A NAD(P)H:quinone oxidoreductase 1 polymorphism is a risk factor for human colon cancer.

Colon cancer is one of the most common cancers in North America and generally develops from colonic epithelial cells following initiation by carcinogens. We have shown that the phase II detoxifying enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1) contributes to the inhibition of carcinogen-induced colon cancer in rats at both the initiation and postinitiation stages. An inactivating polymorphism at base 609 of the NQO1 gene, (609)C (NQO1 *1) --> (609)T (NQO1 *2), occurs at high frequency in the human population. Thus, we carried out a case-control study to determine if this polymorphism is associated with an increased risk of developing colon cancer. A total of 298 patients with colon cancer and 349 healthy controls matched for age, gender, and ethnic origin were enrolled in the study. There was an increased incidence of the NQO1 *2/*2 genotype in patients with colon cancer, with a gender and age-adjusted odds ratio of 2.68 (95% confidence intervals, 1.14-6.28). However, the incidence of the NQO1 *1/*2 genotype was not increased in patients with colon cancer compared with controls. When the patient and control groups were stratified by tobacco and alcohol use, the incidences of the NQO1 *2/*2 genotype were increased in patients with colon cancer for tobacco and alcohol users and nonusers, suggesting that there is no interaction between the NQO1 base 609 polymorphism and tobacco or alcohol use. These results strongly suggest that NQO1 plays a significant role in preventing the development of colon cancer, and individuals with an NQO1 *2/*2 genotype are at an increased risk of developing this disease.     

Preclinical characterization of AEG35156/GEM 640, a second-generation antisense oligonucleotide targeting X-linked inhibitor of apoptosis.

PURPOSE: Cancer cells can use X-linked inhibitor of apoptosis (XIAP) to evade apoptotic cues, including chemotherapy. The antitumor potential of AEG35156, a novel second-generation antisense oligonucleotide directed toward XIAP, was assessed in human cancer models when given as a single agent and in combination with clinically relevant chemotherapeutics. EXPERIMENTAL DESIGN: AEG35156 was characterized for its ability to cause dose-dependent reductions of XIAP mRNA and protein in vitro and in vivo, to sensitize cancer cell lines to death stimuli, and to exhibit antitumor activity in multiple human cancer xenograft models as a single agent or in combination with chemotherapy. RESULTS: AEG35156 reduced XIAP mRNA levels with an EC50 of 8 to 32 nmol/L and decreased XIAP protein levels by >80%. Loss of XIAP protein correlated with increased sensitization to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in Panc-1 pancreatic carcinoma cells. AEG35156 exhibited potent antitumor activity relative to control oligonucleotides in three human cancer xenograft models (prostate, colon, and lung) and was capable of inducing complete tumor regression when combined with taxanes. Antitumor effects of AEG35156 correlated with suppression of tumor XIAP levels. CONCLUSIONS: AEG35156 reduces XIAP levels and sensitizes tumors to chemotherapy. AEG35156 is presently under clinical assessment in multiple phase I trials in cancer patients as a single agent and in combination with docetaxel in solid tumors or cytarabine/idarubicin in leukemia.     

Intramedullary spinal cord metastasis from renal cell carcinoma: detection by positron emission tomography

Although positron emission tomography (PET) is an established diagnostic method in brain and lung cancer, its use is often confined to research. The authors report a case of a minimally symptomatic intramedullary spinal cord metastasis, an uncommon and often diagnostically challenging lesion, that was confirmed by PET. A 37-year-old man with a history of metastatic renal cell carcinoma treated with systemic agents, an autologous stem cell transplant, and local palliative radiotherapy with a 2-month history of vague right foot numbness and right leg dysesthesias was found to have an intramedullary lesion at the level of T12. Although the findings of magnetic resonance imaging suggested central necrosis, a PET scan revealed a metabolically active lesion and confirmed the diagnosis of intramedullary metastasis. PET can be used to detect and confirm intramedullary spinal cord metastatic carcinoma. PET imaging may have a vital role in clinical diagnosis by helping to distinguish diagnostically troublesome lesions based on metabolic activity.     

Nicotine induces endothelial TNF-alpha expression, which mediates growth retardation in vitro

PURPOSE: Atherosclerosis is understood as the common pathologic manifestation of arterial injury caused by a variety of etiologies. One well-established etiologic agent is nicotine. We hypothesized that cytokines of endothelial origin are involved with the pathologic changes found in atherosclerosis associated with smoking. We chose to assay for TNF-alpha due to its many biologic actions that are similar to those found in peripheral vascular disease. METHODS: Human umbilical vein endothelial cells (HUVEC) were plated in endothelial growth medium (EGM-2) on plastic coverslips until 75% confluent. Free base nicotine (FBN) was diluted in EGM-2 to a concentration of 10(-8) M and added to experimental cells. At 1, 3, and 24 h, coverslips were removed and fixed. Immunohistochemical staining was performed using anti-TNF-alpha. Digital image analysis (DIA) was performed to quantify expression of TNF-alpha. An intensity stain index measuring area and intensity of stain/total cellular area was determined for each time point (n = 5). Additional HUVEC were plated in 12-well plates in EGM-2 at 2 x 10(3) cells/cm(2) on T(-2) day. FBN was diluted in medium to 10(-9) M and added to wells with and without 0.9 microg/ml anti-TNF-alpha on T(0) day. Cell counts were performed in triplicate on days T(2-5) utilizing hemocytometry. Data was analyzed using Student's t test and ANOVA, with a 95% confidence interval. RESULTS: Dose response determinations showed that the minimal concentration required to show statistically significant cell retardation is 10 (-9) M. Accordingly, this concentration was used for subsequent proliferation studies. DIA showed a threefold increase in TNF-alpha activity at 1 h and a twofold increase at 3 h. Activity returned to baseline by 24 h. Cell growth was significantly decreased in cells exposed to nicotine when compared to controls on days T(2)-T(5) (P < 0.05). In cells exposed to anti-TNF-alpha and nicotine there was inhibition of the growth retardation seen in the cells containing nicotine alone. Differences between the control group and the anti-TNF-alpha group were not statistically significant. CONCLUSION: These data demonstrate the ability of endothelial cells to secrete TNF-alpha in response to nicotine at levels found in serum after smoking and also shows that endothelial cell growth retardation as a consequence of nicotine exposure may be TNF-alpha mediated.     

Intraoperative ultrasound during renal parenchymal sparing surgery for hereditary renal cancers: a 10-year experience

PURPOSE: We review our 10-year experience with intraoperative ultrasound during renal parenchymal sparing surgery in patients with hereditary renal cancers. MATERIALS AND METHODS: Between 1991 and 2000, 68 nephron sparing procedures were performed on 26 women and 27 men, all but 1 of whom had a hereditary predisposition to renal cancer, for example von Hippel-Lindau, hereditary papillary renal cancer. Intraoperative ultrasound was performed after the surgeon removed all visible or palpable lesions. High frequency transducers (7 MHz.) and color Doppler were used in all cases. Lesions were characterized as simple cysts, complex cysts or solid masses, and were recorded on a map. RESULTS: A total of 935 lesions (mean 12.8 lesions per kidney) were removed in 68 nephron sparing operations performed on 53 patients. Of these lesions 870 were removed without while 65 required intraoperative ultrasound. In 17 of 68 (25%) procedures intraoperative ultrasound identified renal cancers that were not detectable by the surgeon. Mean tumor size of ultrasound detected lesions was 1.0 cm. (range 2 mm. to 4 cm.). Of the 32 cystic lesions identified by intraoperative ultrasound 5 contained renal carcinoma, and 29 of the 33 solid renal masses were renal cell carcinomas. During reoperations ultrasound enabled the surface of the kidney to be evaluated even when it was inaccessible due to scar tissue or adherent perinephric fat. CONCLUSIONS: Intraoperative ultrasound can be performed after all visible lesions have been removed and identifies additional tumors in 25% of patients with hereditary renal cancer, thus ensuring that as many tumors as possible have been removed during renal parenchymal sparing surgery.     

A randomized controlled trial of insecticide-treated bednets and chaddars or top sheets, and residual spraying of interior rooms for the prevention of cutaneous leishmaniasis in Kabul, Afghanistan

Anthroponotic cutaneous leishmaniasis (ACL) is a significant public health problem in many towns and cities of south central Asia and the Middle East, resulting in disfigurement and disability which warrants preventive action. A randomized controlled trial was conducted in 1997/98 amongst a non-immune study population of 3666 people in Kabul, Afghanistan, to compare the efficacy of insecticide-treated nets (ITNs), insecticide-treated Islamic cloth wraps (chaddars) used to sleep in, and residual pyrethroid spraying of individual houses for the prevention of ACL. Dosages of insecticide were: ITNs with permethrin, 0.5 g/m2; chaddars with permethrin, 1 g/m2; rooms with lambdacyhalothrin, 30 mg/m2. Cases of ACL were diagnosed on clinical criteria. At the end of the trial period (15 months) the incidence of ACL amongst controls was 7.2%, amongst ITN users 2.4% (OR 0.31, 95% CI 0.2-0.5), amongst impregnated chaddar users 2.5% (OR 0.33, 95% CI 0.2-0.6) and amongst residents of sprayed houses 4.4% (OR 0.60, 95% CI 0.3-0.95). ITNs and impregnated chaddars were equally effective, providing about 65% protective efficacy, with approximately 40% protective efficacy attributable to individual house spraying. No significant differences for age or sex were found between new cases in the intervention and control groups. No serious side-effects were reported and interventions were generally popular; ITNs were the most popular, followed by residual spraying and then impregnated chaddars.     

Genetic and Environmental Influences on the Covariation Between Hyperactivity and Conduct Disturbance in Juvenile Twins

Structural equation models were applied to the maternal ratings of 265 MZ and 163 DZ male-male, 347 MZ and 160 DZ female-female, and 262 male-female twin pairs, aged 8-16 years, who participated in the Virginia Twin Study of Adolescent Behavioral Development (VTSABD). Substantial additive genetic influences and contrast effects were found for hyperactivity, and additive genetic and shared environmental effects or positive comparison effects (particularly for the girls) for oppositional/conduct disturbance. Bivariate model fitting showed that the covariation between hyperactivity and oppositional/conduct problems in both younger and older boys and girls is almost entirely attributable to genetic factors. However, whereas in the younger males and females the same set of genes explain all the variation in hyperactivity and conduct disturbance, in the older cohort at least some of the genetic effects are behavior- and gender-specific.     

A morphological study of the M-protein of Sendai virus.

A purification scheme is described for the M-protein of Sendai virus and an electron microscope study of the isolated protein is presented. The protein exists as subunits of 6 nm in diam., which possess a central hole; the subunits may be dimers of the polypeptide. They are able to form filamentous aggregates which wind around one another to form a helical structure. It is suggested that these filaments may be the form adopted by the protein in the virus, the filaments lying parallel to one another just beneath the virus membrane to form a shell, but that the helical form is likely to be a property only of the isolated protein.