The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc-induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cel-

Curcumin, a plant polyphenol, is a widely studied chemopreventive agent with demonstrated antitumor activities in preclinical studies and low toxicity profiles in multiple clinical trials against human malignancies. We previously showed that curcumin radiosensitizes cervical tumor cells without increasing the cytotoxic effects of radiation on normal human fibroblasts. Here we report that an inhibitory activity of curcumin on the antioxidant enzyme thioredoxin reductase-1 (TxnRd1) is required for curcumin-mediated radiosensitization of squamous carcinoma cells. Stable knockdown of TxnRd1 in both HeLa and FaDu cells nearly abolished curcumin-mediated radiosensitization. TxnRd1 knockdown cells showed decreased radiation-induced reactive oxygen species and sustained extracellular signal-regulated kinase 1/2 activation, which we previously showed was required for curcumin-mediated radiosensitization. Conversely, overexpressing catalytically active TxnRd1 in HEK293 cells, with low basal levels of TxnRd1, increased their sensitivity to curcumin alone and to the combination of curcumin and ionizing radiation. These results show the critical role of TxnRd1 in curcuminmediated radiosensitization and suggest that TxnRd1 levels in tumors could have clinical value as a predictor of response to curcumin and radiotherapy.

Race and ethnicity are associated with risk of venous thromboembolism in population-based studies. Blacks/African Americans have a higher incidence, while Asians/Pacific Islanders and Hispanics have a lower incidence of venous thromboembolism compared to non-Hispanic Whites. The impact of race/ethnicity on the incidence of cancer-associated thrombosis (CAT), a common complication in patients with malignancy, has not been well-defined. Using the California Cancer Registry linked to the California Patient Discharge Dataset and Emergency Department Utilization database, we studied a large, diverse cohort of patients (n=942,109) from 2005-2017 with the 13 most common, first primary malignancies to determine the association between race/ethnicity and incidence of incident and recurrent CAT. Multivariable Cox proportional hazards regression models were performed to determine the effect of race/ethnicity on the risk of overall CAT, specific CAT by location, and recurrent CAT. Blacks/African Americans had higher incidence of CAT for all tumor types except myeloma, while Asians/Pacific Islanders had consistently lower incidence of CAT compared to non-Hispanic Whites, after adjusting for potential confounders. The main driver for the racial/ethnic differences was incidence of pulmonary embolism. We speculate the association of race/ethnicity with incidence of CAT may be partially due to underlying thrombotic predisposition that varies by ancestry, but we also must consider the impact of social determinants of health on our results.

Background: The impact of time from diagnosis to chemotherapy initiation (time to treatment, TTT) for AML has been a topic of ongoing debate. A prior study reported that TTT ≥5 days adversely impacted overall survival in younger (<60 years of age), but not older (≥60 years of age), patients. However, subsequent studies found either no effect of TTT on overall survival, regardless of age, or an adverse impact of TTT on overall survival for both younger (>10 days) and older patients (>5 days). Prior data also showed no impact of TTT on early mortality. Given these conflicting findings, consensus on the impact of TTT on survival is lacking and warrants further study. Using prospectively collected population-based data, we analyzed a large cohort of adult AML patients to examine the effect of TTT on overall survival. Methods: Using data from the California Cancer Registry and Patient Discharge Dataset between 1999-2012, patients≥15years diagnosed with de novo AML and who received inpatient treatment between 1-90 days from diagnosis were identified (n=5337). Multivariable logistic regression was used to determine factors associated with TTT>5 days vs 1-5 days with data presented as odds ratios (OR) and 95% confidence intervals (CI). The effect of TTT on overall and 60-day survival was estimated using multivariable Cox proportional hazards regression with TTT (1-5, 6-10,>10 days)considered as a time-dependent variable. Patients were stratified by age group (<60,≥60 years) for all analyses.Multivariable models accounted for age, race/ethnicity, sex, number of comorbidities, marital status, neighborhood socioeconomic status, health insurance type, treatment at National Cancer Institute designated (NCI) vs non-NCI designated facility, use ofleukapheresis, and year of diagnosis. Results: Of the 2659 patients <60 years of age, 61.0% were treated within 5 days and 79.7% within 10 days of diagnosis, compared to 43.8% and 65.0%, respectively, of the 2678 patients≥60 years of age. Patients≥60 years were more likely to have 3+ comorbidities compared to the younger age group (43.3% vs 25.9%, P<0.001). The likelihood of TTT>5 days increased with age in both younger and older patients. Across both age groups, patients requiringleukapheresis(age<60: OR 0.19, CI 0.10-0.34; age≥60: OR 0.23, CI 0.12-0.45), treated at a non-NCI (vs NCI) center (age<60: OR 0.62, CI 0.52-0.73; age≥60: OR 0.64, CI 0.52-0.78) and with 1-2 (vs 0) comorbidities (age<60: OR 0.81, CI 0.67-0.98; age≥60: OR 0.69, CI 0.54-0.88) or 3+ (vs 0) comorbidities (age<60: OR 0.77, CI 0.62-0.97; age≥60: OR 0.52, CI 0.41-0.66) had a lower odds of TTT>5 days. Younger (age<60) African Americans (vs non-Hispanic whites) had a higher odds of TTT >5 days (OR 1.43, CI 1.04-1.97). Delaying chemotherapy >10 days (vs 1-5 days) adversely impacted overall survival in both age groups (age<60: HR 1.26, CI 1.11-1.43; age≥60: HR 1.17, CI 1.06-1.28) (Table). However, TTT of 6-10 days (vs 1-5 days) affected overall survival in young (age<60: HR 1.15, CI 1.02-1.31), but not older patients. A TTT of 6-10 days (vs 1-5 days) adversely impacted 60-day survival in both age groups (age<60: HR 1.70, CI 1.24-2.33; age≥60: HR 1.27, CI 1.05-1.54); 60-day survival results were similar for a TTT >10 days (vs 1-5 days) (Table). Conclusions: In a large cohort of patients with de novo AML, TTT of up to 10 days did not have a negative impact on overall survival in patients over the age of 60. In younger patients (<age 60), TTT >5 days was associated with decreased overall survival. Delaying chemotherapy over 5 days adversely impacted 60-day survival in both age groups. Our observation that patients were more likely to have a shorter TTT at non-NCI designated hospitals may relate to delays associated with transfer to or clinical trial enrollment at NCI centers. Our results suggest that waiting to get results of ancillary testing, such as cytogenetic and molecular mutation analyses, in order to inform treatment decisions for AML patients, may be feasible in some patients with AML. In an era of rapidly evolving prognostic and treatment landscapes for AML, our findings may have implications for personalized therapy, including novel targeted therapies, and clinical trial design for patients withAML. Disclosures No relevant conflicts of interest to declare.

<div>Abstract<p>Curcumin, a plant polyphenol, is a widely studied chemopreventive agent with demonstrated antitumor activities in preclinical studies and low toxicity profiles in multiple clinical trials against human malignancies. We previously showed that curcumin radiosensitizes cervical tumor cells without increasing the cytotoxic effects of radiation on normal human fibroblasts. Here we report that an inhibitory activity of curcumin on the antioxidant enzyme thioredoxin reductase-1 (TxnRd1) is required for curcumin-mediated radiosensitization of squamous carcinoma cells. Stable knockdown of TxnRd1 in both HeLa and FaDu cells nearly abolished curcumin-mediated radiosensitization. TxnRd1 knockdown cells showed decreased radiation-induced reactive oxygen species and sustained extracellular signal-regulated kinase 1/2 activation, which we previously showed was required for curcumin-mediated radiosensitization. Conversely, overexpressing catalytically active TxnRd1 in HEK293 cells, with low basal levels of TxnRd1, increased their sensitivity to curcumin alone and to the combination of curcumin and ionizing radiation. These results show the critical role of TxnRd1 in curcumin-mediated radiosensitization and suggest that TxnRd1 levels in tumors could have clinical value as a predictor of response to curcumin and radiotherapy. Cancer Res; 70(5); 1941–50</p></div>