Background: Aspirin (ASA), the mainstay antiplatelet treatment in patients with cardiovascular disease (CVD), has been received by a considerable number of AF patients. This study sought to examine the association between ASA monotherapy and the risk of major adverse cardiac and cerebrovascular events (MACCE) in patients with atrial fibrillation (AF). Methods: A total of 850 patients with AF were identified from a community-based Kailuan study. All patients were assigned to two groups according to their medicine history: an aspirin therapy group (ASA group) (n = 174), and a non-aspirin therapy group (non-ASA group) (n = 676). The clinical endpoints are MACCE, including myocardial infarction (MI), ischemic stroke (IS), and hemorrhagic stroke (HS). Incidence curves for MACCE were plotted using the Kaplan-Meier method, and the Log rank test was used to assess the differences in incidence rates. The hazard ratios (HR) and 95% confidence intervals (CI) for MACCE were analyzed using Cox proportional-hazards analysis regression models. Results: During the 7.2-year follow-up, 30 MACCE occurred in the ASA group, and 101 in the non-ASA group, with a cumulative incidence of 19.88% vs 17.27%, P = 0.511; 3 cases of MI occurred in the ASA group, and 18 cases in the non-ASA group, with a cumulative incidence of 1.78% vs 2.90%, P = 0.305. Twenty-seven cases of IS occurred in the ASA group, and 84 cases in the non-ASA group, with a cumulative incidence of 1.78% vs 2.90%, P = 0.305. Eight cases of HS occurred in the ASA group, and 13 cases in the non-ASA group, with a cumulative incidence of 5.01% vs 2.34%, P = 0.045. Multivariate regression analysis showed that ASA therapy was not associated with MACCE (HR: 1.130, 95% CI: 0.747-1.710, P = 0.562). In addition, ASA therapy was not associated with IS (HR: 1.309, 95% CI: 0.843-2.034, P = 0.231). However, ASA therapy was significantly associated with HS (HR: 2.563, 95% CI: 1.024-6.418, P = 0.044). Conclusion: ASA monotherapy is not associated with a lower risk of ischemic events, while significantly associated with a higher risk of bleeding events. Patients with AF are unlikely to benefit from aspirin monotherapy.
Peripheral nerve injury often leads to symptoms of motor and sensory impairment, and slow recovery of nerves after injury and limited treatment methods will aggravate symptoms or even lead to lifelong disability. Curcumin can promote peripheral nerve regeneration, but how to accurately deliver the appropriate concentration of curcumin in the local peripheral nerve remains to be solved. In this study, we designed a human hair keratin/chitosan (C/K) hydrogel with sodium tripolyphosphate ions crosslinked to deliver curcumin topically. Chitosan improves the mechanical properties of hydrogels and keratin improves the biocompatibility of hydrogels. C/K hydrogel showed good cytocompatibility, histocompatibility and degradability. In vitro experiments showed that hydrogels can continuously release curcumin for up to 10â¯days. In addition, a comprehensive analysis of behavioral, electrophysiological, histology, and target organ recovery results in animal experiments showed that locally delivered curcumin can enhance nerve regeneration in addition to hydrogels. In short, we provide a new method that combines the advantages of human hair keratin, chitosan, and curcumin for nerve damage repair.
BACKGROUND: The burgeoning demand for hepatectomy in elderly patients with hepatocellular carcinoma (HCC) necessitates improved perioperative care. Geriatric populations frequently experience functional decline and frailty, predisposing them to adverse postoperative outcomes. The Barthel Index serves as a reliable measure for assessing functional capacity, and this study evaluates its impact on surgical textbook outcomes (TOs) in elderly HCC patients. METHODS: A multicenter retrospective cohort study analyzed elderly patients (≥70 years) following hepatectomy for HCC between 2013 and 2021. Utilizing a Barthel Index cut-off value of 85, patients were divided into two groups: with and without preoperative functional decline and frailty. The primary outcome was the rate of TO, encompassing seven criteria. TO rates were compared between groups, and multivariate logistic regression analyses identified independent risks for achieving TOs. RESULTS: Of 497 elderly patients, 157 (31.6 â%) exhibited preoperative functional decline and frailty (Barthel Index score <85). The overall TO rate was 58.6 â%. Patients with preoperative Barthel Index score <85 had significantly lower TO rates compared to patients with score ≥85 (29.3 â% vs. 72.1 â%, P â< â0.001). Multivariate analysis revealed preoperative Barthel Index score <85 as an independent risk for achieving TO (odds ratio 3.413, 95 â% confidence interval 1.879-6.198, P â< â0.001). Comparable results were observed in the subgroups of patients undergoing open and laparoscopic hepatectomy. CONCLUSION: Preoperative Barthel Index-based assessment of functional decline and frailty significantly predicts TOs following hepatectomy in elderly HCC patients, enabling identification of high-risk patients and informing preoperative management and postoperative care within geriatric oncology.
Ischemic stroke ranks among the leading causes of death and disability in humans and is accompanied by motor and cognitive impairment. However, the precise mechanisms underlying injury after stroke and effective treatment strategies require further investigation. Peroxiredoxin-1 (PRDX1) triggers an extensive inflammatory cascade that plays a pivotal role in the pathology of ischemic stroke, resulting in severe brain damage from activated microglia. In the present study, we used molecular dynamics simulation and nuclear magnetic resonance to detect the interaction between PRDX1 and a specific interfering peptide. We used behavioral, morphological, and molecular experimental methods to demonstrate the effect of PRDX1-peptide on cerebral ischemia-reperfusion (I/R) in mice and to investigate the related mechanism. We found that PRDX1-peptide bound specifically to PRDX1 and improved motor and cognitive functions in I/R mice. In addition, pretreatment with PRDX1-peptide reduced the infarct area and decreased the number of apoptotic cells in the penumbra. Furthermore, PRDX1-peptide inhibited microglial activation and downregulated proinflammatory cytokines including IL-1ß, IL-6, and TNF-α through inhibition of the TLR4/NF-κB signaling pathway, thereby attenuating ischemic brain injury. Our findings clarify the precise mechanism underlying PRDX1-induced inflammation after ischemic stroke and suggest that the PRDX1-peptide can significantly alleviate the postischemic inflammatory response by interfering with PRDX1 amino acids 70-90 and thereby inhibiting the TLR4/NF-κB signaling pathway. Our study provides a theoretical basis for a new therapeutic strategy to treat ischemic stroke.
The γδ T cells are a subpopulation of T cells that are abundantly found in the skin and mucous membranes. Their reactivity to self-antigens and ability to secrete various cytokines make them a key component in psoriasis development. Although the correlation between the immune repertoire (IR) of γδ T-cell receptors and the occurrence and severity of psoriasis remains incompletely explored, high-throughput sequencing of γδ T cells has led to a deeper understanding of IR in psoriasis. This study investigated the differences between γδ T cells in patients with psoriasis and healthy controls. The γδ T cells were identified via immunofluorescence staining and a correlation analysis was performed according to the psoriasis area and severity index (PASI) scores. The IR sequencing method was used to detect IR in the γδ T-cell receptors. The findings demonstrated more skin γδ T cells in patients with psoriasis, which were positively correlated with the PASI score. There were subtle differences in most variable (V), diversity (D) and joining (J) gene segments and VJ/VDJ combination segments between patients with psoriasis and healthy controls. However, a higher diversity of complementarity-determining region 3 (CDR3) was observed in patients with psoriasis. In summary, the IR of skin γδ T cells was significantly altered in patients with psoriasis, and the diversity in the cell's CDR3 population is a promising biomarker for assessment of psoriasis severity.
The polyphenol-Maillard reaction is considered one of the important pathways in the formation of humic-like substances (HLSs). Glucose serves as a microbial energy source that drives the humification process. However, the effects of changes in glucose, particularly its concentration, on abiotic pathways remain unclear. Given that the polyphenol-Maillard reaction requires high precursor concentrations and elevated temperatures (which are not present in soil), gibbsite was used as a catalyst to overcome energetic barriers. Catechol and glycine were introduced in fixed concentrations into a phosphate-buffered solution containing gibbsite using the liquid shake-flask incubation method, while the concentration of glucose was controlled in a sterile incubation system. The supernatant fluid and HLS components were dynamically extracted over a period of 360 h for analysis, thus revealing the influence of different glucose concentrations on abiotic humification pathways. The results showed the following: (1) The addition of glucose led to a higher degree of aromatic condensation in the supernatant fluid. In contrast, the supernatant fluid without glucose (Glu0) and the control group without any Maillard precursor (CK control group) exhibited lower degrees of aromatic condensation. Although the total organic C (TOC) content in the supernatant fluid decreased in all treatments during the incubation period, the addition of Maillard precursors effectively mitigated the decreasing trend of TOC content. (2) While the C content of humic-like acid (CHLA) and the CHLA/CFLA ratio (the ratio of humic-like acid to fulvic-like acid) showed varying increases after incubation, the addition of Maillard precursors resulted in a more noticeable increase in CHLA content and the CHLA/CFLA ratio compared to the CK control group. This indicated that more FLA was converted into HLA, which exhibited a higher degree of condensation and humification, thus improving the quality of HLS. The addition of glycine and catechol without glucose or with a glucose concentration of 0.06 mol/L was particularly beneficial in enhancing the degree of HLA humification. Furthermore, the presence of glycine and catechol, as well as higher concentrations of glucose, promoted the production of N-containing compounds in HLA. (3) The presence of Maillard precursors enhanced the stretching vibration of the hydroxyl group (-OH) of HLA. After the polyphenol-Maillard reaction of glycine and catechol with glucose concentrations of 0, 0.03, 0.06, 0.12, or 0.24 mol/L, the aromatic C structure in HLA products increased, while the carboxyl group decreased. The presence of Maillard precursors facilitated the accumulation of polysaccharides in HLA with higher glucose concentrations, ultimately promoting the formation of Al-O bonds. However, the quantities of phenolic groups and phenols in HLA decreased to varying extents.
Glucose , Humic Substances , Maillard Reaction , Polyphenols , Humic Substances/analysis , Glucose/chemistry , Glucose/metabolism , Polyphenols/chemistry , Catechols/chemistry
Background: A diet high in purines can impair the function of the gut microbiota and disrupt purine metabolism, which is closely associated with the onset of hyperuricemia. Dietary regulation and intestinal health maintenance are key approaches for controlling uric acid (UA) levels. Investigating the impacts of fermented foods offers potential dietary interventions for managing hyperuricemia. Methods: In this study, we isolated a strain with potent UA-degrading capabilities from "Jiangshui", a fermented food product from Gansu, China. We performed strain identification and assessed its probiotic potential. Hyperuricemic quails, induced by a high-purine diet, were used to assess the UA degradation capability of strain JS-3 by measuring UA levels in serum and feces. Additionally, the UA degradation pathways were elucidated through analyses of the gut microbiome and fecal metabolomics. Results: JS-3, identified as Lacticaseibacillus paracasei, was capable of eliminating 16.11% of uric acid (UA) within 72 h, rapidly proliferating and producing acid within 12 h, and surviving in the gastrointestinal tract. Using hyperuricemic quail models, we assessed JS-3's UA degradation capacity. Two weeks after the administration of JS-3 (2 × 108 cfu/d per quail), serum uric acid (SUA) levels significantly decreased to normal levels, and renal damage in quails was markedly improved. Concurrently, feces from the JS-3 group demonstrated a significant degradation of UA, achieving up to 49% within 24 h. 16S rRNA sequencing revealed JS-3's role in gut microbiota restoration by augmenting the probiotic community (Bifidobacterium, Bacteroides unclassified_f-Lachnospiraceae, and norank_fynorank_o-Clostridia_UCG-014) and diminishing the pathogenic bacteria (Macrococus and Lactococcus). Corresponding with the rise in short-chain fatty acid (SCFA)-producing bacteria, JS-3 significantly increased SCFA levels (p < 0.05, 0.01). Additionally, JS-3 ameliorated metabolic disturbances in hyperuricemic quails, influencing 26 abnormal metabolites predominantly linked to purine, tryptophan, and bile acid metabolism, thereby enhancing UA degradation and renal protection. Conclusions: For the first time, we isolated and identified an active probiotic strain, JS-3, from the "Jiangshui" in Gansu, used for the treatment of hyperuricemia. It modulates host-microbiome interactions, impacts the metabolome, enhances intestinal UA degradation, reduces levels of SUA and fecal UA, alleviates renal damage, and effectively treats hyperuricemia without causing gastrointestinal damage. In summary, JS-3 can serve as a probiotic with potential therapeutic value for the treatment of hyperuricemia.
BACKGROUND: We sought to examine the associations of the Lifestyle for Brain Health (LIBRA) index with cognitive function among rural Chinese older adults and to explore the potential role of cluster of differentiation 33 gene (CD33) in the associations. METHODS: This population-based cross-sectional study included 4914 dementia-free participants (age ≥60 years; 56.43 % women) in the 2018 baseline examination of MIND-China. The LIBRA index was generated from 11 factors. We used a neuropsychological test battery to assess episodic memory, verbal fluency, attention, executive function, and global cognition. The CD33(rs3865444) polymorphism was detected using multiple-polymerase chain reaction amplification. Data were analyzed using the general linear regression models. RESULTS: A higher LIBRA index was associated with multivariable-adjusted ß-coefficient (95 %CI) of -0.011(-0.020- -0.001) for global cognitive z-score, -0.020(-0.033- -0.006) for episodic memory, and -0.016(-0.029- -0.004) for verbal fluency. The CD33(rs3865444) was associated with a lower global cognitive z-score in the additive (CA vs. CC: ß-coefficient=0.042; 95 %CI=0.008-0.077), the dominant (CA+AA vs. CC: 0.040; 0.007-0.073), and the over-dominant (CA vs. CC+AA: 0.043; 0.009-0.077) models. Similar results were obtained for verbal fluency and attention. The CD33 gene showed statistical interactions with LIBRA index on cognitive function (Pinteraction<0.05) such that a higher LIBRA index was significantly associated with lower z-scores of global cognition and attention only among CD33 CC carriers (P < 0.05). CONCLUSIONS: This population-based study reveals for the first time that a higher LIBRA index is associated with worse cognitive performance in rural Chinese older adults and that CD33 gene could modify the association.
The impact of strain on the formation energy and migration behavior of nitrogen vacancies (VNs) in Al1-xScxN has been investigated by first-principles calculations. The formation energy of VNs is obtained by total energy calculations. The migration barrier calculation utilizes the climbing nudged elastic band method. It is found that the formation energy of VNs is highly tunable with respect to the strain. The formation energy of VNs increases with the tensile strain increasing to +4% and decreases with the increasing compressive strain to -4%. A minimum formation energy of 4.11 eV is obtained when -4% strain is applied. Furthermore, the migration behavior of VNs is studied by calculating the migration barriers. Calculation results show that the migration barrier is strongly affected by strain. When the strain is -4%, the barrier is 2.46 eV while the barrier is increased to 2.71 eV under +4% strain. Therefore, a tensile strain can prevent the formation and migration of VNs. These findings suggest that strain engineering may serve as a tool for regulating VNs behavior in Al1-xScxN, potentially alleviating the ferroelectric degradations associated with VNs.
Giant cell reparative granuloma has a very low incidence and is thought to be a response to trauma. While there have been only a few reported cases of orbital giant cell reparative granuloma, we recently observed such a case and analyzed 16 previously reported cases of this type. It is important to note that further investigation is necessary to fully understand the relationship between giant cell reparative granuloma and trauma.
Granuloma, Giant Cell , Orbital Diseases , Tomography, X-Ray Computed , Humans , Granuloma, Giant Cell/diagnosis , Granuloma, Giant Cell/pathology , Granuloma, Giant Cell/surgery , Orbital Diseases/diagnosis , Orbital Diseases/surgery , Male , Female
BACKGROUND: Cyclin-dependent kinase (CDK) 4/6 inhibitor plus endocrine therapy (ET) become standard-of-care for patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (MBC). However, the optimal therapeutic paradigm after progression on CDK4/6 inhibitor remains unclear. This study aimed to evaluate the efficacy and safety of abemaciclib with switching ET versus chemotherapy after progression on prior palbociclib-based ET in Chinese patients with HR+/HER2- MBC. METHODS: From 414 consecutive patients with HR+/HER2- MBC who had been treated with palbociclib plus ET from September 2018 to May 2022 in Peking University Cancer Hospital, we identified 80 patients who received abemaciclib plus switching ET or chemotherapy after progression on palbociclib, matched for age, original stage at diagnosis, disease-free interval, and tumor burden at 1:1 ratio. The primary endpoint was progression-free survival (PFS) compared using the Kaplan-Meier method. A Cox proportional hazard model was performed to identify clinical factors associated with PFS in the abemaciclib group. RESULTS: The median PFS was 6.0 months (95% confidence interval [CI]: 3.94-8.06) in abemaciclib group and 4.0 months (95% CI, 2.52-5.49) in chemotherapy group (p = 0.667). And, there was no difference in median PFS between the sequential and nonsequential arm (6.0 vs. 6.0 months) in the abemaciclib group though fewer lines of prior systemic therapy and longer PFS from prior palbociclib in the sequential arm. However, patients with prior palbociclib as the first-line therapy had a significantly longer median PFS versus prior palbociclib as ≥2nd-line therapy (11.0 vs. 5.0 months, p = 0.043). Based on multivariable analysis, ER+/PR+ was an independent factor associated with longer PFS. There was no significant difference in overall survival between the abemaciclib and chemotherapy groups (p = 0.069). CONCLUSION: Our findings indicate that abemaciclib plus switching ET might be one of feasible treatment options for Chinese patients with HR+/HER2- MBC after progression on prior palbociclib-based therapy in addition to chemotherapy.
Aminopyridines , Antineoplastic Combined Chemotherapy Protocols , Benzimidazoles , Breast Neoplasms , Piperazines , Progression-Free Survival , Pyridines , Receptor, ErbB-2 , Receptors, Estrogen , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/mortality , Breast Neoplasms/metabolism , Middle Aged , Piperazines/administration & dosage , Piperazines/therapeutic use , Pyridines/therapeutic use , Pyridines/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Receptor, ErbB-2/metabolism , Benzimidazoles/administration & dosage , Benzimidazoles/therapeutic use , China , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Aged , Adult , Retrospective Studies , Disease Progression , Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Agents, Hormonal/administration & dosage
BACKGROUND: The growth of mitral leaflets (MLs) adaptive to left ventricluar (LV) remodeling has been observed. However, the elasticity of MLs upon mechanical stimuli would be supposed if it shrinks with LV reverse remodeling (LVRR). MATERIAL AND METHODS: Patients with idiopathic recent-onset dilated cardiomyopathy (RODCM) (n = 82) and 50 matched normal controls (NC) were prospectively enrolled. Echocardiography was performed at baseline and 6 months of follow-up for the anterior and posterior mitral leaflet (AML and PML) length, mitral annular dimension (MAD), and tenting height (TH). LVRR was measured as a ≥ 15% reduction in LV end-diastolic volume (LVEDV). RESULTS: After 6 months, LVRR was achieved in 69.5% of patients. The AML (28 ± 3 vs. 26 ± 3 mm, p = 0.004) and PML (19 ± 4 vs. 17 ± 3 mm, p < 0.001) decreased in length, as well as the MAD (31 ± 5 vs. 28 ± 5 mm, p = 0.001) and TH (10 ± 3 vs. 8 ± 2 mm, p < 0.001). Compared with the NC group, the AML and PML of the RODCM group were 16.7% and 35.7% longer at baseline and remained 8.3% and 21.2% longer at follow-up, respectively. The change in AML or PML correlated moderately with that in LVEDV (r = 0.487, p < 0.001; r = 0.516, p < 0.001, respectively). The AML and PML length decreased in the LVRR (+) subgroup (AML, 28 ± 3 vs. 26 ± 3 mm, p = 0.001; PML, 20 ± 4 vs. 16 ± 3 mm, p < 0.001), but remained the same in the LVRR (-) subgroup (27 ± 4 vs. 28 ± 4 mm, p = 0.318; 17 ± 3 vs. 17 ± 3 mm, p = 0.790). CONCLUSIONS: Enlarged MLs could reverse accompanied by LV reverse remodeling. This study provided the other facet of ML plasticity adaptive to mechanical stretching.
Chemotherapy remains the main approach conserving vision during the treatment of retinoblastoma, the most prevalent eye cancer in children. Unfortunately, the development of chemoresistance stands as the primary reason for treatment failure. Within this study, we showed that prolonged exposure to vincristine led to heightened expression of JAK1 and JAK2 in retinoblastoma cells, while the other members of the JAK family exhibited no such changes. Employing a genetic intervention, we demonstrated the efficacy of depleting either JAK1 or JAK2 in countering vincristine-resistant retinoblastoma cells. In addition, the dual depletion of both JAK1 and JAK2 produced a more potent inhibitory outcome compared to the depletion of either gene alone. We further demonstrated that ruxolitinib, a small molecular inhibitor of JAK1/2, effectively reduced viability and colony formation in vincristine-resistant retinoblastoma cells. It also acts synergistically with vincristine in retinoblastoma cells regardless of inherent cellular and genetic heterogeneity. The effectiveness of ruxolitinib as standalone treatment against chemoresistant retinoblastoma, as well as its combination with vincristine, was validated in multiple retinoblastoma mouse models. Importantly, mice exhibited favorable tolerance to ruxolitinib administration. We confirmed that the underlying mechanism of ruxolitinib's action in chemoresistant retinoblastoma cells is the inhibition of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. Our study reveals that the underlying mechanism driving ruxolitinib's impact on chemoresistant retinoblastoma cells is the inhibition of JAK/STAT signaling. This study reveals the contribution of JAK1/2 to the development of chemoresistance in retinoblastoma and underscores the effectiveness of targeting JAK1/2 as a strategy to sensitize retinoblastoma to chemotherapy.
OBJECTIVE: To identify critical satisfaction gaps in a home nursing mobile application (APP) using a systematic decision-making model. METHODS: Initially, the decision-making trial and evaluation laboratory method was used to analyze the relationship structure and corresponding weights among the indicators. The Importance-Performance Analysis (IPA) method was used to identify the categories of all indicators and their corresponding strategic directions. Twenty-six home nursing specialists currently providing home nursing services were recruited for this study. RESULTS: The IPA results revealed that "Assurance," "Reliability," and "Personal security protection" are critical satisfaction gaps. From the influence network and weight results, "information quality" and "system quality" were the critical quality factors in the home nursing mobile APP. The influence of the network relationship structure and weight demonstrated a 98.12% significance level, indicating good stability. CONCLUSION: Continuous improvement in information and system quality is recommended to optimize the overall quality of the home nursing mobile APP. Additionally, user demands should be considered, and personal safety guarantee functions should be developed and integrated into the system to ensure the safety of home nursing workers.
Osteoarthritis (OA) is a prevalent degenerative joint disease with a lack of effective therapeutic. Chondrocyte ferroptosis contributes to the progression of OA. PUM2 is shown to exacerbate ischemia-reperfusion-induced neuroinflammation by promoting ferroptosis, but its role in OA remains unexplored. Here, primary mouse chondrocytes were stimulated with IL-1ß to mimic OA chondrocyte injury in vitro. And PUM2 was upregulated in OA cartilage tissues and IL-1ß-induced chondrocytes. Silencing PUM2 alleviated IL-1ß-induced chondrocyte inflammation and ECM degradation. Mechanistically, PUM2 facilitated the degradation of NEDD4 mRNA by binding to the 3'UTR of NEDD4 mRNA, which in turn inhibited NEDD4 induced PTEN ubiquitination and degradation. Consistently, NEDD4 silencing reversed the ameliorative effect of PUM2 knockdown on chondrocyte injury, and overexpression of PTEN abolished the improved role of NEDD4 in chondrocyte injury. Moreover, PTEN aggravated IL-1ß-induced ferroptosis in chondrocytes through the Nrf2/HO-1 pathway by increasing the levels of Fe2+, ROS, MDA, and ACSL4 protein, decreasing the activity of SOD and the levels of GSH and GPX4 protein, and aggravating mitochondrial damage. Additionally, destabilized medial meniscus (DMM) were conducted to establish the OA mouse model, and adenovirus-mediated PUM2 shRNA was administered intra-articularly. Silencing PUM2 attenuated OA-induced cartilage damage in vivo. In conclusion, PUM2 promoted OA progression through PTEN-mediated chondrocyte ferroptosis by facilitating NEDD4 mRNA degradation.
Urban ecological spaces are effective thermoregulators under global warming. However, the cooling efficiency of urban ecological spaces during the urbanization has not been studied comprehensively. Here, we investigate the spatio-temporal dynamics of Urban Cold Island (UCI) intensity in 11 typical cities of the Yangtze River Economic Belt (YREB). We determined the impact of ecological landscape trends on these dynamics by using GlobalLand and MODIS 8 d mean land surface temperature (LST) data for three periods (2000, 2010, and 2020), and the landscape pattern index and diversity index. We found that in the past 20 years, the built-up area has increased by sixfold; 62.53 % and 37.47 % of YREB were warming or cooling, with 71.22 % of the daytime cooling and 93 % of the nighttime warming. The average UCI intensity of YREB has increased from 0.518 to 0.847 and is negatively correlated with LST with a decreasing slope. As the UCI intensity of green spaces increased, that of blue spaces decreased. Surface area and landscape pattern are the key determinants of UCI intensity in blue and green spaces, respectively, especially the landscape shape index (LSI). Therefore, maintaining ecological spaces, enriching the structural integrity of green spaces, and improving blue space connectivity can help cities at different development levels cope with heat stress during regional urbanization.
Background: For decades, stratification criteria for first-line clinical studies have been highly uniform. However, there is no principle or consensus for restratification after systemic treatment progression based on immune checkpoint inhibitors (ICIs). The aim of this study was to assess the patterns of disease progression in patients with advanced hepatocellular carcinoma (HCC) who are not eligible for surgical intervention, following the use of immune checkpoint inhibitors. Methods: This is a retrospective study that involved patients with inoperable China liver stage (CNLC) IIIa and/or IIIb. The patients were treated at eight centers across China between January 2017 and October 2022. All patients received at least two cycles of first-line treatment containing immune checkpoint inhibitors. The patterns of disease progression were assessed using RECIST criteria 1.1. Different progression modes have been identified based on the characteristics of imaging progress. The study's main outcome measures were post-progression survival (PPS) and overall survival (OS). Survival curves were plotted using the Kaplan-Meier method to compare the difference among the four groups. Subgroup analysis was conducted to compare the efficacy of different immunotherapy combinations. Variations in the efficacy of immunotherapy have also been noted across patient groups exhibiting alpha-fetoprotein (AFP) levels equal to or exceeding 400ng/mL, in contrast to those with AFP levels below 400ng/mL. Results: The study has identified four distinct patterns of progress, namely p-IIb, p-IIIa, p-IIIb, and p-IIIc. Diverse patterns of progress demonstrate notable variations in both PPS and OS. The group p-IIb had the longest PPS of 12.7m (95% 9.3-16.1) and OS 19.6m (95% 15.6-23.5), the remaining groups exhibited p-IIIb at PPS 10.5 months (95%CI: 7.9-13.1) and OS 19.2 months (95%CI 15.1-23.3). Similarly, p-IIIc at PPS 5.7 months (95%CI: 4.2-7.2) and OS 11.0 months (95%CI 9.0-12.9), while p-IIIa at PPS 3.4 months (95%CI: 2.7-4.1) and OS 8.2 months (95%CI 6.8-9.5) were also seen. Additional stratified analysis was conducted and showed there were no differences of immunotherapy alone or in combination in OS (HR= 0.92, 95%CI: 0.59-1.43, P=0.68) and PPS (HR= 0.88, 95%CI: 0.57-1.36, P=0.54); there was no significant difference in PPS (HR=0.79, 95% CI: 0.55-1.12, P=0.15) and OS (HR=0.86, 95% CI: 0.61-1.24, P=0.39) for patients with AFP levels at or over 400ng/mL. However, it was observed that patients with AFP levels above 400ng/mL experienced a shorter median progression of PPS (8.0 months vs. 5.0 months) after undergoing immunotherapy. Conclusion: In this investigation of advanced hepatocellular carcinoma among Chinese patients treated with immune checkpoint inhibitors, we identified four distinct progression patterns (p-IIb, p-IIIa, p-IIIb and p-IIIc) that showed significant differences in PPS and OS. These findings demonstrate the heterogeneity of disease progression and prognosis after immunotherapy failure. Further validation in large cohorts is necessary to develop prognostic models that integrate distinct progression patterns to guide subsequent treatment decisions. Additionally, post-immunotherapy progression in patients with AFP levels ≥400ng/mL indicates a shortened median PPS. These findings provide valuable insights for future personalized treatment decisions.
Carcinoma, Hepatocellular , Disease Progression , Immune Checkpoint Inhibitors , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/immunology , Liver Neoplasms/therapy , Liver Neoplasms/mortality , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Immune Checkpoint Inhibitors/therapeutic use , Male , Middle Aged , Female , Retrospective Studies , China , Aged , Adult , Neoplasm Staging , alpha-Fetoproteins/metabolism , alpha-Fetoproteins/analysis , Treatment Outcome , East Asian People
The booming development of artificial intelligence (AI) has brought excitement to many research fields that could benefit from its big data analysis capability for causative relationship establishment and knowledge generation. In toxicology studies using zebrafish, the microscopic images and videos that illustrate the developmental stages, phenotypic morphologies, and animal behaviors possess great potential to facilitate rapid hazard assessment and dissection of the toxicity mechanism of environmental pollutants. However, the traditional manual observation approach is both labor-intensive and time-consuming. In this Perspective, we aim to summarize the current AI-enabled image and video analysis tools to realize the full potential of AI. For image analysis, AI-based tools allow fast and objective determination of morphological features and extraction of quantitative information from images of various sorts. The advantages of providing accurate and reproducible results while avoiding human intervention play a critical role in speeding up the screening process. For video analysis, AI-based tools enable the tracking of dynamic changes in both microscopic cellular events and macroscopic animal behaviors. The subtle changes revealed by video analysis could serve as sensitive indicators of adverse outcomes. With AI-based toxicity analysis in its infancy, exciting developments and applications are expected to appear in the years to come.
N6-methyladenine (m6A) and 5-methylcytosine (m5C) are two common forms of RNA methylation that play an important role in the epigenetics of type 2 diabetes mellitus (T2DM). One type of cell death, ferroptosis, has been implicated in islet ß-cell damage in T2DM. Notably, RNA methylation, an upstream regulatory mechanism of mRNAs, can regulate the expression of ferroptosis signaling molecules, thereby affecting cell proliferation and death. Here, we found that the ferroptosis signaling pathway was activated in pancreas of T2DM rats, followed by significant changes in m6A/m5C modification regulatory molecules. These detection data together with the prediction results that m6A and m5C exist in the mRNAs of ferroptosis molecules, we speculate that m6A and m5C are probably involved in pancreatic cell damage by modifying of ferroptosis signaling molecules. In short, our findings provide a new research idea for future studies on the molecular mechanisms of pancreatic cell damage and point to a new direction for exploring the mechanisms of ferroptosis from the perspective of RNA methylation modification.
