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1.
Int Immunol ; 36(4): 155-166, 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38108401

RESUMO

Ulcerative colitis (UC) is a chronic disorder of the large intestine with inflammation and ulceration. The incidence and prevalence of UC have been rapidly increasing worldwide, but its etiology remains unknown. In patients with UC, the accumulation of eosinophils in the large intestinal mucosa is associated with increased disease activity. However, the molecular mechanism underlying the promotion of intestinal eosinophilia in patients with UC remains poorly understood. Here, we show that uridine diphosphate (UDP)-glucose mediates the eosinophil-dependent promotion of colonic inflammation via the purinergic receptor P2Y14. The expression of P2RY14 mRNA was upregulated in the large intestinal mucosa of patients with UC. The P2Y14 receptor ligand UDP-glucose was increased in the large intestinal tissue of mice administered dextran sodium sulfate (DSS). In addition, P2ry14 deficiency and P2Y14 receptor blockade mitigated DSS-induced colitis. Among the large intestinal immune cells and epithelial cells, eosinophils highly expressed P2ry14 mRNA. P2ry14-/- mice transplanted with wild-type bone marrow eosinophils developed more severe DSS-induced colitis compared with P2ry14-/- mice that received P2ry14-deficient eosinophils. UDP-glucose prolonged the lifespan of eosinophils and promoted gene transcription in the cells through P2Y14 receptor-mediated activation of ERK1/2 signaling. Thus, the UDP-glucose/P2Y14 receptor axis aggravates large intestinal inflammation by accelerating the accumulation and activation of eosinophils.


Assuntos
Colite Ulcerativa , Eosinofilia , Humanos , Camundongos , Animais , Uridina Difosfato Glucose/farmacologia , Eosinófilos , Inflamação , Mucosa Intestinal , RNA Mensageiro , Glucose/efeitos adversos , Sulfato de Dextrana , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
2.
Emerg Infect Dis ; 26(1): 11-19, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31855136

RESUMO

Hemotropic mycoplasmas are common pathogens in animals, but it remains unclear what role these pathogens play in human infections. We report clinical and biologic characterization of Candidatus Mycoplasma haemohominis infection in a 42-year-old man in Japan. The patient had severe hemophagocytic syndrome 1 month after an accidental needlestick injury. Metagenomic deep sequencing identified Candidatus M. haemohominis and determined its draft genome for an isolate from serum of the patient. A high copy number of the Candidatus M. haemohominis genome was detected in serum and bone marrow samples. Electron microscopy examination showed morphologic characteristics of Candidatus M. haemohominis. Levofloxacin monotherapy induced resistance caused by a gyrase A gene mutation in the quinolone resistance-determining region, but a combination treatment with moxifloxacin and minocycline was effective. We identified Candidatus M. haemohominis in a patient who had life-threatening symptoms related to multiple organ infection. Human infection with this mycoplasma might occur more frequently than has been generally recognized.


Assuntos
Infecções por Mycoplasma/microbiologia , Mycoplasma , Adulto , Eritema/microbiologia , Eritema/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Japão/epidemiologia , Masculino , Microscopia Eletrônica , Mycoplasma/genética , Infecções por Mycoplasma/diagnóstico , Infecções por Mycoplasma/epidemiologia , Infecções por Mycoplasma/patologia , Prurido/microbiologia , Prurido/patologia , Pele/patologia
3.
Clin Exp Nephrol ; 24(Suppl 1): 25-35, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31760530

RESUMO

BACKGROUND: Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by inhibiting the urate transporter 1 (URAT1). We compared the pharmacokinetics (PK), pharmacodynamics (PD), and safety of dotinurad in subjects with hepatic impairment and normal hepatic function. METHODS: This was a multicenter, open-label, single dose study. A total of 24 subjects were divided into four groups: the normal hepatic function group and the mild, moderate, and severe hepatic impairment groups. The primary endpoints were changes in plasma dotinurad levels and PK parameters. RESULTS: The geometric mean ratio of the maximum plasma concentration (Cmax) [two-sided 90% confidence interval (CI)] of dotinurad in in the mild, moderate, and severe hepatic impairment groups relative to that in the normal hepatic function group was 0.840 (0.674-1.047), 0.798 (0.653-0.976), and 0.747 (0.570-0.979), respectively, showing a lower Cmax in the moderate and severe hepatic impairment groups. Following adjustment for body weight, only the moderate hepatic impairment group had a lower Cmax than the normal hepatic function group. No meaningful differences in other PK parameters were observed between the groups. Regarding the PD of dotinurad, the changes in serum uric acid levels after dosing were similar in all groups. As for safety, no noteworthy concerns were raised in relation to any group. CONCLUSION: The study revealed no clinically meaningful influence of hepatic impairment on the PK, PD, or safety of dotinurad. These findings indicate possibility that dotinurad can be used without dose adjustment in patients with hepatic impairment.


Assuntos
Benzotiazóis/farmacocinética , Hepatopatias/fisiopatologia , Ácido Úrico/sangue , Uricosúricos/farmacocinética , Adulto , Idoso , Benzotiazóis/efeitos adversos , Benzotiazóis/farmacologia , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade
5.
BMC Gastroenterol ; 19(1): 187, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727083

RESUMO

BACKGROUND: Hepatic epithelioid hemangioendothelioma (HEH) is rare; it is reported in < 1 person in 1,000,000 individuals. For accurate diagnosis, information regarding multiple graphic modalities in HEH is required. However, there is very little information concerning Sonazoid® contrast enhanced ultrasonography (CEUS) in HEH. CASE PRESENTATION: The present report describes the histologically proven three HEH cases evaluated using Sonazoid® CEUS. Case 1 was a 33-year-old female patient with no relevant past medical history, who experienced right upper quadrant pain. Conventional abdominal US revealed multiple low echoic liver nodules with vague borderlines. In CEUS, the vascularity of the nodules was similar to that seen in the neighboring normal liver. Later in the portal venous and late phases (PVLP) and post vascular phase, washout of Sonazoid® was detected in the nodules. Case 2 was a 93-year-old female patient with a previous medical history including operations for breast cancer and ovary cancer in her 50's. Conventional abdominal US revealed multiple low echoic nodules, some of which contained cystic lesions. In the early vascular phase of CEUS, nodules excluding the central anechoic regions were enhanced from peripheral sites. Although the enhancement inside the nodules persisted in both the PVLP and post vascular phase, anechoic areas in the center of some nodules were not enhanced at all. Case 3 was a 39-year-old male patient presented with right upper-quadrant pain, without any relevant past medical history. Conventional abdominal US revealed multiple low echoic liver nodules. In the early vascular phase of CEUS, nodules were gradually enhanced from the peripheral sites as ringed enhancement. Sonazoid®was washed out from the nodules in the PVLP and post vascular phase. CONCLUSIONS: The most important feature was peripheral enhancement in the early vascular phase. In case 2, the enhancement of the parenchyma of liver nodules persisted even in the PVLP; indicating the lower degree of malignant potential than others. Actually, the tumors did not extend without any treatment in case 2. Since case 2 is the first case report of HEH with cystic lesions, in patients with liver nodules including cystic lesions, HEH is a potential diagnosis.


Assuntos
Compostos Férricos/farmacologia , Hemangioendotelioma Epitelioide , Ferro/farmacologia , Neoplasias Hepáticas , Óxidos/farmacologia , Ultrassonografia/métodos , Adulto , Idoso de 80 Anos ou mais , Meios de Contraste/farmacologia , Diagnóstico Diferencial , Feminino , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/patologia , Humanos , Aumento da Imagem/métodos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Masculino , Imagem de Perfusão
6.
Hepatol Res ; 49(1): 105-110, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30565816

RESUMO

AIM: In order to know the present status of drug-induced liver injury (DILI) in Japan, we present the data of prospectively collected DILI cases between 2010 and 2018 from 27 hospitals. METHODS: Drug-induced liver injury cases diagnosed by DILI experts from 27 hospitals all over Japan have been prospectively collected since 2010. Alanine aminotransferase level ≥150 U/L and/or alkaline phosphatase ≥2× upper limit of normal were inclusion criteria. RESULTS: In total, data of 307 cases (125 male and 182 female individuals) aged between 17 and 86 years old were collected. The types of liver injury were as follows: 64% hepatocellular type, 20% mixed type, and 16% cholestatic type. A drug-induced lymphocyte stimulation test was carried out in 59% of cases, and was positive in 48% and semipositive in 3% of cases. Eosinophilia ≥6% was observed in 27% of cases. Fifty-three percent of DILI cases occurred within 30 days and 79% of DILI cases occurred within 90 days after starting drug administration. By the diagnostic scale of the Digestive Disease Week (DDW)-Japan 2004 workshop, 93.8% of cases were diagnosed as "highly probable", and 5.9% as "possible". CONCLUSIONS: Japanese DILI patients are somewhat different from those of Europe and North America. The diagnostic scale of the DDW-Japan 2004 workshop has been used in Japan. However, there are many issues to improve the causality assessment of DILI that we must investigate in the future. It is critical to elucidate the mechanisms of drug metabolism and the pathophysiology of liver injury by various drugs to prevent DILI.

7.
Biochem Biophys Res Commun ; 498(1): 64-71, 2018 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-29481805

RESUMO

Chronic hepatitis B virus (HBV) infection is currently a major public health burden. Therefore, there is an urgent need for the development of novel antiviral inhibitors. The stable HBV-producing cell lines of genotype D are widely used to investigate the HBV life cycle and to evaluate antiviral agents. However, stable HBV-producing cell lines of different genotypes do not exist. To construct more convenient and efficient novel cell systems, stable cell lines of genotypes A, B, and C were established using a full-length HBV genome sequence isolated from chronic HBV patients in human hepatoma HepG2 cells. Novel HBV clones were identified and stable HBV-producing cell lines derived from these clones were constructed. HBV replication activities demonstrated time-dependent expression, and the novel cell lines were susceptible to several antiviral inhibitors with no cytotoxicity. Furthermore, infectious viruses were produced from these cell lines. In conclusion, we have established novel stable HBV-producing cell line systems of genotypes A, B, and C. These systems can provide valuable tools for screening antiviral agents and analyzing viral phenotypes in vitro.


Assuntos
Antivirais/análise , Antivirais/farmacologia , Carcinoma Hepatocelular/virologia , Avaliação Pré-Clínica de Medicamentos , Vírus da Hepatite B/fisiologia , Neoplasias Hepáticas/virologia , Adulto , Sequência de Bases , Carcinoma Hepatocelular/genética , Células Clonais , DNA Viral/genética , DNA Viral/metabolismo , Feminino , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Guanina/análogos & derivados , Guanina/farmacologia , Células Hep G2 , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/sangue , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/genética , Masculino , Filogenia , Replicação Viral/efeitos dos fármacos , Adulto Jovem
8.
Artigo em Inglês | MEDLINE | ID: mdl-29427373

RESUMO

BACKGROUND AND AIM: The mechanism underlying hyperglobulinemia in cirrhosis, a long appreciated phenomenon, has never been clearly understood. The aim of this study is to investigate the basis for changes in humoral immunity observed in cirrhosis. METHODS: We retrospectively reviewed our medical record to analyze serum immunoglobulin (Ig) levels in patients with liver disease. We also prospectively analyzed peripheral blood mononuclear cells and sera from liver disease patients. Peripheral blood mononuclear cell surface marker expressions were measured by flow cytometry and serum B-cell-activating factor was measured by enzyme-linked immunosorbent assay. Expression of specific gene expression in magnetically separated B cells was also analyzed by real-time polymerase chain reaction. RESULTS: In retrospective analysis, we found that advancing cirrhosis, irrespective of underlying etiology or hepatocellular carcinoma, resulted in progressively increasing levels of serum IgG and IgA. In prospective analysis using clinical samples, we demonstrated that advancing cirrhosis stage was associated with increased toll-like-receptor (TLR)9 expression in CD27+ B cell and serum B-cell-activating factor levels but decreased CD27+ memory B-cell frequency. The remaining CD27+ B cells in peripheral blood exhibited increased activation-induced cytidine deaminase mRNA expression. Finally, we also demonstrated isolated B cells from advanced cirrhosis were more reactive to TLR9 stimulation that drove antibody secreting cells differentiation leading to hyperimmunoglobulinemia in vitro. CONCLUSIONS: Enhanced TLR9-induced differentiation into antibody secreting cell may explain peripheral reductions of circulating CD27+ memory B cells as well as increased serum Ig levels in cirrhosis.

9.
J Virol ; 89(23): 11945-53, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26378168

RESUMO

UNLABELLED: Anti-hepatitis B virus (HBV) drugs are currently limited to nucleos(t)ide analogs (NAs) and interferons. A challenge of drug development is the identification of small molecules that suppress HBV infection from new chemical sources. Here, from a fungus-derived secondary metabolite library, we identify a structurally novel tricyclic polyketide, named vanitaracin A, which specifically inhibits HBV infection. Vanitaracin A inhibited the viral entry process with a submicromolar 50% inhibitory concentration (IC50) (IC50 = 0.61 ± 0.23 µM), without evident cytotoxicity (50% cytotoxic concentration of >256 µM; selectivity index value of >419) in primary human hepatocytes. Vanitaracin A did not affect the HBV replication process. This compound was found to directly interact with the HBV entry receptor sodium taurocholate cotransporting polypeptide (NTCP) and impaired its bile acid transport activity. Consistent with this NTCP targeting, antiviral activity of vanitaracin A was observed with hepatitis D virus (HDV) but not hepatitis C virus. Importantly, vanitaracin A inhibited infection by all HBV genotypes tested (genotypes A to D) and clinically relevant NA-resistant HBV isolate. Thus, we identified a fungal metabolite, vanitaracin A, which was a potent, well-tolerated, and broadly active inhibitor of HBV and HDV entry. This compound, or its related analogs, could be part of an antiviral strategy for preventing reinfection with HBV, including clinically relevant nucleos(t)ide analog-resistant virus. IMPORTANCE: For achieving better treatment and prevention of hepatitis B virus (HBV) infection, anti-HBV agents targeting a new molecule are in great demand. Although sodium taurocholate cotransporting polypeptide (NTCP) has recently been reported to be an essential host factor for HBV entry, there is a limited number of reports that identify new compounds targeting NTCP and inhibiting HBV entry. Here, from an uncharacterized chemical library, we isolated a structurally new compound, named vanitaracin A, which inhibited the process of entry of HBV and hepatitis D virus (HDV). This compound was suggested to directly interact with NTCP and inhibit its transporter activity. Importantly, vanitaracin A inhibited the entry of all HBV genotypes examined and of a clinically relevant nucleos(t)ide analog-resistant HBV isolate.


Assuntos
Vírus da Hepatite B/fisiologia , Hepatite B/tratamento farmacológico , Vírus Delta da Hepatite/fisiologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Policetídeos/farmacologia , Simportadores/metabolismo , Talaromyces/química , Internalização do Vírus/efeitos dos fármacos , Linhagem Celular , Primers do DNA/genética , Descoberta de Drogas/métodos , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Medições Luminescentes , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Bibliotecas de Moléculas Pequenas , Ressonância de Plasmônio de Superfície
10.
J Gastroenterol Hepatol ; 31(1): 14-22, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26252875

RESUMO

BACKGROUND AND AIM: Daclatasvir combined with asunaprevir is the first all-oral, ribavirin-free treatment of hepatitis C virus genotype 1b infection in Japan. This study compared the efficacy and safety of daclatasvir plus asunaprevir versus telaprevir plus peginterferon/ribavirin in Japanese treatment-naive patients infected with hepatitis C virus genotype 1b. METHODS: Treatment-naive patients (20-70 years; baseline viral load, ≥ 100,000 IU/mL) were randomly assigned (stratified by IL28B rs8099917 TT/non-TT status) to receive either daclatasvir 60 mg tablets once daily and asunaprevir 100 mg softgel capsules twice daily for 24 weeks or telaprevir 750 mg (3 × 250 mg tablets) three times daily for 12 weeks and peginterferon/ribavirin per Japanese prescribing information for 24 weeks. A cohort of prior relapsers to peginterferon/ribavirin (20-75 years; baseline viral load, ≥ 100,000 IU/mL) received daclatasvir plus asunaprevir. RESULTS: In treatment-naive patients, sustained virologic response at post-treatment week 12 in daclatasvir plus asunaprevir recipients was non-inferior (treatment difference, +25.8% in favor of daclatasvir plus asunaprevir) and higher (89.1%, 106/119) than telaprevir plus peginterferon/ribavirin recipients (62.2%, 69/111); sustained viral response was achieved in 95.5% (n = 21/22) of relapsers. Numerically, fewer patients receiving daclatasvir plus asunaprevir compared with telaprevir plus peginterferon/ribavirin experienced serious adverse events (4.2% vs. 5.4%), adverse events leading to discontinuation of any drug (5.0% vs. 62.2%), grade 3/4 treatment-related adverse events (14.3% vs. 72.1%), rash-related events (0% vs. 13.5%), or anemia (0% vs. 47.7%). CONCLUSION: Marked differences were observed in the efficacy and safety profile of daclatasvir in combination with asunaprevir, compared with telaprevir plus peginterferon/ribavirin.


Assuntos
Antivirais/administração & dosagem , Hepatite C/tratamento farmacológico , Imidazóis/administração & dosagem , Interferon-alfa/administração & dosagem , Isoquinolinas/administração & dosagem , Oligopeptídeos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Idoso , Povo Asiático , Carbamatos , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Pirrolidinas , Proteínas Recombinantes/administração & dosagem , Resultado do Tratamento , Valina/análogos & derivados , Adulto Jovem
11.
Rinsho Ketsueki ; 56(1): 30-4, 2015 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-25745965

RESUMO

We report a 38-year-old Nigerian woman with sickle cell disease. Sickle cell disease had been diagnosed when she experienced her first sickle cell crisis episode at age 8 years. Thereafter, she had infrequent minor episodes. She visited a hospital presenting with fever, anemia, jaundice, and systemic pain, and was then transferred to our hospital. Together with rehydration and red blood cell transfusion, analgesics and antibiotics were prescribed, and produced gradual improvement of all symptoms and signs. The patient was discharged on day 9 of hospitalization. Sickle cell crisis is an acute painful episode caused by occlusion of arterioles. The degree of pain and accompanying symptoms, as well as the frequencies of crises, are variable. Moreover, one third of individuals with sickle cell disease never experience a crisis. As our society becomes increasingly globalized, the probabilities of encountering sickle cell disease patients will be higher.


Assuntos
Anemia Falciforme/patologia , Anemia Falciforme/terapia , Antibacterianos/uso terapêutico , Transfusão de Eritrócitos , Dor/etiologia , Doença Aguda , Adulto , Anemia Falciforme/complicações , Feminino , Humanos , Manejo da Dor
12.
Biochem Biophys Res Commun ; 443(3): 808-13, 2014 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-24342612

RESUMO

Hepatitis B virus (HBV) entry has been analyzed using infection-susceptible cells, including primary human hepatocytes, primary tupaia hepatocytes, and HepaRG cells. Recently, the sodium taurocholate cotransporting polypeptide (NTCP) membrane transporter was reported as an HBV entry receptor. In this study, we established a strain of HepG2 cells engineered to overexpress the human NTCP gene (HepG2-hNTCP-C4 cells). HepG2-hNTCP-C4 cells were shown to be susceptible to infection by blood-borne and cell culture-derived HBV. HBV infection was facilitated by pretreating cells with 3% dimethyl sulfoxide permitting nearly 50% of the cells to be infected with HBV. Knockdown analysis suggested that HBV infection of HepG2-hNTCP-C4 cells was mediated by NTCP. HBV infection was blocked by an anti-HBV surface protein neutralizing antibody, by compounds known to inhibit NTCP transporter activity, and by cyclosporin A and its derivatives. The infection assay suggested that cyclosporin B was a more potent inhibitor of HBV entry than was cyclosporin A. Further chemical screening identified oxysterols, oxidized derivatives of cholesterol, as inhibitors of HBV infection. Thus, the HepG2-hNTCP-C4 cell line established in this study is a useful tool for the identification of inhibitors of HBV infection as well as for the analysis of the molecular mechanisms of HBV infection.


Assuntos
Vírus da Hepatite B/fisiologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Internalização do Vírus , Animais , Dimetil Sulfóxido/farmacologia , Células Hep G2 , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Simportadores/genética , Tupaia , Internalização do Vírus/efeitos dos fármacos
13.
Clin J Gastroenterol ; 17(3): 497-504, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38451411

RESUMO

Common extrahepatic metastasis sites of hepatocellular carcinoma (HCC) are the lungs, adrenal glands, and bones. Herein, we report a rare case of metastatic gastric, pancreatic, and renal tumors from HCC simultaneously, and review the relevant literature. A 75-year-old woman presented with right hypochondralgia, appetite loss, and weight loss. Computed tomography revealed suspected metastatic liver, lung, and renal tumors. A blood test revealed a leukocyte count of 26,210/µL and a high inflammatory reaction. As sepsis was suspected, the patient was referred to our hospital. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed a hypovascular liver tumor that was suspected to be metastatic. Upper gastrointestinal endoscopy revealed two suspected metastatic gastric tumors. Liver and gastric tumor biopsies revealed poor carcinoma in both. The patient's condition gradually worsened and she died on day 8 of the illness. Based on autopsy findings, the patient was finally diagnosed with metastatic gastric and renal tumors originating from HCC. Additionally, a metastatic pancreatic tumor originating from the HCC was identified during autopsy. The pathological diagnosis of the pulmonary lesion was primary lung adenocarcinoma. In conclusion, HCC should be suspected in cases with multiple metastases of unknown primary lesions.


Assuntos
Carcinoma Hepatocelular , Neoplasias Renais , Neoplasias Hepáticas , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Feminino , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Carcinoma Hepatocelular/secundário , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/diagnóstico por imagem , Idoso , Neoplasias Renais/patologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/secundário , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/secundário , Neoplasias Pancreáticas/diagnóstico por imagem , Evolução Fatal , Imageamento por Ressonância Magnética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Tomografia Computadorizada por Raios X
14.
Cancer Rep (Hoboken) ; 7(1): e1938, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38014499

RESUMO

BACKGROUND: Hypomethylating agents, including azacytidine (AZA), are standard therapeutics for patients with high-risk myelodysplastic syndromes (MDS), a group of myeloid neoplasms. However, treatment schedules are not unified in real-world practice; in addition to the standard 7-day (standard-dose) schedule, shortened (reduced-dose) schedules are also used. AIMS: The aim of this study was to discover the patient group(s) which show differential efficacy between standard-and reduced-dose AZA to MDS. METHODS AND RESULTS: The outcome of different AZA doses in a cohort of 151 MDS patients were retrospectively analyzed. Overall survival (OS) was not significantly different between standard- and reduced-dose AZA groups by multivariate analysis. However, an interaction was found between either the sex (female vs. male), the platelet counts (< 40 × 103 /µl vs. ≥ 40 × 103 /µl), or the karyotype risk (< poor vs. ≥ poor) and standard-dose AZA for longer OS. Subgroup analyses revealed better OS with standard- over reduced-dose AZA in female patients (HR, 0.27 [95% CI, 0.090-0.79]; p = 0.011), and those with platelet counts ≥ 40 × 103 /µl (HR, 0.51 [95% CI, 0.26-0.99]; p = 0.041). The union of female and preserved platelet count subgroups also benefited from standard-dose AZA. With this as a test cohort, we next analyzed patients registered in the JALSG MDS212 study, for whom 7-day and 5-day AZA treatment strategies were prospectively compared, as a validation cohort (N = 172). That cohort showed the same tendency as the retrospective results. CONCLUSION: We identified the union of female and preserved platelet count subgroups which benefited from standard-dose AZA, imparting crucial information to physicians planning treatment regimens in MDS patients.


Assuntos
Azacitidina , Síndromes Mielodisplásicas , Humanos , Masculino , Feminino , Azacitidina/efeitos adversos , Contagem de Plaquetas , Estudos Retrospectivos , Antimetabólitos Antineoplásicos/efeitos adversos , Resultado do Tratamento , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico
15.
J Viral Hepat ; 19(9): 608-14, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22863264

RESUMO

Cyclooxygenase (COX)-2 is involved in inflammation, anti-apoptosis and carcinogenesis. The -1195GG genotype of single nucleotide polymorphism (SNP) in COX-2 promoter was associated with low platelet counts in patients with chronic hepatitis C. Polymorphism of patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene (rs738409 C>G) have been reported to be associated with cirrhosis, and the major genotype of SNPs near interleukin (IL)28B are related to viral clearance. The present study was designed to assess the contribution of these SNPs to disease progression in patients with chronic hepatitis C. The study enrolled 220 Japanese patients with chronic hepatitis C. Three SNPs, -1195 COX-2, PNPLA3 and IL28B (rs8099917), were genotyped in order to analyze their association with hepatic fibrosis and inflammation. The -1195GG genotype in COX-2 was associated with advanced fibrosis and higher levels of inflammation in the liver tissues. The major genotype of IL28B was also associated with advanced fibrosis, but the polymorphism of PNPLA3 was neither associated with fibrosis nor inflammation. Multivariate analysis showed that -1195GG in COX-2 is an independent factor associated with advanced fibrosis, while the major genotype of IL28B and HCV genotype 2 were other independent factors. In conclusion, the -1195GG genotype in COX-2 is a genetic marker for liver disease progression, while the PNPLA3 genotypes are not associated with disease progression in Japanese patients with chronic hepatitis C.


Assuntos
Ciclo-Oxigenase 2/genética , Hepatite C Crônica/genética , Hepatite C Crônica/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Polimorfismo Genético , Regiões Promotoras Genéticas , Povo Asiático , Progressão da Doença , Feminino , Predisposição Genética para Doença , Hepatite C Crônica/complicações , Humanos , Inflamação/genética , Inflamação/patologia , Interferons , Interleucinas/genética , Lipase/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade
16.
JGH Open ; 5(8): 888-895, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34386596

RESUMO

BACKGROUND AND AIM: We aimed to identify clinical features that suggest that coronavirus disease 2019 (COVID-19) should be a differential diagnosis in patients presenting with a chief complaint of fever and abnormal liver function. METHODS: We retrospectively studied the presence or absence of abnormal liver function in 216 patients diagnosed with mild-moderate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection between February and September 2020. RESULTS: Abnormal liver function was observed in 51 patients with mild-moderate COVID-19. The median peak aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels were 57.5, 75.5, and 332.5 U/L, respectively. The median number of days from symptom onset to peak AST, ALT, and LDH were 8.5, 9, and 8.5, respectively. The median peak LDH/AST ratio was 9.0. Low lymphocyte-to-white blood cell ratio and elevated LDH were found to be independent contributing factors for intensive care unit (ICU) admission on a multivariate analysis. CONCLUSIONS: AST-predominant AST/ALT/LDH elevation peaking 8-9 days after symptom onset and not accompanied by elevated alkaline phosphatase or gamma-glutamyl transferase may be a useful clinical feature for differentiating COVID-19 from other diseases. Since the median LDH/AST ratio was 9.0, it seems that the abnormal liver function caused by SARS-CoV-2 is an indirect damage to liver cells due to elevated cytokine levels caused by liver-infiltrating lymphocytes. SARS-CoV-2 infection should be considered in patients presenting with a chief complaint of fever and liver injury; those with a high lymphocyte-to-white blood cell ratio or and a high LDH/AST ratio may be admitted to the ICU.

17.
J Med Virol ; 82(12): 2064-72, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20981794

RESUMO

Hepatitis C virus (HCV) infection is associated with lymphoproliferative disorders. HCV infection of B cells is a predictive factor for lymphoproliferative disorders in patients with chronic hepatitis C, although its molecular mechanisms remain unknown. Epstein-Barr virus (EBV) is a B cell-tropic virus with the potential to cause lymphoproliferative disorders, and its reactivation is induced by several viruses and cytokines. The possibility that HCV infection triggers reactivation of EBV and induces lymphoproliferative disorders were investigated. Expression of EBV mRNAs was analyzed by RT-PCR in patients infected with HCV and control subjects, and correlations between reactivation of EBV and markers for lymphoproliferative disorders were investigated. BZLF1 mRNA, a starter molecule of reactivation, was detected in peripheral blood mononuclear cells from 12 of 52 (23%), patients infected with HCV and the frequency was higher than in healthy subjects [3 of 43 (9%), P = 0.032]. But the presence of the BZLF1 mRNA was not associated with an abnormality of markers for lymphoproliferative disorders. This study on BZLF1 mRNA expression among lymphoid cell subsets showed that reactivation of EBV was observed specifically in B cells. The BZLF1 mRNA disappeared following anti-viral therapy and remained negative after eradication of HCV in patients with a sustained viral response, while the EBER1 RNA, a marker for persistence of EBV, was detected throughout the therapy. Infection with HCV induces reactivation of EBV in B cells, but this reactivation was not associated directly with lymphoproliferative disorders triggered by HCV.


Assuntos
Linfócitos B/virologia , Infecções por Vírus Epstein-Barr/complicações , Hepatite C Crônica/complicações , Herpesvirus Humano 4/fisiologia , Transtornos Linfoproliferativos/virologia , Ativação Viral , Adulto , Idoso , Infecções por Vírus Epstein-Barr/virologia , Feminino , Hepatite C Crônica/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , Transativadores/genética , Transativadores/metabolismo
18.
Arch Public Health ; 78: 101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33088502

RESUMO

BACKGROUND: An elevated alanine aminotransferase (ALT) and a low aspartate aminotransferase (AST) to ALT ratio (AST/ALT ratio) suggest nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, increasing the risk of liver cirrhosis and hepatocellular carcinoma. In addition, eating quickly has been found to be associated with outcomes such as obesity. This study sought to investigate the relationship between eating quickly and an elevated ALT or a low AST/ALT ratio in Japanese middle-aged adults. METHODS: The present study included 283,073 adults aged 40-64 years who had annual health checkups in Japan from April 2013 to March 2014. The data of serum parameters and lifestyle factors, including eating speed, were analyzed. An elevated ALT was defined as > 40 U/L, and a low AST/ALT ratio was defined as < 1. Logistic regression analysis was performed to calculate the odds ratios (ORs) and the 95% confidence intervals (CIs) for an elevated ALT and a low AST/ALT ratio. RESULTS: Significantly increased ORs for an elevated ALT were observed in men (OR: 1.45, 95% CI: 1.41-1.49) and women (OR: 1.34, 95% CI: 1.25-1.43). Moreover, eating quickly significantly increased the ORs for a low AST/ALT ratio in men (OR: 1.53, 95% CI: 1.50-1.56) and women (OR: 1.36, 95% CI: 1.31-1.41). When the analysis was limited to those with ALT ≤40 U/L, eating quickly had significantly increased ORs for a low AST/ ALT ratio, regardless of sex. CONCLUSIONS: Eating quickly was significantly associated with an elevated ALT and a low AST/ALT ratio. In addition, eating quickly was significantly associated with a low AST/ALT ratio even for those without ALT elevation. This study suggested that modification of eating speed may contribute to reducing the risk for an elevated ALT and a low AST/ALT ratio.

19.
Clin Pharmacol Drug Dev ; 9(6): 699-708, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31833184

RESUMO

Peficitinib (ASP015K) is a novel Janus kinase inhibitor developed for the treatment of rheumatoid arthritis (RA). The impact of hepatic impairment on the peficitinib pharmacokinetic (PK) and safety profile was investigated in non-RA subjects (n = 24) in an open-label, parallel-group, multicenter comparative study in Japan. Subjects received a single, clinically relevant, oral dose of a peficitinib 150 mg tablet under fasting conditions. Plasma PK parameters were measured for peficitinib and its metabolites H1 (sulfate and methylated metabolite), H2 (sulfate metabolite), and H4 (methylated metabolite) in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. The peficitinib area under the plasma-concentration-time curve from time 0 to infinity (AUCinf ) and maximum observed concentration (Cmax ) were not markedly different in subjects with mild hepatic impairment versus normal hepatic function. In subjects with moderate hepatic impairment versus normal hepatic function, the geometric mean ratios for peficitinib AUCinf and Cmax , were 1.92 (90% CI: 1.39, 2.66) and 1.82 (90% CI: 1.24, 2.69), respectively. Five treatment-emergent adverse events (TEAEs) were experienced by 3 subjects, 1 in each group. There were no deaths, no serious TEAEs, and no TEAEs leading to withdrawal. In summary, the PK profile was unaltered in subjects with mild hepatic impairment after a single clinically relevant dose of peficitinib, but exposure almost doubled in subjects with moderate hepatic impairment. Peficitinib dose reduction may be considered in RA patients with moderate hepatic impairment.


Assuntos
Adamantano/análogos & derivados , Povo Asiático , Inibidores de Janus Quinases/administração & dosagem , Hepatopatias/fisiopatologia , Niacinamida/análogos & derivados , Adamantano/administração & dosagem , Adamantano/efeitos adversos , Adamantano/farmacocinética , Administração Oral , Idoso , Área Sob a Curva , Feminino , Humanos , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/farmacocinética , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/farmacocinética , Índice de Gravidade de Doença
20.
Health Sci Rep ; 3(3): e176, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32685701

RESUMO

AIMS: Hepatitis C virus (HCV) infection is monitored by the host innate immunity that includes the endogenous interferon (IFN), which up-regulates IFN-stimulated genes (ISGs). HCV is both hepatotropic and lymphotropic, but HCV replication in lymphoid cells is a controversial issue. Here, we analyzed the mRNA levels of the ISGs in B cells of HCV-infected patients during antiviral therapy and investigated the effects of viral eradication. METHODS: One hundred and eighty-one patients with chronic hepatitis C and 26 healthy volunteers were enrolled in this study. Levels of HCV RNA and mRNA of ISGs in B cells isolated from the patients were monitored before, during, and after antiviral therapy. RESULTS: HCV RNA was detected in B cells of 133/175 (76.0%) patients who achieved sustained virologic response (SVR) before therapy was started. The positive ratio of HCV RNA in B cells was higher in patients with genotype 1 and the non-major genotype of interleukin 28B. HCV RNA in B cells of most patients disappeared 1 week after antiviral therapy was started. The baseline expression of ISG mRNA was significantly higher in the patients than in the healthy volunteers. Levels of ISG mRNA were increased and remained high throughout the IFN-based therapy. In contrast, levels of ISG mRNA in patients who achieved SVR were significantly decreased 1 week after the IFN-free therapy was started and remained low during the therapy. CONCLUSIONS: These results suggested that IFN-free therapy potentially eradicated HCV in the B cells, leading to the down-regulation of endogenous ISGs. The level of ISG mRNA could be used as a marker for viral eradication in B cells.

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