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Publication
Journal: BioImpacts
January/12/2021
Abstract
Despite improvements in systemic therapy options for renal cancer, it remains one of the most drug-resistant malignancies. Interestingly, reports have shown that kahweol and cafestol, natural diterpenes extracted from coffee beans, exhibit anti-cancer activity. However, the multiple potential pharmacological actions of both have yet to be fully understood. This study therefore investigated the effects of kahweol acetate and cafestol on human renal cancer ACHN and Caki-1 cells. Accordingly, the combination of kahweol acetate and cafestol administration synergistically inhibited cell proliferation and migration by inducing apoptosis and inhibiting epithelial-mesenchymal transition. Mechanistic dissection revealed that kahweol acetate and cafestol inhibited Akt and ERK phosphorylation. Moreover, kahweol acetate and cafestol downregulated the expression of not only C-C chemokine receptors 2, 5, and 6 but also programmed death-ligand 1, indicating their effects on the tumor microenvironment. Thus, kahweol acetate and cafestol may be novel therapeutic candidates for renal cancer considering that they exert multiple pharmacological effects.
Publication
Journal: BioImpacts
January/12/2021
Abstract
The plant growth-promoting bacterium Azospirillum brasilense contains several genes encoding proteins involved in the biosynthesis and degradation of the second messenger cyclic-di-GMP, which may control key bacterial functions, such as biofilm formation and motility. Here, we analysed the function and expression of the cdgD gene, encoding a multidomain protein that includes GGDEF-EAL domains and CHASE and PAS domains. An insertional cdgD gene mutant was constructed, and analysis of biofilm and extracellular polymeric substance production, as well as the motility phenotype indicated that cdgD encoded a functional diguanylate protein. These results were correlated with a reduced overall cellular concentration of cyclic-di-GMP in the mutant over 48 h compared with that observed in the wild-type strain, which was recovered in the complemented strain. In addition, cdgD gene expression was measured in cells growing under planktonic or biofilm conditions, and differential expression was observed when KNO3 or NH4Cl was added to the minimal medium as a nitrogen source. The transcriptional fusion of the cdgD promoter with the gene encoding the autofluorescent mCherry protein indicated that the cdgD gene was expressed both under abiotic conditions and in association with wheat roots. Reduced colonization of wheat roots was observed for the mutant compared with the wild-type strain grown in the same soil conditions. The Azospirillum-plant association begins with the motility of the bacterium towards the plant rhizosphere followed by the adsorption and adherence of these bacteria to plant roots. Therefore, it is important to study the genes that contribute to this initial interaction of the bacterium with its host plant.
Publication
Journal: BioImpacts
January/12/2021
Abstract
While numerous techniques can be used to measure and analyze insulin secretion in isolated islets in culture, assessments of insulin secretion in vivo are typically indirect and only semiquantitative. The CpepSfGFP reporter mouse line allows the in vivo imaging of insulin secretion from individual islets after a glucose stimulation, in live, anesthetized mice. Imaging the whole pancreas at high resolution in live mice to track the response of each individual islet over time includes numerous technical challenges and previous reports were only limited in scope and non-quantitative. Elaborating on this previous model-through the development of an improved methodology addressing anesthesia, temperature control and motion blur-we were able to track and quantify longitudinally insulin content throughout a glucose challenge in up to two hundred individual islets simultaneously. Through this approach we demonstrate quantitatively for the first time that while isolated islets respond homogeneously to glucose in culture, their profiles differ significantly in vivo. Independent of size or location, some islets respond sharply to a glucose stimulation while others barely secrete at all. This platform therefore provides a powerful approach to study the impact of disease, diet, surgery or pharmacological treatments on insulin secretion in the intact pancreas in vivo.
Publication
Journal: BioImpacts
January/12/2021
Abstract
Adverse experience in early life can affect the formation of neuronal circuits during postnatal development and exert long-lasting influences on neural functions that can lead to the development of a variety of psychiatric disorders including depression, anxiety disorders, and post-traumatic stress disorder. Many studies have demonstrated that daily repeated maternal separation, an animal model of early-life stress, can induce impairments in emotional behaviours and cognitive function during adolescence and adulthood. However, the behavioural phenotypes of maternally separated mice under long-term group-housing conditions are largely unknown. In this study, we applied our newly developed assay system to investigate the effects of maternal separation on behaviours under group-housing conditions during four days of continuous observations. Using our system, we found that repeated maternal separation resulted in inappropriate social distance from cagemates, altered approach preferences to others, and induced a lower rank in the time spent on the running wheel under group-housing conditions in adult male mice. Focussing on these behavioural abnormalities that appear in an environment with a social context will be important insights to understand the pathogenesis of psychiatric disorders.
Publication
Journal: BioImpacts
January/12/2021
Abstract
In the pharmaceutical manufacturing, drug release behavior development is remained as one of the main challenges to improve the drug effectiveness. Recently, more focus has been done on using mesoporous silica materials as drug carriers for prolonged and superior control of drug release in human body. In this study, release behavior of paracetamol is developed using drug-loaded KCC-1-NH2 mesoporous silica, based on direct compaction method for preparation of tablets. The purpose of this study is to investigate the utilizing of pure KCC-1 mesoporous silica (KCC-1) and amino functionalized KCC-1 (KCC-1-NH2) as drug carriers in oral solid dosage formulations compared to common excipient, microcrystalline cellulose (MCC), to improve the control of drug release rate by manipulating surface chemistry of the carrier. Different formulations of KCC-1 and KCC-NH2 are designed to investigate the effect of functionalized mesoporous silica as carrier on drug controlled-release rate. The results displayed the remarkable effect of KCC-1-NH2 on drug controlled-release in comparison with the formulation containing pure KCC-1 and formulation including MCC as reference materials. The pure KCC-1 and KCC-1-NH2 are characterized using different evaluation methods such as FTIR, SEM, TEM and N2 adsorption analysis.
Publication
Journal: BioImpacts
January/12/2021
Abstract
Herein, a novel nanobiocomposite scaffold based on modifying synthesized cross-linked terephthaloyl thiourea-chitosan hydrogel (CTT-CS hydrogel) substrate using the extracted silk fibroin (SF) biopolymer and prepared Mg(OH)2 nanoparticles was designed and synthesized. The biological capacity of this nanobiocomposite scaffold was evaluated by cell viability method, red blood cells hemolytic and anti-biofilm assays. According to the obtained results from 3 and 7 days, the cell viability of CTT-CS/SF/Mg(OH)2 nanobiocomposite scaffold was accompanied by a considerable increment from 62.5 to 89.6% respectively. Furthermore, its low hemolytic effect (4.5%), and as well, the high anti-biofilm activity and prevention of the P. aeruginosa biofilm formation confirmed its promising hemocompatibility and antibacterial activity. Apart from the cell viability, blood biocompatibility, and antibacterial activity of CTT-CS/SF/Mg(OH)2 nanobiocomposite scaffold, its structural features were characterized using spectral and analytical techniques (FT-IR, EDX, FE-SEM and TG). As well as, given the mechanical tests, it was indicated that the addition of SF and Mg(OH)2 nanoparticles to the CTT-CS hydrogel could improve its compressive strength from 65.42 to 649.56 kPa.
Publication
Journal: BioImpacts
January/12/2021
Abstract
Retinal detachment (RD) causes damage, including disjunction, of the rod photoreceptor-bipolar synapse, which disrupts vision and may contribute to the poor visual recovery observed after retinal reattachment surgery. We created a model of iatrogenic RD in adult female pigs to study damage to the rod-bipolar synapse after injury and the ability of a highly specific Rho-kinase (ROCK) inhibitor to preserve synaptic structure and function. This model mimics procedures used in humans when viral vectors or cells are injected subretinally for treatment of retinal disease. Synaptic disjunction by retraction of rod spherules, quantified by image analysis of confocal sections, was present 2 h after detachment and remained 2 days later even though the retina had spontaneously reattached by then. Moreover, spherule retraction occurred in attached retina 1-2 cms from detached retina. Synaptic damage was significantly reduced by ROCK inhibition in detached retina whether injected subretinally or intravitreally. Dark-adapted full-field electroretinograms were recorded in reattached retinas to assess rod-specific function. Reduction in synaptic injury correlated with increases in rod-driven responses in drug-treated eyes. Thus, ROCK inhibition helps prevent synaptic damage and improves functional outcomes after retinal injury and may be a useful adjunctive treatment in iatrogenic RD and other retinal degenerative diseases.
Publication
Journal: BioImpacts
January/12/2021
Abstract
Endovascular management of small visceral artery aneurysms is an established treatment with satisfactory outcomes. However, when size exceeds 5 cm visceral aneurysms are considered as "giant" (giant visceral artery aneurysms or GVAAs) and management is significantly more complex. Between August 2007 and June 2019 eleven cases of GVAAs that were endovascularly treated were retrospectively reviewed and included in this single center study. Mean size was 80 mm (± 26.3 mm) x 46 mm (+ \-11.8 mm). Nine of the lesions were true aneurysms, and two were pseudoaneurysms. In 8 patients, the lesion was causing compression symptoms in the surrounding organs, one patient developed a contained rupture while 2 patients were completely asymptomatic. However, all patients were hemodynamically stable at the time of treatment. Technical success was defined as immediate complete exclusion of the aneurysmal sac, and clinical success as complete relief from clinical symptoms. Follow-up was performed with CT angiography, ultrasound and clinical examination. Mean follow-up was 45 months (range 6-84). Technical and clinical success were both 91%. Complications were one lack of control of contained rupture that was subsequently operated, one case of self-limiting non-target spleen embolization and one case of splenic abscess. Three patients died, one due to the contained rupture 15 days after procedure, the other two for other causes and occurred during the long-term follow-up. This series suggests that endovascular treatment of giant visceral artery aneurysms and pseudoaneuryms is a valid minimally invasive solution with very satisfactory immediate and long-term outcomes unless the aneurysm is already ruptured. A variety of endovascular tools may be required for successful treatment.
Publication
Journal: BioImpacts
January/12/2021
Abstract
The pyrolysis process of oil shale is significantly affected by atmospheric conditions. In this paper, the pyrolysis experiments of oil shale under non-isothermal conditions are carried out using nitrogen and carbon dioxide as heat-carrying fluids. The results show that the activation energy of the second stage of oil shale pyrolysis under carbon dioxide is less than that under nitrogen. The thermodynamic analysis of the second stage of oil shale pyrolysis shows that Gibbs free energy, activation enthalpy and activation entropy are higher under carbon dioxide than those under nitrogen, which obeys the law of carbon dioxide promoting oil shale pyrolysis. In addition, the volatile release characteristics of oil shale in the second stage of pyrolysis were analyzed, which proves that the volatile release characteristics of oil shale under carbon dioxide are higher than that under nitrogen. Therefore, carbon dioxide is helpful to promote the pyrolysis of oil shale and increases the release of volatile substances during pyrolysis.
Publication
Journal: BioImpacts
January/12/2021
Abstract
We present a detailed analysis of experimental study, which shows clear evidence of a two-stage melting process of a quasi-two-dimensional dusty plasma system in a high-frequency gas discharge. We accurately calculated global parameters of the orientational and translational order, as well as their susceptibilities to determine two critical points, related to "solid-to-hexatic" and "hexatic-to-liquid" phase transitions. The nature of the emerging defects and changes in their mutual concentration, in addition to the estimate of core energy of free dislocations also counts in favor of the formation of an intermediate hexatic phase. These results are fully consistent with the Berezinsky-Kosterlitz-Thouless theory.
Related with
Publication
Journal: Signal Transduction and Targeted Therapy
January/12/2021
Abstract
Epstein-Barr virus-associated diseases are important global health concerns. As a group I carcinogen, EBV accounts for 1.5% of human malignances, including both epithelial- and lymphatic-originated tumors. Moreover, EBV plays an etiological and pathogenic role in a number of non-neoplastic diseases, and is even involved in multiple autoimmune diseases (SADs). In this review, we summarize and discuss some recent exciting discoveries in EBV research area, which including DNA methylation alterations, metabolic reprogramming, the changes of mitochondria and ubiquitin-proteasome system (UPS), oxidative stress and EBV lytic reactivation, variations in non-coding RNA (ncRNA), radiochemotherapy and immunotherapy. Understanding and learning from this advancement will further confirm the far-reaching and future value of therapeutic strategies in EBV-associated diseases.
Publication
Journal: Nature Communications
January/12/2021
Abstract
Genome-wide association studies (GWAS) have discovered numerous genetic variants associated with human behavioural traits. However, behavioural traits are subject to misreports and longitudinal changes (MLC) which can cause biases in GWAS and follow-up analyses. Here, we demonstrate that individuals with higher disease burden in the UK Biobank (n = 455,607) are more likely to misreport or reduce their alcohol consumption levels, and propose a correction procedure to mitigate the MLC-induced biases. The alcohol consumption GWAS signals removed by the MLC corrections are enriched in metabolic/cardiovascular traits. Almost all the previously reported negative estimates of genetic correlations between alcohol consumption and common diseases become positive/non-significant after the MLC corrections. We also observe MLC biases for smoking and physical activities in the UK Biobank. Our findings provide a plausible explanation of the controversy about the effects of alcohol consumption on health outcomes and a caution for future analyses of self-reported behavioural traits in biobank data.
Publication
Journal: Nature Communications
January/12/2021
Abstract
Mechanical ventilation generates injurious forces that exacerbate lung injury. These forces disrupt lung barrier integrity, trigger proinflammatory mediator release, and differentially regulate genes and non-coding oligonucleotides including microRNAs. In this study, we identify miR-146a as a mechanosensitive microRNA in alveolar macrophages that has therapeutic potential to mitigate lung injury during mechanical ventilation. We use humanized in-vitro systems, mouse models, and biospecimens from patients to elucidate the expression dynamics of miR-146a needed to decrease lung injury during mechanical ventilation. We find that the endogenous increase in miR-146a following injurious ventilation is not sufficient to prevent lung injury. However, when miR-146a is highly overexpressed using a nanoparticle delivery platform it is sufficient to prevent injury. These data indicate that the endogenous increase in microRNA-146a during mechanical ventilation is a compensatory response that partially limits injury and that nanoparticle delivery of miR-146a is an effective strategy for mitigating lung injury during mechanical ventilation.
Publication
Journal: Nature Communications
January/12/2021
Abstract
Circular RNAs (circRNA) are a class of covalently closed single-stranded RNAs that have been implicated in cancer progression. Here we identify circNDUFB2 to be downregulated in non-small cell lung cancer (NSCLC) tissues, and to negatively correlate with NSCLC malignant features. Elevated circNDUFB2 inhibits growth and metastasis of NSCLC cells. Mechanistically, circNDUFB2 functions as a scaffold to enhance the interaction between TRIM25 and IGF2BPs, a positive regulator of tumor progression and metastasis. This TRIM25/circNDUFB2/IGF2BPs ternary complex facilitates ubiquitination and degradation of IGF2BPs, with this effect enhanced by N6-methyladenosine (m6A) modification of circNDUFB2. Moreover, circNDUFB2 is also recognized by RIG-I to activate RIG-I-MAVS signaling cascades and recruit immune cells into the tumor microenvironment (TME). Our data thus provide evidences that circNDUFB2 participates in the degradation of IGF2BPs and activation of anti-tumor immunity during NSCLC progression via the modulation of both protein ubiquitination and degradation, as well as cellular immune responses.
Publication
Journal: Nature Communications
January/12/2021
Abstract
The rapid development of a SARS-CoV-2 vaccine is a global priority. Here, we develop two capsid-like particle (CLP)-based vaccines displaying the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. RBD antigens are displayed on AP205 CLPs through a split-protein Tag/Catcher, ensuring unidirectional and high-density display of RBD. Both soluble recombinant RBD and RBD displayed on CLPs bind the ACE2 receptor with nanomolar affinity. Mice are vaccinated with soluble RBD or CLP-displayed RBD, formulated in Squalene-Water-Emulsion. The RBD-CLP vaccines induce higher levels of serum anti-spike antibodies than the soluble RBD vaccines. Remarkably, one injection with our lead RBD-CLP vaccine in mice elicits virus neutralization antibody titers comparable to those found in patients that had recovered from COVID-19. Following booster vaccinations, the virus neutralization titers exceed those measured after natural infection, at serum dilutions above 1:10,000. Thus, the RBD-CLP vaccine is a highly promising candidate for preventing COVID-19.
Publication
Journal: Nature Communications
January/12/2021
Abstract
Smoldering myeloma (SMM) is associated with a high-risk of progression to myeloma (MM). We report the results of a study of 82 patients with both targeted sequencing that included a capture of the immunoglobulin and MYC regions. By comparing these results to newly diagnosed myeloma (MM) we show fewer NRAS and FAM46C mutations together with fewer adverse translocations, del(1p), del(14q), del(16q), and del(17p) in SMM consistent with their role as drivers of the transition to MM. KRAS mutations are associated with a shorter time to progression (HR 3.5 (1.5-8.1), p = 0.001). In an analysis of change in clonal structure over time we studied 53 samples from nine patients at multiple time points. Branching evolutionary patterns, novel mutations, biallelic hits in crucial tumour suppressor genes, and segmental copy number changes are key mechanisms underlying the transition to MM, which can precede progression and be used to guide early intervention strategies.
Publication
Journal: Nature Communications
January/12/2021
Abstract
Magnetized plasma interactions are ubiquitous in astrophysical and laboratory plasmas. Various physical effects have been shown to be important within colliding plasma flows influenced by opposing magnetic fields, however, experimental verification of the mechanisms within the interaction region has remained elusive. Here we discuss a laser-plasma experiment whereby experimental results verify that Biermann battery generated magnetic fields are advected by Nernst flows and anisotropic pressure effects dominate these flows in a reconnection region. These fields are mapped using time-resolved proton probing in multiple directions. Various experimental, modelling and analytical techniques demonstrate the importance of anisotropic pressure in semi-collisional, high-β plasmas, causing a reduction in the magnitude of the reconnecting fields when compared to resistive processes. Anisotropic pressure dynamics are crucial in collisionless plasmas, but are often neglected in collisional plasmas. We show pressure anisotropy to be essential in maintaining the interaction layer, redistributing magnetic fields even for semi-collisional, high energy density physics (HEDP) regimes.
Publication
Journal: Nature Communications
January/12/2021
Abstract
Quantum control of a system requires the manipulation of quantum states faster than any decoherence rate. For mesoscopic systems, this has so far only been reached by few cryogenic systems. An important milestone towards quantum control is the so-called strong coupling regime, which in cavity optomechanics corresponds to an optomechanical coupling strength larger than cavity decay rate and mechanical damping. Here, we demonstrate the strong coupling regime at room temperature between a levitated silica particle and a high finesse optical cavity. Normal mode splitting is achieved by employing coherent scattering, instead of directly driving the cavity. The coupling strength achieved here approaches three times the cavity linewidth, crossing deep into the strong coupling regime. Entering the strong coupling regime is an essential step towards quantum control with mesoscopic objects at room temperature.
Publication
Journal: BioImpacts
January/12/2021
Abstract
Patients with chronic kidney disease (CKD) have elevated circulating levels of trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes and associated with cardiovascular diseases. High circulating levels of TMAO and its dietary precursor, choline, predict increased risk for development of CKD in apparently healthy subjects, and studies in mice fed TMAO or choline suggest that TMAO can contribute to kidney impairment and renal fibrosis. Here we examined the interactions between TMAO, kidney disease, and cardiovascular disease in mouse models. We observed that while female hyperlipidemic apoE KO mice fed a 0.2% adenine diet for 14 weeks developed CKD with elevated plasma levels of TMAO, provision of a non-lethal inhibitor of gut microbial trimethylamine (TMA) production, iodomethylcholine (IMC), significantly reduced multiple markers of renal injury (plasma creatinine, cystatin C, FGF23, and TMAO), reduced histopathologic evidence of fibrosis, and markedly attenuated development of microalbuminuria. In addition, while the adenine-induced CKD model significantly increased heart weight, a surrogate marker for myocardial hypertrophy, this was largely prevented by IMC supplementation. Surprisingly, adenine feeding did not increase atherosclerosis and significantly decreased the expression of inflammatory genes in the aorta compared to the control groups, effects unrelated to TMAO levels. Our data demonstrate that inhibition of TMAO production attenuated CKD development and cardiac hypertrophy in mice, suggesting that TMAO reduction may be a novel strategy in treating CKD and its cardiovascular disease complications.
Publication
Journal: BioImpacts
January/12/2021
Abstract
The ZIPANGU study assessed the efficacy and safety of ranibizumab as a one loading dose + pro re nata (one + PRN) regimen with/without focal/grid laser among treatment-naïve patients suffering from macular edema (ME) following branch retinal vein occlusion (BRVO). ZIPANGU was a phase IV, prospective, randomized, open-label, active-controlled, 12-month, two-arm, multicenter study. Treatment-naïve patients with visual impairment (19-73 letters) caused by ME, defined as central subfield thickness (CSFT) > 300 µm, due to BRVO were randomly assigned to ranibizumab monotherapy (n = 29) or combination therapy (ranibizumab + focal/grid short-pulse laser, n = 30). The primary endpoint was the number of ranibizumab injections. Secondary endpoints were mean changes in best-corrected visual acuity (BCVA) and CSFT, and safety. There were no statistically significant differences in the mean number of ranibizumab injections between monotherapy (4.3 injections) vs. combination (4.1 injections) therapy, or in CSFT. BCVA improvement in the monotherapy arm (22.0 letters) was better than the combination therapy arm (15.0 letters) (p = 0.035). Overall, both regimens appeared to be safe and well tolerated. One + PRN ranibizumab is safe and efficacious in treatment-naïve patients with ME secondary to BRVO. A conjunctive laser treatment did not lead to better functional outcomes or fewer ranibizumab injections.
Publication
Journal: BioImpacts
January/12/2021
Abstract
Melanotransferrin (MTf) is an iron-binding member of the transferrin superfamily that can be membrane-anchored or secreted in serum. On cells, it can mediate transferrin-independent iron uptake and promote proliferation. In serum, it is a transcytotic iron transporter across the blood-brain barrier. MTf has been exploited as a drug delivery carrier to the brain and as an antibody-drug conjugate (ADC) target due to its oncogenic role in melanoma and its elevated expression in triple-negative breast cancer (TNBC). For treatment of TNBC, an MTf-targeting ADC completed a phase I clinical trial (NCT03316794). The structure of its murine, unconjugated Fab fragment (SC57.32) is revealed here in complex with MTf. The MTf N-lobe is in an active and iron-bound, closed conformation while the C-lobe is in an open conformation incompatible with iron binding. This combination of active and inactive domains displays a novel inter-domain arrangement in which the C2 subdomain angles away from the N-lobe. The C2 subdomain also contains the SC57.32 glyco-epitope, which comprises ten protein residues and two N-acetylglucosamines. Our report reveals novel features of MTf and provides a point of reference for MTf-targeting, structure-guided drug design.
Publication
Journal: BioImpacts
January/12/2021
Abstract
Major depressive disorder (MDD) is a common psychiatric disorder with a multifactorial aetiology determined by the interaction between genetic and environmental risk factors. Pieces of evidence indicate that inflammation and immune activation may contribute to the onset of MDD playing a role in the pathogenetic mechanism. To date, it is not known to which extent the association between MDD and inflammation is shaped by the genetic background or by the presence of environmental factors. To clarify this issue, we analyzed genotype and blood RNA profiles of 463 MDD cases and 459 controls (NIMH-Study 88/Site621) estimating the Genetic and Environmental Regulated eXpression component of gene expression (GReX and EReX respectively). Both components were tested for association with MDD. Many genes belonging to the α/β interferon signaling pathway showed an association between MDD and EReX, only two between MDD and GReX. Also other MDD differentially expressed genes were more influenced by the EReX than by GReX. These results suggest that impact of the genetic background on MDD blood gene expression alterations is much lower than the contribution of environmental factors and almost absent for the genes of the interferon pathway.
Publication
Journal: Nature Communications
January/12/2021
Abstract
Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.
Publication
Journal: BioImpacts
January/12/2021
Abstract
Therapeutic hypothermia (TH) enhances pulmonary surfactant performance in vivo by molecular mechanisms still unknown. Here, the interfacial structure and the composition of lung surfactant films have been analysed in vitro under TH as well as the molecular basis of its improved performance both under physiological and inhibitory conditions. The biophysical activity of a purified porcine surfactant was tested under slow and breathing-like dynamics by constrained drop surfactometry (CDS) and in the captive bubble surfactometer (CBS) at both 33 and 37 °C. Additionally, the temperature-dependent surfactant activity was also analysed upon inhibition by plasma and subsequent restoration by further surfactant supplementation. Interfacial performance was correlated with lateral structure and lipid composition of films made of native surfactant. Lipid/protein mixtures designed as models to mimic different surfactant contexts were also studied. The capability of surfactant to drastically reduce surface tension was enhanced at 33 °C. Larger DPPC-enriched domains and lower percentages of less active lipids were detected in surfactant films exposed to TH-like conditions. Surfactant resistance to plasma inhibition was boosted and restoration therapies were more effective at 33 °C. This may explain the improved respiratory outcomes observed in cooled patients with acute respiratory distress syndrome and opens new opportunities in the treatment of acute lung injury.
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