Ulocuplumab (BMS-936564 / MDX1338): a fully human anti-CXCR4 antibody induces cell death in chronic lymphocytic leukemia mediated through a reactive oxygen species-dependent pathway.

The CXCR4 receptor (Chemokine C-X-C motif receptor 4) is highly expressed in different hematological malignancies including chronic lymphocytic leukemia (CLL). The CXCR4 ligand (CXCL12) stimulates CXCR4 promoting cell survival and proliferation, and may contribute to the tropism of leukemia cells towards lymphoid tissues. Therefore, strategies targeting CXCR4 may constitute an effective therapeutic approach for CLL. To address that question, we studied the effect of Ulocuplumab (BMS-936564), a fully human IgG4 anti-CXCR4 antibody, using a stroma--CLL cells co-culture model. We found that Ulocuplumab (BMS-936564) inhibited CXCL12 mediated CXCR4 activation-migration of CLL cells at nanomolar concentrations. This effect was comparable to AMD3100 (Plerixafor--Mozobil), a small molecule CXCR4 inhibitor. However, Ulocuplumab (BMS-936564) but not AMD3100 induced apoptosis in CLL at nanomolar concentrations in the presence or absence of stromal cell support. This pro-apoptotic effect was independent of CLL high-risk prognostic markers, was associated with production of reactive oxygen species and did not require caspase activation. Overall, these findings are evidence that Ulocuplumab (BMS-936564) has biological activity in CLL, highlight the relevance of the CXCR4-CXCL12 pathway as a therapeutic target in CLL, and provide biological rationale for ongoing clinical trials in CLL and other hematological malignancies

Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia.

BackgroundThe CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL.MethodsPatient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model.ResultsPF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognostic markers. The cell death mechanism was dependent on CXCR4 expression, required antibody bivalency, involved reactive oxygen species production, and did not require caspase activation, all characteristics reminiscent of programmed cell death (PCD). PF-06747143 also induced potent B-CLL cytotoxicity via Fc-driven antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity activity (CDC). PF-06747143 had significant combinatorial effect with standard of care (SOC) agents in B-CLL treatment, including rituximab, fludarabine (F-ara-A), ibrutinib, and bendamustine. In a CLL xenograft model, PF-06747143 decreased tumor burden and improved survival as a monotherapy, and in combination with bendamustine.ConclusionsWe show evidence that PF-06747143 has biological activity in CLL primary cells, supporting a rationale for evaluation of PF-06747143 for the treatment of CLL patients

Development and application of process-based simulation models for cotton production: a review of past, present, and future directions

The development and application of cropping system simulation models for cotton production has a long and rich history, beginning in the southeastern United States in the 1960's and now expanded to major cotton production regions globally. This paper briefly reviews the history of cotton simulation models, examines applications of the models since the turn of the century, and identifies opportunities for improving models and their use in cotton research and decision support. Cotton models reviewed include those specific to cotton (GOSSYM, Cotton2K, COTCO2, OZCOT, and CROPGRO-Cotton) and generic crop models that have been applied to cotton production (EPIC, WOFOST, SUCROS, GRAMI, CropSyst, and AquaCrop). Model application areas included crop water use and irrigation water management, nitrogen dynamics and fertilizer management, genetics and crop improvement, climatology, global climate change, precision agriculture, model integration with sensor data, economics, and classroom instruction. Generally, the literature demonstrated increased emphasis on cotton model development in the previous century and on cotton model application in the current century. Although efforts to develop cotton models have a 40-year history, no comparisons among cotton models were reported. Such efforts would be advisable as an initial step to evaluate current cotton simulation strategies. Increasingly, cotton simulation models are being applied by non-traditional crop modelers, who are not trained agronomists but wish to use the models for broad economic or life cycle analyses. While this trend demonstrates the growing interest in the models and their potential utility for a variety of applications, it necessitates the development of models with appropriate complexity and ease-of-use for a given application, and improved documentation and teaching materials are needed to educate potential model users. Spatial scaling issues are also increasingly prominent, as models originally developed for use at the field scale are being implemented for regional simulations over large geographic areas. Research steadily progresses toward the advanced goal of model integration with variable-rate control systems, which use real-time crop status and environmental information to spatially and temporally optimize applications of crop inputs, while also considering potential environmental impacts, resource limitations, and climate forecasts. Overall, the review demonstrates a languished effort in cotton simulation model development, but the application of existing models in a variety of research areas remains strong and continues to grow

Structural and magnetic studies of Co and Fe implanted BaTiO 3 crystals

Singly-charged Co or Fe ions with energy 40 keV were implanted into single-domain ferroelectric plates of barium titanate (BaTiO 3) with high fluences in the range of (0.5-1.5) × 10 17 ion/cm 2 to create new magnetoelectric materials. Scanning electron microscopy (SEM) and conversion electron Mössbauer spectroscopy (CEMS) studies have shown that high-fluence implantation with 3d-ions results in formation of cobalt or iron nanoparticles in the near-surface irradiated region of perovskite-type crystal. With increasing the fluence, the both Co- and Fe-implanted BaTiO 3 samples reveal at first superparamagnetic, and then ferromagnetic properties at room temperature. Analysis of magnetic hysteresis loops measured in the in-plane and out-of-plane geometries have shown that ferromagnetic BaTiO 3:Co(Fe) nanocomposite layers display the "easy plane" magnetic anisotropy similar to that found for thin granular magnetic films. Together with our previous observation of the magnetoelectric effect in these samples, our structural and magnetic investigations show that the ion implantation is suitable to synthesize the desired magnetoelectric nanocomposite materials. © 2011 Elsevier B.V. All rights reserved

Author Correction: Enhanced NF-κB signaling in type-2 dendritic cells at baseline predicts non-response to adalimumab in psoriasis.

Funder: Department of HealthBiologic therapies have transformed the management of psoriasis, but clinical outcome is variable leaving an unmet clinical need for predictive biomarkers of response. Here we perform in-depth immunomonitoring of blood immune cells of 67 patients with psoriasis, before and during therapy with the anti-TNF drug adalimumab, to identify immune mediators of clinical response and evaluate their predictive value. Enhanced NF-κBp65 phosphorylation, induced by TNF and LPS in type-2 dendritic cells (DC) before therapy, significantly correlates with lack of clinical response after 12 weeks of treatment. The heightened NF-κB activation is linked to increased DC maturation in vitro and frequency of IL-17+ T cells in the blood of non-responders before therapy. Moreover, lesional skin of non-responders contains higher numbers of dermal DC expressing the maturation marker CD83 and producing IL-23, and increased numbers of IL-17+ T cells. Finally, we identify and clinically validate LPS-induced NF-κBp65 phosphorylation before therapy as a predictive biomarker of non-response to adalimumab, with 100% sensitivity and 90.1% specificity in an independent cohort. Our study uncovers important molecular and cellular mediators underpinning adalimumab mechanisms of action in psoriasis and we propose a blood biomarker for predicting clinical outcome

Distribution of Cardioembolic Stroke:A Cohort Study

Background: A cardiac origin in ischemic stroke is more frequent than previously assumed, but it is not clear which patients benefit from cardiac work-up if obvious cardiac pathology is absent. We hypothesized that thromboembolic stroke with a cardiac source occurs more frequently in the posterior circulation compared with thromboembolic stroke of another etiology. Methods: We performed a multicenter observational study in 3,311 consecutive patients with ischemic stroke who were enrolled in an ongoing prospective stroke registry of 8 University hospitals between September 2009 and November 2014 in The Netherlands. In this initiative, the so-called Parelsnoer Institute-Cerebrovascular Accident Study Group, clinical data, imaging, and biomaterials of patients with stroke are prospectively and uniformly collected. We compared the proportions of posterior stroke location in patients with a cardiac stroke source with those with another stroke etiology and calculated risk ratios (RR) with corresponding 95% CI with Poisson regression analyses. To assess which patient or disease characteristics were most strongly associated with a cardiac etiology in patients with ischemic stroke, we performed a stepwise backward regression analysis. Results: For the primary aim, 1,428 patients were eligible for analyses. The proportion of patients with a posterior stroke location among patients with a cardiac origin of their stroke (28%) did not differ statistically significant to those with another origin (25%), age and sex adjusted RR 1.16; 95% CI 0.96-1.41. For the secondary aim, 1,955 patients were eligible for analyses. No recent history of smoking, no hyperlipidemia, coronary artery disease, a higher age, and a higher National Institutes of Health Stroke Scale (NIHSS) score were associated with a cardiac etiology of ischemic stroke. Conclusions: We could not confirm our hypothesis that thromboembolic stroke localized in the posterior circulation is associated with a cardioembolic source of ischemic stroke, and therefore posterior stroke localization on itself does not necessitate additional cardiac examination. The lack of determinants of atherosclerosis, for example, no recent history of smoking and no hyperlipidemia, coronary artery disease, a higher age, and a higher NIHSS score are stronger risk factors for a cardiac source of ischemic stroke

Patrones de tratamiento con agentes biológicos. Eficacia y sobrevida a largo plazo en pacientes con artritis reumatoidea

En nuestro país existen pocos datos acerca de los patrones de tratamiento y la sobrevida de las Drogas Modificadoras de la Artritis Reumatoidea biológicas (DMARb) en pacientes con Artritis Reumatoidea (AR). El objetivo de nuestro estudio fue estimar la sobrevida del 1° y 2° agente biológico, determinar sus causas de suspensión y evaluar factores que influyan en la sobrevida de estos agentes

RNAi Targeting of West Nile Virus in Mosquito Midguts Promotes Virus Diversification

West Nile virus (WNV) exists in nature as a genetically diverse population of competing genomes. This high genetic diversity and concomitant adaptive plasticity has facilitated the rapid adaptation of WNV to North American transmission cycles and contributed to its explosive spread throughout the New World. WNV is maintained in nature in a transmission cycle between mosquitoes and birds, with intrahost genetic diversity highest in mosquitoes. The mechanistic basis for this increase in genetic diversity in mosquitoes is poorly understood. To determine whether the high mutational diversity of WNV in mosquitoes is driven by RNA interference (RNAi), we characterized the RNAi response to WNV in the midguts of orally exposed Culex pipiens quinquefasciatus using high-throughput, massively parallel sequencing and estimated viral genetic diversity. Our data demonstrate that WNV infection in orally exposed vector mosquitoes induces the RNAi pathway and that regions of the WNV genome that are more intensely targeted by RNAi are more likely to contain point mutations compared to weakly targeted regions. These results suggest that, under natural conditions, positive selection of WNV within mosquitoes is stronger in regions highly targeted by the host RNAi response. Further, they provide a mechanistic basis for the relative importance of mosquitoes in driving WNV diversification