Epigenetic dysregulation from chromosomal transit in micronuclei.

Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers1-4, but whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei5,6 and subsequent rupture of the micronuclear envelope7 profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice, as well as in cancer and non-transformed cells. Some of the changes in histone PTMs occur because of the rupture of the micronuclear envelope, whereas others are inherited from mitotic abnormalities before the micronucleus is formed. Using orthogonal approaches, we demonstrate that micronuclei exhibit extensive differences in chromatin accessibility, with a strong positional bias between promoters and distal or intergenic regions, in line with observed redistributions of histone PTMs. Inducing CIN causes widespread epigenetic dysregulation, and chromosomes that transit in micronuclei experience heritable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, as well as altering genomic copy number, CIN promotes epigenetic reprogramming and heterogeneity in cancer.

Determinants of overall survival in patients with metastatic uveal melanoma.

BACKGROUND: Despite improvements in the treatment of primary uveal melanoma (UM), patients with metastatic disease continue to exhibit poor survival. METHODS: A retrospective review of metastatic UM patients at Yale (initial cohort) and Memorial Sloan Kettering (validation cohort) was conducted. Cox proportional hazards regression was used to determine baseline factors that are associated with overall survival, including sex, Eastern Cooperative Oncology Group (ECOG) Performance Status Scale, laboratory measurements, metastasis location, and use of anti-CTLA-4 and anti-PD-1 therapies. Differences in overall survival were analyzed using Kaplan-Meier analysis. RESULTS: A total of 89 patients with metastatic UM were identified; 71 and 18, in the initial and validation cohorts, respectively. In the initial cohort, median follow-up was 19.8 months (range, 2-127 months) and median overall survival was 21.8 months (95% CI, 16.6-31.3). Female sex, anti-CTLA-4, and anti-PD-1 therapy were associated with better survival outcomes with adjusted death hazard ratios (HRs) of 0.40 (95% CI, 0.20-0.78), 0.44 (0.20-0.97), and 0.42 (0.22-0.84), respectively, whereas development of hepatic metastases and ECOG score ≥1 (per 1 U/L) were associated with worse survival outcomes with HRs of 2.86 (1.28-7.13) and 2.84 (1.29-6.09), respectively. In both the initial and validation cohorts, use of immune checkpoint inhibitors was associated with improved overall survival after adjusting for sex and ECOG score, with death HRs of 0.22 (0.08-0.56) and 0.04 (0.002-0.26), respectively. CONCLUSIONS: Development of extrahepatic-only metastases, ECOG of 0, immune checkpoint therapy, and female sex were each associated with more than 2-fold reductions in risk of death. PLAIN LANGUAGE SUMMARY: Metastatic uveal melanoma patients face limited treatment options and poor survival rates. Results from this retrospective analysis indicate that immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1 therapies, were associated with improved survival outcomes. Factors such as extrahepatic-only metastases, better baseline performance status, and female sex contributed to a more than 2-fold reduction in death risk. These findings highlight the potential of immunotherapy in treating metastatic uveal melanoma.

Validation of the Prognostic Usefulness of the Gene Expression Profiling Test in Patients with Uveal Melanoma.

PURPOSE: To validate the prognostic usefulness of gene expression profile (GEP) testing in patients with uveal melanoma. To determine whether combining tumor size with the GEP classification provides additional prognostic value. DESIGN: Retrospective analysis. PARTICIPANTS: Patients with a diagnosis of choroidal melanoma examined at Yale New Haven Hospital; University of California, San Diego; and Memorial Sloan Kettering Cancer Center. METHODS: Patients' demographic and clinical data and tumor characteristics were collected. Univariate and multivariate Cox hazard regression analysis were used to assess the association between tumor characteristics and GEP classification with metastasis as an outcome. MAIN OUTCOME MEASURES: Metastasis-free survival (MFS). RESULTS: Of the 337 individuals included in the study, 87 demonstrated metastases. The mean follow-up time was 37.2 (standard deviation [SD], 40.2) months for patients with metastases and 55.0 (SD, 49.3) months for those without metastases. Tumors of larger thickness and GEP class 2 (vs. class 1) were associated significantly with increased risk of metastasis. Tumor thickness showed better prognostic usefulness than GEP classification (Wald statistic, 40.7 and 24.2, respectively). Class 2 tumors with a thickness of 7.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 7.0 mm (hazard ratio [HR], 3.23; 95% confidence interval [CI], 1.61-6.51), whereas class 1 tumors with a thickness of 9.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 9.0 mm (HR, 2.07; 95% CI, 0.86-4.99). No difference in MFS was found between patients with class 1A tumors compared with those with class 1B tumors (P = 0.8). Patients with class 2 tumors showed an observed 5-year MFS of 47.5% (95% CI, 36.0%-62.8%). CONCLUSIONS: Tumor size was the most significant predictor of metastasis and provided additional prognostic value independent of GEP classification. In addition, rates of metastasis for class 2 tumors were lower than estimates reported by Castle Bioscience, and no difference in rates of metastasis were found between class 1A and 1B tumors. This indicates that tumor size should be accounted for when relying on GEP for prognostication and that patients with GEP class 1A or 1B tumors may benefit from the same metastatic surveillance protocols. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Development of a job-exposure matrix-like exposure assessment method for the US general population based on Occupational Information Network (O*NET) job tasks.

BACKGROUND: Job-exposure matrices (JEMs) are often used for exposure assessment in occupational exposure and epidemiology studies. However, general population JEMs are difficult to find and access for workers in the United States of America. OBJECTIVE: We aimed to use publicly available information to develop a JEM-like exposure assessment method to determine exposure to a wide range of occupational agents in a wide range of occupations for US general population studies. METHODS: We used information from the US Department of Labor's Occupational Information Network database (O*NET) for 19,636 job tasks and 974 civilian occupations. We used automated keyword searches to identify 1,804 job tasks that involved exposure to 50 occupational agents. We had 2 reviewers determine whether each identified job task actually involved exposure to the 50 occupational agents. We had a third reviewer, a certified industrial hygienist, assess any job task and exposure for which the first 2 reviewers disagreed. For each U.S. Census 2010 occupation code, we used this information to derive 3 exposure variables for each occupational agent: ever exposure, number of job tasks of exposure, and frequency of exposure. RESULTS: Our keyword searches identified a median of 10 (interquartile range [IQR]: 43.75) job tasks for each occupational agent, and the maximum was 308. We determined job tasks actually involved exposure to 45 occupational agents, including solvents, air pollution, pesticides, radiation, metals, etc. We derived the 3 exposure variables for these 45 occupational agents for 516 U.S. Census 2010 occupation codes. The median percentage for ever exposure to individual occupational agents was 1.16% (IQR: 1.74%), and the maximum was 11.43%. CONCLUSIONS: Our JEM-like exposure assessment method based on O*NET information can be used to determine exposure to a wide range of occupational agents in a wide range of occupations for the US general population.

Effect of pH on the Early Development of the Biofouling Ascidian Ciona robusta.

Ocean acidification (OA) impacts the survival, fertilization, and community structure of marine organisms across the world. However, some populations or species are considered more resilient than others, such as those that are invasive, globally distributed, or biofouling. Here, we tested this assumption by investigating the effect of pH on the larval development of one such tunicate, Ciona robusta, which is currently exposed to a wide range of pH levels. Consistent with our hypothesis, C. robusta larvae developed and metamorphosed at a rate comparable to control (pH 8.0) at modest near-future conditions (pH 7.7) over a 58-hour period. However, development was stunted at the extreme low pH of 6.8 such that no embryo progressed beyond late cleavage after 58 hours. Interestingly, piecewise regression of the proportion of embryos at the most advanced stage at a given time point against pH identified a breakpoint with the highest pH (~pH 7.6) at around hatching. The variation in breakpoint pH throughout ontogeny highlighted that the sensitivity to decreasing pH differs significantly between developmental stages. More broadly, our results show that even a cosmopolitan, biofouling, invasive species could be negatively impacted by decreasing pH.

Negotiation Practices of Athletic Trainers Employed in the Clinical Setting.

CONTEXT: Athletic trainers (ATs) are comparatively underpaid relative to peer health care professionals. Whereas many factors contribute to the salary and benefits of a given employment position, negotiation is a factor of the final salary and benefits package that is achieved. It is unclear to what extent ATs negotiate salary or other terms of employment during the hiring process. OBJECTIVE: To explore the negotiation practices of ATs during the hiring process. DESIGN: Cross-sectional study. SETTING: Web-based survey. PATIENTS OR OTHER PARTICIPANTS: A total of 587 ATs employed in the clinical setting who previously held at least 1 full-time employment position. MAIN OUTCOME MEASURE(S): Independent variables were several demographic factors as well as the current salary range. Dependent variables were participants' responses to various survey items focused on experiences with salary and terms-of-employment negotiation. Summary statistics were used to characterize all variables and multiple χ2 analyses (P < .05) were performed to determine the significant influences of independent variables on negotiation practices. RESULTS: More than half of ATs (57.6%) did not attempt to negotiate their salary, and almost three-quarters of ATs (70.5%) did not negotiate their terms of employment during the hiring process. The most successfully negotiated terms were moving expenses (72.3%) and continuing education funding and reimbursement (62.7%). The influence of demographic factors on negotiation and negotiation success varied, with significant findings for the number of previous full-time employment positions, gender, marital status, salary range, and number of dependents. CONCLUSIONS: It is alarming that more than half of ATs did not negotiate salary or terms of employment during the hiring process. Whereas widespread training on negotiation practices is warranted, our findings suggest it would be most beneficial for early-career and female ATs. All ATs must become comfortable with negotiating salary and terms of employment to effect change in the average salary and employment status of those in the profession.

Negotiation Practices of Athletic Trainers Employed in the Clinical Setting.

CONTEXT: Athletic trainers (ATs) are comparatively underpaid relative to peer healthcare professionals. While many factors contribute to salary and benefits of a given employment position, negotiation is a factor of the final salary and benefits package that is achieved. It is unclear to what extent ATs negotiate salary or other terms of employment during the hiring process. OBJECTIVE: To explore the negotiation practices of ATs during the hiring process. DESIGN: Cross-sectional. SETTING: Web-based survey. PATIENTS OR OTHER PARTICIPANTS: 587 ATs employed in the clinical setting that previously held at least one full-time employment position. MAIN OUTCOME MEASURES: Independent variables included several demographic factors as well as current salary range. Dependent variables were participants' responses to various survey items focused on experiences with salary and terms of employment negotiation. Summary statistics were used to characterize all variables and multiple chi-square analyses (p<.05) were performed to determine significant influences of independent variables on negotiation practices. RESULTS: More than half of ATs did not attempt to negotiate their salary (57.6%), and almost three-quarters of ATs did not negotiate terms of employment (70.5%) during the hiring process. The most successfully negotiated terms were moving expenses (72.3%) and continuing education funding/reimbursement (62.7%). The influence of demographic factors on negotiation and negotiation success varied with significant findings for: number of previous full-time employment positions, gender, marital status, salary range, and number of dependents. CONCLUSIONS: It is alarming that more than half of ATs do not negotiate salary or terms of employment during the hiring process. While widespread training on negotiation practices is warranted, our findings suggest it would be most beneficial for early-career and women ATs. ATs must become comfortable with negotiating salary and terms of employment in order to effect change on the average salary and employment status of those in the profession.

Loads and elimination of trace elements in wastewater in the Great Lakes basin.

The growing use of trace elements in industrialized societies is driving an increase in the occurrence of trace elements in anthropogenic waste streams globally. Yet, the large-scale sources of many trace elements to wastewater and their elimination during treatment remain poorly understood and potential environmental impacts on freshwater systems therefore unclear. We screened 42 wastewater treatment facilities in the North American Great Lakes basin and deployed a black-box approach to calculate representative estimates for average per-capita trace element loads and basin-scale effluent discharge rates, as well as trace element removal efficiencies across different treatment technologies. Our results show different removal of specific groups of trace elements during wastewater treatment: average removal efficiencies were 25% for alkali metals, 50% for alkaline earth metals, 74% for transition metals, and 85% for rare earth elements. Higher elimination of the majority of trace elements was generally achieved by more advanced, tertiary treatment types. Elemental loads generally followed natural abundance patterns, but anomalous loading rates were observed for various trace elements across the sampled facilities. By examining geospatial attributes of the sampled sewersheds, trends in select trace element loads were qualitatively tied to possible point sources and diffuse sources. Overall, these results illustrate the potential of wastewater surveillance to inform environmental management of emerging trace element contaminants.

Post-Traumatic Stress Symptoms in Hematopoietic Stem Cell Transplant Recipients.

Hematopoietic stem cell transplantation (HCT) is an intensive and potentially curative therapy for patients with hematologic malignancies. Patients admitted for HCT experience a prolonged, isolating hospitalization and endure substantial physical and psychological symptoms. However, there is a paucity of research on the impact of HCT on post-traumatic stress disorder (PTSD) symptoms in transplant recipients. This secondary analysis of 250 patients who underwent autologous and allogeneic HCT examined PTSD using the PTSD Checklist-Civilian measured at 6 months after HCT. We used the Functional Assessment of Cancer Therapy-Bone Marrow Transplant, and the Hospital Anxiety and Depression Scale to assess quality of life (QOL) and depression and anxiety symptoms at the time of admission for HCT, week 2 during hospitalization, and 6 months after HCT. We used multivariate regression models to assess factors associated with PTSD symptoms. Given collinearity between QOL, depression, and anxiety symptoms, we modeled these separately. The rate of clinically significant PTSD symptoms at 6 months after HCT was 18.9% (39/206). Participants with clinically significant PTSD symptoms experienced hypervigilance (92.3%), avoidance (92.3%), and intrusion (76.9%) symptoms. Among patients without clinically significant PTSD symptoms, 24.5% had clinically significant hypervigilance symptoms and 13.7% had clinically significant avoidance symptoms. Lower QOL at time of HCT admission (B = -0.04, P = .004) and being single (B = -3.35, P = .027) were associated with higher PTSD symptoms at 6 months after HCT. Higher anxiety at time of HCT admission (B = 1.34, P <.001), change in anxiety during HCT hospitalization (B = 0.59, P =.006), and being single (B = -3.50, P = .017) were associated with higher PTSD symptoms at 6 months. In a separate model using depression, younger age (B = -0.13, P = .017), being single (B = -3.58, P = .018), and higher baseline depression symptoms were also associated with higher PTSD symptoms at 6 months (B = 0.97, P < .001). Approximately one fifth of patients undergoing HCT experience clinically significant PTSD symptoms at 6 months after transplantation. The prevalence of hypervigilance and avoidance symptoms are notable even among patients who do not have clinically significant PTSD symptoms. Interventions to prevent and treat PTSD symptoms in HCT recipients are clearly warranted.

Psychological Distress in Bereaved Caregivers of Patients With Advanced Cancer.

CONTEXT: Individuals caring for patients with advanced cancer (caregivers) experience psychological distress during the patient's illness course. However, data on the prevalence of bereaved caregivers' psychological distress and its relationship with the quality of patient's end of life (EOL) care are limited. OBJECTIVES: To describe rates of depression and anxiety symptoms in bereaved caregivers of patients with advanced cancer and to understand the relationship between these outcomes and patient distress at the EOL. METHODS: We conducted a secondary analysis of 168 caregivers enrolled in a supportive care trial for patients with incurable lung and gastrointestinal cancers and their caregivers. We used the Hospital Anxiety and Depression Scale to assess caregivers' depression and anxiety symptoms at three months after the patient's death. Caregivers also rated the patient's physical and psychological distress in the last week of life on a 10-point scale three months after the patient death. We used linear regression adjusting for caregiver age, sex, randomization, and cancer type to explore the relationship between bereaved caregivers' depression and anxiety symptoms and their ratings of physical and psychological distress in patients at the EOL. RESULTS: Of the 168 bereaved caregivers, 30.4% (n = 51) and 43.4% (n = 73) reported clinically significant depression and anxiety symptoms, respectively. Caregiver ratings of worse physical (B = 0.32; P = 0.009) and psychological (B = 0.50; P < 0.001) distress experienced by the patient at the EOL were associated with worse depression symptoms in bereaved caregivers. Only caregiver rating of worse psychological distress experienced by the patient at the EOL (B = 0.42; P < 0.001) was associated with worse bereaved caregivers' anxiety symptoms. CONCLUSION: Many bereaved caregivers of patients with advanced cancer experience symptoms of depression and anxiety, which are associated with their perceptions of distress in their loved ones at the EOL.