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"Wang, Xia"
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High-dimensional continuous action space control via trust region optimized deep reinforcement learning
The present research introduces the Adaptive Trust Region Policy Optimization for Action Space Compression (ATRPO-ACS) framework, a novel deep reinforcement learning approach optimized through trust region strategies, designed to address adaptive control challenges in high-dimensional continuous action spaces. By integrating distributed KL constraint optimization and manifold projection with residual compensation, the framework achieves significant improvements in sampling efficiency and real-time performance while reducing trajectory tracking errors and voltage limit violations. Experimental validations demonstrate its superior performance, with robotic arm tracking errors maintained within ± 0.08 mm and microgrid scheduling costs reduced by 28.5%. The framework also notably shortens production cycles in automotive welding lines. These advancements provide robust theoretical and technical support for real-time optimization control in industrial intelligent systems.
Journal Article
Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease
Iron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.
Journal Article
A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma
Background
Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM).
Methods
This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m
2
. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 10
6
cells/kg [range, 0.07 to 2.1 × 10
6
]) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group.
Results
At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade ≥ 3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval [CI], 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1 month (range, 0.4 to 3.5). At a median follow-up of 8 months, median progression-free survival was 15 months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached.
Conclusions
LCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM.
Trial registration
ClinicalTrials.gov
,
NCT03090659
; Registered on March 27, 2017, retrospectively registered
Journal Article
Unique Roles of Gold Nanoparticles in Drug Delivery, Targeting and Imaging Applications
Nanotechnology has become more and more potentially used in diagnosis or treatment of diseases. Advances in nanotechnology have led to new and improved nanomaterials in biomedical applications. Common nanomaterials applicable in biomedical applications include liposomes, polymeric micelles, graphene, carbon nanotubes, quantum dots, ferroferric oxide nanoparticles, gold nanoparticles (Au NPs), and so on. Among them, Au NPs have been considered as the most interesting nanomaterial because of its unique optical, electronic, sensing and biochemical properties. Au NPs have been potentially applied for medical imaging, drug delivery, and tumor therapy in the early detection, diagnosis, and treatment of diseases. This review focuses on some recent advances in the use of Au NPs as drug carriers for the intracellular delivery of therapeutics and as molecular nanoprobes for the detection and monitoring of target molecules.
Journal Article
miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1)
Background
Loss-of-function mutations in
PINK1
and
PARKIN
are the most common causes of autosomal recessive Parkinson’s disease (PD). PINK1 is a mitochondrial serine/threonine kinase that plays a critical role in mitophagy, a selective autophagic clearance of damaged mitochondria. Accumulating evidence suggests mitochondrial dysfunction is one of central mechanisms underlying PD pathogenesis. Therefore, identifying regulatory mechanisms of PINK1 expression may provide novel therapeutic opportunities for PD. Although post-translational stabilization of PINK1 upon mitochondrial damage has been extensively studied, little is known about the regulation mechanism of PINK1 at the transcriptional or translational levels.
Results
Here, we demonstrated that microRNA-27a (miR-27a) and miR-27b suppress PINK1 expression at the translational level through directly binding to the 3′-untranslated region (3′UTR) of its mRNA. Importantly, our data demonstrated that translation of PINK1 is critical for its accumulation upon mitochondrial damage. The accumulation of PINK1 upon mitochondrial damage was strongly regulated by expression levels of miR-27a and miR-27b. miR-27a and miR-27b prevent mitophagic influx by suppressing PINK1 expression, as evidenced by the decrease of ubiquitin phosphorylation, Parkin translocation, and LC3-II accumulation in damaged mitochondria. Consequently, miR-27a and miR-27b inhibit lysosomal degradation of the damaged mitochondria, as shown by the decrease of the delivery of damaged mitochondria to lysosome and the degradation of cytochrome c oxidase 2 (COX2), a mitochondrial marker. Furthermore, our data demonstrated that the expression of miR-27a and miR-27b is significantly induced under chronic mitophagic flux, suggesting a negative feedback regulation between PINK1-mediated mitophagy and miR-27a and miR-27b.
Conclusions
We demonstrated that miR-27a and miR-27b regulate PINK1 expression and autophagic clearance of damaged mitochondria. Our data further support a novel negative regulatory mechanism of PINK1-mediated mitophagy by miR-27a and miR-27b. Therefore, our results considerably advance our understanding of PINK1 expression and mitophagy regulation and suggest that miR-27a and miR-27b may represent potential therapeutic targets for PD.
Journal Article
Seawater‐Degradable Polymers—Fighting the Marine Plastic Pollution
Polymers shape human life but they also have been identified as pollutants in the oceans due to their long lifetime and low degradability. Recently, various researchers have studied the impact of (micro)plastics on marine life, biodiversity, and potential toxicity. Even if the consequences are still heavily discussed, prevention of unnecessary waste is desired. Especially, newly designed polymers that degrade in seawater are discussed as potential alternatives to commodity polymers in certain applications. Biodegradable polymers that degrade in vivo (used for biomedical applications) or during composting often exhibit too slow degradation rates in seawater. To date, no comprehensive summary for the degradation performance of polymers in seawater has been reported, nor are the studies for seawater‐degradation following uniform standards. This review summarizes concepts, mechanisms, and other factors affecting the degradation process in seawater of several biodegradable polymers or polymer blends. As most of such materials cannot degrade or degrade too slowly, strategies and innovative routes for the preparation of seawater‐degradable polymers with rapid degradation in natural environments are reviewed. It is believed that this selection will help to further understand and drive the development of seawater‐degradable polymers. Plastic pollution of the oceans is a major concern today due to the long life of commodity polymers. The degradation profiles of conventional biodegradable polymers, such as polylactide, polycaprolactone, and others in seawater, are reviewed. As many of them degrade relatively slowly, additional strategies for the development of seawater‐degradable polymers are highlighted.
Journal Article
Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2)
Background
LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years.
Methods
LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 × 10
6
cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy.
Results
As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade ≥ 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer.
Conclusions
The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM.
Trial registration
Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285.
Journal Article
Nicorandil treatment improves survival and spatial learning in aged granulin knockout mice
Mutations in the human granulin (GRN) gene are associated with multiple diseases, including dementia disorders such as frontotemporal dementia (FTD) and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). We studied a Grn knockout (Grn‐KO) mouse model in order to evaluate a potential therapeutic strategy for these diseases using nicorandil, a commercially available agonist for the ABCC9/Abcc9‐encoded regulatory subunit of the “K+ATP” channel that is well‐tolerated in humans. Aged (13 months) Grn‐KO and wild‐type (WT) mice were treated as controls or with nicorandil (15 mg/kg/day) in drinking water for 7 months, then tested for neurobehavioral performance, neuropathology, and gene expression. Mortality was significantly higher for aged Grn‐KO mice (particularly females), but there was a conspicuous improvement in survival for both sexes treated with nicorandil. Grn‐KO mice performed worse on some cognitive tests than WT mice, but Morris Water Maze performance was improved with nicorandil treatment. Neuropathologically, Grn‐KO mice had significantly increased levels of glial fibrillary acidic protein (GFAP)‐immunoreactive astrocytosis but not ionized calcium binding adaptor molecule 1 (IBA‐1)‐immunoreactive microgliosis, indicating cell‐specific inflammation in the brain. Expression of several astrocyte‐enriched genes, including Gfap, were also elevated in the Grn‐KO brain. Nicorandil treatment was associated with a subtle shift in a subset of detected brain transcript levels, mostly related to attenuated inflammatory markers. Nicorandil treatment improved survival outcomes, cognition, and inflammation in aged Grn‐KO mice. Progranulin knockout mice display a profound reduction in survival, as well as increased inflammation and cognitive impairment. Treatment of these mice with nicorandil—a K+ATP channel agonist, decreased mortality and improves cognitive impairment.
Journal Article
Endothelial dysfunction: molecular mechanisms and clinical implications
Cardiovascular disease (CVD) and its complications are a leading cause of death worldwide. Endothelial dysfunction plays a crucial role in the initiation and progression of CVD, serving as a pivotal factor in the pathogenesis of cardiovascular, metabolic, and other related diseases. The regulation of endothelial dysfunction is influenced by various risk factors and intricate signaling pathways, which vary depending on the specific disease context. Despite numerous research efforts aimed at elucidating the mechanisms underlying endothelial dysfunction, the precise molecular pathways involved remain incompletely understood. This review elucidates recent research findings on the pathophysiological mechanisms involved in endothelial dysfunction, including nitric oxide availability, oxidative stress, and inflammation‐mediated pathways. We also discuss the impact of endothelial dysfunction on various pathological conditions, including atherosclerosis, heart failure, diabetes, hypertension, chronic kidney disease, and neurodegenerative diseases. Furthermore, we summarize the traditional and novel potential biomarkers of endothelial dysfunction as well as pharmacological and nonpharmacological therapeutic strategies for endothelial protection and treatment for CVD and related complications. Consequently, this review is to improve understanding of emerging biomarkers and therapeutic approaches aimed at reducing the risk of developing CVD and associated complications, as well as mitigating endothelial dysfunction. Endothelial dysfunction is commonly linked to various disease states resulting from an imbalance in the production of vasodilators and vasoconstrictors, among other factors. Human diseases associated with endothelial dysfunction include atherosclerosis, diabetes, metabolic syndrome, neurodegenerative diseases, chronic kidney disease, hypertension, heart failure, and stroke.
Journal Article