Insulin-like growth factors and related proteins in plasma and cerebrospinal fluids of HIV-positive individuals.

BackgroundClinically significant dysregulation of the insulin-like growth factor (IGF) family proteins occurs in HIV-infected individuals, but the details including whether the deficiencies in IGFs contribute to CNS dysfunction are unknown.MethodsWe measured the levels of IGF1, IGF2, IGFBP1, IGFBP2, and IGF2 receptor (IGF2R) in matching plasma and cerebrospinal fluid (CSF) samples of 107 HIV+ individuals from CNS HIV Antiretroviral Therapy Effects Research (CHARTER) and analyzed their associations with demographic and disease characteristics, as well as levels of several soluble inflammatory mediators (TNFα, IL-6, IL-10, IL-17, IP-10, MCP-1, and progranulin). We also determined whether IGF1 or IGF2 deficiency is associated with HIV-associated neurocognitive disorder (HAND) and whether the levels of soluble IGF2R (an IGF scavenging receptor, which we also have found to be a cofactor for HIV infection in vitro) correlate with HIV viral load (VL).ResultsThere was a positive correlation between the levels of IGF-binding proteins (IGFBPs) and those of inflammatory mediators: between plasma IGFBP1 and IL-17 (β coefficient 0.28, P = 0.009), plasma IGFBP2 and IL-6 (β coefficient 0.209, P = 0.021), CSF IGFBP1 and TNFα (β coefficient 0.394, P < 0.001), and CSF IGFBP2 and TNF-α (β coefficient 0.14, P < 0.001). As IGFBPs limit IGF availability, these results suggest that inflammation is a significant factor that modulates IGF protein expression/availability in the setting of HIV infection. However, there was no significant association between HAND and the reduced levels of plasma IGF1, IGF2, or CSF IGF1, suggesting a limited power of our study. Interestingly, plasma IGF1 was significantly reduced in subjects on non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART) compared to protease inhibitor-based therapy (174.1 ± 59.8 vs. 202.8 ± 47.3 ng/ml, P = 0.008), suggesting a scenario in which ART regimen-related toxicity can contribute to HAND. Plasma IGF2R levels were positively correlated with plasma VL (β coefficient 0.37, P = 0.021) and inversely correlated with current CD4+ T cell counts (β coefficient -0.04, P = 0.021), supporting our previous findings in vitro.ConclusionsTogether, these results strongly implicate (1) an inverse relationship between inflammation and IGF growth factor availability and the contribution of IGF deficiencies to HAND and (2) the role of IGF2R in HIV infection and as a surrogate biomarker for HIV VL

Interferon regulatory factor 3 plays an anti-inflammatory role in microglia by activating the PI3K/Akt pathway

<p>Abstract</p> <p>Background</p> <p>Microglia are the principal cells involved in the innate immune response in the CNS. Activated microglia produce a number of proinflammatory cytokines implicated in neurotoxicity but they also are a major source of anti-inflammatory cytokines, antiviral proteins and growth factors. Therefore, an immune therapy aiming at suppressing the proinflammatory phenotype while enhancing the anti-inflammatory, growth promoting phenotype would be of great benefit. In the current study, we tested the hypothesis that interferon regulatory factor 3 (IRF3), a transcription factor required for the induction of IFNβ following TLR3 or TLR4 activation, is critical to the microglial phenotype change from proinflammatory to anti-inflammatory, and that this phenotype change can be greatly facilitated by IRF3 gene transfer.</p> <p>Methods</p> <p>Cultures of primary human fetal microglia were transduced with IRF3 using recombinant adenovirus (Ad-IRF3) and subjected to microarray analysis, real-time PCR, immunoblotting and ELISA to determine inflammatory gene expression. Two different types of immune stimuli were tested, the TLR ligands, poly IC (PIC) and LPS, and the proinflammatory cytokines, IL-1/IFNγ. In addition, the role of the PI3K/Akt pathway was examined by use of a pharmacological inhibitor, LY294002.</p> <p>Results</p> <p>Our results show that Ad-IRF3 suppressed proinflammatory genes (IL-1α, IL-1β, TNFα, IL-6, IL-8 and CXCL1) and enhanced anti-inflammatory genes (IL-1 receptor antagonist, IL-10 and IFNβ) in microglia, regardless of the cell stimuli applied. Furthermore, Ad-IRF3 activated Akt, and LY294002 reversed the effects of Ad-IRF3 on microglial inflammatory gene expression. pAkt was critical in LPS- or PIC-induced production of IL-10 and IL-1ra. Significantly, microglial IFNβ protein production was also dependent on pAkt and required both Ad-IRF3 and immunological stimuli (PIC > IL-1/IFNγ). pAkt played much less prominent and variable roles in microglial proinflammatory gene expression. This anti-inflammatory promoting role of PI3K/Akt appeared to be specific to microglia, since astrocyte proinflammatory gene expression (as well as IFNβ expression) required PI3K/Akt.</p> <p>Conclusions</p> <p>Our results show a novel anti-inflammatory role for the PI3K/Akt signaling pathway in microglia. They further suggest that IRF3 gene therapy could facilitate the microglial phenotype switch from proinflammatory ("M1-like") to anti-inflammatory and immunomodulatory ("M2-like"), in part, by augmenting the level of pAkt.</p

Thermionic Emission as a tool to study transport in undoped nFinFETs

Thermally activated sub-threshold transport has been investigated in undoped triple gate MOSFETs. The evolution of the barrier height and of the active cross-section area of the channel as a function of gate voltage has been determined. The results of our experiments and of the Tight Binding simulations we have developed are both in good agreement with previous analytical calculations, confirming the validity of thermionic approach to investigate transport in FETs. This method provides an important tool for the improvement of devices characteristics.Comment: 3 pages, 3 figure, 1 tabl

Electronic structure of realistically extended atomistically resolved disordered Si:P delta-doped layers

The emergence of scanning tunneling microscope (STM) lithography and low temperature molecular beam epitaxy (MBE) opens the possibility of creating scalable donor based quantum computing architectures. In particular, atomically precise Si:P monolayer structures (delta-doped layers) serve as crucial contact regions and in-plane gates in single impurity devices. In this paper we study highly confined delta-doped layers to explain the disorder in the P dopant placements in realistically extended systems. The band structure is computed using the tight-binding formalism and charge-potential self-consistency. The exchange-correlation corrected impurity potential pulls down subbands below the silicon valley minima to create impurity bands. Our methodology is benchmarked and validated against other theoretical methods for small ordered systems. The doping density is shown to linearly control the impurity bands. Disorder within the Si:P delta-doped layer is examined using an extended domain to describe the effects of experimentally unavoidable randomness through explicitly disordered dopant placement. Disorder in the delta-doped layer breaks the symmetry in the supercell and creates band splitting in every subband. Vertical segregation of dopants is shown to dramatically reduce valley splitting (VS). Such VS can be used as a measure of ideality of the fabricated Si:P delta-doped layer. Although the resulting disorder induces density of states fluctuations, this theoretical analysis shows that delta-doped layers can serve as quasimetallic 2D electron sources even in the presence of strong nonidealities

Interface trap density metrology from sub-threshold transport in highly scaled undoped Si n-FinFETs

Channel conductance measurements can be used as a tool to study thermally activated electron transport in the sub-threshold region of state-of-art FinFETs. Together with theoretical Tight-Binding (TB) calculations, this technique can be used to understand the evolution of source-to-channel barrier height (Eb) and of active channel area (S) with gate bias (Vgs). The quantitative difference between experimental and theoretical values that we observe can be attributed to the interface traps present in these FinFETs. Therefore, based on the difference between measured and calculated values of (i) S and (ii) |dEb/dVgs| (channel to gate coupling), two new methods of interface trap density (Dit) metrology are outlined. These two methods are shown to be very consistent and reliable, thereby opening new ways of analyzing in situ state-of-the-art multi-gate FETs down to the few nm width limit. Furthermore, theoretical investigation of the spatial current density reveal volume inversion in thinner FinFETs near the threshold voltage.Comment: 12 figures, 13 pages, Submitted to Journal of Applied Physic

Electric field reduced charging energies and two-electron bound excited states of single donors in silicon

We present atomistic simulations of the D0 to D- charging energies of a gated donor in silicon as a function of applied fields and donor depths and find good agreement with experimental measure- ments. A self-consistent field large-scale tight-binding method is used to compute the D- binding energies with a domain of over 1.4 million atoms, taking into account the full bandstructure of the host, applied fields, and interfaces. An applied field pulls the loosely bound D- electron towards the interface and reduces the charging energy significantly below the bulk values. This enables formation of bound excited D-states in these gated donors, in contrast to bulk donors. A detailed quantitative comparison of the charging energies with transport spectroscopy measurements with multiple samples of arsenic donors in ultra-scaled FinFETs validates the model results and provides physical insights. We also report measured D-data showing for the first time the presence of bound D-excited states under applied fields

Enhanced priming of adaptive immunity by a proapoptotic mutant of Mycobacterium tuberculosis

The inhibition of apoptosis of infected host cells is a well-known but poorly understood function of pathogenic mycobacteria. We show that inactivation of the secA2 gene in Mycobacterium tuberculosis, which encodes a component of a virulence-associated protein secretion system, enhanced the apoptosis of infected macrophages by diminishing secretion of mycobacterial superoxide dismutase. Deletion of secA2 markedly increased priming of antigen-specific CD8+ T cells in vivo, and vaccination of mice and guinea pigs with a secA2 mutant significantly increased resistance to M. tuberculosis challenge compared with standard M. bovis bacille Calmette-Guérin vaccination. Our results define a mechanism for a key immune evasion strategy of M. tuberculosis and provide what we believe to be a novel approach for improving mycobacterial vaccines

Structural and functional analyses of minimal phosphopeptides targeting the polo-box domain of polo-like kinase 1

Polo-like kinase-1 (Plk1) has a pivotal role in cell proliferation and is considered a potential target for anticancer therapy. The noncatalytic polo-box domain (PBD) of Plk1 forms a phosphoepitope binding module for protein-protein interaction. Here, we report the identification of minimal phosphopeptides that specifically interact with the PBD of human PLK1, but not those of the closely related PLK2 and PLK3. Comparative binding studies and analyses of crystal structures of the PLK1 PBD in complex with the minimal phosphopeptides revealed that the C-terminal SpT dipeptide functions as a high-affinity anchor, whereas the N-terminal residues are crucial for providing specificity and affinity to the interaction. Inhibition of the PLK1 PBD by phosphothreonine mimetic peptides was sufficient to induce mitotic arrest and apoptotic cell death. The mode of interaction between the minimal peptide and PBD may provide a template for designing therapeutic agents that target PLK1.National Institutes of Health (U.S.) (Grant R01 GM60594)National Cancer Institute (U.S.)National Institutes of Health (U.S.) (Contract N01-CO-12400)National Institutes of Health (U.S.) (HHSN261200800001E

A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study

Se trata de la publicación del estudio de fase 3 ASPEN que comparó en pacientes con macro-globulinemia de Waldenström (WM) la eficacia y la seguridad de ibrutinib, un inhibidor de la tirosi-na quinasa Bruton (BTK) de primera generación, familia que ha demostrado ser un tratamiento eficaz en estos pacientes, frente a zanubrutinib, un nuevo inhibidor de BTK de 2ª generación, altamente selectivo. Los pacientes con enfermedad MYD88L265P se asignaron al azar 1:1 al tratamiento con ibrutinib o zanubrutinib. El criterio principal de valoración fue la proporción de pa-cientes que lograron una respuesta completa (RC) o una respuesta parcial muy buena (RPMB) mediante una revisión independiente. Los criterios secundarios clave de valoración incluyeron la tasa de respuesta mayor (RM), la supervivencia libre de progresión (SLP), la duración de la res-puesta (DR), la carga de la enfermedad y la seguridad. Se randomizaron 201 pacientes y 199 recibieron al menos 1 dosis del tratamiento del estudio. Veintinueve (28%) pacientes tratados con zanubrutinib y 19 (19%) pacientes tratados con ibrutinib lograron una RPMB, diferencia que no alcanzó la significación estadística (P = 0,09). Las RM fueron del 77% y del 78%, respectivamen-te. No se alcanzó la mediana de DR y SLP, ya que el 84% y el 85% de los pacientes tratados con ibrutinib y zanubrutinib estaban libres de progresión a los 18 meses. La fibrilación auricular, hema-tomas, diarrea, edema periférico, hemorragia, espasmos musculares y neumonía, así como los eventos adversos que condujeron a interrumpir el tratamiento, fueron menos frecuentes entre los receptores de zanubrutinib. La incidencia de neutropenia fue mayor con zanubrutinib, aunque las tasas de infección de grado ≥3 fueron similares en ambos grupos (1,2 y 1,1 eventos por 100 me-ses-persona). Estos resultados demuestran que zanubrutinib e ibrutinib son altamente efectivos en el tratamiento de la WM, pero zanubrutinib se asoció con menor toxicidad y una tendencia hacia una mejor calidad de respuesta y menos toxicidad, particularmente toxicidad cardiovascular.[EN]Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.BeiGene CoBeiGene C

Prevention and Therapy of Hepatocellular Carcinoma by Vaccination with TM4SF5 Epitope-CpG-DNA-Liposome Complex without Carriers

Although peptide vaccines have been actively studied in various animal models, their efficacy in treatment is limited. To improve the efficacy of peptide vaccines, we previously formulated an efficacious peptide vaccine without carriers using the natural phosphodiester bond CpG-DNA and a special liposome complex (Lipoplex(O)). Here, we show that immunization of mice with a complex consisting of peptide and Lipoplex(O) without carriers significantly induces peptide-specific IgG2a production in a CD4+ cells- and Th1 differentiation-dependent manner. The transmembrane 4 superfamily member 5 protein (TM4SF5) has gained attention as a target for hepatocellular carcinoma (HCC) therapy because it induces uncontrolled growth of human HCC cells via the loss of contact inhibition. Monoclonal antibodies specific to an epitope of human TM4SF5 (hTM4SF5R2-3) can recognize native mouse TM4SF5 and induce functional effects on mouse cancer cells. Pre-immunization with a complex of the hTM4SF5R2-3 epitope and Lipoplex(O) had prophylactic effects against tumor formation by HCC cells implanted in an mouse tumor model. Furthermore, therapeutic effects were revealed regarding the growth of HCC when the vaccine was injected into mice after tumor formation. These results suggest that our improved peptide vaccine technology provides a novel prophylaxis measure as well as therapy for HCC patients with TM4SF5-positive tumors