98 research outputs found
Identifying chemokines as therapeutic targets in renal disease: Lessons from antagonist studies and knockout mice
Chemokines, in concert with cytokines and adhesion molecules, play multiple roles in local and systemic immune responses. In the kidney, the temporal and spatial expression of chemokines correlates with local renal damage and accumulation of chemokine receptor-bearing leukocytes. Chemokines play important roles in leukocyte trafficking and blocking chemokines can effectively reduce renal leukocyte recruitment and subsequent renal damage. However, recent data indicate that blocking chemokine or chemokine receptor activity in renal disease may also exacerbate renal inflammation under certain conditions. An increasing amount of data indicates additional roles of chemokines in the regulation of innate and adaptive immune responses, which may adversively affect the outcome of interventional studies. This review summarizes available in vivo studies on the blockade of chemokines and chemokine receptors in kidney diseases, with a special focus on the therapeutic potential of anti-chemokine strategies, including potential side effects, in renal disease. Copyright (C) 2004 S. Karger AG, Basel
Prospective Observational Study of Pazopanib in Patients with Advanced Renal Cell Carcinoma (PRINCIPAL Study)
Background: Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC). Subjects, Materials, and Methods: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups. Results: Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2–12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. Conclusion: PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting. Implications for Practice: PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors’ knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months
Novel Retinoic Acid Receptor Alpha Agonists for Treatment of Kidney Disease
Development of pharmacologic agents that protect podocytes from injury is a critical strategy for the treatment of kidney glomerular diseases. Retinoic acid reduces proteinuria and glomerulosclerosis in multiple animal models of kidney diseases. However, clinical studies are limited because of significant side effects of retinoic acid. Animal studies suggest that all trans retinoic acid (ATRA) attenuates proteinuria by protecting podocytes from injury. The physiological actions of ATRA are mediated by binding to all three isoforms of the nuclear retinoic acid receptors (RARs): RARα, RARβ, and RARγ. We have previously shown that ATRA exerts its renal protective effects mainly through the agonism of RARα. Here, we designed and synthesized a novel boron-containing derivative of the RARα-specific agonist Am580. This new derivative, BD4, binds to RARα receptor specifically and is predicted to have less toxicity based on its structure. We confirmed experimentally that BD4 binds to RARα with a higher affinity and exhibits less cellular toxicity than Am580 and ATRA. BD4 induces the expression of podocyte differentiation markers (synaptopodin, nephrin, and WT-1) in cultured podocytes. Finally, we confirmed that BD4 reduces proteinuria and improves kidney injury in HIV-1 transgenic mice, a model for HIV-associated nephropathy (HIVAN). Mice treated with BD4 did not develop any obvious toxicity or side effect. Our data suggest that BD4 is a novel RARα agonist, which could be used as a potential therapy for patients with kidney disease such as HIVAN
The Pierre Auger Observatory Open Data
The Pierre Auger Collaboration has embraced the concept of open access to
their research data since its foundation, with the aim of giving access to the
widest possible community. A gradual process of release began as early as 2007
when 1% of the cosmic-ray data was made public, along with 100% of the
space-weather information. In February 2021, a portal was released containing
10% of cosmic-ray data collected from 2004 to 2018, during Phase I of the
Observatory. The Portal included detailed documentation about the detection and
reconstruction procedures, analysis codes that can be easily used and modified
and, additionally, visualization tools. Since then the Portal has been updated
and extended. In 2023, a catalog of the 100 highest-energy cosmic-ray events
examined in depth has been included. A specific section dedicated to
educational use has been developed with the expectation that these data will be
explored by a wide and diverse community including professional and
citizen-scientists, and used for educational and outreach initiatives. This
paper describes the context, the spirit and the technical implementation of the
release of data by the largest cosmic-ray detector ever built, and anticipates
its future developments.Comment: 19 pages, 8 figure
Radio Measurements of the Depth of Air-Shower Maximum at the Pierre Auger Observatory
The Auger Engineering Radio Array (AERA), part of the Pierre Auger
Observatory, is currently the largest array of radio antenna stations deployed
for the detection of cosmic rays, spanning an area of km with 153
radio stations. It detects the radio emission of extensive air showers produced
by cosmic rays in the MHz band. Here, we report the AERA measurements
of the depth of the shower maximum (), a probe for mass
composition, at cosmic-ray energies between to eV,
which show agreement with earlier measurements with the fluorescence technique
at the Pierre Auger Observatory. We show advancements in the method for radio
reconstruction by comparison to dedicated sets of CORSIKA/CoREAS
air-shower simulations, including steps of reconstruction-bias identification
and correction, which is of particular importance for irregular or sparse radio
arrays. Using the largest set of radio air-shower measurements to date, we show
the radio resolution as a function of energy, reaching a
resolution better than g cm at the highest energies, demonstrating
that radio measurements are competitive with the established
high-precision fluorescence technique. In addition, we developed a procedure
for performing an extensive data-driven study of systematic uncertainties,
including the effects of acceptance bias, reconstruction bias, and the
investigation of possible residual biases. These results have been
cross-checked with air showers measured independently with both the radio and
fluorescence techniques, a setup unique to the Pierre Auger Observatory.Comment: Submitted to Phys. Rev.
Demonstrating Agreement between Radio and Fluorescence Measurements of the Depth of Maximum of Extensive Air Showers at the Pierre Auger Observatory
We show, for the first time, radio measurements of the depth of shower
maximum () of air showers induced by cosmic rays that are
compared to measurements of the established fluorescence method at the same
location. Using measurements at the Pierre Auger Observatory we show full
compatibility between our radio and the previously published fluorescence data
set, and between a subset of air showers observed simultaneously with both
radio and fluorescence techniques, a measurement setup unique to the Pierre
Auger Observatory. Furthermore, we show radio resolution as a
function of energy and demonstrate the ability to make competitive
high-resolution measurements with even a sparse radio array.
With this, we show that the radio technique is capable of cosmic-ray mass
composition studies, both at Auger and at other experiments.Comment: Submitted to Phys. Rev. Let
Ground observations of a space laser for the assessment of its in-orbit performance
The wind mission Aeolus of the European Space Agency was a groundbreaking
achievement for Earth observation. Between 2018 and 2023, the space-borne lidar
instrument ALADIN onboard the Aeolus satellite measured atmospheric wind
profiles with global coverage which contributed to improving the accuracy of
numerical weather prediction. The precision of the wind observations, however,
declined over the course of the mission due to a progressive loss of the
atmospheric backscatter signal. The analysis of the root cause was supported by
the Pierre Auger Observatory in Argentina whose fluorescence detector
registered the ultraviolet laser pulses emitted from the instrument in space,
thereby offering an estimation of the laser energy at the exit of the
instrument for several days in 2019, 2020 and 2021. The reconstruction of the
laser beam not only allowed for an independent assessment of the Aeolus
performance, but also helped to improve the accuracy in the determination of
the laser beam's ground track on single pulse level. The results presented in
this paper set a precedent for the monitoring of space lasers by ground-based
telescopes and open new possibilities for the calibration of cosmic-ray
observatories.Comment: 10 pages, 10 figure
AugerPrime Surface Detector Electronics
Operating since 2004, the Pierre Auger Observatory has led to major advances
in our understanding of the ultra-high-energy cosmic rays. The latest findings
have revealed new insights that led to the upgrade of the Observatory, with the
primary goal of obtaining information on the primary mass of the most energetic
cosmic rays on a shower-by-shower basis. In the framework of the upgrade,
called AugerPrime, the 1660 water-Cherenkov detectors of the surface array are
equipped with plastic scintillators and radio antennas, allowing us to enhance
the composition sensitivity. To accommodate new detectors and to increase
experimental capabilities, the electronics is also upgraded. This includes
better timing with up-to-date GPS receivers, higher sampling frequency,
increased dynamic range, and more powerful local processing of the data. In
this paper, the design characteristics of the new electronics and the enhanced
dynamic range will be described. The manufacturing and test processes will be
outlined and the test results will be discussed. The calibration of the SD
detector and various performance parameters obtained from the analysis of the
first commissioning data will also be presented
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