A Resident-Driven Mobile Evaluation System Can Be Used to Augment Traditional Surgery Rotation Evaluations.

BACKGROUND: The Accreditation Council for Graduate Medical Education requires residents to receive milestone-based evaluations in key areas. Shortcomings of the traditional evaluation system (TES) are a low completion rate and delay in completion. We hypothesized that adoption of a mobile evaluation system (MES) would increase the number of evaluations completed and improve their timeliness. METHODS: Traditional evaluations for a general surgery residency program were converted into a web-based form via a widely available, free, and secure application and implemented in August 2017. After 8 months, MES data were analyzed and compared to that of our TES. RESULTS: 122 mobile evaluations were completed; 20% were solicited by residents. Introduction of the MES resulted in an increased number of evaluations per resident (P = .0028) and proportion of faculty completing evaluations (P = .0220). Timeliness also improved, with 71% of evaluations being completed during one's clinical rotation. CONCLUSIONS: A resident-driven MES is an inexpensive and effective method to augment traditional end-of-rotation evaluations.

Resident Endoscopy Experience Correlates Poorly with Performance on a Virtual Reality Simulator.

Background Endoscopy training has become increasingly emphasized during general surgery residency as reflected by introduction of the Fundamentals of Endoscopic Surgery (FES) examination, which includes testing of skills on virtual reality (VR) simulators. Although studies exist to assess the ability of the simulator to differentiate between novices and experienced endoscopists, it is not well understood how simulators can differentiate skills among resident cohort. Objective To assess the utility of the VR simulator, we evaluated the correlation between resident endoscopy experience and performance on two VR simulator colonoscopy modules on the GI-BRONCH Mentor (Simbionix Ltd, Airport City, Israel). Methods Postgraduate years 2 to 5 residents completed "easy" and "difficult" VR colonoscopies, and performance metrics were recorded from October 2017 to February 2018 at Rutgers' two general surgery residency programs. Resident endoscopy experience was obtained through Accreditation Council for Graduate Medical Education case logs. Correlations between resident endoscopy experience and VR colonoscopy performance metrics were assessed using Spearman's rho (ρ) correlation statistic and bivariate logistic regression. Results Fifty-five residents out of 65 (84.6%) eligible participants completed the study. There were limited correlations found between resident endoscopy experience and FES performance metrics and no correlations were found between resident endoscopy experience and binary metrics of colonoscopy-ability to complete colonoscopy, ability to retroflex, and withdrawal time of less than 6 minutes. Conclusion The VR simulator may have a limited ability to discriminate between experience levels among resident cohort. Future studies are needed to further understand how well the VR simulator metrics correlate with resident endoscopy experience.

Surgical Skills Olympiad: A 4-Year Experience in a General Surgery Residency Program.

Background The acquisition of operative skills is the critical defining component of general surgery training. Performing simulated tasks has been shown to increase a resident's technical skills. As such, we devised the Surgical Skills Olympiad, an annual simulation-based skills competition. We examined our 4-year experience with the Olympiad at a large academic general surgery residency program. Objective This study aimed to use competition to motivate trainees to increase the time they spent practicing basic surgical skills, resulting in improved performance over time. Methods Teams were formed from members of each postgraduate year (PGY) class. Competition tasks were level specific: knot tying for PGY-1, basic laparoscopy for PGY-2, handsewn bowel anastomosis for PGY-3, vascular anastomosis for PGY-4, and advanced laparoscopy for PGY-5. Task scores over a 4-year period (2014-2017) were analyzed and a survey of participating teaching faculty was conducted. Results Ten faculty members responded to the survey, for a response rate of 63%. A total of 50% respondents felt that the caliber of surgical skills increased since the Olympiad was implemented. Ninety percent agreed that the Olympiad was beneficial for residents to assess their skills against their peers. Over 4 years, there was an improvement in scores for suturing task, advanced laparoscopy, and bowel anastomosis ( p < 0.05 for all three). Conclusion A residency-wide surgical skills competition can improve resident performance in technical tasks and promote faculty engagement in resident skills training.

BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program.

PURPOSE: Lineage plasticity in prostate cancer-most commonly exemplified by loss of androgen receptor (AR) signaling and a switch from a luminal to alternate differentiation program-is now recognized as a treatment resistance mechanism. Lineage plasticity is a spectrum, but neuroendocrine prostate cancer (NEPC) is the most virulent example. Currently, there are limited treatments for NEPC. Moreover, the incidence of treatment-emergent NEPC (t-NEPC) is increasing in the era of novel AR inhibitors. In contradistinction to de novo NEPC, t-NEPC tumors often express the AR, but AR's functional role in t-NEPC is unknown. Furthermore, targetable factors that promote t-NEPC lineage plasticity are also unclear. EXPERIMENTAL DESIGN: Using an integrative systems biology approach, we investigated enzalutamide-resistant t-NEPC cell lines and their parental, enzalutamide-sensitive adenocarcinoma cell lines. The AR is still expressed in these t-NEPC cells, enabling us to determine the role of the AR and other key factors in regulating t-NEPC lineage plasticity. RESULTS: AR inhibition accentuates lineage plasticity in t-NEPC cells-an effect not observed in parental, enzalutamide-sensitive adenocarcinoma cells. Induction of an AR-repressed, lineage plasticity program is dependent on activation of the transcription factor E2F1 in concert with the BET bromodomain chromatin reader BRD4. BET inhibition (BETi) blocks this E2F1/BRD4-regulated program and decreases growth of t-NEPC tumor models and a subset of t-NEPC patient tumors with high activity of this program in a BETi clinical trial. CONCLUSIONS: E2F1 and BRD4 are critical for activating an AR-repressed, t-NEPC lineage plasticity program. BETi is a promising approach to block this program.

Alternative splicing of LSD1+8a in neuroendocrine prostate cancer is mediated by SRRM4.

Neuroendocrine prostate cancer (NEPC) is the most virulent form of prostate cancer. Importantly, our recent work examining metastatic biopsy samples demonstrates NEPC is increasing in frequency. In contrast to prostate adenocarcinomas that express a luminal gene expression program, NEPC tumors express a neuronal gene expression program. Despite this distinction, the diagnosis of NEPC is often challenging, demonstrating an urgent need to identify new biomarkers and therapeutic targets. Our prior work demonstrated that the histone demethylase LSD1 (KDM1A) is important for survival of prostate adenocarcinomas, but little was known about LSD1's role in NEPC. Recently, a neural-specific transcript variant of LSD1-LSD1+8a-was discovered and demonstrated to activate neuronal gene expression in neural cells. The splicing factor SRRM4 was previously shown to promote LSD1+8a splicing in neuronal cells, and SRRM4 promotes NEPC differentiation and cell survival. Therefore, we sought to determine if LSD1+8a might play a role in NEPC and whether LSD1+8a splicing was linked to SRRM4. To investigate a potential role for LSD1+8a in NEPC, we examined a panel of prostate adenocarcinoma and NEPC patient-derived xenografts and metastatic biopsies. LSD1+8a was expressed exclusively in NEPC samples and correlated significantly with elevated expression of SRRM4. Using SRRM4-overexpressing cell lines, we determined that SRRM4 mediates alternative splicing of LSD1+8a. Finally, using gain of function studies, we confirmed that LSD1+8a and SRRM4 co-regulate target genes distinct from canonical LSD1. Our findings suggest further study of the interplay between SRRM4 and LSD1+8a and mechanisms by which LSD1+8a regulates gene expression in NEPC is warranted.

BET bromodomain inhibition blocks the function of a critical AR-independent master regulator network in lethal prostate cancer.

BET bromodomain inhibitors block prostate cancer cell growth at least in part through c-Myc and androgen receptor (AR) suppression. However, little is known about other transcriptional regulators whose suppression contributes to BET bromodomain inhibitor anti-tumor activity. Moreover, the anti-tumor activity of BET bromodomain inhibition in AR-independent castration-resistant prostate cancers (CRPC), whose frequency is increasing, is also unknown. Herein, we demonstrate that BET bromodomain inhibition blocks growth of a diverse set of CRPC cell models, including those that are AR-independent or in which c-Myc is not suppressed. To identify transcriptional regulators whose suppression accounts for these effects, we treated multiple CRPC cell lines with the BET bromodomain inhibitor JQ1 and then performed RNA-sequencing followed by Master Regulator computational analysis. This approach identified several previously unappreciated transcriptional regulators that are highly expressed in CRPC and whose suppression, via both transcriptional or post-translational mechanisms, contributes to the anti-tumor activity of BET bromodomain inhibitors.

Maintenance of MYC expression promotes de novo resistance to BET bromodomain inhibition in castration-resistant prostate cancer.

The BET bromodomain protein BRD4 is a chromatin reader that regulates transcription, including in cancer. In prostate cancer, specifically, the anti-tumor activity of BET bromodomain inhibition has been principally linked to suppression of androgen receptor (AR) function. MYC is a well-described BRD4 target gene in multiple cancer types, and prior work demonstrates that MYC plays an important role in promoting prostate cancer cell survival. Importantly, several BET bromodomain clinical trials are ongoing, including in prostate cancer. However, there is limited information about pharmacodynamic markers of response or mediators of de novo resistance. Using a panel of prostate cancer cell lines, we demonstrated that MYC suppression-rather than AR suppression-is a key determinant of BET bromodomain inhibitor sensitivity. Importantly, we determined that BRD4 was dispensable for MYC expression in the most resistant cell lines and that MYC RNAi + BET bromodomain inhibition led to additive anti-tumor activity in the most resistant cell lines. Our findings demonstrate that MYC suppression is an important pharmacodynamic marker of BET bromodomain inhibitor response and suggest that targeting MYC may be a promising therapeutic strategy to overcome de novo BET bromodomain inhibitor resistance in prostate cancer.

Robot-Assisted Repair of E1 Biliary Ductal Injury with Roux-en-Y Hepaticojejunostomy.

Background: Common bile duct (CBD) injury is a serious complication of laparoscopic and open cholecystectomy. Early identification and minimally invasive repair, when possible, can prevent much of the morbidity associated with this injury. Materials and Methods: A 36-year-old woman referred in the immediate perioperative period for CBD injury at the time of laparoscopic cholecystectomy. We present a case of early robot-assisted repair of a Strasberg class E1 bile duct injury with Roux-en-Y hepaticojejunostomy. Results: Total console time of 4 hours with minimal blood loss and no requirement for transfusion with length of stay of 3 days. No intra- or perioperative complications of the surgery were noted. Conclusion: The degrees of freedom and stability of the robotic platform were instrumental during several key steps, including exposure of the hepatic hilum, positioning of the Roux limb, and suturing of the CBD. Successful minimally invasive repair of this patient's CBD injury minimized the morbidity of the index operation, blood loss, hospital length of stay, and potential legal consequences.

LSD1 activates a lethal prostate cancer gene network independently of its demethylase function.

Medical castration that interferes with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, clinical progression is universal, and tumors with AR-independent resistance mechanisms appear to be increasing in frequency. Consequently, there is an urgent need to develop new treatments targeting molecular pathways enriched in lethal prostate cancer. Lysine-specific demethylase 1 (LSD1) is a histone demethylase and an important regulator of gene expression. Here, we show that LSD1 promotes the survival of prostate cancer cells, including those that are castration-resistant, independently of its demethylase function and of the AR. Importantly, this effect is explained in part by activation of a lethal prostate cancer gene network in collaboration with LSD1's binding protein, ZNF217. Finally, that a small-molecule LSD1 inhibitor-SP-2509-blocks important demethylase-independent functions and suppresses castration-resistant prostate cancer cell viability demonstrates the potential of LSD1 inhibition in this disease.

Improving cancer patient emergency room utilization: A New Jersey state assessment.

INTRODUCTION: Due to its increasing incidence and its major contribution to healthcare costs, cancer is a major public health problem in the United States. The impact across different services is not well documented and utilization of emergency departments (ED) by cancer patients is not well characterized. The aim of our study was to identify factors that can be addressed to improve the appropriate delivery of quality cancer care thereby reducing ED utilization, decreasing hospitalizations and reducing the related healthcare costs. METHODS: The New Jersey State Inpatient and Emergency Department Databases were used to identify the primary outcome variables; patient disposition and readmission rates. The independent variables were demographics, payer and clinical characteristics. Multivariable unconditional logistic regression models using clinical and demographic data were used to predict hospital admission or emergency department return. RESULTS: A total of 37,080 emergency department visits were cancer related with the most common diagnosis attributed to lung cancer (30.0%) and the most common presentation was pain. The disposition of patients who visit the ED due to cancer related issues is significantly affected by the factors of race (African American OR=0.6, p value=0.02 and Hispanic OR=0.5, p value=0.02, respectively), age aged 65 to 75years (SNF/ICF OR 2.35, p value=0.00 and Home Healthcare Service OR 5.15, p value=0.01, respectively), number of diagnoses (OR 1.26, p value=0.00), insurance payer (SNF/ICF OR 2.2, p value=0.02 and Home Healthcare Services OR 2.85, p value=0.07, respectively) and type of cancer (breast OR 0.54, p value=0.01, prostate OR 0.56, p value=0.01, uterine OR 0.37, p value=0.02, and other OR 0.62, p value=0.05, respectively). In addition, comorbidities increased the likelihood of death, being transferred to SNF/ICF, or utilization of home healthcare services (OR 1.6, p value=0.00, OR 1.18, p value=0.00, and OR 1.16, p value=0.04, respectively). Readmission is significantly affected by race (American Americans OR 0.41, standard error 0.08, p value=0.001 and Hispanics OR 0.29, standard error 0.11, p value=0.01, respectively), income (Quartile 2 OR 0.98, standard error 0.14, p value 0.01, Quartile 3 OR 1.07, standard error 0.13, p value 0.01, and Quartile 4 OR 0.88, standard error 0.12, p value 0.01, respectively), and type of cancer (prostate OR 0.25, standard error 0.09, p value=0.001). CONCLUSION: Web based symptom questionnaires, patient navigators, end of life nursing and clinical cancer pathways can identify, guide and prompt early initiation of treat before progression of symptoms in cancer patients most likely to visit the ED. Thus, improving cancer patient satisfaction, outcomes and reduce health care costs.

Speed dating for mentors: a novel approach to mentor/mentee pairing in surgical residency.

BACKGROUND: Resident-resident mentoring offers significant benefits. Previous works have shown that the quality of the mentorship pairing is important, but techniques of pairing have seldom been described. We describe a system for mentor-mentee pairing that we call "Speed Dating for Mentors" (SDM). METHODS: The SDM activity took place in an academic general surgery residency program in the Northeast. Senior residents met with junior residents (JR) in 90-second intervals. On completion of interviews, residents documented their top three choices-this was used to create senior-junior resident pairings. A cross-sectional Likert survey was conducted with univariate analysis of satisfaction with the SDM event. RESULTS: Forty-two surgical residents participated in SDM-23 junior residents and 19 senior residents-resulting in 23 mentor-mentee pairings. Fourteen pairs were generated, where both mentor and mentee were among top three choices, seven pairings generated where either/or was a top three choice, and two pairings were assigned; six pairs were assigned for nonattendees. A total of 36 surveys were completed-28 (78%) respondents participated in SDM compared to eight (22%) who did not. Eighty-five percent of respondents who attended were "satisfied" or "very satisfied" with their pairing compared to only 12% of nonattendees (P = 0.001). CONCLUSIONS: "Speed dating" is a novel approach to forming mentorship pairings and identifying mentors/mentees with similar interests. Residents who attended the event were satisfied with the event and with the outcome of their mentor/mentee pairing. Further investigations are warranted to determine what effects resident mentoring has on resident performance, stress levels, and well-being.

Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors.

Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination repair (HRR) such as BRCA2 HRR defects confer synthetic lethality to PARP inhibitors (PARPi) such as olaparib and talazoparib. In ovarian or breast cancers, olaparib resistance has been associated with HRR restoration, including by BRCA2 mutation reversion. Whether similar mechanisms operate in prostate cancer, and could be detected in liquid biopsies, is unclear. Here, we identify BRCA2 reversion mutations associated with olaparib and talazoparib resistance in patients with prostate cancer. Analysis of circulating cell-free DNA (cfDNA) reveals reversion mutation heterogeneity not discernable from a single solid-tumor biopsy and potentially allows monitoring for the emergence of PARPi resistance.Significance: The mechanisms of clinical resistance to PARPi in DNA repair-deficient prostate cancer have not been described. Here, we show BRCA2 reversion mutations in patients with prostate cancer with metastatic disease who developed resistance to talazoparib and olaparib. Furthermore, we show that PARPi resistance is highly multiclonal and that cfDNA allows monitoring for PARPi resistance. Cancer Discov; 7(9); 999-1005. ©2017 AACR.See related commentary by Domchek, p. 937See related article by Kondrashova et al., p. 984See related article by Goodall et al., p. 1006This article is highlighted in the In This Issue feature, p. 920.

Integrative molecular network analysis identifies emergent enzalutamide resistance mechanisms in prostate cancer.

Recent work demonstrates that castration-resistant prostate cancer (CRPC) tumors harbor countless genomic aberrations that control many hallmarks of cancer. While some specific mutations in CRPC may be actionable, many others are not. We hypothesized that genomic aberrations in cancer may operate in concert to promote drug resistance and tumor progression, and that organization of these genomic aberrations into therapeutically targetable pathways may improve our ability to treat CRPC. To identify the molecular underpinnings of enzalutamide-resistant CRPC, we performed transcriptional and copy number profiling studies using paired enzalutamide-sensitive and resistant LNCaP prostate cancer cell lines. Gene networks associated with enzalutamide resistance were revealed by performing an integrative genomic analysis with the PAthway Representation and Analysis by Direct Reference on Graphical Models (PARADIGM) tool. Amongst the pathways enriched in the enzalutamide-resistant cells were those associated with MEK, EGFR, RAS, and NFKB. Functional validation studies of 64 genes identified 10 candidate genes whose suppression led to greater effects on cell viability in enzalutamide-resistant cells as compared to sensitive parental cells. Examination of a patient cohort demonstrated that several of our functionally-validated gene hits are deregulated in metastatic CRPC tumor samples, suggesting that they may be clinically relevant therapeutic targets for patients with enzalutamide-resistant CRPC. Altogether, our approach demonstrates the potential of integrative genomic analyses to clarify determinants of drug resistance and rational co-targeting strategies to overcome resistance.

Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor.

Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) - the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation.

A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer.

INTRODUCTION: 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. PURPOSE: 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. METHODS: 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 (<50%). There was also a significant lengthening of the on-treatment PSA doubling time (PSADT) compared with the pre-treatment PSADT [6.1 months pre-treatment vs. 9.6 months on-treatment (p = 0.044)]. Finally, treatment with sulforaphane-rich extracts was safe with no Grade 3 adverse events. CONCLUSIONS: Treatment with 200 µmoles/day of sulforaphane-rich extracts did not lead to ≥50% PSA declines in the majority of patients. However, because of the safety of treatment and the effects on PSADT modulation, further studies, including those with higher doses, may be warranted to clarify the role of sulforaphane as a prevention agent or treatment agent.

Immunohistochemical expression of ERG in the molecular epidemiology of fatal prostate cancer study.

BACKGROUND: Gene fusions between the ERG transcription factor and the androgen-regulated gene TMPRSS2 occur in a subset of prostate cancers and contribute to transformation of prostatic epithelial cells. Prior reports have used fluorescence in situ hybridization (FISH) or quantitative PCR (QPCR) to determine the presence of TMPRSS2-ERG fusions or ERG expression, respectively. Recently, several groups have reported on immunohistochemistry (IHC) to measure ERG expression, which is much more readily performed in clinical practice. However, the prior studies examining ERG expression by IHC had small sample sizes or they failed to clarify the association of ERG protein expression with important clinico-pathological features or prostate cancer-specific mortality. METHODS: To address these deficits, we evaluated ERG expression by IHC in 208 radical prostatectomy samples from the Kaiser Permanente Molecular Epidemiology of Fatal Prostate Cancer (MEFPC) study, a case-control study of prostate cancer-specific mortality. RESULTS: Nuclear ERG expression was seen in neoplastic prostate epithelia in 49 of the samples (23.7%). ERG expression in tumor cells was associated with higher tumor stage (OR = 2.0, 95% confidence interval 1.0-4.0, P value = 0.04). ERG immunoreactivity was positively associated with prostate cancer-specific mortality, although the confidence interval was wide (OR = 1.9, 95% confidence interval 0.88-4.0, P value = 0.10). CONCLUSIONS: Our results demonstrate that ERG protein expression is readily quantifiable with an existing commercial antibody. Evaluating ERG protein expression may improve our ability to identify the subset of more aggressive, invasive prostate cancers.

Androgen receptor promotes ligand-independent prostate cancer progression through c-Myc upregulation.

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.

Synthetic cyclohexenyl chalcone natural products possess cytotoxic activities against prostate cancer cells and inhibit cysteine cathepsins in vitro.

A number of cyclohexenyl chalcone Diels-Alder natural products possess promising biological properties including strong cytotoxicity in various human cancer cells. Herein, we show that natural products in this class including panduratin A and nicolaioidesin C inhibit cysteine cathepsins as indicated by protease profiling assays and cell-free cathepsin L enzyme assays. Owing to the critical roles of cathepsins in the biology of human tumor progression, invasion, and metastasis, these findings should pave the way for development of novel antitumor agents for use in clinical settings.

A DNA methylation microarray-based study identifies ERG as a gene commonly methylated in prostate cancer.

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 1505 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.