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1.
Cancer Immunol Res ; 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32132105

RESUMO

The identification of biomarkers for patient stratification is fundamental to precision medicine efforts in oncology. Here, we identified two baseline, circulating immune cell subsets associated with overall survival in metastatic pancreatic cancer patients who were enrolled in two phase 2 randomized studies of GVAX pancreas and CRS-207 immunotherapy. Single-cell mass cytometry was used to simultaneously measure 38 cell surface or intracellular markers in peripheral blood mononuclear cells obtained from a phase 2a patient sub-cohort (N=38). CITRUS, an algorithm for identification of stratifying subpopulations in multidimensional cytometry datasets, was used to identify single-cell signatures associated with clinical outcome. Patients with a higher abundance of CD8+CD45RO-CCR7-CD57+ cells and a lower abundance of CD14+CD33+CD85j+ cells had improved overall survival (median OS, range (days) 271, 43-1247) compared to patients with a lower abundance of CD8+CD45RO-CCR7-CD57+ cells and higher abundance of CD14+CD33+CD85j+ cells (77, 24-1247 days; P=0.0442). The results from this prospective-retrospective biomarker analysis were validated by flow cytometry in 200 pancreatic cancer patients enrolled in a phase 2b study (P=0.0047). The identified immune correlates provide potential prognostic or predictive signatures that could be employed for patient stratification.

2.
Trials ; 20(1): 741, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847861

RESUMO

BACKGROUND: Chemotherapy after surgery for breast cancer plays a fundamental role in reducing the risk of distant and local recurrence. An increasing number of patients seek traditional Chinese medicine (TCM) during adjuvant chemotherapy to relieve symptom discomfort and side effects as well as to strengthen the body's defenses. However, evidence on how concurrent TCM treatment affects prognosis is scarce. This trial aims to evaluate the association between TCM treatment and disease-free survival outcomes for patients with early breast cancer who are undergoing adjuvant chemotherapy. METHODS/DESIGN: This is a non-randomized, single center, prospective cohort study begun in November 2018 in Kaohsiung, Taiwan. A sample of 310 participants diagnosed with early breast cancer was recruited from the Breast Cancer Research Team and will be followed up every 3 to 6 months until October 2023. Detailed information of the participants, including general information, history of cancer, quality of life, side effects and safety of treatment, TCM body constitution, and meridian energy analysis, was collected face to face at baseline. DISCUSSION: This is the first prospective observational cohort study on TCM in patients with early breast cancer who are receiving adjuvant chemotherapy to evaluate the prognosis. Through this trial, we hope to assess the feasibility of a larger-scale clinical trial in the future and formulate an integrated TCM care program. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03797248. Registered on 5 January 2019.

4.
CNS Drugs ; 33(3): 225-238, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30758782

RESUMO

BACKGROUND: Clozapine is the most effective medication for treatment-refractory schizophrenia. However, it has a high burden of adverse events, including common adverse events such as sialorrhea. Sialorrhea can lead to severe physical complications such as aspiration pneumonia, as well as psychological complications including embarrassment and low self-esteem. Compromised adherence and treatment discontinuation can occur due to intolerability. There have been no meta-analyses examining strategies to mitigate clozapine-induced sialorrhea. METHODS: We systematically searched Chinese and Western research databases for randomised controlled trials examining agents for clozapine-induced sialorrhea. No limit to language or date were applied to the search. Where sufficient data for individual agents was available, pairwise meta-analyses were conducted. Results were provided as risk ratios and number needed to treat. Sensitivity analysis was conducted by study quality. Adverse events were provided as number needed to harm. RESULTS: 19 studies provided data for use in the meta-analysis. Improvement in clozapine-induced sialorrhea was seen in meta-analyses of propantheline (studies = 6, risk ratio [RR] 2.38, 95% confidence interval [CI] 1.52-3.73; number needed to treat [NNT] 3, 95% CI 1.9-2.7), diphenhydramine (studies = 5, RR 3.09, 95% CI 2.36-4.03; NNT 2, 95% CI 1.5-2.0), chlorpheniramine (studies = 2, RR 2.37, 95% CI 1.59-3.55; NNT 3, 95% CI 1.6-3.5), and benzamide derivatives (odds ratio [OR] 6.93, 95% CI 3.03-15.86). When meta-analyses were limited to high-quality studies, all these results remained significant. Single studies of benzhexol, cyproheptadine, doxepin and Kongyan Tang showed promise. Propantheline increased rates of constipation with a number needed to harm (NNH) of 9 (95% CI 4.2-204.1). CONCLUSION: Clozapine-induced sialorrhea is a potentially serious adverse event. Included studies in this meta-analysis were limited by poor study quality. Diphenhydramine, chlorpheniramine and benzamide derivatives appear to have the best supporting evidence and lowest reported adverse events. Caution should be exercised when using propantheline given its increased risk of constipation.

5.
Complement Ther Med ; 42: 226-232, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30670246

RESUMO

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is a progressive, prolonged, and often irreversible side effect of many chemotherapeutic agents. The development of neuropathic pain is still poorly managed by clinically available drugs at present. METHODS: In this mini-review, we summarized the current knowledge of pathobiology for CIPN, and selected evidence on the application of complementary therapies in experimental studies. RESULTS: Medicinal plants are considered to be the most common complementary therapy modalities for CIPN. Therefore, we identified ten medicinal herbal extracts as well as their phytochemicals, and three herbal formulas. Multiple complementary therapies have been used and studied for decades, and their effects against CIPN are focus on anti-oxidative activity. However, there is still controversial due to the diverse manifestations of different antineoplastic agents and complex drug interactions. CONCLUSIONS: Novel therapies or drugs that have proven to be effective in animals require further investigation, so confirmation of their efficacy and safety will require time.


Assuntos
Antineoplásicos/efeitos adversos , Terapias Complementares/métodos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Preparações de Plantas/farmacologia , Preparações de Plantas/uso terapêutico , Plantas Medicinais/química , Animais , Humanos , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico
6.
Nature ; 564(7736): 425-429, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30518860

RESUMO

Haematopoiesis is an essential process that evolved in multicellular animals. At the heart of this process are haematopoietic stem cells (HSCs), which are multipotent and self-renewing, and generate the entire repertoire of blood and immune cells throughout an animal's life1. Although there have been comprehensive studies on self-renewal, differentiation, physiological regulation and niche occupation in vertebrate HSCs, relatively little is known about the evolutionary origin and niches of these cells. Here we describe the haematopoietic system of Botryllus schlosseri, a colonial tunicate that has a vasculature and circulating blood cells, and interesting stem-cell biology and immunity characteristics2-8. Self-recognition between genetically compatible B. schlosseri colonies leads to the formation of natural parabionts with shared circulation, whereas incompatible colonies reject each other3,4,7. Using flow cytometry, whole-transcriptome sequencing of defined cell populations and diverse functional assays, we identify HSCs, progenitors, immune effector cells and an HSC niche, and demonstrate that self-recognition inhibits allospecific cytotoxic reactions. Our results show that HSC and myeloid lineage immune cells emerged in a common ancestor of tunicates and vertebrates, and also suggest that haematopoietic bone marrow and the B. schlosseri endostyle niche evolved from a common origin.


Assuntos
Hematopoese , Sistema Hematopoético/citologia , Mamíferos/sangue , Filogenia , Urocordados/citologia , Animais , Diferenciação Celular , Linhagem da Célula , Citotoxicidade Imunológica , Feminino , Citometria de Fluxo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Imunidade Celular , Isoantígenos/imunologia , Masculino , Mamíferos/anatomia & histologia , Células Mieloides/citologia , Células Mieloides/imunologia , Fagocitose/imunologia , Nicho de Células-Tronco , Transcriptoma/genética , Urocordados/anatomia & histologia , Urocordados/genética , Urocordados/imunologia
7.
Nat Commun ; 9(1): 4906, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30464173

RESUMO

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a powerful tool for human disease modeling and therapeutic testing. However, their use remains limited by their immaturity and heterogeneity. To characterize the source of this heterogeneity, we applied complementary single-cell RNA-seq and bulk RNA-seq technologies over time during hiPSC cardiac differentiation and in the adult heart. Using integrated transcriptomic and splicing analysis, more than half a dozen distinct single-cell populations were observed, several of which were coincident at a single time-point, day 30 of differentiation. To dissect the role of distinct cardiac transcriptional regulators associated with each cell population, we systematically tested the effect of a gain or loss of three transcription factors (NR2F2, TBX5, and HEY2), using CRISPR genome editing and ChIP-seq, in conjunction with patch clamp, calcium imaging, and CyTOF analysis. These targets, data, and integrative genomics analysis methods provide a powerful platform for understanding in vitro cellular heterogeneity.


Assuntos
Diferenciação Celular , Heterogeneidade Genética , Miócitos Cardíacos/metabolismo , Análise de Célula Única/métodos , Potenciais de Ação , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fator II de Transcrição COUP/metabolismo , Sinalização do Cálcio , Humanos , Células-Tronco Pluripotentes Induzidas , Proteínas Repressoras/metabolismo , Análise de Sequência de RNA , Proteínas com Domínio T/metabolismo , Transcriptoma
8.
Proc Natl Acad Sci U S A ; 115(35): E8236-E8245, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-30104385

RESUMO

During neural development, growing axons express specific surface receptors in response to various environmental guidance cues. These axon guidance receptors are regulated through intracellular trafficking and degradation to enable navigating axons to reach their targets. In Caenorhabditis elegans, the UNC-5 receptor is necessary for dorsal migration of developing motor axons. We previously found that MAX-1 is required for UNC-5-mediated axon repulsion, but its mechanism of action remained unclear. Here, we demonstrate that UNC-5-mediated axon repulsion in C. elegans motor axons requires both max-1 SUMOylation and the AP-3 complex ß subunit gene, apb-3 Genetic interaction studies show that max-1 is SUMOylated by gei-17/PIAS1 and acts upstream of apb-3 Biochemical analysis suggests that constitutive interaction of MAX-1 and UNC-5 receptor is weakened by MAX-1 SUMOylation and by the presence of APB-3, a competitive interactor with UNC-5. Overexpression of APB-3 reroutes the trafficking of UNC-5 receptor into the lysosome for protein degradation. In vivo fluorescence recovery after photobleaching experiments shows that MAX-1 SUMOylation and APB-3 are required for proper trafficking of UNC-5 receptor in the axon. Our results demonstrate that SUMOylation of MAX-1 plays an important role in regulating AP-3-mediated trafficking and degradation of UNC-5 receptors during axon guidance.


Assuntos
Axônios/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Sumoilação/fisiologia , Fatores de Transcrição/metabolismo , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Ligação a DNA/genética , Proteínas do Tecido Nervoso/genética , Transporte Proteico/fisiologia , Fatores de Transcrição/genética
9.
Complement Ther Med ; 38: 67-73, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29857882

RESUMO

OBJECTIVE: Hypotension during hemodialysis (HD) is the most common complication that negatively affects the quality of life of patients. The objective of the current study was to evaluate the preliminary efficacy and safety of herbal acupoint therapy (HAT) for intradialytic hypotension (IDH). METHODS: A randomized, placebo-controlled trial was performed in 32 HD patients to determine whether HAT was more effective than a sham treatment for the treatment of IDH. The outcomes were frequency of IDH episodes and number of nursing interventions during HD sessions, pre- and post-dialysis BP, subjective change in fatigue as measured by the Visual Analogue Scale (VAS), and recovery time from fatigue after dialysis at the 0th and 4th week. Data analyses were performed using per-protocol population. RESULTS: In all, 27 patients (84%) completed the entire study. At the end of the intervention, the patients in the HAT group were found to have a significantly lower frequency of IDH episodes, fewer nursing interventions, a lower intervention failure rate, and earlier discontinuation of dialysis than those in the sham group (p < .05). The improvement in degree of fatigue (p = .001) was greater and recovery time from fatigue after dialysis (p = .03) was shorter in the group treated with HAT than in the sham group. HAT was safe, with 2 withdrawal cases due to local erythema caused by the patch. CONCLUSIONS: HAT appears to be safe and efficacious for improving IDH-related symptoms and intervention in HD patients. Larger studies are needed to confirm the benefit of this technique for IDH.


Assuntos
Pontos de Acupuntura , Hipotensão/etiologia , Hipotensão/terapia , Fitoterapia , Diálise Renal/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Moxibustão , Projetos Piloto
10.
Zoo Biol ; 37(3): 183-195, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29722905

RESUMO

Hematology and serum biochemistry reference values are essential for health evaluation and disease diagnosis in penguins. However, there are currently no published physiological values for captive Adélie (Pygoscelis adeliae) and Chinstrap penguins (P. antarcticus), nor for wild or captive Macaroni penguins (Eudyptes chrysolophus). The present study is the first investigation regarding hematology and serum biochemistry reference values for captive Adélie, Gentoo (P. papua), Chinstrap, and Macaroni penguins in Asia. Fixed effect models for repeated measure were applied to determine the influence of penguin species, age, gender, and age-gender interaction on each blood parameter. Hematology and serum biochemical data from 122 apparently healthy penguins (24 Adélie, 38 Chinstrap, 46 Gentoo, and 14 Macaroni) were collected between 2009 and 2014. The effects of penguin species were observed for most blood parameters, except total bilirubin, creatine kinase (CK), creatinine, and potassium ion (K+ ). Values of mean corpuscular volume, mean corpuscular hemoglobin (MCH), heterophil, ratio of heterophils to lymphocytes (H/L), alanine aminotransferase (ALT), and chloride ion (Cl- ) had significant positive correlation with age, while significant negative correlation with age was observed in total red blood cells (RBCs), lymphocytes, thrombocytes, alkaline phosphatase (ALP), CK, lactate dehydrogenase (LDH), and plasma iron. Compared to male penguins, females had lower mean corpuscular hemoglobin concentration (MCHC) and blood urea nitrogen (BUN) but higher calcium ion (Ca2+ ) values. As for age-gender interaction, significant positive correlation was shown in MCHC and K+ , and the reverse was true in H/L ratio.


Assuntos
Animais de Zoológico , Spheniscidae/sangue , Animais , Glicemia , Proteínas Sanguíneas , Nitrogênio da Ureia Sanguínea , Creatinina , Contagem de Eritrócitos/veterinária , Feminino , Contagem de Leucócitos/veterinária , Lipídeos/sangue , Masculino , Minerais/sangue , Valores de Referência , Albumina Sérica , Taiwan
11.
Cell Rep ; 22(7): 1875-1888, 2018 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-29444438

RESUMO

We have performed an in-depth single-cell phenotypic characterization of high-grade serous ovarian cancer (HGSOC) by multiparametric mass cytometry (CyTOF). Using a CyTOF antibody panel to interrogate features of HGSOC biology, combined with unsupervised computational analysis, we identified noteworthy cell types co-occurring across the tumors. In addition to a dominant cell subset, each tumor harbored rarer cell phenotypes. One such group co-expressed E-cadherin and vimentin (EV), suggesting their potential role in epithelial mesenchymal transition, which was substantiated by pairwise correlation analyses. Furthermore, tumors from patients with poorer outcome had an increased frequency of another rare cell type that co-expressed vimentin, HE4, and cMyc. These poorer-outcome tumors also populated more cell phenotypes, as quantified by Simpson's diversity index. Thus, despite the recognized genomic complexity of the disease, the specific cell phenotypes uncovered here offer a focus for therapeutic intervention and disease monitoring.


Assuntos
Citometria de Fluxo/métodos , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antineoplásicos/metabolismo , Carboplatina/farmacologia , Linhagem Celular Tumoral , Análise por Conglomerados , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fenótipo , Prognóstico
12.
Cytometry A ; 91(12): 1150-1163, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29205767

RESUMO

Mass cytometry (or CyTOF) is an atomic mass spectrometry-based single-cell immunoassay technology, which has provided an increasingly systematic and sophisticated view in basic biological and clinical studies. Using elemental reporters composed of stable heavy metal isotopes, more than 50 cellular parameters are measured simultaneously. However, this current multiplexing does not meet the theoretical capability of CyTOF instrumentation with 135 detectable channels, primarily due to the limitation of available chemistries for conjugating elemental mass tags to affinity reagents. To address this issue, we develop herein additional metallic mass tag based on bismuth-209 (209 Bi) for efficient conjugation to monoclonal antibody. This enables the use of an addtional channel m/z = 209 of CyTOF for single-cell immunoassays. Bismuth has nearly the same charge-to-radius ratio as lanthanide elements; thus, bismuth(III) cations (209 Bi3+ ) could coordinate with DTPA chelators in the same geometry of O- and N-donor groups as that of lanthanide. In this report, the coordination chemistry of 209 Bi3+ with DTPA chelators and Maxpar® X8 polymers were investigated in details. Accordingly, the protocols of conjugating antibody with bismuth mass tag were provided. A method based on UV-Vis absorbance at 280 nm of 209 Bi3+ -labeling DTPA complexes was developed to evaluate the stoichiometric ratio of 209 Bi3+ cations to the conjugated antibody. Side-by-side single-cell analysis experiments with bismuth- and lanthanide-tagged antibodies were carried out to compare the analytical sensitivities. The measurement accuracy of bismuth-tagged antibody was validated within in vitro assay using primary human natural killer cells. Furthermore, bismuth-tagged antibodies were successfully employed in cell cycle measurements and high-dimensional phenotyping immunoassays. © 2017 International Society for Advancement of Cytometry.


Assuntos
Bismuto/química , Citometria de Fluxo/métodos , Células Matadoras Naturais , Espectrometria de Massas/métodos , Análise de Célula Única/métodos , Anticorpos Monoclonais/química , Humanos , Imunoensaio , Imunoconjugados/química
13.
Oncotarget ; 8(52): 90465-90476, 2017 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-29163845

RESUMO

Background: No previous studies have evaluated the effects of traditional Chinese medicine (TCM) treatment on patients with heart failure (HF). Hence, in this study, we determined whether TCM treatment affects the healthcare burden and survival of HF patients. Methods: Samples were retrieved from the registry of catastrophic illness patients of the Taiwan National Health Insurance Research Database (NHIRD). Based on a frequency (1:1) matched case-control design, patients with HF between 2000 and 2010 were designated as cases (TCM users) and controls (non-TCM users). TCM treatment for patients with HF was analyzed. Results: Among these patients, 312 used TCM for HF treatment and exhibited significantly increased 5-year survival (p < .0001), with multivariate adjustment, compared with those without TCM use. Mean outpatient clinic visits at 1 year and 5 years after HF diagnosis were higher in TCM users, and accumulated medical costs were lower than in non-TCM users at 1 year. The hospitalization cost at 1-year follow-up was lower for TCM users than for non-TCM users. We found that, compared with non-TCM users, TCM users had an 86% reduction in risk of mortality in the compensated group, and a 68% reduction in the decompensated group receiving TCM treatment (aHR 0.32, 95% CI 0.20-0.52). The hazard ratio (HR) of Chinese herbal medicine (CHM) users with HF was significantly lower than that of non-users (aHR 0.24, 95% CI 0.16-0.35). We also analyzed the most commonly used herbal products as well as the HRs associated with their use, thus providing future research avenues. Conclusions: This nationwide retrospective cohort study finds that combined therapy with TCM may improve survival in HF patients. This study also suggests that TCM may be used as an integral element of HF interventions on health care costs.

14.
Circulation ; 136(20): 1920-1935, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-28935667

RESUMO

BACKGROUND: Immune dysregulation has been linked to occlusive vascular remodeling in pulmonary arterial hypertension (PAH) that is hereditary, idiopathic, or associated with other conditions. Circulating autoantibodies, lung perivascular lymphoid tissue, and elevated cytokines have been related to PAH pathogenesis but without a clear understanding of how these abnormalities are initiated, perpetuated, and connected in the progression of disease. We therefore set out to identify specific target antigens in PAH lung immune complexes as a starting point toward resolving these issues to better inform future application of immunomodulatory therapies. METHODS: Lung immune complexes were isolated and PAH target antigens were identified by liquid chromatography tandem mass spectrometry, confirmed by enzyme-linked immunosorbent assay, and localized by confocal microscopy. One PAH antigen linked to immunity and inflammation was pursued and a link to PAH pathophysiology was investigated by next-generation sequencing, functional studies in cultured monocytes and endothelial cells, and hemodynamic and lung studies in a rat. RESULTS: SAM domain and HD domain-containing protein 1 (SAMHD1), an innate immune factor that suppresses HIV replication, was identified and confirmed as highly expressed in immune complexes from 16 hereditary and idiopathic PAH versus 12 control lungs. Elevated SAMHD1 was localized to endothelial cells, perivascular dendritic cells, and macrophages, and SAMHD1 antibodies were prevalent in tertiary lymphoid tissue. An unbiased screen using metagenomic sequencing related SAMHD1 to increased expression of human endogenous retrovirus K (HERV-K) in PAH versus control lungs (n=4). HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase mRNAs were elevated in PAH versus control lungs (n=10), and proteins were localized to macrophages. HERV-K deoxyuridine triphosphate nucleotidohydrolase induced SAMHD1 and proinflammatory cytokines (eg, interleukin 6, interleukin 1ß, and tumor necrosis factor α) in circulating monocytes, pulmonary arterial endothelial cells, and also activated B cells. Vulnerability of pulmonary arterial endothelial cells (PAEC) to apoptosis was increased by HERV-K deoxyuridine triphosphate nucleotidohydrolase in an interleukin 6-independent manner. Furthermore, 3 weekly injections of HERV-K deoxyuridine triphosphate nucleotidohydrolase induced hemodynamic and vascular changes of pulmonary hypertension in rats (n=8) and elevated interleukin 6. CONCLUSIONS: Our study reveals that upregulation of the endogenous retrovirus HERV-K could both initiate and sustain activation of the immune system and cause vascular changes associated with PAH.


Assuntos
Hipertensão Pulmonar/imunologia , Mediadores da Inflamação/imunologia , Regulação para Cima/fisiologia , Proteínas Virais/biossíntese , Proteínas Virais/imunologia , Adolescente , Adulto , Animais , Complexo Antígeno-Anticorpo/biossíntese , Complexo Antígeno-Anticorpo/imunologia , Células Cultivadas , Criança , Técnicas de Cocultura , Feminino , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Lactente , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Proteína 1 com Domínio SAM e Domínio HD/biossíntese , Proteína 1 com Domínio SAM e Domínio HD/imunologia , Adulto Jovem
15.
Exp Mol Pathol ; 103(1): 56-70, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28684217

RESUMO

Interaction between the activating NKG2D receptor on lymphocytes and its ligands MICA, MICB, and ULBP1-6 modulate T and NK cell activity and may contribute to the pathogenesis of Crohn's disease (CD). NKG2D ligands are generally not expressed on the cell surface of normal, non-stressed cells, but expression of MICA and MICB in CD intestine has been reported. In this exploratory study, we further characterize the expression of NKG2D and its ligands, including the less well-described ULBP4-6, in CD, and test if NKG2D ligand interactions are involved in the migration of activated T cells into the affected mucosal compartments. Intestinal tissue from CD patients and healthy controls were analyzed by flow cytometry, mass cytometry, and immunohistochemistry for expression of NKG2D and ligands, and for cytokine release. Furthermore, NKG2D-dependent chemotaxis of activated CD8+ T cells across a monolayer of ligand-expressing human intestinal endothelial cells was examined. Activated lymphocytes down-regulated NKG2D expression upon accumulation in inflamed CD intestine. NKG2D expression on CD56+ T and γδ T cells from inflamed tissue seemed inversely correlated with CRP levels and cytokine release. B cells, monocytes, mucosal epithelium, and vascular endothelium expressed NKG2D ligands in inflamed CD intestine. The expression of NKG2D ligands was correlated with cytokine release, but was highly variable between patients. Stimulation of vascular intestinal endothelial cells in vitro induced expression of NKG2D ligands, including MICA/B and ULBP2/6. Blockade of NKG2D on CD8+ T cells inhibited the migration over ligand-expressing endothelial cells. Intestinal induction of NKG2D ligands and ligand-induced down-regulation of NKG2D in CD suggest that the NKG2D-ligand interaction may be involved in both the activation and recruitment of NKG2D+ lymphocytes into the inflamed CD intestine.


Assuntos
Linfócitos T CD8-Positivos/citologia , Movimento Celular , Doença de Crohn/genética , Regulação para Baixo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Adulto , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/citologia , Ligantes , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
16.
Sci Signal ; 10(485)2017 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-28655861

RESUMO

Natural killer (NK) cells perform immunosurveillance of virally infected and transformed cells, and their activation depends on the balance between signaling by inhibitory and activating receptors. Cytokine receptor signaling can synergize with activating receptor signaling to induce NK cell activation. We investigated the interplay between the signaling pathways stimulated by the cytokine interleukin-2 (IL-2) and the activating receptor NKG2D in immature (CD56bright) and mature (CD56dim) subsets of human primary NK cells using mass cytometry experiments and in silico modeling. Our analysis revealed that IL-2 changed the abundances of several key proteins, including NKG2D and the phosphatase CD45. Furthermore, we found differences in correlations between protein abundances, which were associated with the maturation state of the NK cells. The mass cytometry measurements also revealed that the signaling kinetics of key protein abundances induced by NKG2D stimulation depended on the maturation state and the pretreatment condition of the NK cells. Our in silico model, which described the multidimensional data with coupled first-order reactions, predicted that the increase in CD45 abundance was a major enhancer of NKG2D-mediated activation in IL-2-treated CD56bright NK cells but not in IL-2-treated CD56dim NK cells. This dependence on CD45 was verified by measurement of CD107a mobilization to the NK cell surface (a marker of activation). Our mathematical framework can be used to glean mechanisms underlying synergistic signaling pathways in other activated immune cells.


Assuntos
Regulação da Expressão Gênica , Interleucina-2/farmacologia , Células Matadoras Naturais/imunologia , Antígenos Comuns de Leucócito/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Animais , Antígeno CD56/metabolismo , Citocinas/metabolismo , Humanos , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Modelos Teóricos , Transdução de Sinais
17.
Complement Ther Med ; 32: 61-65, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28619306

RESUMO

OBJECTIVE: Viral oral ulcers are common presentations in pediatric clinics. Although self-limiting, painful ulcerative lesions and inflamed mucosa can decrease oral intake and lead to dehydration. Despite the widespread use of Chinese herbal medicine (CHM) for pediatric upper respiratory disease in Taiwan, there is little evidence for its effectiveness as an antipyretic or in aiding ulcer healing for children with viral oral ulcers. We report two cases of children who presented with viral oral ulcers to illustrate the potential efficacy of CHM treatment in recovery from herpangina (HA) and herpetic gingivostomatitis (HGS). CLINICAL FEATURES AND OUTCOME: A 10-year-old girl with HA presented with an acute febrile illness associated with small vesicular or ulcerative lesions on the posterior oropharyngeal structures. The family refused western medicine due to a prior anaphylactic skin rash when she had taken sulfa drugs. The other patient was a 4-year-old boy with complaints of painful ulcers and hemorrhagic crusts on the lips. He was diagnosed with HGS and had received ibuprofen and supportive treatments such as hydration and local anesthesia spray for days, characterized by fever, anorexia, and nausea to no effect. Because the patients were suffering from the damp-heat syndrome according to Traditional Chinese Medicine (TCM) differentiation, both were treated using the same herbal formulas powder prescription, named Liang Ge San (LGS) and Gan Lu Xiao Du Dan (GLXDD). After several days of CHM treatment, the oral ulcers were in regression. Follow-up of the frontal view in both patients showed satisfactory disappearance of the sick furred tongue. CONCLUSIONS: The results of these case reports show that the early prescription of CHM is an effective modality of alternative treatment for viral oral ulcers. To our knowledge, this is the first report of CHM treatment hastening the recovery from febrile disease with viral oral ulcers in Taiwan. Future experimental studies to determine the definitive mechanism and clinical trials are warranted.


Assuntos
Medicamentos de Ervas Chinesas , Úlceras Orais , Viroses , Criança , Pré-Escolar , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Humanos , Masculino , Boca/patologia , Úlceras Orais/tratamento farmacológico , Úlceras Orais/patologia , Úlceras Orais/virologia , Viroses/tratamento farmacológico , Viroses/patologia , Viroses/virologia
18.
Clinics (Sao Paulo) ; 72(4): 254-257, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28492726

RESUMO

OBJECTIVES:: The Meridian Energy Analysis Device is currently a popular tool in the scientific research of meridian electrophysiology. In this field, it is generally believed that measuring the electrical conductivity of meridians provides information about the balance of bioenergy or Qi-blood in the body. METHODS AND RESULTS:: PubMed database based on some original articles from 1956 to 2014 and the authors clinical experience. In this short communication, we provide clinical examples of Meridian Energy Analysis Device application, especially in the field of traditional Chinese medicine, discuss the reliability of the measurements, and put the values obtained into context by considering items of considerable variability and by estimating sample size. CONCLUSION:: The Meridian Energy Analysis Device is making a valuable contribution to the diagnosis of Qi-blood dysfunction. It can be assessed from short-term and long-term meridian bioenergy recordings. It is one of the few methods that allow outpatient traditional Chinese medicine diagnosis, monitoring the progress, therapeutic effect and evaluation of patient prognosis. The holistic approaches underlying the practice of traditional Chinese medicine and new trends in modern medicine toward the use of objective instruments require in-depth knowledge of the mechanisms of meridian energy, and the Meridian Energy Analysis Device can feasibly be used for understanding and interpreting traditional Chinese medicine theory, especially in view of its expansion in Western countries.


Assuntos
Medicina Tradicional Chinesa/instrumentação , Meridianos , Qi , Pontos de Acupuntura , Sangue , Condutividade Elétrica/uso terapêutico , Humanos , Medicina Tradicional Chinesa/métodos , Reprodutibilidade dos Testes , Tamanho da Amostra
19.
Proc Natl Acad Sci U S A ; 114(18): 4757-4762, 2017 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-28424250

RESUMO

Fibrotic diseases are not well-understood. They represent a number of different diseases that are characterized by the development of severe organ fibrosis without any obvious cause, such as the devastating diseases idiopathic pulmonary fibrosis (IPF) and scleroderma. These diseases have a poor prognosis comparable with endstage cancer and are uncurable. Given the phenotypic differences, it was assumed that the different fibrotic diseases also have different pathomechanisms. Here, we demonstrate that many endstage fibrotic diseases, including IPF; scleroderma; myelofibrosis; kidney-, pancreas-, and heart-fibrosis; and nonalcoholic steatohepatosis converge in the activation of the AP1 transcription factor c-JUN in the pathologic fibroblasts. Expression of the related AP1 transcription factor FRA2 was restricted to pulmonary artery hypertension. Induction of c-Jun in mice was sufficient to induce severe fibrosis in multiple organs and steatohepatosis, which was dependent on sustained c-Jun expression. Single cell mass cytometry revealed that c-Jun activates multiple signaling pathways in mice, including pAkt and CD47, which were also induced in human disease. αCD47 antibody treatment and VEGF or PI3K inhibition reversed various organ c-Jun-mediated fibroses in vivo. These data suggest that c-JUN is a central molecular mediator of most fibrotic conditions.


Assuntos
Fibrose Pulmonar Idiopática , Mielofibrose Primária , Proteínas Proto-Oncogênicas c-jun , Escleroderma Sistêmico , Fator de Transcrição AP-1 , Antígeno 2 Relacionado a Fos/genética , Antígeno 2 Relacionado a Fos/metabolismo , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Mielofibrose Primária/genética , Mielofibrose Primária/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/metabolismo , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo
20.
Clinics ; 72(4): 254-257, Apr. 2017. graf
Artigo em Inglês | LILACS | ID: biblio-840069

RESUMO

OBJECTIVES: The Meridian Energy Analysis Device is currently a popular tool in the scientific research of meridian electrophysiology. In this field, it is generally believed that measuring the electrical conductivity of meridians provides information about the balance of bioenergy or Qi-blood in the body. METHODS AND RESULTS: PubMed database based on some original articles from 1956 to 2014 and the authoŕs clinical experience. In this short communication, we provide clinical examples of Meridian Energy Analysis Device application, especially in the field of traditional Chinese medicine, discuss the reliability of the measurements, and put the values obtained into context by considering items of considerable variability and by estimating sample size. CONCLUSION: The Meridian Energy Analysis Device is making a valuable contribution to the diagnosis of Qi-blood dysfunction. It can be assessed from short-term and long-term meridian bioenergy recordings. It is one of the few methods that allow outpatient traditional Chinese medicine diagnosis, monitoring the progress, therapeutic effect and evaluation of patient prognosis. The holistic approaches underlying the practice of traditional Chinese medicine and new trends in modern medicine toward the use of objective instruments require in-depth knowledge of the mechanisms of meridian energy, and the Meridian Energy Analysis Device can feasibly be used for understanding and interpreting traditional Chinese medicine theory, especially in view of its expansion in Western countries.


Assuntos
Humanos , Meridianos , Qi , Medicina Tradicional Chinesa/instrumentação , Sangue , Pontos de Acupuntura , Reprodutibilidade dos Testes , Tamanho da Amostra , Condutividade Elétrica/uso terapêutico , Medicina Tradicional Chinesa/métodos
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