Targeting the gp130/STAT3 Axis Attenuates Tumor Microenvironment Mediated Chemoresistance in Group 3 Medulloblastoma Cells.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Of the four molecular subgroups, Group 3 MB is the most aggressive and has the worst prognosis. To understand the origins of chemoresistance involving IL-6/STAT3 signaling, we used in vitro co-culture systems to investigate the contribution of microglia as a brain tumor microenvironment cellular source of paracrine cytokines that promotes acquired drug resistance in Group 3 MB.

HIV-1 Vpu Promotes Phagocytosis of Infected CD4 T Cells by Macrophages through Downregulation of CD47.

Human immunodeficiency virus (HIV) remodels the cell surface of infected cells to facilitate viral dissemination and promote immune evasion. The membrane-associated viral protein U (Vpu) accessory protein encoded by HIV-1 plays a key role in this process by altering cell surface levels of multiple host proteins. Using an unbiased quantitative plasma membrane profiling approach, we previously identified CD47 as a putative host target downregulated by Vpu.

FAM13A as potential therapeutic target in modulating TGF-β-induced airway tissue remodeling in COPD.

Genome-wide association studies have shown that a gene variant in the Family with sequence similarity 13, member A (FAM13A) is strongly associated with reduced lung function and the appearance of respiratory symptoms in patients with chronic obstructive pulmonary disease (COPD). A key player in smoking-induced tissue injury and airway remodeling is the transforming growth factor-β1 (TGF-β1). To determine the role of FAM13A in TGF-β1 signaling, airway epithelial cells were generated using CRISPR-Cas9, whereas overexpression of FAM13A was achieved using lipid nanoparticles.

Autocrine IL-6/STAT3 signaling aids development of acquired drug resistance in Group 3 medulloblastoma.

Medulloblastoma (MB) is a high-grade pediatric brain malignancy that originates from neuronal precursors located in the posterior cranial fossa. In this study, we evaluated the role of STAT3 and IL-6 in a tumor microenvironment mediated drug resistance in human MBs. We established that the Group 3 MB cell line, Med8A, is chemosensitive (hence Med8A-S), and this is correlated with a basal low phosphorylated state of STAT3, while treatment with IL-6 induced robust increases in pY705-STAT3.

CD47 (Cluster of differentiation 47): an anti-phagocytic receptor with a multitude of signaling functions.

CD47 is a tumor-associated antigen best known for its ability to bind counter-receptors on the surface of professional phagocytes as an immune-evasion strategy. ⁣Recently, CD47 has been shown to play a role as a signaling receptor, involving a number of cell physiological processes.⁣⁣ This review provides a comprehensive survey of the signaling pathways triggered by CD47 ligand-mediated cell death in tumor cells.

Integrins and ERp57 Coordinate to Regulate Cell Surface Calreticulin in Immunogenic Cell Death.

Therapy-induced presentation of cell surface calreticulin (CRT) is a pro-phagocytic immunogen beneficial for invoking anti-tumor immunity. Here, we characterized the roles of ERp57 and α-integrins as CRT-interacting proteins that coordinately regulate CRT translocation from the ER to the surface during immunogenic cell death. Using T-lymphoblasts as a genetic cell model, we found that drug-induced surface CRT is dependent on ERp57, while drug-induced surface ERp57 is independent of CRT.

Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions.

Cell-based therapy with CD4 FOXP3 regulatory T cells (Tregs) is a promising strategy to limit organ rejection and graft-vs-host disease. Ongoing clinical applications have yet to consider how human Tregs could be modified to direct their migration to specific inflammation sites and/or tissues for more targeted immunosuppression. We show here that stable, homing-receptor-tailored human Tregs can be generated from thymic Tregs isolated from pediatric thymus or adult blood.

CD47-ligation induced cell death in T-acute lymphoblastic leukemia.

CD47 is a cell-surface marker well recognized for its anti-phagocytic functions. As such, an emerging avenue for targeted cancer therapies involves neutralizing the anti-phagocytic function using monoclonal antibodies (mAbs) to enhance tumour cell immunogenicity. A lesser known consequence of CD47 receptor ligation is the direct induction of tumour cell death.

α-Integrin expression and function modulates presentation of cell surface calreticulin.

Calreticulin presentation on the cell surface is an important hallmark of immunogenic cell death (ICD), serving as the prophagocytic signal for macrophages. Cell adhesion is a physiologically relevant stimulus previously shown to increase calreticulin interaction with α-integrins via the juxtamembrane, cytosolic GFFKR motif. This study assessed whether integrin function can regulate surface calreticulin levels in ICD.

Direct evidence of anomalous interfacial magnetization in metamagnetic Pd doped FeRh thin films.

Palladium doped iron rhodium is a magnetic material of significant interest for it's close to room temperature magnetostructural phase transition from antiferromagnetic (AF) to ferromagnetic (FM) ordering. Here we report on the peculiarities of the magnetization distribution in thin films of FeRh(Pd) probed by Polarized Neutron Reflectometry. Remarkably, we've found thin interfacial regions with strong magnetization that have unique thermomagnetic properties as compared to the rest of the system.

Variability in a Community-Structured SIS Epidemiological Model.

We study an SIS epidemiological model of a population partitioned into groups referred to as communities, households, or patches. The system is studied using stochastic spatial simulations, as well as a system of ordinary differential equations describing moments of the distribution of infectious individuals. The ODE model explicitly includes the population size, as well as the variability in infection levels among communities and the variability among stochastic realizations of the process.

CD47-independent effects mediated by the TSP-derived 4N1K peptide.

4N1K is a peptide fragment derived from the C-terminal, globular domain of thrombospondin which has been shown to mediate integrin-dependent cell adhesion and promote integrin activation acting via the cell-surface receptor, CD47. However, some studies found that 4N1K could act independently of CD47, putting in question the specificity of 4N1K for CD47. This led us to characterize the cellular and non-cellular effects of 4N1K.

The membrane-proximal KXGFFKR motif of α-integrin mediates chemoresistance.

Cell adhesion-mediated drug resistance contributes to minimal residual disease and relapse in hematological malignancies. Here, we show that adhesion of Jurkat T-acute lymphoblastic leukemia cells to substrates engaging α4β1-integrin or α5β1-integrin promotes chemoresistance to doxorubicin-induced apoptosis. Reconstituted expression of α4δ, a truncated α4-integrin with KXGFFKR as the cytoplasmic motif, in α4-deficient cells promoted chemoresistance to doxorubicin in a manner independent of α4-mediated adhesion.

Altered cardiac bradykinin metabolism in experimental diabetes caused by the variations of angiotensin-converting enzyme and other peptidases.

The peptidases angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) mediate most of the kinin catabolism in normal cardiac tissue and are the molecular targets of inhibitory drugs that favorably influence diabetic complications. We studied the variations of those kininases in the myocardium of rats in experimental diabetes.

Magnetodielectric effect in Bi(2)NiMnO(6)-La(2)NiMnO(6) superlattices.

Multilayer superlattices consisting of multiferroic Bi(2)NiMnO(6) (BNMO) and La(2)NiMnO(6) (LNMO) have been grown heteroepitaxially on pure and Nb-doped SrTiO(3) substrates using the pulsed laser deposition technique. In a series of superlattice structures grown with a fixed BNMO layer thickness of ten unit cells, we find that the c-axis lattice parameter, Curie temperature and magnetocapacitance are strongly dependent upon the number of stacked LNMO unit cells in the repeating units. The thickness-dependent magnetodielectric effect is attributed to the fluctuations in electric and magnetic dipole ordering due to the substrate and interface induced stress in the superlattice structures.

Kondo effect in magnetic tunnel junctions.

Tunneling magnetoresistance was found to be suppressed with decreasing temperature for magnetic tunnel junctions (MTJs) oxidized under high plasma power. A strong temperature dependence of the junction resistance was observed, along with zero-bias anomalies of dynamic resistance at low temperatures. Resistance shows a logarithmic dependence on temperature, and resistance versus temperature exhibits a scaling behavior.

Carrier-controlled ferromagnetism in transparent oxide semiconductors.

The search for an ideal magnetic semiconductor with tunable ferromagnetic behaviour over a wide range of doping or by electrical gating is being actively pursued as a major step towards realizing spin electronics. A magnetic semiconductor having a high Curie temperature, capable of independently controlled carrier density and magnetic doping, is crucial for developing spin-based multifunctional devices. Cr-doped In(2)O(3) is such a unique system, where the electrical and magnetic behaviour-from ferromagnetic metal-like to ferromagnetic semiconducting to paramagnetic insulator-can be controllably tuned by the defect concentration.

Coexistence of ferromagnetism and superconductivity in Ni/Bi bilayers.

In spite of a lack of superconductivity in bulk crystalline Bi, thin film Bi deposited on thin Ni underlayers are strong-coupled superconductors below approximately 4 K. We unambiguously demonstrate that by tuning the Ni thickness the competition between ferromagnetism and superconductivity in the Ni/Bi can be tailored. For a narrow range of Ni thicknesses, the coexistence of both a superconducting energy gap and conduction electron spin polarization are visible within the Ni side of the Ni/Bi bilayers, independent of any particular theoretical model.

All-optical probe of coherent spin waves.

A novel, all-optical method to excite and detect spin waves in magnetic materials is presented. By exploiting the temperature dependence of the magnetic anisotropy, an ultrashort laser pulse is efficiently converted in a picosecond "anisotropy field" pulse that triggers a coherent precession of the magnetization. Recording the temporal evolution of the precessing spins by a time-delayed probe-pulse provides a quantitative method to study locally the magnetic anisotropy, as well as switching and damping phenomena in micromagnetic structures.

Band structure and density of States effects in co-based magnetic tunnel junctions.

Utilizing Co/Al(2)O(3)/Co magnetic tunnel junctions with Co electrodes of different crystalline phases, a clear relationship between electrode crystal structure and junction transport properties is presented. For junctions with one fcc(111) textured and one polycrystalline (polyphase and polydirectional) Co electrode, a strong asymmetry is observed in the magnetotransport properties, while when both electrodes are polycrystalline the magnetotransport is essentially symmetric. These observations are successfully explained within a model based on ballistic tunneling between the calculated band structures (density of states) of fcc-Co and hcp-Co.

Interfacial density of states in magnetic tunnel junctions.

Large zero-bias resistance anomalies as well as a collapse of magnetoresistance were observed in Co/Al2O3/Co magnetic tunnel junctions with thin Cr interfacial layers. The tunnel magnetoresistance decays exponentially with nominal Cr interlayer thickness with a length scale of approximately 1 A more than twice as fast as for Cu interlayers. The strong suppression of magnetoresistance, as well as the zero-bias anomalies, can be understood by considering a strong spin-dependent modification of the density of states at Co/Cr interfaces.

Apparent spin polarization decay in Cu-dusted Co/Al2O3/Co tunnel junctions.

Co/Al2O3/Co magnetic tunnel junctions with an interfacial Cu layer have been investigated with in situ growth characterization and ex situ magnetotransport measurements. Cu interlayers grown on Co give an approximately exponential decay of the tunneling magnetoresistance with xi approximately 0.26 nm while those grown on Al2O3 have a decay length of 0.

Iron reduction before and during interferon therapy of chronic hepatitis C: results of a multicenter, randomized, controlled trial.

Patients with chronic hepatitis C and low serum and hepatic iron stores may have an improved response to interferon (IFN). We tested whether iron reduction before and during IFN therapy would lead to an improved sustained biochemical and virological response compared with IFN alone. Eighty-two previously untreated patients with chronic hepatitis C were randomized to either: group A IFN-alpha2b 3 MU 3 times per week for 6 months, or group B iron reduction before and during IFN-alpha2b 3 MU 3 times per week for 6 months.