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This article explores the dissipative control for a class of nonlinear DP-CPS (distributed parameter cyber physical system) within a finite-time interval. By utilizing a Takagi-Sugeno (T-S) fuzzy model to represent the system's nonlinear aspects, the studied system is formulated as a class of fuzzy parabolic partial differential equation (PDE). In order to optimize network resources, both the system state and input signal are subjected to quantization using dynamic quantizers. Subsequently, a dynamic state control strategy is proposed, taking into account potential DoS attack. The finite-time boundedness of the fuzzy parabolic PDE is analyzed, with respect to the influence of quantization, through the construction of an appropriate Lyapunov functional. The article then presents the conditions for finite-time dissipative control design, alongside the adjustment parameters for the dynamic quantizers within the fuzzy closed-loop system. Furthermore, the decoupling of interlinked nonlinear terms in the control design conditions is achieved by using an arbitrary matrix. Finally, an example is provided and the simulation results indicate the effectiveness of the dissipative control method proposed.
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Lógica Difusa , Algoritmos , Modelos Teóricos , Dinámicas no Lineales , Simulación por Computador , Seguridad ComputacionalRESUMEN
Prostate cancer (PCa) has garnered significant attention due to its rising incidence, variable therapeutic outcomes, and the absence of reliable prognostic markers. The significance of different cell death patterns in tumor development underscores their potential as predictors of PCa prognosis. This study utilized The Cancer Genome Atlas (TCGA) datasets to evaluate the prognostic capabilities of 15 cell death patterns and established a Cell Death Index (CDI) signature based on necrosis and cuproptosis-related genes. The predictive efficacy of the CDI signature was validated in our PCa cohort and in two public datasets: Deutsches Krebsforschungszentrum (DKFZ) and Memorial Sloan-Kettering Cancer Center (MSKCC) PCa cohorts. Our comprehensive analysis examined the relationship between CDI signature and clinical characteristics, published prognostic signatures, gene mutations, immune cell infiltration, enrichment pathways, and drug sensitivity in PCa. In vitro and in vivo studies assessed the impact of EDA2R and LOXL2 on PCa progression. The CDI signature exhibited robust predictive performance across three independent validation sets, with 1-, 2-, 3-, 4-, and 5-year area under the curve (AUC) values in the TCGA cohort of 0.866, 0.77, 0.836, 0.776, and 0.787, respectively. Higher CDI scores were correlated with advanced T and N stages, elevated Gleason scores, increased immune cell infiltration, gene mutations, and drug sensitivity. EDA2R inhibited PCa cell proliferation and migration, related to tumor necrosis, while LOXL2 promoted these processes and was associated with cuproptosis. In summary, our study identified a novel CDI signature as an effective indicator for diagnosis, personalized treatment, and prognostic assessment in PCa.
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Objective: To identify factors that influence the severity of tinnitus via a hierarchical multiple linear regression model. Methods: The study was a retrospective cross-sectional analysis. The study included 331 patients experiencing tinnitus as their primary concern, who visited Shanghai Changzheng Hospital of the Navy Medical University between 2019 and 2021. Data on general health status and disease characteristics were collected from all patients. With their consent, participants underwent audiological evaluatons and completed questionnaires to analyze the characteristics of their tinnitus and the factors influencing its severity. Results: The correlation analysis showed a positive relationship between tinnitus frequency, tinnitus loudness, SAS scores, and PSQI scores with THI scores (P < 0.05) among nine examined variables (gender, handedness, employment status, age, BMI, tinnitus frequency, tinnitus loudness, SAS scores, and PSQI scores). The variables that were extracted from the multiple regression were; for the constant; ß = -51.797, t = -4.484, P < 0.001, variable is significant; for the tinnitus loudness; ß = 0.161, t = 2.604, P < 0.05, variable is significant; for the tinnitus frequency; ß = 0.000, t = 1.269, P = 0.206, variable is not significant; for the SAS scores; ß = 1.310, t = 7.685, P < 0.001, variable is significant; for the PSQI scores; ß = 1.680, t = 5.433, P < 0.001, variable is significant. Therefore, the most accurate model for predicting severity in tinnitus patients is a linear combination of the constant, tinnitus loudness, SAS scores, and PSQI scores, Y(Tinnitus severity) = ß 0 + ß 1 (Tinnitus loudness) + ß 2 (SAS scores) + ß 3 (PSQI scores). ß 0, ß 1, ß 2, and ß 3 are -51.797, 0.161, 1.310 and 1.680, respectively. Conclusion: Tinnitus severity is positively associated with loudness, anxiety levels, and sleep quality. To effectively manage tinnitus in patients, it is essential to promptly identify and address these accompanying factors and related symptoms.
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ABSTRACT: Gliomas are the most common primary neuroepithelial tumors of the central nervous system in adults, of which glioblastoma is the deadliest subtype. Apart from the intrinsically indestructible characteristics of glioma (stem) cells, accumulating evidence suggests that the tumor microenvironment also plays a vital role in the refractoriness of glioblastoma. The primary functions of platelets are to stop bleeding and regulate thrombosis under physiological conditions. Furthermore, platelets are also active elements that participate in a variety of processes of tumor development, including tumor growth, invasion, and chemoresistance. Glioma cells recruit and activate resting platelets to become tumor-educated platelets (TEPs), which in turn can promote the proliferation, invasion, stemness, and chemoresistance of glioma cells. TEPs can be used to obtain genetic information about gliomas, which is helpful for early diagnosis and monitoring of therapeutic effects. Platelet membranes are intriguing biomimetic materials for developing efficacious drug carriers to enhance antiglioma activity. Herein, we review the recent research referring to the contribution of platelets to the malignant characteristics of gliomas and focusing on the molecular mechanisms mediating the interaction between TEPs and glioma (stem) cells, as well as present the challenges and opportunities in targeting platelets for glioma therapy.
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OBJECTIVE: To compare a 0-10 physician subglobal estimate of inflammatory activity (DOCINF) on a RheuMetric checklist to a formal swollen joint count (SJC) and other rheumatoid arthritis (RA) Core data set measures in a disease activity score 28 (DAS28), clinical disease activity index (CDAI), and simplified disease activity index (SDAI) in patients with RA, recognizing that RA measures, index scores and physician global assessment (DOCGL) may be elevated by joint damage and patient distress, independent of inflamamtory activity, and that formal joint counts are not recorded at most routine care visits. METHODS: A cross-sectional study at a routine care visit included a RheuMetric checklist completed by a rheumatologist, with four 0-10 visual numeric scales (VNS) for DOCGL, and three sub-global estimates for inflammatory activity (DOCINF), joint damage (DOCDAM), and patient distress (DOCDIS), e.g., anxiety, depression, and/or fibromyalgia, etc. Variation in SJC according to other individual measures in the DAS28, CDAI, and SDAI, and in the indices was analyzed using Spearman correlation coefficients and regressions with and without DOCINF as an independent variable. RESULTS: In 173 patients with long disease duration, regressions which included individual DAS28, CDAI or SDAI measures and added DOCINF as an independent variable explained 46 % of variation in SJC, compared to 23 % if DOCINF was not included. DOCINF was more explanatory of SJC than even the DAS28 or CDAI indices themselves, although SJC is a component of these indices. CONCLUSION: In routine care RA patients with long disease duration, DOCINF depicts SJC as effectively as RA indices which require 90-100 seconds to record, and may provide a feasible, informative quantitative clinical measure without recording formal joint counts.
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Artritis Reumatoide , Índice de Severidad de la Enfermedad , Humanos , Artritis Reumatoide/fisiopatología , Estudios Transversales , Femenino , Masculino , Persona de Mediana Edad , Articulaciones/fisiopatología , Adulto , AncianoRESUMEN
Protein Disulfide-Isomerase A2 (PDIA2) is a gene that encodes proteins, responsible for protein folding and modification within cells. The development and course of many disorders are intimately linked to the aberrant expression of PDIA2. Nevertheless, more research is necessary to fully understand PDIA2's biological significance in pan-cancer, notably in prostate cancer (PCa). PDIA2 expression is elevated in various tumors and closely related to patient prognosis. Patients with prostate cancer who express PDIA2 high in particular have a bad prognosis in terms of progression-free survival. In addition, the upregulation of PDIA2 expression in prostate cancer patients is accompanied by higher Gleason scores, advanced tumor staging, lymph node metastasis, and elevated PSA levels. Detailed experiments further demonstrate that PDIA2 is a carcinogenic gene affecting prostate cancer cells' response to dasatinib therapy. For patients with prostate cancer, there is a clear positive connection between the expression level of PDIA2 and a bad prognosis. The prostate cancer treatment efficacy of dasatinib is hampered by PDIA2, which is intimately linked to the growth, invasion, and metastasis of PCa cells. In summary, our research highlights the potential of PDIA2 as a biomarker for the diagnosis and management of PCa.
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Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata , Proteína Disulfuro Isomerasas , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Proteína Disulfuro Isomerasas/metabolismo , Proteína Disulfuro Isomerasas/genética , Pronóstico , Línea Celular Tumoral , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Regulación hacia AbajoRESUMEN
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Inhibiting the shuttle of polysulfides is of great significance for promoting the practical application of lithium-sulfur batteries (LSBs). Here, an imine-linked covalent organic framework@carbon nanotube (COF@CNT) interlayer composed of triazine and boroxine rings is constructed between the sulfur cathode and the separator for polysulfides reception and reutilization. The introduction of CNT imparts the conductor characteristic to the interlayer attributed to electron tunneling in thin COF shell, and creates a hierarchical porous architecture for accommodating polysulfides. The uniform distribution of amphiphilic adsorption sites in COF microporous structure not only enables efficient entrapment of polysulfides while allowing the penetration of Li+ ions, but also provides a stable electrocatalytic channel for bidirectional conversion of active sulfur to achieve the substantially improved capacity and stability. The interlayer-incorporated LSBs deliver an ultrahigh capacity of 1446 mA g-1 at 0.1C and an ultralow capacity decay rate of 0.019% at 1C over 1500 cycles. Even at an electrolyte/sulfur ratio of 6 µL mg-1, an outstanding capacity of 995 mAh g-1 and capacity retention of 74.1% over 200 cycles at 0.2C are obtained. This work offers a compelling polysulfides entrapment and reactivation strategy for stimulating the study on ultra-stable LSBs.
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Background: Intervertebral disc degeneration (IDD) can lead to disc herniation and spinal instability, sometimes requiring surgical intervention. Currently, estrogen has a potential protective effect on IDD, and estrogen is associated with an increased risk of some cancers, such as breast and endometrial cancer. Therefore, it is important to identify natural compounds that estrogen analogues treat IDD while reducing the risk of tumor development. Objective: This study aims to explore a natural metabolic treatment strategy by targeting CRISP2 with the natural compound Hesperidin to mimic the protective effects of estrogen on IDD and reduce the risk of tumor development. Methods: Microarray data from healthy volunteers and IDD patients were extracted from the Gene Expression Omnibus (GEO) database, and RNA sequencing and clinical data from various cancer types were analyzed. Differentially expressed genes (DEGs) were identified using the Bioconductor Limma package, followed by principal component analysis, volcano plot, and heatmap visualization. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, CIBERSORT and ssGSEA immune cell infiltration assessments, survival analysis, metabolite enrichment analysis, and molecular docking were performed. Hesperidin's interaction with CRISP2 was further validated through molecular docking and experimental studies. Results: Hesperidin significantly reduced the expression of CRISP2, iNOS, and COX2 in IDD models, decreased reactive oxygen species (ROS) and apoptosis, and diminished inflammatory markers. CIBERSORT and ssGSEA analyses revealed a correlation between CRISP2 and immune cell infiltration. Survival analysis demonstrated that CRISP2 expression levels were associated with patient survival across various cancer types. Hesperidin was found to mimic estrogen's effects on IDD and reduce tumor progression. Cell culture and experimental validation confirmed Hesperidin's protective effects on nucleus pulposus cells (NPCs). Conclusion: Hesperidin, as a potential natural metabolic regulator, not only has therapeutic effects on IDD but may also synergize with estrogen therapy to promote spinal health without increasing cancer risk. This study presents a new clinical approach for IDD treatment and lays the foundation for further drug development and experimental research.
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The inability of articular cartilage to self-repair following injuries frequently precipitates osteoarthritis, profoundly affecting patients' quality of life. Given the limitations inherent in current clinical interventions, an urgent need exists for more effective cartilage regeneration methodologies. Previous studies have underscored the potential of electrical stimulation in cartilage repair, thus motivating the investigation of innovative strategies. The present study introduces a three-dimensional scaffold fabricated through a composite technique that leverages the synergy between piezoelectricity and biofactors to enhance cartilage repair. This scaffold is composed of polylactic acid (PLLA) and barium titanate (BT) for piezoelectric stimulation and at the bottom with a collagen-coated layer infused with fibroblast growth factor-18 (FGF-18) for biofactor delivery. Designed to emulate the properties of natural cartilage, the scaffold enables controlled generation of piezoelectric charges and the sustained release of biofactors. In vitro tests confirm that the scaffold promotes chondrocyte proliferation, matrix hyperplasia, cellular migration, and the expression of genes associated with cartilage formation. Moreover, in vivo studies on rabbits have illustrated its efficacy in catalyzing the in situ regeneration of articular cartilage defects and remodeling the extracellular matrix. This innovative approach offers significant potential for enhancing cartilage repair and holds profound implications for regenerative medicine.
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Cartílago Articular , Regeneración , Andamios del Tejido , Cartílago Articular/efectos de los fármacos , Animales , Andamios del Tejido/química , Conejos , Regeneración/efectos de los fármacos , Poliésteres/química , Proliferación Celular/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Condrocitos/citología , Condrocitos/efectos de los fármacosRESUMEN
The failure of bone regeneration has been considered as a serious problem that troubling patients for decades, most of which was resulted by the poor angiogenesis and chronic inflammation after surgery. Among multiple materials applied in the repair of bone defect, silicate bioceramics attracted researchers because of its excellent bioactivity. The purpose of this study was to detect the effect of specific bioactive glass ceramic (AP40, based on crystalline phases of apatite and wollastonite) on angiogenesis and the subsequent bone growth through the modulation of macrophages. Two groups were included in this study: control group (macrophages without any stimulation, denominated as Control) and AP40 group (macrophages incubated on AP40). This study investigated the effect of AP40 on macrophages polarization (RAW264.7) and angiogenesis in vitro and in vivo. Additionally, the changes of angiogenic ability regulated by macrophages were explored. AP40 showed excellent angiogenesis potential and the expression of CD31 was promoted through the modulation of macrophages toward M2 subtype. Additionally, the macrophages incubated on AP40 synthesized more PDGF-BB comparing to macrophages without any stimulation, which contributed to the improved angiogenetic ability of human umbilical vein endothelial cells (HUVECs). Results of in vivo studies indicated increased bone ingrowth along the implants, which indicated the potential of bioceramics for bone defect repair clinically.
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Regeneración Ósea , Cerámica , Células Endoteliales de la Vena Umbilical Humana , Macrófagos , Neovascularización Fisiológica , Impresión Tridimensional , Silicatos , Cerámica/farmacología , Cerámica/química , Animales , Ratones , Silicatos/química , Silicatos/farmacología , Regeneración Ósea/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Macrófagos/metabolismo , Humanos , Células RAW 264.7 , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Porosidad , Conejos , AngiogénesisRESUMEN
Objective: By evaluating the level of serum procalcitonin (PCT), thromboelastography (TEG) and platelet count (PLT) of patients with septic shock in intensive care unit (ICU), the predictive value of the combination of the three indicators on the short-term progression was discussed, which provided a new basis for early clinical diagnosis and disease evaluation. Methods: The clinical data of 130 patients with septic shock admitted to the IUC of our hospital from December 2021 to December 2023 were analyzed retrospectively. These subjects were divided into good prognosis group (n=78) and poor prognosis group (n=52) according to the 28 d deaths. The influencing factors were explored using the Multivariate logistic regression analysis. The value of single or combined PCT, PLT and TEG in predicting poor short-term prognosis was assessed using the receiver operating characteristic (ROC) curve. Results: The patients in poor prognosis group had higher Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, serum PCT level, coagulation reaction time (R value) and coagulation formation time (K value), but lower PLT levels, final strength of coagulation (MA value) and coagulation formation rate (α angle) than those in good prognosis group (P<0.001). PCT, R value and K value were risk factors (P<0.001), while PLT, MA value and α angle were protective factors (P<0.001). The area under the curve (AUC) of PCT, PLT and TEG predicting poor short-term progression was 0.813, 0.658 and 0.752, respectively. The AUC of combined three indicators was 0.905, which had the highest predictive value. Conclusion: Serum levels of PCT, PLT and TEG had certain value in predicting poor short-term progression of septic shock patients, and their combined diagnostic value was higher. Therefore, regular monitoring of these three indicators could provide certain guiding significance for the prevention and treatment of poor short-term prognosis in patients with septic shock.
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Taste perception is one of the important senses in mammals. Taste dysfunction causes significant inconvenience in daily life, leading to subhealth and even life-threatening condition. Aging is a major cause to taste dysfunction, while the underlying feature related to gustatory aging is still not known. Using single-cell RNA Sequencing, differentially expressed genes between aged and young taste papillae are identified, including upregulated mt-Nd4l and Xist, as well as downregulated Hsp90ab1 and Tmem59. In the Tmem59-/- circumvallate papillae (CVP), taste mature cell generation is impaired by reduction in the numbers of PLCß2+ and Car4+ cells, as well as decreases in expression levels of taste transduction genes. Tmem59-/- mice showed deficits in sensitivities to tastants. Through screening by GenAge and DisGeNET databases, aging-dependent genes and oral disease-associated genes are identified in taste papillae. In the CVP, aging promotes intercellular communication reciprocally between (cycling) basal cell and mature taste cell by upregulated Crlf1/Lifr and Adam15/Itga5 signaling. By transcriptional network analysis, ribosome proteins, Anxa1, Prdx5, and Hmgb1/2 are identified as transcriptional hubs in the aged taste papillae. Chronological aging-associated transcriptional changes throughout taste cell maturation are revealed. Aged taste papillae contain more Muc5b+ cells that are not localized in gustatory gland. Collectively, this study shows molecular and cellular features associated with taste papilla aging.
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Importance: Nonlinear changes in brain function during aging are shaped by a complex interplay of factors, including sex, age, genetics, and modifiable health risk factors. However, the combined effects and underlying mechanisms of these factors on brain functional connectivity remain poorly understood. Objective: To comprehensively investigate the combined associations of sex, age, APOE genotypes, and ten common modifiable health risk factors with brain functional connectivities during aging. Design Setting and Participants: This analysis used data from 36,630 UK Biobank participants, aged 44-81, who were assessed for sex, age, APOE genotypes, 10 health risk factors, and brain functional connectivities through resting-state functional magnetic resonance imaging. Main Outcomes and Measures: Brain functional connectivities were evaluated through within- and between-network functional connectivities and connectivity strength. Associations between risk factors and brain functional connectivities, including their interaction effects, were analyzed. Results: Hypertension, BMI, and education were the top three influential factors. Sex-specific effects were also observed in interactions involving APOE4 gene, smoking, alcohol consumption, diabetes, BMI, and education. Notably, a negative sex-excessive alcohol interaction showed a stronger negative effect on functional connectivities in males, particularly between the dorsal attention network and the language network, while moderate alcohol consumption appeared to have protective effects. A significant negative interaction between sex and APOE4 revealed a greater reduction in functional connectivity between the cingulo-opercular network and the posterior multimodal network in male APOE4 carriers. Additional findings included a negative age-BMI interaction between the visual and dorsal attention networks, and a positive age-hypertension interaction between the frontoparietal and default mode networks. Conclusions and Relevance: The findings highlight significant sex disparities in the associations between age, the APOE-ε4 gene, modifiable health risk factors, and brain functional connectivity, emphasizing the necessity of jointly considering these factors to gain a deeper understanding of the complex processes underlying brain aging.
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BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a significant health problem. Dietary intervention plays an important role in patients with MAFLD. OBJECTIVES: We aimed to provide a reference for dietary patterns in patients with MAFLD. METHODS: The presence of MAFLD was determined in the United Kingdom Biobank cohort. Nine dietary pattern scores were derived from the dietary records. Multivariable Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). The contrast test was employed to calculate the heterogeneity across MAFLD statuses. RESULTS: We identified 175,300 patients with MAFLD at baseline. Compared with non-MAFLD, MAFLD was significantly associated with chronic liver disease (CLD) (HR: 3.48; 95% CI: 3.15, 3.84), severe liver disease (SLD) (HR: 2.87; 95% CI: 2.63, 3.14), liver cancer (HR: 1.93; 95% CI: 1.67, 2.23), and liver-related death (LRD) (HR: 1.93; 95% CI: 1.67, 2.23). In the overall cohort, the alternate Mediterranean diet (aMED) (HRCLD: 0.53; 95% CI: 0.37, 0.76; HRSLD: 0.52; 95% CI: 0.37, 0.72), planetary health diet (PHD) (HRCLD: 0.62; 95% CI: 0.47, 0.81; HRSLD: 0.65; 95% CI: 0.51, 0.83), plant-based low-carbohydrate diet (pLCD) (HRCLD: 0.65; 95% CI: 0.49, 0.86; HRSLD: 0.66; 95% CI: 0.51, 0.85), and healthful plant-based diet index (hPDI) (HRCLD: 0.63; 95% CI: 0.47, 0.84; HRSLD: 0.61; 95% CI: 0.47, 0.78) were associated with a lower risk of CLD and SLD. Additionally, unhealthful plant-based diet index (uPDI) was associated with increased risk of CLD (HR: 1.42; 95% CI: 1.09,1.85), SLD (HR: 1.50; 95% CI: 1.19, 1.90), and LRD (HR: 1.88; 95% CI: 1.28-2.78). The aforementioned associations remained consistently strong within the MAFLD subgroup while exhibiting less pronounced in the non-MAFLD group. However, no significant heterogeneity was observed across different MAFLD statuses. CONCLUSIONS: These findings highlight the detrimental effects of MAFLD on the development of subsequent liver diseases and the importance of dietary patterns in managing MAFLD.
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Dieta , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Anciano , Estudios de Cohortes , Adulto , Reino Unido/epidemiología , Progresión de la Enfermedad , Hígado Graso/etiología , Enfermedad del Hígado Graso no Alcohólico/etiología , Hepatopatías/etiología , Hepatopatías/epidemiología , Patrones DietéticosRESUMEN
Purpose: This study aimed to analyze articles on the diagnosis and treatment of bone and soft tissue sarcoma using positron emission tomography (PET)/computed tomography (CT) published in the last 13 years. The objective was to conduct a bibliometric analysis and identify the research hotspots and emerging trends. Methods: Web of Science was used to search for articles on PET/CT diagnosis and treatment of bone and soft tissue sarcoma published from January 2010 to June 2023. CiteSpace was utilized to import data for bibliometric analysis. Results: In total, 425 relevant publications were identified. Publications have maintained a relatively stable growth rate for the past 13 years. The USA has the highest number of published articles (139) and the highest centrality (0.35). The UDICE-French Research Universities group is the most influential institution. BYUN BH is a prominent contributor to this field. The Journal of Clinical Oncology has the highest impact factor in the field. Conclusion: The clinical application of PET/CT is currently a research hotspot. Upcoming areas of study concentrate on the merging of PET/CT with advanced machine learning and/or alternative imaging methods, novel imaging substances, and the fusion of diagnosis and therapy. The use of PET/CT has progressively become a crucial element in the identification and management of sarcomas. To confirm its efficacy, there is a need for extensive, multicenter, prospective studies.
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Background: CD38 and CD47 are expressed in many hematologic malignancies, including multiple myeloma (MM), B-cell non-Hodgkin lymphoma (NHL), B-cell acute lymphoblastic leukemia (ALL), and B-cell chronic lymphocytic leukemia (CLL). Here, we evaluated the antitumor activities of CD38/CD47 bispecific antibodies (BsAbs). Methods: Five suitable anti-CD38 antibodies for co-targeting CD47 and CD38 BsAb were developed using a 2 + 2 "mAb-trap" platform. The activity characteristics of the CD38/CD47 BsAbs were evaluated using in vitro and in vivo systems. Results: Using hybridoma screening technology, we obtained nine suitable anti-CD38 antibodies. All anti-CD38 antibodies bind to CD38+ tumor cells and kill tumor cells via antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Five anti-CD38 antibodies (4A8, 12C10, 26B4, 35G5, and 65A7) were selected for designing CD38/CD47 BsAbs (IMM5605) using a "mAb-trap" platform. BsAbs had higher affinity and binding activity to the CD38 target than those to the CD47 target, decreasing the potential on-target potential and off-tumor effects. The CD38/CD47 BsAbs did not bind to RBCs and did not induce RBC agglutination; thus, BsAbs had much lower blood toxicity. The CD38/CD47 BsAbs had a greater ability to block the CD47/SIRPα signal in CD38+/CD47+ tumor cells than IMM01 (SIRPα Fc fusion protein). Through Fc domain engineering, CD38/CD47 BsAbs were shown to kill tumors more effectively by inducing ADCC and ADCP. IMM5605-26B4 had the strongest inhibitory effect on cellular CD38 enzymatic activity. IMM5605-12C10 had the strongest ability to directly induce the apoptosis of tumor cells. The anti-CD38 antibody 26B4 combined with the SIRPα-Fc fusion proteins showed strong antitumor effects, which were better than any of the mono-therapeutic agents used alone in the NCI-H929 cell xenograft model. The CD38/CD47 BsAbs exhibited strong antitumor effects; specifically, IMM5605-12C10 efficiently eradicated all established tumors in all mice. Conclusion: A panel of BsAbs targeting CD38 and CD47 developed based on the "mAb-tarp" platform showed potent tumor-killing ability in vitro and in vivo. As BsAbs had lower affinity for binding to CD47, higher affinity for binding to CD38, no affinity for binding to RBCs, and did not induce RBC agglutination, we concluded that CD38/CD47 BsAbs are safe and have a satisfactory tolerability profile.
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ADP-Ribosil Ciclasa 1 , Antígeno CD47 , Neoplasias Hematológicas , Antígeno CD47/inmunología , Antígeno CD47/antagonistas & inhibidores , Antígeno CD47/metabolismo , ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , ADP-Ribosil Ciclasa 1/inmunología , ADP-Ribosil Ciclasa 1/metabolismo , Humanos , Animales , Ratones , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/inmunología , Línea Celular Tumoral , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/antagonistas & inhibidores , Citotoxicidad Celular Dependiente de Anticuerpos , Femenino , Antineoplásicos Inmunológicos/farmacologíaRESUMEN
Purpose: The 68Ga/177Lu-FAP-2286 is a newly developed tumor imaging agent that shows potential for visualizing and treating tumor stroma. The objective of this research was to evaluate the effectiveness of 68Ga-FAP-2286 PET/CT and 18F-FDG PET/CT in diagnosing advanced lung cancer. Methods: In this prospective study, patients with lung cancer who underwent 68Ga-FAP-2286 and 18F-FDG PET/CT examinations between September 2022 and June 2023 were analyzed. Lesion uptake was converted to SUVmax. A paired T-test was used to compare the SUVmax, and the number of positive lesions detected by the two methods was recorded. Results: In total, 31 participants (median age: 56 years) were assessed. The uptake of 68Ga-FAP-2286 was significantly higher than that of 18F-FDG in primary lesions (9.90 ± 5.61 vs. 6.09 ± 2.84, respectively, P < 0.001), lymph nodes (7.95 ± 2.75 vs. 5.55 ± 1.59, respectively, P=0.01), and bone metastases (7.74 ± 3.72 vs. 5.66 ± 3.55, respectively, P=0.04). Furthermore, the detection sensitivity of lymph nodes using 68Ga-FAP-2286 PET/CT was superior to that with 18F-FDG PET/CT [100% (137/137) vs. 78.8% (108/137), respectively], as well as for bone metastases [100% (384/384) vs. 68.5% (263/384), respectively]. However, the detection sensitivity for primary tumors using both modalities was comparable [100% (13/13) for both]. Conclusion: Compared to 18F-FDG PET/CT, 68Ga-FAP-2286 PET/CT demonstrated better lesion detection capabilities for lung cancer, particularly in lymph nodes and bone metastases, providing compelling imaging evidence for the efficacy of 177Lu-FAP-2286 treatment.