Clinicopathologic and prognostic significance of the histologic activity of noncancerous liver tissue in hepatitis B virus-associated hepatocellular carcinoma

We prospectively studied 66 patients infected with the hepatitis B virus who underwent liver resection for hepatocellular carcinoma (HCC) to evaluate the influence of the histologic activity of noncancerous liver tissue on clinicopathologic features and prognosis. Based on the histologic activity index (HAI) score of nontumorous liver tissue, patients were classified into 3 groups: mild, moderate, or severe hepatitis. Overall, higher HAI scores were more frequent in patients with poorer liver function: lower serum albumin levels and higher indocyanine green retention at 15 minutes. Moreover, patients with moderate hepatitis had more frequent venous invasion, and the tumor size decreased with increasing HAI scores. Similar results were observed when the fibrosis category was excluded in the calculation of HAI scores. The overall or disease-free survival rates did not differ significantly among the 3 groups of patients. However, higher fibrosis scores were associated significantly with shorter disease-free survival rates. HAI scores correlated significantly with certain clinicopathologic features. In patients with hepatitis B-related HCC, a higher fibrosis score in the nontumorous liver tissue, but not histologic hepatitic activity, seems to be a significant factor predisposing to shorter survival.     

Global bioheat model for quick evaluation of the human physiological thermal profiles under differing conditions

The paper presents a physical and mathematical model of the thermoregulatory system of the human body. The model takes into account tissue physiology, structure and general physiological parameters such as blood flow. The global response of the body to underlying physiological variations as well as to any change in ambient conditions can be simulated. The analysis is based on a one-dimensional tissue layer and a two-node core and shell array of the entire body. Application of the model indicates that the body is particularly sensitive to ambient changes in the cold, where a slight drop in gain produces an adverse change in the temperature profile of the physiological system. The gain, G, of the feedback system also suggests that it is an essential parameter in determining the range of the negative feedback as well as the sensitivity of the unacclimizated body to its surroundings. It is also the critical parameter to determine how hard the feedback system works to maintain a homeostatic state. At temperature extremes, G either will cause the system to attain beyond the critical temperatures needed for survival or it will cease to cause the system to respond further to any more changes in the external environment.     

Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva,on downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma

Pancreatic cancer is the fifth leading cause of cancer death in North America. Gemcitabine improves the quality of life of patients but fails to significantly reduce mortality. Our laboratory has demonstrated previously that the phosphatidylinositol 3'-kinase inhibitor wortmannin promotes gemcitabine antitumor activity (S. S. W. Ng et al., Clin. Cancer Res., 7: 3269-3275, 2001). The present study examined the effects of the epidermal growth factor receptor (EGFR) inhibitor OSI-774 ("Tarceva") alone and in combination with wortmannin and/or gemcitabine on downstream signaling molecules, as well as apoptosis in primary pancreatic cancer xenografts implanted orthotopically in severely combined immunodeficient mice. Tumors established from two pancreatic cancer patients [Ontario Cancer Institute Pancreas number (OCIP#) 2 and OCIP#7] were treated with various combinations of the above three drugs and harvested for analyses of the following: the levels of phosphorylated and nonphosphorylated forms of EGFR, protein kinase B (PKB/Akt) and extracellular-regulated kinase (ERK1/2), and the extent of apoptosis using immunofluorescence image analysis and TUNEL assay, respectively. OSI-774 alone significantly inhibited phosphorylation of EGFR in both of the primary xenografts. Phosphorylation of pERK decreased in OCIP#2, but not in OCIP#7. No significant effects on pPKB because of OSI-774 were observed in either tumor type. The extent of apoptosis was significantly increased by 2-fold in OCIP#2 tumors treated with gemcitabine and wortmannin in combination; an additional 2-fold increase in apoptosis was evident in the presence of OSI-774. Although wortmannin failed to enhance gemcitabine-induced apoptosis in OCIP#7 tumors, the extent of apoptosis was significantly increased with the inclusion of OSI-774 in the combination. Taken together, these findings support the use of OSI-774 plus a phosphatidylinositol 3'-kinase inhibitor in combination with gemcitabine in the treatment of pancreatic cancer.     

PS-341, a novel proteasome inhibitor,induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis

Treatment with the proteasome inhibitor, PS-341 resulted in concentration- and time-dependent effects on Bcl-2 phosphorylation and cleavage in H460 cells that coincided with the PS-341-induced G2-M phase arrest. The observed Bcl-2 cleavage paralleled the degree of PS-341-induced apoptosis but was detected to a similar extent with comparable concentrations of two other proteasome inhibitors (MG-132 and PSI). Calpain inhibitors, ALLM and ALLN, and the caspase inhibitors, Z-VAD and AC-YVAD did not induce BcI-2 phosphorylation and cleavage. Exposure to PS-341 resulted in an additional Mr 25,000 cleavage fragment of Bcl-2, whereas only a Mr 23,000 fragment was observed with other anticancer agents. The formation of the Mr 25,000 fragment was not prevented by caspase inhibitors unlike the Mr 23,000 fragment, which suggests mediation by a caspase-independent pathway. Cell fractionation studies revealed that the Bcl-2 cleaved fragments localize within membrane structures and was an early event (at approximately 12 h, posttreatment), and before the observed cleavage of poly(ADP-ribose) polymerase (PARP), beta-catenin, and DNA fragmentation (at approximately 36 h posttreatment). The Mr 23,000 Bcl-2 cleavage product was inhibited by the pan-caspase inhibitor and the inhibitors of capase-3, -8, -9; but the PARP cleavage was prevented only by the pan-caspase and caspase-3 inhibitors, which suggests that the Mr 23,000 Bcl-2 cleavage occurred at both the initiation and execution stages of apoptosis. The inhibition of the ubiquitin/proteasome pathway by PS-341 leads, at an early stage of apoptosis, to Bcl-2 phosphorylation and a unique proteolytic cleavage product, which are associated with G2-M phase arrest and the induction of apoptosis.     

Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms

The murine VEGF gene is alternatively transcribed to yield the VEGF(120), VEGF(164), and VEGF(188) isoforms, which differ in their potential to bind to heparan sulfate and neuropilin-1 and to stimulate endothelial growth. Here, their role in retinal vascular development was studied in mice selectively expressing single isoforms. VEGF(164/164) mice were normal, healthy, and had normal retinal angiogenesis. In contrast, VEGF(120/120) mice exhibited severe defects in vascular outgrowth and patterning, whereas VEGF(188/188) mice displayed normal venular outgrowth but impaired arterial development. It is noteworthy that neuropilin-1, a receptor for VEGF(164), was predominantly expressed in retinal arterioles. These findings reveal distinct roles of the various VEGF isoforms in vascular patterning and arterial development in the retina.     

Efficacy of a single dose of cefazolin as a prophylactic antibiotic in primary arthroplasty

We analyzed the wound infection rate of 1,367 primary total hip and knee arthroplasties performed between 1991 and 1999. Two hundred and fifteen arthroplasties were performed with 3 doses (3 x 750 mg) of cefuroxime, and 1,152 arthroplasties were performed with a single preoperative dose (1 x 1 g) of cefazolin as antimicrobial prophylaxis. All wound infections that occurred within 2 years of the index surgery were analyzed. The deep wound infection rate of total hip arthroplasty was 1.1% (95% confidence interval [CI], 0%-3.3%) in the cefuroxime group and 1.1% (95% CI, 0%-2.2%) in the cefazolin group (Fisher's exact test, P = 1.0). The deep wound infection rate of total knee arthroplasty in the cefuroxime group (1.6%; 95% CI, 0%-3.8%) was not significantly different from the cefazolin group (1.0%; 95% CI, 0.3%-1.7%) (Fisher's exact test, P =.63). We concluded that a single dose (1 g) of cefazolin given at anesthetic induction offered similar protection to 3 doses (3 x 750 mg) of cefuroxime in preventing infection in primary total joint arthroplasty.