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1.
Int J Mol Sci ; 20(24)2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31847135

RESUMO

Tumor necrosis factor-α (TNF-α)-driven inflammatory reaction plays a crucial role in the initiation of liver fibrosis. We herein attempted to design genetically engineered adipose-derived stem cells (ASCs) producing etanercept (a potent TNF-α inhibitor), and to determine the anti-fibrotic potential of the secretome released from the etanercept-synthesizing ASCs (etanercept-secretome). First, we generated the etanercept-synthesizing ASCs by transfecting the ASCs with mini-circle plasmids containing the gene insert encoding for etanercept. We subsequently collected the secretory material released from the etanercept-synthesizing ASCs and determined its anti-fibrotic effects both in vitro (in thioacetamide [TAA]-treated AML12 and LX2 cells) and in vivo (in TAA-treated mice) models of liver fibrosis. We observed that while etanercept-secretome increased the viability of the TAA-treated AML12 hepatocytes (p = 0.021), it significantly decreased the viability of the TAA-treated LX2 HSCs (p = 0.021). In the liver of mice with liver fibrosis, intravenous administration of the etanercept-secretome induced significant reduction in the expression of both fibrosis-related and inflammation-related markers compared to the control group (all Ps < 0.05). The etanercept-secretome group also showed significantly lower serum levels of liver enzymes as well as pro-inflammatory cytokines, such as TNF-α (p = 0.020) and IL-6 (p = 0.021). Histological examination of the liver showed the highest reduction in the degree of fibrosis in the entanercept-secretome group (p = 0.006). Our results suggest that the administration of etanercept-secretome improves liver fibrosis by inhibiting TNF-α-driven inflammation in the mice with liver fibrosis. Thus, blocking TNF-α-driven inflammation at the appropriate stage of liver fibrosis could be an efficient strategy to prevent fibrosis.

2.
World J Stem Cells ; 11(11): 990-1004, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31768225

RESUMO

BACKGROUND: Recently, the exclusive use of mesenchymal stem cell (MSC)-secreted molecules, called secretome, rather than cells, has been evaluated for overcoming the limitations of cell-based therapy, while maintaining its advantages. However, the use of naïve secretome may not fully satisfy the specificity of each disease. Therefore, it appears to be more advantageous to use the functionally reinforced secretome through a series of processes involving physico-chemical adjustments or genetic manipulation rather than to the use naïve secretome. AIM: To determine the therapeutic potential of the secretome released from miR-122-transfected adipose-derived stromal cells (ASCs). METHODS: We collected secretory materials released from ASCs that had been transfected with antifibrotic miR-122 (MCM) and compared their antifibrotic effects with those of the naïve secretome (CM). MCM and CM were intravenously administered to the mouse model of thioacetamide-induced liver fibrosis, and their therapeutic potentials were compared. RESULTS: MCM infusion provided higher therapeutic potential in terms of: (A) Reducing collagen content in the liver; (B) Inhibiting proinflammatory cytokines; and (C) Reducing abnormally elevated liver enzymes than the infusion of the naïve secretome. The proteomic analysis of MCM also indicated that the contents of antifibrotic proteins were significantly elevated compared to those in the naïve secretome. CONCLUSION: We could, thus, conclude that the secretome released from miR-122-transfected ASCs has higher antifibrotic and anti-inflammatory properties than the naïve secretome. Because miR-122 transfection into ASCs provides a specific way of potentiating the antifibrotic properties of ASC secretome, it could be considered as an enhanced method for reinforcing secretome effectiveness.

3.
J Korean Med Sci ; 34(45): e273, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31760709

RESUMO

BACKGROUND: Secretome refers to the total set of molecules secreted or surface-shed by stem cells. The limitations of stem cell research have led numerous investigators to turn their attention to the use of secretome instead of stem cells. In this study, we intended to reinforce antifibrotic properties of the secretome released from adipose-derived stem cells (ASCs) transfected with miR-214. METHODS: We generated miR-214-transfected ASCs, and extracted the secretome (miR214-secretome) from conditioned media of the transfected ASCs through a series of ultrafiltrations. Subsequently, we intravenously injected the miR-214-secretome into mice with liver fibrosis, and determined the effects of miR-214-secretome on liver fibrosis. RESULTS: Compared with that by naïve secretome, liver fibrosis was ameliorated by intravenous infusion of miR-214-secretome into mice with liver fibrosis, which was demonstrated by significantly lower expression of fibrosis-related markers (alpha-smooth muscle actin, transforming growth factor-ß, and metalloproteinases-2) in the livers as well as lower fibrotic scores in the special stained livers compared with naïve secretome. The infusion of miR-214-secretome also led to lesser local and systemic inflammation, higher expression of an antioxidant enzyme (superoxide dismutase), and higher liver proliferative and synthetic function. CONCLUSION: MicroRNA-214 transfection stimulates ASCs to release the secretome with higher antifibrotic and anti-inflammatory properties. miR-214-secretome is thus expected to be one of the prominent ways of overcoming liver fibrosis, if further studies consistently validate its safety and efficiency.

4.
Int J Mol Sci ; 20(22)2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31717375

RESUMO

Peroxisome proliferator activated receptor λ coactivator 1α (PGC-1α) is a potent regulator of mitochondrial biogenesis and energy metabolism. In this study, we investigated the therapeutic potential of the secretome released from the adipose-derived stem cells (ASCs) transfected with PGC-1α (PGC-secretome). We first generated PGC-1α-overexpressing ASCs by transfecting ASCs with the plasmids harboring the gene encoding PGC-1α. Secretory materials released from PGC-1α-overexpressing ASCs were collected and their therapeutic potential was determined using in vitro (thioacetamide (TAA)-treated AML12 cells) and in vivo (70% partial hepatectomized mice) models of liver injury. In the TAA-treated AML12 cells, the PGC-secretome significantly increased cell viability, promoted expression of proliferation-related markers, such as PCNA and p-STAT, and significantly reduced the levels of reactive oxygen species (ROS). In the mice, PGC-secretome injections significantly increased liver tissue expression of proliferation-related markers more than normal secretome injections did (p < 0.05). We demonstrated that the PGC-secretome does not only have higher antioxidant and anti-inflammatory properties, but also has the potential of significantly enhancing liver regeneration in both in vivo and in vitro models of liver injury. Thus, reinforcing the mitochondrial antioxidant potential by transfecting ASCs with PGC-1α could be one of the effective strategies to enhance the therapeutic potential of ASCs.

5.
World J Gastroenterol ; 25(39): 5936-5952, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31660031

RESUMO

BACKGROUND: The use of methyl-tertiary butyl ether (MTBE) to dissolve gallstones has been limited due to concerns over its toxicity and the widespread recognition of the safety of laparoscopic cholecystectomy. The adverse effects of MTBE are largely attributed to its low boiling point, resulting in a tendency to evaporate. Therefore, if there is a material with a higher boiling point and similar or higher dissolubility than MTBE, it is expected to be an attractive alternative to MTBE. AIM: To determine whether tert-amyl ethyl ether (TAEE), an MTBE analogue with a relatively higher boiling point (102 °C), could be used as an alternative to MTBE in terms of gallstone dissolubility and toxicity. METHODS: The in vitro dissolubility of MTBE and TAEE was determined by measuring the dry weights of human gallstones at predetermined time intervals after placing them in glass containers with either of the two solvents. The in vivo dissolubility was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after the direct infusion of each solvent into the gallbladder in both hamster models with cholesterol and pigmented gallstones. RESULTS: The in vitro results demonstrated a 24 h TAEE-dissolubility of 76.7%, 56.5% and 38.75% for cholesterol, mixed, and pigmented gallstones, respectively, which represented a 1.2-, 1.4-, and 1.3-fold increase in dissolubility compared to that of MTBE. In the in vitro experiment, the 24 h-dissolubility of TAEE was 71.7% and 63.0% for cholesterol and pigmented gallstones, respectively, which represented a 1.4- and 1.9-fold increase in dissolubility compared to that of MTBE. In addition, the results of the cell viability assay and western blot analysis indicated that TAEE had a lower toxicity towards gallbladder epithelial cells than MTBE. CONCLUSION: We demonstrated that TAEE has higher gallstone dissolubility properties and safety than those of MTBE. As such, TAEE could present an attractive alternative to MTBE if our findings regarding its efficacy and safety can be consistently reproduced in further subclinical and clinical studies.

6.
J Transl Med ; 17(1): 195, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182117

RESUMO

BACKGROUND: Although methyl-tertiary butyl ether (MTBE) is the only clinical topical agent for gallstone dissolution, its use is limited by its side effects mostly arising from a relatively low boiling point (55 °C). In this study, we developed the gallstone-dissolving compound containing an aromatic moiety, named 2-methoxy-6-methylpyridine (MMP) with higher boiling point (156 °C), and compared its effectiveness and toxicities with MTBE. METHODS: The dissolubility of MTBE and MMP in vitro was determined by placing human gallstones in glass containers with either solvent and, then, measuring their dry weights. Their dissolubility in vivo was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after directly injecting each solvent into the gallbladder in hamster models with cholesterol and pigmented gallstones. RESULTS: In the in vitro dissolution test, MMP demonstrated statistically higher dissolubility than did MTBE for cholesterol and pigmented gallstones (88.2% vs. 65.7%, 50.8% vs. 29.0%, respectively; P < 0.05). In the in vivo experiments, MMP exhibited 59.0% and 54.3% dissolubility for cholesterol and pigmented gallstones, respectively, which were significantly higher than those of MTBE (50.0% and 32.0%, respectively; P < 0.05). The immunohistochemical stains of gallbladder specimens obtained from the MMP-treated hamsters demonstrated that MMP did not significantly increase the expression of cleaved caspase 9 or significantly decrease the expression of proliferation cell nuclear antigen. CONCLUSIONS: This study demonstrated that MMP has better potential than does MTBE in dissolving gallstones, especially pigmented gallstones, while resulting in lesser toxicities.

7.
J Surg Res ; 241: 254-263, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31035140

RESUMO

BACKGROUND: Clinically, liver fibrosis and cholestasis are two major disease entities, ultimately leading to hepatic failure. Although autophagy plays a substantial role in the pathogenesis of these diseases, its precise mechanism has not been determined yet. MATERIALS AND METHODS: Mouse models of liver fibrosis or cholestasis were obtained after the serial administration of thioacetamide (TAA) or surgical bile duct ligation (BDL), respectively. Then, after obtaining liver specimens at specific time points, we compared the expression of makers related to apoptosis (cleaved caspases), inflammation (CD68), necrosis (high-mobility group box 1), phospho-c-Jun N-terminal kinase (p-JNK), and autophagy (microtubule-associated protein light chain 3B and p62) in the fibrotic or cholestatic mouse livers, by polymerase chain reaction, Western blot analysis, immunohistochemistry, and immunofluorescence. RESULTS: Although cholestatic livers exhibited the tendency of progressively increasing the expression of most apoptosis-related markers (cleaved caspases), it was not prominent when it was compared with the tendency found in the livers of TAA-treated mice. Contrastingly, the necrosis-related factor (high-mobility group box 1) was significantly increased in the livers of BDL mice over time, reaching their peak values on day 7 after BDL. In addition, the inflammation-related factor (CD68) was highly expressed in BDL mice compared with TAA-treated mice over time. Autophagy marker studies indicated that autophagy was upregulated in fibrotic livers, whereas it was downregulated in cholestatic livers. We also observed mild to moderate activation of p-JNK in the livers of TAA-treated mice, whereas significantly higher p-JNK activation was detected in the livers of BDL mice. CONCLUSIONS: Unlike TAA-treated mice, BDL mice exhibited higher expression of the markers related with inflammation and necrosis, especially including p-JNK, while maintaining low levels of autophagic process. Therefore, obstructive cholestasis is characterized by higher p-JNK activation, which could be related with marked necrotic cell death resulting from extensive inflammation and little chance of compensatory autophagy.

8.
Nat Commun ; 9(1): 3284, 2018 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-30115930

RESUMO

Cytokines are involved in early host defense against pathogen infections. In particular, tumor necrosis factor (TNF) and interferon-gamma (IFN-γ) have critical functions in non-cytopathic elimination of hepatitis B virus (HBV) in hepatocytes. However, the molecular mechanisms and mediator molecules are largely unknown. Here we show that interleukin-32 (IL-32) is induced by TNF and IFN-γ in hepatocytes, and inhibits the replication of HBV by acting intracellularly to suppress HBV transcription and replication. The gamma isoform of IL-32 (IL-32γ) inhibits viral enhancer activities by downregulating liver-enriched transcription factors. Our data are validated in both an in vivo HBV mouse model and primary human hepatocytes. This study thus suggests that IL-32γ functions as intracellular effector in hepatocytes for suppressing HBV replication to implicate a possible mechanism of non-cytopathic viral clearance.


Assuntos
Antivirais/metabolismo , Citocinas/metabolismo , Vírus da Hepatite B/fisiologia , Interleucinas/metabolismo , Espaço Intracelular/metabolismo , Animais , Sequência de Bases , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação para Baixo , Elementos Facilitadores Genéticos/genética , Hepatite B Crônica/metabolismo , Hepatite B Crônica/patologia , Fatores Nucleares de Hepatócito/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Modelos Biológicos , Ligação Proteica , Transcrição Genética , Replicação Viral
9.
Cancer Res Treat ; 50(3): 1023-1038, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29121714

RESUMO

Purpose: Everolimus only inhibits mammalian target of rapamycin complex 1 (mTORC1), whereas Ku0063794 inhibits both mTORC1 and mTORC2. Although they have similar anticancer effects, their combination has a synergistic effect against hepatocellular carcinoma (HCC) cells. We aimed to determine the mechanism underlying the synergistic effects of everolimus and Ku0063794 associated with autophagy in HCC cells. Materials and Methods: We compared the effects of everolimus and Ku0063794, individually or in combination, on both the in vitro and in vivo models of HCCs. Results: HepG2 cells treated with both agents had significantly lower rates of cell proliferation and higher apoptosis than the individual monotherapies (p < 0.05). Autophagic studies consistently indicated that, unlike the monotherapies, the combination therapy significantly reduced autophagy (p < 0.05). Autophagic blockage directly promoted the pro-apoptotic effects of combination therapy, suggesting autophagy as the survival mechanism of HCC cells. Unlike the monotherapies, combination therapy showed the potential to inhibit sirtuin 1 (SIRT1), the positive regulator of autophagy. SIRT1 overexpression abrogated the autophagy-inhibiting and pro-apoptotic effects of combination therapy. In a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with combination therapy than in mice treated with the respective monotherapies (p < 0.05). The immunohistochemical and immunofluorescence stains of the tumor obtained from the xenograft model showed that combination therapy had the potential of reducing autophagy and promoting apoptosis. Conclusion: The combination of everolimus and Ku0063794 potentiates anticancer effects on HCCs through a decrease in autophagy, which is prompted by SIRT1 downregulation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Everolimo/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Morfolinas/administração & dosagem , Pirimidinas/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Everolimo/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Camundongos , Morfolinas/farmacologia , Pirimidinas/farmacologia , Sirtuína 1/metabolismo , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Gut ; 67(1): 166-178, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28341749

RESUMO

OBJECTIVE: Interferons (IFNs) mediate direct antiviral activity. They play a crucial role in the early host immune response against viral infections. However, IFN therapy for HBV infection is less effective than for other viral infections. DESIGN: We explored the cellular targets of HBV in response to IFNs using proteome-wide screening. RESULTS: Using LC-MS/MS, we identified proteins downregulated and upregulated by IFN treatment in HBV X protein (HBx)-stable and control cells. We found several IFN-stimulated genes downregulated by HBx, including TRIM22, which is known as an antiretroviral protein. We demonstrated that HBx suppresses the transcription of TRIM22 through a single CpG methylation in its 5'-UTR, which further reduces the IFN regulatory factor-1 binding affinity, thereby suppressing the IFN-stimulated induction of TRIM22. CONCLUSIONS: We verified our findings using a mouse model, primary human hepatocytes and human liver tissues. Our data elucidate a mechanism by which HBV evades the host innate immune system.


Assuntos
Regiões 5' não Traduzidas/genética , Ilhas de CpG/genética , Vírus da Hepatite B/imunologia , Interferons/imunologia , Antígenos de Histocompatibilidade Menor/genética , Proteínas Repressoras/genética , Proteínas com Motivo Tripartido/genética , Animais , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Epigênese Genética , Regulação da Expressão Gênica/imunologia , Hepatócitos/metabolismo , Humanos , Evasão da Resposta Imune , Fígado/metabolismo , Metilação , Camundongos , Antígenos de Histocompatibilidade Menor/biossíntese , Proteoma , Proteínas Repressoras/biossíntese , Proteínas com Motivo Tripartido/biossíntese
11.
Oncotarget ; 8(34): 56473-56489, 2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28915605

RESUMO

Heat shock protein 90 (HSP90) stabilizes numerous oncoproteins and, therefore, its inhibition has emerged as a promising antineoplastic strategy for diverse malignancies. In this study, we determined the therapeutic effects and mechanisms of action of a specific HSP90 inhibitor, 17-dimethylamino-ethylamino-17-demethoxygeldanamycin (17-DMAG), in gastric cancer cell lines (AGS, SNU-1, and KATO-III), patient-derived tissues, and a mouse xenograft model. 17-DMAG exerted anticancer effects against gastric cancer cells, manifested by significantly decreased proliferation rates (P < 0.05) and increased expression of apoptotic markers. Flow cytometry using dichlorofluorescein (DCF) diacetate revealed that 17-DMAG dose-dependently increases reactive oxygen species (ROS) levels in gastric cancer cells. Inhibition of ROS by N-acetyl-L-cysteine (NAC) abrogated the proapoptotic effects of 17-DMAG, as demonstrated by the decreased expression of proapoptotic proteins. In addition, 17-DMAG dose- and time-dependently reduced the expression of antioxidants such as catalase and glutathione peroxidase (GPx). Moreover, 17-DMAG reduced the expression of nuclear respiratory factor (NRF)-1 and NRF-2, and prevented them from migrating from the cytoplasm to the nucleus dose-dependently. Finally, in a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with 17-DMAG than in control mice (P < 0.05). Taken altogether, our results suggest that 17-DMAG exerts potent antineoplastic activity against gastric cancer cells primarily by promoting ROS generation and suppressing antioxidant enzyme activities.

12.
Stem Cell Res Ther ; 8(1): 181, 2017 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-28774345

RESUMO

BACKGROUND: A hypoxic-preconditioned secretome from stem cells reportedly promotes the functional and regenerative capacity of the liver more effectively than a control secretome. However, the optimum oxygen partial pressure (pO2) in the cell culture system that maximizes the therapeutic potential of the secretome has not yet been determined. METHODS: We first determined the cellular alterations in adipose tissue-derived stem cells (ASCs) cultured under different pO2 (21%, 10%, 5%, and 1%). Subsequently, partially hepatectomized mice were injected with the secretome of ASCs cultured under different pO2, and then sera and liver specimens were obtained for analyses. RESULTS: Of all AML12 cells cultured under different pO2, the AML12 cells cultured under 1% pO2 showed the highest mRNA expression of proliferation-associated markers (IL-6, HGF, and VEGF). In the cell proliferation assay, the AML12 cells cultured with the secretome of 1% pO2 showed the highest cell proliferation, followed by the cells cultured with the secretome of 21%, 10%, and 5% pO2, in that order. When injected into the partially hepatectomized mice, the 1% pO2 secretome most significantly increased the number of Ki67-positive cells, reduced serum levels of proinflammatory mediators (IL-6 and TNF-α), and reduced serum levels of liver transaminases. In addition, analysis of the liver specimens indicated that injection with the 1% pO2 secretome maximized the expression of the intermediate molecules of the PIP3/Akt and IL-6/STAT3 signaling pathways, all of which are known to promote liver regeneration. CONCLUSIONS: The data of this study suggest that the secretome of ASCs cultured under 1% pO2 has the highest liver reparative and regenerative potential of all the secretomes tested here.


Assuntos
Tecido Adiposo/metabolismo , Meios de Cultivo Condicionados/farmacologia , Regeneração Hepática/efeitos dos fármacos , Oxigênio/farmacologia , Células-Tronco/metabolismo , Animais , Linhagem Celular , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oxigênio/metabolismo , Pressão Parcial
13.
J Hepatobiliary Pancreat Sci ; 24(10): 550-558, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28834296

RESUMO

BACKGROUND: In cases of acute cholecystitis (AC), postoperative antibiotic prophylaxis is generally used for the purpose of preventing subsequent infections. However, there is still no standardized guideline regarding antibiotic administration after cholecystectomy. METHODS: A total of 200 patients at five participating hospitals who were admitted for cholecystectomy to treat grade I or II AC were enrolled and randomly allocated to a group given a placebo (group A) or a group given postoperative antibiotics (group B). Surgical outcomes and incidence of postoperative infectious morbidities were reviewed. RESULTS: A total of 188 patients (95 patients in group A and 93 patients in group B) were finally analyzed. The incidence rate of infectious complications (seven cases, 7.4%, in group A and eight cases, 8.6%, in group B, P = 0.794) and overall non-infectious complications (seven cases, 7.4%, in group A and six cases, 6.5%, in group B, P = 1.000) showed no significant difference between the two groups. CONCLUSIONS: Absence of postoperative antibiotic administration did not lead to an increase in postoperative infections in cases of mild to moderate AC. Avoidance of unnecessary antibiotic use will reduce the adverse effects of antibiotics and also allow for a tailored treatment strategy according to the severity of cholecystitis.


Assuntos
Antibacterianos/administração & dosagem , Colecistectomia Laparoscópica/métodos , Colecistite Aguda/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Idoso , Colecistectomia Laparoscópica/efeitos adversos , Colecistite Aguda/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Cuidados Pós-Operatórios/métodos , Prognóstico , Estudos Prospectivos , Valores de Referência , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento
14.
Surg Endosc ; 31(12): 5289-5294, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28593410

RESUMO

BACKGROUND: Xanthogranulomatous cholecystitis is an inflammatory disease with pathologically distinct characteristics such as accumulation of lipid-laden macrophages, fibrous tissue, and acute and chronic inflammatory cells. It often involves adjacent organs and mimics gallbladder cancer. The purpose of this study was to review the clinical findings of xanthogranulomatous cholecystitis and to determine the appropriate treatment plan. METHODS: We retrospectively analyzed clinical demographics, operation records, and postoperative results of 31 patients with a pathological diagnosis of xanthogranulomatous cholecystitis who underwent surgery between January 2010 and 2015 at two university hospitals. RESULTS: Xanthogranulomatous cholecystitis was found in 0.81% (31/3820) of cholecystectomy patients in our hospital over 5 years. The most frequently observed clinical symptom was abdominal pain (21 patients, 67.7%). Preoperative radiological studies showed cholelithiasis in 23 patients (74.2%), thickening of the gallbladder wall in 23 patients (74.2%), and suspicious cancer in 2 patients (6.5%), but there were no cases of gallbladder cancer accompanying xanthogranulomatous cholecystitis. Laparoscopic cholecystectomy was planned in all patients and was converted to open cholecystectomy in five patients. T-tube choledocholithotomy was needed in one patient due to common bile duct injury. Mean operation time was 149.2 min, and estimated blood loss was 270.1 mL. There were two patients with complications greater than Clavien-Dindo Classification grade III (CBD injury, pleural effusion). CONCLUSION: An initial laparoscopic approach is possible for xanthogranulomatous cholecystitis. However, it is troublesome and challenging, with significantly higher conversion and complication rates compared to standard laparoscopic cholecystectomy.


Assuntos
Colecistectomia Laparoscópica/métodos , Colecistite/cirurgia , Xantomatose/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Colecistectomia Laparoscópica/efeitos adversos , Colecistite/diagnóstico , Conversão para Cirurgia Aberta/estatística & dados numéricos , Feminino , Vesícula Biliar/patologia , Vesícula Biliar/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Período Pós-Operatório , Estudos Retrospectivos , Xantomatose/diagnóstico
15.
Oncotarget ; 8(2): 2936-2948, 2017 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-27935857

RESUMO

There is lots of evidence to support the critical involvement of mTOR signaling in the carcinogenesis of hepatocellular carcinoma (HCC). However, it has not been determined how the roles of individual mTORC1 and mTORC2 inhibitors played in the HCC therapeutics. We thus compared the effects of everolimus, Ku0063794, and a combination of the two therapies on HCC cells, using various in vitro studies (HepG2, Hep3B, and Huh7 cells), ex vivo culturing of HCC tissues obtained from patients, and the in vivo mouse xenograft model of HCC cells. Our in vitro, ex vivo, and in vivo experiments consistently demonstrated that everolimus and Ku0063794 combination therapy was superior to individual monotherapies, as manifested by higher reduction of proliferation, migration, and invasion of HCC cells, and the higher inhibition of EMT process as well. Although individual monotherapies could not inhibit SIRT1 (positive regulator of EMT) expression, the combination therapy significantly inhibited SIRT1 expression. However, overexpression of SIRT1 mitigated the EMT-inhibiting effect of the combination therapy, suggesting that the combination therapy inhibits the EMT by way of suppressing SIRT1 expression. Therefore, when considering everolimus as an anti-HCC agent, the improved anticancer effects provided by combining it with an inhibitor of both mTORC1 and mTORC2 should be recognized.


Assuntos
Antineoplásicos/farmacologia , Everolimo/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Expressão Gênica , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/genética , Sirtuína 1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Asian J Surg ; 40(5): 367-374, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26922627

RESUMO

BACKGROUND: Because acute cholecystitis has a different prognosis according to the degree of inflammation, early detection and prompt operation of severe cholecystitis are critical to the success of treatment. However, computed tomography (CT) has a low discriminative value for differentiating between simple and severe cholecystitis. Therefore, to enhance the diagnostic accuracy of CT scan, the imaging studies should be supplemented by preoperative clinical variables. METHODS: Patients undergoing laparoscopic cholecystectomy for simple and severe cholecystitis between 2007 and 2014 were compared. Severe cholecystitis included hemorrhagic, gangrenous, emphysematous, xanthogranulomatous, and perforated cholecystitis. Prediction models for severe cholecystitis were developed based on multivariate analyses of preoperative clinical and radiologic variables. RESULTS: Independent factors related with severe cholecystitis were age ≥65 years, male gender, body mass index (BMI) ≥25, serum leukocyte count ≥10,000/mm3, serum neutrophil fraction ≥80%, serum platelet count ≥20,000/mm3, serum alanine transaminase (ALT) level ≥40 IU/L, admission via the emergency department, and radiologic features of gallbladder wall thickening ≥4 mm, and presence of pericholecystic fluid collection (p < 0.05). A standard risk assessment scale (range: 0-77) for severe cholecystitis was developed based on the individual hazard rate of these variables. Patients scoring ≥28 on the risk assessment scale showed an 8.6 higher odds of severe cholecystitis than those scoring <28 (p < 0.01). CONCLUSION: Standard and quick-and-easy predictive models for severe cholecystitis have been developed based on preoperative radiological and clinical variables, which is expected to help improve surgical outcome of patients with cholecystitis.


Assuntos
Colecistectomia Laparoscópica , Colecistite Aguda/diagnóstico , Técnicas de Apoio para a Decisão , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Colecistite Aguda/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Medição de Risco , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto Jovem
17.
Ann Surg Treat Res ; 91(5): 233-238, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27847795

RESUMO

PURPOSE: Single incision laparoscopic cholecystectomy (SILC) has some technical problems. Our group has performed needlescopic grasper assisted SILC (nSILC) to overcome these problems. In this study, we introduce our technique and evaluate the safety and feasibility of this technique compared with the conventional laparoscopic cholecystectomy (CLC). METHODS: The medical records of 485 patients who received nSILC and CLC were reviewed retrospectively. Surgical outcomes including operative time, hospital stay, postoperative pain and perioperative complication were compared between the 2 techniques. RESULTS: Although wound complications were developed more frequently in nSILC group, there was no significant difference between groups in other surgical outcomes. In subgroup analysis, surgical outcomes of nSILC were similar with those of CLC not only in easy group but also in difficult group. CONCLUSION: It seems that nSILC is safe and feasible not only in selected patients but also in difficult cases such as acute cholecystitis.

18.
Ann Surg Treat Res ; 91(2): 66-73, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27478811

RESUMO

PURPOSE: As several years have passed since the implementation of the Korean diagnosis-related group (DRG) payment system for appendicitis, its early outcomes should be assessed to determine if further improvements are warranted. METHODS: We retrospectively analyzed clinical data from Korean patients who underwent appendectomy, dividing the sample into 2 groups of those who received services before and after implementation of the DRG system. Based on the DRG code classification, patient data were collected including the amount of DRG reimbursement and the total in-patient costs. We subsequently performed univariate and multivariate analyses to identify independent factors contributing to higher total in-patient cost. RESULTS: Although implementation of the DRG system for appendicitis significantly reduced postoperative length of stay (2.8 ± 1.0 days vs. 3.4 ± 1.9 days, P < 0.001), it did not reduce total in-hospital cost. The independent factors related to total inhospital cost included patient age of 70 years or more (odds ratio [OR], 3.214; 95% confidence interval [CI], 1.769-5.840; P < 0.001) and operation time longer than 100 minutes (OR, 3.690; 95% CI, 2.007-6.599, P < 0.001). In addition, older patients (≥70 years) showed a nearly 10 times greater relative risk for having a comorbid condition (95% CI, 5.141-20.214; P < 0.001) and a 3.255 times greater relative risk for having higher total in-hospital cost (95% CI, 1.731-6.119, P < 0.001). CONCLUSION: It appears that older patients (>70 years) have greater comorbidities, which contribute to higher inpatient costs. Thus, our study suggests that patient age be considered as a DRG classification variable.

19.
World J Gastroenterol ; 21(45): 12857-64, 2015 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-26668510

RESUMO

AIM: To investigate the safety and feasibility of needlescopic grasper-assisted single-incision laparoscopic common bile duct exploration (nSIL-CBDE) by comparing the surgical outcomes of this technique with those of conventional laparoscopic CBDE (CL-CBDE). METHODS: We retrospectively analyzed the clinical data of patients who underwent CL-CBDE or nSIL-CBDE for the treatment of common bile duct (CBD) stones between January 2000 and December 2014. For performing nSIL-CBDE, a needlescopic grasper was also inserted through a direct puncture below the right subcostal line after introducing a single-port through the umbilicus. The needlescopic grasper helped obtain the critical view of safety by retracting the gallbladder laterally and by preventing crossing or conflict between laparoscopic instruments. The gallbladder was then partially dissected from the liver bed and used for retraction. CBD stones were usually extracted through a longitudinal supraduodenal choledochotomy, mostly using flushing a copious amount of normal saline through a ureteral catheter. Afterward, for the certification of CBD clearance, CBDE was performed mostly using a flexible choledochoscope. The choledochotomy site was primarily closed without using a T-tube, and simultaneous cholecystectomies were performed. RESULTS: During the study period, 40 patients underwent laparoscopic CBDE. Of these patients, 20 underwent CL-CBDE and 20 underwent nSIL-CBDE. The operative time for nSIL-CBDE was significantly longer than that for CL-CBDE (238 ± 76 min vs 192 ± 39 min, P = 0.007). The stone clearance rate was 100% (40/40) in both groups. Postoperatively, the nSIL-CBDE group required less intravenous analgesic (pethidine) (46.5 ± 63.5 mg/kg vs 92.5 ± 120.1 mg/kg, P = 0.010) and had a shorter hospital stay than the CL-CBDE group (3.8 ± 2.0 d vs 5.1 ± 1.7 d, P = 0.010). There was no significant difference in the incidence of postoperative complications between the two groups. CONCLUSION: The results of this study suggest that nSIL-CBDE could be safe and feasible while improving cosmetic outcomes when performed by surgeons trained in conventional laparoscopic techniques.


Assuntos
Ducto Colédoco/cirurgia , Cálculos Biliares/cirurgia , Laparoscopia , Adulto , Idoso , Procedimentos Cirúrgicos do Sistema Biliar/efeitos adversos , Procedimentos Cirúrgicos do Sistema Biliar/instrumentação , Endoscópios , Desenho de Equipamento , Estudos de Viabilidade , Feminino , Cálculos Biliares/diagnóstico , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/instrumentação , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Irrigação Terapêutica , Resultado do Tratamento
20.
Ann Surg Treat Res ; 88(4): 181-6, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25844351

RESUMO

PURPOSE: Despite recommendations for introducing student internships (SI) in undergraduate medical education in Korea, the feasibility of surgical SIs has not been demonstrated in the Korean context. We thus identified tasks that could be performed by surgical student interns in a Korean education hospital. METHODS: The opinions of surgery clerkship directors of medical schools nationwide, regarding the tasks, symptoms and signs, disease entities, and procedures that student interns could perform in their hospitals, were subjected to descriptive analysis. RESULTS: Out of the 41 medical schools in Korea, 32 responded. Five implemented an optimal-quality SI program. Two schools considered third-year clerkship as SI. The respondents replied that student interns could be involved in basic nonspecific tasks such as history taking, physical examination, medial recording, reporting patients' status, and assisting during surgery. However, more surgery-specific tasks such as perioperative management or caring for a patient with acute abdominal pain were considered difficult for student interns to encounter in the Korean context. CONCLUSION: Surgical educators should determine a specific role for student interns and encourage them to perform surgery-specific tasks. We recommend societal and system support, and curriculum renovation to establish an SI program in Korea.

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