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No abstract available. Article truncated after 150 words. A 31-year-old male fire fighter with a history of recurrent “atypical pneumonia,” environmental and drug allergies, nasal polyps, asthma, and Crohn's disease (not on immunosuppressants) was transferred from an outside hospital for management of acute hypoxic respiratory failure with peripheral eosinophilia. Prior to admission he reported a 2-week history of worsening dyspnea, productive cough and wheezing, prompting an urgent care visit where he was prescribed amoxicillin-clavulanate for suspected community acquired pneumonia. Despite multiple days on this medication, his symptoms significantly worsened until he was unable to lie flat without coughing or wheezing. He was ultimately admitted to an outside hospital where his labs were notable for a leukocytosis to 22,000 and peripheral eosinophilia with an absolute eosinophil count of 9700 cells/microL. His blood cultures and urine cultures were negative, and a radiograph of the chest demonstrated bilateral nodular infiltrates. With these imaging findings combined with the peripheral eosinophilia there was …

No abstract available. Article truncated after 150 words. A 78-year-old- man with cerebral palsy requiring an in-home caregiver presented to the emergency room in hypovolemic shock post-sudden cardiac arrest in the setting of hematemesis. The caregiver noticed the patient become unresponsive after having one episode of bright red emesis. EMS arrived and found the patient to be pulseless and performed three rounds of CPR and gave 1 mg of epinephrine before return of spontaneous circulation was obtained. The caregiver reported the patient had been complaining of diarrhea for the past few days after being started on magnesium citrate for constipation by his PCP. In the ED patient was intubated, sedated, and started on pressors due to undifferentiated shock. CT abdomen pelvis demonstrated diffuse dilation of the colon with massive stool burden and markedly distended rectum with impacted stool and circumferential rectal wall thickening consistent with stercoral colitis (Figures 1 and 2). In addition, there was a large hiatal …

High consumption of cruciferous vegetables is associated with a reduced risk of prostate cancer in epidemiological studies. There is preliminary evidence that sulforaphane, derived from glucoraphanin found in a number of crucifers, may prevent and induce regression of prostate cancer and other malignancies in preclinical models, but the mechanisms that may explain these effects are not fully defined. Recent reports show that sulforaphane may impair prostate cancer growth through inhibition of histone deacetylases, which are up-regulated in cancer. Indeed, one of these enzymes, histone deacetylase 6 (HDAC6), influences the acetylation state of a key androgen receptor (AR) chaperone, HSP90. AR is the central signaling pathway in prostate cancer, and its inhibition is used for both prevention and treatment of this disease. However, it is not known whether the effects of sulforaphane involve suppression of AR. We hypothesized that sulforaphane treatment would lead to hyperacetylation of HSP90 and that this would destabilize AR and attenuate AR signaling. We confirmed this by demonstrating that sulforaphane enhances HSP90 acetylation, thereby inhibiting its association with AR. Moreover, AR is subsequently degraded in the proteasome, which leads to reduced AR target gene expression and reduced AR occupancy at its target genes. Finally, sulforaphane inhibits HDAC6 deacetylase activity, and the effects of sulforaphane on AR protein are abrogated by overexpression of HDAC6 and mimicked by HDAC6 siRNA. The inactivation by sulforaphane of HDAC6-mediated HSP90 deacetylation and consequent attenuation of AR signaling represents a newly defined mechanism that may help explain this agent's effects in prostate cancer.

Diets high in cruciferous vegetables are associated with lower risk of incidence of prostate cancer, including aggressive forms of this disease. Human intervention studies with cruciferous vegetable-rich diets also demonstrate modulation of gene expression in important pathways in prostate cells. Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on multiple tumor models. Our own work demonstrates that sulforaphane inhibits AR signaling in prostate cancer cells. Here, we report results from the first clinical trial of sulforaphane-rich extracts in men with prostate cancer. We treated 20 patients who had recurrent prostate cancer with 200 μmoles/day of sulforaphane-rich extracts for a maximum period of 20 weeks and determined the proportion of patients with ≥50 % PSA declines, the primary endpoint. Only one subject experienced a ≥50 % PSA decline. Thus, the primary endpoint was not achieved. Seven patients experienced smaller PSA declines (

DNA methylation of promoter regions is a common event in prostate cancer, one of the most common cancers in men worldwide. Because prior reports demonstrating that DNA methylation is important in prostate cancer studied a limited number of genes, we systematically quantified the DNA methylation status of 1,505 CpG dinucleotides for 807 genes in 78 paraffin-embedded prostate cancer samples and three normal prostate samples. The ERG gene, commonly repressed in prostate cells in the absence of an oncogenic fusion to the TMPRSS2 gene, was one of the most commonly methylated genes, occurring in 74% of prostate cancer specimens. In an independent group of patient samples, we confirmed that ERG DNA methylation was common, occurring in 57% of specimens, and cancer-specific. The ERG promoter is marked by repressive chromatin marks mediated by polycomb proteins in both normal prostate cells and prostate cancer cells, which may explain ERG's predisposition to DNA methylation and the fact that tumors with ERG DNA methylation were more methylated, in general. These results demonstrate that bead arrays offer a high-throughput method to discover novel genes with promoter DNA methylation such as ERG, whose measurement may improve our ability to more accurately detect prostate cancer.

Anal electric stimulation has been described as effective for fecal incontinence in several case series, but no study has addressed possible mechanism of benefit. We wished to examine whether anal electric stimulation, using an anal probe electrode, used on a daily basis at home for eight weeks, in the absence of any adjunctive exercises or advice, would improve symptoms of fecal incontinence and anal sphincter pressures when compared with “sham” electric stimulation. Ninety patients (9 males, 81 females), with median age of 55 (range, 30–77) years were randomized, 47 to active anal stimulation at 35 Hz and 43 to “sham” stimulation at 1 Hz. Outcome measures included a one-week bowel diary, symptom questionnaire, manometry, and patients' evaluation of outcome. Seventy patients completed the study. On an intention-to-treat analysis, there was no difference between the two groups on any of the outcome measures after eight weeks. Of those who completed stimulation, 44 (63 percent) felt the stimulation had improved their continence. Those with intact anal sphincters were not likely to rate their change more positively than those with sphincter disruption (P = 0.71). Median patient rating of bowel control increased from 3 of 10 before stimulation to 5 of 10 after stimulation (P = 0.001). Eight weeks of anal electric stimulation was rated by patients as having improved their bowel control to a modest extent. There was no statistically significant difference detected between the groups, suggesting that 1 Hz was as effective as 35 Hz. This raises the possibility that the main effect is not sphincter contraction but sensitization of the patient to the anal area, or simply the effect of intervening per se. Home electric stimulation is a relatively cheap and generally well-tolerated therapy in the conservative treatment of fecal incontinence.

The androgen receptor (AR) is the principal therapeutic target in prostate cancer. For the past 70 years, androgen deprivation therapy (ADT) has been the major therapeutic focus. However, some patients do not benefit, and those tumors that do initially respond to ADT eventually progress. One recently described mechanism of such an effect is growth and survival-promoting effects of the AR that are exerted independently of the AR ligands, testosterone and dihydrotestosterone. However, specific ligand-independent AR target genes that account for this effect were not well characterized. We show here that c-Myc, which is a key mediator of ligand-independent prostate cancer growth, is a key ligand-independent AR target gene. Using microarray analysis, we found that c-Myc and AR expression levels strongly correlated with each other in tumors from patients with castration-resistant prostate cancer (CRPC) progressing despite ADT. We confirmed that AR directly regulates c-Myc transcription in a ligand-independent manner, that AR and c-Myc suppression reduces ligand-independent prostate cancer cell growth, and that ectopic expression of c-Myc attenuates the anti-growth effects of AR suppression. Importantly, treatment with the bromodomain inhibitor JQ1 suppressed c-Myc function and suppressed ligand-independent prostate cancer cell survival. Our results define a new link between two critical proteins in prostate cancer - AR and c-Myc - and demonstrate the potential of AR and c-Myc-directed therapies to improve prostate cancer control.

Prostate cancer is the most common cancer in men in the United States and the second leading cause of cancer death. The androgen receptor (AR) is the central signaling pathway in prostate cancer. Because of this, androgen deprivation therapy (ADT), which involves reducing levels of androgen ligands or interfering with binding of ligands to AR, has been the major therapeutic focus for the past 70 years. However, in many patients there is no benefit from ADT, and all prostate cancers eventually progress. At progression on ADT, the AR is ubiquitously expressed. For this reason, we contend that AR-dependent mechanisms are critical for prostate cancer progression after ADT. Indeed, recent work demonstrates that the AR can function independently of ligands to promote prostate cancer cell survival. However, specific ligand-independent AR target genes that account for this effect were not well-characterized. We show here that c-Myc, which is a key mediator of ligand-independent prostate cancer progression, is a key ligand-independent AR target gene. Using microarray analysis, we found that c-Myc and AR expression levels strongly correlated with each other in tumors from patients with castration-resistant prostate cancer (CRPC) progressing despite ADT. We confirmed that AR directly regulates c-Myc transcription in a ligand-independent manner, that AR and c-Myc suppression reduces ligand-independent prostate cancer cell growth, and that ectopic expression of c-Myc attenuates the anti-tumor activity of AR suppression. Importantly, treatment with the bromodomain inhibitor JQ1 suppressed c-Myc function and suppressed ligand-independent prostate cancer cell survival. Our results define a new link between two critical proteins in prostate cancer - AR and c-Myc - and demonstrate the potential of AR and c-Myc-directed therapies to improve prostate cancer control. Citation Format: Lina Gao, Jacob Schwartzman, Angela Gibbs, Richard Kleinschmidt, Beth Wilmot, Daniel Bottomly, Ilsa Coleman, Peter Nelson, Shannon McWeeney, Joshi J. Alumkal. Androgen receptor promotes ligand-independent prostate cancer progression through c-Myc upregulation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3131. doi:10.1158/1538-7445.AM2013-3131