This is the first prospective study of the effects of human gut microbiota and metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma patients. Whereas many melanoma ...patients exhibit profound response to ICT, there are fewer options for patients failing ICT—particularly with BRAF-wild-type disease. In preclinical studies, specific gut microbiota promotes regression of melanoma in mice. We therefore conducted a study of the effects of pretreatment gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid Tumors response in 39 metastatic melanoma patients treated with ipilimumab, nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67% responses and 8% stable disease; P achieved 23% responses and 23% stable disease. ICT responders for all types of therapies were enriched for Bacteroides caccae. Among IN responders, the gut microbiome was enriched for Faecalibacterium prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P responders, the microbiome was enriched for Dorea formicogenerans. Unbiased shotgun metabolomics revealed high levels of anacardic acid in ICT responders. Based on these pilot studies, both additional confirmatory clinical studies and preclinical testing of these bacterial species and metabolites are warranted to confirm their ICT enhancing activity.
Summary
Background
Many bacterial components in indoor dust can evoke inflammatory pulmonary diseases. Bacteria secrete nanometre‐sized vesicles into the extracellular milieu, but it remains to be ...determined whether bacteria‐derived extracellular vesicles in indoor dust are pathophysiologically related to inflammatory pulmonary diseases.
Objective
To evaluate whether extracellular vesicles (EV) in indoor air are related to the pathogenesis of pulmonary inflammation and/or asthma.
Methods
Indoor dust was collected from a bed mattress in an apartment. EV were prepared by sequential ultrafiltration and ultracentrifugation. Innate and adaptive immune responses were evaluated after airway exposure of EV.
Results
Repeated intranasal application of indoor‐dust‐induced neutrophilic pulmonary inflammation accompanied by lung infiltration of both Th1 and Th17 cells. EV 50–200 nm in diameter were present (102.5 μg protein concentration/g dust) in indoor dust. These vesicles were internalized by airway epithelial cells and alveolar macrophages, and this process was blocked by treatment of polymyxin B (an antagonist of lipopolysaccharide, an outer‐membrane component of Gram‐negative bacteria). Intranasal application of 0.1 or 1 μg of these vesicles for 4 weeks elicited neutrophilic pulmonary inflammation. This phenotype was accompanied by lung infiltration of both Th1 and Th17 cells, which were reversed by treatment of polymyxin B. Serum dust EV‐reactive IgG1 levels were significantly higher in atopic children with asthma than in atopic healthy children and those with rhinitis or dermatitis.
Conclusion & Clinical Relevance
Indoor dust EV, especially derived from Gram‐negative bacteria, is a possible causative agent of neutrophilic airway diseases.
All issuers in China’s local government bond market, which is nascent but growing rapidly, have the same AAA ratings. However, we provide evidence that the credit rating agency’s reputation can ...certify differences in ratings’ reliability and further impact bond pricing. On the basis of a sample of 7941 local government bonds issued from 2015 to 2021, results show that risk premium is significantly low for bonds rated by prestigious credit rating agencies, which means that issuers can save borrowing costs. Moreover, local governments regarded as less transparent in fiscal information disclosure enjoy more cost savings for their bonds by hiring more reputable agencies. Regression results are affirmed with the Heckman two-stage model, difference-in-differences regression, and machine learning method to solve the potential endogeneity issue. This paper’s findings contribute to the debate on the credit rating agency’s reputation hypothesis and present three implications. First, investors can rely on the credit rating agency’s reputation to complement credit risk analysis. Second, local government policymakers should implement appropriate policies to reduce debt costs and improve public finance sustainability. Lastly, regulators should considerably focus on the supervision of credit rating agencies, given their substantial impact on bond pricing and the market’s information asymmetry.
Vascular endothelial growth factor (VEGF) induces adhesion molecules on endothelial cells during inflammation. Here we examined the mechanisms underlying VEGF-stimulated expression of intercellular ...adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin in human umbilical vein endothelial cells. VEGF (20 ng/ml) increased expression of ICAM-1, VCAM-1, and E-selectin mRNAs in a time-dependent manner. These effects were significantly suppressed by Flk-1/kinase-insert domain containing receptor (KDR) antagonist and by inhibitors of phospholipase C, nuclear factor (NF)-κB, sphingosine kinase, and protein kinase C, but they were not affected by inhibitors of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1/2 or nitric-oxide synthase. Unexpectedly, the phosphatidylinositol (PI) 3′-kinase inhibitor wortmannin enhanced both basal and VEGF-stimulated adhesion molecule expression, whereas insulin, a PI 3′-kinase activator, suppressed both basal and VEGF-stimulated expression. Gel shift analysis revealed that VEGF stimulated NF-κB activity. This effect was inhibited by phospholipase C, NF-κB, or protein kinase C inhibitor. VEGF increased VCAM-1 and ICAM-1 protein levels and increased leukocyte adhesiveness in a NF-κB-dependent manner. These results suggest that VEGF-stimulated expression of ICAM-1, VCAM-1, and E-selectin mRNAs was mainly through NF-κB activation with PI 3′-kinase-mediated suppression, but was independent of nitric oxide and MEK. Thus, VEGF simultaneously activates two signal transduction pathways that have opposite functions in the induction of adhesion molecule expression. The existence of parallel inverse signaling implies that the induction of adhesion molecule expression by VEGF is very finely regulated.
The classic 'size principle' of motor control describes how increasingly forceful movements arise by the recruitment of motoneurons of progressively larger size and force output into the active pool. ...We explored the activity of pools of spinal interneurons in larval zebrafish and found that increases in swimming speed were not associated with the simple addition of cells to the active pool. Instead, the recruitment of interneurons at faster speeds was accompanied by the silencing of those driving movements at slower speeds. This silencing occurred both between and within classes of rhythmically active premotor excitatory interneurons. Thus, unlike motoneurons, there is a continuous shift in the set of cells driving the behavior, even though changes in the speed of the movements and the frequency of the motor pattern appear to be smoothly graded. We conclude that fundamentally different principles may underlie the recruitment of motoneuron and interneuron pools.
The integration of environmental psychology into the broader domain of water demand research is a growing aspect of water policy. This article contends that effective water demand management policies ...can only be developed through an identification of the key psychosocial drivers of water use and conservation. By situating goal-framing theory in the context of residential water consumption in Singapore, the article analyzes the determinants of water conservation behaviour. Appealing for a shift away from policies designed to gratify people's hedonic and gain goals, it asserts that greater priority should be placed on strengthening people's normative goals towards water conservation.
About the Authors: Andrew Y. Koh * E-mail: andrew.koh@utsouthwestern.edu Affiliations Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of ...America, Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America, Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America ORCID http://orcid.org/0000-0003-2172-5126Citation: Koh AY (2017) The microbiome in hematopoietic stem cell transplant recipients and cancer patients: ...cancer and stem cell transplant (SCT) patients often receive multiple antibiotics for long durations of time, and many patients never have a laboratory-documented infection. ...specific antibiotic therapies, particularly those that destroy specific anaerobic commensal communities, appear to be linked to the development of these complications 5, 8-10. The major host immune deficits that promote bacterial and fungal translocation from the GI tract include deficiencies in cellular immunity (particularly neutropenia); impaired intestinal barriers (an adverse consequence of cytotoxic chemotherapy, also referred to as mucositis); and GI microbiota imbalance (often driven by use of broad-spectrum antibiotics). In preclinical models emulating the development of gut-derived bacteremia and fungemia, all 3 host defense mechanisms need to be impaired to promote microbial dissemination from the gut: antibiotics to deplete gut commensal microbiota, allowing high levels of pathogenic microbial colonization (i.e., P. aeruginosa or Candida albicans) and cytotoxic chemotherapy (e.g., cyclophosphamide) to both deplete neutrophils and damage GI epithelium 11, 12. Whereas severe neutropenia and gut mucosal damage are, more or less, experienced by all cancer and SCT patients, there is emerging evidence...
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