Falls are one of the most critical health care risks for elderly people, being, in some adverse circumstances, an indirect cause of death. Furthermore, demographic forecasts for the future show a growing elderly population worldwide. In this context, models for automatic fall detection and prediction are of paramount relevance, especially AI applications that use ambient, sensors or computer vision. In this paper, we present an approach for fall detection using computer vision techniques. Video sequences of a person in a closed environment are used as inputs to our algorithm. In our approach, we first apply the V2V-PoseNet model to detect 2D body skeleton in every frame. Specifically, our approach involves four steps: (1) the body skeleton is detected by V2V-PoseNet in each frame; (2) joints of skeleton are first mapped into the Riemannian manifold of positive semidefinite matrices of fixed-rank 2 to build time-parameterized trajectories; (3) a temporal warping is performed on the trajectories, providing a (dis-)similarity measure between them; (4) finally, a pairwise proximity function SVM is used to classify them into fall or non-fall, incorporating the (dis-)similarity measure into the kernel function. We evaluated our approach on two publicly available datasets URFD and Charfi. The results of the proposed approach are competitive with respect to state-of-the-art methods, while only involving 2D body skeletons.

Cancers co-opt stress response pathways to drive oncogenesis, dodge immune surveillance, and resist cytotoxic therapies. Several of these pathways also provide protection from ferroptosis, an iron-dependent oxidative cell death pathway triggered by clinically available drugs, including chemotherapies, rheumatologic agents, and novel ferroptosis inducers under evaluation in clinical trials. In this study, we found that disrupting cap-dependent translation initiation in diffuse large B-cell lymphoma (DLBCL) sensitizes cells to ferroptosis. Specifically, the eIF4A1 inhibitor zotatifin synergized with pharmacologic ferroptosis inducers primarily through suppression of glutathione production, which protects polyunsaturated fatty acids from ferroptotic oxidation. Loss of nuclear factor erythroid 2–related factor 2 (NRF2) translation, a master regulator of antioxidant genes, was a key consequence of rocaglates, including zotatifin, and other disruptors of cap-dependent initiation. Although NRF2 loss alone was insufficient to trigger ferroptosis, it lowered the antioxidant threshold, sensitizing cells to lipid peroxidation and ferroptotic death under additional oxidative stress. In vivo, combining zotatifin with the optimized ferroptosis inducer imidazole ketone erastin significantly reduced tumor burden in DLBCL patient-derived xenografts. Treatment with zotatifin in combination with chimeric antigen receptor (CAR) T cells, a vital treatment modality for patients with DLBCL, revealed that zotatifin preexposure sensitized DLBCL tumors to CD19-directed CAR T cells in vitro and extended survival of CAR T-cell–treated immunocompetent mice bearing syngeneic DLBCL tumors in vivo. Overall, eIF4A1 inhibition–induced translational disruption provides opportunities to leverage the therapeutic impacts of ferroptosis inducers, including cytotoxic immunotherapies. Significance: Translational disruption causes NRF2 loss that sensitizes lymphomas to ferroptosis and enhances CAR T-cell and drug efficacy, highlighting eIF4A1 targeting as a promising therapeutic strategy for treating cancer.

CD19-directed chimeric antigen receptor (CAR-19) T cells are breakthrough therapies for large B-cell lymphomas (LBCL), but fewer than half of patients achieve durable responses. We previously showed that RHOA deletions are enriched in progressing cases, but the role of RHOA deficiency is poorly defined despite its frequent occurrence in newly diagnosed disease. In this study, we show that RHOA loss downregulates CD19, promoting cell-intrinsic resistance to CAR-19 in vitro and in vivo. CD19 decline, however, provides an incomplete explanation of resistance and does not explain high frequency of the deletion in newly diagnosed cases. We therefore performed single-cell assessments of immunocompetent RHOA-deficient lymphoma microenvironments (LME), revealing remarkable concordance with features in CAR-19–resistant patients. Despite increased microenvironmental production of interferon gamma, RHOA-deficient tumor cells themselves show an impaired response to the cytokine, including failed induction of class I MHC molecules. Overall, we describe for the first time how a single-gene alteration recurrent in CAR-19–resistant lymphoma contributes to treatment failures. Significance: RHOA loss of function, which predicts CAR T-cell treatment failure and is present in one in six newly diagnosed LBCL cases, impairs MHC class I display, reprograms LMEs, and downregulates CD19 to promote antigen escape. Del 3p21.31 is therefore a single-gene alteration in LBCL selected for immunotherapy resistance. See related commentary by Perkey and Kline, p. 852

Disclosures. No relevant conflicts of interest to declare.

Zotatifin-induced oxidative stress and ferroptosis in DLBCL cells assessed by BODIPY oxidation, GSH/GSSG ratio, MitoSOX, and DHE staining.