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Bronchoalveolar lavage is commonly performed to assess inflammation and identify responsible pathogens in lung diseases, and its findings might be used to evaluate the immune profile of the lung tumor microenvironment (TME). To investigate whether bronchoalveolar lavage fluid (BALF) analysis can help identify non-small cell lung cancer (NSCLC) patients who respond to immune checkpoint inhibitors (ICIs), BALF and blood were prospectively collected before initiating nivolumab. The secreted molecules, microbiome, and cellular profiles based on BALF and blood analysis were compared regarding therapeutic effect in 12 patients. Compared to ICI non-responders, responders showed significantly higher CXCL9 levels and a greater diversity of the lung microbiome profile in BALF, along with a greater frequency of the CD56+ subset in blood T cells, whereas no significant difference in PD-L1 expression was found in tumor cells. Antibiotic treatment in a preclinical lung cancer model significantly decreased CXCL9 in the lung TME, resulting in reduced sensitivity to anti-PD-1 antibody, which was reversed by CXCL9 induction in tumor cells. Thus, CXCL9 might be associated with the lung TME microbiome, and their balance could contribute to nivolumab sensitivity in NSCLC patients. BALF analysis can help predict the efficacy of ICIs when performed along with currently approved examinations.
Kentaro Masuhiro, Motohiro Tamiya, Kosuke Fujimoto, Shohei Koyama, Yujiro Naito, Akio Osa, Takashi Hirai, Hidekazu Suzuki, Norio Okamoto, Takayuki Shiroyama, Kazumi Nishino, Yuichi Adachi, Takuro Nii, Yumi Kinugasa-Katayama, Akiko Kajihara, Takayoshi Morita, Seiya Imoto, Satoshi Uematsu, Takuma Irie, Daisuke Okuzaki, Taiki Aoshi, Yoshito Takeda, Toru Kumagai, Tomonori Hirashima, Atsushi Kumanogoh
BACKGROUND. Breakthrough SARS-CoV-2 infections in vaccinated individuals have been previously associated with suboptimal humoral immunity. However, less is known about breakthrough infections with the Omicron variant. METHODS. We analyzed SARS-CoV-2 specific antibody and cellular responses in healthy vaccine recipients who experienced breakthrough infections a median of 50 days after receiving a booster mRNA vaccine with an ACE2 binding inhibition assay and an ELISpot assay respectively.Results: We found high levels of antibodies that inhibited vaccine strain spike protein binding to ACE2 but lower levels that inhibited Omicron variant spike protein binding to ACE2 in four boosted vaccine recipients prior to infection. The levels of antibodies that inhibited vaccine strain and Omicron spike protein binding after breakthrough in 18 boosted vaccine recipients were similar to levels seen in COVID-19 negative boosted vaccine recipients. In contrast, boosted vaccine recipients had significantly stronger T cells responses to both vaccine strain and Omicron variant spike proteins at the time of breakthrough. CONCLUSIONS. Our data suggest that breakthrough infections with the Omicron variant can occur despite robust immune responses to the vaccine strain spike protein. FUNDING. This work was supported by the Johns Hopkins COVID-19 Vaccine-related Research Fund and by funds from the National Institute of Allergy and Infectious Disease intramural program as well as awards from the National Cancer Institute (U54CA260491) and the National Institutes of Allergy and Infectious Disease (K08AI156021 and U01AI138897)
Bezawit A. Woldemeskel, Caroline C. Garliss, Tihitina Y. Aytenfisu, Trevor S. Johnston, Evan J. Beck, Arbor G. Dykema, Nicole Frumento, Desiree A. Wright, Andrew H. Yang, Alexander I. Damanakis, Oliver Laeyendecker, Andrea L. Cox, Heba H. Mostafa, Andrew H. Karaba, Joel N. Blankson
Shortness of breath, chest pain, and palpitations occur as post-acute sequelae of COVID-19 (PASC), but whether symptoms are associated with echocardiographic abnormalities, cardiac biomarkers, or markers of systemic inflammation remains unknown. In a cross-sectional analysis, we assessed symptoms, performed echocardiograms, and measured biomarkers among adults >8 weeks after confirmed SARS-CoV-2 infection. We modeled associations between symptoms and baseline characteristics, echocardiographic findings, and biomarkers using logistic regression. We enrolled 102 participants at a median 7.2 months (IQR 4.1-9.1) following COVID-19 onset; 47 individuals reported dyspnea, chest pain, or palpitations. Median age was 52 years (range 24-86) and 41% were women. Female sex, hospitalization, IgG antibody to SARS-CoV-2 receptor binding domain and C-reactive protein were associated with symptoms. Regarding echocardiographic findings, 4/47 (9%) with symptoms had pericardial effusions compared to 0/55 without symptoms (p=0.038); those with effusions had a median 4 symptoms compared to 1 without (p<0.001). There was no strong evidence for a relationship between symptoms and echocardiographic functional parameters or other biomarkers. Among adults >8 weeks after SARS-CoV-2 infection, SARS-CoV-2 RBD antibodies, markers of inflammation and, possibly, pericardial effusions are associated with cardiopulmonary symptoms. Investigation into inflammation as a mechanism underlying PASC is warranted.
Matthew S. Durstenfeld, Michael J. Peluso, J. Daniel Kelly, Sithu Win, Shreya Swaminathan, Danny Li, Victor M. Arechiga, Victor Antonio Zepeda, Kaiwen Sun, Shirley J. Shao, Christopher Hill, Mireya I. Arreguin, Scott Lu, Rebecca Hoh, Viva W. Tai, Ahmed Chenna, Brandon C. Yee, John W. Winslow, Christos J. Petropoulos, John Kornak, Timothy J. Henrich, Jeffrey N. Martin, Steven G. Deeks, Priscilla Y. Hsue
The ongoing COVID-19 pandemic calls for more effective diagnostic tools. T cell response assessment serves as an independent indicator of prior COVID-19 exposure while also contributing to a more comprehensive characterization of SARS-CoV-2 immunity. In this study, we systematically assessed the immunogenicity of 118 epitopes with immune cells collected from multiple cohorts of vaccinated, convalescent, healthy unexposed, and SARS-CoV-2 exposed donors. We identified 75 immunogenic epitopes, 24 of which were immunodominant. We further confirmed HLA restriction for 49 epitopes, and described association with more than one HLA allele for 14 of these. Exclusion of two cross-reactive epitopes that generated a response in pre-pandemic samples, left us with a 73-epitope set that offered excellent diagnostic specificity without losing sensitivity compared to full-length antigens, which evoked a robust cross-reactive response. We subsequently incorporated this set of epitopes into an in vitro diagnostic ‘Corona-T-test’ which achieved a diagnostic accuracy of 95% in a clinical trial. In a cohort of asymptomatic seronegative individuals with a history of prolonged SARS-CoV-2 exposure, we observed a complete absence of T cell response to our epitope panel. In combination with strong reactivity to full-length antigens, this suggests that a cross-reactive response might protect these individuals.
Aleksei Titov, Regina Shaykhutdinova, Olga V. Shcherbakova, Yana V. Serdyuk, Savely A. Sheetikov, Ksenia V. Zornikova, Alexandra V. Maleeva, Alexandra Khmelevskaya, Dmitry V. Dianov, Naina T. Shakirova, Dmitry B. Malko, Maxim Shkurnikov, Stepan Nersisyan, Alexander Tonevitsky, Ekaterina Khamaganova, Anton V. Ershov, Elena Y. Osipova, Ruslan V. Nikolaev, Dmitry E. Pershin, Viktoria A. Vedmedskia, Mikhail Maschan, Victoria R. Ginanova, Grigory A. Efimov
Erythropoietin (EPO) has multiple non-erythropoietic functions including immune modulation, but EPO’s effects in transplantation remain incompletely understood. We tested the mechanisms linking EPO administration to prolongation of murine heterotopic heart transplantation using wild type (WT) and conditional EPO receptor (EPOR) knockout mice as recipients. In WT controls, peri-transplant administration of EPO synergized with CTLA4-Ig to prolong allograft survival (P < 0.001), reduce frequencies of donor-reactive effector CD8+ T cells in the spleen (P < 0.001) and in the graft (P < 0.05), and increase frequencies and total numbers of donor-reactive regulatory T cells (TREG, P < 0.01 for each) vs. CTLA4-Ig alone. Studies performed in conditional EPOR knockout recipients showed that each of these differences required EPOR expression in myeloid cells, but not in T cells. Analysis of mRNA isolated from spleen monocytes showed that EPO/EPOR ligation upregulated macrophage-expressed, anti-inflammatory, regulatory and pro-efferocytosis genes, and downregulated selected pro-inflammatory genes. Together, the data support the conclusion that EPO promotes TREG-dependent murine cardiac allograft survival by crucially altering the phenotype and function of macrophages. Coupled with our previous documentation that EPO promotes TREG expansion in humans, the data support the need for testing the addition of EPO to costimulatory blockade-containing immunosuppression regimens in an effort to prolong human transplant survival.
Julian K. Horwitz, Sofia Bin, Robert L. Fairchild, Karen S, Keslar, Zhengzi Yi, Weijia Zhang, Vasile I. Pavlov, Yansui Li, Joren C. Madsen, Paolo Cravedi, Peter S. Heeger
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