Rajiv Kumar Jha

Review of therapeutic strategies for osteosarcoma, chondrosarcoma, and Ewing’s sarcoma

Summary The most prevalent forms of bone cancer are osteosarcoma, chondrosarcoma, and Ewing’s sarcoma. Although chemotherapy and radiotherapy have replaced traditional surgical treatments, survival rates have undergone only marginal improvements. Current knowledge of the molecular pathways involved in each type of cancer has led to better approaches in cancer treatment. A number of cell signaling molecules are involved in tumorigenesis, and specific targets have been identified based on these signal transducers. This review highlights some of the important cellular pathways and potential therapeutic targets, tumor site-specific irradiation techniques, and novel drug delivery systems used to administer these drugs.

Resveratrol ameliorates hepatic injury via the mitochondrial pathway in rats with severe acute pancreatitis

To gain insight into the processes by which severe acute pancreatitis induced apoptosis takes place in the liver, and to observe the protective effect of resveratrol on hepatic injury, a rat model of severe acute pancreatitis was induced by administering 4% sodium taurocholate through the common biliopancreatic duct. Pancreatic and hepatic injury was assessed by histology. Serum ALT (alanine aminotransferase), AST (aspartate aminotransferase) and total bilirubin were determined by reaction rate assay, and the serum levels of TNF-alpha (tumor necrosis factor-alpha) and IL-6 (interleukin-6) were detected by ELISA (enzyme linked immunosorbent assay). We investigated cytochrome c released from mitochondria and used the RT-PCR (reverse transcription PCR), Western blot technique to evaluate Bax, Bcl-2, and caspase-3 expression levels in hepatic tissue over the time course of apoptosis. Changes in hepatic cell mitochondrial membrane potential were observed by confocal laser scanning microscopy. The majority of cytochrome c release occurred early in apoptosis from mitochondria, which undergo gradual hepatic impairment. The released cytochrome c can be reduced by resveratrol through both up-regulation of Bcl-2 and down-regulation of Bax and caspase-3. These data provide substantial evidence that apoptosis is involved in hepatic injury during the severe acute pancreatitis process and that resveratrol can ameliorate the situation, thus protecting liver function in rats with severe acute pancreatitis.

Current status of percutaneous vertebroplasty and percutaneous kyphoplasty – a review

Percutaneous vertebroplasty (PV) and kyphoplasty (PK) are the 2 vertebral augmentation procedures that have emerged as minimally invasive surgical options to treat painful vertebral compression fractures (VCF) during the last 2 decades. VCF may either be osteoporotic or tumor-associated. Two hundred million women are affected by osteoporosis globally. Vertebral fracture may result in acute pain around the fracture site, loss of vertebral height due to vertebral collapse, spinal instability, and kyphotic deformity. The main goal of the PV and PK procedures is to give immediate pain relief to patients and restore the vertebral height lost due to fracture. In percutaneous vertebroplasty, bone cement is injected through a minimal incision into the fractured site. Kyphoplasty involves insertion of a balloon into the fractured site, followed by inflation-deflation to create a cavity into which the filler material is injected, and the balloon is taken out prior to cement injection. This literature review presents a qualitative overview on the current status of vertebral augmentation procedures, especially PV and PK, and compares the efficacy and safety of these 2 procedures. The review consists of a brief history of the development of these 2 techniques, a discussion on the current research on the bone cement, clinical outcome of the 2 procedures, and it also sheds light on ongoing and future research to maximize the efficacy and safety of vertebral augmentation procedures.

RESVERATROL AMELIORATES LUNG INJURY VIA INHIBITION OF APOPTOSIS IN RATS WITH SEVERE ACUTE PANCREATITIS

The objective of this study was to evaluate the protective effects of resveratrol on lung injury in rats with severe acute pancreatitis. Ninety-six male Sprague-Dawley rats were randomly classified into 4 equal groups (n = 24): control, model, resveratrol-treated, and dexamethasone-treated. The rats were evaluated at 3, 6, and 12 hours after induction of pancreatitis. The following were assessed: PaO2by arterial blood gas analysis; pancreatic and lung injury by histology; and ultrastructure of lung tissue by transmission electron microscopy. The authors investigated mitochondrial cytochrome c release and evaluated the Bax, Bcl-2, and caspase-3 expression levels in lung tissue over the time course of apoptosis. Changes in lung cell mitochondrial membrane potential were evaluated by confocal laser scanning microscopy. In the model group, lung congestion, edema, inflammatory-cell infiltration, mitochondrial swelling, and cell apoptosis were apparent. In the resveratrol and dexamethasone groups, the morphological changes of the lungs were alleviated. The expression level of Bcl-2 was significantly higher and those of Bax, caspase-3, and cytochrome c were significantly lesser in the resveratrol group than in the model group. Apoptosis is involved in lung injury associated with severe acute pancreatitis, and resveratrol can ameliorate this injury, thus protecting lung function in rats with severe acute pancreatitis.

Trypsin is the culprit of multiple organ injury with severe acute pancreatitis

The consistently high proportion of early deaths in patients with severe acute pancreatitis (SAP) has been associated mainly with the development of multiple organ dysfunction syndromes (MODS). So far, scholars believed that the main reasons of MODS with SAP are systemic microcirculation dysfunction and inflammatory mediator induced cascading effect on the basis of pancreas digesting itself. However, there is some special pathological phenomenon in the process of SAP which could not be explained by current theories. First, it has been evident that the pancreatic tissue bleeding and necrosis is special pathological change in pancreas autodigestive effect from digestive enzymes such as trypsin in SAP. However, we found that the liver, the lung, the intestine, the brain and the kidney have the same pathological changes in experimental animal models of SAP. Secondly, unlike the general inflammatory response, a significantly amount of bloody ascites and pleural effusion was often in patients with SAP and in experimental SAP animal models. It indicates that the vascular permeability significantly increased leading to the red blood cells extravasation. Thirdly, apart from dual blood supply, liver bears a strong compensatory function. However, liver has the highest incidence of injury in SAP when compared with other organs. In addition, we found a very interesting phenomenon after reading texts and clinical records. From the pancreatic venous drainage from the point of view, the farther the organ from the pancreas, the lower injury incidence rate observed. How to explain these mysteries? We postulate that the trypsin is the culprit of multiple organs dysfunction in SAP. The activated trypsin destroy the pancreas itself, causing pancreatic tissue bleeding and necrosis, at the same time, through venous flow it flow into the blood circulation and destroy the vascular endothelial barrier, leading to highly increased vascular permeability. So, a large number of bloody exudates leakages from the vessels, resulting in patients early circulatory disorders, multiple organ bleeding, bloody pleural effusion and ascites. This pathological change is the most apparent in the liver because the liver is the first organ to receive the pancreatic venous flow having the highest concentration of trypsin. Thus, if the quantity of trypsin decreases in blood, its ability to damage other organs also shows a trend of gradually reducing. These mysteries can be explained by this hypothesis and might help us to understand more clearly about the mechanism of SAP-associated MODS.

Protective effect of resveratrol in severe acute pancreatitis-induced brain injury.

Objectives: The aim of this study was to study the effects of resveratrol on severe acute pancreatitis (SAP)-induced brain injury. Methods: Ninety-six male Sprague-Dawley rats were randomly divided into 4 equal groups: sham operation, SAP, resveratrol-treated (RES), and dexamethasone-treated. Each group was evaluated at 3, 6, and 12 hours. Levels of serum myelin basic protein and zonula occludens 1 (Zo-1) were determined by enzyme-linked immunosorbent assay. The brain and pancreatic tissues were examined using electron microscopy. Expressions of Bax, Bcl-2, and caspase-3 were observed using immunohistochemistry, reverse transcriptase polymerase chain reaction, and Western blotting. Cytochrome c was detected using Western blotting alone. Results: Myelin basic protein and Zo-1 levels of the RES group were lower than the SAP group at all time points (P < 0.05). The RES group had significantly improved pathologic brain, increase in Bcl-2 expression, and decrease in Bax and caspases-3 expressions compared with the SAP group. Conclusions: The degradation of Zo-1 is involved in the pathophysiology of brain injury in SAP; MBP can be used as a marker of brain injury in SAP. The protective effect of resveratrol might be associated with the up-regulation of Bcl-2 and down-regulation of Bax and caspase-3.

Advances in diagnosis and treatment of hilar cholangiocarcinoma -- a review.

Hilar cholangiocarcinoma (HC) is a rare tumor that causes devastating disease. In the late stages, this carcinoma primarily invades the portal vein and metastasizes to the hepatic lobes; it is associated with a poor prognosis. HC is diagnosed by its clinical manifestation and results of imaging techniques such as ultrasound, computed tomography, magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiography, and percutaneous transhepatic cholangiography. Preoperative hepatic bile drainage can improve symptoms associated with insufficient liver and kidney function, coagulopathy, and jaundice. Surgical margin-negative (R0) resection, including major liver resection, is the most effective and potentially curative treatment for HC. If the tumor is not resected, then liver transplantation with adjuvant management can improve survival. We conducted a systematic review of developments in imaging studies and major surgical hepatectomy for HC with positive outcomes regarding quality of life.

Elevated expression of adrenomedullin is correlated with prognosis and disease severity in osteosarcoma

The treatment for osteosarcoma is a formidable challenge. Currently, treatment is not sufficiently effective, and new therapeutic targets are urgently needed. The aim of this study is to determine the expression of adrenomedullin (ADM) in human osteosarcoma tissue and to assess its effect on the proliferation of MG-63 cells and in vivo in an animal model of osteosarcoma. First, we collected clinical specimens from osteosarcoma patients and healthy controls and measured ADM expression by immunohistochemistry, RT-PCR, and radioimmunoassay. We also analyzed clinical data to investigate the relationship between ADM expression, malignancy, and tumor prognosis. Based on these data, we used RNA interference (RNAi) against ADM delivered by lentivirus vector transfected into the osteosarcoma cell line MG-63 to downregulate the expression of ADM. Finally, we observed the effect of ADM on the proliferation of MG-63 cells in vitro, and in vivo, in an animal model of osteosarcoma. We found that ADM was overexpressed in human osteosarcoma tissue, whereas expression was low in the adjacent tissue and little expression was observed in normal tissue. ADM RNAi significantly inhibited the proliferation of MG-63 cells. Therefore, the growth of osteosarcoma could be inhibited by decreasing the expression of ADM. Thus, we conclude that ADM expression is highly correlated with the degree of malignancy and metastasis of osteosarcoma.

Changes in portal hemodynamics after TIPS in liver cirrhosis and portal hypertension.

Abstract Objective. The objective of this study is to analyze the changes in portal hemodynamics that occurs in portal hypertension before and after transjugular intrahepatic portosystemic shunt (TIPS), to investigate the relationship between these changes and portal pressure (PP) and to determine the significance of sonographic parameters in measuring PP. Methods. Ultrasonography of the portal and splenic veins and direct measurement of the PP were performed in 92 patients before and after TIPS. The differences observed in the portal and splenic vein diameters, the blood flow velocity in the portal and splenic veins and the PP were measured, and the correlations between PP and the other parameters were assessed using the SPSS 13 (SPSS Inc., Chicago, IL, USA). P < 0.05 was considered statistically significant. Results. We observed a significant decrease in the PP and the diameters of the portal and splenic veins compared to preoperative conditions (p < 0.001). The velocity of blood flow in the portal and splenic veins was significantly increased after TIPS (p < 0.001). The PP correlated with the diameter and velocity of blood flow in portal (r = 0.46, p = 0.020; r = 0.47, p = 0.017) and splenic vein (r = 0.57, p = 0.003; r = 0.33, p = 0.003) only in Childs A and was absent in Childs B cirrhosis patients. Conclusion. The PP is influenced by the complex interaction between intrahepatic vascular resistance, collaterals and the amount of portal blood flow, which varies considerably between individuals. Once a certain pressure threshold is reached, collaterals form, and the correlation between the ultrasonographic parameters and PP becomes limited.

Relationship of Fibronectin and CD44v6 Expression with Invasive Growth and Metastasis of Liver Cancer

Fibronectin and CD44v6 are involved in tumor invasion and metastasis. We examined fibronectin and CD44v6 expression in normal liver and liver cancer by immunohistochemistry. Fibronectin expression was identified in 37.5% of liver cancer specimens. Well-differentiated tumors and expansive growth were associated with continuous periacinar, or cytoplasmic and periacinar fibronectin expression; poorly differentiated and invasive tumors showed interrupted periacinar or vascular mesenchymal fibronectin expression. CD44v6 expression was absent in controls but was observed in 67.5% of liver cancers. Increased CD44v6 expression was more common with poor clinical tumor characteristics. FN and CD44v6 are potential markers for determining liver cancer invasion and metastasis.