splits the nodes into clusters based on their location information. In each cluster, the cluster member with maximum node connectivity is chosen as the cluster head. When the aggregator receives data from the source, it identifies node failures in the received data by classifying the faulty data using SVM. Furthermore, a reserve node-based fault recovery mechanism is developed to prevent data loss. Through simulations, we show that the proposed technique minimises the transmission overhead and increases reliability.     

Magnetic sensor-based simultaneous state and parameter estimation using a nonlinear observer

This paper presents an observer design technique for a newly developed non-intrusive position estimation system based on magnetic sensors. Typically, the magnetic field of an object as a function of position needs to be represented by a highly nonlinear measurement equation. Previous results on observer design for nonlinear systems have mostly assumed that the measurement equation is linear, even if the process dynamics are nonlinear. Hence, a new nonlinear observer design method for a Wiener system composed of a linear process model together with a nonlinear measurement equation is developed in this paper. First, the design of a two degree-of-freedom nonlinear observer is proposed that relies on a Lure system representation of the observer error dynamics. To improve the performance in the presence of parametric uncertainty in the measurement model, the nonlinear observer is augmented to estimate both the state and unknown parameters simultaneously. A rigorous nonlinear observability analysis is also presented to show that a dual sensor configuration is a sufficient and necessary condition for simultaneous state and parameter estimation. Finally, the developed observer design technique is applied to non-intrusive position estimation of the piston inside a pneumatic cylinder. Experimental results show that both position and unknown parameters can be reliably estimated in this application.     

Energy management for commercial servers

Servers: high-end, multiprocessor systems running commercial workloads, have typically included extensive cooling systems and resided in custom-built rooms for high-power delivery. Recently, as transistor density and demand for computing resources have rapidly increased, even these high-end systems face energy-use constraints. Commercial-server energy management now focuses on conserving power in the memory and microprocessor subsystems. Because their workloads are typically structured as multiple application programs, system-wide approaches are more applicable to multiprocessor environments in commercial servers than techniques that primarily apply to single-application environments, such as those based on compiler optimizations.