The transcription factor early growth response protein 1 (EGR1) is overexpressed in a majority of human prostate cancers and is implicated in the regulation of several genes important for prostate tumor progression. Here we have assessed the effect of Egr1 deficiency on tumor development in two transgenic mouse models of prostate cancer (CR2-T-Ag and TRAMP). Using a combination of high-resolution magnetic resonance imaging and histopathological and survival analyses, we show that tumor progression was significantly impaired in Egr1-/- mice. Tumor initiation and tumor growth rate were not affected by the lack of Egr1; however, Egr1 deficiency significantly delayed the progression from prostatic intra-epithelial neoplasia to invasive carcinoma. These results indicate a unique role for Egr1 in regulating the transition from localized, carcinoma in situ to invasive carcinoma.
Dicumyl peroxide (di-CuOOH) and benzoyl peroxide (BzOOH) act as tumor promoters in SENCAR mice, whereas di-tert-butylhydroperoxide does not. Tumor promotion requires the removal of growth suppression by inhibition of gap junctional intercellular communication (GJIC) and the induction of mitogenic intracellular pathways. We showed that di-CuOOH and BzOOH both reversibly inhibited GJIC and transiently activated mitogen-activated protein kinase, specifically, the extracellular receptor kinase at noncytotoxic conditions in WB-F344 rat liver epithelial cells, whereas the non-tumor-promoting di-tert-butylhydroperoxide did not inhibit GJIC or activate extracellular receptor kinase. di-CuOOH but not BzOOH inhibited GJIC through a phosphatidylcholine-specific phospholipase C-dependent mechanism. N-acetylcysteine (NAC) was needed to prevent a cytotoxic, glutathione-depleting effect of BzOOH, whereas di-CuOOH was noncytotoxic and did not alter glutathione levels at all doses and times tested. Pretreatment of WB-F344 cells with resveratrol, a polyphenolic antioxidant present in red wine, prevented at physiological doses the inhibition of GJIC by di-CuOOH but not from BzOOH and was effective in significantly preventing extracellular receptor kinase activation by both peroxides. NAC did not prevent any of the peroxide effects on either GJIC or extracellular receptor kinase, suggesting a specific antioxidant effect of resveratrol.
Although adrenal involvement from renal cell carcinoma is rare, removal of the adrenal during radical nephrectomy continues to be standard practice. To assess the actual need for adrenalectomy, we elected to evaluate whether malignant involvement of the adrenal gland could be reliably diagnosed preoperatively by a computerized tomogram (CT) of the abdomen. A blinded retrospective review of preoperative abdominal CT in 157 patients with renal cancer revealed an abnormality of the ipsilateral adrenal gland in 38. Histopathology confirmed malignant involvement of the adrenal in 10 patients. Significantly, all 119 adrenal glands judged to be normal on the preoperative CT were confirmed to be uninvolved by the renal cancer on histopathological study. We conclude that abdominal CT is reliable in the preoperative evaluation of the ipsilateral adrenal gland and assessment of its noninvolvement with renal carcinoma. In such cases adrenal sparing nephrectomy may be considered (76% of our patients). None of these 119 patients had either macroscopic or microscopic adrenal involvement. When the adrenal is not identified, displaced or enlarged on CT (24% of our patients) adrenalectomy should be routinely performed as part of radical nephrectomy. Even in this select group adrenal involvement was present in only 26% of the cases.
We report a case of percutaneous removal of a staghorn calculus that was accomplished in a morbidly obese patient while he was in a full flank position. In this position, the stone could be successfully accessed and fragmented without compromising the pulmonary status of the patient.
Laparoscopic nephrectomy with ablative intent has been performed clinically. The current study aimed to determine whether a physiologically and anatomically intact kidney suitable for transplantation could be harvested laparoscopically. Three weeks after an ablative laparoscopic right nephrectomy, 15 pigs were divided into two groups: the study group (n = 10) underwent a laparoscopic live-donor left nephrectomy of the solitary kidney and conventional autotransplantation; the control group (n = 5) underwent an open live-donor left nephrectomy of the solitary kidney and conventional autotransplantation. All study kidneys underwent laparoscopic in situ hypothermic perfusion. The mean length of the left renal artery and vein were similar in the study and control groups: 3.1 cm and 3.4 cm, respectively, in the study group compared with 2.5 cm and 3.8 cm, respectively, in the control group (P = 0.5). No intraoperative renal vascular injuries or postoperative ureteral complications were noted in either group. Renal histopathologic examination immediately after live-donor nephrectomy and at 1 month post-transplant showed similar findings in the two groups. The mean serum creatinine at 7 and 30 days postoperatively was not significantly different: 2.1 mg/dL and 1.6 mg/dL, respectively, in the study group and 1.7 mg/dL, and 1.4 mg/dL, respectively, in the control group (P = 0.4). We conclude that laparoscopic live-donor nephrectomy can be performed safely and reproducibly in the porcine model.
High-grade prostatic intraepithelial neoplasia (HGPIN) is the most likely precursor proliferation of peripheral zone, moderately to poorly differentiated prostatic adenocarcinomas. The usual cell type of the epithelial lining of HGPIN is a glandular epithelial cell with characteristic nuclear abnormalities. Here we report nine cases of unusual types of HGPIN, including three cases of signet-ring cell HGPIN, one case of small cell neuroendocrine HGPIN, and five cases of HGPIN with distinctive mucinous features. The three examples of signet-ring cell PIN were all associated with an invasive primary signet-ring cell carcinoma of the prostate. The HGPIN assumed a classical tufted and micropapillary architectural growth pattern, with the constituent cells exhibiting a morphologic appearance identical to that of the invasive signet-ring cells. The intraepithelial and invasive signet-ring cells were mucin negative and were immunoreactive for prostate-specific antigen (PSA). A fourth case displayed a mixed intraepithelial glandular-small cell neoplastic proliferation, where intraepithelial small cells were histologically identical to surrounding invasive small cell carcinoma cells. The small cell HGPIN and invasive small cell carcinoma cells were positive for the neuroendocrine markers chromogranin, synaptophysin, and neuron-specific enolase. In five cases, mucinous distension of HGPIN glands, producing a flat pattern of the epithelial lining layer, comprised the third unusual pattern of HGPIN. These blue mucinous secretions were readily detected by hematoxylin and eosin staining and were composed of both neutral (periodic acid-Schiff-positive) and acidic (alcian blue-positive) mucins. Herein we document the existence of an intraepithelial proliferation of neoplastic cell types-small cell neuroendocrine and signet-ring cell-that are usually considered as stromal-invasive cells in the prostate. The presence of these rare prostatic cell types in both HGPIN and invasive carcinoma provides further support for a close relationship between HGPIN and invasive carcinoma of the prostate. All three unusual types of HGPIN-signet-ring cell, small cell neuroendocrine, and mucinous-are important to diagnostically recognize because of the strength of association of HGPIN with invasive carcinoma.
Many tumor promoters suppress the immune system; however, the direct effect of immunosuppressants on the tumorigenic pathways of nonimmune cells in solid tissue has not been well documented. Cannabinoids were chosen to explore this question further. Cannabinoids are immune modulators that affect specific intracellular signaling pathways in leukocytes. Since these compounds are nongenotoxic, any tumorigenic effect that might be associated with these compounds would need to occur through an epigenetic mechanism. Therefore, we determined the effect of ⌬ 9 -THC and CBN, 2 plant-derived cannabinoids, on 2 key epigenetic markers of tumor promotion: inhibition of GJIC, which is essential in removing a cell from growth suppression, and activation of the ERK-MAPK pathway, which is crucial in activating the appropriate genes for mitogenesis. Both ⌬ 9 -THC and CBN reversibly inhibited GJIC at noncytotoxic doses (15 M) in a normal diploid WB rat liver epithelial oval cell line within 20 min and activated ERK1 and ERK2 within 5 min. Inhibition of MEK with PD98059 prevented the inhibition of GJIC by either cannabinoid, suggesting that inhibition of GJIC was MEK-dependent. Based on RT-PCR analysis and employment of an antagonist of CB1 and CB2, the effects on GJIC and MAPK were independent of both cannabinoid receptors. Cannabinoids affected crucial epigenetic pathways associated with cell proliferation in a rodent liver epithelial cell model system.
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