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2.
Int J Mol Sci ; 20(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640144

RESUMO

Progranulin (PGRN) plays a crucial role in diverse biological processes, including cell proliferation and embryonic development. PGRN can be cleaved by neutrophil elastase to release granulin (GRN). PGRN has been found to inhibit inflammation. Whereas, GRN plays a role as a pro-inflammatory factor. However, the pathophysiological roles of PGRN and GRN, at early stages after cerebral ischemia, have not yet been fully understood. The aim of this study was to obtain further insight into the pathologic roles of PGRN and GRN. We demonstrated that the amount of PGRN was significantly increased in microglial cells after cerebral ischemia in rats and that neutrophil elastase activity was also increased at an early stage after cerebral ischemia, resulting in the production of GRN. The inhibition of neutrophil elastase activity suppressed PGRN cleavage and GRN production, as well as the increase in pro-inflammatory cytokines, after cerebral ischemia. The administration of an elastase inhibitor decreased the number of injured cells and improved the neurological deficits test scores. Our findings suggest that an increase in the activity of elastase to cleave PGRN, and to produce GRN, was involved in an inflammatory response at the early stages after cerebral ischemia, and that inhibition of elastase activity could suppress the progression of cerebral ischemic injury.

3.
Chem Biol Interact ; 314: 108849, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610157

RESUMO

To provide novel insight into approaches designed to combat glioblastoma, the molecular details of the cytotoxicity of gamabufotalin, were investigated in the human glioblastoma cell line U-87. A dose-dependent cytotoxicity was observed in the cells, whereas no detectable toxicity was confirmed in mouse primary astrocytes. LDH leakage was only observed in the cells treated with a relatively high concentration (>80 ng/ml). Downregulation of the expression levels of Aurora B, cdc25A, cdc25C, cdc2, Cyclin B1 and survivin, and upregulation of the expression level of p21 were observed in treated cells and occurred in parallel with G2/M phase arrest. Treatment with gamabufotalin also downregulated the expression level of uPA, CA9, and upregulated the expression level of TIMP3, all of which are closely associated with invasion/metastasis. Autophagy induction was observed in the treated cells and the addition of wortmannin, a potent autophagy inhibitor, significantly rescued U-87 cells. These results indicate that gamabufotalin exhibits cytotoxicity against cancerous glial cells with high potency and selectivity through multiple cytotoxic signaling pathways. The activation of p38 MAPK pathway along with the upregulation of VEGF/VEGFR2 was observed in the treated cells, both of which are likely to be compensatory changes in response to gamabufotalin treatment. Intriguingly, a specific inhibitor of p38 MAPK enhanced the cytotoxicity of the drug, suggesting an important prosurvival role for p38 MAPK. We thus suggest that developing a new combination regimen of gamabufotalin plus a p38 MAPK inhibitor and/or inhibitors for VEGF/VEGFR could improve the efficacy of the drug, and may provide more therapeutic benefits to patients with glioblastoma.


Assuntos
Apoptose/efeitos dos fármacos , Bufanolídeos/farmacologia , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Autofagia/efeitos dos fármacos , Bufanolídeos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Wortmanina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
4.
Cancer Chemother Pharmacol ; 84(5): 987-992, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31482225

RESUMO

BACKGROUND/AIM: Sunitinib is used for the treatment of metastatic renal cell carcinoma (mRCC). Asian patients, including Japanese, tend not to tolerate long-term sunitinib therapy of 50 mg p.o. once daily for 4 weeks, followed by 2 week off treatment due to severe adverse events at this dosage level. The aim of this retrospective study was to investigate the optimal dose of sunitinib for long-term continuation in Asian patients with mRCC. PATIENTS AND METHODS: The study cases were 50 patients with mRCC who were treated with sunitinib between June 2008 and December 2017. Risk analysis for "unacceptable" adverse events (depending on the physician, ranging from grade 2 to ≥ grade 3) leading to discontinuation of sunitinib was determined by time-dependent Cox proportional hazard regression analysis. RESULTS: A total of 54 unacceptable adverse events leading to discontinuation occurred. Multivariable analysis indicated that a sunitinib dose of ≤ 37.5 mg/day significantly reduced the risk of discontinuation due to adverse events in comparison with 50 mg/day [hazard ratio (HR) 0.08, 95% confidence interval (CI) 0.03-0.21, p < 0.001). The progression-free survival (PFS) with a sunitinib dose ≤ 37.5 mg/day was longer than that associated with a dose of 50 mg/day, albeit not to a statistically significant degree (120 days for ≤ 37.5 mg/day vs 41 days for 50 mg/day, HR 0.39, 95% CI 0.10-1.44, p = 0.157). CONCLUSION: Our findings suggest that the optimal dose of sunitinib for Asian, including Japanese, patients with mRCC is ≤ 37.5 mg/day.

5.
Sci Rep ; 9(1): 11782, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409872

RESUMO

The N-methyl-D-aspartate (NMDA) receptor has been implicated in several neurodegenerative diseases, including stroke. Low-density lipoprotein receptor-related protein 1 (LRP1) plays pivotal roles in endocytosis and signaling in the cell. Immature LRP1 is processed by furin in the trans-Golgi network (TGN) and transported to the cell surface as its mature form. Activation of mature LRP1 exerts a protective effect against glutamate-induced degeneration of the rat retinal ganglion cells, as was shown in our previous study. However, the roles of LRP1 in the pathogenesis of excitotoxic neuronal injuries remain to be determined. The aim of this present study was to achieve further insight into the pathophysiologic roles of LRP1 after excitotoxic neuronal injuries. Our findings are the first to demonstrate that LRP1 was significantly cleaved by furin after cerebral ischemia in rats as well as after exposure of cultured cortical neurons to NMDA. It was noteworthy that the intracellular domain (ICD) of LRP1 was co-localized with TGN and furin. Furthermore, a furin inhibitor inhibited the cleavage of LRP1 and co-localization of LRP1-ICD with TGN or furin. Our findings suggest that furin-mediated cleavage of LRP1 and changes in the localization of LRP1-ICD were involved in the excitotoxic neuronal injury.

6.
Lung Cancer ; 134: 1-6, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31319966

RESUMO

OBJECTIVES: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) represent the first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer. Afatinib is a second-generation EGFR-TKI with excellent therapeutic effects. However, severe diarrhea and skin disorders are observed at high frequencies, often leading to treatment interruption because of low quality of life (QOL). The relationship between individual variations and the onset of these side effects remains to be elucidated. This study aimed to reveal the association among these side effects, pharmacokinetics, and related genetic polymorphisms. MATERIALS AND METHODS: In total, 33 patients were recruited between July 2014 and June 2017. Afatinib plasma concentrations were measured at day 9 when the concentrations reached a steady state (early phase) and when the prescription dose was stable for more than 1 month (stable phase). We analyzed single nucleotide polymorphisms in the genes ATP-binding cassette sub-family B member 1 (ABCB1), ABCG2, and flavin-containing monooxygenase 3. RESULTS: The incidences of both diarrhea and acneiform eruption were greater than 80%. Afatinib plasma concentration and the severity of diarrhea in the early phase were correlated. Pharmacokinetics-related genetic polymorphisms influenced the severity of diarrhea. Particularly, the afatinib plasma concentration was higher and diarrhea was more severe in patients carrying the A allele of ABCG2 C421A. Onset of side effects, genetic polymorphisms, and diarrhea in the maintenance phase or acneiform eruption in the early or maintenance phases were not correlated. The severity of diarrhea is influenced by drug plasma concentrations in the early phase and genetic polymorphisms related to afatinib pharmacokinetics. CONCLUSION: Particular genetic polymorphisms can be screened before afatinib administration and the dose adapted to individual patients can be controlled, leading to reduced side effects, improved QOL, and better patient compliance to maintain the therapeutic effects.

7.
Virology ; 532: 82-87, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31035110

RESUMO

Cytoplasmic tails of envelope (Env) glycoproteins of many retroviruses inhibit their membrane fusion activity. The cytoplasmic 16-amino acid peptide of ecotropic murine leukemia virus (E-MLV) Env protein, called the R-peptide, also inhibits the membrane fusion activity of the Env protein. However, the molecular mechanism of the inhibition has not been elucidated yet. In this study, we found that R-peptide-containing Env protein of E-MLV binds to the cell surface receptor cationic amino acid transporter-1 (CAT-1) with weaker affinity than R-peptide-truncated Env protein. Consistent with this result, R-peptide-containing Env protein had less efficient inhibition of E-MLV vector infection than R-peptide-truncated Env protein. R-peptide truncation has been reported to induce conformational change in the surface subunit of E-MLV Env protein that interacts with the receptor. Taken together, our findings indicate that R-peptide truncation induces conformational change in the receptor-binding domain of the E-MLV Env protein and facilitates the Env-receptor interaction.

8.
Ann Surg Oncol ; 26(6): 1805-1813, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30977014

RESUMO

BACKGROUND: Postoperative docetaxel plus S-1 (DS) chemotherapy is expected to be the standard therapeutic strategy for pStage III gastric cancer based on the results of the JACCRO GC-07 study. Neoadjuvant chemotherapy (NAC) is thought to have several advantages over adjuvant settings. OBJECTIVE: This study aimed to compare the efficacies of NAC DS and the surgery-first strategy for advanced gastric cancer patients with D2 gastrectomy. METHODS: This was a retrospective, single-institution observational study. Of 171 patients with locally advanced (cStage IIB or III) gastric cancer who underwent curative D2 gastrectomy and received NAC DS and/or S-1 adjuvant chemotherapy between 2011 and 2017, 76 (after propensity score matching for 132 patients who met the eligibility criteria) were enrolled in this study. The 3-year progression-free survival (PFS) rate was used to directly compare efficacies between NAC DS patients and surgery-first patients. RESULTS: The 3-year PFS rates for the NAC DS group were significantly higher than those for the surgery-first group (80.0 vs. 58.7; p = 0.037), and the progression hazard ratio of the NAC DS group compared with the surgery-first group was 0.394 (95% confidence interval 0.159-0.978; p = 0.045). CONCLUSIONS: The NAC DS group showed a high 3-year PFS compared with the surgery-first group, with standard S-1 postoperative chemotherapy or observation. NAC DS can be expected to be beneficial as the standard therapy for advanced gastric cancer and should be adopted for the test arm of a randomized controlled phase III trial.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/mortalidade , Terapia Neoadjuvante/mortalidade , Pontuação de Propensão , Neoplasias Gástricas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Docetaxel/administração & dosagem , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/administração & dosagem , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Tegafur/administração & dosagem
9.
Molecules ; 24(5)2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30823418

RESUMO

This study presents a simple, accurate, and selective bioanalytical method of bevacizumab detection from plasma samples based on aptamer affinity purification⁻high-temperature reversed-phased liquid chromatography (HT-RPLC) with fluorescence detection. Bevacizumab in plasma samples was purified using magnetic beads immobilized with an anti-idiotype DNA aptamer for bevacizumab. The purified bevacizumab was separated with HT-RPLC and detected with its native fluorescence. Using aptamer affinity beads, bevacizumab was selectively purified and detected as a single peak in the chromatogram. HT-RPLC achieved good separation for bevacizumab with a sharp peak within 10 min. The calibration curves of the two monoclonal antibodies ranged from 1 to 50 µg/mL and showed good correlation coefficients (r² > 0.999). The limit of detection (LOD) and lower limit of quantification (LLOQ) values for bevacizumab were 0.15 and 0.51 µg/mL, respectively. The proposed method was successfully applied to the bioanalysis of the plasma samples obtained from the patients with lung cancer and may be extended to plan optimal therapeutic programs and for the evaluation of biological equivalencies in the development of biosimilars.


Assuntos
Aptâmeros de Nucleotídeos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/isolamento & purificação , Bevacizumab/administração & dosagem , Bevacizumab/farmacocinética , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
Int J Clin Pract ; 73(5): e13332, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30810264

RESUMO

BACKGROUND: Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has the potential to permit early organism identification and optimization of antibiotic therapy. However, MALDI-TOF MS combined with antimicrobial stewardship is available at only a limited number of institutions. Here, we evaluated the clinical impact of implementing MALDI-TOF MS combined with antimicrobial stewardship intervention in patients with bloodstream infections. METHODS: We conducted a single-centre, prospective cohort study to evaluate the clinical impact of implementing MALDI-TOF MS combined with antimicrobial stewardship intervention in patients with bloodstream infections. Processes and clinical outcomes in patients with bloodstream infections were compared before and after implementation of MALDI-TOF MS. RESULTS: Compared with the conventional identification method, MALDI-TOF MS combined with antimicrobial stewardship intervention significantly decreased the time to organism identification (48.6 ± 46.0 hours vs 78.1 ± 38.9 hours, P < 0.001), effective antimicrobial therapy (12.9 ± 19.0 hours vs 26.2 ± 44.8 hours, P < 0.001) and optimal antimicrobial therapy (53.3 ± 55.0 hours vs 91.7 ± 88.7 hours, P < 0.001. Moreover, the rate of clinical failure (14.0% vs 33.3%, P < 0.001) and incidence of adverse events (7.5% vs 23.9%, P < 0.001) was lower in the MALDI-TOF MS group than in the conventional identification group. A multivariate Cox proportional hazard analysis indicated that implementation of MALDI-TOF MS was a protective factor against clinical failure in patients with bloodstream infections (hazard ratio, 0.61; 95% confidence interval, 0.38-0.99; P = 0.047). CONCLUSIONS: Implementation of the MALDI-TOF MS combined with antimicrobial stewardship intervention facilitated early optimization of antimicrobial therapy with a remarkable concomitant reduction in clinical failure and adverse events in patients with bloodstream infections.


Assuntos
Gestão de Antimicrobianos/métodos , Bacteriemia/tratamento farmacológico , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Idoso , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Bacteriemia/diagnóstico , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Centros de Atenção Terciária , Fatores de Tempo
11.
Anal Chem ; 91(4): 3125-3130, 2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30667211

RESUMO

We propose a highly selective, sensitive, accurate, and high-throughput bioanalysis method for bevacizumab utilizing an anti-idiotype DNA aptamer. With this method, bevacizumab in a plasma sample was reacted in a 96-well plate immobilized with the aptamer and further reacted with a protein A-HRP conjugate. The resulting HRP activity was colorimetrically detected using a microplate reader. The calibration curve of bevacizumab ranged from 0.05 to 5.0 µg/mL, and showed a good correlation coefficient ( r2 = 1.000). The limit of detection was 2.09 ng/mL. We also demonstrated both the possibility of highly sensitive detection using luminol chemiluminescence and the repeated use of affinity plates. The proposed method is applicable for planning optimal therapeutic programs and for an evaluation of the biological equivalencies in the development of biosimilars.

12.
J Clin Pharm Ther ; 44(3): 409-414, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30604428

RESUMO

WHAT IS KNOWN AND OBJECTIVE: The target trough concentration of tacrolimus for ulcerative colitis is recommended to be 10-15 ng/mL in the initial two weeks and 5-10 ng/mL in the later phase. However, the effectiveness of rapid attainment of these target trough concentrations of tacrolimus in patients with ulcerative colitis is still unclear. In the present study, we evaluated the clinical efficacy and safety of rapid attainment of target trough concentrations of tacrolimus in patients with ulcerative colitis. METHODS: A prospective cohort was conducted at Gifu University Hospital in Gifu, Japan. Hospitalized patients who received tacrolimus for the treatment of ulcerative colitis between April 2009 and March 2017 were enrolled. Since June 2011, the initial loading dose of tacrolimus increased from 0.05 to 0.1-0.2 mg/kg/d, and the maintenance dose to achieve the target trough concentration was determined to be 12.5 ng/mL by proportional calculation with measured blood concentration. The period required to attain target trough concentration and the clinical efficacy before and after dosage modification was compared. RESULTS: The initial dose after dosage modification was significantly increased compared to that before dosage modification (0.10 [0.04-0.22], median [range] mg/kg/d vs 0.05 [0.03-0.05] mg/kg/d, P < 0.001). The period required to attain a target trough concentration over 10 ng/mL was significantly shortened by dosage modification (6 [4-14] days before dosage modification vs 4.5 [2-8] days after modification, P = 0.048). Further, stool frequency score was significantly improved after dosage modification, without affecting the incidence of adverse events. WHAT IS NEW AND CONCLUSION: Our findings suggest that rapid attainment of the target trough concentration of tacrolimus improves clinical symptoms in patients with ulcerative colitis.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Imunossupressores/administração & dosagem , Tacrolimo/administração & dosagem , Adolescente , Adulto , Idoso , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
13.
BMC Cancer ; 18(1): 1261, 2018 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-30558575

RESUMO

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) are associated with poor prognoses in patients with gastric cancer; however, few studies have focused on the dynamic changes in these ratios during the treatment of patients with gastric cancer. Here, we assessed the clinical utility of changes in these ratios as prognostic indicators in patients with stage II or III gastric cancer who received adjuvant chemotherapy. METHODS: We retrospectively reviewed 100 patients who received S-1 adjuvant chemotherapy at ≥70% of the relative dose intensity, and their NLRs and PLRs were evaluated at different times: prior to gastrectomy and upon commencement and termination of adjuvant chemotherapy. To assure the clinical utility of the changes in NLR and PLR as prognostic indicators, other clinical factors were assessed as well. RESULTS: Disease recurred in 35 patients as follows: lymph node metastasis (17 patients, 17.0%), peritoneal metastasis (12 patients, 12.0%), and hematogenous metastasis (6 patients, 6.0%); 24 patients died. An increase in the NLR during adjuvant chemotherapy with S-1 was identified as an independent indicator associated with overall survival (hazard ratio [HR] 6.736, 95% confidence interval [CI] 2.420-18.748; P < 0.001), and relapse-free survival (HR 5.309, 95% CI 2.585-10.901; P < 0.001). CONCLUSION: An increase in the NLR during S-1 adjuvant chemotherapy may be a useful prognostic indicator in patients with stage II or III gastric cancer.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Neutrófilos/citologia , Ácido Oxônico/administração & dosagem , Neoplasias Gástricas/sangue , Neoplasias Gástricas/tratamento farmacológico , Tegafur/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Combinação de Medicamentos , Feminino , Gastrectomia , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ácido Oxônico/uso terapêutico , Prognóstico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Análise de Sobrevida , Tegafur/uso terapêutico , Resultado do Tratamento
14.
Int J Oncol ; 53(6): 2488-2502, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30272276

RESUMO

Glioblastoma is the most common and lethal intracranial tumor type, characterized by high angiogenic and infiltrative capacities. To provide a novel insight into therapeutic strategies against glioblastoma, the cytotoxicity of arenobufagin and hellebrigenin was investigated in the human glioblastoma cell line, U-87. Similar dose-dependent cytotoxicity was observed in the cells, whereas no detectable toxicity was confirmed in mouse primary astrocytes. Treatment with each drug downregulated the expression levels of Cdc25C, Cyclin B1 and survivin, which occurred in parallel with G2/M phase arrest. Necrotic-like cell death was only observed in the cells treated with a relatively high concentration (>100 ng/ml). These results indicate that the two drugs exhibited distinct cytotoxicity against cancerous glial cells with high potency and selectivity, suggesting that growth inhibition associated with G2/M phase arrest and/or necrosis were attributed to their toxicities. Activation of the p38 mitogen activated protein kinase (MAPK) signaling pathway was also observed in treated cells. Notably, a specific inhibitor of p38 MAPK, SB203580, itself caused a significant decrease in cell viability, and further enhanced the cytotoxicity of the two drugs, suggesting an important pro-survival role for p38 MAPK. Given that p38 MAPK serves an essential role in promoting glioblastoma cell survival, developing a novel combination regimen of arenobufagin/hellebrigenin plus a p38 MAPK inhibitor may improve the efficacy of the two drugs, and may provide more therapeutic benefits to patients with glioblastoma. The qualitative assessment demonstrated the existence of arenobufagin in the cerebrospinal fluid of arenobufagin-treated rats, supporting its clinical application.

15.
J Oncol Pharm Pract ; : 1078155218808074, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30304984

RESUMO

Introduction Cancer patients undergoing hemodialysis might be under-treated because the pharmacokinetics of anti-cancer drugs in such patients remain unknown and out of concern related to the potential development of severe adverse effects. However, patients with chemosensitive cancer, such as esophageal cancer, should receive chemotherapy at a dose that is sufficient to attain a favorable therapeutic effect. We herein present an interesting case involving an esophageal cancer patient who was successfully treated with subtotal thoracic esophagectomy, and adjuvant full-dose chemotherapy with cisplatin and 5-fluorouracil while concomitantly undergoing hemodialysis. We carried out a pharmacokinetics analysis of cisplatin, and also conducted a systematic review on the dose and pharmacokinetics. Case report A 57-year-old male patient with esophageal cancer who was undergoing hemodialysis was referred to our hospital. He underwent subtotal thoracic esophagectomy. The pathological diagnosis was T1b, N2 (5/26), M0, ly2, v2, stage IIIA (Union for International Cancer Control, 8th edition). Because of the high degree of lymph node metastasis, adjuvant chemotherapy with cisplatin was recommended. Cisplatin (80 mg/m2) was infused intravenously within 30 min on day 1, and 5-fluorouracil (800 mg/m2) was infused continuously on days 1-5 of a 28-day cycle. Thrombocytopenia (grade 3) occurred on day 16, leucopenia (grade 3) occurred on day 23, and anemia (grade 3) occurred on day 30. The onset of hematologic toxicities was prolonged in comparison to patients with a normal renal function.

16.
J Med Case Rep ; 12(1): 280, 2018 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-30266098

RESUMO

BACKGROUND: Metformin-associated lactic acidosis is a well-known life-threatening complication of metformin. We here report the case of a patient who developed metformin-associated lactic acidosis without organ manifestations, due to the simultaneous ingestion of an overdose of metformin and alcohol, and who recovered with high-flow high-volume intermittent hemodiafiltration. CASE PRESENTATION: A 44-year-old Asian woman with type 2 diabetes attempted suicide by ingesting 10 tablets of metformin 500 mg and drinking approximately 600 mL of Japanese sake containing 15% alcohol. She was transferred to our emergency department because of disturbed consciousness. Continuous intravenous administration of noradrenalin (0.13 µg/kg per minute) was given because she was in shock. Laboratory findings included a lactate level of 119 mg/dL (13.2 mmol/L), bicarbonate of 14.5 mmol/L, and serum metformin concentration of 1138 ng/mL. She was diagnosed as having metformin-associated lactic acidosis worsened by alcohol. After 4560 mL of bicarbonate ringer (Na+ 135 mEq/L, K+ 4 mEq/L, Cl- 113 mEq/L, HCO3- 25 mEq/L) was administered, high-flow high-volume intermittent hemodiafiltration. (dialysate flow rate: 500 mL/min, substitution flow rate: 3.6 L/h) was carried out for 6 h to treat metabolic acidosis and remove lactic acid and metformin. Consequently, serum metformin concentration decreased to 136 ng/mL and noradrenalin administration became unnecessary to maintain normal vital signs. On hospital day 12, she was moved to the psychiatry ward. CONCLUSIONS: HFHV-iHDF may be able to remove metformin and lactic acid efficiently and may improve the condition of hemodynamically unstable patients with metformin-associated lactic acidosis.

17.
Front Microbiol ; 9: 1912, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210460

RESUMO

Host-cell expression of the ezrin protein is required for CXCR4 (X4)-tropic HIV-1 infection. Ezrin function is regulated by phosphorylation at threonine-567. This study investigates the role of ezrin phosphorylation in HIV-1 infection and virion release. We analyzed the effects of ezrin mutations involving substitution of threonine-567 by alanine (EZ-TA), a constitutively inactive mutant, or by aspartic acid (EZ-TD), which mimics phosphorylated threonine. We also investigated the effects of ezrin silencing on HIV-1 virion release using a specific siRNA. We observed that X4-tropic HIV-1 vector infection was inhibited by expression of the EZ-TA mutant but increased by expression of the EZ-TD mutant, suggesting that ezrin phosphorylation in target cells is required for efficient HIV-1 entry. Expression of a dominant-negative mutant of ezrin (EZ-N) and ezrin silencing in HIV-1 vector-producing cells significantly reduced the infectivity of released virions without affecting virion production. This result indicates that endogenous ezrin expression is required for virion infectivity. The EZ-TD but not the EZ-TA inhibited virion release from HIV-1 vector-producing cells. Taken together, these findings suggest that ezrin phosphorylation in target cells is required for efficient HIV-1 entry but inhibits virion release from HIV-1 vector-producing cells.

18.
Blood Adv ; 2(17): 2262-2272, 2018 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-30206099

RESUMO

During maturation, megakaryocytes (MKs) express ß1-tubulin (TUBB1) and rearrange their microtubule components to enlarge, form proplatelets, and eventually release platelets. The development of a platform to identify in vitro conditions that would efficiently promote MK development could potentially enable large-scale platelet production. Here, we show that an immortalized MK cell line (imMKCL) genetically modified to express the ß1-tubulin-Venus reporter provides a practical system to efficiently monitor the in vitro production of platelet-like particles (PLPs). The Venus transgene was inserted downstream of the TUBB1 locus in imMKCLs using CRISPR/Cas9, and the expression was visualized by Venus fluorescence intensity. This imMKCL reporter line was then used for high-throughput drug screening. We identified several compounds that significantly improved the efficiency of PLP production in vitro under feeder-free conditions and showed a significant tendency to recover platelets in vivo in a mouse thrombocytopenia model induced by anti-GPIbα antibody administration. Interestingly, most of these compounds, including a WNT signaling pathway inhibitor, Wnt-C59, antagonized the aryl hydrocarbon receptor (AhR) to increase PLP production, confirming the crucial role of AhR inhibition in MK maturation. Consistently, small interfering RNA treatment against AhR increased the Venus intensity and PLP production. TCS 359, an FLT3 inhibitor, significantly increased PLP production independently of FLT3 or AhR. This study highlights the usefulness of the ß1-tubulin reporter MK line as a useful tool to study the mechanisms underlying thrombopoiesis and to identify novel inducers of ex vivo platelet production.

19.
Cancer Cell Int ; 18: 113, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30123091

RESUMO

Background: Triple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its aggressive, metastatic behavior, and a lack of a targeted therapy. Trivalent arsenic derivatives (arsenite, AsIII) with remarkable clinical efficacy in acute promyelocytic leukemia has been demonstrated to exhibit inhibitory effect against breast cancer cells. To provide novel insight into the development of new therapeutic strategies, antitumor activity of AsIII and tetrandrine (Tetra), a Chinese plant-derived alkaloid, against the TNBC cell line MDA-MB-231 in vitro and in vivo was investigated. Methods: Cytotoxicity was evaluated using cell viability, lactate dehydrogenase leakage and cell cycle assay. Alterations of genes related to cell proliferation and death were analyzed using western blotting. In vivo antitumor activity of AsIII alone or in combination with Tetra was studied using MDA-MB-231 xenografts in nude mice. Results: Synergistic cytotoxic effects of two drugs were observed in the cells. In vivo study also showed that co-administration of AsIII and Tetra significantly reduced tumor volume and weight, directly supporting its in vitro antitumor activity. No deaths and reduction of body-weight were observed after a long-term co-administration, indicating its good tolerability. S-phase arrest associated with the upregulation of FOXO3a, p27 along with decreased Cyclin D1 expression was observed in the cells treated with the combined regimen. A substantial upregulated p21 expression and downregulated phospho-FOXO3a and Cyclin D1 expression was observed in the tumor tissues of mice co-administered with AsIII and Tetra. Autophagy induction was observed in the combination treatment in vitro and in vivo. The addition of wortmannin, a potent autophagy inhibitor, significantly rescued MDA-MB-231 cells from their cytotoxicity of AsIII and Tetra. Conclusions: S-phase arrest, autophagic and necrotic cell death contribute to the cytocidal effects of the combined regimen of AsIII and Tetra. Considering our previous study showing synergistic cytotoxic effects of the combined regimen in estrogen receptor-positive breast cancer cell line MCF-7, these results suggest that development of the combination regimen of AsIII plus Tetra may offer many benefits to patients with different types of breast cancer.

20.
Heliyon ; 4(6): e00639, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30009269

RESUMO

Background: Cardiac hypertrophy is a well-known risk factor for heart failure and sudden cardiac death (SCD). On the other hand, physiological cardiac hypertrophy is often observed in young healthy men, and it is difficult to predict SCD in cardiac hypertrophy subjects who do not show symptoms of heart failure. MicroRNAs (miRNAs) widely regulate biological activity and play pivotal roles in heart failure progression. In this study, we investigated whether miRNA expression is altered in SCD with cardiac hypertrophy (SCH). Methods: Cardiac tissues were sampled at autopsy from SCH patients, compensated cardiac hypertrophy (CCH) subjects who died of causes other than heart failure, and control cases without cardiac hypertrophy or heart failure. After histopathological examination, we performed deep sequencing and quantitative PCR of cardiac miRNAs. Results and discussion: Although SCH and CCH showed indistinguishable histological features, their miRNA expression signatures were distinct. Among the 240 miRNAs stably detected in the heart, 8 were differentially expressed between SCH and CCH. Specifically, miR-221 increased in SCH compared to CCH and control cases. The significant elevation of cardiac miR-221 in SCH patients is correlated with lethal outcomes. Thus, our results indicate that an elevated miR-221 level is potentially associated with an increased risk of SCD in subjects with cardiac hypertrophy.

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