Direction specific error patterns during continuous tracking of the subjective visual vertical

The aim of this study was to characterize the error pattern of continuously tracking the perceived earth-vertical during roll rotations from upright to right or left ear-down and from right or left ear-down to upright. We compared the tracking responses of two paradigms, which either continuously activated the otoliths organs alone (constant velocity tilt) or both the otolith organs and the semicircular canals (constant acceleration tilt). The tracking responses of the subjective visual vertical showed characteristic differences depending on starting position and tilt direction relative to gravity. The error patterns in the constant-velocity and constant-acceleration tilt paradigm were reversed. Estimations during tracking, when otolith information was continuously changing, were more precise compared to estimations following fast tilts to fixed roll tilt positions. We conclude that the central processing underlying these perceptual tracking responses requires, besides the otolith input, information from the vertical semicircular canal

Neuronal Activity in the Human Subthalamic Nucleus Encodes Decision Conflict during Action Selection

The subthalamic nucleus (STN), which receives excitatory inputs from the cortex and has direct connections with the inhibitory pathways\ud of the basal ganglia, is well positioned to efficiently mediate action selection. Here, we use microelectrode recordings captured during\ud deep brain stimulation surgery as participants engage in a decision task to examine the role of the human STN in action selection. We\ud demonstrate that spiking activity in the STN increases when participants engage in a decision and that the level of spiking activity\ud increases with the degree of decision conflict. These data implicate the STN as an important mediator of action selection during decision\ud processes.\u

Gambogic acid potentiates gemcitabine induced anticancer activity in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the most frequent type of lung cancer accounting up to 80-85% of all lung cancer (LC) cases. Gemcitabine (Gem), a pyrimidine nucleoside antimetabolite, is widely used chemotherapy offering several months survival benefit in patients with NSCLC. The emergence of Gem resistance is a main clinical concern in cancer treatment and thus a continuous demand for development of new therapeutic strategies to improve its antitumor activity. Hence, we report an adjuvant therapeutic regimen based on natural compound, gambogic acid (GA) which has been shown to enhanced Gem induced inhibition of cancer cell growth, arrest cell cycle, and induce apoptosis by enhanced accumulation of Gem. The in vitro cell viability, clonogenicity, invasion, and migration assays demonstrated a significant higher therapeutic effect of Gem when it was combined with GA in A549 and H1299 cells. A better access of internalization of drug molecules achieved in rhodamine 123 assay when GA was used as adjuvant treatment. Further, GA and Gem combination significantly reduced tubular formation of HUVEC cells indicates lowering angiogenesis potential. Microarray and Western blot studies confirm that GA + Gem co-treatment strategy promotes cancer cell death by downregulating anti-apoptotic proteins, chemoresistance-associated proteins, and upregulation of apoptosis proteins. More importantly, a significant higher therapeutic benefit was noticed for GA and Gem combination in A549 xenograft mice model. Together, these results offer a rationale to evaluate the clinical translational possibility of GA as adjuvant therapy to overcome Gem resistance. This combination regimen can be a new therapeutic concept to eradicate this devastating disease

Hall Coefficient of Equilibrium Supercurrents Flowing inside Superconductors

We study augmented quasiclassical equations of superconductivity with the Lorentz force, which is missing from the standard Ginzburg-Landau and Eilenberger equations. It is shown that the magnetic Lorentz force on equilibrium supercurrents induces finite charge distribution and the resulting electric field to balance the Lorentz force. An analytic expression is obtained for the corresponding Hall coefficient of clean type-II superconductors with simultaneously incorporating the Fermi-surface and gap anisotropies. It has the same sign and magnitude at zero temperature as the normal state for an arbitrary pairing, having no temperature dependence specifically for the s-wave pairing. The gap anisotropy may bring a considerable temperature dependence in the Hall coefficient and can lead to its sign change as a function of temperature, as exemplified for a model d-wave pairing with a two-dimensional Fermi surface. The sign change may be observed in some high-$T_{c}$ superconductors.Comment: 7 pages, 3 figure

miRNA nanotherapeutics for cancer

miRNAs are noncoding RNA molecules that regulate gene expression through diverse mechanisms. Increasing evidence suggests that miRNA-based therapies, either restoring or repressing miRNA expression and activity, hold great promise. However, the efficient delivery of miRNAs to target tissues is a major challenge in the transition of miRNA therapy to the clinic. Cationic polymers or viral vectors are efficient delivery agents but their systemic toxicity and immunogenicity limit their clinical usage. Efficient targeting and sustained release of miRNAs/ anti-miRNAs using nanoparticles (NPs) conjugated with antibodies and/or peptides could reduce the required therapeutic dosage while minimizing systemic and cellular toxicity. Given their importance in clinical oncology, here we focus on the development of miRNA nanoformulations to achieve enhanced cellular uptake, bioavailability, and accumulation at the tumor site

Magnetic Nanoformulations for Prostate Cancer

Magnetic nanoparticles (MNPs) play a vital role for improved imaging applications. Recently, a number of studies demonstrate MNPs can be applied for targeted delivery, sustained release of therapeutics, and hyperthermia. Based on stable particle size and shape, biocompatibility, and inherent contrast enhancement characteristics, MNPs have been encouraged for pre-clinical studies and human use. As a theranostic platform development, MNPs need to balance both delivery and imaging aspects. Thus, this review provides significant insight and advances in the theranostic role of MNPs through the documentation of unique magnetic nanoparticles used in prostate cancer, their interaction with prostate cancer cells, in vivo fate, targeting, and biodistribution. Specific and custom-made applications of various novel nanoformulations in prostate cancer are discussed

Optical detection of structural properties of tumor tissues generated by xenografting of drug-sensitive and drug-resistant cancer cells using partial wave spectroscopy (PWS)

The quantitative measurement of structural alterations at the nanoscale level is important for understanding the physical state of biological samples. Studies have shown that the progression of cancer is associated with the rearrangements of building blocks of cells/tissues such as DNA, RNA, lipids, etc. Partial wave spectroscopy is a recently developed mesoscopic physics-based spectroscopic imaging technique which can detect such nanoscale changes in cells/tissues. At present, chemotherapy drug treatment is the only effective form of treatment; however, the development of drug-resistant cancer cells is a major challenge for this treatment. Earlier PWS analyses of prostate cancer cells, a 2D structure, have shown that drug-resistant cancer cells have a higher degree of structural disorder compared to drug-sensitive cancer cells. At the same time, structural properties of the metastasize tumor grown to 3D structure from drug-resistant and drug-sensitive cancer cells within the body is not well studied. In this paper, the structural properties of tissues from grown 3D tumors, generated from docetaxel drug-sensitive and drug-resistant prostate cancer cells xenografted into a mouse model, are studied. The results show that xenografted tumor tissues from drug-resistant cells have higher disorder strength than the tumor generated from drug-sensitive prostate cancer cells. Potential applications of the technique to assess chemotherapy effectiveness in cancer treatment are discussed.Comment: 5 figures, 13 page

Novel Paclitaxel Nanoformulation Impairs De Novo Lipid Synthesis in Pancreatic Cancer Cells and Enhances Gemcitabine Efficacy

Pancreatic cancer (PanCa) is a highly lethal disease with a poor 5 year survival rate, less than 7%. It has a dismal prognosis, and more than 50% of cases are detected at an advanced and metastatic stage. Gemcitabine (GEM) is a gold standard chemotherapy used for PanCa treatment. However, GEM-acquired resistance in cancer cells is considered as a major setback for its continued clinical implementation. This phenomenon is evidently linked to de novo lipid synthesis. PanCa cells rely on de novo lipid synthesis, which is a prime event in survival and one of the key drivers for tumorigenesis, cancer progression, and drug resistance. Thus, the depletion of lipogenesis or lipid metabolism can not only improve treatment outcomes but also overcome chemoresistance, which is an unmet clinical need. Toward this effort, our study reports a unique paclitaxel−poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PPNPs) formulation which can target lipid metabolism and improve anticancer efficacy of GEM in PanCa cells. PPNPs inhibit excessive lipid formation and alter membrane stability with compromised membrane integrity, which was confirmed by Fourier transform infrared and zeta potential measurements. The effective interference of PPNPs in lipid metabolic signaling was determined by reduction in the expression of FASN, ACC, lipin, and Cox-2 proteins. This molecular action profoundly enhances efficacy of GEM as evident through enhanced inhibitory effects on the tumorigenic and metastasis assays in PanCa cells. These data clearly suggest that the ablation of lipid metabolism might offer an innovative approach for the improved therapeutic outcome in PanCa patients

Development of polyvinylpyrrolidone/paclitaxel self-assemblies for breast cancer

The goal of this investigation was to develop and demonstrate a polymer/paclitaxel self-assembly (PTX-SA) formulation. Polymer/PTX-SAs were screened based on smaller size of formulation using dynamic light scattering analysis. Additionally, fluorescence microscopy and flow cytometry studies exhibited that polyvinylpyrrolidone (PVP)-based PTX-SAs (PVP/PTX-SAs) had superior cellular internalization capability in MCF7 and MDA-MB-231 breast cancer cells. The optimized PVP/PTX-SAs exhibited less toxicity to human red blood cells indicating a suitable formulation for reducing systemic toxicity. The formation of PVP and PTX self-assemblies was confirmed using fluorescence quenching and transmission electron microscopy which indicated that the PVP/PTX-SAs were spherical in shape with an average size range of 53.81 nm as detected by transmission electron microscopy (TEM). FTIR spectral analysis demonstrates incorporation of polymer and paclitaxel functional groups in PVP/PTX-SAs. Both proliferation (MTS) and clonogenic (colony formation) assays were used to validate superior anticancer activity of PVP/PTX-SAs in breast cancer cells over paclitaxel. Such superior anticancer activity was also demonstrated by downregulation of the expression of pro-survival protein (Bcl-xL), upregulation of apoptosis-associated proteins (Bid, Bax, cleaved caspase 7, and cleaved PARP) and β-tubulin stabilization. These results support the hypothesis that PVP/PTX-SAs improved paclitaxel delivery to cancer cells

Pharmacological restoration of PKD1: A novel strategy for prostate cancer therapy

Background: Prostate cancer has poor prognosis owing to late diagnosis and ineffective multimodal clinical treatment. Extensive efforts are ongoing to establish methods that can resolve the expression of genes implicated in disease development and treatment. Previously, we reported that Protein Kinase D1 (PKD1), a serine threonine kinase, controls a number of tumor suppressor functions including cell aggregation, cell motility, cell proliferation, and cell invasion. Thus, PKD1 is considered as an emerging therapeutic target for prostate cancer treatment. Objective: To investigate the restoration of PKD1 by a pharmacological modulator ormeloxifene, which showed well-defined PK/PD and safety profiles in humans. Methods: Proliferation, clonogenicity, migration, invasion, western blotting and qPCR analysis were performed to investigate the anticancer effect of ORM, docetaxel and/or their combination on PKD1 and related signaling mechanisms in prostate cancer. Results: ORM treatment inhibited cell proliferation, invasion, migration and colony formation abilities of prostate cancer cells in a dose-dependent manner compared to vehicle treated group. ORM treatment selectively induces the expression of PKD1 both at mRNA and protein levels in C4-2 cells. Moreover, our results have also shown that ORM effectively attenuates MTA1 expression in prostate cancer cells. MTA1 physically interact and shown to have inverse relationship with PKD1. In addition, we observed that ORM treatment enhances the therapeutic efficacy of docetaxel in C4-2 cells. Our results also indicate that ORM treatment potentiate the effects of docetaxel as determined by MTS and colony formation assays. Conclusion: These results suggest that ORM exhibit potent anticancer activity via restoration of PKD1 in prostate cancer