The breaking of immune tolerance against autologous angiogenic endothelial cells should be a useful approach for cancer therapy. Here we show that immunotherapy of tumors using fixed xenogeneic whole ...endothelial cells as a vaccine was effective in affording protection from tumor growth, inducing regression of established tumors and prolonging survival of tumor-bearing mice. Furthermore, autoreactive immunity targeting to microvessels in solid tumors was induced and was probably responsible for the anti-tumor activity. These observations may provide a new vaccine strategy for cancer therapy through the induction of an autoimmune response against the tumor endothelium in a cross-reaction.
LaFe11.6Si1.4/16 wt%La70Co30 composites were fabricated by hot-pressing (HP) followed by thermal diffusion treatment in the temperature range of 923–1273 K. Significant microstructural and phase ...evolution occurred during diffusion heat treatment. Thermal decomposition (TD) occurred between 1023 and 1223 K, which increased the Curie temperature (TC) but smeared out the magnetic transition, decreasing magnetic entropy change (–ΔSM). Co atoms first diffused into the α-Fe(Si) and LaFeSi (1:1:1) phases. And then, the α-Fe(Co,Si) and La(Fe,Co)Si phases, attached to large LaFe11.6Si1.4 particles, transformed to a NaZn13-type La(Fe,Co,Si)13 (1:13) phase at 1273 K. Hence, a core-shell La(Fe,Co,Si)13 phase formed, resulting in a table-like magnetic entropy change over a wide temperature range (∼202–292 K). Greater Co diffusion and more homogeneity of the composition of the 1:13 phase could be achieved by increasing the annealing time. The maximum magnetic entropy change (–ΔSM)max of the composites at 0–2 T could be increased from 5.62 J/(kg·K) at ∼196 K to 8.81 J/(kg·K) at ∼244 K.
•La–Fe–Si/La–Co magnetocalric composites were fabricated by HP and high temperature annealing.•The process and mechanism of Co diffusion during GBD process was investigated.•The diffusion of Co was realized by firstly forming La(Fe,Co)Si (1:1:1) and α-Fe(Co,Si) phases.•1:1:1 and α-Fe(Co,Si) phases transformed to the 1:13 phase during diffusion annealing.•The (–ΔSM)max of the composites increases from 5.62J/kg·K at 196K to 8.81J/kg·K at 244K (2T).
Intracellular Ca
cycling determines myocardial contraction and relaxation in response to physiological demands. SERCA2a (sarcoplasmic/endoplasmic reticulum Ca
-ATPase 2a) is responsible for the ...sequestration of cytosolic Ca
into intracellular stores during cardiac relaxation, and its activity is reversibly inhibited by PLN (phospholamban). However, the regulatory hierarchy of SERCA2a activity remains unclear.
Cardiomyocyte-specific ZBTB20 knockout mice were generated by crossing ZBTB20
mice with Myh6-Cre mice. Echocardiography, blood pressure measurements, Langendorff perfusion, histological analysis and immunohistochemistry, quantitative reverse transcription-PCR, Western blot analysis, electrophysiological measurements, and chromatin immunoprecipitation assay were performed to clarify the phenotype and elucidate the molecular mechanisms.
Specific ablation of ZBTB20 in cardiomyocyte led to a significant increase in basal myocardial contractile parameters both in vivo and in vitro, accompanied by an impairment in cardiac reserve and exercise capacity. Moreover, the cardiomyocytes lacking ZBTB20 showed an increase in sarcoplasmic reticular Ca
content and exhibited a remarkable enhancement in both SERCA2a activity and electrically stimulated contraction. Mechanistically, PLN expression was dramatically reduced in cardiomyocytes at the mRNA and protein levels by ZBTB20 deletion or silencing, and PLN overexpression could largely restore the basal contractility in ZBTB20-deficient cardiomyocytes.
These data point to ZBTB20 as a fine-tuning modulator of PLN expression and SERCA2a activity, thereby offering new perspective on the regulation of basal contractility in the mammalian heart.
Atmospheric aerosols play a crucial role in regional radiative
budgets. Previous studies on clear-sky aerosol direct radiative forcing
(ADRF) have mainly been limited to site-scale observations or ...model
simulations for short-term cases, and long-term distributions of ADRF in
China have not been portrayed yet. In this study, an accurate fine-resolution
ADRF estimate at the surface was proposed. Multiplatform datasets, including
satellite (MODIS aboard Terra and Aqua) and reanalysis datasets, served as
inputs to the Santa Barbara Discrete Atmospheric Radiative Transfer (SBDART)
model for ADRF simulation with consideration of the aerosol vertical profile
over eastern China during 2000–2016. Specifically, single-scattering albedo
(SSA) from the Modern-Era Retrospective Analysis for Research and
Application, Version 2 (MERRA-2) was validated with sun photometers over eastern
China. The gridded asymmetry parameter (ASY) was then simulated by matching
the calculated top-of-atmosphere (TOA) radiative fluxes from the radiative
transfer model with satellite observations (Clouds and the Earth's Radiant
Energy System, CERES). The high correlation and small discrepancy (6–8 W m−2) between simulated and observed radiative fluxes at three sites
(Baoshan, Fuzhou, and Yong'an) indicated that ADRF retrieval is feasible and
has high accuracy over eastern China. Then this method was applied in each grid
of eastern China, and the overall picture of ADRF distributions over eastern China
during 2000–2016 was displayed. ADRF ranges from −220 to −20 W m−2, and
annual mean ADRF is −100.21 W m−2, implying that aerosols have a strong
cooling effect at the surface in eastern China. With the economic development
and rapid urbanization, the spatiotemporal changes of ADRF during the past 17 years are mainly attributed to the changes of anthropogenic emissions in
eastern China. Our method provides the long-term ADRF distribution over eastern
China for the first time, highlighting the importance of aerosol radiative
impact under climate change.
Cancer‐related fatigue (CRF) is a common symptom affecting 60–90% of cancer survivors, and effective management for CRF is not yet available. Recently, an increasing number of trials examining the ...use of psychotropic drugs for the treatment of CRF have been performed, but these trials have yielded inconsistent results. Therefore, we conducted a meta‐analysis aimed at assessing the effect and safety of psychotropic drugs for the management of CRF. Ten eligible trials of the psychotropic drugs methylphenidate and modafinil in a total of 1582 participants treated for CRF were subjected to statistical analyses. A meta‐analysis of seven of these studies indicated that methylphenidate was superior to placebo for the treatment of CRF. Another meta‐analysis of three studies evaluating modafinil found that this drug was no better than placebo. Adverse events were similar between both methylphenidate and modafinil and the placebo groups. Our meta‐analysis indicated that the treatment of CRF with methylphenidate appears to be effective, whereas modafinil provides no benefit. These results of this analysis warrant further trials to confirm the efficacy and safety of psychotropic drugs for the treatment of CRF.
Millions of cis-regulatory elements are predicted to be present in the human genome, but direct evidence for their biological function is scarce. Here we report a high-throughput method, ...cis-regulatory element scan by tiling-deletion and sequencing (CREST-seq), for the unbiased discovery and functional assessment of cis-regulatory sequences in the genome. We used it to interrogate the 2-Mb POU5F1 locus in human embryonic stem cells, and identified 45 cis-regulatory elements. A majority of these elements have active chromatin marks, DNase hypersensitivity, and occupancy by multiple transcription factors, which confirms the utility of chromatin signatures in cis-element mapping. Notably, 17 of them are previously annotated promoters of functionally unrelated genes, and like typical enhancers, they form extensive spatial contacts with the POU5F1 promoter. These results point to the commonality of enhancer-like promoters in the human genome.
Particles directly produced at electron–positron colliders, such as the J/ψ meson, decay with relatively high probability into a baryon–antibaryon pair1. For spin-1/2 baryons, the pair can have the ...same or opposite helicites. A non-vanishing phase ΔΦ between the transition amplitudes to these helicity states results in a transverse polarization of the baryons2–4. From the joint angular distribution of the decay products of the baryons, this phase as well as the parameters characterizing the baryon and the antibaryon decays can be determined. Here, we report the measurement of ΔΦ = 42.4 ± 0.6 ± 0.5° using Λ → pπ− and Λ¯→p¯π+,n¯π0 decays at BESIII. We find a value for the Λ → pπ− decay parameter of α− = 0.750 ± 0.009 ± 0.004, 17 ± 3% higher than the current world average, which has been used as input for all Λ polarization measurements since 19785,6. For Λ¯→p¯π+ we find α+ = −0.758 ± 0.010 ± 0.007, giving ACP = (α− + α+)/(α− − α+) = −0.006 ± 0.012 ± 0.007, a precise direct test of charge–parity symmetry (CP) violation in Λ decays.The decay asymmetry and helicity phase of polarized baryon–antibaryon pairs are measured at the BESIII experiment, testing charge–parity symmetry and revealing a discrepancy of the Λ → pπ− decay asymmetry with respect to the current world average.
Post-translational modifications (PTMs) of therapeutic monoclonal antibodies (mAbs) are important product quality attributes (PQAs) that can potentially impact drug stability, safety, and efficacy. ...The PTMs of a mAb may change remarkably in the bloodstream after drug administration compared to in vitro conditions. Thus, monitoring in vivo PTM changes of mAbs helps evaluate the criticality of PQAs during the product risk assessment. In addition, quantitation of the subject exposures to PTM variants helps assess the impact of PTMs on the safety and efficacy of therapeutic mAbs. Here, we developed an immunocapture-liquid chromatography/mass spectrometry (LC/MS) method to quantify in vivo PTM changes a therapeutic mAb overtime in single- and multiple-dose monkey pharmacokinetic (PK) studies. We also built mathematical models to predict the in vivo serum concentrations of PQAs, the subject exposures to PQAs, and the relative abundance of PQAs in single- and multiple-dose regimens. The model predictions are in good agreement with the experimental results. The immunocapture-LC/MS method and mathematical models enable bioanalytical chemists to quantitatively assess the criticality of PQAs during drug development.
Migraine and other primary headache disorders affect a large population and cause debilitating pain. Establishing animal models that display behavioral correlates of long-lasting and ongoing ...headache, the most common and disabling symptom of migraine, is vital for the elucidation of disease mechanisms and identification of drug targets. We have developed a mouse model of headache, using dural application of capsaicin along with a mixture of inflammatory mediators (IScap) to simulate the induction of a headache episode. This elicited intermittent head-directed wiping and scratching as well as the phosphorylation of c-Jun N-terminal kinase in trigeminal ganglion neurons. Interestingly, dural application of IScap preferentially induced FOS protein expression in the excitatory but not inhibitory cervical/medullary dorsal horn neurons. The duration of IScap-induced behavior and the number of FOS-positive neurons correlated positively in individual mice; both were reduced to the control level by the pretreatment of antimigraine drug sumatriptan. Dural application of CGRP(8-37), the calcitonin gene-related peptide (CGRP) receptor antagonist, also effectively blocked IScap-induced behavior, which suggests that the release of endogenous CGRP in the dura is necessary for IScap-induced nociception. These data suggest that dural IScap-induced nocifensive behavior in mice may be mechanistically related to the ongoing headache in humans. In addition, dural application of IScap increased resting time in female mice. Taken together, we present the first detailed study using dural application of IScap in mice. This headache model can be applied to genetically modified mice to facilitate research on the mechanisms and therapeutic targets for migraine headache.
Abstract Aim Sirolimus (SRL) acts as a primary immunosuppressant or antitumor agent. The aim of the present study was to evaluate the influence of SRL on the recurrence rate and survival of patients ...after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) exceeding the Milan criteria. Materials and Methods We retrospectively examined 73 consecutive patients who underwent OLT for HCC exceeding the Milan criteria from March 2004 through December 2005. Among them, 27 patients were treated with SRL-based immunosuppressive protocols after OLT, and 46 patients by an FK506-based protocol. Statistical analysis was based on the intent-to-treat method. Results The 2 groups were comparable in all clinicopathologic parameters. The mean overall survival was 594 ± 35 days in the SRL group and 480 ± 42 days in the FK506 group ( P = .011); the mean disease-free survival period was 519 ± 43 days in the SRL group and 477 ± 48 days in the FK506 group ( P = .234). Multivariate analysis revealed Child's status ( P = .004) and immunosuppressive protocol ( P = .015) were the significant factors affecting overall survival. Only microvascular invasion ( P = .004) was significantly associated with disease-free survival. Among 24 surviving patient in the SRL group, 2 patients had SRL discontinued for toxicity; 10 had SRL monotherapy immunosuppression. Conclusion The SRL-based immunosuppressive protocol improved the overall survival of patients after OLT for HCC exceeding the Milan criteria, probably by postponing recurrence and with better tolerability.
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