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1.
Nat Commun ; 12(1): 5525, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535664

RESUMO

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.


Assuntos
Descoberta de Drogas , Fígado/patologia , Modelos Biológicos , Animais , Carcinogênese/patologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Quimioprevenção , Estudos de Coortes , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Hepacivirus/fisiologia , Hepatite C/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Vigilância Imunológica/efeitos dos fármacos , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Knockout , Nizatidina/farmacologia , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/genética
2.
BMC Gastroenterol ; 21(1): 306, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34332532

RESUMO

BACKGROUND: We previously reported on the trends in the etiologies of hepatocellular carcinoma (HCC) diagnosed in patients between 1995 and 2009. The aims of our updated study were to evaluate the incidence, nonhepatitis B and nonhepatitis C viral (NBNC) etiologies, and clinical characteristics of HCCs occurring in patients between 1992 and 2018. METHODS: The study enrolled 2171 consecutive patients with HCC between 1992 and 2018. Their medical records were reviewed. The patients were divided into two groups, patients with early diagnoses from 1992 to 2009 and those with late diagnoses from 2010 to 2018. RESULTS: NBNC-HCC occurred in 514 patients (23.6%). The percentage of patients with HCC who had NBNC-HCC increased from 26.5% in 2009 to 46.3% in 2018. Patients with NBNC-HCC were older (median ages from 67 to 73 years). Type 2 diabetes mellitus (48.5-60.3%: P = 0.008), hypertension (48.5-57.4%: P = 0.047), and hyperlipidemia (39.2-53.8%: P = 0.001) increased significantly in recent years. The median FIB-4 index decreased (4.37-3.61: P = 0.026) and the median platelet count increased (15.1-17.9 × 104/µL: P = 0.013). Among the 514 patients with NBNC-HCC, 194 underwent hepatic resection for nonalcoholic steatohepatitis (NASH) (15%), alcoholic liver disease (ALD) (29%), and cryptogenic hepatitis (56%). Cirrhosis was detected in 72%, 39%, and 16% of patients with NASH, ALD, and cryptogenic hepatitis, respectively. The prevalence of cirrhosis in patients with NASH was significantly higher than the prevalence of cirrhosis in the other groups (P < 0.001). Overall, 70% of the non-malignant liver tissue of patients with NBNC-HCC was not involved with cirrhosis. On the other hand, the median FIB-4 index in patients with cryptogenic HCC was 2.56, which was a significantly lower value than those values in the other groups of patients. The FIB-4 index considered as one of useful screening of HCC. CONCLUSIONS: The prevalence of NBNC-HCC has increased rapidly even in a regional university hospital. Metabolic syndrome may be an important risk factor for HCC. HCC was also found in patients with non-cirrhotic livers. The FIB-4 index may be a useful screening method for HCC in patients with NBNC.


Assuntos
Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Idoso , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/etiologia , Humanos , Incidência , Cirrose Hepática/complicações , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia
3.
J Toxicol Sci ; 46(8): 359-369, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334557

RESUMO

Predicting drug-induced side effects in the cardiovascular system is very important because it can lead to the discontinuation of new drugs/candidates or the withdrawal of marketed drugs. Although chronic assessment of cardiac contractility is an important issue in safety pharmacology, an in vitro evaluation system has not been fully developed. We previously developed an imaging-based contractility assay system to detect acute cardiotoxicity using human iPS cell-derived cardiomyocytes (hiPSC-CMs). To extend the system to chronic toxicity assessment, we examined the effects of the anti-hepatitis C virus (HCV) drug candidate BMS-986094, a guanosine nucleotide analogue, which was withdrawn from phase 2 clinical trials because of unexpected contractility toxicities. Additionally, we examined sofosbuvir, another nucleotide analogue inhibitor of HCV that has been approved as an anti-HCV drug. Motion imaging analysis revealed the difference in cardiotoxicity between the cardiotoxic BMS-986094 and the less toxic sofosbuvir in hiPSC-CMs, with a minimum of 4 days of treatment. In addition, we found that BMS-986094-induced contractility impairment was mediated by a decrease in calcium transient. These data suggest that chronic treatment improves the predictive power for the cardiotoxicity of anti-HCV drugs. Thus, hiPSC-CMs can be a useful tool to assess drug-induced chronic cardiotoxicity in non-clinical settings.

4.
Cancers (Basel) ; 13(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34439111

RESUMO

The aim of this study was to investigate the early tumor response and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma in real-world practice. Forty patients with Child-Pugh class A liver function and eastern cooperative oncology group performance status 0 or 1 were enrolled. The objective response rate (ORR) at six weeks after the start of treatment, changes in α-fetoprotein (AFP) and des-γ-carboxyprothrombin, incidence of adverse events (AEs), and changes in albumin-bilirubin (ALBI) score and serum ammonia level, were evaluated. Among 40 patients, 24 had histories of prior molecular targeted agents (MTAs). The ORR was 22.5% based on mRECIST. Multivariate analysis showed that an AFP ratio <1.0 at three weeks (odds ratio 39.2, 95% confidence interval CI 2.37-649.0, p = 0.0103) was the only significant factor for predicting early response. There was no significant difference in the frequency of AEs between patients receiving first-line treatments and others. Fatigue, proteinuria, and ascites were more frequent in patients who experienced prior treatment. No decrease in ALBI score or increase in serum ammonia level was observed. Our study demonstrated that AFP may be useful in assessing early response and that this treatment is safe, including in patients with prior MTA treatments.

5.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298877

RESUMO

Growing evidence suggests that breast cancer originates from a minor population of cancer cells termed cancer stem cells (CSCs), which can be identified by aldehyde dehydrogenase (ALDH) activity-based flow cytometry analysis. However, novel therapeutic drugs for the eradication of CSCs have not been discovered yet. Recently, drug repositioning, which finds new medical uses from existing drugs, has been expected to facilitate drug discovery. We have previously reported that sphingosine kinase 1 (SphK1) induced proliferation of breast CSCs. In the present study, we focused on the immunosuppressive agent FTY720 (also known as fingolimod or Gilenya), since FTY720 is known to be an inhibitor of SphK1. We found that FTY720 blocked both proliferation of ALDH-positive cells and formation of mammospheres. In addition, we showed that FTY720 reduced the expression of stem cell markers such as Oct3/4, Sox2 and Nanog via upregulation of protein phosphatase 2A (PP2A). These results suggest that FTY720 is an effective drug for breast CSCs in vitro.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Cloridrato de Fingolimode/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Proteína Fosfatase 2/metabolismo , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Imunossupressores/farmacologia , Células MCF-7 , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Regulação para Cima/efeitos dos fármacos
6.
Opt Express ; 29(14): 21313-21319, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34265921

RESUMO

We propose a plasmonic diffraction structure combined with deep trench isolation (DTI) filled with highly reflective metal to enhance the near-infrared (NIR) sensitivity of image sensors. The plasmonic diffraction structure has a silver grating on the light-illuminated surface of a typical silicon backside-illuminated CMOS image sensor. The structural parameters of the silver grating were investigated through simulations, and the mechanism of the NIR sensitivity enhancement was clarified. Under the quasi-resonant conditions of surface plasmon polaritons, incident NIR light effectively diffracted as a propagating light to the sensor silicon layer. The diffracted light travelled back and forth between the DTIs. The effective propagation length in silicon was extended to six times by silver-filled DTI, resulting in approximately five times improvement of the 3-µm-thick silicon absorption at a wavelength of 940 nm.

7.
Clin J Gastroenterol ; 14(5): 1517-1524, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34291386

RESUMO

The overall survival of patients with advanced hepatocellular carcinoma with tumor thrombosis of the main trunk or bilobar branches of the portal vein is extremely poor. Moreover, there is no standard treatment established for the condition. Herein, we present the case of a 65-year-old man who were treated the patient with hepatic arterial infusion chemotherapy, radiation therapy for tumor thrombosis, portal vein stent placement, lenvatinib administration, and renal venous shunt embolization. A complete response was observed according to mRECIST and the patient has been alive for 14 months since treatment initiation with no tumor recurrence.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Trombose , Idoso , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/terapia , Humanos , Infusões Intra-Arteriais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Masculino , Recidiva Local de Neoplasia , Veia Porta , Trombose/etiologia , Trombose/terapia
8.
J Viral Hepat ; 28(9): 1304-1311, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34105859

RESUMO

While the preS1 region of the large hepatitis B surface protein plays an essential role in hepatitis B virus (HBV) infection, the effect of preS1 on liver fibrosis and hepatocarcinogenesis in chronic hepatitis B (CHB) patients is not well known. In this study, we measured serum preS1 levels by chemiluminescent immunoassay technology in 690 CHB patients and evaluated the correlation between serum preS1 levels and HBV, liver function markers and liver inflammation, fibrosis assessed by histological findings. Predictive factors for hepatocellular carcinoma (HCC) development in patients who had no previous history of HCC at the time of preS1 level measurement were also analysed. Median hepatitis B surface antigen (HBsAg) and preS1 levels were 3.08 log IU/mL and 98 ng/mL, respectively. PreS1 values were significantly correlated with serum HBsAg (p <0.001), hepatitis B core-related antigen (HBcrAg) (p <0.001) and HBV DNA levels (p <0.01). PreS1 values were also significantly correlated with serum alanine aminotransferase levels (p <0.001) and were significantly higher in patients who had higher grading of liver inflammatory activity (p <0.05). HBsAg level was correlated, but preS1/HBsAg ratio reflected liver fibrosis staging more directly than HBsAg alone. Multivariate analysis identified age ≥53 years (hazard ratio [HR], 18.360 for <53 years; p = 0.021) and preS1/HBsAg ratio ≥0.12 (HR, 6.205 for <0.12; p = 0.040) as significant and independent factors for HCC development in CHB patients. The preS1/HBsAg ratio directly reflects liver fibrosis, and the ratio might be a predictive marker for HCC development in CHB patients.


Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiologia , DNA Viral , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Humanos , Cirrose Hepática/diagnóstico , Neoplasias Hepáticas/diagnóstico , Pessoa de Meia-Idade
9.
Toxicol Sci ; 183(1): 227-239, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34142159

RESUMO

Coronavirus disease 2019 (COVID-19) continues to spread across the globe, with numerous clinical trials underway seeking to develop and test effective COVID-19 therapies, including remdesivir. Several ongoing studies have reported hydroxychloroquine-induced cardiotoxicity, including development of torsade de pointes (TdP). Meanwhile, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are expected to serve as a tool for assessing drug-induced cardiotoxicity, such as TdP and contraction impairment. However, the cardiotoxicity of COVID-19 treatments has not been fully assessed using hiPSC-CMs. In this study, we focused on drug repurposing with various modes of actions and examined the TdP risk associated with COVID-19 treatments using field potential using multi-electrode array system and motion analysis with hiPSC-CMs. Hydroxychloroquine induced early after depolarization, while remdesivir, favipiravir, camostat, and ivermectin had little effect on field potentials. We then analyzed electromechanical window, which is defined as the difference between field potential and contraction-relaxation durations. Hydroxychloroquine decreased electromechanical window of hiPSC-CMs in a concentration-dependent manner. In contrast, other drugs had little effect. Our data suggest that hydroxychloroquine has proarrhythmic risk and other drugs have low proarrhythmic risk. Thus, hiPSC-CMs represent a useful tool for assessing the comprehensive cardiotoxicity caused by COVID-19 treatments in nonclinical settings.


Assuntos
COVID-19 , Células-Tronco Pluripotentes Induzidas , COVID-19/tratamento farmacológico , Cardiotoxicidade , Células Cultivadas , Humanos , Miócitos Cardíacos , SARS-CoV-2
10.
J Exp Clin Cancer Res ; 40(1): 215, 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34174931

RESUMO

BACKGROUND: There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN). METHOD: We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated. RESULTS: In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAFmean) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAFmean for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed. CONCLUSION: Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice.

11.
Regul Toxicol Pharmacol ; 124: 104963, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34102240

RESUMO

Recently we provided a new interpretation that increased serum ALP in dogs is not adverse if no hepatotoxic finding coexists in the analysis of toxicity studies of over 200 pesticides evaluated in Japan (Yokoyama et al., 2019). We also proposed a decision tree to evaluate the adversity of the increased ALP. The present analysis was conducted to validate the reliability of this interpretation with 129 pesticides more recently evaluated. Before applying, the decision tree was revised to be consistent in all steps. The pesticides showed similar characterization of increased ALP to the previous analysis in that the increase was more frequent than in rats and that liver hypertrophy and hepatotoxicity commonly coexisted with an increase in ALP in dogs. When short- and long-term studies of 58 pesticides inducing ALP activity in dogs were applied to the revised tree, the increased ALP in 8 pesticides was judged not adverse in either study. The revision of the tree did not affect the NOAEL judgment of these pesticides; however, the revised routes contributed to the judgment more robustly. This study showed the reliability of our interpretation and applicability of the decision tree to evaluate the adversity of increased ALP in dogs.

12.
BMC Womens Health ; 21(1): 198, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33985484

RESUMO

BACKGROUND: Ovarian abscesses, which occur mostly in sexually active women via recurrent salpingitis, occur rarely in virginal adolescent girls. Here, we present a case of an ovarian abscess in a virginal adolescent girl who was diagnosed and treated by laparoscopy. CASE PRESENTATION: A 13-year-old healthy girl presented with fever lasting for a month without abdominal pain. Computed tomography scan and magnetic resonance imaging indicated a right ovarian abscess. Laparoscopic surgery revealed a right ovarian abscess with intact uterus and fallopian tubes. The abscess was caused by Staphylococcus aureus. The patient recovered completely after excision of the abscess, followed by antibiotic treatment. CONCLUSIONS: Ovarian abscess may occur in virginal adolescent girls; Staphylococcus aureus, an uncommon species causing ovarian abscess, may cause the infection.


Assuntos
Laparoscopia , Doenças Ovarianas , Salpingite , Abscesso/diagnóstico por imagem , Abscesso/tratamento farmacológico , Abscesso/cirurgia , Adolescente , Antibacterianos/uso terapêutico , Feminino , Humanos , Doenças Ovarianas/diagnóstico por imagem , Doenças Ovarianas/cirurgia , Salpingite/tratamento farmacológico , Staphylococcus aureus
13.
Biochem Biophys Res Commun ; 559: 78-83, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-33932902

RESUMO

Combination therapy with glecaprevir and pibrentasvir (PIB) has high efficacy for patients with hepatitis C virus (HCV) infection except among those who experienced NS5A-P32 deletion (del) mutation during prior DAA treatment failure. However, some patients fail to achieve SVR through combination treatment even in the absence of NS5A-P32del. We analyzed emergence of NS5A resistance-associated substitutions (RASs) against PIB using HCV-infected mice. Male human hepatocyte transplanted mice were infected with genotype 1b wild-type HCV. Mice were treated with PIB, resulting in a transient decrease in serum HCV RNA levels but followed by relapse during the treatment. Direct sequence analysis showed emergences of various mutations in the NS5A region, including L31V/P32del, L31F/P32del/Y93H, NS5A-P29del/Y85C, and NS5A-F37Y. PIB was less effective in mice with NS5A-F37Y mutations compared to mice with wild-type HCV. NS5A-F37Y showed 5.4-fold resistance to PIB relative to wild-type based on analysis using HCV subgenomic replicon systems. The present in vivo and in vitro studies identified NS5A-F37Y as a novel RAS against PIB and showed the possibility of emergence of various NS5A RASs including P29del, P32del and F37Y following PIB treatment. These mutations might emerge and lead to failure to respond to DAA therapies including PIB-based regimens in chronic hepatitis C patients.


Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Farmacorresistência Viral , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Pirrolidinas/farmacologia , Animais , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Hepacivirus/genética , Hepatite C/virologia , Hepatócitos/virologia , Humanos , Masculino , Camundongos , Camundongos SCID , Mutação/efeitos dos fármacos , Pirrolidinas/uso terapêutico
14.
Food Chem Toxicol ; 152: 112206, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33887398

RESUMO

We describe the characterisation and validation of an androgen receptor (AR) transactivation assay for detection of AR agonists and antagonists using a stably transfected human prostate cancer cell line. This 22Rv1/mouse mammary tumour virus glucocorticoid knock-out cell line based AR transactivation assay was validated by criteria in Organisation for Economic Cooperation and Development Guidance Document 34 to determine if the assay performed equally well to the AR EcoScreen Assay included in Test Guideline for AR Transactivation (OECD TG 458). There was no Glucocorticoid Receptor (GR) crosstalk, and no changes in the AR DNA sequence in cells after the successful knock out of GR. Subsequently, the concordance of classifications of the 22 test chemicals was 100% in all laboratories. The AR agonistic and antagonistic inter-laboratory coefficients of variation based on log[10% effect for 10 nM DHT, PC10] and log[inhibitory response of 800 pM DHT by at 30%, IC30] from comprehensive tests were 2.75% and 2.44%, respectively. The AR agonist/antagonist test chemical classifications were consistent across AR EcoScreen ARTA assay data for 82/89%, and the balanced accuracy, sensitivity, and specificity were 83/90%, 88/100% and 78/80%, respectively. This assay was successfully validated and was approved for inclusion in TG 458 in 2020.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Androgênios/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Receptores Androgênicos/metabolismo , Animais , Linhagem Celular Tumoral , Técnicas de Inativação de Genes , Humanos , Vírus do Tumor Mamário do Camundongo , Camundongos , Receptores de Glucocorticoides/deficiência , Receptores de Glucocorticoides/genética , Reprodutibilidade dos Testes , Ativação Transcricional/efeitos dos fármacos
15.
J Appl Toxicol ; 41(2): 303-329, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33124715

RESUMO

The Amino acid Derivative Reactivity Assay (ADRA) is a convenient and effective in chemico test method for assessing covalent binding of test chemicals with protein-derived nucleophilic reagents as a means of predicting skin sensitization potential. Although the original molar-concentration approach to ADRA testing was not suitable for testing multiconstituent substances of an unknown composition, a weight-concentration approach that is suitable for such substances was developed, which also led to the realization that test chemical solutions prepared to molar concentrations higher than the original 1 mM would reduce false negative results as well as enhance predictive capacity. The present study determined an optimal molar-concentration that achieves even higher predictive capacity than the original ADRA. Eight chemicals that were false negatives when tested with 1 mM test chemical solutions were retested with test chemical solutions between 2 and 5 mM, which showed 4 mM to be the optimal molar-concentration for ADRA testing. When 82 chemicals used in the original development were retested with 4 mM test chemical solutions, false negative results were reduced by four. When an additional 85 chemicals used to evaluate the weight-concentration approach to ADRA were retested, the results essentially replicated those obtained with 0.5 mg/ml test chemical solutions and gave 10 fewer false negatives than original ADRA with 1 mM solutions. A comparison of these results for 136 chemicals showed that ADRA testing with 4 mM solutions achieved a four percentage point improvement in accuracy over original ADRA and a two percentage point improvement over DPRA testing.

16.
Cancer Lett ; 498: 111-120, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33129954

RESUMO

Despite recent advances in cancer immunotherapy, the efficacy of colorectal cancer (CRC) immunotherapy regimens is limited. This study evaluated the combined effect of an anti-PD-1 antibody and a platelet-derived growth factor receptor inhibitor (imatinib) on CRC progression using an orthotopic transplanted mouse model that reproduced the three histological phenotypes of CRC (inflamed-, excluded-, and desert-type). The frequency of each of these phenotypes in 196 human CRC tissue samples was also evaluated. Excluded-type CRC had the highest frequency in human tissue samples. In the mouse model, imatinib suppressed stromal reaction and increased sensitivity to anti-PD-1 treatment in excluded-type CRC. Antitumor effect was observed in mice with excluded-type tumors only after concomitant administration of anti-PD-1 antibody and imatinib. Immunohistological analysis revealed a reduction in stromal volume and an increase in the number of CD8-positive T cells in the tumor nest following combination therapy. RNA sequencing revealed significant activation of immune-related pathways and suppression of stromal-related pathways in transplanted tumors treated with combination therapy compared with tumors treated with anti-PD-1 antibody monotherapy. This combination therapy may prove effective for CRC cases that are unresponsive to anti-PD-1 antibody monotherapy.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/terapia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Idoso , Animais , Anticorpos/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Mesilato de Imatinib/farmacologia , Imunoterapia/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Receptor de Morte Celular Programada 1/metabolismo , Estudos Retrospectivos
17.
J Viral Hepat ; 28(2): 400-409, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33197288

RESUMO

Although glucocorticoids have been used for immunosuppression of patients with primary hepatitis B virus (HBV) infection-induced severe hepatitis, the treatment is associated with a high frequency of adverse events. We conducted a pilot study for evaluating the efficacy and safety of abatacept, a cytotoxic T lymphocyte antigen-4 immunoglobulin (CTLA4), for acute hepatitis B. Five patients with severe acute hepatitis B (prothrombin activity ≤ 60%) were treated for immunosuppression by abatacept. Four patients received abatacept concurrently with methylprednisolone, and another patient was treated with abatacept alone. Rapid decrease in serum alanine aminotransferase levels, increase in prothrombin activity and improvement of general condition were obtained in four out of five patients. The patient with the most severe hepatitis underwent liver transplantation due to exacerbation of hepatitis in spite of treatment with both abatacept and methylprednisolone. None of the patients developed significant adverse events associated with the use of abatacept. Hepatitis B surface antigen (HBsAg) became negative in all five patients. The effect of abatacept and methylprednisolone for severe hepatitis B was compared using a mouse model. Rapid reduction in mouse serum HBV DNA and human albumin levels and elevation of serum interferon-gamma and granzyme A levels were observed in HBV-infected human hepatocyte-transplanted immunodeficient mice that were administered human peripheral blood mononuclear cells. These hepatocyte injuries were inhibited to a greater extent by abatacept compared to methylprednisolone. Abatacept might be an effective therapy alternative to methylprednisolone to reduce acute massive liver damage for patients with severe acute hepatitis caused by HBV infection.

18.
Pediatr Int ; 63(6): 710-715, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33325065

RESUMO

BACKGROUND: Large changes in height standard deviation score (SDS) have been reported from birth to 3 years of age. We analyzed how early these changes start and whether they are affected by nutrition. METHODS: The longitudinal growth of 1,849 children born between March 1 2007 and August 31 2007 or between March 1, 2009 and August 31 2009 with five records from birth to 3 years of age was analyzed. RESULTS: The height SDS at birth was positively correlated with body mass index (BMI) SDS at birth (r = 0.224, P < 0.0001). The height SDS at birth decreased among children with a positive height SDS and increased among children with a negative height SDS. The changes occurred immediately after birth and became more modest as children aged. Regarding the change in the height SDS from birth to 3 years of age, 33.4% of children increased more than 0.5 SDs, 39.8% of children decreased more than 0.5 SDs, and 34.4% of children remained within ±0.5 SDs. The change in height SDS displayed a strong positive correlation with the change in weight during the four periods. From birth till 3 months, from 3 months till 6 months, from 6 months till 1.5 years, and from 1.5 years till 3 years. CONCLUSIONS: The significant positive correlation between height SDS and BMI SDS suggests an effect of children's nutrition status in utero. The height SDS change started immediately after birth and the change was largest from birth to 3 months. A positive correlation between changes in height SDS and weight suggest that growth during early childhood depends on nutritional status.


Assuntos
Estatura , Estado Nutricional , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Humanos , Recém-Nascido
19.
Mol Med Rep ; 23(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33179077

RESUMO

Non­alcoholic steatohepatitis (NASH) may progress via liver fibrosis along with hepatic stellate cell (HSC) activation. A single nucleotide polymorphism (SNP; rs58542926) located in transmembrane 6 superfamily 2 (TM6SF2) has been reported to be significantly associated with fibrosis in patients with NASH, but the precise mechanism is still unknown. The present study aimed to explore the role of TM6SF2 in HSC activation in vitro. Plasmids producing TM6SF2 wild-type (WT) and mutant type (MT) containing E167K amino acid substitution were constructed, and the activation of LX­2 cells was analyzed by overexpressing or knocking down TM6SF2 under transforming growth factor ß1 (TGFß) treatment. Intracellular α­smooth muscle actin (αSMA) expression in LX­2 cells was significantly repressed by TM6SF2­WT overexpression and increased by TM6SF2 knockdown. Following treatment with TGFß, αSMA expression was restored in TM6SF2­WT overexpressed LX­2 cells and was enhanced in TM6SF2 knocked­down LX­2 cells. Comparing αSMA expression under TM6SF2­WT or ­MT overexpression, expression of αSMA in TM6SF2­MT overexpressed cells was higher than that in TM6SF2­WT cells and was further enhanced by TGFß treatment. The present study demonstrated that intracellular αSMA expression in HCS was negatively regulated by TM6SF2 while the E167K substitution released this negative regulation and led to enhanced HSC activation by TGFß. These results suggest that the SNP in TM6SF2 may relate to sensitivity of HSC activation.


Assuntos
Actinas/genética , Células Estreladas do Fígado/citologia , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Humanos , Modelos Biológicos , Fator de Crescimento Transformador beta/farmacologia
20.
Gut ; 70(1): 157-169, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32217639

RESUMO

OBJECTIVE: Hepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related mortality with chronic viral hepatitis and non-alcoholic steatohepatitis (NASH) as major aetiologies. Treatment options for HCC are unsatisfactory and chemopreventive approaches are absent. Chronic hepatitis C (CHC) results in epigenetic alterations driving HCC risk and persisting following cure. Here, we aimed to investigate epigenetic modifications as targets for liver cancer chemoprevention. DESIGN: Liver tissues from patients with NASH and CHC were analysed by ChIP-Seq (H3K27ac) and RNA-Seq. The liver disease-specific epigenetic and transcriptional reprogramming in patients was modelled in a liver cell culture system. Perturbation studies combined with a targeted small molecule screen followed by in vivo and ex vivo validation were used to identify chromatin modifiers and readers for HCC chemoprevention. RESULTS: In patients, CHC and NASH share similar epigenetic and transcriptomic modifications driving cancer risk. Using a cell-based system modelling epigenetic modifications in patients, we identified chromatin readers as targets to revert liver gene transcription driving clinical HCC risk. Proof-of-concept studies in a NASH-HCC mouse model showed that the pharmacological inhibition of chromatin reader bromodomain 4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients. CONCLUSION: Our results unravel the functional relevance of metabolic and virus-induced epigenetic alterations for pathogenesis of HCC development and identify chromatin readers as targets for chemoprevention in patients with chronic liver diseases.


Assuntos
Carcinoma Hepatocelular/prevenção & controle , Epigênese Genética , Hepatite C Crônica/complicações , Neoplasias Hepáticas/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/complicações , Animais , Carcinoma Hepatocelular/etiologia , Modelos Animais de Doenças , Hepatite C Crônica/genética , Hepatite C Crônica/patologia , Humanos , Neoplasias Hepáticas/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia
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