Wang, Jing

Objective To estimate the proportion of female patients from Mayo Clinic Family Medicine and Community Internal Medicine clinics who are aware of alcohol use as a breast cancer (BC) risk factor. Patients and Methods One thousand women aged 21 to 70 completed a survey collecting information on demographics, medical/family history, frequency and quantity of alcohol consumption, and other health behaviors. Participants were also asked to grade how likely certain factors were to increase lifetime BC risk. Results Most participants (844/990 [85.3%]) identified a family history of BC as a BC risk factor. In contrast, 48.4% (475/982) identified alcohol use as a BC risk factor. The remaining 51.6% (507/982) reported either they were not sure about alcohol consumption as a risk factor (341/982 [34.7%]), believed that there was no association (143/982 [14.6%]), or believed that alcohol consumption decreases the risk of BC (23/982 [2.3%]). In multivariable analyses, factors associated with awareness of alcohol consumption and BC risk included having never been pregnant ( P = 0.048), more education ( P < 0.001), and higher frequency of alcohol consumption in the past 12 months ( P = 0.005). Conclusion Further education of patients and the public is needed to promote awareness of alcohol as a risk factor for BC.

Abstract Bone marrow (BM) niche plays critical roles in promoting progression and chemoresistance of multiple myeloma (MM), but the iron metabolism bridging the malignant plasma cells and BM stromal cells (BMSCs) has not been well elucidated. Using in vitro and in vivo models of interaction of MM and BMSCs, we identified that iron level was augmented due to the elevated expression of transferrin in MM cells, and the accumulation of iron desensitized MM cells to proteasome inhibitors (PIs) treatment and promoted productions of cholesterol and lanosterol. Simultaneously, direct contact with BMSCs remarkably upregulated the protein level of GPX4, a ROS eraser, to obviate ferroptosis in MM cells. Mechanistic studies revealed that CD40/CD40 ligand (CD40L) signaling promoted the expressions of transferrin and SUMO-specific protease 3 (SENP3), and SENP3 stabilized GPX4 protein via deSUMOylation modification. GPX4 inhibitor induced ferroptosis was cell-cell contact dependent, since blocking CD40/CD40L interaction, or depletion of Cd40l in BMSCs from Cd40lfl/fl;Prx1Cre/+ mice, eliminated the anti-MM efficacy of RSL3 in the Vk*MYC mouse model of myeloma, but not in the patient-derived xenografts (PDX) model. Our study deciphers mechanism of iron metabolism in regulating MM chemoresistance, and clarifies the therapeutic potential of non-apoptosis strategies in managing refractory or relapsed MM patients.