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1.
Eur J Pharmacol ; 983: 176824, 2024 Sep 10.
Article in English | MEDLINE | ID: mdl-39265882

ABSTRACT

Intimal hyperplasia (IH) is an innegligible issue for patients undergoing interventional therapy. The proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor-BB (PDGF-BB) are critical events in the development of IH. While the exact mechanism and effective target for IH needs further investigation. Metabolic disorders of arachidonic acid (ARA) are involved in the occurrence and progression of various diseases. In this study, we found that the expressions of soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) were significantly increased in the VSMCs during balloon injury-induced IH. Then, we employed a COX-2/sEH dual inhibitor PTUPB to increase the concentration of epoxyeicosatrienoic acids (EETs) while prevent the release of pro-inflammatory prostaglandins. Results showed that PTUPB treatment significantly reduced neointimal thickening induced by balloon injury in rats in vivo and inhibited PDGF-BB-induced proliferation and migration of VSMCs in vitro. Our results showed that PTUPB may reverse the phenotypic transition of VSMCs by inhibiting Pttg1 expression. In conclusion, we found that the dysfunction of ARA metabolism in VSMCs contributes to IH, and the COX-2/sEH dual inhibitor PTUPB attenuates IH progression by reversing the phenotypic switch in VSMC through the Sirt1/Pttg1 pathway.

2.
Nano Lett ; 24(37): 11476-11481, 2024 Sep 18.
Article in English | MEDLINE | ID: mdl-39231136

ABSTRACT

Metal-insulator transitions (MITs) in resistive switching materials can be triggered by an electric stimulus that produces significant changes in the electrical response. When these phases have distinct magnetic characteristics, dramatic changes in the spin excitations are also expected. The transition metal oxide La0.7Sr0.3MnO3 (LSMO) is a ferromagnetic metal at low temperatures and a paramagnetic insulator above room temperature. When LSMO is in its metallic phase, a critical electrical bias has been shown to lead to an MIT that results in the formation of a paramagnetic resistive barrier transverse to the applied electric field. Using spin-transfer ferromagnetic resonance spectroscopy, we show that even for electrical biases less than the critical value that triggers the MIT, there is magnetic phase separation, with the spin-excitation resonances varying systematically with applied bias. Therefore, voltage-triggered MITs in LSMO can alter magnetic resonance characteristics, offering an effective method for tuning synaptic weights in neuromorphic circuits.

3.
World J Oncol ; 15(5): 784-791, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39328326

ABSTRACT

Background: Endometrial cancer is one of the most common female cancers globally and in China. Although timely assessment of 5-year relative survival is crucial for guiding secondary prevention and early screening programs for endometrial cancer patients, those kinds of data are scarce in China. We aimed to provide a timely and accurate assessment of 5-year relative survival for patients with endometrial cancer from eastern China. Methods: Overall, 945 patients diagnosed with endometrial cancer during 2004 - 2018 from four cancer registries with high-quality data from Taizhou, eastern China were included. Period analysis was used to calculate 5-year relative survival for overall and the stratification by age at diagnosis and region. Model-based period analysis was used to predict the 5-year relative survival for the upcoming period of 2019 - 2023. Results: We found that 5-year relative survival during 2014 - 2018 reached 86.4% for overall, while urban areas had higher survival compared to rural areas (91.3% vs. 85.3%). Furthermore, there was a clear age gradient, decreasing from 89.3% for age < 55 years to 80.5% for age > 74 years. Predicted 5-year relative survival for the upcoming period 2019 - 2023 could reach 88.4%. Conclusions: We provide, a timely and accurate assessment of 5-year relative survival for patients with endometrial cancer from Taizhou, eastern China, reaching 86.4% for overall. Our finding has important implications for the overall evaluation of early detection and screening programs for patients with endometrial cancer in eastern China.

4.
Quant Imaging Med Surg ; 14(9): 6711-6723, 2024 Sep 01.
Article in English | MEDLINE | ID: mdl-39281164

ABSTRACT

Background: Selecting the appropriate preoperative neoadjuvant chemotherapy (NACT) regimen for patients with advanced gastric cancer (GC) is critical to effective treatment. The aim of this study was to develop nomograms based on pretherapeutic computed tomography (CT) features to predict response to NACT with S-1 and oxaliplatin (SOX) or that with docetaxel and SOX (DOS) in patients with advanced GC. Methods: This study enrolled 311 consecutive patients with confirmed advanced GC undergoing contrast-enhanced CT before and after the three cycles of NACT with DOS (n=152) or SOX (n=159), who were randomized into a training cohort (TC) (NACT with DOS: n=111; NACT with SOX: n=120) and validation cohort (VC) (NACT with DOS: n=41; NACT with SOX: n=39). The objective response rate (ORR) was used to evaluate the response to NACT. In the TC, ORR was compared between the DOS and SOX regimens, and independent predictors including CT features and tumor differentiation were determined by univariate and binary logistic regression analyses. Individual nomograms were constructed for the SOX and DOS regimens in the TC, and the predictive accuracy was validated in the VC. Results: After NACT, the percentage of ORR was higher in patients receiving DOS than in those receiving SOX in TC (P value <0.05). The independent predictors after DOS and SOX were pretherapeutic cT stage [odds ratio (OR) =7.364; OR =8.848], cN stage (OR =1.027; OR =1.345), degree of differentiation (OR =7.127; OR =7.835), and gross tumor volume (OR =8.960; OR =8.161) (all P values <0.05). The concordance indexes of the individual nomograms developed using these predictors were 0.940 and 0.932 after DOS or SOX in the TC, respectively, which was validated by calibration plots with a slope close to 45° in the TC and VC. Conclusions: Despite there being a superior response to DOS compared with SOX, nomograms for predicting response to both NACT regimens were similar, with each demonstrating good predictive performance.

6.
Angle Orthod ; 2024 Sep 25.
Article in English | MEDLINE | ID: mdl-39317377

ABSTRACT

OBJECTIVES: To establish a reference system for assessing the anteroposterior (A-P) position of the subnasal and lower-facial soft tissues for whole facial harmony. MATERIALS AND METHODS: Forty Asian and 40 Caucasian females with attractive profiles were selected as the "attractive" samples, with "ordinary" samples for comparison. Each profile was analyzed, and comparisons were made to reveal the interracial commonalities and differences. Esthetically essential parameters were established. An averaged attractive profile for each race was created by digital morphing and then modified into 30 variations based on combined variations of the esthetically essential parameters. Assessments were performed to investigate the esthetic ranges. RESULTS: A-P position of the subnasal and lower-facial landmarks harmonized with the forehead for female profile esthetics. In addition to balanced soft tissue subnasale (sSn)- and soft titssue pogonion (Pos)-to-forehead A-P relations, harmonizing lower-facial soft tissues to sSn was indispensable for profile attractiveness. sSn-to-glabella, Pos-to-glabella, and Pos-to-sSn A-P relations were esthetically essential. Perceived by orthodontists, the attractive Asian female profiles had sSn-to-glabella A-P relations ranging from 0.5 mm to 4.5 mm, Pos-to-sSn from -9.0 mm to -5.5 mm, and Pos-to-glabella from -8.5 mm to -1.0 mm. Compared with Asians, the attractive Caucasian female profiles had more anteriorly and widely distributed sSn relative to the forehead, wider ranges of Pos-to-sSn A-P relations, and more prominent chins. CONCLUSIONS: A reference system comprising sSn-glabella, Pos-sSn, and Pos-glabella horizontal distances was constructed for facial profile analysis. This system could aid treatment planning for surgical or orthopedic repositioning of the maxilla and chin.

7.
Front Immunol ; 15: 1455899, 2024.
Article in English | MEDLINE | ID: mdl-39308854

ABSTRACT

Background: Severe burns can lead to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) due to inflammation-immunity dysregulation. This study aimed to identify key immune-related molecules and potential drugs for immune regulation in severe burn treatment. Method: Microarray datasets GSE77791 and GSE37069 were analyzed to identify immune-related differentially expressed genes (DEGs), enriched pathways and prognosis-related genes. The DGIdb database was used to identify potentially clinically relevant small molecular drugs for hub DEGs. Hub DEGs were validated by total RNA from clinical blood samples through qPCR. The efficacy of drug candidates was tested in a severe burn mouse model. Pathologic staining was used to observe organ damage. Enzyme Linked Immunosorbent Assay (ELISA) was used to detect the serum IL-1b, IL-6, TNF-a and MCP-1 contents. Activation of the NF-κB inflammatory pathway was detected by western blotting. Transcriptome sequencing was used to observe inflammatory-immune responses in the lung. Results: A total of 113 immune-related DEGs were identified, and the presence of immune overactivation was confirmed in severe burns. S100A8 was not only significantly upregulated and identified to be prognosis-related among the hub DEGs but also exhibited an increasing trend in clinical blood samples. Methotrexate, which targets S100A8, as predicted by the DGIdb, significantly reduces transcription level of S100A8 and inflammatory cytokine content in blood, organ damage (lungs, liver, spleen, and kidneys) and mortality in severely burned mice when combined with fluid resuscitation. The inflammatory-immune response was suppressed in the lungs. Conclusion: S100A8 with high transcription level in blood is a potential biomarker for poor severe burn prognosis. It suggested that methotrexate has a potential application in severe burn immunotherapy. Besides, it should be emphasized that fluid resuscitation is necessary for the function of methotrexate.


Subject(s)
Burns , Burns/immunology , Animals , Mice , Humans , Prognosis , Male , Gene Expression Profiling , Disease Models, Animal , Methotrexate/therapeutic use , Cytokines/metabolism , Cytokines/blood , Computational Biology/methods , Transcriptome , Mice, Inbred C57BL , Female , Biomarkers
8.
Asia Pac J Oncol Nurs ; 11(9): 100554, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39308940

ABSTRACT

Objective: To identify the potential subgroups of postoperative rehabilitation management self-efficacy in patients with lung cancer and explore the association between these subgroups and symptom burden. Methods: This cross-sectional study enrolled 231 lung cancer patients who underwent surgery between May and August 2023. Latent profile analysis, univariate analysis, and disordered multinomial logistic regression were performed to explore postoperative rehabilitation management self-efficacy profiles and identify interindividual variability. ANOVA, LSD, and Tamhane's T2 method were used for multiple comparisons between symptom burden and self-efficacy subgroups. Results: The three subgroups of postoperative rehabilitation management self-efficacy identified included low level group (17.7%), medium level group (63.2%), and high level group (19.0%). Patients with junior high school education were more likely to be classified as medium level groups, and patients with higher levels of social support and better resilience were more likely to be classified as medium and high level groups. Symptom severity and symptom interference of lung cancer patients after surgery varied considerably among the three classes. In the lung cancer module, the high level group had fewer symptoms than the medium level group (P < 0.05). Conclusions: Postoperative rehabilitation management self-efficacy has different classification features among patients with lung cancer. Educational background, resilience, and social support were the influencing factors of postoperative rehabilitation management self-efficacy. Lung cancer patients with higher self-efficacy in postoperative rehabilitation management showed fewer symptom burdens. Medical staff should actively pay attention to patients with low self-efficacy and provide precise interventions for patients with different subgroups.

9.
Sci Adv ; 10(38): eadp6905, 2024 Sep 20.
Article in English | MEDLINE | ID: mdl-39292791

ABSTRACT

High-precision sensors are of fundamental importance in modern society and technology. Although numerous sensors have been developed, obtaining sensors with higher levels of sensitivity and stronger robustness has always been expected. Here, we propose theoretically and demonstrate experimentally an alternative class of sensors with superior performances based on exotic properties of high-order non-Hermitian topological physics. The frequency shift induced by perturbations for these sensors can show an exponential growth with respect to the size of the device, which can grow well beyond the limitations of conventional sensors. The fully integrated circuit chips have been designed and fabricated in a standard 65-nanometer complementary metal-oxide semiconductor process technology. Not only has the sensitivity of systems less than 10-3 femtofarad been experimentally verified, but these systems are also robust against disorders. Our proposed ultrasensitive integrated circuit sensors can have a wide range of applications in various fields and show an exciting prospect for next-generation sensing technologies.

10.
Small ; : e2405150, 2024 Sep 20.
Article in English | MEDLINE | ID: mdl-39301975

ABSTRACT

Zeolites with band-like charge transport properties have exhibited their potential activities in sensing, optics, and electronics. Herein, a precisely designed Cu@ZSM-5 catalyst is presented with an ultra-wide bandgap of 4.27 eV, showing excellent photocatalytic activity in hydroxylation of benzene with benzene conversion 27.9% and phenol selectivity 97.6%. The SXRD and Rietveld refinement results illustrate that Cu@ZSM-5 has an average of 0.8 Cu atoms per unit cell and the single Cu atoms located in the cross-section of the sinusoidal and straight channels. XANES and EXAFS further demonstrate that the Cu atoms have an oxidation state of +2, coordinated with three OMFI-framework atoms and one ─OH group. Detailed characterizations demonstrate that the Cu@ZSM-5 with tailored bandgap is able to enhance the photoinduced electron-hole separation and hence promote selective hydroxylation of benzene to phenol via the superoxide radical route. This work may open a new way for designing electrically conductive zeolite-supported photocatalysts.

11.
Abdom Radiol (NY) ; 2024 Sep 21.
Article in English | MEDLINE | ID: mdl-39305294

ABSTRACT

PURPOSE: To propose and validate a CT radiomics model utilizing radiomic features from lymph nodes (LNs) with maximum short axis diameter (MSAD) < 1 cm for predicting small metastatic LN (sMLN) in patients with resectable esophageal squamous cell carcinoma (ESCC). METHODS: A total of 196 resectable patients with ESCC undergoing surgery were retrospectively enrolled, among whom 25% had sMLN. 146 out of 196 patients (from hospital 1) were randomly divided into the training (n = 116) and testing cohorts (n = 30) at an 8:2 ratio, while the remaining 50 patients from hospital 2 constituted the external validation cohort. Least absolute shrinkage and selection operator binary logistic regression was employed for radiomics feature dimensionality reduction and selection, and multivariable logistic regression analysis was used to construct the radiomics prediction model. The clinical features were statistically selected to develop the clinical model. And both the selected radiomics and clinical features were used to develop the combined model. The predictive value of models was assessed using the area under the receiver operating characteristic curves (AUC). RESULTS: The LN radiomics model was constructed with 9 radiomics features, the clinical model was developed with 3 clinical features, and the combined model was developed using both the LN radiomics and clinical features. However, no statistical radiomics features from ESCC were extracted in dimensionality reduction. Compared to the clinical model, the combined model exhibited superior predictive ability (AUC: 0.893 vs. 0.766, P = 0.003), and the LN radiomics model showed slightly better predictive ability (AUC: 0.860 vs. 0.766, P = 0.153). It was validated in the test and external validation cohorts. CONCLUSION: The combined model could assist in preoperatively identifying sMLN in resectable ESCC. It is beneficial for more accurate N staging and clinical comprehensive staging of ESCC, thereby facilitating the clinical physician to make more personalized and standardized treatment strategies.

12.
Eur Radiol Exp ; 8(1): 107, 2024 Sep 20.
Article in English | MEDLINE | ID: mdl-39302546

ABSTRACT

BACKGROUND: To explore an artificial intelligence (AI) technology employing YOLOv8 for quality control (QC) on elbow joint radiographs. METHODS: From January 2022 to August 2023, 2643 consecutive elbow radiographs were collected and randomly assigned to the training, validation, and test sets in a 6:2:2 ratio. We proposed the anteroposterior (AP) and lateral (LAT) models to identify target detection boxes and key points on elbow radiographs using YOLOv8. These identifications were transformed into five quality standards: (1) AP elbow positioning coordinates (XA and YA); (2) olecranon fossa positioning distance parameters (S17 and S27); (3) key points of joint space (Y3, Y4, Y5 and Y6); (4) LAT elbow positioning coordinates (X2 and Y2); and (5) flexion angle. Models were trained and validated using 2,120 radiographs. A test set of 523 radiographs was used for assessing the agreement between AI and physician and to evaluate clinical efficiency of models. RESULTS: The AP and LAT models demonstrated high precision, recall, and mean average precision for identifying boxes and points. AI and physicians showed high intraclass correlation coefficient (ICC) in evaluating: AP coordinates XA (0.987) and YA (0.991); olecranon fossa parameters S17 (0.964) and S27 (0.951); key points Y3 (0.998), Y4 (0.997), Y5 (0.998) and Y6 (0.959); LAT coordinates X2 (0.994) and Y2 (0.986); and flexion angle (0.865). Compared to manual methods, using AI, QC time was reduced by 43% for AP images and 45% for LAT images (p < 0.001). CONCLUSION: YOLOv8-based AI technology is feasible for QC of elbow radiography with high performance. RELEVANCE STATEMENT: This study proposed and validated a YOLOv8-based AI model for automated quality control in elbow radiography, obtaining high efficiency in clinical settings. KEY POINTS: QC of elbow joint radiography is important for detecting diseases. Models based on YOLOv8 are proposed and perform well in image QC. Models offer objective and efficient solutions for QC in elbow joint radiographs.


Subject(s)
Artificial Intelligence , Elbow Joint , Quality Control , Radiography , Humans , Elbow Joint/diagnostic imaging , Radiography/methods , Male , Female , Middle Aged , Adult
13.
Zhongguo Zhong Yao Za Zhi ; 49(17): 4723-4733, 2024 Sep.
Article in Chinese | MEDLINE | ID: mdl-39307820

ABSTRACT

Zhongfeng Xingnao Decoction(ZFXN) has been utilized for treating intracerebral hemorrhage(ICH) in China, while the pharmacological mechanism of ZFXN remains unclear. Exploring the pharmacological roles of ZFXN is critical for guiding the treatment of cerebrovascular diseases. In this study, a rat model of ICH was constructed by injection of Ⅶ collagenase in the right caudate nucleus. SD rats were randomly assigned into five groups, and the neurological function of rats was evaluated based on the Bederson score. Magnetic resonance imaging(MRI) was used to assess the volume of ICH. Hematoxylin-eosin(HE) staining and transmission electron microscopy(TEM) were employed to observe the pathological and ultrastructural changes in the brain tissue. The levels of reactive oxygen species(ROS) were measured by flow cytometry. The immunofluorescence assay was employed to detect the expression of glutathione peroxidase 4(GPX4) in neurons surrounding the hematoma. Finally, Western blot was employed to determine the expression of ferroptosis-related proteins upstream frameshift 1(UPF1), ferroportin(FPN), acyl-CoA ligase 4(ACSL4), cyclooxyge-nase-2(COX-2), GPX4, NADPH oxidase 1(NOX1), and solute carrier family 7 member 11(SLC7A11) after ICH. Compared with the model(ICH) group, ZFXN treatment for 5 days attenuated neurological dysfunction, reduced the hematoma volume, and alleviated the pathological changes induced by ICH. Meanwhile, ZFXN lowered the levels of Fe~(2+) and oxidative stress and up-regulated the expression of proteins inhibiting ferroptosis. ZFXN improved the prognosis of ICH in rats by inhibiting neuronal ferroptosis, which provided a valuable guide for the clinical application of ZFXN. ZFXN may inhibit ferroptosis by promoting the expression of SLC7A11 and FPN.


Subject(s)
Cerebral Hemorrhage , Drugs, Chinese Herbal , Ferroptosis , Neurons , Rats, Sprague-Dawley , Animals , Cerebral Hemorrhage/drug therapy , Cerebral Hemorrhage/metabolism , Ferroptosis/drug effects , Rats , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/pharmacology , Male , Neurons/drug effects , Neurons/metabolism , Brain Injuries/drug therapy , Brain Injuries/metabolism , Brain Injuries/etiology , Reactive Oxygen Species/metabolism , Humans
14.
Acta Biochim Biophys Sin (Shanghai) ; 56(8): 1208-1220, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-39225075

ABSTRACT

Aging, a complex biological process, involves the progressive decline of physiological functions across various systems, leading to increased susceptibility to neurodegenerative diseases. In society, demographic aging imposes significant economic and social burdens due to these conditions. This review specifically examines the association of protein glycosylation with aging and neurodegenerative diseases. Glycosylation, a critical post-translational modification, influences numerous aspects of protein function that are pivotal in aging and the pathophysiology of diseases such as Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions. We highlight the alterations in glycosylation patterns observed during aging, their implications in the onset and progression of neurodegenerative diseases, and the potential of glycosylation profiles as biomarkers for early detection, prognosis, and monitoring of these age-associated conditions, and delve into the mechanisms of glycosylation. Furthermore, this review explores their role in regulating protein function and mediating critical biological interactions in these diseases. By examining the changes in glycosylation profiles associated with each part, this review underscores the potential of glycosylation research as a tool to enhance our understanding of aging and its related diseases.


Subject(s)
Aging , Neurodegenerative Diseases , Protein Processing, Post-Translational , Humans , Glycosylation , Aging/metabolism , Neurodegenerative Diseases/metabolism , Alzheimer Disease/metabolism , Animals , Biomarkers/metabolism , Parkinson Disease/metabolism
15.
Article in English | MEDLINE | ID: mdl-39291989

ABSTRACT

BACKGROUND: The incidence of liver cancer has shown different temporal trends across populations, while the underlying reasons remain unclear. METHODS: We examined temporal trends in the incidence of liver cancer in Hong Kong, Sweden, and the United States since the 1970s through 2021 using joinpoint regression and age-period-cohort analysis. RESULTS: The age-standardized incidence rate of liver cancer in Hong Kong steadily decreased (average annual percentage change [AAPC] -2.2%, 95% confidence interval [CI] -2.8% to -1.7% in men; AAPC -2.1%, 95%CI -3.1% to -1.1% in women) in 1983-2020. The rate in Sweden increased on average by 0.8% (95%CI 0.2% to 1.4%) per year in men and was stable in women (AAPC 0.2%, 95%CI -0.9% to 1.4%) in 1970-2021. The rate in the United States increased by 2.1% (95%CI 1.5% to 2.8%) per year in men and by 2.1% (95%CI 1.6% to 2.5%) in women in 1975-2020, but decreasing trends were noted in 2015-2020 (AAPC -6.6%, 95%CI -8.3% to -4.9% in men; AAPC -4.2%, 95%CI -7.5% to -0.5% in women). Stratified analysis by histological type showed such decrease in recent years was limited to hepatocellular carcinoma, rather than intrahepatic cholangiocarcinoma. We observed distinct changes in trends across age groups and different trends across birth cohorts. CONCLUSION: The incidence of liver cancer has decreased in Hong Kong but increased in Sweden and the United States since the 1980s, despite decreasing incidence in the United States since 2015. Such disparities may be explained by different etiology and implementation of preventive measures across populations.

16.
Nat Commun ; 15(1): 7720, 2024 Sep 04.
Article in English | MEDLINE | ID: mdl-39231990

ABSTRACT

PbI6 octahedron as a fundamental framework endows the perovskite with excellent photoelectric properties, but also the defective and flimsy surface. Here, we report that the treatment of perovskite surface by bidentate ligands molecules N, N'-Dimethyl-1,2-ethanediamine can in-situ form a lead iodide chelates layer with excellently robust chelated lead octahedron, leading to effectively stabilize and passivate the underlying perovskite. The strong chelation with the lead enables the surface to largely inhibit the defects generation, iodide ion migration and skeleton collapse under external stimuli. It also prolongs the carrier lifetime and adjusts the surface energy-level of perovskite. The resultant perovskite solar cells deliver a power conversion efficiency of 25.7% (certified 25.04%) and retain >90% of their initial value after almost 1000 hours aging at maximum power point under simulated AM1.5 illumination.

17.
Int J Biol Sci ; 20(11): 4513-4531, 2024.
Article in English | MEDLINE | ID: mdl-39247812

ABSTRACT

Large-scale phase III clinical trials of Olaparib have revealed benefits for ovarian cancer patients with BRCA gene mutations or homologous recombination deficiency (HRD). However, fewer than 50% of ovarian cancer patients have both BRCA mutations and HRD. Therefore, improving the effect of Olaparib in HR-proficient patients is of great clinical value. Here, a combination strategy comprising Olaparib and CDK12-IN-3 effectively inhibited the growth of HR-proficient ovarian cancer in cell line, patient-derived organoid (PDO), and mouse xenograft models. Furthermore, the combination strategy induced severe DNA double-strand break (DSB) formation, increased NHEJ activity in the G2 phase, and reduced HR activity in cancer cells. Mechanistically, the combination treatment impaired Ku80 poly(ADP-ribosyl)ation (PARylation) and phosphorylation, resulting in PARP1-Ku80 complex dissociation. After dissociation, Ku80 occupancy at DSBs and the resulting Ku80-primed NHEJ activity were increased. Owing to Ku80-mediated DNA end protection, MRE11 and Rad51 foci formation was inhibited after the combination treatment, suggesting that this treatment suppressed HR activity. Intriguingly, the combination strategy expedited cGAS nuclear relocalization, further suppressing HR and, conversely, increasing genomic instability. Moreover, the inhibitory effect on cell survival persisted after drug withdrawal. These findings provide a rationale for the clinical application of CDK12-IN-3 in combination with Olaparib.


Subject(s)
Genomic Instability , Ovarian Neoplasms , Phthalazines , Piperazines , Phthalazines/pharmacology , Phthalazines/therapeutic use , Piperazines/pharmacology , Piperazines/therapeutic use , Female , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/genetics , Humans , Animals , Cell Line, Tumor , Mice , Genomic Instability/drug effects , Cell Death/drug effects , Cyclin-Dependent Kinases/metabolism , Ku Autoantigen/metabolism , DNA Breaks, Double-Stranded/drug effects
18.
Environ Pollut ; 360: 124673, 2024 Nov 01.
Article in English | MEDLINE | ID: mdl-39103040

ABSTRACT

Numerous studies have explored the health impacts of individual metal exposures, yet the effects of metal mixtures on human endogenous metabolism remain largely unexplored. We aimed to assess the serum metabolic signatures of people exposed to metal mixtures. Serum and urine samples were collected from 186 workers at a steel factory in Anhui, China, in September 2019. Inductively coupled plasma mass spectrometry was used to analyze the concentrations of 23 metal elements. The serum metabolome was determined by liquid chromatography-mass spectrometry (LC-MS). A metabolome-wide association study (MWAS) was performed across the metal exposures and metabolism using quantile g-computation modeling. Pathway enrichment analysis was performed using MetaboAnalyst. We identified 226 metabolites associated with metal mixtures, primarily involving lipid metabolism (glycerophospholipids, sphingolipids), amino acid metabolism (arginine and proline, alanine, aspartate and glutamate metabolism) and caffeine metabolic pathways. Exposure to metal mixtures is mainly associated with alterations in lipid metabolism and amino acid metabolism, particularly in the glycerophospholipid and arginine and proline metabolism pathways.


Subject(s)
Metabolome , Metals , Humans , China , Metals/metabolism , Metabolome/drug effects , Adult , Male , Middle Aged , Occupational Exposure , Female
19.
Stem Cell Res Ther ; 15(1): 249, 2024 Aug 07.
Article in English | MEDLINE | ID: mdl-39113098

ABSTRACT

Inflammation is a key pathological feature of many diseases, disrupting normal tissue structure and resulting in irreversible damage. Despite the need for effective inflammation control, current treatments, including stem cell therapies, remain insufficient. Recently, extracellular vesicles secreted by adipose-derived stem cells (ADSC-EVs) have garnered attention for their significant anti-inflammatory properties. As carriers of bioactive substances, these vesicles have demonstrated potent capabilities in modulating inflammation and promoting tissue repair in conditions such as rheumatoid arthritis, osteoarthritis, diabetes, cardiovascular diseases, stroke, and wound healing. Consequently, ADSC-EVs are emerging as promising alternatives to conventional ADSC-based therapies, offering advantages such as reduced risk of immune rejection, enhanced stability, and ease of storage and handling. However, the specific mechanisms by which ADSC-EVs regulate inflammation under pathological conditions are not fully understood. This review discusses the role of ADSC-EVs in inflammation control, their impact on disease prognosis, and their potential to promote tissue repair. Additionally, it provides insights into future clinical research focused on ADSC-EV therapies for inflammatory diseases, which overcome some limitations associated with cell-based therapies.


Subject(s)
Adipose Tissue , Extracellular Vesicles , Inflammation , Humans , Extracellular Vesicles/metabolism , Inflammation/therapy , Inflammation/metabolism , Inflammation/pathology , Adipose Tissue/cytology , Adipose Tissue/metabolism , Animals , Stem Cells/metabolism , Stem Cells/cytology , Wound Healing
20.
Scand Stat Theory Appl ; 51(2): 672-696, 2024 Jun.
Article in English | MEDLINE | ID: mdl-39101047

ABSTRACT

This article proposes a distance-based framework incentivized by the paradigm shift towards feature aggregation for high-dimensional data, which does not rely on the sparse-feature assumption or the permutation-based inference. Focusing on distance-based outcomes that preserve information without truncating any features, a class of semiparametric regression has been developed, which encapsulates multiple sources of high-dimensional variables using pairwise outcomes of between-subject attributes. Further, we propose a strategy to address the interlocking correlations among pairs via the U-statistics-based estimating equations (UGEE), which correspond to their unique efficient influence function (EIF). Hence, the resulting semiparametric estimators are robust to distributional misspecification while enjoying root-n consistency and asymptotic optimality to facilitate inference. In essence, the proposed approach not only circumvents information loss due to feature selection but also improves the model's interpretability and computational feasibility. Simulation studies and applications to the human microbiome and wearables data are provided, where the feature dimensions are tens of thousands.

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