Multiple Acquired Renal Carcinoma Tumor Capabilities Abolished upon Silencing of ADAM17

Malignancy is a manifestation of acquired defects in regulatory circuits that direct normal cell proliferation and homeostasis. Most of these circuits operate through cell autonomous pathways, whereas others potentially involve the neighboring microenvironment. We report that the metalloprotease ADAM17 plays a pivotal role in several acquired tumor cell capabilities by mediating the availability of soluble transforming growth factor-alpha, an epidermal growth factor receptor (EGFR) ligand, and thus the establishment of a key autocrine signaling pathway. Silencing of ADAM17 in human renal carcinoma cell lines corrects critical features associated with cancer cells, including growth autonomy, tumor inflammation, and tissue invasion. Highly malignant renal carcinoma cancer cells fail to form in vivo tumors in the absence of ADAM17, confirming the essential function of this molecule in tumorigenesis. These data show that ligand shedding is a crucial step in endogenous EGFR activation and endorse prospective therapeutic strategies targeting ADAM17 in human cancer

The RNA-Binding Protein HuR Promotes Cell Migration and Cell Invasion by Stabilizing the β-actin mRNA in a U-Rich-Element-Dependent Manner▿ †

A high expression level of the β-actin protein is required for important biological mechanisms, such as maintaining cell shape, growth, and motility. Although the elevated cellular level of the β-actin protein is directly linked to the long half-life of its mRNA, the molecular mechanisms responsible for this effect are unknown. Here we show that the RNA-binding protein HuR stabilizes the β-actin mRNA by associating with a uridine-rich element within its 3′ untranslated region. Using RNA interference to knock down the expression of HuR in HeLa cells, we demonstrate that HuR plays an important role in the stabilization but not in the nuclear/cytoplasmic distribution of the β-actin mRNA. HuR depletion in HeLa cells alters key β-actin-based cytoskeleton functions, such as cell adhesion, migration, and invasion, and these defects correlate with a loss of the actin stress fiber network. Together our data establish that the posttranscriptional event involving HuR-mediated β-actin mRNA stabilization could be a part of the regulatory mechanisms responsible for maintaining cell integrity, which is a prerequisite for avoiding transformation and tumor formation

Structured electronic operative reporting: Comparison with dictation in kidney cancer surgery

► First study operative report quality in kidney cancer surgery. ► First system evaluated that: (i) uses real time POC documentation embedded in the EPR; (ii) uses data fields that are searchable for research and quality assessment. ► Documentation with structured electronic templates improves quality of OR note. The purpose of this study was to evaluate the functionality of eKidney as a structured reporting tool in operative note generation. To do this, we compared completeness and timeliness of eKidney template-generated nephrectomy OR notes with standard narrative dictation. A group of academic uro-oncologists and medical informaticians at the University Health Network designed and adopted an electronic online, point-of-care clinical documentation tool, eCancerCareKidney (eKidney) for kidney cancer patient care. The optimal components of clinic and operative note templates, including those for nephrectomy, were agreed upon by expert consensus of the uro-oncologists. Clinician nephrectomy OR reports were analyzed for completeness, comparing those generated in eKidney with conventionally dictated notes. Patterns of missing information from both dictated and eKidney-generated reports were analyzed. The procedure, note completion and transcription dates were recorded which generated time intervals between these events. The records of 189 procedures were included in the analysis. Comparison of clinicians who used both note generation modalities, revealed a mean completion rate of 92% for eKidney/structured notes and 68% for dictated notes (p<0.0001). There was no significant difference in completion rates between attending staff and trainees (residents and fellows) (p=0.131). Most notes were dictated/entered on the day of surgery. Dictated notes were transcribed to EPR a median of 2 days after dictation, however roughly 30% of dictated notes took 5 days or more to get transcribed. All notes generated using eKidney were uploaded to the EPR immediately. Our study has three significant limitations. Firstly, our study was not randomized: physicians could elect to dictate or use eKidney. Secondly, we did not identify data from dictated notes that were not captured by eKidney. Third, we did not compare the time it took physicians to complete the fields in eKidney with the time it takes to dictate a note. We have demonstrated that the use of structured reporting improves the completeness and timeliness of documentation in kidney cancer surgery. eKidney is an example of the power of templates in ensuring that important details of a procedure are recorded. Future studies looking at user satisfaction, and research and educational potential of eKidney would be valuable

State of the Science: An Update on Renal Cell Carcinoma

Renal cell carcinomas (RCC) are emerging as a complex set of diseases with major socioeconomic impact and a continued rise in incidence throughout the world. As the field of urologic oncology faces these trends, several major genomic and mechanistic discoveries have altered our core understanding of this multitude of cancers, including several new rare subtypes of renal cancers. This review will examine these new findings, and place them in the context of the well-established association of clear cell RCC (ccRCC) with mutations in the von Hippel-Lindau (VHL) gene and resultant aberrant hypoxia inducible factor (HIF) signaling. The impact of novel ccRCC-associated genetic lesions on chromatin remodeling and epigenetic regulation is explored. The effects of VHL mutation on primary ciliary function, extracellular matrix homeostasis, and tumor metabolism are discussed. VHL proteostasis is reviewed, with the goal of harnessing the proteostatic machinery to refunctionalize mutant VHL. Translational efforts using molecular tools to understand discriminating features of ccRCC tumors and develop improved prognostic and predictive algorithms are presented and new therapeutics arising from the earliest molecular discoveries in ccRCC are summarized. By creating an integrated review of the key genomic and molecular biological disease characteristics of ccRCC and placing these data in the context of the evolving therapeutic landscape, we intend to facilitate interaction between basic, translational and clinical researchers involved in the treatment of this devastating disease, and accelerate progress towards its ultimate eradication