Renovascular hypertension

Renovascular disease is one of the most common causes of secondary hypertension. Recent technical advances have changed the management principles, which include a more aggressive approach to the diagnosis and treatment of renovascular hypertension (RVH). We experienced a total of 95 cases with RVH between 1958 and 1999. The mean age of all patients was 31.8 years old, ranging from 3 to 64 years. The three major basal diseases that caused RVH were fibromuscular dysplasia (34/95), arteriosclerosis (26/95), and aortitis (12/95). Ninety-two kidneys were treated in 79 of the 95 patients. The major therapeutic modalities performed were reconstruction of renal artery (6/79), nephrectomy (21/79), autotransplantation (26/79), and percutaneous transluminal angioplasty (PTA) (25/79). PTA is now the treatment of choice for the initial management of patients with RVH. Surgical treatment is generally reserved for patients in whom PTA fails. Pharmacotherapy is used on patients awaiting angioplasty or revascularization, those who are too ill for intervention, and those who have failed to respond to intervention.     

Clinical scale electroloading of mature dendritic cells with melanoma whole tumor cell lysate is superior to conventional lysate co-incubation in triggering robust in vitro expansion of functional antigen-specific CTL

Recent commercial approval of cancer vaccine, demonstrating statistically significant improvement in overall survival of prostate cancer patients has spurred renewed interest in active immunotherapies; specifically, strategies that lead to enhanced biological activity and robust efficacy for dendritic cell vaccines. A simple, widely used approach to generating multivalent cancer vaccines is to load tumor whole cell lysates into dendritic cells (DCs). Current DC vaccine manufacturing processes require co-incubation of tumor lysate antigens with immature DCs and their subsequent maturation. We compared electroloading of tumor cell lysates directly into mature DCs with the traditional method of lysate co-incubation with immature DCs. Electroloaded mature DCs were more potent in vitro, as judged by their ability to elicit significantly (p < 0.05) greater expansion of peptide antigen-specific CD8⁺ T cells, than either lysate-electroloaded immature DCs or lysate-co-incubated immature DCs, both of which must be subsequently matured. Expanded CD8⁺ T cells were functional as judged by their ability to produce IFN-γ upon antigen-specific re-stimulation. The electroloading technology used herein is an automated, scalable, functionally closed cGMP-compliant manufacturing technology supported by a Master File at CBER, FDA and represents an opportunity for translation of enhanced potency DC vaccines at clinical/commercial scale.     

Blockade of Rho/Rho-associated coiled coil-forming kinase signaling can prevent progression of hepatocellular carcinoma in matrix metalloproteinase-dependent manner

Aim:  There is growing evidence that the Rho/Rho-associated coiled coil-forming kinase (ROCK) signaling pathway is upregulated in tumors and plays a key role in cancer invasion and metastasis. Our aim was to test the anticancer effects of Rho/ROCK inhibitor, Y-27632, including possible mechanisms in a highly-metastasizing hepatocellular carcinoma (HCC) mouse model on its secretion of matrix metalloproteinase (MMP) and tumor progression.
Methods:  Following orthotopic implantation of CBO140C12 HCC tumor fragments into the liver of mice, the mice were randomly assigned to a Y-27632-treated group or control group. After treatment for 4 weeks, specimens were obtained to evaluate tumor size, metastases, and immunohistochemical findings. In vitro , we examined the effects of Y-27632 and RhoC siRNA on MMP-2 and -9 expressions, invasiveness, and apoptosis in cultured tumor cells.
Results:  Both RhoA and RhoC were upregulated in HCC-bearing livers, and Y-27632 significantly inhibited not only tumor growth and intrahepatic metastasis ( P  < 0.05), but also tumoral MMP-9 expression. Moreover, Y-27632 treatment resulted in large necrotic areas in tumors. In vitro , Y-27632 and RhoC siRNA reduced MMP-2 and -9 expressions, as well as the chemotactic migration of tumor cells dose-dependently, and increased apoptosis eight times.
Conclusion:  Y-27632 suppresses progression and limits the intrahepatic metastasis of established HCC. This could be linked to the decreased MMP expression and induction of apoptosis in tumor cells. Rho signaling may prove to be a productive target in anticancer therapy.     

Proteoglycan obtained from bovine aorta suppress thrombin-induced platelet aggregation.

Proteoglycan (PG), isolated and purified from bovine aorta (intima-media), consisted of 68.6% chondroitin 4/6-sulfate (CS 4/6-S), 30% dermatan sulfate (DS), 1.4% heparan sulfate (HS), and a trace of hyaluronic acid (HA). PG did not affect platelet aggregation induced by ADP, collagen, and epinephrine, but inhibited that induced by thrombin. Of the standard GAGs investigated, hyaluronic acid (HA) and CS-4/6-S slightly inhibited only thrombin-induced platelet aggregation. However, PG and standard GAGs did not affect the thrombin induced aggregation of washed platelets. The effect of PG after papain digestion on thrombin-induced platelet aggregation was less potent than that before. It is suggested by the results of this study that PG in the aorta inactivates plasma thrombin, probably by inhibiting thrombin activators or potentiating substances which inactivate thrombin and that these effect of PG would be mainly due to PG-DS and partly due to PG-HS.     

Repeated piezoelectric lithotripsy for gallstones with and without ursodeoxycholic acid dissolution: A multicenter study

The use of bile acid dissolution therapy in extracorporeal shockwave lithotripsy of gallstones, remains controversial. Our study examined whether chemolitholysis after sufficient disintegration enhanced stone clearance within 6 months of the first lithotripsy. A total of 143 patients who developed one to three radiolucent stones measuring⪯30 mm in diameter were randomly separated into two treatment groups: 47% were given lithotripsy alone, and 53% lithotripsy plus ursodeoxycholic acid (UDCA). Repeated piezoelectric lithotripsy was given, with no limit on the total number of treatment sessions, to pulverize or disintegrate stones into fragments<3 mm. Stones were disintegrated in 97% of all patients, and the fragments were ⪯2 mm in 50% of these patients. According to an intention-to-treat analysis, 52% in the lithotripsy alone group and 58% in the UDCA group were free of stones 6 months after the first lithotripsy (P=0.61). Of the patients with fragments⪯2 mm, 71% in the former and 86% in the latter group were free of stones 6 months after the first lithotripsy, with no significant difference between the groups. Biliary pain occurred in 25% of all patients, including 3 with acute cholecystitis. We concluded that the sufficient disintegration of gallstones achieved with repeated lithotripsy enhanced the early clearance of fragments, regardless of whether chemolitholysis was employed.