Bishnuhari Paudyal - Academia.edu (original) (raw)

Papers by Bishnuhari Paudyal

Scientific reports, 2015

Obesity is a risk factor for the development of acute respiratory distress syndrome (ARDS) but me... more Obesity is a risk factor for the development of acute respiratory distress syndrome (ARDS) but mechanisms mediating this association are unknown. While obesity is known to impair systemic blood vessel function, and predisposes to systemic vascular diseases, its effects on the pulmonary circulation are largely unknown. We hypothesized that the chronic low grade inflammation of obesity impairs pulmonary vascular homeostasis and primes the lung for acute injury. The lung endothelium from obese mice expressed higher levels of leukocyte adhesion markers and lower levels of cell-cell junctional proteins when compared to lean mice. We tested whether systemic factors are responsible for these alterations in the pulmonary endothelium; treatment of primary lung endothelial cells with obese serum enhanced the expression of adhesion proteins and reduced the expression of endothelial junctional proteins when compared to lean serum. Alterations in pulmonary endothelial cells observed in obese mic...

Autoimmunity - Pathogenesis, Clinical Aspects and Therapy of Specific Autoimmune Diseases, 2015

Experimental and therapeutic medicine, Sep 1, 2010

The aim of this study was to evaluate the effectiveness of oral iron to manage anemia in long-ter... more The aim of this study was to evaluate the effectiveness of oral iron to manage anemia in long-term hemodialysis (HD) patients using ultrapure dialysate. This study was prospectively conducted on 23 patients (11 males and 12 females; median age 60 years, range 35-81) who underwent HD in our hospital from March to September 2007. The patients were randomly assigned to two treatment groups. The first group of 11 patients received ferrous fumarate 305 mg per oral tablet once a day, while the second group of 12 patients received infusions of 50 mg iron in a 0.9% sodium chloride solution. At the end of the 6-month treatment, patients receiving oral iron and intravenous iron had a significant increase in transferrin saturation from baseline (20.1±8.9 to 29.7±7.2; p=0.011 and 17.4±6.1 to 33.7±8.6; p=0.0001, respectively) and ferritin (32.6±15.4 to 115.4±28.2; p=0.0001 and 57.8±26.7 to 183.5±47.5; p=0.0002, respectively). In both groups, hemoglobin, hematocrit and dry weight were increased, ...

Journal of Manmohan Memorial Institute of Health Sciences, 2014

Journal of Biomedical Science, 2014

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease whose etiology remains l... more Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease whose etiology remains largely unknown. The uncontrolled oxidative stress in SLE contributes to functional oxidative modifications of cellular protein, lipid and DNA and consequences of oxidative modification play a crucial role in immunomodulation and trigger autoimmunity. Measurements of oxidative modified protein, lipid and DNA in biological samples from SLE patients may assist in the elucidation of the pathophysiological mechanisms of the oxidative stress-related damage, the prediction of disease prognosis and the selection of adequate treatment in the early stage of disease. Application of these biomarkers in disease may indicate the early effectiveness of the therapy. This review is intended to provide an overview of various reactive oxygen species (ROS) formed during the state of disease and their biomarkers linking with disease. The first part of the review presents biochemistry and pathophysiology of ROS and antioxidant system in disease. The second part of the review discusses the recent development of oxidative stress biomarkers that relates pathogenesis in SLE patients and animal model. Finally, this review also describes the reported clinical trials of antioxidant in the disease that have evaluated the efficacy of antioxidant in the management of disease with ongoing conventional therapy.

Cancer Biotherapy and Radiopharmaceuticals, 2016

The authors have conjugated chelating agents (DOTA and NODAGA) with a peptide (pituitary adenylat... more The authors have conjugated chelating agents (DOTA and NODAGA) with a peptide (pituitary adenylate cyclase-activating peptide [PACAP] analogue) that has a high affinity for VPAC1 receptors expressed on cancer cells. To determine a suitable chelating agent for labeling with (68)Ga, they have compared the labeling kinetics and stability of these peptide conjugates. For labeling, (68)GaCl3 was eluted in 0.1 M HCl from a [(68)Ge-(68)Ga] generator. The influences of peptide concentration, pH, and temperature on the radiolabeling efficiency were studied. The stability was evaluated in saline, human serum, DTPA, transferrin, and metallic ions (FeCl3, CaCl2, and ZnCl2). Cell binding assay was performed using human breast cancer cells (T47D). Tissue biodistribution was studied in normal athymic nude mice. Optimal radiolabeling (>95.0%) of the DOTA-peptide conjugates required a higher (50°C-90°C) temperature and 10 minutes of incubation at pH 2-5. The NODAGA-peptide conjugate needed incubation only at 25°C for 10 minutes. Both radiocomplexes were stable in saline, serum, as well as against transchelation and transmetallation. Cell binding at 37°C for 15 minutes of incubation with (68)Ga-NODAGA-peptide was 34.0% compared to 24.5% for (68)Ga-DOTA-peptide. Tissue biodistribution at 1 hour postinjection of both (68)Ga-labeled peptide conjugates showed clearance through the kidneys. NODAGA-peptide showed more convenient radiolabeling features than that of DOTA-peptide.

Cancer Sci, 2009

Non-small cell lung carcinomas (NSCLC) overexpress the Her2/ /neu gene in approximately 59% of ca... more Non-small cell lung carcinomas (NSCLC) overexpress the Her2/ /neu gene in approximately 59% of cases. Trastuzumab, a humanized monoclonal antibody, interferes with Her2 signaling and is approved for the treatment of Her2/ /neu overexpressing breast cancer. However, its therapeutic use in Her2/ /neu overexpressing NSCLC remains obscure. The present study aimed to determine the role of 64 Cu-labeled trastuzumab positron emission tomography (PET) for non-invasive imaging of Her2/ /neu expression in NSCLC. Trastuzumab was conjugated with the bifunctional chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) and radiolabeled with 64 Cu. The molecular specificity of DOTA-trastuzumab was determined in NSCLC cell lines with Her2/ /neu overexpression (NCI-H2170) and negative expression (NCI-H520). Imaging of Her2/ /neu expression was performed in NCI-H2170 tumor-bearing mice with 64 Cu-DOTA-trastuzumab PET and 64 Cu-DOTA-IgG. In vitro studies revealed specific binding of DOTA-trastuzumab in the Her2/ /neu positive NCI-H2170 cells, while no binding was seen in the Her2/ /neu negative NCI-H520 cell line. Biodistribution and PET studies revealed a significantly high accumulation of 64 Cu-DOTA-trastuzumab in the Her2/ /neu overexpressing NCI-H2170 tumor at 24 and 48 h post-injection (21.4 ± 1.4% and 23.2 ± 5.1% injection dose/ /gram (% ID/g), respectively). PET imaging of Her2/ / neu negative NCI-H520 tumors showed much less uptake of 64 Cu-DOTA-trastuzumab (4.0% ID/g). The NCI-H2170 tumor uptake of 64 Cu-DOTA-trastuzumab was significantly higher than that of 64 Cu-DOTA-IgG (P < 0.0001). 64 Cu-DOTA-trastuzumab showed a very clear image of a Her2/ /neu positive tumor and appeared to be effective as a PET tracer for imaging of Her2/neu gene expression in NSCLC, suggesting its potential clinical use for identifying patients that might benefit from trastuzumab-based therapy. (Cancer Sci 2010; 101: 1045-1050 L ung cancer is one of the world's leading causes of death, with a 5-year survival rate of less than 10%. (1) Activation of ras genes and human epidermal growth factor receptor 2 (Her2/neu) genes is encountered in subpopulations of non-small cell lung carcinoma (NSCLC) patients and has been linked to shortened survival. Overexpression of the Her2/neu gene is closely associated with intrinsic multiple drug resistance in NSCLC cell lines. (2) Her2/neu is a transmembrane tyrosine kinase belonging to the surface receptor family. It does not bind ligand but instead acts as a preferred heterodimerization partner for ligand-activated sibling members to amplify mitotic signaling. (3) Trastuzumab, a humanized monoclonal antibody that targets Her2/neu, inhibits neoplastic cell proliferation both in vitro and in vivo. (4) In breast cancer, overexpression of Her2/neu is seen in 40% of cases, and its activation follows heterodimerization with a member of the EGFR family and triggers important biological effects such as proliferation, migration and differenti-ation. (5) Trastuzumab significantly increases the survival of patients with advanced metastatic breast cancer. Overexpression of Her2/neu is reported in up to 59% of cases of NSCLC and the 2+/3+ overexpression rate is 5-20% in adenocarcinomas. (8-10) As in breast cancer, studies have suggested that the overexpression of Her2/neu in NSCLC is associated with a worse prognosis than negative expression of Her2/ neu. The role of trastuzumab targeting Her2/neu expression in the NSCLC has been largely marginalized. Even though NSCLC is usually chemoresistant, the synergistic effect between trastuzumab and chemotherapeutic agents was found to be greater in Her2/neu positive NSCLC than in breast cancer cell lines. NSCLC patients with Her2/neu overexpression (3+) in immunohistochemistry (IHC) had better survival when treated with trastuzumab-based therapy than the overall population, but only a small percentage of patients benefited. (10) The marked variation in functional anatomy and pathophysiology within human tumors and within individual patients may account for the high variability of responses observed in patients.

Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2013

Jpn J Radiol, 2009

The aim of this study was to compare the maximum-slope (MS) and dual-input one-compartment model ... more The aim of this study was to compare the maximum-slope (MS) and dual-input one-compartment model (DOCM) methods in hepatic perfusion computed tomography (CT). A total of 37 patients with known or suspected liver disease underwent single-location dynamic CT after arterial or venous bolus injection of contrast material. Perfusion CT images were created by the MS (dividing the peak gradient of the time-attenuation curve by the peak vessel CT number) and DOCM-calculating from the equation dC ( L )(t)/dt = k ( a ) C ( a )(t - tau( a )) + k ( p ) C ( p )(t - tau( p )) - k ( v ) C ( L )(t)-methods. The perfusion parameters hepatic arterial perfusion (HAP), portal venous perfusion (PVP), and hepatic perfusion index (HPI) were determined. The PVP of the tumor-free hepatic parenchyma determined by the MS method was lower than that obtained by the DOCM method (P &amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) with both injections. HAP determined by the MS method was lower than that obtained by the DOCM method with venous injection (P = 0.001), although there was no difference between the methods for HAP with arterial injection (P = 0.154). Most of the perfusion parameters showed linear correlations between the two analytical methods. Except for HAP with arterial injection, the perfusion parameters obtained with the MS method were lower than those obtained with the DOCM method.

Cancer Science, Jan 10, 2011

Vascular endothelial growth factor (VEGF) is considered to be a major angiogenic factor responsib... more Vascular endothelial growth factor (VEGF) is considered to be a major angiogenic factor responsible for the development of tumor vasculature. The aim of this study was to image VEGF expression with 64 Cu-labeled anti-VEGF antibody (bevacizumab) non-invasively, and to see whether or not the expression was correlated with tumor accumulation in colorectal cancer xenografts. Bevacizumab was conjugated with the bifunctional chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) and radiolabeled with 64 Cu. In vivo biodistribution studies and positron emission tomography (PET) imaging were performed on mice bearing human colorectal cancer (HT29) xenografts after injection of 64 Cu-DOTA-bevacizumab, which showed clear accumulation of 64 Cu-DOTA-bevacizumab in the tumor (22.7 ± 1.0 %ID ⁄ g, 24 ± 0.2 %ID ⁄ g, 19.0 ± 2.5 %ID ⁄ g at 24, 48 and 72 h, respectively). Tumor accumulation of 64 Cu-DOTA-bevacizumab was significantly correlated with VEGF expression as measured by western blot (q = 0.81, P = 0.004). Vascular endothelial growth factor blocking with unlabeled bevacizumab significantly reduced tumor accumulation of 64 Cu-DOTA-bevacizumab (9.7 ± 1.2 %ID ⁄ g, P < 0.001) at 48 h. Interestingly, the blood concentration of VEGF in the mice treated with excess fold of bevacizumab was significantly higher than those without at 48 h (25.5 ± 4.6 %ID ⁄ g vs 6.5 ± 2.1 %ID ⁄ g, P = 0.0016). Liver uptake decreased from 24 h (17.2 ± 1.7 %ID ⁄ g) to 48 h (13.0 ± 4.2 %ID ⁄ g) and 72 h (10.6 ± 1.5 %ID ⁄ g) due to hepatic clearance of the tracer. The present study successfully showed 64 Cu-DOTA-bevacizumab as a potential PET tracer for noninvasive imaging of VEGF expression in colorectal cancer xenografts. (Cancer Sci 2011; 102: 117-121) V ascular endothelial growth factor (VEGF) is considered to be a major angiogenic factor responsible for the development of the tumor vasculature network having leaky blood vessels and insufficient blood flow and high interstitial blood pressure. Because almost all kinds of tumor progression is dependent on angiogenesis, it has gained a lot of interest among scientists to search for antiangiogenic molecules and to design antiangiogenic strategies for cancer treatment and the prevention of cancer recurrence or metastasis. Bevacizumab, a humanized monoclonal antibody, binds to all VEGF isoforms and thereby prevents interaction with its receptor tyrosine kinase VEGFR-1 and VEGFR-2, thus blocking VEGF-induced endothelial cell proliferation, permeability, survival and growth. In animal models, administration of bevacizumab blocked the growth of human tumor xenografts and reduced the size and number of metastases. (6) Hurwitz et al. found that adding bevacizumab in combination with chemotherapy improved survival and produced consistent results across all patient subgroups with metastatic colorectal cancer (mCRC). Kabbinavar et al. (8) conducted a randomized phase II trial com-paring bevacizumab in combination with chemotherapy versus chemotherapy alone in mCRC patients. Those receiving bevacizumab in combination with chemotherapy experienced a higher response rate, longer median time to disease progression, and longer median survival time. A subsequent randomized, phase II trial involving 209 patients confirmed the clinical efficacy of first-line bevacizumab in mCRC. Despite these promising results of bevacizumab-based therapy, selection of the right patients for bevacizumab-based treatment is a vital criterion; therefore, there is a need to monitor in vivo VEGF downregulation as an immediate response to bevacizumab-based therapy. Imaging of VEGF is more challenging than imaging VEGF receptors because of its complex and dynamic nature. In recent studies, VEGF expression has been non-invasively investigated with radiolabeled bevacizumab in ovarian cancer models, (10) colon cancer models and in 12 patients with liver metastasis (12) using single photon emission computed tomography (SPECT) or positron emission tomography (PET). The results are very promising and pave a new road to non-invasive imaging of VEGF. 64

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease whose etiology remains l... more Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease whose etiology remains largely unknown. The uncontrolled oxidative stress in SLE contributes to functional oxidative modifications of cellular protein, lipid and DNA and consequences of oxidative modification play a crucial role in immunomodulation and trigger autoimmunity. Measurements of oxidative modified protein, lipid and DNA in biological samples from SLE patients may assist in the elucidation of the pathophysiological mechanisms of the oxidative stress-related damage, the prediction of disease prognosis and the selection of adequate treatment in the early stage of disease. Application of these biomarkers in disease may indicate the early effectiveness of the therapy. This review is intended to provide an overview of various reactive oxygen species (ROS) formed during the state of disease and their biomarkers linking with disease. The first part of the review presents biochemistry and pathophysiology of ROS and antioxidant system in disease. The second part of the review discusses the recent development of oxidative stress biomarkers that relates pathogenesis in SLE patients and animal model. Finally, this review also describes the reported clinical trials of antioxidant in the disease that have evaluated the efficacy of antioxidant in the management of disease with ongoing conventional therapy.

Molecular Cancer Research, 2014

Japanese journal of radiology, 2011

We report the case of 58-year-old man with pulmonary artery intimal sarcoma. He initially present... more We report the case of 58-year-old man with pulmonary artery intimal sarcoma. He initially presented with cough, right-sided chest pain, and shortness of breath. Although the diagnosis of pulmonary embolism had been considered, chest radiograph and pulmonary perfusion scintigraphy showed a mass in the right hilum and no perfusion in the right lung. (18)F-fluorodeoxyglucose positron emission computed tomography (FDGPET) showed increased FDG uptake in the mass obstructing the right pulmonary artery. Fine-needle biopsy revealed a pathological diagnosis of pulmonary artery intimal sarcoma. The patient was successfully treated with radiotherapy and adjuvant chemotherapy. FDG-PET was used for monitoring the response to therapy.

Japanese journal of radiology, 2009

The aim of this study was to compare the maximum-slope (MS) and dual-input one-compartment model ... more The aim of this study was to compare the maximum-slope (MS) and dual-input one-compartment model (DOCM) methods in hepatic perfusion computed tomography (CT). A total of 37 patients with known or suspected liver disease underwent single-location dynamic CT after arterial or venous bolus injection of contrast material. Perfusion CT images were created by the MS (dividing the peak gradient of the time-attenuation curve by the peak vessel CT number) and DOCM-calculating from the equation dC ( L )(t)/dt = k ( a ) C ( a )(t - tau( a )) + k ( p ) C ( p )(t - tau( p )) - k ( v ) C ( L )(t)-methods. The perfusion parameters hepatic arterial perfusion (HAP), portal venous perfusion (PVP), and hepatic perfusion index (HPI) were determined. The PVP of the tumor-free hepatic parenchyma determined by the MS method was lower than that obtained by the DOCM method (P < 0.001) with both injections. HAP determined by the MS method was lower than that obtained by the DOCM method with venous injecti...

International journal of oncology, 2008

Hepatocellular carcinoma (HCC) has variable 18F-fluoro-2-deoxy-D-glucose (18F-FDG) uptake and the... more Hepatocellular carcinoma (HCC) has variable 18F-fluoro-2-deoxy-D-glucose (18F-FDG) uptake and the relationship between 18F-FDG uptake with the expression of glucose transporters (Gluts) and hexokinase II (HK-II) has not been extensively examined. Present study explored the role of 18F-FDG positron emission tomography (PET) as a clinical significance and the association with Gluts and HK-II in patients with HCC. Whole body 18F-FDG PET, immunohistochemistry and western blot analysis of Glut-1 to Glut-5 and HK-II were performed in 31 patients (24 male and 7 female, range 48-75 years) with HCC. Significant correlation was found between 18F-FDG uptake and overall expression of Glut-2 (rho=0.55, p=0.002) and HK-II (rho=0.37, p=0.04). Expression of HK-II was correlated with Glut-2 (rho=0.57, p=0.0009) but not with other Gluts, which indicated that Glut-2 is a major glucose transporter. The prognosis of patients with SUV >/=2 and positive Glut-2 were significantly worse than that with SU...

Cancer Research, 2014

Src family kinases (SFK) integrate signal transduction for multiple receptors, regulating cellula... more Src family kinases (SFK) integrate signal transduction for multiple receptors, regulating cellular proliferation, invasion, and metastasis in human cancer. Although Src is rarely mutated in human prostate cancer, SFK activity is increased in the majority of human prostate cancers. To determine the molecular mechanisms governing prostate cancer bone metastasis, FVB murine prostate epithelium was transduced with oncogenic v-Src. The prostate cancer cell lines metastasized in FVB mice to brain and bone. Gene expression profiling of the tumors identified activation of a CCR5 signaling module when the prostate epithelial cell lines were grown in vivo versus tissue cultures. The whole body, bone, and brain metastatic prostate cancer burden was reduced by oral CCR5 antagonist. Clinical trials of CCR5 inhibitors may warrant consideration in patients with CCR5 activation in their tumors.

Scientific reports, 2015

Obesity is a risk factor for the development of acute respiratory distress syndrome (ARDS) but me... more Obesity is a risk factor for the development of acute respiratory distress syndrome (ARDS) but mechanisms mediating this association are unknown. While obesity is known to impair systemic blood vessel function, and predisposes to systemic vascular diseases, its effects on the pulmonary circulation are largely unknown. We hypothesized that the chronic low grade inflammation of obesity impairs pulmonary vascular homeostasis and primes the lung for acute injury. The lung endothelium from obese mice expressed higher levels of leukocyte adhesion markers and lower levels of cell-cell junctional proteins when compared to lean mice. We tested whether systemic factors are responsible for these alterations in the pulmonary endothelium; treatment of primary lung endothelial cells with obese serum enhanced the expression of adhesion proteins and reduced the expression of endothelial junctional proteins when compared to lean serum. Alterations in pulmonary endothelial cells observed in obese mic...

Autoimmunity - Pathogenesis, Clinical Aspects and Therapy of Specific Autoimmune Diseases, 2015

Experimental and therapeutic medicine, Sep 1, 2010

The aim of this study was to evaluate the effectiveness of oral iron to manage anemia in long-ter... more The aim of this study was to evaluate the effectiveness of oral iron to manage anemia in long-term hemodialysis (HD) patients using ultrapure dialysate. This study was prospectively conducted on 23 patients (11 males and 12 females; median age 60 years, range 35-81) who underwent HD in our hospital from March to September 2007. The patients were randomly assigned to two treatment groups. The first group of 11 patients received ferrous fumarate 305 mg per oral tablet once a day, while the second group of 12 patients received infusions of 50 mg iron in a 0.9% sodium chloride solution. At the end of the 6-month treatment, patients receiving oral iron and intravenous iron had a significant increase in transferrin saturation from baseline (20.1±8.9 to 29.7±7.2; p=0.011 and 17.4±6.1 to 33.7±8.6; p=0.0001, respectively) and ferritin (32.6±15.4 to 115.4±28.2; p=0.0001 and 57.8±26.7 to 183.5±47.5; p=0.0002, respectively). In both groups, hemoglobin, hematocrit and dry weight were increased, ...

Journal of Manmohan Memorial Institute of Health Sciences, 2014

Journal of Biomedical Science, 2014

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease whose etiology remains l... more Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease whose etiology remains largely unknown. The uncontrolled oxidative stress in SLE contributes to functional oxidative modifications of cellular protein, lipid and DNA and consequences of oxidative modification play a crucial role in immunomodulation and trigger autoimmunity. Measurements of oxidative modified protein, lipid and DNA in biological samples from SLE patients may assist in the elucidation of the pathophysiological mechanisms of the oxidative stress-related damage, the prediction of disease prognosis and the selection of adequate treatment in the early stage of disease. Application of these biomarkers in disease may indicate the early effectiveness of the therapy. This review is intended to provide an overview of various reactive oxygen species (ROS) formed during the state of disease and their biomarkers linking with disease. The first part of the review presents biochemistry and pathophysiology of ROS and antioxidant system in disease. The second part of the review discusses the recent development of oxidative stress biomarkers that relates pathogenesis in SLE patients and animal model. Finally, this review also describes the reported clinical trials of antioxidant in the disease that have evaluated the efficacy of antioxidant in the management of disease with ongoing conventional therapy.

Cancer Biotherapy and Radiopharmaceuticals, 2016

The authors have conjugated chelating agents (DOTA and NODAGA) with a peptide (pituitary adenylat... more The authors have conjugated chelating agents (DOTA and NODAGA) with a peptide (pituitary adenylate cyclase-activating peptide [PACAP] analogue) that has a high affinity for VPAC1 receptors expressed on cancer cells. To determine a suitable chelating agent for labeling with (68)Ga, they have compared the labeling kinetics and stability of these peptide conjugates. For labeling, (68)GaCl3 was eluted in 0.1 M HCl from a [(68)Ge-(68)Ga] generator. The influences of peptide concentration, pH, and temperature on the radiolabeling efficiency were studied. The stability was evaluated in saline, human serum, DTPA, transferrin, and metallic ions (FeCl3, CaCl2, and ZnCl2). Cell binding assay was performed using human breast cancer cells (T47D). Tissue biodistribution was studied in normal athymic nude mice. Optimal radiolabeling (&amp;amp;amp;amp;amp;amp;gt;95.0%) of the DOTA-peptide conjugates required a higher (50°C-90°C) temperature and 10 minutes of incubation at pH 2-5. The NODAGA-peptide conjugate needed incubation only at 25°C for 10 minutes. Both radiocomplexes were stable in saline, serum, as well as against transchelation and transmetallation. Cell binding at 37°C for 15 minutes of incubation with (68)Ga-NODAGA-peptide was 34.0% compared to 24.5% for (68)Ga-DOTA-peptide. Tissue biodistribution at 1 hour postinjection of both (68)Ga-labeled peptide conjugates showed clearance through the kidneys. NODAGA-peptide showed more convenient radiolabeling features than that of DOTA-peptide.

Cancer Sci, 2009

Non-small cell lung carcinomas (NSCLC) overexpress the Her2/ /neu gene in approximately 59% of ca... more Non-small cell lung carcinomas (NSCLC) overexpress the Her2/ /neu gene in approximately 59% of cases. Trastuzumab, a humanized monoclonal antibody, interferes with Her2 signaling and is approved for the treatment of Her2/ /neu overexpressing breast cancer. However, its therapeutic use in Her2/ /neu overexpressing NSCLC remains obscure. The present study aimed to determine the role of 64 Cu-labeled trastuzumab positron emission tomography (PET) for non-invasive imaging of Her2/ /neu expression in NSCLC. Trastuzumab was conjugated with the bifunctional chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) and radiolabeled with 64 Cu. The molecular specificity of DOTA-trastuzumab was determined in NSCLC cell lines with Her2/ /neu overexpression (NCI-H2170) and negative expression (NCI-H520). Imaging of Her2/ /neu expression was performed in NCI-H2170 tumor-bearing mice with 64 Cu-DOTA-trastuzumab PET and 64 Cu-DOTA-IgG. In vitro studies revealed specific binding of DOTA-trastuzumab in the Her2/ /neu positive NCI-H2170 cells, while no binding was seen in the Her2/ /neu negative NCI-H520 cell line. Biodistribution and PET studies revealed a significantly high accumulation of 64 Cu-DOTA-trastuzumab in the Her2/ /neu overexpressing NCI-H2170 tumor at 24 and 48 h post-injection (21.4 ± 1.4% and 23.2 ± 5.1% injection dose/ /gram (% ID/g), respectively). PET imaging of Her2/ / neu negative NCI-H520 tumors showed much less uptake of 64 Cu-DOTA-trastuzumab (4.0% ID/g). The NCI-H2170 tumor uptake of 64 Cu-DOTA-trastuzumab was significantly higher than that of 64 Cu-DOTA-IgG (P < 0.0001). 64 Cu-DOTA-trastuzumab showed a very clear image of a Her2/ /neu positive tumor and appeared to be effective as a PET tracer for imaging of Her2/neu gene expression in NSCLC, suggesting its potential clinical use for identifying patients that might benefit from trastuzumab-based therapy. (Cancer Sci 2010; 101: 1045-1050 L ung cancer is one of the world's leading causes of death, with a 5-year survival rate of less than 10%. (1) Activation of ras genes and human epidermal growth factor receptor 2 (Her2/neu) genes is encountered in subpopulations of non-small cell lung carcinoma (NSCLC) patients and has been linked to shortened survival. Overexpression of the Her2/neu gene is closely associated with intrinsic multiple drug resistance in NSCLC cell lines. (2) Her2/neu is a transmembrane tyrosine kinase belonging to the surface receptor family. It does not bind ligand but instead acts as a preferred heterodimerization partner for ligand-activated sibling members to amplify mitotic signaling. (3) Trastuzumab, a humanized monoclonal antibody that targets Her2/neu, inhibits neoplastic cell proliferation both in vitro and in vivo. (4) In breast cancer, overexpression of Her2/neu is seen in 40% of cases, and its activation follows heterodimerization with a member of the EGFR family and triggers important biological effects such as proliferation, migration and differenti-ation. (5) Trastuzumab significantly increases the survival of patients with advanced metastatic breast cancer. Overexpression of Her2/neu is reported in up to 59% of cases of NSCLC and the 2+/3+ overexpression rate is 5-20% in adenocarcinomas. (8-10) As in breast cancer, studies have suggested that the overexpression of Her2/neu in NSCLC is associated with a worse prognosis than negative expression of Her2/ neu. The role of trastuzumab targeting Her2/neu expression in the NSCLC has been largely marginalized. Even though NSCLC is usually chemoresistant, the synergistic effect between trastuzumab and chemotherapeutic agents was found to be greater in Her2/neu positive NSCLC than in breast cancer cell lines. NSCLC patients with Her2/neu overexpression (3+) in immunohistochemistry (IHC) had better survival when treated with trastuzumab-based therapy than the overall population, but only a small percentage of patients benefited. (10) The marked variation in functional anatomy and pathophysiology within human tumors and within individual patients may account for the high variability of responses observed in patients.

Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2013

Jpn J Radiol, 2009

The aim of this study was to compare the maximum-slope (MS) and dual-input one-compartment model ... more The aim of this study was to compare the maximum-slope (MS) and dual-input one-compartment model (DOCM) methods in hepatic perfusion computed tomography (CT). A total of 37 patients with known or suspected liver disease underwent single-location dynamic CT after arterial or venous bolus injection of contrast material. Perfusion CT images were created by the MS (dividing the peak gradient of the time-attenuation curve by the peak vessel CT number) and DOCM-calculating from the equation dC ( L )(t)/dt = k ( a ) C ( a )(t - tau( a )) + k ( p ) C ( p )(t - tau( p )) - k ( v ) C ( L )(t)-methods. The perfusion parameters hepatic arterial perfusion (HAP), portal venous perfusion (PVP), and hepatic perfusion index (HPI) were determined. The PVP of the tumor-free hepatic parenchyma determined by the MS method was lower than that obtained by the DOCM method (P &amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) with both injections. HAP determined by the MS method was lower than that obtained by the DOCM method with venous injection (P = 0.001), although there was no difference between the methods for HAP with arterial injection (P = 0.154). Most of the perfusion parameters showed linear correlations between the two analytical methods. Except for HAP with arterial injection, the perfusion parameters obtained with the MS method were lower than those obtained with the DOCM method.

Cancer Science, Jan 10, 2011

Vascular endothelial growth factor (VEGF) is considered to be a major angiogenic factor responsib... more Vascular endothelial growth factor (VEGF) is considered to be a major angiogenic factor responsible for the development of tumor vasculature. The aim of this study was to image VEGF expression with 64 Cu-labeled anti-VEGF antibody (bevacizumab) non-invasively, and to see whether or not the expression was correlated with tumor accumulation in colorectal cancer xenografts. Bevacizumab was conjugated with the bifunctional chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) and radiolabeled with 64 Cu. In vivo biodistribution studies and positron emission tomography (PET) imaging were performed on mice bearing human colorectal cancer (HT29) xenografts after injection of 64 Cu-DOTA-bevacizumab, which showed clear accumulation of 64 Cu-DOTA-bevacizumab in the tumor (22.7 ± 1.0 %ID ⁄ g, 24 ± 0.2 %ID ⁄ g, 19.0 ± 2.5 %ID ⁄ g at 24, 48 and 72 h, respectively). Tumor accumulation of 64 Cu-DOTA-bevacizumab was significantly correlated with VEGF expression as measured by western blot (q = 0.81, P = 0.004). Vascular endothelial growth factor blocking with unlabeled bevacizumab significantly reduced tumor accumulation of 64 Cu-DOTA-bevacizumab (9.7 ± 1.2 %ID ⁄ g, P < 0.001) at 48 h. Interestingly, the blood concentration of VEGF in the mice treated with excess fold of bevacizumab was significantly higher than those without at 48 h (25.5 ± 4.6 %ID ⁄ g vs 6.5 ± 2.1 %ID ⁄ g, P = 0.0016). Liver uptake decreased from 24 h (17.2 ± 1.7 %ID ⁄ g) to 48 h (13.0 ± 4.2 %ID ⁄ g) and 72 h (10.6 ± 1.5 %ID ⁄ g) due to hepatic clearance of the tracer. The present study successfully showed 64 Cu-DOTA-bevacizumab as a potential PET tracer for noninvasive imaging of VEGF expression in colorectal cancer xenografts. (Cancer Sci 2011; 102: 117-121) V ascular endothelial growth factor (VEGF) is considered to be a major angiogenic factor responsible for the development of the tumor vasculature network having leaky blood vessels and insufficient blood flow and high interstitial blood pressure. Because almost all kinds of tumor progression is dependent on angiogenesis, it has gained a lot of interest among scientists to search for antiangiogenic molecules and to design antiangiogenic strategies for cancer treatment and the prevention of cancer recurrence or metastasis. Bevacizumab, a humanized monoclonal antibody, binds to all VEGF isoforms and thereby prevents interaction with its receptor tyrosine kinase VEGFR-1 and VEGFR-2, thus blocking VEGF-induced endothelial cell proliferation, permeability, survival and growth. In animal models, administration of bevacizumab blocked the growth of human tumor xenografts and reduced the size and number of metastases. (6) Hurwitz et al. found that adding bevacizumab in combination with chemotherapy improved survival and produced consistent results across all patient subgroups with metastatic colorectal cancer (mCRC). Kabbinavar et al. (8) conducted a randomized phase II trial com-paring bevacizumab in combination with chemotherapy versus chemotherapy alone in mCRC patients. Those receiving bevacizumab in combination with chemotherapy experienced a higher response rate, longer median time to disease progression, and longer median survival time. A subsequent randomized, phase II trial involving 209 patients confirmed the clinical efficacy of first-line bevacizumab in mCRC. Despite these promising results of bevacizumab-based therapy, selection of the right patients for bevacizumab-based treatment is a vital criterion; therefore, there is a need to monitor in vivo VEGF downregulation as an immediate response to bevacizumab-based therapy. Imaging of VEGF is more challenging than imaging VEGF receptors because of its complex and dynamic nature. In recent studies, VEGF expression has been non-invasively investigated with radiolabeled bevacizumab in ovarian cancer models, (10) colon cancer models and in 12 patients with liver metastasis (12) using single photon emission computed tomography (SPECT) or positron emission tomography (PET). The results are very promising and pave a new road to non-invasive imaging of VEGF. 64

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease whose etiology remains l... more Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease whose etiology remains largely unknown. The uncontrolled oxidative stress in SLE contributes to functional oxidative modifications of cellular protein, lipid and DNA and consequences of oxidative modification play a crucial role in immunomodulation and trigger autoimmunity. Measurements of oxidative modified protein, lipid and DNA in biological samples from SLE patients may assist in the elucidation of the pathophysiological mechanisms of the oxidative stress-related damage, the prediction of disease prognosis and the selection of adequate treatment in the early stage of disease. Application of these biomarkers in disease may indicate the early effectiveness of the therapy. This review is intended to provide an overview of various reactive oxygen species (ROS) formed during the state of disease and their biomarkers linking with disease. The first part of the review presents biochemistry and pathophysiology of ROS and antioxidant system in disease. The second part of the review discusses the recent development of oxidative stress biomarkers that relates pathogenesis in SLE patients and animal model. Finally, this review also describes the reported clinical trials of antioxidant in the disease that have evaluated the efficacy of antioxidant in the management of disease with ongoing conventional therapy.

Molecular Cancer Research, 2014

Japanese journal of radiology, 2011

We report the case of 58-year-old man with pulmonary artery intimal sarcoma. He initially present... more We report the case of 58-year-old man with pulmonary artery intimal sarcoma. He initially presented with cough, right-sided chest pain, and shortness of breath. Although the diagnosis of pulmonary embolism had been considered, chest radiograph and pulmonary perfusion scintigraphy showed a mass in the right hilum and no perfusion in the right lung. (18)F-fluorodeoxyglucose positron emission computed tomography (FDGPET) showed increased FDG uptake in the mass obstructing the right pulmonary artery. Fine-needle biopsy revealed a pathological diagnosis of pulmonary artery intimal sarcoma. The patient was successfully treated with radiotherapy and adjuvant chemotherapy. FDG-PET was used for monitoring the response to therapy.

Japanese journal of radiology, 2009

The aim of this study was to compare the maximum-slope (MS) and dual-input one-compartment model ... more The aim of this study was to compare the maximum-slope (MS) and dual-input one-compartment model (DOCM) methods in hepatic perfusion computed tomography (CT). A total of 37 patients with known or suspected liver disease underwent single-location dynamic CT after arterial or venous bolus injection of contrast material. Perfusion CT images were created by the MS (dividing the peak gradient of the time-attenuation curve by the peak vessel CT number) and DOCM-calculating from the equation dC ( L )(t)/dt = k ( a ) C ( a )(t - tau( a )) + k ( p ) C ( p )(t - tau( p )) - k ( v ) C ( L )(t)-methods. The perfusion parameters hepatic arterial perfusion (HAP), portal venous perfusion (PVP), and hepatic perfusion index (HPI) were determined. The PVP of the tumor-free hepatic parenchyma determined by the MS method was lower than that obtained by the DOCM method (P < 0.001) with both injections. HAP determined by the MS method was lower than that obtained by the DOCM method with venous injecti...

International journal of oncology, 2008

Hepatocellular carcinoma (HCC) has variable 18F-fluoro-2-deoxy-D-glucose (18F-FDG) uptake and the... more Hepatocellular carcinoma (HCC) has variable 18F-fluoro-2-deoxy-D-glucose (18F-FDG) uptake and the relationship between 18F-FDG uptake with the expression of glucose transporters (Gluts) and hexokinase II (HK-II) has not been extensively examined. Present study explored the role of 18F-FDG positron emission tomography (PET) as a clinical significance and the association with Gluts and HK-II in patients with HCC. Whole body 18F-FDG PET, immunohistochemistry and western blot analysis of Glut-1 to Glut-5 and HK-II were performed in 31 patients (24 male and 7 female, range 48-75 years) with HCC. Significant correlation was found between 18F-FDG uptake and overall expression of Glut-2 (rho=0.55, p=0.002) and HK-II (rho=0.37, p=0.04). Expression of HK-II was correlated with Glut-2 (rho=0.57, p=0.0009) but not with other Gluts, which indicated that Glut-2 is a major glucose transporter. The prognosis of patients with SUV >/=2 and positive Glut-2 were significantly worse than that with SU...

Cancer Research, 2014

Src family kinases (SFK) integrate signal transduction for multiple receptors, regulating cellula... more Src family kinases (SFK) integrate signal transduction for multiple receptors, regulating cellular proliferation, invasion, and metastasis in human cancer. Although Src is rarely mutated in human prostate cancer, SFK activity is increased in the majority of human prostate cancers. To determine the molecular mechanisms governing prostate cancer bone metastasis, FVB murine prostate epithelium was transduced with oncogenic v-Src. The prostate cancer cell lines metastasized in FVB mice to brain and bone. Gene expression profiling of the tumors identified activation of a CCR5 signaling module when the prostate epithelial cell lines were grown in vivo versus tissue cultures. The whole body, bone, and brain metastatic prostate cancer burden was reduced by oral CCR5 antagonist. Clinical trials of CCR5 inhibitors may warrant consideration in patients with CCR5 activation in their tumors.