Bishnuhari Paudyal

Oxidative stress and its biomarkers in systemic lupus erythematosus.

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.

Positron emission tomography imaging and biodistribution of vascular endothelial growth factor with 64Cu-labeled bevacizumab in colorectal cancer xenografts.

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 64Cu‐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 64Cu. In vivo biodistribution studies and positron emission tomography (PET) imaging were performed on mice bearing human colorectal cancer (HT29) xenografts after injection of 64Cu‐DOTA‐bevacizumab, which showed clear accumulation of 64Cu‐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 64Cu‐DOTA‐bevacizumab was significantly correlated with VEGF expression as measured by western blot (ρ = 0.81, P = 0.004). Vascular endothelial growth factor blocking with unlabeled bevacizumab significantly reduced tumor accumulation of 64Cu‐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 64Cu‐DOTA‐bevacizumab as a potential PET tracer for non‐invasive imaging of VEGF expression in colorectal cancer xenografts. (Cancer Sci 2011; 102: 117–121)

Expression of glucose transporters and hexokinase II in cholangiocellular carcinoma compared using [18F]-2-fluro-2-deoxy-D-glucose positron emission tomography.

Cholangiocellular carcinoma (CCC) has been reported to have a high glucose uptake; however, the mechanism of glucose entry into these cells is still unclear. We investigated the relationship between [18F]‐2‐fluro‐2‐deoxy‐d‐glucose (18F‐FDG) uptake and the expression of facilitative glucose transporters (Glut) and hexokinase (HK) II, as well as the association between the expression of different histological types of CCC. The expression of Glut (1–5) and HK II was studied using immunohistochemistry of 26 patients with CCC who underwent whole‐body 18F‐FDG positron emission tomography before surgery or biopsy. CCC expressed immunohistochemically detectable Glut 1 in 81%, Glut 2 in 54%, Glut 3 in 19%, and HK II in 77% of the total cases. Glut 1, Glut 2, Glut 3, and HK II were more often detected in moderately differentiated and poorly differentiated than in well‐differentiated CCC. A significant correlation was observed between 18F‐FDG uptake and the staining scores of Glut 1 and HK II (P = 0.02, ρ = 0.45 and P = 0.001, ρ = 0.59). The staining scores of Glut 1 and HK II were also significantly correlated (P = 0.002, ρ = 0.3). Multivariate regression analysis revealed that lymph‐node metastasis was independently associated with 18F‐FDG uptake. Our study showed a significant association between the expression of Glut 1 and HK II with 18F‐FDG uptake, indicating that Glut 1 is a major glucose transporter expressed in CCC and that HK II contributes to the increased metabolism of glucose, especially in moderately and poorly differentiated CCC. (Cancer Sci 2008; 99: 260–266)

Diagnosis of maxillofacial tumor withl-3-[18F]-fluoro-α-methyltyrosine (FMT) PET: a comparative study with FDG-PET

Objectives: To comparel-3-[18F]-fluoro-α-methyltyrosine (FMT)-positron emission tomography (PET) and 2-[18F]-fluoro-2-deoxy-d-glucose (FDG)-PET in the differential diagnosis of maxillofacial tumors.Methods: This study included 36 patients (16 males, 20 females; 31–90 years old) with untreated malignant tumors (34 squamous cell carcinoma, one mucoepidermoid carcinoma, one rhabdomyosarcoma) and seven patients (five males, two females; 32–81 years old) with benign lesions. In all patients, both FMT-PET and FDG-PET were performed within two weeks before biopsy or treatment of the lesions. To evaluate the diagnostic usefulness of FMT-PET and FDG-PET, visual interpretation and semiquantitative analysis were performed. PET images were rated according to the contrast of tumor uptake as compared with background, and were statistically analyzed. As a semiquantitative analysis, standardized uptake values (SUV) of the primary tumors were measured, and the SUV data were analyzed using receiver operating characteristic (ROC) curves.Results: The mean SUV of the malignant lesions were significantly higher than those of the benign lesions in both FMT-PET (2.62±1.58 vs. 1.20±0.30, p<0.01) and FDG-PET (9.17±5.06 vs. 3.14±1.34, p<0.01). A positive correlation (r=0.567, p<0.0001, n=46) was noted between FMT and FDG. ROC analysis revealed that there was no statistically significant difference in SUVs between FMT and FDG for differentiating malignant tumors. In 27 of 36 patients, FMT-PET had better contrast of malignant tumor visualization to the surrounding normal structures by visual assessment (p<0.005, binomial proportion test).Conclusions: Differential diagnosis of FMT-PET based on the uptake in maxillofacial tumors is equivalent to FDG-PET. However, the contrast of FMT uptake between maxillofacial tumors and the surrounding normal structures is higher than that of FDG, indicating the possibility of accurate diagnosis of maxillofacial tumors by FMT-PET.

Obesity-induced adipokine imbalance impairs mouse pulmonary vascular endothelial function and primes the lung for injury

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 mice were associated with enhanced susceptibility to LPS-induced lung injury. Restoring serum adiponectin levels reversed the effects of obesity on the lung endothelium and attenuated susceptibility to acute injury. Our work indicates that obesity impairs pulmonary vascular homeostasis and enhances susceptibility to acute injury and provides mechanistic insight into the increased prevalence of ARDS in obese humans.

Imaging and biodistribution of Her2/neu expression in non-small cell lung cancer xenografts with 64Cu-labeled trastuzumab PET

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 64Cu‐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 64Cu. 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 64Cu‐DOTA‐trastuzumab PET and 64Cu‐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 64Cu‐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 64Cu‐DOTA‐trastuzumab (4.0% ID/g). The NCI‐H2170 tumor uptake of 64Cu‐DOTA‐trastuzumab was significantly higher than that of 64Cu‐DOTA‐IgG (P < 0.0001). 64Cu‐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.

Clinicopathological presentation of varying 18F-FDG uptake and expression of glucose transporter 1 and hexokinase II in cases of hepatocellular carcinoma and cholangiocellular carcinoma

We report the results of 18F-fluorodeoxyglucose positron emission tomography (FDG PET) and immunohistochemical staining of glucose transporter 1 (Glut-1) and hexokinase II (HK-II) in patients with hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) to observe the variation in 18F-FDG uptake and variation in expression of Glut-1 and HK-II in these hepatic tumors. In the case of HCC, moderate 18F-FDG uptake and strong expression of HK-II were detected, whereas Glut-1 was not expressed. Conversely, CCC showed high 18F-FDG uptake and increased expression of Glut-1 but HK-II was not expressed. The variation in the 18F-FDG uptake and expression of Glut 1 and HK-II in HCC and CCC might be owing to the difference in origin and the different mechanisms involved in glucose uptake, rate of glucose transporters, and hexokinase activity involved in the glycolytic pathway.

Quantification of hepatic arterial and portal perfusion with dynamic computed tomography: comparison of maximum-slope and dual-input one-compartment model methods

PurposeThe 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).Materials and methodsA 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 dCL(t)/dt = kaCa(t − τa) + kpCp(t − τp) − kvCL(t)—methods. The perfusion parameters hepatic arterial perfusion (HAP), portal venous perfusion (PVP), and hepatic perfusion index (HPI) were determined.ResultsThe 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 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.ConclusionExcept for HAP with arterial injection, the perfusion parameters obtained with the MS method were lower than those obtained with the DOCM method.

CCR5 Receptor Antagonists Block Metastasis to Bone of v-Src Oncogene–Transformed Metastatic Prostate Cancer Cell Lines

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.

Pulmonary artery intimal sarcoma: the role of 18 F-fluorodeoxyglucose positron emission tomography in monitoring response to treatment

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. 18F-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.