Utilizing clinical, pathological and radiological information to guide postoperative radiotherapy in prostate cancer.

INTRODUCTION: A detectable and rising PSA following radical prostatectomy is indicative of recurrent prostate cancer. Salvage radiotherapy (SRT) with/without androgen deprivation therapy represents the main treatment option for these patients and has been historically associated with a biochemical control rate of ~70%. To determine the optimal timing, diagnostic workup, radiotherapy dosefractionation, treatment volume, and use of systemic therapy, several informative studies have been conducted in the last decade. AREAS COVERED: This review examines the recent evidence to guide radiotherapy decision making in the SRT setting. Key topics include adjuvant vs salvage RT, utilization of molecular imaging and genomic classifiers, length of androgen deprivation therapy, inclusion of elective pelvic volume, and emerging role for hypofractionation. EXPERT OPINION: Recently reported trials, conducted in an era prior to the routine use of molecular imaging and genomic classifiers, have been pivotal in establishing the current standard of care for SRT in prostate cancer. However, decisions about radiation treatment and systemic therapy may be tailored based on available prognostic and predictive biomarkers. Data from contemporary clinical trials are awaited to define and establish individualized, biomarker-driven approaches for SRT.

A Ubiquitination Cascade Regulating the Integrated Stress Response and Survival in Carcinomas.

Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 1,086 cancer cell lines to identify selective coessentiality modules and found that a ubiquitin ligase complex composed of UBA6, BIRC6, KCMF1, and UBR4 is required for the survival of a subset of epithelial tumors that exhibit a high degree of aneuploidy. Suppressing BIRC6 in cell lines that are dependent on this complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) by stabilization of the heme-regulated inhibitor, a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations uncover a novel ubiquitination cascade that regulates ISR and highlight the potential of ISR activation as a new therapeutic strategy. SIGNIFICANCE: We describe the identification of a heretofore unrecognized ubiquitin ligase complex that prevents the aberrant activation of the ISR in a subset of cancer cells. This provides a novel insight on the regulation of ISR and exposes a therapeutic opportunity to selectively eliminate these cancer cells. See related commentary Leli and Koumenis, p. 535. This article is highlighted in the In This Issue feature, p. 517.

VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system.

Collateral lethality occurs when loss of a gene/protein renders cancer cells dependent on its remaining paralog. Combining genome-scale CRISPR/Cas9 loss-of-function screens with RNA sequencing in over 900 cancer cell lines, we found that cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, required the nuclear kinase vaccinia-related kinase 1 (VRK1) for their survival in vivo. VRK1 dependency was inversely correlated with expression of its paralog VRK2. VRK2 knockout sensitized cells to VRK1 loss, and conversely, VRK2 overexpression increased cell fitness in the setting of VRK1 loss. DNA methylation of the VRK2 promoter was associated with low VRK2 expression in human neuroblastomas and adult and pediatric gliomas. Mechanistically, depletion of VRK1 reduced barrier-to-autointegration factor phosphorylation during mitosis, resulting in DNA damage and apoptosis. Together, these studies identify VRK1 as a synthetic lethal target in VRK2 promoter-methylated adult and pediatric gliomas and neuroblastomas.

Laryngeal involvement in a patient with active postprimary tuberculosis: Case report of a rare extrapulmonary manifestation.

A 43-year-old woman was found to have active post-primary tuberculosis and a lateral neck radiograph showing a thickened epiglottis. Bronchoscopy-guided biopsies of the epiglottis and lung were acid fast bacilli stain positive. Histopathology from both showed multiple caseating granulomas. The patient's condition improved with RIPE therapy. This case illustrates the importance for physicians to be aware of possible laryngeal involvement in tuberculosis and that it can present even without evidence of active or latent tuberculosis.

Impact of post-orthodontic dental occlusion on masticatory performance and chewing efficiency.

BACKGROUND: Whether precise orthodontic detailing of occlusion impacts masticatory function is unknown. In this study, we aimed to assess the impact of post-orthodontic dental occlusion on masticatory performance and chewing efficiency. MATERIALS AND METHODS: Fifty-four adults who completed orthodontic treatment were categorized into two groups using the American Board of Orthodontics (ABO) model grading system: one meeting ABO standards (ABO, N = 29), the other failing to meet them (non-ABO, N = 25). The electromyographic (EMG) signals of the anterior temporalis (AT) and superficial masseter muscles were recorded bilaterally during static (clenching) and dynamic (gum chewing) tests. Chewing efficiency was measured by calculating the median particle size (MPS) and broadness of particle distribution (BPD) after five chewing trials of experimental silicone food at a standardized chewing rate. RESULTS: Participants of the ABO group had a slightly more symmetric activation of the AT muscles during clenching (P = 0.016) and chewed a gum at a slower rate (P = 0.030). During the standardized chewing test with silicone food, ABO subjects had slightly greater EMG potentials at all muscle locations than non-ABO individuals (all P < 0.05). MPS and BDP did not differ significantly between groups (all P > 0.05). LIMITATIONS: The severity of the initial malocclusion of the study participants was not in the statistical model as a potential confounder on the outcome measures. CONCLUSIONS: Meeting ABO standards contributes to a slightly more balanced activation of the temporalis muscles during clenching and more efficient muscle recruitment during chewing but does not improve chewing efficiency.