Aberrant CREB1 activation in prostate cancer disrupts normal prostate luminal cell differentiation.

The molecular mechanisms of luminal cell differentiation are not understood well enough to determine how differentiation goes awry during oncogenesis. Using RNA-Seq analysis, we discovered that CREB1 plays a central role in maintaining new luminal cell survival and that oncogenesis dramatically changes the CREB1-induced transcriptome. CREB1 is active in luminal cells, but not basal cells. We identified ING4 and its E3 ligase, JFK, as CREB1 transcriptional targets in luminal cells. During luminal cell differentiation, transient induction of ING4 expression is followed by a peak in CREB1 activity, while JFK increases concomitantly with CREB1 activation. Transient expression of ING4 is required for luminal cell induction; however, failure to properly down-regulate ING4 leads to luminal cell death. Consequently, blocking CREB1 increased ING4 expression, suppressed JFK, and led to luminal cell death. Thus, CREB1 is responsible for the suppression of ING4 required for luminal cell survival and maintenance. Oncogenic transformation by suppressing PTEN resulted in constitutive activation of CREB1. However, the tumor cells could no longer fully differentiate into luminal cells, failed to express ING4, and displayed a unique CREB1 transcriptome. Blocking CREB1 in tumorigenic cells suppressed tumor growth in vivo, rescued ING4 expression, and restored luminal cell formation, but ultimately induced luminal cell death. IHC of primary prostate tumors demonstrated a strong correlation between loss of ING4 and loss of PTEN. This is the first study to define a molecular mechanism whereby oncogenic loss of PTEN, leading to aberrant CREB1 activation, suppresses ING4 expression causing disruption of luminal cell differentiation.

Human stroma and epithelium co-culture in a microfluidic model of a human prostate gland.

The prostate is a walnut-sized gland that surrounds the urethra of males at the base of the bladder comprising a muscular portion, which controls the release of urine, and a glandular portion, which secretes fluids that nourish and protect sperms. Here, we report the development of a microfluidic-based model of a human prostate gland. The polydimethylsiloxane (PDMS) microfluidic device, consisting of two stacked microchannels separated by a polyester porous membrane, enables long-term in vitro cocultivation of human epithelial and stromal cells. The porous separation membrane provides an anchoring scaffold for long-term culturing of the two cell types on its opposite surfaces allowing paracrine signaling but not cell crossing between the two channels. The microfluidic device is transparent enabling high resolution bright-field and fluorescence imaging. Within this coculture model of a human epithelium/stroma interface, we simulated the functional development of the in vivo human prostate gland. We observed the successful differentiation of basal epithelial cells into luminal secretory cells determined biochemically by immunostaining with known differentiation biomarkers, particularly androgen receptor expression. We also observed morphological changes where glandlike mounds appeared with relatively empty centers reminiscent of prostatic glandular acini structures. This prostate-on-a-chip will facilitate the direct evaluation of paracrine and endocrine cross talk between these two cell types as well as studies associated with normal vs disease-related events such as prostate cancer.

Is the rabbit ear model, in its present state, prophetic of acnegenicity?

The rabbit ear model has been proposed as a useful bioassay to establish the comedogenic and acnegenic qualities of chemical compounds and finished products, pharmaceutical and cosmetic, for topical application. This review highlights the many problems in performance of the test method, the absence of correlation with experience in the human, and, consequently, the serious limitations of the conclusions that can reasonably be drawn, especially for the clinical dermatologist.

Treatment of acne with topical antibiotics.

The introduction of topical antibiotics for acne vulgaris has ushered in a new era in the treatment of this troublesome disorder. Tetracycline, erythromycin, and clindamycin can now be prepared in lotion form in vehicles that are capable of carrying the antibiotic into the follicular canal, where the primary lesion of acne occurs. Topical antibiotics are practically as effective as oral antibiotics in treating acne and are particularly useful for mild papular acne of puberty and early adolescence and papular-pustular acne of adult women. Use of topical antibiotics avoids the possibility of the adverse effects of systemic therapy; the side effects from the formulations reported here are negligible. Above all, antibiotic lotions do not produce the dryness and scaling that occur with most other topical acne preparations.

An update on acne vulgaris.

Seven important therapeutic measures in managing acne are described, for the treatment of the 7 types of acne. These therapeutic measures are retinoic acid, benzoyl peroxide gel, topical antibiotics, oral antibiotics, intralesional corticosteroids, liquid nitrogen and oral corticosteroids.

Topical treatment of acne with a tetracycline preparations: results of a multi-group study.

This report presents the results of a 13-week study done on 300 patients with acne vulgaris treated with a tetracycline topical lotion alone. The vehicle used was an aqueous-ethanol solution containing the penetration enhancer, n-decyl methyl sulfoxide. On a 0-8 grading scale, 81% of the patients improved by one or more grade points, 57% by two or more points and 31% by three or more points. Analysis indicated that concomitant variables such as severity, age, type of acne, sex and season of the year did not alter the conclusion as to efficacy. Detailed statistical analysis indicates that the conclusion is valid that the tetracycline preparation is beneficial in the treatment of acne vulgaris. No adverse reactions were observed in the patients treated. Hemograms, blood studies and urinalyses were completed on 37 patients. No disturbing trends were uncovered.