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MAGE proteins are well-known cancer testis antigens (CTAs) that are selectively expressed in cancer and germline cells. Characterized by the highly conserved MAGE homology domain (MHD), MAGEs are increasingly reported to play pivotal roles in promoting and sustaining aggressive cancer types. It is suspected that targeting MAGEs will lead to new cancer specific therapeutics. MAGE-A4, in particular, increases DNA damage tolerance and chemoresistance in a variety of cancers by stabilizing the E3-ligase RAD18 and thereby promoting trans-lesion synthesis (TLS). Accordingly, inhibition of the MAGE-A4:RAD18 axis could attenuate the DNA damage response and sensitize cancer cells to chemotherapeutics like platinating agents. However, there are currently no known inhibitors of this interaction and limited structural information makes the design of selective MAGE-A4 inhibitors challenging. We use mRNA display of thioether cyclized peptides to identify a series of macrocyclic inhibitors of the MAGE-A4:RAD18 interaction. Our lead macrocycle, MTP-1 exhibits an in vitro IC(50) of 21nM and is highly selective for MAGE-A4 over other MAGE A-family members. A co-crystal structure shows that linear MTP-1 binds in a pocket that is conserved across MHDs but takes advantage of A4-specific residues to achieve high isoform selectivity. The binding mode of MTP-1 also helps to elucidate in part, the mechanism of RAD18 recognition. We exploit the potent selectivity of MTP-1 to specifically detect MAGE-A4 in lysate-based ELISA assays. Cumulatively, our data represent the first reported inhibitor of the MAGE-A4:RAD18 interaction and establishes biochemical tools and structural insights for the future development of MAGE-A4 targeted cellular probes.

In Alaska, an outbreak of spruce beetles ( Dendroctonus rufipennis ) recently infested over one million hectares of spruce ( Picea spp.) forest. As a result, land management agencies have applied different treatments to infested forests to minimize fire hazard and economic loss and facilitate forest regeneration. In this study we investigated the effects of high-intensity burning, whole-tree harvest, whole-tree harvest with nitrogen (N) fertilization, and conventional harvest of beetle-killed stands 4 years after treatment, as well as clear-cut salvage harvest 6 years after treatment. We measured available soil ammonium and nitrate and estimated N loss from leaching using in situ cation and anion resin exchange capsules. We also assessed spruce regeneration and responses of understory plant species. Availability and losses of N did not differ among any of the management treatments. Even a substantial application of N fertilizer had no effect on N availability. Spruce regeneration significantly increased after high-intensity prescribed burning, with the number of seedlings averaging 8.9 m −2 in burn plots, as compared to 0.1 m −2 in plots that did not receive treatment. Biomass of the pervasive grass bluejoint ( Calamagrostis canadensis ) was significantly reduced by burning, with burn plots having 9.5% of the C. canadensis biomass of plots that did not receive treatment. N fertilization doubled C. canadensis biomass, suggesting that N fertilization without accompanying measures to control C. canadensis is the least viable method for promoting rapid spruce regeneration.

The Job Descriptive Index family of job attitude measures includes the Job in General (JIG) scale, a measure of global satisfaction with one’s job. The scale was originally developed and validated by Ironson, Smith, Brannick, Gibson, and Paul. Following structured scale reduction procedures developed by Stanton, Sinar, Balzer, and Smith, the current authors developed an abridged version of the JIG for use by practitioners and researchers of organizational behavior. They report the results of three validation studies documenting the process of scale reduction and the psychometric suitability of the reduced-length scale.

Many organizations have policies concerning the use of technology to monitor the communications of employees. The present study explored the effects of these policies on beliefs and preferences of Black job applicants. Using a simulated job advertisement, we varied organizational monitoring policies and application submission methods in a 2 × 2 between-subjects experiment with 600 participants from a professional organization of Black engineers. Using a multiple stakeholder model of organizational privacy as a theoretical framework, we measured the perceived potential for discrimination and the degree to which the simulated organization was seen as an attractive workplace for minorities. Results indicated that failing to protect employees’ and applicants’ privacy made the organization seem less attractive as an employer. Likewise, a lack of privacy protection was seen as a potential source of discrimination. These findings supported theoretical assertions concerning two of four normative bases of privacy preferences.

Although considerable research attention has been directed at understanding perceptions of salary fairness, very little attention has been given to how salary expectations are formed or how trivial elements of the job search context may influence these expectations. Two experiments demonstrated how the simple manipulation of response options for a multiple-choice item may influence subsequent salary expectations and salary satisfaction. Results are discussed in light of Parducci's (1995) contextual theory.

BACKGROUND: The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear. METHODS: In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point. RESULTS: A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P