Citations

ABSTRACT Reduced levels of the cardiac human (h)ERG ion channel protein and the corresponding repolarizing current IKr can cause arrhythmia and sudden cardiac death, but the underlying cellular mechanisms controlling hERG surface expression are not well understood. Here, we identified TRIOBP-1, an F-actin-binding protein previously associated with actin polymerization, as a putative hERG-interacting protein in a yeast-two hybrid screen of a cardiac library. We corroborated this interaction by performing Förster resonance energy transfer (FRET) in HEK293 cells and co-immunoprecipitation in HEK293 cells and native cardiac tissue. TRIOBP-1 overexpression reduced hERG surface expression and current density, whereas reducing TRIOBP-1 expression via shRNA knockdown resulted in increased hERG protein levels. Immunolabeling in rat cardiomyocytes showed that native TRIOBP-1 colocalized predominantly with myosin-binding protein C and secondarily with rat ERG. In human stem cell-derived cardiomyocytes, TRIOBP-1 overexpression caused intracellular co-sequestration of hERG signal, reduced native IKr and disrupted action potential repolarization. Ca2+ currents were also somewhat reduced and cell capacitance was increased. These findings establish that TRIOBP-1 interacts directly with hERG and can affect protein levels, IKr magnitude and cardiac membrane excitability.

2 Background: Significant genomic diversity exists in the androgen receptor ( AR) and its activity (AR-A) in mCRPC. In localized prostate cancer, the biologic, prognostic, and therapeutic clinical implications of AR-A heterogeneity have yet to be interrogated Methods: Genome-wide expression profiles of FFPE RP or biopsy tumor samples were evaluated from a prospective registry cohort (n = 5,239, NCT02609269) and six retrospective institutional cohorts (n = 1,170). AR-A was calculated based on expression of 9 targets of AR.. Results: Utilizing 6,409 localized prostate adenocarcinomas with full transcriptomic data, we found there was marked inter-individual transcriptomic diversity in AR and AR-A expression, and weak correlation between them (r = 0.08 to 0.36 based on cohort), in contrast to mCRPC that has a strong correlation between AR and AR-A expression (r = 0.76). Additionally, serum PSA had no correlation to intratumoral AR-A (r = 0.06). Unsupervised hierarchical clustering identified a distinct subclass of low AR-A prostate tumors, which had increased markers of immunogenicity (decreased T-regs and MDSCs, and increased CD3 effector T-cells), increased neuroendocrine marker expression ( NCAM1, ENO2, and SCG2), and decreased DNA repair pathway expression (all p < 0.001). Clinically, low AR-A tumors had more rapid development of metastatic disease in three independent cohorts, were more prone to develop resistance to hormonal therapy and develop CRPC, and were found at an increased frequency in African-American men. Interrogating in vitro drug sensitivity analyses utilizing the NCI-60 panel, low AR-A tumors appear more sensitive to platinum chemotherapy and PARP inhibition, and less sensitive to hormone therapy and taxanes. Conclusions: The diversity in AR-signaling in localized prostate cancer represents important biological heterogeneity that is both prognostic and predictive of treatment response. These findings are provocative in that low AR-A tumors may be more susceptible to immunotherapy, PARP inhibition, platinum chemotherapy, and/or radiotherapy. Patients with low AR-A tumors warrant dedicated biomarker enhanced clinical trials.

125 Background: Men with lymph node involvement (LNI) at prostatectomy (RP) are at high risk of dying from prostate cancer. However, survival following RP is highly variable, with some men apparently cured. Nomograms developed for men with LNI have been based on series where all or the vast majority of men received adjuvant treatment. Because administration of adjuvant treatment is not universal, even for LNI, we evaluated whether the Decipher genomic classifier (GC) can improve upon clinical models to predict metastasis within 5 years (MET5) and prostate cancer specific mortality within 10 years (PCSM10) in a cohort of LNI patients, the majority of whom did not receive adjuvant treatment. Methods: 141 patients from 4 institutions (Johns Hopkins, Mayo Clinic, Leuven, MD Anderson) had LNI at RP, had adequate tissue and clinical data for analysis of MET5, and 86 were analyzed for PCSM10. 43% of men received adjuvant therapy. RP tumor tissue was analyzed by Affymetrix Human Exon 1.0 ST GeneChip; the GC was calculated based on 22 genes in the previously trained and validated algorithm. Logistic regression evaluated whether the GC, dichotomized as high risk (GC score > 0.6) vs low-intermediate risk (≤0.6), improved prediction of MET5 and PCSM10 beyond that achieved with established clinical prognostic factors. Results: 62 men (43%) developed MET5, and 35 (41%) developed PCSM10. For both MET5 and PCSM10 CAPRA-S, number of positive lymph nodes, and age were significant; adjuvant therapy was not significant. GC was a significant independent strong prognostic factor when added to the clinical model for prediction of MET5, odds ratio = 4.04 (95% CI: 1.48, 11.02), p = 0.006, and prediction of PCSM10, odds ratio = 6.71 (95% CI: 2.01, 22.38), p = 0.002. Addition of GC to the clinical model improved the AUC from 0.77 to 0.79 for MET5, and from 0.65 to 0.74 for PCSM10. Conclusions: The Decipher GC significantly improves upon clinical variables to predict metastasis and prostate cancer specific mortality in men at high risk due to LNI. This is the first study to show a genomic classifier predicts outcomes in men with LNI; validation is needed to determine if Decipher can improve treatment decisions in men with LNI.

AbstractPurposeDevelop a framework to quantify the size, location and severity of femoral and acetabular‐sided cartilage and labral damage observed in patients undergoing hip arthroscopy, and generate a database of individual defect parameters to facilitate future research and treatment efforts.MethodsThe size, location, and severity of cartilage and labral damage were prospectively collected using a custom, standardized post‐operative template for 100 consecutive patients with femoroacetabular impingement syndrome. Chondrolabral junction damage, isolated intrasubstance labral damage, isolated acetabular cartilage damage and femoral cartilage damage were quantified and recorded using a combination of Beck and ICRS criteria. Radiographic measurements including alpha angle, head–neck offset, lateral centre edge angle and acetabular index were calculated and compared to the aforementioned chondral data using a multivariable logistic regression model and adjusted odd’s ratio. Reliability among measurements were assessed using the kappa statistic and intraclass coefficients were used to evaluate continuous variables.ResultsDamage to the acetabular cartilage originating at the chondrolabral junction was the most common finding in 97 hips (97%) and was usually accompanied by labral damage in 65 hips (65%). The width (p = 0.003) and clock‐face length (p = 0.016) of the damaged region both increased alpha angle on anteroposterior films. 10% of hips had femoral cartilage damage while only 2 (2%) of hips had isolated defects to either the acetabular cartilage or labrum. The adjusted odds of severe cartilage (p = 0.022) and labral damage (p = 0.046) increased with radiographic cam deformity but was not related to radiographic measures of acetabular coverage.ConclusionsDamage at the chondrolabral junction was very common in this hip arthroscopy cohort, while isolated defects to the acetabular cartilage or labrum were rare. These data demonstrate that the severity of cam morphology, quantified through radiographic measurements, is a primary predictor of location and severity of chondral and labral damage and focal chondral defects may represent a unique subset of patients that deserve further study.Level of evidenceIV.

Abstract Tumor-associated macrophages (TAM) play a critical role in cancer development and progression. However, the heterogeneity of TAM presents a major challenge to identify clinically relevant markers for protumor TAM. Here, we report that expression of adipocyte/macrophage fatty acid–binding protein (A-FABP) in TAM promotes breast cancer progression. Although upregulation of A-FABP was inversely associated with breast cancer survival, deficiency of A-FABP significantly reduced mammary tumor growth and metastasis. Furthermore, the protumor effect of A-FABP was mediated by TAM, in particular, in a subset of TAM with a CD11b+F4/80+MHCII−Ly6C− phenotype. A-FABP expression in TAM facilitated protumor IL6/STAT3 signaling through regulation of the NFκB/miR-29b pathway. Collectively, our results suggest A-FABP as a new functional marker for protumor TAM. Significance: These findings identify A-FABP as a functional marker for protumor macrophages, thus offering a new target for tumor immunotherapy. Cancer Res; 78(9); 2343–55. ©2018 AACR.

Combining DNA methylation markers with a swallowable device for sampling the distal esophagus effectively detects Barrett’s neoplasias.