4 research outputs found
Fall Detection of Elderly People Using the Manifold of Positive Semidefinite Matrices
International audienceFalls 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
Recommended from our members
Abstract 4878: Transcriptional response to rocaglate translation inhibitors in lymphoma shows cellular adaptation through induction of stress and survival pathways
Abstract Background: 40% of diffuse large B-cell lymphoma (DLBCL) patients do not achieve cure in response to the standard immunochemotherapy. Relapsed and refractory tumors respond poorly to targeted signaling inhibitors due to pathway redundancies in this genetically heterogenous disease. Pharmacologic disruption of the cap-initiation complex eIF4F is an emerging clinical treatment strategy to bypass resistance. In preclinical experiments, B-lymphomas show high susceptibility to rocaglates, natural and synthetic cap-dependent translation inhibitors. Among these compounds, eFT226 (zotatifin), is currently in phase I/II clinical evaluation for solid tumors. Rocaglate mechanisms remain incompletely defined for use in B-cell lymphoma. Recent findings in our laboratory revealed translationally mediated adaptation that increased synthesis of many targets. Proteins (i.e.CD98hc) that paradoxically increase in production contribute to persistence of cells that survive treatment. By contrast, transcriptional responses to rocaglates remain minimally studied. Here we sought to fill this gap through unbiased transcriptomics. Method: RNA sequencing (RNA-seq) was performed on zotatifin treated DLBCL cells (SU-DHL10) vs DMSO controls. Genes with a false discovery rate p-value (FDR) ≤0.05, logarithm of counts per million reads (logCPM) ≥ 0 and P value ≤0.05 were considered differentially expressed. Log2 fold change (FC) ≥ +/-2-fold for a specific gene was considered significantly differentially expressed between the two groups. Pathway analysis was performed using Gene Set Enrichment Analysis (GSEA). Results: We found 4450 differentially expressed genes, 12 significantly upregulated, and 42 significantly downregulated in response to zotatifin (FC ≥ 2). Further pathways analyses showed 4/25 gene sets significantly upregulated, and 3/22 gene sets significantly downregulated (FDR <0.25). We found significantly upregulated genes related to mechanisms stress and survival pathways including NF-kB induction by TNF signaling (normalized enriched score (NES)=2.28; p-value <0.0001), genes induced in response to hypoxia translational stress responses (NES=1.85; nominal p-value=0.008). Conclusions: These results implicate induction of specific survival pathways that induce transcriptionally mediated adaptation to the stress of rocaglate therapy, but it is unclear if these responses can result in altered protein production in the context of eIF4A inhibition. Parallel assessment of the translatome currently under analysis will provide a more complete picture of overall adaptation and provide rational combination targets for rocaglates in lymphoma as clinical development progresses. Citation Format: Paola Manara, Tyler Andrew Cunningham, Jr Jyun David Ho, Olivia B. Lightfuss, Abdessamad Youssfi Alaoui, Jonathan Harry Schatz. Transcriptional response to rocaglate translation inhibitors in lymphoma shows cellular adaptation through induction of stress and survival pathways. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4878
Recommended from our members
Enhanced Ferroptosis Induction Susceptibility in Diffuse Large B-Cell Lymphoma through Rocaglate-Mediated Translation Inhibition
Introduction: Diffuse Large B-cell Lymphoma (DLBCL) is a genomically complex hematologic malignancy characterized by heterogeneous pathogenesis across multiple molecular subtypes. Despite recent advances, standard frontline treatment options leave a third of patients with relapsed or refractory disease due to tumor populations resistant to therapy by a wide variety of mechanisms. Ferroptosis, an iron-dependent non-programmed cell death mechanism driven by lipid peroxidation, has emerged as a promising therapeutic opportunity in DLBCL. DLBCL demonstrates distinct sensitivity to ferroptosis activators compared to other cancer types, yet the implications in DLBCL prognosis, immune infiltration, and drug resistance remain elusive. Notably, the loss of histone deubiquitinase MYSM1 in hematopoietic stem cells significantly reduces protein synthesis, leading to reduced ferroptosis suppressors, ultimately rendering the cells more susceptible to ferroptosis. Moreover, NRF2, encoded by NFE2L, a known modulator of ferroptosis, has been linked to resistance to rocaglates (cap-dependent translation inhibitors). Intriguingly, our preliminary data indicate that rocaglates induce translation of key proteins involved in oxidative stress (i.e. SDHB) and transcription factors related to the oxidative stress response (NRF1, ATF2, NRF2). Additionally, our published findings in glioblastoma suggest the upregulation of the ferroptosis suppressor 4F2 ( SLC3A2) under translation inhibition conditions. Furthermore, our investigations uncover another potential mechanism, wherein rocaglates induce NF-κB, which was previously shown to be suppressed by dimethyl fumarate (DMF) upon ferroptosis induction in DLBCL. However, the intricate interplay between ferroptosis and translation inhibition in DLBCL remains uninvestigated, prompting our hypothesis that protein synthesis inhibitors might enhance therapeutic ferroptosis induction. Method: To test our hypothesis, we conducted a comprehensive analysis, employing TMT-pSILAC to assess the global transcriptome response to rocaglates treatment, and subsequently verified significant findings via western blot analysis. Additionally, we quantified reduced glutathione (GSH) levels, reactive oxygen species (ROS) levels, and synergy with ferroptosis inducers (e.g., erastin, RSL3) to elucidate the mechanism of rocaglates in enhancing susceptibility to the ferroptosis pathway. Moreover, we explored NF-κB, previously identified as a ferroptosis regulator in our RNAseq analysis, using ELISA and NF-κB reporter assays. Results: Our TMT-pSILAC analysis unveiled upregulation of key ferroptosis suppressors, specifically NFS1, CBS, and 4F2. Concurrent treatment with rocaglates resulted in a notable increase in GSH levels, which was attenuated when administered in combination with ferroptosis inducers (p-value 10) and antagonism with ferroptosis inhibitors (Bliss δ synergy score < -10). Furthermore, our investigation revealed a noteworthy upregulation of NFKB1 at the translatome level, accompanied by a significant increase in TNF-α expression at 48 hours. The NF-κB-EGFP reporter assay confirmed the enhanced expression of NF-κB in response to the treatment. Conclusion: In conclusion, rocaglate-induced stress upregulates multiple ferroptosis suppressors, suggesting that cap-dependent translation disruption triggers a protective response against ferroptosis. Strikingly, these factors did not protect DLBCL tumors from ferroptosis inducers, which synergized remarkably with rocaglates, yielding promising new combination drug strategies. The proteomic basis for ferroptosis sensitization by rocaglate therapy remains under active investigation. Understanding the intricate interplay between these pathways may unveil potential key mechanisms for DLBCL treatment, potentially offering novel therapeutic targets to improve patient outcomes
Recommended from our members
Abstract C051: Alteration of protein translation by eIF4A1 inhibition exquisitely primes lymphoma cells to induction of ferroptosis
Abstract Background: Ferroptosis induction as a cancer therapy faces challenges establishing clinical therapeutic windows. Cells employ diverse mechanisms to prevent iron-mediated oxidation of membrane polyunsaturated fatty acids that causes ferroptosis, but populations with low rates of protein synthesis such as hematopoietic stem cells are more susceptible. Therefore, we hypothesized protein synthesis inhibitors might enhance therapeutic ferroptosis induction. Rocaglates, inhibitors targeting eIF4A1, have entered clinical trials with promising potential against diffuse large B-cell lymphoma (DLBCL), which also exhibits pre-clinical susceptibility to ferroptosis induction. Up to 40% of patients with DLBCL, the most common lymphoma type, have poor outcomes requiring new approaches to address these persistent unmet clinical needs. Our results reveal striking synergy of rocaglates, including the clinical compound zotatifin (eFT226), with ferroptosis inducers. TMT-pSILAC and RNA-seq analyses revealed profound deregulation of ferroptotic protection resulting from rocalate effects on protein synthesis. Methods: We used RNA-seq and TMT-pSILAC followed by mass spectrometry to analyze transcriptome and protein output in SU-DHL-10 DLBCL cells treated with zotatifin or DMSO for 24h. Enrichment analyses (Enrichr platform, ChIP-X Enrichment Analysis 3, GSEA) identified differentially expressed genes, proteins and transcription factors. We explored synergy between zotatifin and ferroptosis modulators in DLBCL cell lines and measured a wide variety of associated cellular endpoints including lipid peroxidation, glutathione levels, and glutathione peroxidase 4 (GPX4) expression. Results: TMT-pSILAC translatome assessment during rocaglate exposure revealed expression alteration(log2FC ≥ 1.5) of numerous key proteins involved in oxidative stress (i.e. SDHB, SDHA, TRAP1, SCO1, UQCRH, ETFA, COX7C) and enrichment of factors indicating induction of an antioxidant response (CD98HC, NRF1, ATF2, SP2, and NFE2L). These changes led to high synergy of zotatifin in combination with a wide variety of ferroptosis inducers (Bliss δ synergy score > 10) and antagonism with ferroptosis inhibitors (Bliss δ synergy score < - 10). These results were consistent across multiple DLBCL mouse and human experimental systems, and preliminarily appear present also in models of T-cell lymphomas. Lipid peroxidation levels were significantly enhanced when zotatifin was combined with erastin (p-value < 0.0005). Moreover, zotatifin treatment resulted in elevated levels of reduced glutathione (GSH), an effect overcome by addition of ferroptosis inducers (p-value < 0.005). Consistently, GPX4 expression was also impaired. Conclusions: Rocaglates induce novel alterations in oxidative stress factors and associated response pathways, sensitizing B and T lymphomas to therapeutic ferroptosis induction. These findings provide valuable insights for using rocaglates in combination with ferroptosis induction to overcome heterogeneous resistance pathways in high-risk lymphoma patients. Citation Format: Paola Manara, Alexa Marie Barroso, Abdessamad Youssfi Alaoui, Olivia Barbara Lightfuss, Tyler Andrew Cunningham, Kyle Hoffman, Caroline Alice Coughlin, Jonathan Harry Schatz. Alteration of protein translation by eIF4A1 inhibition exquisitely primes lymphoma cells to induction of ferroptosis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C051