Structural basis for the regulatory role of the PPxY motifs in the thioredoxin-interacting protein TXNIP.

TXNIP (thioredoxin-interacting protein) negatively regulates the antioxidative activity of thioredoxin and participates in pleiotropic cellular processes. Its deregulation is linked to various human diseases, including diabetes, acute myeloid leukaemia and cardiovascular diseases. The E3 ubiquitin ligase Itch (Itchy homologue) polyubiquitinates TXNIP to promote its degradation via the ubiquitin-proteasome pathway, and this Itch-mediated polyubiquitination of TXNIP is dependent on the interaction of the four WW domains of Itch with the two PPxY motifs of TXNIP. However, the molecular mechanism of this interaction of TXNIP with Itch remains elusive. In the present study, we found that each of the four WW domains of Itch exhibited different binding affinities for TXNIP, whereas multivalent engagement between the four WW domains of Itch and the two PPxY motifs of TXNIP resulted in their strong binding avidity. Our structural analyses demonstrated that the third and fourth WW domains of Itch were able to recognize both PPxY motifs of TXNIP simultaneously, supporting a multivalent binding mode between Itch and TXNIP. Interestingly, the phosphorylation status on the tyrosine residue of the PPxY motifs of TXNIP serves as a molecular switch in its choice of binding partners and thereby downstream biological signalling outcomes. Phosphorylation of this tyrosine residue of TXNIP diminished the binding capability of PPxY motifs of TXNIP to Itch, whereas this phosphorylation is a prerequisite to the binding activity of TXNIP to SHP2 [SH2 (Src homology 2) domain-containing protein tyrosine phosphatase 2] and their roles in stabilizing the phosphorylation and activation of CSK (c-Src tyrosine kinase).

Derivation and validation of text search algorithms for renal and adrenal lesion identification in radiology text reports.

INTRODUCTION: Most cohort studies are limited by sampling and accrual bias. The capability to detect specific lesions identified in radiological text reports could eliminate these biases and benefit patient care, clinical research, and trial recruitment. This study derived and internally validated text search algorithms to identify four common urological lesions (solid renal masses, complex renal cysts, adrenal masses, and simple renal cysts) using radiology text reports. METHODS: A simple random sample of 10 000 abdominal ultrasound (US) and computed tomography (CT) reports was drawn from our hospital's data warehouse. Reports were manually reviewed to determine the true status of the four lesions. Using commonly available software, we created logistic regression models having as predictors the status of a priori selected text terms in the report. We used bootstrap sampling with 95th percentile thresholds to select variables for the final models, which were modified into point systems. A second independent, random sample of 2855 reports, stratified by the number of points for each abnormality, was reviewed in a blinded fashion to measure the accuracy of each lesion's point system. RESULTS: The prevalence of solid renal mass, complex renal cyst, adrenal mass, and simple renal cyst, was 2.0%, 1.7%, 3.2%, and 20.0%, respectively. Each model contained between one and five text terms with c-statistics ranging between 0.66 and 0.90. In the independent validation, the scoring systems accurately predicted the probability that a text report cited the four lesions. CONCLUSIONS: Textual radiology reports can be analyzed using common statistical software to accurately determine the probability that important abnormalities of the kidneys or adrenal glands exist. These methods can be used for case identification or epidemiological studies.

Reducing overtreatment of prostate cancer by radical prostatectomy in Eastern Ontario: a population-based cohort study.

BACKGROUND: Canadian guidelines recommend against population-based screening for prostate cancer because of the risk of overdiagnosis and overtreatment. We sought to assess whether a higher proportion of patients receiving surgery had clinically significant cancer over time. METHODS: All hospitals in Eastern Ontario that perform prostatectomy participate in a Prostate Cancer Community of Practice, which prospectively maintains a database for the region. Using these data, we conducted a retrospective cohort study that included all patients who underwent prostatectomy from 2009 to 2015 in the region. We examined trends in biopsy findings, clinical stage, prostate-specific antigen level and Gleason score. We then determined whether the proportion of patients with clinically significant cancer (Gleason score ≥ 7 or stage pT3) increased over time. RESULTS: During the study period, 1897 patients underwent prostatectomy in Eastern Ontario (mean 271 surgeries/yr). The proportion of patients who were determined to have National Comprehensive Cancer Network intermediate or high-risk disease increased from 46.7% in 2009 to 90.2% in 2015. The proportion of men with clinically significant cancer on prostatectomy increased from 59.7% in 2009 to 93.1% in 2015. Adjusted analyses suggested that the proportion of patients with clinically significant cancer increased by 5% per year during the study period. INTERPRETATION: There has been a change in the tumour characteristics of patients who undergo prostatectomy in Eastern Ontario. In recent years, almost all patients have had clinically significant cancer, which suggests that overtreatment of prostate cancer has decreased.

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation.

Chromatin structure is dynamically modulated by various chromatin modifications, such as histone/DNA methylation and demethylation. We have reviewed histone methyltransferases and methyllysine binders in terms of small molecule screening and drug discovery in the first part of this review series. In this part, we will summarize recent progress in chemical probe and drug discovery of histone demethylases and DNA methyltransferases. Histone demethylation and DNA methylation have attracted a lot of attention regarding their biology and disease implications. Correspondingly, many small molecule compounds have been designed to modulate the activity of histone demethylases and DNA methyltransferases, and some of them have been developed into therapeutic drugs or put into clinical trials.