AIM: Previous studies suggest that loss of bone mineral density (BMD) frequently occurs in patients with chronic viral liver disease, presenting with histologically proven liver cirrhosis. However, little is known abo...AIM: Previous studies suggest that loss of bone mineral density (BMD) frequently occurs in patients with chronic viral liver disease, presenting with histologically proven liver cirrhosis. However, little is known about the occurrence of bone disease in non-cirrhotic patients with chronic hepatitis B or C. Therefore, it was the aim of this study to evaluate this particular population for BMD and bone turnover markers. METHODS: Biochemical markers of bone turnover and BMD were measured in 43 consecutive patients with HCV (n = 30) or HBV (n = 13) infection without histological evidence for liver cirrhosis. Mean age was 49 years (range 26-77 years). BMD was measured by dual X-ray absorptiometry in the femoral neck (FN) and the lumbar spine (LS) region. In addition, bone metabolism markers were measured. RESULTS: BMD was lowered in 25 (58%) of the patients with chronic hepatitis B or C (FN; 0.76 (0.53-0.99); LS: 0.96 (0.62-1.23) g/cm2). Eight (32%) osteopenic patients were diagnosed with osteoporosis. Bone-specific alkaline phosphatase (P= 0.005) and intact parathyroid hormone (iPTH) (P = 0.001) were significantly elevated in the more advanced stages of fibrosis. Mean T-score value was lower in patients with chronic hepatitis C as compared to patients suffering from chronic hepatitis B; however, the difference was not statistically significant (P= 0.09). CONCLUSION: There was a significantly reduced BMD in non-cirrhotic patients with chronic hepatitis B or C infection. Alterations of bone metabolism already occurred in advanced liver fibrosis without cirrhosis. According to our results, these secondary effects of chronic viral hepatitis should be further investigated.展开更多
AIM： To investigate the c-kit expression in biliary tract cancer cell lines and histological sections from patients with extrahepatic cholangiocarcinoma （CC） and to evaluate the efficacy of in vitro and in vitro tr...AIM： To investigate the c-kit expression in biliary tract cancer cell lines and histological sections from patients with extrahepatic cholangiocarcinoma （CC） and to evaluate the efficacy of in vitro and in vitro treatment with imatinib mesilate. METHODS： The protein expression of c-kit in the human biliary tract cancer cell lines Mz-ChA-2 and EGI-1 and histological sections from 19 patients with extrahepatic CC was assessed by immunoblotting, immunocytochemistry, and immunohistochemistry. The anti-proliferative effect of imatinib mesilate on biliary tract cancer cell lines Mz-ChA-2 and EGI-1 was studied in vitro by automated cell counting. In addition, immunodeficient NMRI mice （Taconic^TM） were subcutaneously injected with 5 × 10^6 cells of cell lines MzChA-2 and EGI-1. After having reached a tumour volume of 200 mm^3, daily treatment was started intraperitoneally with imatinib mesilate at a dose of 50 mgikg or normal saline （NS）. Tumor volume was calculated with a Vernier caliper. After 14 d, mice were sacrificed with tumors excised and tumor mass determined.RESULTS： Immunoblotting revealed presence of c-kit in Mz-ChA-2 and absence in EGI-1 cells. Immunocytochemistry with c-kit antibodies displayed a cytoplasmatic and membraneous localization of receptor protein in Mz-ChA-2 cells and absence of c-kit in EGI-1 cells, c-kit was expressed in 7 of 19 （37%） extrahepatic humanCC tissue samples, 2 showed a moderate and 5 a rather weak immunostaining. Imatinib mesilate at a low concentration of 5 μmoliL caused a significant growth inhibition in the c-kit positive cell line Mz-ChA-2 （31%）, but not in the c-kit negative cell line EGI-1 （0%） （P〈0.05）. Imatinib mesilate at an intermediate concentration of 10 μmoliL inhibited cellular growth of both cell lines （51% vs 57%）. Imatinib mesilate at a higher concentration of 20 μmoliL seemed to have a general toxic effect on both cell lines. The IC50 values were 9.7 μmoliL and 11 μmoliL, respectively. After 14 d of in vitro treatment展开更多
AIM： To investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer. METHODS： Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was stud...AIM： To investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer. METHODS： Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay. In addition, the antitumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for acH4 and p21^WAFl/CIP-1, PARP assay, cell cycle analysis, TUNEL assay, and immunhistochemistry for MIB-1. RESULTS： In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines [mean IC50 （3 d） 0.11 and 0.05 μmol/L, respectively], and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21^WAF-1/CIP-1, induction of apoptosis （PARP cleavage）, and cell cycle arrest at G2/M checkpoint. After 28 d, NVP- LBH589 significantly reduced tumor mass by 66% （bile duct cancer） and 87% （gallbladder cancer） in vivo in comparison to placebo, and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed increased apoptosis by TUNEL assay and reduced cell proliferation （MIB-1）. CONCLUSION： Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human biliary tract cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended.展开更多
AIM:To investigate in vitro and in vivo treatment with histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 in pancreatic cancer. METHODS:Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in...AIM:To investigate in vitro and in vivo treatment with histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 in pancreatic cancer. METHODS:Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 8 human pancreatic cancer cell lines using the 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide(MTT) assay. In addition,the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral activity of the drugs was assessed by immunoblotting for p21WAF-1,acH4,cell cycle analysis,TUNEL assay,and immunohistochemistry for MIB-1. RESULTS:In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines and was associated with hyperacetylation of nucleosomal histone H4,increased expression of p21WAF-1,cell cycle arrest at G2/M-checkpoint,and increased apoptosis. In vivo,NVP-LBH589 alone significantly reduced tumor mass and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed slightly increased apoptosis and no significant reduction of cell proliferation.CONCLUSION:Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human pancreatic cancer,although the precise mechanism of in vivo drug action is not yet completely understood. Therefore,further preclinical and clinical studies for the treatment of pancreatic cancer are recommended.展开更多
AIM:To investigate in vitro treatment with NVPAEW541,a small molecule inhibitor of insulin-like growth factor-1 receptor(IGF-1R),in biliary tract cancer (BTC),since this disease is associated with a poor prognosis due...AIM:To investigate in vitro treatment with NVPAEW541,a small molecule inhibitor of insulin-like growth factor-1 receptor(IGF-1R),in biliary tract cancer (BTC),since this disease is associated with a poor prognosis due to wide resistance to chemotherapeutic agents and radiotherapy.METHODS:Cell growth inhibition by NVP-AEW541 was studied in vitro in 7 human BTC cell lines by automated cell counting.In addition,the anti-tumoral mechanism of NVP-AEW541 was studied by Western blotting,cell cycle analysis and reverse transcription-polymerase chain reaction(RT-PCR).Anti-tumoral drug effect in combination with gemcitabine,5-fluorouracil(5-FU)and Polo-like kinase 1 inhibitor BI2536 was also studied. RESULTS:In vitro treatment with NVP-AEW541 suppressed growth in all human BTC cell lines,however response was lower in gallbladder cancer.Treatment withNVP-AEW541 was associated with dephosphorylation of IGF-1R and AKT.In contrast,phosphorylation of p42/p44 and Stat3 and expression of Bcl-xL were inconsistently downregulated.In addition,treated cells showed cell cycle arrest at the G1/S-checkpoint and an increase in sub-G1 peak.Moreover,IGF-1R and its ligands IGF-1 and IGF-2 were co-expressed in RT-PCR,suggesting an autocrine loop of tumor cell activation.Combined with gemcitabine,NVP-AEW541 exerted synergistic effects, particularly at low concentrations,while effects of combination with 5-FU or BI 2536 were only additive. CONCLUSION:Our findings suggest that NVP-AEW541 is active against BTC in vitro and potentiates the efficacy of gemcitabine.展开更多
Congenital diaphragmatic hernia consists of a defect in the embryonic development of the diaphragm that allows the passage of the abdominal viscera into the thoracic cavity,its diagnosis during pregnancy is quite rare...Congenital diaphragmatic hernia consists of a defect in the embryonic development of the diaphragm that allows the passage of the abdominal viscera into the thoracic cavity,its diagnosis during pregnancy is quite rare.We present the case of a 31-year-old woman,with 23 weeks of gestation,who consulted for epigastric pain,nausea,and repetitive emetic episodes,without improvement with the medication provided.Due to the intense abdominal pain,a computed tomography of the abdomen and thorax was performed where the 28 mm defect was found at the left diaphragmatic level with protrusion of the gastric fundus to the thoracic cavity.She was taken to surgical management by laparoscopy with abdominal and thoracic approach,with a successful result and without maternal perinatal complications.Although the integrity of the diaphragmatic suture could be feared in relation to the increase in intraabdominal pressure due to uterine growth,the evolution of our patient and previous reports show that postoperative complications are not frequent.Successful vaginal delivery has even been described in some reports.Diaphragmatic hernias diagnosed during pregnancy are quite rare.We suggest that the optimal management of them during pregnancy is immediate surgical correction in case of persistent symptoms,more studies are needed to establish firm recommendations on the management of this pathology.展开更多
文摘AIM: Previous studies suggest that loss of bone mineral density (BMD) frequently occurs in patients with chronic viral liver disease, presenting with histologically proven liver cirrhosis. However, little is known about the occurrence of bone disease in non-cirrhotic patients with chronic hepatitis B or C. Therefore, it was the aim of this study to evaluate this particular population for BMD and bone turnover markers. METHODS: Biochemical markers of bone turnover and BMD were measured in 43 consecutive patients with HCV (n = 30) or HBV (n = 13) infection without histological evidence for liver cirrhosis. Mean age was 49 years (range 26-77 years). BMD was measured by dual X-ray absorptiometry in the femoral neck (FN) and the lumbar spine (LS) region. In addition, bone metabolism markers were measured. RESULTS: BMD was lowered in 25 (58%) of the patients with chronic hepatitis B or C (FN; 0.76 (0.53-0.99); LS: 0.96 (0.62-1.23) g/cm2). Eight (32%) osteopenic patients were diagnosed with osteoporosis. Bone-specific alkaline phosphatase (P= 0.005) and intact parathyroid hormone (iPTH) (P = 0.001) were significantly elevated in the more advanced stages of fibrosis. Mean T-score value was lower in patients with chronic hepatitis C as compared to patients suffering from chronic hepatitis B; however, the difference was not statistically significant (P= 0.09). CONCLUSION: There was a significantly reduced BMD in non-cirrhotic patients with chronic hepatitis B or C infection. Alterations of bone metabolism already occurred in advanced liver fibrosis without cirrhosis. According to our results, these secondary effects of chronic viral hepatitis should be further investigated.
基金the Deutsche Forschungsgemeinschaft (grant SFB 410)the German-Israeli Foundation for Scientific Research and Development (grant 881/05)+4 种基金the NSF(grant DMR-0342832)the U.S.Department of EnergyOffice of Basic Energy Sciencesunder contract DE-AC03-76SF00515Focus Center Research Program (FCRP) Center on Functional Engineered Nanoarchitectonics (FENA)
基金Supported by the Deutsche Krebshilfe, No. 10-2106-Wi1
文摘AIM： To investigate the c-kit expression in biliary tract cancer cell lines and histological sections from patients with extrahepatic cholangiocarcinoma （CC） and to evaluate the efficacy of in vitro and in vitro treatment with imatinib mesilate. METHODS： The protein expression of c-kit in the human biliary tract cancer cell lines Mz-ChA-2 and EGI-1 and histological sections from 19 patients with extrahepatic CC was assessed by immunoblotting, immunocytochemistry, and immunohistochemistry. The anti-proliferative effect of imatinib mesilate on biliary tract cancer cell lines Mz-ChA-2 and EGI-1 was studied in vitro by automated cell counting. In addition, immunodeficient NMRI mice （Taconic^TM） were subcutaneously injected with 5 × 10^6 cells of cell lines MzChA-2 and EGI-1. After having reached a tumour volume of 200 mm^3, daily treatment was started intraperitoneally with imatinib mesilate at a dose of 50 mgikg or normal saline （NS）. Tumor volume was calculated with a Vernier caliper. After 14 d, mice were sacrificed with tumors excised and tumor mass determined.RESULTS： Immunoblotting revealed presence of c-kit in Mz-ChA-2 and absence in EGI-1 cells. Immunocytochemistry with c-kit antibodies displayed a cytoplasmatic and membraneous localization of receptor protein in Mz-ChA-2 cells and absence of c-kit in EGI-1 cells, c-kit was expressed in 7 of 19 （37%） extrahepatic humanCC tissue samples, 2 showed a moderate and 5 a rather weak immunostaining. Imatinib mesilate at a low concentration of 5 μmoliL caused a significant growth inhibition in the c-kit positive cell line Mz-ChA-2 （31%）, but not in the c-kit negative cell line EGI-1 （0%） （P〈0.05）. Imatinib mesilate at an intermediate concentration of 10 μmoliL inhibited cellular growth of both cell lines （51% vs 57%）. Imatinib mesilate at a higher concentration of 20 μmoliL seemed to have a general toxic effect on both cell lines. The IC50 values were 9.7 μmoliL and 11 μmoliL, respectively. After 14 d of in vitro treatment
文摘AIM： To investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer. METHODS： Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay. In addition, the antitumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for acH4 and p21^WAFl/CIP-1, PARP assay, cell cycle analysis, TUNEL assay, and immunhistochemistry for MIB-1. RESULTS： In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines [mean IC50 （3 d） 0.11 and 0.05 μmol/L, respectively], and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21^WAF-1/CIP-1, induction of apoptosis （PARP cleavage）, and cell cycle arrest at G2/M checkpoint. After 28 d, NVP- LBH589 significantly reduced tumor mass by 66% （bile duct cancer） and 87% （gallbladder cancer） in vivo in comparison to placebo, and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed increased apoptosis by TUNEL assay and reduced cell proliferation （MIB-1）. CONCLUSION： Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human biliary tract cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended.
文摘AIM:To investigate in vitro and in vivo treatment with histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 in pancreatic cancer. METHODS:Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 8 human pancreatic cancer cell lines using the 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide(MTT) assay. In addition,the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral activity of the drugs was assessed by immunoblotting for p21WAF-1,acH4,cell cycle analysis,TUNEL assay,and immunohistochemistry for MIB-1. RESULTS:In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines and was associated with hyperacetylation of nucleosomal histone H4,increased expression of p21WAF-1,cell cycle arrest at G2/M-checkpoint,and increased apoptosis. In vivo,NVP-LBH589 alone significantly reduced tumor mass and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed slightly increased apoptosis and no significant reduction of cell proliferation.CONCLUSION:Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human pancreatic cancer,although the precise mechanism of in vivo drug action is not yet completely understood. Therefore,further preclinical and clinical studies for the treatment of pancreatic cancer are recommended.
基金Supported by Grant No. 934000-258 from Novartis Oncology (to Wiedmann M)
文摘AIM:To investigate in vitro treatment with NVPAEW541,a small molecule inhibitor of insulin-like growth factor-1 receptor(IGF-1R),in biliary tract cancer (BTC),since this disease is associated with a poor prognosis due to wide resistance to chemotherapeutic agents and radiotherapy.METHODS:Cell growth inhibition by NVP-AEW541 was studied in vitro in 7 human BTC cell lines by automated cell counting.In addition,the anti-tumoral mechanism of NVP-AEW541 was studied by Western blotting,cell cycle analysis and reverse transcription-polymerase chain reaction(RT-PCR).Anti-tumoral drug effect in combination with gemcitabine,5-fluorouracil(5-FU)and Polo-like kinase 1 inhibitor BI2536 was also studied. RESULTS:In vitro treatment with NVP-AEW541 suppressed growth in all human BTC cell lines,however response was lower in gallbladder cancer.Treatment withNVP-AEW541 was associated with dephosphorylation of IGF-1R and AKT.In contrast,phosphorylation of p42/p44 and Stat3 and expression of Bcl-xL were inconsistently downregulated.In addition,treated cells showed cell cycle arrest at the G1/S-checkpoint and an increase in sub-G1 peak.Moreover,IGF-1R and its ligands IGF-1 and IGF-2 were co-expressed in RT-PCR,suggesting an autocrine loop of tumor cell activation.Combined with gemcitabine,NVP-AEW541 exerted synergistic effects, particularly at low concentrations,while effects of combination with 5-FU or BI 2536 were only additive. CONCLUSION:Our findings suggest that NVP-AEW541 is active against BTC in vitro and potentiates the efficacy of gemcitabine.
文摘Congenital diaphragmatic hernia consists of a defect in the embryonic development of the diaphragm that allows the passage of the abdominal viscera into the thoracic cavity,its diagnosis during pregnancy is quite rare.We present the case of a 31-year-old woman,with 23 weeks of gestation,who consulted for epigastric pain,nausea,and repetitive emetic episodes,without improvement with the medication provided.Due to the intense abdominal pain,a computed tomography of the abdomen and thorax was performed where the 28 mm defect was found at the left diaphragmatic level with protrusion of the gastric fundus to the thoracic cavity.She was taken to surgical management by laparoscopy with abdominal and thoracic approach,with a successful result and without maternal perinatal complications.Although the integrity of the diaphragmatic suture could be feared in relation to the increase in intraabdominal pressure due to uterine growth,the evolution of our patient and previous reports show that postoperative complications are not frequent.Successful vaginal delivery has even been described in some reports.Diaphragmatic hernias diagnosed during pregnancy are quite rare.We suggest that the optimal management of them during pregnancy is immediate surgical correction in case of persistent symptoms,more studies are needed to establish firm recommendations on the management of this pathology.
