We implemented a 3-3-1 algorithm in order to provide safe and simple self-titration in patients who newly initiated BOT as well as who were already on BOT and evaluated its utility in clinical setting. A total of 46 p...We implemented a 3-3-1 algorithm in order to provide safe and simple self-titration in patients who newly initiated BOT as well as who were already on BOT and evaluated its utility in clinical setting. A total of 46 patients, 21 patients in the newly-initiated group and 25 patients in the existing BOT group performed dose adjustment using 3-3-1 algorithm. HbA1c was significantly improved 4 weeks after the initiation from 8.5% ± 1.2% at baseline to 7.3% ± 0.7% at the final evaluation (p 0.01, vs. Baseline). The average daily insulin units increased throughout the study period from 10.1 ± 6.7 at baseline to 14.6 ± 8.9 units at the final evaluation. Weight didn’t significantly change throughout the study (p = 0.12). The incidents of hypoglycemia were 0.8/month during the insulin dose self-adjustment period and 0.4/month during the follow-up period. The 3-3-1 algorithm using insulin glargine provided a safe and simple dose adjustment and demonstrated its utility in patients who were newly introduced to insulin treatment as well as who were already on BOT.展开更多
AIM:The effects of vitamin D3 have been investigated on various tumors, including colorectal cancer (CRC). 25-hydroxyvitamin-D3-24-hydroxylase (CYP24A1), the enzyme that inactivates the active vitamin D3 metabolite 1,...AIM:The effects of vitamin D3 have been investigated on various tumors, including colorectal cancer (CRC). 25-hydroxyvitamin-D3-24-hydroxylase (CYP24A1), the enzyme that inactivates the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25-D3), is considered to be the main enzyme determining the biological halflife of 1,25-D3. During colorectal carcinogenesis, the expression and concentration of CYP24A1 increases significantly, suggesting that this phenomenon could be responsible for the proposed efficacy of 1,25-D3 in the treatment of CRC. The aim of this study was to investigate the anti-tumor effects of vitamin D3 on the human CRC cell line Caco-2 after inhibition of the cytochrome P450 component of CYP24A1 activity. METHODS:We examined the expression of CYP24A1 mRNA and the effects of 1,25-D3 on the cell line Caco-2 after inhibition of CYP24A1. Cell viability and proliferation were determined by means of sulforhodamine-B staining and bromodeoxyuridine incorporation, respectively, while cytotoxicity was estimated via the lactate dehydrogenase content of the cell culture supernatant. CYP24A1 expression was measured by realtime reverse transcription polymerase chain reaction. A number of tetralone compounds were synthesized to investigate their CP24A1 inhibitory activity. RESULTS:In response to 1,25-D3, CYP24A1 mRNA expression was enhanced significantly, in a time- and dose-dependent manner. Caco-2 cell viability and proliferation were not influenced by the administration of 1,25-D3 alone, but were markedly reduced by coadministration of 1,25-D3 and KD-35, a CYP24A1-inhibiting tetralone. Our data suggest that the mechanism of action of co-administered KD-35 and 1,25-D3 does not involve a direct cytotoxic effect, but rather the inhibition of cell proliferation. CONCLUSION:These findings demonstrate that the selective inhibition of CYP24A1 by compounds such as KD-35 may be a new approach for enhancement of the anti-tumor effect of 1,25-D3 on CRC.展开更多
AIM To investigate the underlying molecularmechanisms of miR-451 to inhibit proliferation ofesophageal carcinoma cell line EC9706.METHODS： Assays for cell growth, apoptosis andinvasion were used to evaluate the effec...AIM To investigate the underlying molecularmechanisms of miR-451 to inhibit proliferation ofesophageal carcinoma cell line EC9706.METHODS： Assays for cell growth, apoptosis andinvasion were used to evaluate the effects of miR-451expression on EC cells. Luciferase reporter and Westernblot assays were used to test whether cyclin-dependentkinase inhibitor 2D （CDKN2D） and MAP3K1 act as majortargets of miR-451.RESULTS： The results showed that CDKN2D andMAP3K1 are direct targets of miR-451. CDKN2D andMAP3K1 overexpression reversed the effect of miR-451.MiR-451 inhibited the proliferation of EC9706 bytargeting CDKN2D and MAP3K1.CONCLUSION： These findings suggest that miR-451might be a novel prognostic biomarker and a potentialtarget for the treatment of esophageal squamous cellcarcinoma in the future.展开更多
AIM: Activated pancreatic stellate cells (PSCs) are implicated in the pathogenesis of pancreatic inflammation and fibrosis,where oxidative stress is thought to play a key role. 4-hydroxy-2,3-nonenal (HNE) is generated...AIM: Activated pancreatic stellate cells (PSCs) are implicated in the pathogenesis of pancreatic inflammation and fibrosis,where oxidative stress is thought to play a key role. 4-hydroxy-2,3-nonenal (HNE) is generated endogenously during the process of lipid peroxidation, and has been accepted as a mediator of oxidative stress. The aim of this study was to clarify the effects of HNE on the activation of signal transduction pathways and cellular functions in PSCs.METHODS: PSCs were isolated from the pancreas of male Wistar rats after perfusion with collagenase P, and used in their culture-activated, myofibroblast-like phenotype unless otherwise stated. PSCs were treated with physiologically relevant and non-cytotoxic concentrations (up to 5 μmol/L) of HNE. Activation of transcription factors was examined by electrophoretic mobility shift assay and luciferase assay.Activation of mitogen-activated protein (MAP) kinases was assessed by Western blotting using anti-phosphospecific antibodies. Cell proliferation was assessed by measuring the incorporation of 5-bromo-2'-deoxyuridine. Production of type Ⅰ collagen and monocyte chemoattractant protein-1 was determined by enzyme-linked immunosorbent assay.The effect of HNE on the transformation of freshly isolated PSCs in culture was also assessed.RESULTS: HNE activated activator protein-1, but not nuclear factor KB. In addition, HNE activated three classes of MAP kinases: extrcellular signal-regulated kinase, c-jun N-terminal kinase, and p38 MAP kinase. HNE increased type I collagen production through the activation of p38 MAP kinase and c-jun N-terminal kinase. HNE did not alter the proliferation,or monocyte chemoattractant protein-1 production. HNE did not initiate the transformation of freshly isolated PSCs to myofibroblast-like phenotype.CONCLUSION: Spedflc activation of these signal transduction pathways and altered cell functions such as collagen production by HNE may play a role in the pathogenesis of pancreatic disorders.展开更多
The synthesis of 3-(2'-hydroxybutyl）isobenzofuran-1(3H)-onel from phthalicanhydride via the intermediate 3-(2'-oxoethyl) isobenzofuran-1(3H)-one 6 was described．
Diisopropylidenated α-D-glucofuranose (1) was oxidated with CrO3-pyridine complex.Oxidated product and its hydrate were separated and were reduced together to synthesize diisopropylidenated α-D-allofuranose (3). The...Diisopropylidenated α-D-glucofuranose (1) was oxidated with CrO3-pyridine complex.Oxidated product and its hydrate were separated and were reduced together to synthesize diisopropylidenated α-D-allofuranose (3). The yield of 3 increased by 8% than that with only oxidated product as reduction substrate. Benzoylated derivative of 3 was selectively hydrolyzed and dimesylated to synthesize 3-O-benzoyl-1,2- O- isopropylidene-α-D-allofuranose (5) and its dimesylated deriva tive respectively. The overall yield of 5 from 1 was 36%. Each step and final products were anal yzed by 1H-NMR spectra and other methods. The experiments showed that the influence of acetic acid concentration on selective hydrolysis was obvious. The hydrolysis yield was 81.8%. Oxidation, reduction and other procedures were practical and had application potential.展开更多
目的探讨T_2 star mapping、T_1 images与3D DESS融合伪彩图在关节软骨损伤中的诊断价值。方法对26例关节软骨损伤患者行T_2 star mapping、T_1 images和3D DESS扫描,并将T_1 images、T_2 star mapping与3D DESS图像融合,评价患者股骨...目的探讨T_2 star mapping、T_1 images与3D DESS融合伪彩图在关节软骨损伤中的诊断价值。方法对26例关节软骨损伤患者行T_2 star mapping、T_1 images和3D DESS扫描,并将T_1 images、T_2 star mapping与3D DESS图像融合,评价患者股骨、胫骨、髌骨关节软骨损伤程度并与关节镜结果对比,计算融合伪彩图诊断软骨损伤的特异性、敏感性及与关节镜诊断结果一致性。结果 T_1 images-3D DESS融合伪彩图诊断关节软骨损伤的敏感度、特异度及Kappa值分别为92.8%、93.0%、0.769,T_2 star mapping-3D DESS融合伪彩图诊断关节软骨损伤的敏感度、特异度及Kappa值分别为91.4%、94.2%、0.787。结论 T_2 star mapping、T_1 images与3D DESS融合伪彩图在关节软骨早期损伤评价上优于关节镜。展开更多
Objective:The tyrosine phosphatase SHP2 has a dual role in cancer initiation and progression in a tissue type-dependent manner.Several studies have linked SHP2 to the aggressive behavior of breast cancer cells and poo...Objective:The tyrosine phosphatase SHP2 has a dual role in cancer initiation and progression in a tissue type-dependent manner.Several studies have linked SHP2 to the aggressive behavior of breast cancer cells and poorer outcomes in people with cancer.Nevertheless,the mechanistic details of how SHP2 promotes breast cancer progression remain largely undefined.Methods:The relationship between SHP2 expression and the prognosis of patients with breast cancer was investigated by using the TCGA and GEO databases.The expression of SHP2 in breast cancer tissues was analyzed by immunohistochemistry.CRISPR/Cas9 technology was used to generate SHP2-knockout breast cancer cells.Cell-counting kit-8,colony formation,cell cycle,and EdU incorporation assays,as well as a tumor xenograft model were used to examine the function of SHP2 in breast cancer proliferation.Quantitative RT-PCR,western blotting,immunofluorescence staining,and ubiquitination assays were used to explore the molecular mechanism through which SHP2 regulates breast cancer proliferation.Results:High SHP2 expression is correlated with poor prognosis in patients with breast cancer.SHP2 is required for the proliferation of breast cancer cellsin vitro and tumor growthin vivo through regulation of Cyclin D1 abundance,thereby accelerating cell cycle progression.Notably,SHP2 modulates the ubiquitin–proteasome-dependent degradation of Cyclin D1viathe PI3K/AKT/GSK3βsignaling pathway.SHP2 knockout attenuates the activation of PI3K/AKT signaling and causes the dephosphorylation and resultant activation of GSK3β.GSK3βthen mediates phosphorylation of Cyclin D1 at threonine 286,thereby promoting the translocation of Cyclin D1 from the nucleus to the cytoplasm and facilitating Cyclin D1 degradation through the ubiquitin–proteasome system.Conclusions:Our study uncovered the mechanism through which SHP2 regulates breast cancer proliferation.SHP2 may therefore potentially serve as a therapeutic target for breast cancer.展开更多
文摘We implemented a 3-3-1 algorithm in order to provide safe and simple self-titration in patients who newly initiated BOT as well as who were already on BOT and evaluated its utility in clinical setting. A total of 46 patients, 21 patients in the newly-initiated group and 25 patients in the existing BOT group performed dose adjustment using 3-3-1 algorithm. HbA1c was significantly improved 4 weeks after the initiation from 8.5% ± 1.2% at baseline to 7.3% ± 0.7% at the final evaluation (p 0.01, vs. Baseline). The average daily insulin units increased throughout the study period from 10.1 ± 6.7 at baseline to 14.6 ± 8.9 units at the final evaluation. Weight didn’t significantly change throughout the study (p = 0.12). The incidents of hypoglycemia were 0.8/month during the insulin dose self-adjustment period and 0.4/month during the follow-up period. The 3-3-1 algorithm using insulin glargine provided a safe and simple dose adjustment and demonstrated its utility in patients who were newly introduced to insulin treatment as well as who were already on BOT.
基金Supported by Research Grants ETT022/2006 and ETT151/2009 from the Ministry of Health,HungaryTáMOP-4.2.1/B-09/1/KONV-2010-0005 from Creating the Center of Excellence at the University of Szegedsupported by the European Union and cofinanced by the European Regional Fund
文摘AIM:The effects of vitamin D3 have been investigated on various tumors, including colorectal cancer (CRC). 25-hydroxyvitamin-D3-24-hydroxylase (CYP24A1), the enzyme that inactivates the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25-D3), is considered to be the main enzyme determining the biological halflife of 1,25-D3. During colorectal carcinogenesis, the expression and concentration of CYP24A1 increases significantly, suggesting that this phenomenon could be responsible for the proposed efficacy of 1,25-D3 in the treatment of CRC. The aim of this study was to investigate the anti-tumor effects of vitamin D3 on the human CRC cell line Caco-2 after inhibition of the cytochrome P450 component of CYP24A1 activity. METHODS:We examined the expression of CYP24A1 mRNA and the effects of 1,25-D3 on the cell line Caco-2 after inhibition of CYP24A1. Cell viability and proliferation were determined by means of sulforhodamine-B staining and bromodeoxyuridine incorporation, respectively, while cytotoxicity was estimated via the lactate dehydrogenase content of the cell culture supernatant. CYP24A1 expression was measured by realtime reverse transcription polymerase chain reaction. A number of tetralone compounds were synthesized to investigate their CP24A1 inhibitory activity. RESULTS:In response to 1,25-D3, CYP24A1 mRNA expression was enhanced significantly, in a time- and dose-dependent manner. Caco-2 cell viability and proliferation were not influenced by the administration of 1,25-D3 alone, but were markedly reduced by coadministration of 1,25-D3 and KD-35, a CYP24A1-inhibiting tetralone. Our data suggest that the mechanism of action of co-administered KD-35 and 1,25-D3 does not involve a direct cytotoxic effect, but rather the inhibition of cell proliferation. CONCLUSION:These findings demonstrate that the selective inhibition of CYP24A1 by compounds such as KD-35 may be a new approach for enhancement of the anti-tumor effect of 1,25-D3 on CRC.
基金Supported by National Natural Science Foundation of China,No.81301726
文摘AIM To investigate the underlying molecularmechanisms of miR-451 to inhibit proliferation ofesophageal carcinoma cell line EC9706.METHODS： Assays for cell growth, apoptosis andinvasion were used to evaluate the effects of miR-451expression on EC cells. Luciferase reporter and Westernblot assays were used to test whether cyclin-dependentkinase inhibitor 2D （CDKN2D） and MAP3K1 act as majortargets of miR-451.RESULTS： The results showed that CDKN2D andMAP3K1 are direct targets of miR-451. CDKN2D andMAP3K1 overexpression reversed the effect of miR-451.MiR-451 inhibited the proliferation of EC9706 bytargeting CDKN2D and MAP3K1.CONCLUSION： These findings suggest that miR-451might be a novel prognostic biomarker and a potentialtarget for the treatment of esophageal squamous cellcarcinoma in the future.
基金Supported by Grant-in-Aid for Encouragement of Young Scientists from Japan Society for the Promotion of Science(to A.M.),by Pancreas Research Foundation of Japan(to A.M.),and by the Kanae Foundation for Life and Socio-Medical Science(to A.M.)
文摘AIM: Activated pancreatic stellate cells (PSCs) are implicated in the pathogenesis of pancreatic inflammation and fibrosis,where oxidative stress is thought to play a key role. 4-hydroxy-2,3-nonenal (HNE) is generated endogenously during the process of lipid peroxidation, and has been accepted as a mediator of oxidative stress. The aim of this study was to clarify the effects of HNE on the activation of signal transduction pathways and cellular functions in PSCs.METHODS: PSCs were isolated from the pancreas of male Wistar rats after perfusion with collagenase P, and used in their culture-activated, myofibroblast-like phenotype unless otherwise stated. PSCs were treated with physiologically relevant and non-cytotoxic concentrations (up to 5 μmol/L) of HNE. Activation of transcription factors was examined by electrophoretic mobility shift assay and luciferase assay.Activation of mitogen-activated protein (MAP) kinases was assessed by Western blotting using anti-phosphospecific antibodies. Cell proliferation was assessed by measuring the incorporation of 5-bromo-2'-deoxyuridine. Production of type Ⅰ collagen and monocyte chemoattractant protein-1 was determined by enzyme-linked immunosorbent assay.The effect of HNE on the transformation of freshly isolated PSCs in culture was also assessed.RESULTS: HNE activated activator protein-1, but not nuclear factor KB. In addition, HNE activated three classes of MAP kinases: extrcellular signal-regulated kinase, c-jun N-terminal kinase, and p38 MAP kinase. HNE increased type I collagen production through the activation of p38 MAP kinase and c-jun N-terminal kinase. HNE did not alter the proliferation,or monocyte chemoattractant protein-1 production. HNE did not initiate the transformation of freshly isolated PSCs to myofibroblast-like phenotype.CONCLUSION: Spedflc activation of these signal transduction pathways and altered cell functions such as collagen production by HNE may play a role in the pathogenesis of pancreatic disorders.
文摘The synthesis of 3-(2'-hydroxybutyl）isobenzofuran-1(3H)-onel from phthalicanhydride via the intermediate 3-(2'-oxoethyl) isobenzofuran-1(3H)-one 6 was described．
基金Supported by Tianjin Natural Science Foundation ( No. 05YFJMJC09600).
文摘Diisopropylidenated α-D-glucofuranose (1) was oxidated with CrO3-pyridine complex.Oxidated product and its hydrate were separated and were reduced together to synthesize diisopropylidenated α-D-allofuranose (3). The yield of 3 increased by 8% than that with only oxidated product as reduction substrate. Benzoylated derivative of 3 was selectively hydrolyzed and dimesylated to synthesize 3-O-benzoyl-1,2- O- isopropylidene-α-D-allofuranose (5) and its dimesylated deriva tive respectively. The overall yield of 5 from 1 was 36%. Each step and final products were anal yzed by 1H-NMR spectra and other methods. The experiments showed that the influence of acetic acid concentration on selective hydrolysis was obvious. The hydrolysis yield was 81.8%. Oxidation, reduction and other procedures were practical and had application potential.
文摘目的探讨T_2 star mapping、T_1 images与3D DESS融合伪彩图在关节软骨损伤中的诊断价值。方法对26例关节软骨损伤患者行T_2 star mapping、T_1 images和3D DESS扫描,并将T_1 images、T_2 star mapping与3D DESS图像融合,评价患者股骨、胫骨、髌骨关节软骨损伤程度并与关节镜结果对比,计算融合伪彩图诊断软骨损伤的特异性、敏感性及与关节镜诊断结果一致性。结果 T_1 images-3D DESS融合伪彩图诊断关节软骨损伤的敏感度、特异度及Kappa值分别为92.8%、93.0%、0.769,T_2 star mapping-3D DESS融合伪彩图诊断关节软骨损伤的敏感度、特异度及Kappa值分别为91.4%、94.2%、0.787。结论 T_2 star mapping、T_1 images与3D DESS融合伪彩图在关节软骨早期损伤评价上优于关节镜。
基金This work was supported by grants from the National Natural S&ence Foundation of China(grant Nos.81372844,81472474,81772804 and 81903092)Tianjin Municipal Science and Technology Commission(grant No.16JCYBJC25400)+1 种基金Changjiang Researchers and Innovative Research Team(grant No.IRT_14R40)Postgraduate Innovation Fund of"13th Five-Year Comprehensive Investment,"Tianjin Medical University(grant No.YJSCX201716).
文摘Objective:The tyrosine phosphatase SHP2 has a dual role in cancer initiation and progression in a tissue type-dependent manner.Several studies have linked SHP2 to the aggressive behavior of breast cancer cells and poorer outcomes in people with cancer.Nevertheless,the mechanistic details of how SHP2 promotes breast cancer progression remain largely undefined.Methods:The relationship between SHP2 expression and the prognosis of patients with breast cancer was investigated by using the TCGA and GEO databases.The expression of SHP2 in breast cancer tissues was analyzed by immunohistochemistry.CRISPR/Cas9 technology was used to generate SHP2-knockout breast cancer cells.Cell-counting kit-8,colony formation,cell cycle,and EdU incorporation assays,as well as a tumor xenograft model were used to examine the function of SHP2 in breast cancer proliferation.Quantitative RT-PCR,western blotting,immunofluorescence staining,and ubiquitination assays were used to explore the molecular mechanism through which SHP2 regulates breast cancer proliferation.Results:High SHP2 expression is correlated with poor prognosis in patients with breast cancer.SHP2 is required for the proliferation of breast cancer cellsin vitro and tumor growthin vivo through regulation of Cyclin D1 abundance,thereby accelerating cell cycle progression.Notably,SHP2 modulates the ubiquitin–proteasome-dependent degradation of Cyclin D1viathe PI3K/AKT/GSK3βsignaling pathway.SHP2 knockout attenuates the activation of PI3K/AKT signaling and causes the dephosphorylation and resultant activation of GSK3β.GSK3βthen mediates phosphorylation of Cyclin D1 at threonine 286,thereby promoting the translocation of Cyclin D1 from the nucleus to the cytoplasm and facilitating Cyclin D1 degradation through the ubiquitin–proteasome system.Conclusions:Our study uncovered the mechanism through which SHP2 regulates breast cancer proliferation.SHP2 may therefore potentially serve as a therapeutic target for breast cancer.
