The identification of biomarkers that distinguish between aggressive and indolent forms of prostate cancer (PCa) is crucial for diagnosis and treatment. In this study, we used cultured cells derived from prostate tissue from patients with PCa to define a molecular mechanism underlying the most aggressive form of PCa that involves the functional activation of eNOS and HIFs in association with estrogen receptor β (ERβ). Cells from patients with poor prognosis exhibited a constitutively hypoxic phenotype and increased NO production. Upon estrogen treatment, formation of ERβ/eNOS, ERβ/HIF-1α, or ERβ/HIF-2α combinatorial complexes led to chromatin remodeling and transcriptional induction of prognostic genes. Tissue microarray analysis, using an independent cohort of patients, established a hierarchical predictive power for these proteins, with expression of eNOS plus ERβ and nuclear eNOS plus HIF-2α being the most relevant indicators of adverse clinical outcome. Genetic or pharmacologic modulation of eNOS expression and activity resulted in reciprocal conversion of the transcriptional signature in cells from patients with bad or good outcome, respectively, highlighting the relevance of eNOS in PCa progression. Our work has considerable clinical relevance, since it may enable the earlier diagnosis of aggressive PCa through routine biopsy assessment of eNOS, ERβ, and HIF-2α expression. Furthermore, proposing eNOS as a therapeutic target fosters innovative therapies for PCa with NO inhibitors, which are employed in preclinical trials in non-oncological diseases. IntroductionIn the clinical management of prostate cancer (PCa), the second most common neoplasia in men worldwide (1), the ability to distinguish between aggressive and indolent forms of the disease is critical. Thus, therapeutic approaches would be substantially improved by the identification of the molecular mechanisms involved in tumor progression and the key biomarkers capable of improving patients' stratification at diagnosis, by discriminating between those at risk for relapse and those with indolent tumors not requiring further intervention beyond surgery.

The histopathologic and molecular heterogeneity of prostate cancer and the limited availability of human tumor tissue make unraveling the mechanisms of prostate carcinogenesis a challenging task. Our goal was to develop an ex vivo model that could be reliably

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Electrical stimulation of spiral ganglion neurons in a deafened cochlea, via a cochlear implant, provides a means of investigating the effects of the removal and subsequent restoration of afferent input on the functional organization of the primary auditory cortex (AI). We neonatally deafened 17 cats before the onset of hearing, thereby abolishing virtually all afferent input from the auditory periphery. In seven animals the auditory pathway was chronically reactivated with environmentally derived electrical stimuli presented via a multichannel intracochlear electrode array implanted at 8 weeks of age. Electrical stimulation was provided by a clinical cochlear implant that was used continuously for periods of up to 7 months. In 10 long‐term deafened cats and three age‐matched normal‐hearing controls, an intracochlear electrode array was implanted immediately prior to cortical recording. We recorded from a total of 812 single unit and multiunit clusters in AI of all cats as adults using a combination of single tungsten and multichannel silicon electrode arrays. The absence of afferent activity in the long‐term deafened animals had little effect on the basic response properties of AI neurons but resulted in complete loss of the normal cochleotopic organization of AI. This effect was almost completely reversed by chronic reactivation of the auditory pathway via the cochlear implant. We hypothesize that maintenance or reestablishment of a cochleotopically organized AI by activation of a restricted sector of the cochlea, as demonstrated in the present study, contributes to the remarkable clinical performance observed among human patients implanted at a young age. J. Comp. Neurol. 512:101–114, 2009. © 2008 Wiley‐Liss, Inc.

BACKGROUND The conventional treatment of brain metastases not amenable to surgery is most often radiotherapy. Until now, pharmacologic issues related to the blood brain barrier (BBB) prevented a wide evaluation of chemotherapy. The authors previously reported that the combination of cisplatin (P) and etoposide (E) had strikingly high activity in patients with brain metastases from breast carcinoma. The purpose of this study was to assess, in a larger prospective study, the front‐line activity of that combination against brain metastases from breast carcinoma (BC), nonsmall cell lung carcinoma (NSCLC), and malignant melanoma (MM) in patients previously untreated with radiotherapy. METHODS From December 1986 to July 1993, 116 patients received P 100 mg/m2 on Day 1 and E 100 mg/m2 on Days 1, 3, and 5 or on Days 4, 6, and 8 every 3 weeks. An insignificant change in the E schedule using the same dose on a random basis assured the prospective enrollment and the registration of all cases. Six patients were not eligible and three patients were excluded from the analysis because they were lost to follow‐up shortly after the date of registration. One‐hundred seven patients were considered for analysis. The distribution according to the primary tumor site was BC in 56 patients (52%), NSCLC in 43 (40%), and MM in 8 (8%). The first evaluation of response was performed after two cycles. In cases of no disease progression, chemotherapy was continued to a maximum of six cycles. RESULTS Among the 56 patients with BC, 7 achieved complete response (CR) (13%), 14 achieved partial response (PR), 12 had no change (NC), 15 had progressive disease (PD), and 8 had insufficient treatment or response was not assessed. The CR plus rate was 38%. Among the 43 patients with NSCLC, 3 achieved CR (7%), 10 achieved PR, 15 had SD, 7 had PD, and 8 had insufficient treatment or response was not assessed. The CR plus PR rate was 30%. None of the eight patients with MM achieved an objective response. The median survival was 31 weeks for patients with BC (range, 0–287), 32 for patients with NSCLC (0–392+), and 17 for patients with MM (2–48). CONCLUSIONS The combination of P and E is effective for patients with brain metastases from BC and NSCLC. In this study, the response rate was of the same order as that reported for disseminated disease without central nervous system involvement. The survival figures compare favorably with some others reported in the literature for patients given radiotherapy. A randomized study is warranted to compare this chemotherapy followed by radiotherapy with radiotherapy alone for patients with brain metastases from BC or NSCLC not amenable to surgery or radiosurgery. Cancer 1999;85:1599–605. © 1999 American Cancer Society.