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2.
PLoS Biol ; 19(8): e3001373, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34358229

RESUMO

Challenges in using cytokine data are limiting Coronavirus Disease 2019 (COVID-19) patient management and comparison among different disease contexts. We suggest mitigation strategies to improve the accuracy of cytokine data, as we learn from experience gained during the COVID-19 pandemic.


Assuntos
COVID-19/imunologia , COVID-19/terapia , COVID-19/epidemiologia , Citocinas/imunologia , Humanos , Pandemias , Assistência ao Paciente/métodos , SARS-CoV-2/imunologia
3.
Sci Signal ; 14(690)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230210

RESUMO

Coronavirus disease 2019 (COVID-19) has poorer clinical outcomes in males than in females, and immune responses underlie these sex-related differences. Because immune responses are, in part, regulated by metabolites, we examined the serum metabolomes of COVID-19 patients. In male patients, kynurenic acid (KA) and a high KA-to-kynurenine (K) ratio (KA:K) positively correlated with age and with inflammatory cytokines and chemokines and negatively correlated with T cell responses. Males that clinically deteriorated had a higher KA:K than those that stabilized. KA inhibits glutamate release, and glutamate abundance was lower in patients that clinically deteriorated and correlated with immune responses. Analysis of data from the Genotype-Tissue Expression (GTEx) project revealed that the expression of the gene encoding the enzyme that produces KA, kynurenine aminotransferase, correlated with cytokine abundance and activation of immune responses in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes in COVID-19, suggesting a positive feedback between metabolites and immune responses in males.


Assuntos
COVID-19/imunologia , Ácido Cinurênico/imunologia , SARS-CoV-2 , Adulto , Idoso , COVID-19/sangue , Estudos de Casos e Controles , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Ácido Cinurênico/sangue , Modelos Logísticos , Masculino , Redes e Vias Metabólicas/imunologia , Metabolômica , Pessoa de Meia-Idade , Análise Multivariada , Índice de Gravidade de Doença , Fatores Sexuais , Transdução de Sinais/imunologia , Triptofano/metabolismo
4.
Hinyokika Kiyo ; 67(5): 191-195, 2021 May.
Artigo em Japonês | MEDLINE | ID: mdl-34126662

RESUMO

75 year-old man followed up regularly for the treatment of lung cancer came to our hospital with a chief complaint of general malaise. Blood test results showed deterioration in the renal function, and computed tomography (CT) confirmed left hydronephrosis. He was admitted to the hospital with the diagnosis of obstructive pyelonephritis. Despite antibiotic therapy after the left ureteral stent placement, CT on day 19 of hospitalization showed an enlarged soft tissue shadow along the renal pelvis and ureter, which was suspected to be peripelvic urinary extravasation caused by stent occlusion. We decided that conservative treatment would not improve his condition and conducted surgical therapy considering the possibility of malignancy. Intraoperatively, viscous and fragile tumor affected the renal pelvis and ureter. The operation resulted in left nephrectomy because radical resection was impossible. The pathological diagnosis was sarcomatoid urothelial carcinoma of the renal pelvis with ureter origin. He died due to multipleorgan failureon day 20 after theope ration. Were port a caseof sarcomatoid urothelial carcinoma in the upper urinary tract that was difficult to diagnose preoperatively based on imaging studies.


Assuntos
Carcinoma de Células de Transição , Neoplasias Renais , Ureter , Neoplasias Ureterais , Carcinoma de Células de Transição/diagnóstico por imagem , Carcinoma de Células de Transição/cirurgia , Humanos , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/cirurgia , Pelve Renal/diagnóstico por imagem , Pelve Renal/cirurgia , Masculino , Nefrectomia , Neoplasias Ureterais/diagnóstico por imagem , Neoplasias Ureterais/cirurgia
6.
medRxiv ; 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32935119

RESUMO

Coronavirus disease-2019 (COVID-19) has poorer clinical outcomes in males compared to females, and immune responses underlie these sex-related differences in disease trajectory. As immune responses are in part regulated by metabolites, we examined whether the serum metabolome has sex-specificity for immune responses in COVID-19. In males with COVID- 19, kynurenic acid (KA) and a high KA to kynurenine (K) ratio was positively correlated with age, inflammatory cytokines, and chemokines and was negatively correlated with T cell responses, revealing that KA production is linked to immune responses in males. Males that clinically deteriorated had a higher KA:K ratio than those that stabilized. In females with COVID-19, this ratio positively correlated with T cell responses and did not correlate with age or clinical severity. KA is known to inhibit glutamate release, and we observed that serum glutamate is lower in patients that deteriorate from COVID-19 compared to those that stabilize, and correlates with immune responses. Analysis of Genotype-Tissue Expression (GTEx) data revealed that expression of kynurenine aminotransferase, which regulates KA production, correlates most strongly with cytokine levels and aryl hydrocarbon receptor activation in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes, in COVID-19 infection.

7.
Nature ; 588(7837): 315-320, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32846427

RESUMO

There is increasing evidence that coronavirus disease 2019 (COVID-19) produces more severe symptoms and higher mortality among men than among women1-5. However, whether immune responses against severe acute respiratory syndrome coronavirus (SARS-CoV-2) differ between sexes, and whether such differences correlate with the sex difference in the disease course of COVID-19, is currently unknown. Here we examined sex differences in viral loads, SARS-CoV-2-specific antibody titres, plasma cytokines and blood-cell phenotyping in patients with moderate COVID-19 who had not received immunomodulatory medications. Male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. By contrast, female patients had more robust T cell activation than male patients during SARS-CoV-2 infection. Notably, we found that a poor T cell response negatively correlated with patients' age and was associated with worse disease outcome in male patients, but not in female patients. By contrast, higher levels of innate immune cytokines were associated with worse disease progression in female patients, but not in male patients. These findings provide a possible explanation for the observed sex biases in COVID-19, and provide an important basis for the development of a sex-based approach to the treatment and care of male and female patients with COVID-19.


Assuntos
COVID-19/imunologia , Citocinas/imunologia , Imunidade Inata/imunologia , SARS-CoV-2/imunologia , Caracteres Sexuais , Linfócitos T/imunologia , COVID-19/sangue , COVID-19/virologia , Quimiocinas/sangue , Quimiocinas/imunologia , Estudos de Coortes , Citocinas/sangue , Progressão da Doença , Feminino , Humanos , Ativação Linfocitária , Masculino , Monócitos/imunologia , Fenótipo , Prognóstico , RNA Viral/análise , SARS-CoV-2/patogenicidade , Carga Viral
9.
Nature ; 584(7821): 463-469, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32717743

RESUMO

Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19)1-4. However, the longitudinal immunological correlates of disease outcome remain unclear. Here we serially analysed immune responses in 113 patients with moderate or severe COVID-19. Immune profiling revealed an overall increase in innate cell lineages, with a concomitant reduction in T cell number. An early elevation in cytokine levels was associated with worse disease outcomes. Following an early increase in cytokines, patients with moderate COVID-19 displayed a progressive reduction in type 1 (antiviral) and type 3 (antifungal) responses. By contrast, patients with severe COVID-19 maintained these elevated responses throughout the course of the disease. Moreover, severe COVID-19 was accompanied by an increase in multiple type 2 (anti-helminths) effectors, including interleukin-5 (IL-5), IL-13, immunoglobulin E and eosinophils. Unsupervised clustering analysis identified four immune signatures, representing growth factors (A), type-2/3 cytokines (B), mixed type-1/2/3 cytokines (C), and chemokines (D) that correlated with three distinct disease trajectories. The immune profiles of patients who recovered from moderate COVID-19 were enriched in tissue reparative growth factor signature A, whereas the profiles of those with who developed severe disease had elevated levels of all four signatures. Thus, we have identified a maladapted immune response profile associated with severe COVID-19 and poor clinical outcome, as well as early immune signatures that correlate with divergent disease trajectories.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Citocinas/análise , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19 , Análise por Conglomerados , Citocinas/imunologia , Eosinófilos/imunologia , Feminino , Humanos , Imunoglobulina E/análise , Imunoglobulina E/imunologia , Interleucina-13/análise , Interleucina-13/imunologia , Interleucina-5/análise , Interleucina-5/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Linfócitos T/citologia , Linfócitos T/imunologia , Carga Viral , Adulto Jovem
10.
Hinyokika Kiyo ; 66(7): 229-234, 2020 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-32723978

RESUMO

A 37-year-old man with no symptoms or family history of tuberous sclerosis complex presented to our hospital with abdominal pain in 2013. Abdominal computed tomography (CT) revealed a rupture in the right renal angiomyolipoma (AML) having a maximum diameter of 7 cm. He had undergone a transarterial embolization. Follow-up CT showed an increase in the size of the right tumor to 11 cm, and therefore, right nephrectomy was performed in 2016. The diagnosis of epithelioid AML (EAML) was confirmed. In 2019, he was diagnosed with a solitary tumor near right-sided transverse colon, which was resected and showed recurrence of EAML. He was disease-free 6 months after surgery. EAML has malignant potential, with 30-50% of reported EAML cases resulting in local recurrence or distant metastasis. Previous recurrence or metastasis may occur 0.25-12 years postoperatively. Furthermore, multiple and unresectable recurrences or metastases, arising early in the postoperative period may lead to a poor outcome. Therefore, close and long-term follow-up is required.


Assuntos
Cavidade Abdominal , Angiomiolipoma/cirurgia , Neoplasias Renais/cirurgia , Adulto , Humanos , Masculino , Recidiva Local de Neoplasia , Nefrectomia
11.
Arthritis Rheumatol ; 72(12): 2136-2146, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32627966

RESUMO

OBJECTIVE: In prevous studies, we established a new animal model, KLF5+/- ;Fli-1+/- mice, in which fundamental pathologic features of systemic sclerosis (SSc) are broadly recapitulated. SSc vasculopathy is believed to occur as a result of impaired vascular remodeling, but its detailed mechanism of action remains unknown. To address this, the present study investigated the properties of dermal microvascular endothelial cells (DMECs), bone marrow-derived endothelial progenitor cells (BM-EPCs), and bone marrow-derived mesenchymal stem cells (BM-MSCs), a precursor of pericytes, in KLF5+/- ;Fli-1+/- mice. METHODS: Neovascularization and angiogenesis were assessed in KLF5+/- ;Fli-1+/- mice by in vivo Matrigel plug assay and in vitro tube formation assay, respectively. The properties of mouse BM-EPCs and BM-MSCs were assessed with in vitro studies. Dermal vasculature was visualized in vivo by injecting the mice with fluorescein isothiocyanate-conjugated dextran. RESULTS: Neovascularization was diminished in skin-embedded Matrigel plugs from KLF5+/- ;Fli-1+/- mice. DMECs from KLF5+/- ;Fli-1+/- mice showed defective tubulogenic activity, decreased expression of VE-cadherin and CD31, and an imbalance in the expression of Notch1/Dll4, suggesting that angiogenesis and anastomosis are disturbed. KLF5+/- ;Fli-1+/- mouse BM-MSCs exhibited enhanced proliferation and migration and increased collagen production following stimulation with transforming growth factor ß1, indicating that these cells differentiate preferentially into myofibroblasts rather than pericytes. KLF5+/- ;Fli-1+/- mouse BM-EPCs displayed a transition toward mesenchymal cells, suggesting that vasculogenesis is impaired. Wound healing was delayed in KLF5+/- ;Fli-1+/- mice (mean ± SD healing time 15.67 ± 0.82 days versus 13.50 ± 0.84 days; P = 0.0017), and the vascular network was poorly developed in wound scar tissue. CONCLUSION: The characteristics observed in the KLF5+/- ;Fli-1+/- mouse model - specifically, impaired neovascularization and vascular maturation - are similar to those observed in human SSc, and could be at least partially attributable to the induction of SSc-like properties in DMECs, BM-EPCs, and BM-MSCs. These findings indicate the critical contribution of Klf5 and Fli1 deficiency in vascular cells and related cell precursors to the development of SSc vasculopathy.


Assuntos
Células Endoteliais/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Células-Tronco Mesenquimais/metabolismo , Neovascularização Patológica/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Escleroderma Sistêmico/metabolismo , Vasculite/metabolismo , Animais , Modelos Animais de Doenças , Células Endoteliais/patologia , Fatores de Transcrição Kruppel-Like/genética , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Knockout , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Proteína Proto-Oncogênica c-fli-1/genética , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Vasculite/genética , Vasculite/patologia
12.
Nat Microbiol ; 5(10): 1299-1305, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32651556

RESUMO

The recent spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exemplifies the critical need for accurate and rapid diagnostic assays to prompt clinical and public health interventions. Currently, several quantitative reverse transcription-PCR (RT-qPCR) assays are being used by clinical, research and public health laboratories. However, it is currently unclear whether results from different tests are comparable. Our goal was to make independent evaluations of primer-probe sets used in four common SARS-CoV-2 diagnostic assays. From our comparisons of RT-qPCR analytical efficiency and sensitivity, we show that all primer-probe sets can be used to detect SARS-CoV-2 at 500 viral RNA copies per reaction. The exception for this is the RdRp-SARSr (Charité) confirmatory primer-probe set which has low sensitivity, probably due to a mismatch to circulating SARS-CoV-2 in the reverse primer. We did not find evidence for background amplification with pre-COVID-19 samples or recent SARS-CoV-2 evolution decreasing sensitivity. Our recommendation for SARS-CoV-2 diagnostic testing is to select an assay with high sensitivity and that is regionally used, to ease comparability between outcomes.


Assuntos
Betacoronavirus/genética , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , RNA Viral/análise , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Betacoronavirus/isolamento & purificação , COVID-19 , Teste para COVID-19 , Técnicas de Laboratório Clínico/estatística & dados numéricos , Infecções por Coronavirus/epidemiologia , Variação Genética , Genoma Viral , Humanos , Técnicas de Sonda Molecular/estatística & dados numéricos , Pandemias , Pneumonia Viral/epidemiologia , RNA/genética , Sondas RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/estatística & dados numéricos , SARS-CoV-2 , Sensibilidade e Especificidade
13.
medRxiv ; 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32577695

RESUMO

A growing body of evidence indicates sex differences in the clinical outcomes of coronavirus disease 2019 (COVID-19)1-4. However, whether immune responses against SARS-CoV-2 differ between sexes, and whether such differences explain male susceptibility to COVID-19, is currently unknown. In this study, we examined sex differences in viral loads, SARS-CoV-2-specific antibody titers, plasma cytokines, as well as blood cell phenotyping in COVID-19 patients. By focusing our analysis on patients with mild to moderate disease who had not received immunomodulatory medications, our results revealed that male patients had higher plasma levels of innate immune cytokines and chemokines including IL-8, IL-18, and CCL5, along with more robust induction of non-classical monocytes. In contrast, female patients mounted significantly more robust T cell activation than male patients during SARS-CoV-2 infection, which was sustained in old age. Importantly, we found that a poor T cell response negatively correlated with patients age and was predictive of worse disease outcome in male patients, but not in female patients. Conversely, higher innate immune cytokines in female patients associated with worse disease progression, but not in male patients. These findings reveal a possible explanation underlying observed sex biases in COVID-19, and provide important basis for the development of sex-based approach to the treatment and care of men and women with COVID-19.

14.
J Dermatol ; 47(6): 609-614, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32232898

RESUMO

Endothelial dysfunction is a hallmark of vasculopathy associated with systemic sclerosis (SSc). Reactive hyperemia peripheral arterial tonometry is a rapid and non-invasive technique to assess peripheral microvascular endothelial function by measuring changes in digital pulse volume during reactive hyperemia. Low scores of the reactive hyperemia index (RHI) imply an impaired vasodilatory response and, accordingly, impaired endothelial and vascular health. To investigate the clinical significance of the RHI in SSc patients, RHI values were measured in 43 SSc patients and 10 healthy controls. In diffuse cutaneous SSc (dcSSc) patients, RHI values were significantly decreased compared with healthy controls, and inversely correlated with disease duration. In total SSc patients, there was a significant inverse correlation between RHI values and skin score, and interstitial lung disease was associated with the decrease in RHI values. Among vascular symptoms, the current and past history of digital ulcers was seen more frequently in patients with decreased RHI values than in those with normal RHI values. Although no SSc patients had pulmonary arterial hypertension, an inverse correlation was evident between RHI values and mean pulmonary arterial pressure measured by right heart catheterization. These results indicate that the decrease in RHI values is associated with skin fibrosis, interstitial lung disease, digital ulcers and pulmonary vascular involvement leading to pulmonary arterial hypertension, supporting the canonical idea that endothelial dysfunction is a critical event underlying the development of tissue fibrosis and vascular complications in SSc.


Assuntos
Hiperemia/diagnóstico , Doenças Pulmonares Intersticiais/epidemiologia , Hipertensão Arterial Pulmonar/epidemiologia , Esclerodermia Difusa/complicações , Úlcera Cutânea/epidemiologia , Idoso , Endotélio Vascular/fisiopatologia , Feminino , Fibrose , Humanos , Hiperemia/fisiopatologia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Pulso Arterial/métodos , Estudos Retrospectivos , Medição de Risco/métodos , Esclerodermia Difusa/patologia , Esclerodermia Difusa/fisiopatologia , Pele/irrigação sanguínea , Pele/patologia , Pele/fisiopatologia , Úlcera Cutânea/etiologia , Úlcera Cutânea/fisiopatologia , Vasodilatação/fisiologia
15.
Clin Pharmacol Ther ; 108(3): 586-595, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32034953

RESUMO

Regorafenib treatment improves survival of patients with metastatic colorectal cancer, but it is also characterized by detrimental side effects that may require modified dosing or interval schedules. Regorafenib is metabolized by cytochrome P450 3A4 in the liver to its active metabolites, M-2 and M-5. We examined area under the unbound plasma concentration-time curve (AUCu) to these compounds to establish pharmacokinetic bases for individualized dosing strategies. The plasma protein binding of M-2 and M-5 was approximately 10-fold lower than that of regorafenib, whereas AUCu values for active metabolites on both days 1 and 15 were significantly higher than that of regorafenib. Patients with higher AUCu values of M-2 or M-5 on day 1 showed significantly shorter progression-free survival than others, likely due, at least in part, to treatment discontinuation as a result of adverse events, especially occurred during first cycle.


Assuntos
Antineoplásicos/farmacocinética , Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/farmacocinética , Piridinas/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Ativação Metabólica , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/mortalidade , Citocromo P-450 CYP3A/metabolismo , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Variantes Farmacogenômicos , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/sangue , Polimorfismo Genético , Intervalo Livre de Progressão , Estudos Prospectivos , Ligação Proteica , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/sangue
16.
J Dermatol Sci ; 97(2): 125-134, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31959382

RESUMO

BACKGROUND: Skin fibrosis of systemic sclerosis (SSc) is believed to be driven by complex processes including immune abnormalities, but the underlying immune response remains enigmatic. In particular, the role of dermal dendritic cells (DCs) is totally unknown. OBJECTIVE: We investigated the impact of CD103 loss on bleomycin-induced skin fibrosis because CD103 is a critical molecule determining DC phenotypes. METHODS: Bleomycin-induced skin fibrosis was generated with Cd103-/- mice. The alterations of tissue fibrosis and related inflammation were investigated by histologic examination, hydroxyproline assay, quantitative reverse transcription PCR and flow cytometry. SSc skin samples were evaluated by immunofluorescence. RESULTS: CD103 loss decreased bleomycin-induced dermal thickness and collagen contents, along with TGF-ß1 and CTGF suppression. Treg proportion was increased, while Th1/Th2/Th17 cell proportions were decreased in the skin of bleomycin-treated Cd103-/- mice. Bleomycin injection enhanced CD11b-CD103- DC proportion in wild-type mice, which was further augmented in Cd103-/- mice. Importantly, RALDH1/ALDH1A1 enzyme oxidizing retinaldehyde to retinoic acid, an inducer of Tregs, was preferentially expressed by CD11b-CD103- DCs and its expression levels were elevated in bleomycin-injected skin lesions, to a greater extent in Cd103-/- mice than in wild-type mice. Importantly, the number of RALDH1-positive DCs was decreased in the lesional skin of SSc patients and tended to inversely correlate with skin fibrosis severity. CONCLUSION: This study identified a critical role of dermal DCs as a regulator of Treg development through RALDH1 in bleomycin-treated mice and possibly in human SSc. This finding sheds new light on dermal DCs as a new therapeutic target of SSc.


Assuntos
Família Aldeído Desidrogenase 1/metabolismo , Células de Langerhans/metabolismo , Retinal Desidrogenase/metabolismo , Esclerodermia Localizada/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos CD/genética , Bleomicina/toxicidade , Comunicação Celular/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Cadeias alfa de Integrinas/genética , Células de Langerhans/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Esclerodermia Localizada/induzido quimicamente , Esclerodermia Localizada/genética , Esclerodermia Localizada/patologia , Pele/citologia , Pele/imunologia , Pele/patologia , Linfócitos T Reguladores/metabolismo , Tretinoína/metabolismo
17.
Rheumatology (Oxford) ; 59(8): 2005-2015, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31782787

RESUMO

OBJECTIVES: Adipsin, or complement factor D, is a serine proteinase catalysing complement factor C3 breakdown, leading to the production of opsonin (C3b), membrane attack complex (C5b-C9) and anaphylatoxins (C3a and C5a). Since adipsin is potentially associated with pulmonary arterial hypertension in SSc, we investigated adipsin expression in dermal small vessels of SSc-involved skin, the mechanism regulating adipsin expression in endothelial cells, and the correlation of serum adipsin levels with SSc clinical symptoms. METHODS: Adipsin expression was assessed by immunohistochemistry with skin sections of SSc and healthy subjects. mRNA levels of target genes and transcription factor binding to the ADIPSIN promoter were evaluated by quantitative reverse transcription PCR and chromatin immunoprecipitation, respectively. Serum adipsin levels were determined by enzyme-linked immunosorbent assay. RESULTS: Adipsin expression was remarkably increased in dermal small vessels of SSc-involved skin as compared with those of healthy control skin. Consistent with the notion that Fli1 deficiency induces SSc-like phenotypes in various types of cells, FLI1 siRNA enhanced adipsin expression at protein and mRNA levels and Fli1 bound to the ADIPSIN promoter in human dermal microvascular endothelial cells. Serum adipsin levels were significantly lower in diffuse cutaneous SSc patients than in limited cutaneous SSc patients and healthy controls, and were associated positively with elevated right ventricular systolic pressure and inversely with interstitial lung disease by multivariate regression analysis. CONCLUSION: Adipsin is up-regulated at least partially by Fli1 deficiency in endothelial cells, potentially contributing to the development of pulmonary vascular involvement in SSc.


Assuntos
Fator D do Complemento/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Proteína Proto-Oncogênica c-fli-1/genética , Hipertensão Arterial Pulmonar/genética , Escleroderma Sistêmico/genética , Pele/metabolismo , Adulto , Idoso , Animais , Feminino , Inativação Gênica , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Proteína Proto-Oncogênica c-fli-1/metabolismo , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/metabolismo , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/metabolismo , Pele/irrigação sanguínea
18.
J Dermatol ; 46(11): 1006-1013, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31502326

RESUMO

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the most frequent cause of death for SSc but there is still no sufficient treatment available. Although cyclophosphamide (CYC) therapy is a common treatment which has shown statistical efficacy against SSc-ILD to date, its effects are temporary and not enough. Rituximab (RTX), the anti-CD20 monoclonal antibody, has recently shown efficacy in many autoimmune diseases. In SSc-ILD, RTX is also considered to be one of the novel treatment candidates. However, studies of SSc-ILD in Japanese treated with RTX have only a few case reports. Therefore, in this study, we retrospectively compared nine patients treated with RTX and 30 patients treated with CYC to investigate the efficacy of RTX treatment for Japanese anti-topoisomerase I-positive SSc-ILD patients. At the 24-month evaluation, the improvement rates of percent predicted of forced vital capacity and percent predicted of diffusing capacity of the lung carbon monoxide in the RTX-treated group were significantly higher than those in the CYC-treated group (20.6 ± 8.8% vs 1.1 ± 3.9%; P < 0.05 and 34.0 ± 6.0% vs -1.5 ± 2.8%; P < 0.01, respectively). In addition, skin thickness scores also showed a marked improvement from 13.5 points before the start of treatment to 5.8 points after 24 months by RTX therapy (P < 0.05). These results suggest that RTX treatment is more effective for Japanese SSc-ILD patients than CYC treatment. In the future, it is expected that large-scale clinical trials will show the usefulness of RTX treatment for SSc-ILD.


Assuntos
Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Rituximab/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Adulto , DNA Topoisomerases Tipo I/imunologia , Feminino , Humanos , Japão , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/imunologia , Adulto Jovem
19.
J Dermatol Sci ; 94(2): 259-265, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31079997

RESUMO

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by three cardinal pathological features, such as autoimmunity/inflammation, vasculopathy and extensive organ fibrosis. Therefore, numerous interests have been put on the roles of immune cells, vascular cells (endothelial cells and pericytes/vascular smooth muscle cells) and interstitial fibroblasts as well as their precursors in the field of SSc research. However, recent studies with clinical samples and animal models have drawn much attention to the potential role of epithelial cells as a member of critical drivers and/or modifiers in the pathogenesis of SSc. Indeed, phenotypically altered epithelial cells possibly explain the selective organ fibrosis in the skin, esophagus and lung, the origin of autoimmunity and Köbner phenomenon-associated localized scleroderma-like lesions, the mechanisms of which had remained unknown in the canonical idea of SSc pathogenesis. This article overviews the recent progress in understanding the contribution of epithelial cells to the pathogenesis of SSc. Although further studies are required to confirm the potential role of epithelial cells in SSc development, this notion may provide us with a missing piece of the puzzle to solve the unanswered questions in the pathogenesis of SSc.


Assuntos
Células Epiteliais/imunologia , Esôfago/patologia , Pulmão/patologia , Escleroderma Sistêmico/imunologia , Pele/patologia , Animais , Autoimunidade , Modelos Animais de Doenças , Células Epiteliais/patologia , Esôfago/citologia , Esôfago/imunologia , Fibrose , Humanos , Pulmão/citologia , Pulmão/imunologia , Escleroderma Sistêmico/patologia , Pele/citologia
20.
Cancer Chemother Pharmacol ; 83(6): 1127-1135, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30972456

RESUMO

PURPOSE: Several retrospective studies have shown that the antitumor efficacy of capecitabine-containing chemotherapy decreases when co-administered with a proton pump inhibitor (PPI). Although a reduction in capecitabine absorption by PPIs was proposed as the underlying mechanism, the effects of PPIs on capecitabine pharmacokinetics remain unclear. We prospectively examined the effects of rabeprazole on the pharmacokinetics of capecitabine and its metabolites. METHODS: We enrolled patients administered adjuvant capecitabine plus oxaliplatin (CapeOX) for postoperative colorectal cancer (CRC) patients and metastatic CRC patients receiving CapeOX with/without bevacizumab. Patients receiving a PPI before registration were allocated to the rabeprazole group, and the PPI was changed to rabeprazole (20 mg/day) at least 1 week before the initiation of capecitabine treatment. On day 1, oral capecitabine (1000 mg/m2) was administered 1 h after rabeprazole intake. Oxaliplatin (and bevacizumab) administration on day 1 was shifted to day 2 for pharmacokinetic analysis of the first capecitabine dose. Plasma concentrations of capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil were analyzed by high-performance liquid chromatography. Effects of rabeprazole on inhibition of cell proliferation by each capecitabine metabolite were examined with colon cancer cells (COLO205 and HCT116). RESULTS: Five and 9 patients enrolled between September 2017 and July 2018 were allocated to rabeprazole and control groups, respectively. No significant effects of rabeprazole on area under the plasma concentration-time curve divided by capecitabine dose for capecitabine and its three metabolites were observed. Rabeprazole did not affect the proliferation inhibition of colon cancer cells by the respective capecitabine metabolites. CONCLUSION: Rabeprazole does not affect capecitabine pharmacokinetics.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Capecitabina/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Inibidores da Bomba de Prótons/administração & dosagem , Rabeprazol/administração & dosagem , Idoso , Antimetabólitos Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Área Sob a Curva , Capecitabina/farmacocinética , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Interações Medicamentosas , Feminino , Floxuridina/farmacocinética , Fluoruracila/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores da Bomba de Prótons/farmacologia , Rabeprazol/farmacologia
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