Student–teacher relationships are important to student outcomes and may be especially pivotal at the high school transition and for minoritized racial/ethnic groups. Although interventions exist to ...improve student–teacher relationships, none have been shown to be effective among high school students or in narrowing racial/ethnic disparities in student outcomes. This study was conducted to examine the effects of an equity-explicit student–teacher relationship intervention (Equity-Explicit Establish Maintain Restore, or E-EMR) for high school teachers and students. A cluster-randomized pilot trial was conducted with 94 ninth grade teachers and 417 ninth grade students in six high schools. Teachers in three schools were randomized to receive E-EMR training and follow-up supports for one year. Teachers in three control schools conducted business as usual. Student–teacher relationships, sense of school belonging, academic motivation, and academic engagement were collected via student self-report in September and January of their ninth-grade year. Longitudinal models revealed non-significant main effects of E-EMR. However, there were targeted benefits for students who started with low scores at baseline, for Asian, Latinx, multicultural, and (to a lesser extent) Black students. We also found some unexpected effects, where high-performing and/or advantaged groups in the E-EMR condition had less favorable outcomes at post, compared to those in the control group, which may be a result of the equity-explicit focus of E-EMR. Implications and directions for future research are discussed.
Student-teacher relationships are critical to ensuring successful transitions to high school, but programs focused on building strong relationships have been concentrated at younger school levels. ...Therefore, the purpose of this study was to gather feedback from ninth grade students, teachers/staff, and administrators regarding an existing student-teacher relationship intervention, Establish-Maintain-Restore (EMR), to inform a “scaling-out” adaptation of EMR for high schools. Data were collected from 7 administrators, 8 teachers/staff, and 10 ninth-grade students from diverse ethnic/ racial backgrounds. Participants quantitatively rated the acceptability and effectiveness of EMR strategy for the high school context and then described their rationale for their ratings in focus groups. ANOVAs were used to examine differences in appropriateness and effectiveness of EMR strategies across participant groups. We then used content analysis to explore identified problems and recommendations regarding discrepant strategies. We discuss implications for relationships at the high school level and for scaling-out interventions to novel developmental contexts.
Increased rates of locoregional recurrence are observed in patients with basal-like breast cancer (BC) despite the use of radiation therapy (RT); therefore, approaches that result in ...radiosensitization of basal-like BC are critically needed. Using patients' tumor gene expression data from 4 independent data sets, we correlated gene expression with recurrence to find genes significantly correlated with early recurrence after RT. The highest-ranked gene, TTK, was most highly expressed in basal-like BC across multiple data sets. Inhibition of TTK by both genetic and pharmacologic methods enhanced radiosensitivity in multiple basal-like cell lines. Radiosensitivity was mediated, at least in part, through persistent DNA damage after treatment with TTK inhibition and RT. Inhibition of TTK impaired homologous recombination (HR) and repair efficiency, but not nonhomologous end-joining, and decreased the formation of Rad51 foci. Reintroduction of wild-type TTK rescued both radioresistance and HR repair efficiency after TTK knockdown; however, reintroduction of kinase-dead TTK did not. In vivo, TTK inhibition combined with RT led to a significant decrease in tumor growth in both heterotopic and orthotopic, including patient-derived xenograft, BC models. These data support the rationale for clinical development of TTK inhibition as a radiosensitizing strategy for patients with basal-like BC, and efforts toward this end are currently underway.
Balanced blood product resuscitation with red blood cells, plasma, and platelets can be achieved using whole blood (WB) or component therapy (CT). However, balanced resuscitation of younger children ...with severe traumatic hemorrhage may be complicated by delays in delivering all blood components and concerns regarding multiple product exposures. We hypothesized that WB achieves balanced resuscitation faster than CT, with fewer product exposures and improved clinical outcomes.
Children younger than 12 years receiving balanced resuscitation within 4 hours of arrival were identified from the 2017 to 2019 Trauma Quality Improvement Program database. Time to balanced resuscitation was defined as the time of initiation of WB or all three components. Patient characteristics, resuscitation details, and outcomes were compared between WB and CT groups. Time to balanced resuscitation was compared using Kaplan-Meier analysis and Cox regression modeling to adjust for covariates. Additional multivariable regression models compared number of transfusion exposures, intensive care unit (ICU) length of stay, and mortality.
There were 390 patients (109 WB, 281 CT) with median age 7 years, 12% penetrating mechanism, 42% severe traumatic brain injury, and 49% in-hospital mortality. Time to balanced resuscitation was shorter for WB versus CT (median, 28 vs. 87 minutes; hazard ratio HR, 2.93; 95% confidence interval CI, 2.31-3.72; p < 0.0001). Whole blood patients received fewer transfusion exposures (mean, 3.2 vs. 3.9; adjusted incidence rate ratio, 0.82; 95% CI, 0.72-0.92; p = 0.001) and lower total product volumes (50 vs. 85 mL/kg; p = 0.01). Intensive care unit stays trended shorter for WB versus CT (median, 10 vs. 12 days; adjusted HR, 1.32; 95% CI, 0.93-1.86), while in-hospital mortality was similar (50% vs. 45%; adjusted odds ratio, 1.11; 95% CI, 0.65-1.88).
In critically injured preadolescent children receiving emergent transfusion, WB was associated with faster time to balanced resuscitation, fewer transfusion exposures, lower blood product volumes, and a trend toward shorter ICU stays than CT.
Prognostic and Epidemiological; Level III.
Increased rates of locoregional recurrence (LR) have been observed in triple negative breast cancer (TNBC) despite multimodality therapy, including radiation (RT). Recent data suggest inhibiting the ...androgen receptor (AR) may be an effective radiosensitizing strategy, and AR is expressed in 15-35% of TNBC tumors. The aim of this study was to determine whether seviteronel (INO-464), a novel CYP17 lyase inhibitor and AR antagonist, is able to radiosensitize AR-positive (AR+) TNBC models. In cell viability assays, seviteronel and enzalutamide exhibited limited effect as a single agent (IC50 > 10 μM). Using clonogenic survival assays, however, AR knockdown and AR inhibition with seviteronel were effective at radiosensitizing cells with radiation enhancement ratios of 1.20-1.89 in models of TNBC with high AR expression. AR-negative (AR-) models, regardless of their estrogen receptor expression, were not radiosensitized with seviteronel treatment at concentrations up to 5 μM. Radiosensitization of AR+ TNBC models was at least partially dependent on impaired dsDNA break repair with significant delays in repair at 6, 16, and 24 h as measured by immunofluorescent staining of γH2AX foci. Similar effects were observed in an
AR+ TNBC xenograft model where there was a significant reduction in tumor volume and a delay to tumor doubling and tripling times in mice treated with seviteronel and radiation. Following combination treatment with seviteronel and radiation, increased binding of AR occurred at DNA damage response genes, including genes involved both in homologous recombination and non-homologous end joining. This trend was not observed with combination treatment of enzalutamide and RT, suggesting that seviteronel may have a different mechanism of radiosensitization compared to other AR inhibitors. Enzalutamide and seviteronel treatment also had different effects on AR and AR target genes as measured by immunoblot and qPCR. These results implicate AR as a mediator of radioresistance in AR+ TNBC models and support the use of seviteronel as a radiosensitizing agent in AR+ TNBC.
Unmet clinical needs in breast cancer (BC) management include the identification of patients at high risk of local failure despite adjuvant radiation and an understanding of the biology of these ...recurrences. We previously reported a radiation response signature and here extend those studies to identify a signature predictive of recurrence timing (before or after 3 years).
Two independent patient cohorts were used. The training cohort included 119 patients with in-breast tumor recurrence (343 total), and the validation testing cohort had 16 patients with recurrences (112 total). All patients received radiation treatment after breast-conserving surgery. Initial feature selection used Spearman rank correlation, and a linear model was trained and locked before testing and validation. Cox regression was used for univariate and multivariable analyses (UVA and MVA, respectively). Biologically related concepts were identified using gene set enrichment analysis.
Spearman correlation identified 485 genes whose expression was significantly associated with recurrence time (early vs late). Feature reduction further refined the list to 41 genes retained within the signature. In training, the correlation of score to recurrence time was 0.85 (P value < 1.3 × 10
) with an area under the curve (AUC) of 0.91. Application of this early versus late signature to an independent BC testing and validation set accurately identified patients with early versus late recurrences (Spearman correlation = 0.75, P value = .001, AUC = 0.92, sensitivity = 0.75, specificity = 1.0, positive predictive value = 1.0, and negative predictive value = 0.8). Unique associations of breast cancer intrinsic subtype to timing of local recurrence were identified. In UVA and MVA the early versus late recurrence signature remained the most significant factor associated with recurrence. Gene set enrichment analysis identified proliferation and epidermal growth factor receptor concepts associated with early recurrences and luminal and ER-signaling pathways associated with late recurrences. Knockdown of genes associated with the early and late recurrences demonstrated novel effects on proliferation and clonogenic survival, respectively.
We report a breast cancer gene signature that may identify patients unlikely to respond to adjuvant radiation and may be used to predict timing of recurrences with implications for potential treatment intensification and duration of follow-up for women with breast cancer treated with radiation.
Although older adults commonly take multivitamin-multimineral (MVM) supplements to promote health, evidence on the use of daily MVMs on invasive cancer is limited.
The study objective was to ...determine if a daily MVM decreases total invasive cancer among older adults.
We performed a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of a daily MVM and cocoa extract for prevention of cancer and cardiovascular disease (CVD) among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y) free of major CVD and recently diagnosed cancer. The intervention phase was from June 2015 through December 2020. This article reports on the MVM intervention. Participants were randomly assigned to daily MVM or placebo. The primary outcome was total invasive cancer, excluding nonmelanoma skin cancer. Secondary outcomes included major site-specific cancers, total CVD, all-cause mortality, and total cancer risk among those with a baseline history of cancer.
During a median follow-up of 3.6 y, invasive cancer occurred in 518 participants in the MVM group and 535 participants in the placebo group (HR: 0.97; 95% CI: 0.86, 1.09; P = 0.57). We observed no significant effect of a daily MVM on breast cancer (HR: 1.06; 95% CI: 0.79, 1.42) or colorectal cancer (HR: 1.30; 95% CI: 0.80, 2.12). We observed a protective effect of a daily MVM on lung cancer (HR: 0.62; 95% CI: 0.42, 0.92). The composite CVD outcome occurred in 429 participants in the MVM group and 437 participants in the placebo group (HR: 0.98; 95% CI: 0.86, 1.12). MVM use did not significantly affect all-cause mortality (HR: 0.93; 95% CI: 0.81, 1.08). There were no safety concerns.
A daily MVM supplement, compared with placebo, did not significantly reduce the incidence of total cancer among older men and women. Future studies are needed to determine the effects of MVMs on other aging-related outcomes among older adults. This trial is registered at www.clinicaltrials.gov as NCT02422745.
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Increased rates of locoregional recurrence have been observed in triple-negative breast cancer despite chemotherapy and radiation therapy. Thus, approaches that combine therapies for ...radiosensitization in triple-negative breast cancer are critically needed. We characterized the radiation therapy response of 21 breast cancer cell lines and paired this radiation response data with high-throughput drug screen data to identify androgen receptor as a top target for radiosensitization. Our radiosensitizer screen nominated bicalutamide as the drug most effective in treating radiation therapy-resistant breast cancer cell lines. We subsequently evaluated the expression of androgen receptor in >2100 human breast tumor samples and 51 breast cancer cell lines and found significant heterogeneity in androgen receptor expression with enrichment at the protein and RNA level in triple-negative breast cancer. There was a strong correlation between androgen receptor RNA and protein expression across all breast cancer subtypes (
= 0.72,
< 0.01). In patients with triple-negative breast cancer, expression of androgen receptor above the median was associated with increased risk of locoregional recurrence after radiation therapy (hazard ratio for locoregional recurrence 2.9-3.2)) in two independent data sets, but there was no difference in locoregional recurrence in triple-negative breast cancer patients not treated with radiation therapy when stratified by androgen receptor expression. In multivariable analysis, androgen receptor expression was most significantly associated with worse local recurrence-free survival after radiation therapy (hazard ratio of 3.58) suggesting that androgen receptor expression may be a biomarker of radiation response in triple-negative breast cancer. Inhibition of androgen receptor with MDV3100 (enzalutamide) induced radiation sensitivity (enhancement ratios of 1.22-1.60) in androgen receptor-positive triple-negative breast cancer lines, but did not affect androgen receptor-negative triple-negative breast cancer or estrogen-receptor-positive, androgen receptor-negative breast cancer cell lines. androgen receptor inhibition with MDV3100 significantly radiosensitized triple-negative breast cancer xenografts in mouse models and markedly delayed tumor doubling/tripling time and tumor weight. Radiosensitization was at least partially dependent on impaired dsDNA break repair mediated by DNA protein kinase catalytic subunit. Our results implicate androgen receptor as a mediator of radioresistance in breast cancer and identify androgen receptor inhibition as a potentially effective strategy for the treatment of androgen receptor-positive radioresistant tumors.
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