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BACKGROUND AND AIMS: The mechanism underlying liver regeneration following partial hepatectomy (PH) is not fully elucidated. We aimed to characterize collagen gene expressing hepatic cells following PH and examine their contribution to liver regeneration. APPROACH AND RESULTS: Col-GFP mice, which express GFP under the control of the collagen gene promoter, were used to detect collagen gene expressing cells following PH. The GFP-expressing cells were analyzed via single-cell RNA sequencing (scRNA-seq). Additionally, Col-ER Cre/RFP and Col-ER Cre/DTA mice were utilized to examine the cell fates and functional roles of collagen gene expressing cells in liver regeneration, respectively. The number of collagen gene expressing cells was found to be increased on day 3 and subsequently decreased on day 7 following PH. ScRNA-seq analysis of sorted collagen gene expressing cells showed that the regenerating liver was characterized by three distinct hepatic stellate cell (HSC) clusters, including one representing classic myofibroblasts. The other HSC clusters included an intermediately activated HSC cluster and a proliferating HSC cluster. Of these, the latter cluster was absent in the CCl 4 -induced liver fibrosis model. Cell fate tracing analysis using Col-ER Cre/RFP mice demonstrated that the collagen gene expressing cells escaped death during regeneration and remained in an inactivated state in the liver. Further, depletion of these cells using Col-ER Cre/DTA mice resulted in impaired liver regeneration. CONCLUSIONS: Heterogeneous HSC clusters, one of which was a unique proliferating cluster, were found to appear in the liver following PH. Collagen gene expressing cells, including HSCs, were found to promote liver regeneration.
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Hepatectomia , Hepatócitos , Camundongos , Animais , Hepatócitos/metabolismo , Fígado/metabolismo , Cirrose Hepática/patologia , Células Estreladas do Fígado/metabolismo , Colágeno/metabolismoRESUMO
BACKGROUND AND AIM: Autotaxin (ATX) is an extracellular lysophospholipase D that catalyzes the hydrolysis of lysophosphatidylcholine into lysophosphatidic acid (LPA). Recent accumulating evidence indicates the biological roles of ATX in malignant tumors. However, the expression and clinical implications of ATX in human cholangiocarcinoma (CCA) remain elusive. METHODS: In this study, the expression of ATX in 97 human CCA tissues was evaluated by immunohistochemistry. Serum ATX levels were determined in CCA patients (n = 26) and healthy subjects (n = 8). Autotaxin expression in cell types within the tumor microenvironment was characterized by immunofluorescence staining. RESULTS: High ATX expression in CCA tissue was significantly associated with a higher frequency of lymph node metastasis (p = 0.050). High ATX expression was correlated with shorter overall survival (p = 0.032) and recurrence-free survival (RFS) (p = 0.001) than low ATX expression. In multivariate Cox analysis, high ATX expression (p = 0.019) was an independent factor for shorter RFS. Compared with low ATX expression, high ATX expression was significantly associated with higher Ki-67-positive cell counts (p < 0.001). Serum ATX levels were significantly higher in male CCA patients than in healthy male subjects (p = 0.030). In the tumor microenvironment of CCA, ATX protein was predominantly expressed in tumor cells, cancer-associated fibroblasts, plasma cells, and biliary epithelial cells. CONCLUSIONS: Our study highlights the clinical evidence and independent prognostic value of ATX in human CCA.
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PURPOSE: Prognostic value of liver volumetric regeneration (LVR) in patients with hepatocellular carcinoma (HCC) who undergo major hepatectomy remains unknown. The aim of this study was to investigate the impact of LVR on long-term outcomes in these patients. METHODS: Data of 399 consecutive patients with HCC who underwent major hepatectomy between 2000 to 2018 were retrieved from a prospectively maintained institutional database. The LVR-index was defined as the relative increase in liver volume from 7 days to 3 months (RLV3m/RLV7d, where RLV3m and RLV7d is the remnant liver volume around 3 months and postoperative 7 days after surgery). The optimal cut-off value was determined using the median value of LVR-index. RESULTS: A total of 131 patients were eligible in this study. The optimal cut off value of LVR-index was 1.194. The 1-, 3-, 5- and 10-year overall survival (OS) rate of patients in the high LVR-index group were significantly better compared to those in the low LVR-index group (95.5%, 84.8%, 75.4% and 49.1% vs. 95.4%, 70.2%, 56.4%, and 19.9%, p = 0.002). Meanwhile, there was no significant difference with regards to time to recurrence between the two groups (p = 0.607). Significance of LVR-index for OS was retained after adjusting for known prognostic factors (p = 0.002). CONCLUSION: In patients with HCC undergoing major hepatectomy, LVR-index may serve as a prognostic indicator for OS.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Hepatectomia , Neoplasias Hepáticas/patologia , Estudos Retrospectivos , PrognósticoRESUMO
Herein, we report the design, synthesis and evaluation of novel (E)-3-(3-oxo-4-substituted-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-N-hydroxypropenamides (4 a-i, 7 a-g) targeting histone deacetylases. Three human cancer cell lines were used to test the cytotoxicity of the synthesized compounds (SW620, colon; PC-3, prostate; NCI-H23, lung cancer); inhibitory activity towards HDAC; anticancer activity; as well as their impact on the cell cycle and apoptosis. As a result, compounds 4 a-i bearing the alkyl substituents seemed to be less potent than the benzyl-containing compounds 7 a-g in all biological assays. Compounds 7 e-f were found to be the most active HDAC inhibitors with IC50 of 1.498±0.020â µM and 1.794±0.159â µM, respectively. In terms of cytotoxicity and anticancer assay, 7 e and 7 f also showed good activity with IC50 values in the micromolar range. In addition, the cell cycle and apoptosis of SW620 were affected by compound 7 f in almost a similar manner to that of reference compound SAHA. Docking assays were carried out for analysis the binding mode and selectivity of this compound toward 8 HDAC isoforms. Overall, our data confirmed that the inhibition of HDAC plays a pivotal role in their anticancer activity.
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Antineoplásicos , Inibidores de Histona Desacetilases , Humanos , Inibidores de Histona Desacetilases/química , Relação Estrutura-Atividade , Antineoplásicos/química , Linhagem Celular Tumoral , Ácidos Hidroxâmicos , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Desenho de Fármacos , Simulação de Acoplamento MolecularRESUMO
Multi-target drug development has become an attractive strategy in the discovery of drugs to treat of Alzheimer's disease (AzD). In this study, for the first time, a rule-based machine learning (ML) approach with classification trees (CT) was applied for the rational design of novel dual-target acetylcholinesterase (AChE) and ß-site amyloid-protein precursor cleaving enzyme 1 (BACE1) inhibitors. Updated data from 3524 compounds with AChE and BACE1 measurements were curated from the ChEMBL database. The best global accuracies of training/external validation for AChE and BACE1 were 0.85/0.80 and 0.83/0.81, respectively. The rules were then applied to screen dual inhibitors from the original databases. Based on the best rules obtained from each classification tree, a set of potential AChE and BACE1 inhibitors were identified, and active fragments were extracted using Murcko-type decomposition analysis. More than 250 novel inhibitors were designed in silico based on active fragments and predicted AChE and BACE1 inhibitory activity using consensus QSAR models and docking validations. The rule-based and ML approach applied in this study may be useful for the in silico design and screening of new AChE and BACE1 dual inhibitors against AzD.
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Acetilcolinesterase , Doença de Alzheimer , Humanos , Acetilcolinesterase/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Inibidores da Colinesterase/química , Simulação de Acoplamento Molecular , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Precursor de Proteína beta-AmiloideRESUMO
Kinesio taping is widely used in musculoskeletal conditions. We performed a systematic review and meta-analysis on the efficacy of kinesio taping in musculoskeletal disorders compared to other interventions. Twelve electronic databases were used for systemic search and data relevant to pain and disability were extracted. The protocol was registered in PROSPERO (CRD42018087606). Meta-analysis was performed to compare the efficacy of kinesio taping to other modalities of musculoskeletal disorders. As a result, 36 studies were included in the quantitative analysis. Kinesio taping was found to provide an improvement of both pain and disability when applied to any region of the body. In the first five days of application, kinesio taping significantly reduced the pain in all body regions (SMD = -0.63, 95%CI: -0.87, -0.39). This was also noted after four-to-six weeks of application (SMD = -0.76, 95%CI: -1.07, -0.45). When kinesio taping was used for disability in low back pain patients, it significantly reduced the disability within five days of application (SMD = -0.70, 95%CI: -1.29, -0.11). Finally, kinesio taping has shown an improvement of the disability in all body regions after four-to-six weeks of application (SMD = -0.59, 95%CI: -0.96, -0.22). Our findings support kinesio taping as an adjuvant to other treatments for musculoskeletal disorders. Abbreviations KT = Kinesio taping; MSK = musculoskeletal; SD = standard deviation; CR = conventional rehabilitation; NDI = Neck Disability Index; NPS = Numerical Pain Scale; CTM = Cervical Thrust Manipulation; PIR = Post-isometric muscle relaxation; NPRS Numerical Pain Rating Scale; OA = osteoarthritis; ROM = Range of motion; VAS = visual analogue scale; VAS-W = visual analogue scale-worst pain; VAS-U = visual analogue scale-usual pain; VAS-R = visual analogue scale-resting pain; VAS-A = visual analogue scale-activity pain; VAS-N = visual analogue scale-night pain; NPDS = Neck Pain Disability Scale; QA = Quality assessment.
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Fita Atlética , Pessoas com Deficiência , Dor Lombar , Doenças Musculoesqueléticas , Humanos , Doenças Musculoesqueléticas/terapia , Dor Lombar/terapia , Amplitude de Movimento ArticularRESUMO
In our continuing search for novel small-molecule anticancer agents, we designed and synthesized a series of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides (5), focusing on the modification of substitution in the quinazolin-4(3H)-one moiety. The biological evaluation showed that all 13 designed and synthesized compounds displayed significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5l displayed cytotoxicity up to 213-fold more potent than 5-fluorouracil and 87-fold more potent than PAC-1, the first procaspase-activating compound. Structure-activity relationship analysis revealed that substitution of either electron-withdrawing or electron-releasing groups at positions 6 or 7 on the quinazolin-4(3H)-4-one moiety increased the cytotoxicity of the compounds, but substitution at position 6 seemed to be more favorable. In the caspase activation assay, compound 5l was found to activate the caspase activity by 291% in comparison to PAC-1, which was used as a control. Further docking simulation also revealed that this compound may be a potent allosteric inhibitor of procaspase-3 through chelation of the inhibitory zinc ion. Physicochemical and ADMET calculations for 5l provided useful information of its suitable absorption profile and some toxicological effects that need further optimization to be developed as a promising anticancer agent.
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Antineoplásicos/farmacologia , Compostos de Benzilideno/farmacologia , Hidrazinas/farmacologia , Quinolonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/química , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Fluoruracila/farmacologia , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Simulação de Acoplamento Molecular , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-AtividadeRESUMO
There is a need for improved treatment of patients with chronic hepatitis B (CHB). We reviewed the literature to explore the efficacy of HB vaccines alone or in combination therapy (CT) with antiviral drugs in CHB patients and to meta-analyze data from randomized controlled trials. We conducted a systematic search in ten databases. All studies investigating the efficacy of HBV vaccine in HBV infected patients were included with no restrictions. Among 1359 studies initially identified, 23 studies (n = 1956 patients) were included for the final analysis. CT showed a significant reduction of HBV DNA compared with analogue monotherapy (AM) at the 12-month follow-up period (odds ratio (OR) = 2.835, 95% confidence interval (CI) [1.275, 6.306], p = .011). Additionally, CT also remarkably induce HbsAg loss in comparison with AM (OR = 11.736, 95% CI [1.841, 74.794], p = .009). Our pooled data revealed no difference between treatment and control regarding alanine aminotransferase normalization, HBeAg seroconversion, and HBeAg disappearance. In addition, CT using vaccine and NAs resulted in a statistically significant higher incidence of adverse effects than AM. The therapeutic effects of combination therapy for patients with CHB were encouraging, but future studies need to investigate all possible treatment combinations and assess their cost-effectiveness.
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Vacinas contra Hepatite B/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Adolescente , Adulto , Criança , Feminino , Antígenos E da Hepatite B/genética , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND AND AIM: Studies on the resolution of liver fibrosis are becoming more important in this era of etiologic eradication. In contrast to the extensive research on the recovery of liver fibrosis induced by hepatotoxic injuries, regression of cholestatic liver fibrosis has been insufficiently examined owing to the limited availability of animal models. METHODS: We examined our novel recanalization mice model of biliary obstruction, involving anastomosis between the gallbladder and jejunum (G-J anastomosis) by invagination. Transgenic mice expressing green fluorescent protein (GFP) under the collagen 1(α)1 promoter underwent G-J anastomosis 14 days after bile duct ligation (BDL) and were sacrificed 14 days later. RESULTS: Transaminase and total bilirubin levels decreased to almost normal values on day 14 after G-J anastomosis. G-J anastomosis resulted in dramatic reversal of liver fibrosis induced by BDL. Activated portal fibroblasts (PFs) double-positive for GFP and Thy-1 on immunofluorescence in the liver of BDL-injured mice became less noticeable following G-J anastomosis. Messenger RNA expression of markers for activated PFs in the liver was downregulated after anastomosis. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were induced by BDL. After anastomosis, expressions of MMP-3, 8 as well as hepatocyte growth factor were further upregulated, whereas those of TIMP-1 and TIMP-3 were markedly downregulated. CONCLUSIONS: Our established G-J anastomosis model is associated with fibrosis resolution and reduced PF activation through reopening of bile duct obstruction and will be valuable for studying the recovery process of cholestatic liver fibrosis.
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Colestase , Vesícula Biliar , Anastomose Cirúrgica , Animais , Ductos Biliares/cirurgia , Colestase/etiologia , Colestase/patologia , Modelos Animais de Doenças , Ligadura , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Camundongos , Camundongos TransgênicosRESUMO
BACKGROUND: Several studies have suggested that laparoscopic liver resection (LLR) is associated with fewer postoperative complications than open liver resection (OLR) for hepatocellular carcinoma (HCC). However, this issue remains controversial since the data may have been attributable to an imbalance in patients' background. METHODS: We retrospectively analyzed 290 hepatectomies for HCC undertaken between 2011 and 2019. Liver resection difficulty was based on the 3 levels of the Institut Mutualiste Montsouris classification. Resection ratio was calculated using computed tomography volumetry. Patient characteristics were compared between the LLR and OLR groups. Propensity score matching (PSM) was adopted to adjust the imbalance between the cohorts, and the incidence of postoperative complications was compared. RESULTS: The difficulty and resection ratio were significantly lower in LLR (n = 112) than in OLR (n = 178) (difficulty grade I/II/III: 84/10/18 vs. 43/39/96, p < 0.001; resection ratio: 11.4 ± 12.7 vs. 22.7 ± 17.2%, p < 0.001). The incidence of postoperative complications (Clavien-Dindo grade III or more) was lower in LLR (2.7% vs. 21.9%, p < 0.001), which was mainly attributable to fewer incidences of ascites and pleural effusion. PSM generated 68 well-matched patients in each group. The lower incidence of postoperative complications in LLR was also maintained in the PSM cohort (2.9% vs. 16.2%, p = 0.017). On multivariate analysis, LLR was the independent predictor of postoperative complications (OR 0.184, 95% CI 0.051-0.672, p = 0.010). CONCLUSION: The present study demonstrated that a laparoscopic approach reduces the incidence of postoperative complications in liver resection for HCC.
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Carcinoma Hepatocelular , Laparoscopia , Neoplasias Hepáticas , Carcinoma Hepatocelular/cirurgia , Hepatectomia/efeitos adversos , Humanos , Tempo de Internação , Neoplasias Hepáticas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Pontuação de Propensão , Estudos RetrospectivosRESUMO
PURPOSE: Although decreased antithrombin-III (AT-III) is a risk factor for portal vein thrombosis (PVT) in patients with liver cirrhosis, the association between postoperative PVT and postoperative AT-III levels is unknown in patients undergoing hepatectomy. METHODS: Patients who underwent hepatectomy between 2015 and 2018 were retrospectively analyzed. Postoperative PVT was assessed on CT at days 6-9 after hepatectomy. One-to-one propensity score (PS) matching was used to match the baseline characteristics. RESULTS: Of the 295 patients included in this analysis, 19 patients (6.4%) were diagnosed with postoperative PVT. The AT-III level on postoperative day (POD) 3 predicted postoperative PVT with a sensitivity/specificity of 74%/59% (AUC, 0.644; cut-off value, 60%; p = 0.032). Multivariate analysis revealed that AT-III levels ≤ 60% on POD3 (OR, 3.01; 95% CI 1.02-8.89; p = 0.046), cirrhosis (OR, 5.88; 95% CI 1.92-18.0; p = 0.002) and right-sided hepatectomy (OR, 4.16; 95% CI 1.45-11.9; p = 0.0079) were significant risk factors for postoperative PVT. After PS matching, 56 patients with and without AT-III supplementation were analyzed. The two groups had a similar incidence of PVT (p = 0.489). CONCLUSIONS: Patients with AT-III levels ≤ 60% on POD3 should be carefully followed up regarding postoperative PVT. Our results did not support the efficacy of routine AT-III supplementation for the prophylaxis of postoperative PVT.
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Antitrombina III , Hepatectomia/efeitos adversos , Fígado/cirurgia , Veia Porta , Complicações Pós-Operatórias/diagnóstico , Trombose/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antitrombina III/administração & dosagem , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Pontuação de Propensão , Trombose/etiologia , Trombose/prevenção & controle , Adulto JovemRESUMO
BACKGROUND: Breastfeeding is beneficial to both mother and infant. However, overlap of lactation with pregnancy and short recuperative intervals may impact mothers nutritionally. We aimed to investigate the possible effects of pregnancy during breastfeeding. METHODS: In October 2018, we searched systematically in nine electronic databases to investigate any association of breastfeeding during pregnancy with fetal and/or maternal outcomes. The study protocol was registered in PROSPERO (CRD41017056490). A meta-analysis was done to detect maternal and fetal outcomes and complications during pregnancy. Quality assessment was performed using the Australian Cancer Council bias tool for included studies. RESULTS: With 1992 studies initially identified, eight were eligible for qualitative analysis and 12 for quantitative analysis. Our results showed no significant difference in different abortion subtypes between lactating and non-lactating ones. In delivery, no difference between two groups regarding the time of delivery in full-term healthy, preterm delivery and preterm labor. No significant difference was detected in rates of antepartum, postpartum hemorrhage and prolonged labor between two groups. The women with short reproductive intervals may have higher supplemental intake and greater reduction fat store. The present studies showed that breastfeeding during pregnancy does not lead to adverse outcomes in the mother and her fetus in normal low-risk pregnancy, although it may lead to the nutritional burden on the mother. CONCLUSION: The present studies showed that breastfeeding during pregnancy did not lead to the adverse outcomes in the mother and her fetus.
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Aleitamento Materno , Complicações do Trabalho de Parto , Austrália/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Lactação , Período Pós-Parto , GravidezRESUMO
INTRODUCTION: Approximately 1000 children die each year due to preventable water and sanitation-related diarrheal diseases. Six in 10 people lacked access to safely managed sanitation facilities in 2015. Numerous community- and school-based approaches have been implemented to eradicate open defecation practices, promote latrine ownership, improve situation sanitation, and reduce waterborne disease. OBJECTIVE: Given that current evidence for sanitation interventions seem promising, the aim of this study was to systematically summarize existing research on the effectiveness of community- and school-based randomized controlled sanitation intervention in improving (1) free open defecation (safe feces disposal), (2) latrine usage, (3) latrine coverage or access, and (4) improved latrine coverage or access. METHODS: Eight electronic databases were searched: PubMed, Scopus, WHO Global Health Library (GHL), Virtual Health Library (VHL), POPLINE, Web of Science, Cochrane, and Google Scholar up to 26 April 2019. Original randomized clinical trials addressing community-based or school-based intervention that reported feces disposal and latrine coverage were deemed eligible. More than two researchers independently contributed to screening of papers, data extraction, and bias assessment. We conducted a meta-analysis by random-effects model. The risk of bias was assessed by the Cochrane risk of bias tool. RESULTS: Eighteen papers that matched all criteria and 16 studies were included in the final meta-analysis. Compared to the control, the sanitation intervention significantly increased safe feces disposal (OR 2.19, 95% CI 1.51-3.19, p < 0.05, I2 = 97.28), latrine usage (OR 3.72, 95% CI 1.71-8.11, p < 0.05, I2 = 91.52), latrine coverage or access (OR 3.95, 95% CI 2.08-7.50, p < 0.05, I2 = 99.07), and improved latrine coverage or access (OR 3.68, 95% CI 1.52-8.91, p < 0.05, I2 = 99.11). A combination of education and latrine construction was more effective compared to educational intervention alone. CONCLUSION: Our study showed strong evidence for both community- and school-based sanitation interventions as effective for the safe disposal of human excreta. The finding suggests major implications for health policy and design of future intervention in developing countries.
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Participação da Comunidade/estatística & dados numéricos , Saneamento/instrumentação , Serviços de Saúde Escolar/estatística & dados numéricos , Banheiros/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Several novel indirubin-based N-hydroxybenzamides, N-hydropropenamides and N-hydroxyheptanamides (4a-h, 7a-h, 10a-h) were designed using a fragment-based approach with structural features extracted from several previously reported HDAC inhibitors, such as SAHA (vorinostat), MGCD0103 (mocetinostat), nexturastat A and PXD-101 (belinostat). The biological results reveal that our compounds showed excellent cytotoxicity toward three common human cancer cell lines (SW620, PC-3 and NCI-H23) with IC50 values ranging from 0.09 to 0.007 µM. The cytotoxicity of the compounds was equipotent or even up to 10-times more potent than adriamycin and up to 205-times more potent than SAHA. Among the series of N-hydroxypropenamides, compounds 10a-d were the most potent HDAC inhibitors as well as cytotoxicity toward the cell lines tested. In addition, the strong inhibitory activites toward HDAC of our compounds were observed with IC50 values of below-micromolar range. Especially, compound 4a inhibited HDAC6 with an IC50 value of 29-fold lower than that against HDAC2 isoform. Representative compounds 4a and 7a were found to significantly arrest SW620 cells at G0/G1 phase. Compounds 7a and 10a were found to strongly induce apoptosis in SW620 cells. Docking studies revealed some important features affecting the selectivity against HDAC6 isoform. The results clearly demonstrate the potential of the indirubin-hydroxamic acid hybrids and these compounds should be very promising for further development.
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Amidas/farmacologia , Antineoplásicos/farmacologia , Histona Desacetilase 2/antagonistas & inibidores , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Amidas/síntese química , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilase 2/metabolismo , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Indóis/química , Indóis/farmacologia , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The risk factors and clinical impact of post-transplantation splenomegaly (SM) are poorly understood. We investigated the predictors and impacts of post-transplantation SM in 415 LT patients at Kyoto University Hospital from April 2006 to December 2015. First, the predictors and clinical consequences of SM three years post-transplantation were analyzed among spleen-preserved recipients. Second, the clinical data of surviving recipients three years post-transplantation were compared between splenectomized and spleen-preserved recipients. There was no difference in indication for liver transplantation between these two groups. Third, survival outcomes were compared between splenectomized and spleen-preserved recipients. SM was determined as a SV/body surface area (BSA) higher than 152 ml/m2 . In the first analysis, preoperative SM occurred in 79.9% recipients and SM persisted three years post-transplantation in 72.6% recipients among them. Preoperative SV/BSA was the only independent predictor of three year post-transplantation SM, which was associated with lower platelet (PLT), white blood cell (WBC) counts and significant graft fibrosis (21.4% vs. 2.8%). In the second analysis, spleen-preservation was related to lower PLT, WBC counts and a higher proportion of significant graft fibrosis (26.7% vs. 7.1%) three years post-transplantation. In the third analysis, spleen-preserved recipients showed worse survival than splenectomized recipients. In conclusion, preoperative SM frequently persists more than three years post-transplantation and is associated with subclinical hypersplenism, graft fibrosis, graft loss, and even death.
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Hiperesplenismo , Transplante de Fígado , Fibrose , Sobrevivência de Enxerto , Humanos , Transplante de Fígado/efeitos adversos , Estudos Retrospectivos , Esplenomegalia/etiologiaRESUMO
Aim: Little is known about the association between specific primary lymph node (LN) sites and the risk of developing second primary cancers in Hodgkin lymphoma (HL) patients. Materials & methods: To fill this knowledge gap, we used the multiple primary standardized incidence ratio function of the SEER*stat program to explore such an association for multiple latency periods. Results: Several SPCs occurred at various time points following different primary LN presentations of HL. Conclusion: HL survivors may benefit from a tailored primary LN site-specific follow-up screening.
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Doença de Hodgkin/epidemiologia , Doença de Hodgkin/patologia , Linfonodos/patologia , Segunda Neoplasia Primária/epidemiologia , Adulto , Idoso , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/patologia , Risco , Programa de SEER/estatística & dados numéricosRESUMO
Several novel series of hydroxamic acids bearing 2-benzamidooxazole/thiazole (5a-g, 6a-g) or 2-phenylsulfonamidothiazole (8a-c) were designed and synthesized. The compounds were obtained straightforwards via a two step pathway, starting from commercially available ethyl 2-aminooxazole-4-carboxylate or ethyl 2-aminothiazole-4-carboxylate. Biological evaluation showed that these hydroxamic acids generally exhibited good cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer), with IC50 values in low micromolar range and comparable to that of SAHA. These compounds also comparably inhibited HDACs with IC50 values in sub-micromolar range (0.010-0.131 µM) and some compounds (e.g 5f, IC50, 0.010 µM) were even more potent than SAHA (IC50, 0.025 µM) in HDAC inhibition. Representative compounds 6a and 8a appeared to arrest the SW620 cell cycle at G2 phase and significantly induced both early and late apoptosis of SW620 colon cancer cells. Docking experiments on HDAC2 and HDAC6 isozymes revealed favorable interactions at the tunnel of the HDAC active site which positively contributed to the inhibitory activity of synthesized compound. The binding affinity predicted by docking program showed good correlation with the experimental IC50 values. This study demonstrates that simple 1,3-oxazole- and 1,3-thiazole-based hydroxamic acids are also promising as antitumor agents and HDAC inhibitors and these results should provide valuable information for further design of more potent HDAC inhibitors and antitumor agents.
Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Oxazóis/química , Tiazóis/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/química , Simulação de Acoplamento Molecular , Análise Espectral/métodos , Relação Estrutura-AtividadeRESUMO
In continuity of our search for novel anticancer agents acting as procaspase activators, we have designed and synthesised two series of (E)-N'-benzylidene-carbohydrazides (4a-m) and (Z)-N'-(2-oxoindolin-3-ylidene)carbohydrazides (5a-g) incorporating 1-(4-chlorobenzyl)-1H-indole core. Bioevaluation showed that the compounds, especially compounds in series 4a-m, exhibited potent cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). Within series 4a-m, compounds with 2-OH substituent (4g-i) exhibited very strong cytotoxicity in three human cancer cell lines assayed with IC50 values in the range of 0.56-0.83 µM. In particular, two compounds 4d and 4f bearing 4-Cl and 4-NO2 substituents, respectively, were the most potent in term of cytotoxicity with IC50 values of 0.011-0.001 µM. In caspase activation assay, compounds 4b and 4f were found to activate caspase activity by 314.3 and 270.7% relative to PAC-1. This investigation has demonstrated the potential of these simple acetohydrazides, especially compounds 4b, 4d, and 4f, as anticancer agents.
Assuntos
Antineoplásicos/síntese química , Inibidores de Caspase/síntese química , Caspases Iniciadoras/metabolismo , Hidrazinas/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Inibidores de Caspase/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/farmacologia , Isatina/química , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
In our search for new small molecules activating procaspase-3, we have designed and synthesized a series of new acetohydrazides incorporating both 2-oxoindoline and 4-oxoquinazoline scaffolds. Biological evaluation showed that a number of these acetohydrazides were comparably or even more cytotoxic against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer) in comparison to PAC-1, a first procaspase-3 activating compound, which was used as a positive control. One of those new compounds, 2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N'-[(3Z)-5-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]acetohydrazide activated the caspase-3 activity in U937 human lymphoma cells by 5-fold higher than the untreated control. Three of the new compounds significantly induced necrosis and apoptosis in U937 cells.
Assuntos
Antineoplásicos/farmacologia , Caspase 3/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Hidrazinas/farmacologia , Oxindóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxindóis/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Two series of 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-ones and N-(1-benzylpiperidin-4-yl)quinazolin-4-amines were designed initially as potential acetylcholine esterase inhibitors. Biological evaluation demonstrated that N-(1-benzylpiperidin-4-yl)quinazolin-4-amines significantly inhibited AChE activity. Especially, two compounds of them were found to be the most potent with relative AChE inhibition percentages of 87 % in comparison to donepezil. The docking studies with AChE showed similar interactions between donepezil and four derivatives. N-(1-Benzylpiperidin-4-yl)quinazolin-4-amines also exhibited significant DPPH scavenging effects. The two series of compound also exerted moderate to good cytotoxicity against three human cancer cell lines, including SW620 (human colon cancer), PC-3 (prostate cancer), and NCI-H23 (lung cancer), with 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one being the most cytotoxic agent. 3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one significantly induced early apoptosis and arrested the SW620 cells at G2/M phase. From this study, two compounds of N-(1-benzylpiperidin-4-yl)quinazolin-4-amines could serve as new leads for further design and AChE inhibitors, while 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one could serve as a new lead for the design and development of more potent anticancer agents.