Induction of Squamous Cell Carcinomas in the Salivary Glands of Rats by Potassium Iodide

In a 2-year carcinogenicity study of potassium iodide (KI) in F344/DuCrj rats, squamous cell carcinomas (SCCs) were observed in the salivary glands of 4/40 males and 3/40 females receiving 1000 ppm KI in the drinking water. Ductular proliferation with lobular atrophy was observed at high incidence in the submandibular glands of the high-dose animals, and squamous metaplasia was frequently evident within the proliferative ductules and the larger interlobular ducts. A transition from metaplasia to SCC was apparent. The results suggest that squamous metaplasia in proliferative ductules, occurring secondarily to lobular impairment induced by KI, may develop into SCCs via a non-genotoxic, proliferation-dependent mechanism.     

Absence of p53 Overexpression and Favorable Response to Cisplatin-based Neoadjuvant Chemotherapy in Urothelial Carcinomas

It has been controversial whether cancer cells harboring loss or inactivation of the tumor suppressor p53 are resistant or sensitive to DNA-damaging agents including cisplatin and doxorubicin. Overexpression of mdm2 oncoprotein, a negative regulator of p53, is assumed to be an alternative to p53 dysfunction. Archival urothelial carcinoma specimens obtained from 60 patients prior to cisplatin-based chemotherapy were immunohistochemically studied for overexpression of p53 and mdm2. Thirty-two patients (group I) were treated with chemotherapy in the neoadjuvant setting, while 28 patients (group II) underwent chemotherapy for distant metastases or inoperable locoregional tumors. In group I, the responsiveness was correlated with staining status of p53 ( P =0.0225) and the combination of p53 and mdm2 ( P =0.0497). Negative staining of p53 and negative for both p53 and mdm2 could have predicted favorable response to chemotherapy in 16 of 18 (88.9%) and in 12 of 13 (92.3%) tumors, respectively. On the other hand, p53-positive and p53 and/or mdm2-positive staining could have predicted poor response only in 7 of 14 (50.0%) and 8 of 19 (42.1%) tumors, respectively. Disease-specific survival of the p53-negative group was significantly superior to that of the p53-positive group ( P =0.0086). Difference in survival did not become more significant when overexpression of mdm2 was taken into consideration ( P =0.0456). In contrast, in group II, there was no correlation of responsiveness to chemotherapy or survival with p53- or p53/mdm2-staining status. The patients with urothelial carcinomas negative for overexpression of p53 will benefit from neoadjuvant chemotherapy. From clinical viewpoint, however, p53 status alone or the combination of p53 and mdm2 status is not enough to identify those patients who will not benefit from the treatment.     

Pathological analyses of early recurrence and malignant transformation in meningiomas

We investigated factors of the early recurrence and malignant transformation of histologically benign meningiomas using immunohistochemistry for MIB-1 positive indices (PI) and p53 protein expression, a flow cytometric DNA analysis, and the examination of numerical chromosomal aberrations detected by fluorescence in situ hybridization using an α-satellite DNA probe and abcr gene locus-specific probe. Twenty-six meningiomas of 23 patients were classified into two groups: the 3 patients in whom a recurrence was defined within two years after initial surgery and who showed histologically malignant features were classified as the early recurrent group, and the other 20 patients in whom recurrence did not develop during the same period were classified as the nonrecurrent group. DNA aneuploidy was observed in 40% of the nonrecurrent patients and in 67% of the early recurrent patients. Loss of chromosome 22 was the most common numerical aberration, but the aberrations characteristic of early recurrent meningiomas were not detected. The MIB-1 PI values of the early recurrent meningiomas were higher than those of nonrecurrent meningiomas, suggesting that MIB-1 PI is very important for biological and histopathological analyses and prediction of the future recurrence of meningiomas.     

Molecular epidemiological evidence for ascending urethral infection in acute bacterial prostatitis

PURPOSE: To test the ascending urethral infection in the pathogenesis of acute bacterial prostatitis, we assessed the clonality of Escherichia coli strains isolated from urine and rectal swab of patients with acute bacterial prostatitis using molecular typing methods. MATERIALS AND METHODS: A total of 50 E. coli strains each isolated from urine and rectal swabs of 9 men with acute bacterial prostatitis at diagnosis were examined for 6 urovirulence determinant profiles and pulsed field gel electrophoresis patterns. In 1 case E. coli isolates from the rectal swab of the patient's wife were also examined at diagnosis and after 5 weeks. RESULTS: The urovirulence profile and pulsed field gel electrophoresis demonstrated that causative E. coli was monoclonal in each case, and present in the rectal swab as a predominant (96% to 100%) fecal clone in 2 and a minority clone (2% to 8%) in 4. Furthermore, causative E. coli dominated in the rectal swab of the 1 patient's wife. CONCLUSIONS: Our results are consistent with the ascending route of infection in acute bacterial prostatitis. However, causative E. coli might possibly originate from either intestinal reservoir of the host or household member. Owing to limitations of the cross-sectional design of this study, longitudinal studies are necessary to establish the ascending route of infection in this disease.     

Overexpression of the aldo-keto reductase family protein AKR1B10 is highly correlated with smokers' non-small cell lung carcinomas.

PURPOSE: Squamous cell carcinoma (SCC) and adenocarcinoma of the lung are currently subject to similar treatment regimens despite distinct differences in histology and epidemiology. The aim of this study is to identify a molecular target with diagnostic and therapeutic values for SCC. EXPERIMENTAL DESIGN: Genes specifically up-regulated in SCC were explored through microarray analysis of 5 SCCs, 5 adenocarcinomas, 10 small cell lung carcinomas, 27 normal tissues, and 40 cancer cell lines. Clinical usefulness of these genes was subsequently examined mainly by immunohistochemical analysis. RESULTS: Seven genes, including aldo-keto reductase family 1, member B10 (AKR1B10), were identified as SCC-specific genes. AKR1B10 was further examined by immunohistochemical analysis of 101 non-small cell lung carcinomas (NSCLC) and its overexpression was observed in 27 of 32 (84.4%) SCCs and 19 of 65 (29.2%) adenocarcinomas. Multiple regression analysis showed that smoking was an independent variable responsible for AKR1B10 overexpression in NSCLCs (P < 0.01) and adenocarcinomas (P < 0.01). AKR1B10 staining was occasionally observed even in squamous metaplasia, a precancerous lesion of SCC. CONCLUSION: AKR1B10 was overexpressed in most cases with SCC, which is closely associated with smoking, and many adenocarcinoma cases of smokers. These results suggest that AKR1B10 is a potential diagnostic marker specific to smokers' NSCLCs and might be involved in tobacco-related carcinogenesis.     

Treatment of human tumor xenografts with monoclonal antibody 806 in combination with a prototypical epidermal growth factor receptor-specific antibody generates enhanced antitumor activity.

Monoclonal antibody (mAb) 806 is a novel epidermal growth factor receptor (EGFR) antibody with significant antitumor activity that recognizes a mutant EGFR commonly expressed in glioma known as delta2-7 EGFR (de2-7 EGFR or EGFRvIII) and a subset of the wild-type (wt) EGFR found in cells that overexpress the receptor. We have used two human xenograft mouse models to examine the efficacy of mAb 806 in combination with mAb 528, a prototypical anti-EGFR antibody with similar specificity to cetuximab. Treatment of nude mice, bearing s.c. or i.c. tumor human xenografts expressing the wt or de2-7 EGFR, with mAbs 806 and 528 in combination resulted in additive and in some cases synergistic, antitumor activity. Interestingly, mAb 528 was also effective against xenografts expressing the ligand independent de2-7 EGFR when used as a single agent, showing that its antitumor activity is not merely mediated through inhibition of ligand binding. When used as single agents, neither mAbs 806 or 528 induced down-regulation of the de2-7 EGFR either in vitro or in vivo. In contrast, the combination of antibodies produced a rapid and dramatic decrease in the total cell surface de2-7 EGFR both in vitro and in xenografts. Consistent with this decrease in total cell surface de2-7 EGFR, we observed up-regulation of the cell cycle inhibitor p27(KIP1) and a decrease in tumor cell proliferation as measured by Ki-67 immunostaining when the antibodies were used in combination in vivo. Thus, mAb 806 can synergize with other EGFR-specific antibodies thereby providing a rationale for its translation into the clinic.     

Relationship between striatal [123I]β-CIT binding and four major clinical signs in Parkinson’s disease

We investigated the correlation between clinical severity and striatal [123I]-CIT binding in 12 patients with Parkinson's Disease (PD: 6 men and 6 women, age: 65 +/- 7 years, Hoehn & Yahr stage: 1 to 3). The clinical severity of PD patients was measured with the Unified Parkinson's Disease Rating Scale (UPDRS) after withdrawal of antiparkinsonian medication at least 12 hours before assessment. [123I]beta-CIT binding in the caudate and putamen was measured at 3 hours [V'3 (day 1)], and at 24 hours [V'3 (day 2)) after tracer injection with small square ROIs. The specific striatal uptake index (day 2) was calculated with large square ROIs that encompassed the whole striatum. The best correlation (r = -0.82, p < 0.0012) was between putamenal V'3 (day 2) and the motor UPDRS scores. When the motor UPDRS scores were divided into four subscales, bradykinesia was the only sign that correlated significantly with putamenal V'3 (day 2) (r = -0.81, p < 0.002). [123I]beta-CIT SPECT is a useful marker of disease severity in PD with potential utility in the serial monitoring of disease progression.     

Evaluation of the toxicity of enzymatically decomposed rutin with 13-weeks dietary administration to Wistar rats.

The subchronic toxicity of enzymatically decomposed rutin, which consists mainly of isoquercitrin, was investigated in male and female Wistar rats with dietary administration at concentrations of 0, 0.2, 1 and 5% for 13 weeks. No mortality or abnormal clinical signs were observed throughout the experimental period in any groups. Body weight gain was reduced from week 10 to the end of the experiment in the 5% dosed males as compared to the 0% controls. Decreased erythrocytic parameters, i.e. red blood cell count, hemoglobin concentration and hematocrit, and significantly lowered serum triglyceride levels were also detected in the 5% males. Organ weight measurement, macro and microscopic observation revealed no test substance-related toxicological changes. Based on the above findings, no-observed-adverse-effect levels (NOAELs) for male and female rats were estimated to be 1 and 5%, respectively, translating into 539 and 3227 mg/kg b.w./day.