Coumarin-Furoxan Hybrid Suppressed the Proliferation and Metastasis of Triple-Negative Breast Cancer by Activating Mitochondrial Stress and Cell Apoptosis.

Triple-negative breast cancer (TNBC) typically manifests as higher invasive carcinoma correlated with a worse prognosis that primarily relies on chemotherapy. There is growing evidence that nitric oxide (NO) donor drugs have the potential for anticancer therapy. On this basis, we constructed and evaluated a novel coumarin-furoxan hybrid 4A93 as an effective antitumor candidate drug. 4A93 exhibits low IC50 values in three TNBC cell lines and inhibits colony formation and DNA synthesis, probably due to the release of high concentrations of NO in mitochondria, which induces oxidative stress, mitochondrial dysfunction, and apoptosis. Further research suggests that 4A93 might destroy mitochondria by opening the mitochondrial permeability transition pore (mPTP), depolarizing the mitochondrial membrane potential (MMP), and promoting the release of cytochrome c into the cytoplasm. Intrinsic apoptosis is induced finally, along with Akt/Erk signaling suppression. Additionally, 4A93 underregulates the Epithelial-mesenchymal transition process to inhibit cell migration and invasion. In 4T1 subcutaneous and hematogenous models of mice, 4A93 therapy suppresses the tumor growth and prevented lung metastasis with favorable biosafety. Our results provide insights into 4A93 in TNBC treatment and validate the contribution of NO donors in tumor therapy.

Enhancing the tumor penetration of multiarm polymers by collagenase modification.

Tumor penetration is a critical determinant of the therapy efficacy of nanomedicines. However, the dense extracellular matrix (ECM) in tumors significantly hampers the deep penetration of nanomedicines, resulting in large drug-untouchable areas and unsatisfactory therapy efficacy. Herein, we synthesized a third-generation PAMAM-cored multiarm copolymer and modified the polymer with collagenase to enhance its tumor penetration. Each arm of the copolymer was a diblock copolymer of poly(glutamic acid)-b-poly(carboxybetaine), in which the polyglutamic acid block with abundant side groups was used to link the anticancer agent doxorubicin through the pH-sensitive acylhydrazone linkage, and the zwitterionic poly(carboxybetaine) block provided desired water solubility and anti-biofouling capability. The collagenase was conjugated to the ends of the arms via the thiol-maleimide reaction. We demonstrated that the polymer-bound collagenase could effectively catalyze the degradation of the collagen in the tumor ECM, and consequently augmented the tumor penetration and antitumor efficacy of the drug-loaded polymers.

Model construction and application for predicting pre-eclampsia by Sonoclot coagulation analyzer.

Maternal age has significantly increased among Chinese women, thereby posing risk of pregnancy-related complications. Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality, and coagulation analysis in conjunction with clinical signs and symptoms are generally used for its diagnosis with limited efficacy. Sonoclot coagulation analyzer is effective in assessing coagulation function used during cerebral surgery and cardiovascular surgery. However, its use has not been explored in preeclampsia. Here, we investigated the potential use of Sonoclot in diagnosing preeclampsia in obstetrics cases. Subjects meeting the screening criteria were divided either into a test group or a control group, according to whether they were preeclamptic or not. We recorded the Sonoclot-derived coagulation and the routine coagulation parameters including platelet function (PF), activated clotting time (ACT) and clot rate (CR), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), and platelet count. Regression analysis was done on the relevant parameters to assess the feasibility of Sonoclot analyzer in preeclampsia diagnosis. In parallel, changes in preeclampsia lncRNAs was also evaluated. Significant differences were recorded in PT and ACT between the two groups. In the monovariant logistic regression, PT and ACT appeared to be reliable predictor variables. In the multinomial logistic regression, a total of five regression steps were performed with decreasing AIC values. The K-fold cross validation resulted in an accuracy rate (ACC) of 77.5%, a false positive rate of 16.4%, and a false negative rate of 33.2%. lncRNAs ANRIL and HOXD-AS1 were found deregulated. Our findings indicate that Sonoclot may be useful for diagnosis of preeclampsia in obstetrics.

A preliminary study on analysis of lower limb energy during walking in the patients with knee replacement.

Background: Knee replacement surgeries are used to reduce pain and enhance functionality for individuals with knee arthritis. It is predicted that the annual volume of total knee replacement surgeries conducted in the US will surge by a substantial 673% by 2030. Though a lot of studies have done gait analysis on patients with knee replacement, little research is on energy changes in the lower limbs during gait. This study aimed to investigate the mechanical energy changes in the lower limbs for patients with total knee arthroplasty (TKA) and unicondylar knee arthroplasty (UKA), and ultimately to provide a specific tool to analyze limb energy during gait in clinical practice. Methods: 10 TKA and 8 UKA patients were recruited for gait analysis. The control group consisted of 11 individuals without knee replacement surgery. Vicon motion capture system and Plug-in-Gait model were used to collect gait data to obtain marker coordinates and gait parameters. The kinetic energy, potential energy, and rotational energy for each segment in the lower limbs were calculated. The energies in the centre of pelvis were considered as the approximate to the centre of mass. The energy recovery coefficients were analysed for each segment during gait. SPSS was used to identify the differences between different groups. Results: The results showed that during walking, the upper leg had the highest recovery coefficient, approximately 40%, followed by the foot at 10%, and the lowest recovery coefficient was observed in the lower leg, approximately 1-3%. However, the energy recovery coefficients at the centre of pelvis were significantly higher in the control group than the TKA and UKA groups by roughly 12%-15%. Conclusions: The energy difference between the operative and non-operative sides is not significant regardless of the type of surgery. The TKA and UKA groups were more active in potential energy than control group. The upper leg has the highest recovery efficiency of kinetic and potential energy exchanges when walking. The control group used the energy for whole body is better than the patient groups. This study provides a new and useful way to analyze mechanical energy in the lower limbs during gait and could be applied in clinical practice.

A coumarin-furoxan hybrid as novel nitric oxide donor induced cell apoptosis and ferroptosis in NSCLC by promoting S-nitrosylation of STAT3 and negative regulation of JAK2-STAT3 pathway.

Non-small cell lung cancer (NSCLC) still lacks effective treatment because of its extensive mutation diversity and frequent drug resistance. Therefore, it is urgent to develop new therapeutic strategies for NSCLC. In this study, we evaluated the inhibitory effect of a new coumarin-furoxan hybrid compound 9, a nitric oxide (NO) donor drug, on NSCLC proliferation and its mechanism. Our results show that compound 9 can inhibit the growth of four NSCLC cell lines and H1975 xenograft model in a dose-dependent manner. Compound 9 effectively releases high concentrations of NO within the mitochondria, leading to cellular oxidative stress, mitochondrial dysfunction, and apoptosis. Moreover, compound 9 inhibits JAK2/STAT3 protein phosphorylation and induces S-nitrosylation modification of STAT3, ultimately resulting in endogenous apoptosis in NSCLC. Additionally, compound 9 significantly induces NSCLC ferroptosis by depleting intracellular GSH, elevating MDA levels, inhibiting SLC7A11/GSH protein expression, and negatively regulating the JAK2/STAT3 pathway. In summary, this study elucidates the inhibitory effects of compound 9 on NSCLC proliferation and provides insights into the underlying mechanisms, offering new possibilities for NSCLC treatment strategies.

Internet-Based Self-Help Mindful Self-Compassion Intervention for Parents of Children With Cancer: A Pilot Study.

BACKGROUND: Parents of children with cancer may experience persistent psychological distress and impaired physical health throughout their children's diagnosis and treatment. OBJECTIVE: This study aimed to develop a mindful self-compassion program for parents of children with cancer and explore its effect. METHODS: This pre-post-test study without a control group was conducted with 34 Chinese parents of children with cancer, using mixed methods. Participants received a 6-week internet-based self-help mindful self-compassion intervention. Self-compassion, post-traumatic stress symptoms, depression, and sleep quality were measured at baseline and at 10 weeks post-baseline. Semi-structured interviews were conducted with 9 completers within 10 days after the intervention was completed. RESULTS: Significant differences were observed in self-compassion, re-experiencing, physical depressive symptoms, and sleep quality. Two participants reported feeling miserable or recalling distressing experiences, of which one withdrew from the study while the other completed the intervention. CONCLUSION: The program could improve self-compassion, re-experiencing, physical depressive symptoms, and sleep quality in parents of children with cancer, which demonstrated the feasibility of delivering a self-help mindful self-compassion intervention through the internet. Increasing retention rates in future studies merits further discussion.

The Importance of M1-and M2-Polarized Macrophages in Glioma and as Potential Treatment Targets.

Glioma is the most common and malignant tumor of the central nervous system. Glioblastoma (GBM) is the most aggressive glioma, with a poor prognosis and no effective treatment because of its high invasiveness, metabolic rate, and heterogeneity. The tumor microenvironment (TME) contains many tumor-associated macrophages (TAMs), which play a critical role in tumor proliferation, invasion, metastasis, and angiogenesis and indirectly promote an immunosuppressive microenvironment. TAM is divided into tumor-suppressive M1-like (classic activation of macrophages) and tumor-supportive M2-like (alternatively activated macrophages) polarized cells. TAMs exhibit an M1-like phenotype in the initial stages of tumor progression, and along with the promotion of lysing tumors and the functions of T cells and NK cells, tumor growth is suppressed, and they rapidly transform into M2-like polarized macrophages, which promote tumor progression. In this review, we discuss the mechanism by which M1- and M2-polarized macrophages promote or inhibit the growth of glioblastoma and indicate the future directions for treatment.

Structural and functional analyses of a germline KRAS T50I mutation provide insights into Raf activation.

A T50I substitution in the K-Ras interswitch domain causes Noonan syndrome and emerged as a third-site mutation that restored the in vivo transforming activity and constitutive MAPK pathway activation by an attenuated KrasG12D,E37G oncogene in a mouse leukemia model. Biochemical and crystallographic data suggested that K-RasT50I increases MAPK signal output through a non-GTPase mechanism, potentially by promoting asymmetric Ras:Ras interactions between T50 and E162. We generated a "switchable" system in which K-Ras mutant proteins expressed at physiologic levels supplant the fms like tyrosine kinase 3 (FLT3) dependency of MOLM-13 leukemia cells lacking endogenous KRAS and used this system to interrogate single or compound G12D, T50I, D154Q, and E162L mutations. These studies support a key role for the asymmetric lateral assembly of K-Ras in a plasma membrane-distal orientation that promotes the formation of active Ras:Raf complexes in a membrane-proximal conformation. Disease-causing mutations such as T50I are a valuable starting point for illuminating normal Ras function, elucidating mechanisms of disease, and identifying potential therapeutic opportunities for Rasopathy disorders and cancer.

Function of the R2R3-MYB Transcription Factors in Dalbergia odorifera and Their Relationship with Heartwood Formation.

R2R3-MYB transcription factors (TFs) form one of the most important TF families involved in regulating various physiological functions in plants. The heartwood of Dalbergia odorifera is a kind of high-grade mahogany and valuable herbal medicine with wide application. However, the role of R2R3-MYB genes in the growth and development of D. odorifera, especially their relevance to heartwood formation, has not been revealed. A total of 126 R2R3-MYBs were screened from the D. odorifera genome and named DodMYB1-126 based on their location on 10 chromosomes. The collinearity results showed that purification selection was the main driving force for the evolution of the R2R3-MYB TFs family, and whole genome/fragment replication event was the main form for expanding the R2R3-MYB family, generating a divergence of gene structure and function. Comparative phylogenetic analysis classified the R2R3-MYB TFs into 33 subfamilies. S3-7,10,12-13,21 and N4-7 were extensively involved in the metabolic process; S9,13,16-19,24-25 and N1-3,8 were associated with the growth and development of D. odorifera. Based on the differential transcriptional expression levels of R2R3-MYBs in different tissues, DodMYB32, DodMYB55, and DodMYB89 were tentatively screened for involvement in the regulatory process of heartwood. Further studies have shown that the DodMYB89, localized in the nucleus, has transcriptional activation activity and is involved in regulating the biosynthesis of the secondary metabolites of heartwood by activating the promoters of the structural genes DodI2'H and DodCOMT. This study aimed to comprehensively analyze the functions of the R2R3-MYB TFs and screen for candidate genes that might be involved in heartwood formation of D. odorifera.

HBV precore G1896A mutation promotes growth of hepatocellular carcinoma cells by activating ERK/MAPK pathway.

Chronic hepatitis B virus (HBV) infection is one of the leading causes of hepatocellular carcinoma (HCC). The HBV genome is prone to mutate and several variants are closely related to the malignant transformation of liver disease. G1896A mutation (G to A mutation at nucleotide 1896) is one of the most frequently observed mutations in the precore region of HBV, which prevents HBeAg expression and is strongly associated with HCC. However, the mechanisms by which this mutation causes HCC are unclear. Here, we explored the function and molecular mechanisms of the G1896A mutation during HBV-associated HCC. G1896A mutation remarkably enhanced the HBV replication in vitro. Moreover, it increased tumor formation and inhibited apoptosis of hepatoma cells, and decreased the sensitivity of HCC to sorafenib. Mechanistically, the G1896A mutation could activate ERK/MAPK pathway to enhanced sorafenib resistance in HCC cells and augmented cell survival and growth. Collectively, our study demonstrates for the first time that the G1896A mutation has a dual regulatory role in exacerbating HCC severity and sheds some light on the treatment of G1896A mutation-associated HCC patients.

A Multi-factor Analysis of Revision in Total Hip Replacement Using the Collarless-Polished-Tapered Stems with Different Cups.

OBJECTIVE: Collarless-polished-tapered (CPT) stems have been widely used in total hip replacement (THR). Given that various types of cups are combined with CPT in clinical practice, however, what cup type performs the best for use with CPT is still unclear. This study aimed to investigate the effects of three types of commonly used cups with CPT on revision and survival life using multi-factor analysis. METHODS: This study is a cohort study using the data between October 1998 to September 2021. The data of THR patients with ZCA All-poly Acetabular Cup, Continuum Acetabular System, and Trilogy Acetabular System with CPT were collected from several hospitals in the UK. The patients aged from 20 to 97 (n = 5981, 2345 male and 3636 female). Age, gender, body mass index, diagnosis, surgeon grade, cup material, cup size, surgical approach, survival life, complications, and Harris hip scores (HHS) were analyzed in relation to revision status. SPSS statistical software was used to analyze the relationship among various factors. The main statistical methods included chi-square with cross tables, analysis of variance (ANOVA) and survival analysis. RESULTS: The results in relation to HHS shows that the continuum cup has the best outcome in the postoperative period of 1 and 5 years (1 year = 90.7, 5 years = 91.3; P < 0.001); the Trilogy cup was the second (1 year = 88.4, 5 years = 87.3; P < 0.001); and the ZCA cup was the third (1 year = 84.6, 5 years = 82.4; P < 0.001). However, the Trilogy cup performed the best regarding survival life on revision while the Continuum cup was the worst. CONCLUSION: When the CPT stem is combined with different cups, the trilogy cup shows the best characteristics in terms of survival trends with revision ratios compared with the continuum and ZCA cups, and is therefore recommended by this study.

Detrimental role of SIX1 in hepatic lipogenesis and fibrosis of non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Aberrant lipid metabolism and accumulation of extracellular matrix proteins are hallmarks of the disease, but the underlying mechanisms are largely unknown. This study aims to elucidate the key role of sine oculis homeobox homologue 1 (SIX1) in the development of NAFLD. METHODS: Alb-Cre mice were administered the AAV9 vector for SIX1 liver-specific overexpression or knockdown. Metabolic disorders, hepatic steatosis, and inflammation were monitored in mice fed with HFHC or MCD diet. High throughput CUT&Tag analysis was employed to investigate the mechanism of SIX1 in diet-induced steatohepatitis. RESULTS: Here, we found increased SIX1 expression in the livers of NAFLD patients and animal models. Liver-specific overexpression of SIX1 using adeno-associated virus serotype 9 (AAV9) provoked more severe inflammation, metabolic disorders, and hepatic steatosis in the HFHC or MCD-induced mice model. Mechanistically, we demonstrated that SIX1 directly activated the expression of liver X receptor α (LXRα) and liver X receptor ß (LXRß), thus inducing de novo lipogenesis (DNL). In addition, our results also illustrated a critical role of SIX1 in regulating the TGF-ß pathway by increasing the levels of type I and II TGF-ß receptor (TGFßRI/TGFßRII) in hepatic stellate cells (HSCs). Finally, we found that liver-specific SIX1 deficiency could ameliorate diet-induced NAFLD pathogenesis. CONCLUSION: Our findings suggest a detrimental function of SIX1 in the progression of NAFLD. The direct regulation of LXRα/ß and TGF-ß signalling by SIX1 provides a new regulatory mechanism in hepatic steatosis and fibrosis.

Inhalable Microparticles Embedding Biocompatible Magnetic Iron-Doped Hydroxyapatite Nanoparticles.

Recently, there has been increasing interest in developing biocompatible inhalable nanoparticle formulations, as they have enormous potential for treating and diagnosing lung disease. In this respect, here, we have studied superparamagnetic iron-doped calcium phosphate (in the form of hydroxyapatite) nanoparticles (FeCaP NPs) which were previously proved to be excellent materials for magnetic resonance imaging, drug delivery and hyperthermia-related applications. We have established that FeCaP NPs are not cytotoxic towards human lung alveolar epithelial type 1 (AT1) cells even at high doses, thus proving their safety for inhalation administration. Then, D-mannitol spray-dried microparticles embedding FeCaP NPs have been formulated, obtaining respirable dry powders. These microparticles were designed to achieve the best aerodynamic particle size distribution which is a critical condition for successful inhalation and deposition. The nanoparticle-in-microparticle approach resulted in the protection of FeCaP NPs, allowing their release upon microparticle dissolution, with dimensions and surface charge close to the original values. This work demonstrates the use of spray drying to provide an inhalable dry powder platform for the lung delivery of safe FeCaP NPs for magnetically driven applications.

Design, synthesis and biological evaluation of seco-DSP/DCK derivatives reversing P-glycoprotein-mediated paclitaxel resistance in A2780/T cells.

P-glycoprotein transporter (P-gp, ABCB1) is a major contributor to multidrug resistance, making it a valuable target for the development of novel P-gp inhibitor to overcome multidrug resistance. In this study, forty-nine novel seco-DSPs and seco-DMDCK derivatives were synthesized and evaluated their chemo-sensitize abilities to paclitaxel in A2780/T cell lines. Most of them exhibited a comparable reversal multidrug-resistance activity than verapamil. Especially, compound 27f showed a remarkable chemo-sensitization with more than 425-fold reversal ratio in A2780/T cells. The study of preliminary pharmacological mechanism displayed that compound 27f was more effective to increase the accumulation of paclitaxel and Rhodamine 123 than verapamil via inhibiting P-gp for reversing multidrug-resistance. In addition, a higher than 40 µM IC50 values of hERG potassium channel inhibition concentration suggested that compound 27f hardly had relevant cardiac toxicity. These results indicated that compound 27f might be a potential candidate to further investigate for the development of chemosensitizer with MDR reversal activity.

Defect-Modified nano-BaTiO3 as a Sonosensitizer for Rapid and High-Efficiency Sonodynamic Sterilization.

Multidrug-resistant bacteria caused by the unlimited overuse of antibiotics pose a great challenge to global health. An antibacterial method based on reactive oxygen species (ROS) is one of the effective strategies without inducing bacterial resistance. Owing to the ability of generating ROS, piezocatalytic material-mediated sonodynamic therapy (SDT) has drawn much attention. However, its major challenge is the low ROS generation efficiency in the piezocatalytic process due to the poor charge carrier concentration of piezoelectric materials. Vacancy engineering can regulate the charge density and largely promote ROS generation under ultrasound (US) irradiation. Herein, a US-responsive self-doped barium titanate with controlled oxygen vacancy (Vo) concentrations was successfully synthesized through a facile thermal reduction treatment at different temperatures (i.e., 350, 400, and 450 °C), and the corresponding samples were named as BTO-350, BTO-400, and BTO-450, respectively. Then, the effect of Vo concentrations on ROS generation efficiency during the piezocatalytic process was systematically studied. And BTO-400 was found to possess the highest piezocatalytic activity and excellent sonodynamic antibacterial performance against Escherichia coli and Staphylococcus aureus. Furthermore, its antibacterial mechanism was confirmed that the ROS generated under US could damage bacterial cell membrane and cause considerable leakage of cytoplasmic components and irreversible death of bacteria. Notably, the in vivo results illustrated that the BTO-400 could serve as an effective antibacterial agent and accelerate skin healing via SDT therapy. In all, the Vo defect-modified nano-BaTiO3 has a noticeable potential to induce a rapid and efficient sterilization as well as skin tissue repair by SDT.

Homologous cancer cell membrane-camouflaged nanoparticles target drug delivery and enhance the chemotherapy efficacy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common digestive tract malignancy that seriously threatens human life and health. Early HCC may be treated by intervention, surgery, and internal radiotherapy, while the choice for late HCC is primarily chemotherapy to prolong patient survival. Lenvatinib (LT) is a Food and Drug Administration (FDA)-approved frontline drug for the treatment of advanced liver cancer and has achieved excellent clinical efficacy. However, its poor solubility and severe side effects cannot be ignored. In this study, a bionic nanodrug delivery platform was successfully constructed. The platform consists of a core of Lenvatinib wrapped with a pH-sensitive polymer, namely, poly(ß-amino ester)-polyethylene glycol-amine (PAE-PEG-NH2), and a shell formed by a cancer cell membrane (CCM). The prepared nanodrugs have high drug loading capacity, long-term stability, good biocompatibility, and a long retention time. In addition, the targeting effect of tumor cell membranes and the pH-responsive characteristics of the polymer materials enable them to precisely target tumor cells and achieve responsive release in the tumor microenvironment, which makes them suitable for effective drug delivery. In vivo experiments revealed that the nanodrug showed superior tumor accumulation and therapeutic effects in subcutaneous tumor mice model and could effectively eliminate tumors within 21 days. As a result, it opens up a new way to reduce side effects and improve the specific therapeutic effect of first-line clinical medications to treat tumors.

ALDH2 attenuates ischemia and reperfusion injury through regulation of mitochondrial fusion and fission by PI3K/AKT/mTOR pathway in diabetic cardiomyopathy.

The function of mitochondrial fusion and fission is one of the important factors causing ischemia-reperfusion (I/R) injury in diabetic myocardium. Aldehyde dehydrogenase 2 (ALDH2) is abundantly expressed in heart, which involved in the regulation of cellular energy metabolism and stress response. However, the mechanism of ALDH2 regulating mitochondrial fusion and fission in diabetic myocardial I/R injury has not been elucidated. In the present study, we found that the expression of ALDH2 was downregulated in rat diabetic myocardial I/R model. Functionally, the activation of ALDH2 resulted in the improvement of cardiac hemodynamic parameters and myocardial injury, which were abolished by the treatment of Daidzin, a specific inhibitor of ALDH2. In H9C2 cardiomyocyte hypoxia-reoxygenation model, ALDH2 regulated the dynamic balance of mitochondrial fusion and fission and maintained mitochondrial morphology stability. Meanwhile, ALDH2 reduced mitochondrial ROS levels, and apoptotic protein expression in cardiomyocytes, which was associated with the upregulation of phosphorylation (p-PI3KTyr458, p-AKTSer473, p-mTOR). Moreover, ALDH2 suppressed the mitoPTP opening through reducing 4-HNE. Therefore, our results demonstrated that ALDH2 alleviated the ischemia and reperfusion injury in diabetic cardiomyopathy through inhibition of mitoPTP opening and activation of PI3K/AKT/mTOR pathway.

Efficacy and safety of granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in COVID-19 patients: a meta-analysis.

OBJECTIVE: This study aims to determine the efficacy and safety of granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in COVID-19 patients. METHODS: We searched Cochrane Library, PubMed, Embase, and ClinicalTrials.gov databases until July 27, 2022. Both randomized control trials (RCTs) and cohort studies were included and analyzed separately. The outcomes included mortality, incidence of invasive mechanical ventilation (IMV), ventilation improvement rate (need oxygen therapy to without oxygen therapy), secondary infection, and adverse events (AEs). The odds ratio (OR) with a 95% confidence interval (CI) was calculated by a random-effects meta-analysis model. RESULTS: Five RCTs and 2 cohort studies with 1726 COVID-19 patients were recruited (n = 866 in the GM-CSF antibody group and n = 891 in the control group). GM-CSF antibodies treatment reduced the incidence of IMV, which was supported by two cohort studies (OR 0.16; 95% CI 0.03, 0.74) and three RCTs (OR 0.62; 95% CI 0.41, 0.94). GM-CSF antibodies resulted in slight but not significant reductions in mortality (based on two cohort studies and five RCTs) and ventilation improvement (based on one cohort study and two RCTs). The sensitive analysis further showed the results of mortality and ventilation improvement rate became statistically significant when one included study was removed. Besides, GM-CSF antibodies did not increase the risks of the second infection (based on one cohort study and five RCTs) and AEs (based on five RCTs). CONCLUSION: GM-CSF antibody treatments may be an efficacious and well-tolerant way for the treatment of COVID-19. Further clinical evidence is still warranted.

Taking precautions in advance: a lower level of activities of daily living may be associated with a higher likelihood of memory-related diseases.

Introduction: Memory-related diseases (MDs) pose a significant healthcare challenge globally, and early detection is essential for effective intervention. This study investigates the potential of Activities of Daily Living (ADL) as a clinical diagnostic indicator for MDs. Utilizing data from the 2018 national baseline survey of the China Health and Retirement Longitudinal Study (CHARLS), encompassing 10,062 Chinese individuals aged 45 or older, we assessed ADL using the Barthel Index (BI) and correlated it with the presence of MDs. Statistical analysis, supplemented by machine learning algorithms (Support Vector Machine, Decision Tree, and Logistic Regression), was employed to elucidate the relationship between ADL and MDs. Background: MDs represent a significant public health concern, necessitating early detection and intervention to mitigate their impact on individuals and society. Identifying reliable clinical diagnostic signs for MDs is imperative. ADL have garnered attention as a potential marker. This study aims to rigorously analyze clinical data and validate machine learning algorithms to ascertain if ADL can serve as an indicator of MDs. Methods: Data from the 2018 national baseline survey of the China Health and Retirement Longitudinal Study (CHARLS) were employed, encompassing responses from 10,062 Chinese individuals aged 45 or older. ADL was assessed using the BI, while the presence of MDs was determined through health report questions. Statistical analysis was executed using SPSS 25.0, and machine learning algorithms, including Support Vector Machine (SVM), Decision Tree Learning (DT), and Logistic Regression (LR), were implemented using Python 3.10.2. Results: Population characteristics analysis revealed that the average BI score for individuals with MDs was 70.88, significantly lower than the average score of 87.77 in the control group. Pearson's correlation analysis demonstrated a robust negative association (r = -0.188, p < 0.001) between ADL and MDs. After adjusting for covariates such as gender, age, smoking status, drinking status, hypertension, diabetes, and dyslipidemia, the negative relationship between ADL and MDs remained statistically significant (B = -0.002, ß = -0.142, t = -14.393, 95% CI = -0.002, -0.001, p = 0.000). The application of machine learning models further confirmed the predictive accuracy of ADL for MDs, with area under the curve (AUC) values as follows: SVM-AUC = 0.69, DT-AUC = 0.715, LR-AUC = 0.7. Comparative analysis of machine learning outcomes with and without the BI underscored the BI's role in enhancing predictive abilities, with the DT model demonstrating superior performance. Conclusion: This study establishes a robust negative correlation between ADL and MDs through comprehensive statistical analysis and machine learning algorithms. The results validate ADL as a promising diagnostic indicator for MDs, with enhanced predictive accuracy when coupled with the Barthel Index. Lower levels of ADL are associated with an increased likelihood of developing memory-related diseases, underscoring the clinical relevance of ADL assessment in early disease detection.

ITGB4 deficiency induces DNA damage by downregulating HDAC1 in airway epithelial cells under stress stimulation.

BACKGROUND: DNA damage in airway epithelia under exogenous disruptors can trigger various pulmonary diseases. Integrin beta 4 (ITGB4) is a structural adhesion molecule, which is indicated to regulate the process of DNA damage in airway epithelia for its unique long cytoplasmic domain subunit. METHODS: The expression level of ITGB4 and the degree of DNA damage were observed in the house dust mite (HDM)-stressed model and ozone-challenged model, respectively. Besides, ITGB4 conditional knockout mice and ITGB4-deficient airway epithelial cells were constructed to observe the influence of ITGB4 deficiency on DNA damage. Furthermore, the influence of ITGB4 deficiency on HDAC1 expression in airway epithelia was determined under stress stimulation. Finally, corresponding intervention strategies were carried out to verify the involvement of the ITGB4-mediated HDAC1 pathway in DNA damage of airway epithelial cells. RESULTS: HDM stress and ozone challenge reduced the expression of ITGB4, which is accompanied by the increased expression of 8-oxoG and γ-H2AX both in vivo and in vitro. Moreover, ITGB4 deficiency in airway epithelia aggravates the degree of DNA damage under HDM stimulation and ozone stress, respectively. Furthermore, ITGB4 deficiency downregulated the expression of HDAC1 during DNA damage, and restoring HDAC1 can reverse the enhanced DNA damage in airway epithelial cells after exogenous stress. CONCLUSIONS: This study confirmed the involvement of ITGB4 in the regulation of DNA damage through mediating HDAC1 in airway epithelial cells under exogenous stress. These results supply some useful insights into the mechanism of DNA damage in airway epithelial cells, which would provide possible targets for early prediction and intervention of pulmonary diseases.