Generation of cytotoxic aptamers specifically targeting fibroblast-like synoviocytes by CSCT-SELEX for treatment of rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is an autoimmune disease characterised by aggressive fibroblast-like synoviocytes (FLSs). Very few RA patients-derived FLSs (RA-FLSs)-specific surface signatures have been identified, and there is currently no approved targeted therapy for RA-FLSs. This study aimed to screen therapeutic aptamers with cell-targeting and cytotoxic properties against RA-FLSs and to uncover the molecular targets and mechanism of action of the screened aptamers. METHODS: We developed a cell-specific and cytotoxic systematic evolution of ligands by exponential enrichment (CSCT-SELEX) method to screen the therapeutic aptamers without prior knowledge of the surface signatures of RA-FLSs. The molecular targets and mechanisms of action of the screened aptamers were determined by pull-down assays and RNA sequencing. The therapeutic efficacy of the screened aptamers was examined in arthritic mouse models. RESULTS: We obtained an aptamer SAPT8 that selectively recognised and killed RA-FLSs. The molecular target of SAPT8 was nucleolin (NCL), a shuttling protein overexpressed on the surface and involved in the tumor-like transformation of RA-FLSs. Mechanistically, SAPT8 interacted with the surface NCL and was internalised to achieve lysosomal degradation of NCL, leading to the upregulation of proapoptotic p53 and downregulation of antiapoptotic B-cell lymphoma 2 (Bcl-2) in RA-FLSs. When administrated systemically to arthritic mice, SAPT8 accumulated in the inflamed FLSs of joints. SAPT8 monotherapy or its combination with tumour necrosis factor (TNF)-targeted biologics was shown to relieve arthritis in mouse models. CONCLUSIONS: CSCT-SELEX could be a promising strategy for developing cell-targeting and cytotoxic aptamers. SAPT8 aptamer selectively ablates RA-FLSs via modulating NCL-p53/Bcl-2 signalling, representing a potential alternative or complementary therapy for RA.

Theaflavin -3,3'-digallate/ethanol: a novel cross-linker for stabilizing dentin collagen.

Objectives: To study the ability of theaflavin-3,3'-digallate (TF3)/ethanol solution to crosslink demineralized dentin collagen, resist collagenase digestion, and explore the potential mechanism. Methods: Fully demineralized dentin blocks were prepared using human third molars that were caries-free. Then, these blocks were randomly allocated into 14 separate groups (n = 6), namely, control, ethanol, 5% glutaraldehyde (GA), 12.5, 25, 50, and 100 mg/ml TF3/ethanol solution groups. Each group was further divided into two subgroups based on crosslinking time: 30 and 60 s. The efficacy and mechanism of TF3's interaction with dentin type I collagen were predicted through molecular docking. The cross-linking, anti-enzymatic degradation, and biomechanical properties were studied by weight loss, hydroxyproline release, scanning/transmission electron microscopy (SEM/TEM), in situ zymography, surface hardness, thermogravimetric analysis, and swelling ratio. Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy were utilized to explore its mechanisms. Statistical analysis was performed using one and two-way analysis of variance and Tukey's test. Results: TF3/ethanol solution could effectively crosslink demineralized dentin collagen and improve its resistance to collagenase digestion and biomechanical properties (p < 0.05), showing concentration and time dependence. The effect of 25 and 50 mg/ml TF3/ethanol solution was similar to that of 5% GA, whereas the 100 mg/mL TF3/ethanol solution exhibited better performance (p < 0.05). TF3 and dentin type I collagen are mainly cross-linked by hydrogen bonds, and there may be covalent and hydrophobic interactions. Conclusion: TF3 has the capability to efficiently cross-link demineralized dentin collagen, enhancing its resistance to collagenase enzymatic hydrolysis and biomechanical properties within clinically acceptable timeframes (30 s/60 s). Additionally, it exhibits promise in enhancing the longevity of dentin adhesion.

Repurposing AS1411 for constructing ANM-PROTACs.

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands joined by a linker, enabling them to simultaneously bind with an E3 ligase and a protein of interest (POI) and trigger proteasomal degradation of the POI. Limitations of PROTAC include lack of potent E3 ligands, poor cell selectivity, and low permeability. AS1411 is an antitumor aptamer specifically recognizing a membrane-nucleus shuttling nucleolin (NCL). Here, we repurpose AS1411 as a ligand for an E3 ligase mouse double minute 2 homolog (MDM2) via anchoring the NCL-MDM2 complex. Then, we construct an AS1411-NCL-MDM2-based PROTAC (ANM-PROTAC) by conjugating AS1411 with large-molecular-weight ligands for "undruggable" oncogenic STAT3, c-Myc, p53-R175H, and AR-V7. We show that the ANM-PROTAC efficiently penetrates tumor cells, recruits MDM2 and degrades the POIs. The ANM-PROTAC achieves tumor-selective distribution and exhibits excellent antitumor activity with no systemic toxicity. This is a PROTAC with built-in tumor-targeting and cell-penetrating capacities.

Prevalence of suicide ideation, self-harm, and suicide among Chinese patients with schizophrenia: a systematic review and meta-analysis.

Aims: Suicide ideation, self-harm, and suicide are common in patients with schizophrenia, but the reported prevalence vary largely across studies. Improved prevalence estimates and identification of moderators of the above self-directed violence are needed to enhance recognition and care, and to guide future management and research. This systematic review aims to estimate the pooled prevalence and identify moderators of suicide ideation, self-harm, and suicide among patients diagnosed with schizophrenia in China. Methods: Relevant articles published until September 23, 2021, were searched using PubMed, EBSCO, Web of Science, Embase, Science Direct, CNKI, CBM, VIP, and Wanfang databases. Eligible studies published in English or Chinese which reported the prevalence of suicide ideation, self-harm, or suicide among Chinese patients with schizophrenia were collected. All studies passed a quality evaluation. This systematic review was registered with PROSPERO (registration number CRD42020222338). PRISMA guidelines were used in extracting and reporting data. Random-effects meta-analyses were generated using the meta package in R. Results: A total of 40 studies were identified, 20 of which were evaluated as high-quality studies. Based on these studies, the prevalence of lifetime suicide ideation was 19.22% (95% CI: 7.57-34.50%), prevalence of suicide ideation at the time of investigation was 18.06% (95% CI: 6.49-33.67%), prevalence of lifetime self-harm was 15.77% (95% CI: 12.51-19.33%), and prevalence of suicide was 1.49% (95% CI: 0.00-7.95%). Multivariate meta-regression analysis revealed that age (ß = - 0.1517, p = 0.0006) and dependency ratio (ß = 0.0113, p < 0.0001) were associated with the lifetime prevalence of self-harm. Study assessment score (ß = 0.2668, p < 0.0001) and dependency ratio (ß = 0.0050, p = 0.0145) were associated with the lifetime prevalence of suicide ideation. Results of the spatial analysis showed that the prevalence of self-directed violence varied greatly across different provinces. Conclusion: This systematic review provides estimates of the prevalence of self-directed violence among Chinese patients with schizophrenia and explores its moderators and spatial patterns. Findings also have important implications for allocating prevention and intervention resources to targeted high-risk populations in high prevalence areas.

Prevalence of violence to others among individuals with schizophrenia in China: A systematic review and meta-analysis.

Background: Violence to others (hereinafter referred to as "violence-TO") is common in individuals with schizophrenia. The reported prevalence of violence-TO among schizophrenics ranges widely in existing studies. Improved prevalence estimates and identification of moderators are needed to guide future management and research. Methods: We searched EBSCO, EMBASE, Medline, PubMed, Science Direct, Web of Science, CNKI, VIP, WANFANG data, and CBM for relevant articles published before June 5, 2022. Meanwhile, violence-TO was summarized into four categories: (a) violence-TO on the reviews of official criminal or psychiatric records (type I); (b) less serious forms of violence-TO (type II); (c) physical acts causing demonstrable harm to victims (type III); (d) homicide (type IV). We did meta-analysis for the above types of violence-TO, respectively, and applied subgroup analyses and meta-regression analyses to investigate the source of heterogeneity. Results: A total of 56 studies were eligible in this study and 34 of them were high-quality. The prevalence of type I to type IV in individuals with schizophrenia in China was 23.83% (95% CI: 18.38-29.75%), 23.16% (95% CI: 8.04-42.97%), 17.19% (95%CI: 8.52-28.04%), and 0.62% (95% CI: 0.08-1.54%) respectively. The results of the subgroup analysis showed that the prevalence of type I was higher among subjects in the inland than in the coastal non-economic zone, while the prevalence of type III was the highest in the coastal economic zone, followed by the inland region and the lowest in the coastal non-economic zone. The results of multivariate meta-regression analyses showed that: patient source in type I (ß = 0.15, P < 0.01), patient source (ß = 0.47, P < 0.01), and proportion of male (ß = 0.19, P < 0.01) in type II, age (ß = 0.25, P < 0.01), and GDP per capita (ß = 0.05, P = 0.01) in type III were statistically significant. Conclusion: The prevalence of different types of violence-TO and their influencing factors varied. Therefore, the authorities should take different management measures. In addition to individual factors, regional factors may also affect violence-TO, which suggests the need for a multi-sectorial approach to prevention and treatment for subjects in different regions and adopting targeted control strategies. Systematic Review Registration: [www.ClinicalTrials.gov], identifier [CRD42021269767].

Association between tumor morphology and dosimetric parameters of organs at risk after intensity-modulated radiotherapy in esophagus cancer.

PURPOSE: We explored the effects of geometrical topological properties of tumors such as tumor length and "axial cross-sectional area (ACSA)" of tumors (planning target volume [PTV] volume /PTV length) on the dosimetric parameters of organs at risk (lung and heart) in patients with esophagus cancer (EPC) treated by way of intensity-modulated radiation therapy (IMRT), so as to provide a guideline for the dosimetric limitation for organs at risk in IMRT treatment. METHODS: A retrospective analysis was done on 103 cases of patients with EPC who were treated by IMRT from November 2010 to August 2019, in which PTV-G stood for the externally expanded planning target volume (PTV) of the gross tumor volume (GTV) and PTV-C for the externally expanded volume of the clinical target volume (CTV). A linear regression model was employed to analyze the several pairs of correlation: the 1st one between the relative length of tumors (PTV length/lung length) and pulmonary dose-volume parameters, the 2nd one between ACSA of tumors and pulmonary dose-volume parameters, the 3rd one between PTV length and the dosimetric parameters of the heart, and the last one between ACSA of tumors and the dosimetric parameters of the heart. RESULTS: (i) There was a strong positive correlation between the relative length of tumors (PTV length/lung length) and V5 (p < 0.001, r = 0.73), and V10 (p < 0.001, r = 0.66) of the lung. There was a moderate positive correlation between the relative length of tumors and V30 (p < 0.001, r = 0.44) of the lung, and a weak positive correlation between the relative length of tumors and V20 (p < 0.001, r = 0.39) of the lung. (ii) There was a strong positive correlation between ACSA of tumors (PTV volume/PTV length) and V30 (p < 0.001, r = 0.67) of the lung, a moderate positive correlation between ACSA of tumors and V20 (p <0.001, r = 0.51) of the lung, and a weak positive correlation between ACSA of tumors and V10 (p = 0.019, r = 0.23) of the lung, yet there was not an obvious correlation between ACSA of tumors and V5 p > 0.05) of the lung. (iii) There was a moderate positive correlation between PTV length and V40 (p < 0.001, r = 0.58), and Dmean (p < 0.001, r = 0.52) of the heart, yet there was no obvious correlation between ACSA of tumors and Dmean and V40 of the heart (p > 0.05). CONCLUSIONS: (i) Compared with the high-dose region of the lung, the relative length of tumors (PTV length/lung length) has a greater impact on the low-dose region of the lung. The linear regression equation of scatter plot showed that when the relative length of tumors increased by 0.1, the lung dose-volume parameters of V5 , V10 , V20 , and V30 increased by approximately 5.37%, 3.59%, 1.05%, and 1.08%, respectively. When PTV length increased by 1 cm, Dmean and V40 of the heart increased by approximately 153.6 cGy and 2.03%, respectively. (ii) Compared with the low-dose region of the lung, the value of ACSA of tumors (PTV volume/PTV length) has a greater impact on the high-dose region of the lung. However, the value of ACSA of tumors has no significant effect on the dosimetric parameters of the heart (Dmean and V40 ). The linear regression equation of scatter plot showed that when ACSA of tumors increased by 10 cm2 , the lung dose-volume parameters of V10 , V20, and V30 increased by approximately 3.11%, 3.37%, and 4.01%, respectively.

Characterization of the Pathology, Biochemistry, and Immune Response in Kunming (KM) Mice Following Fasciola gigantica Infection.

As a putative model of Fasciola gigantica infection, detailed data in Kunming (KM) mice infected with F. gigantica are lacking. In this study, KM mice were orally infected with 15 metacercaria for 8 weeks. Macroscopic and microscopic changes, serum biochemistry, cytokine responses, and changes in parasite-specific immunoglobulin G (IgG) antibody levels were monitored at 1, 3, 5, 7, and 8 weeks post-infection (wpi), respectively. The serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) increased after infection, while that of albumin (ALB) decreased, which was positively correlated with the degree of liver damage. Between 5 and 7 wpi, the mice showed symptoms of anemia and weight loss, possibly caused by the decrease of alkaline phosphatase (ALP). Moreover, the changing tendencies of the levels of globulin (GLB) and parasite-specific IgG antibody were similar, suggesting a potential correlation between GLB production and adaptive immune response in the host. Coordinated variations in interferon gamma (IFN-γ) and interleukin 4 (IL-4) indicated a mixed T helper 1 (Th1)/Th2 cellular immune response. Furthermore, the serum IgG antibody increased after infection and peaked at 5 wpi, and it was positively correlated with the average parasite burdens. The worms collected from mice were approximately 1 cm in length at 8 wpi, their digestive and reproductive systems were well developed, and no eggs were found in the uterus. To the best of our knowledge, this is the first report describing detailed histological, biochemical, and immunological indices in KM mice infected with F. gigantica, which provides basic information on KM mice against infection with F. gigantica.

The growth feature and its diagnostic value for benign and malignant pulmonary nodules met in routine clinical practice.

BACKGROUND: Growth rate is an independent risk factor for lung cancer in screened pulmonary nodules. This study aimed to clarify growth characteristics of pulmonary nodules in routine clinical practice and examine whether volume doubling time (VDT) can predict the malignancy of these nodules. METHODS: We retrospectively enrolled patients with 5-30-mm-sized pulmonary nodules that had been surgically resected after a follow-up of at least 3 months. Two follow-up computed tomography (CT) images with similar thickness and long interval were obtained. Then, three-dimensional (3D) manual segmentation for all nodules was performed on two follow-up CT scans. Subsequently, VDT was calculated for nodules with a change in volume of at least 25%. RESULTS: Overall, 305 pulmonary nodules in 305 patients (men, 36.7%; median age, 57) were included. The mean increased diameter, mass, and volume of benign (n=86) and malignant (n=219) nodules were 0.09 vs. 2.37 mm, 0.10 vs. 0.66 g, and 32.74 vs. 1,871.28 mm3, respectively (P<0.05). In total, 24 of 86 benign nodules (28%, 18 grew and 6 shrank) and 121 of 219 malignant nodules (55%, 114 grew and 7 shrank) changed over time. The median VDTs of growing benign and malignant nodules were 389 and 526 days, respectively, (P=0.18), and the area under the receiver operating characteristic (ROC) curve was 0.67 (0.55-0.78), with a sensitivity and specificity of 69% and 58%, respectively. The median VDT for growing nodules was 339 days for inflammatory pseudotumors, 226 days for granulomas, 640 days for benign tumors, 1,541 days for enlarged lymph nodes, 762 days for adenocarcinoma in situ, 954 days for microinvasive adenocarcinoma, 534 days for invasive adenocarcinoma, and 118 days for squamous cell carcinoma. CONCLUSIONS: In routine clinical practice, many malignant nodules could grow slowly or even remain stable over time. Regarding growing nodules, the diagnostic value of VDT was limited.

Newly excysted juveniles (NEJs) of Fasciola gigantica induce mice liver fibrosis and M2 macrophage-like phenotype in vivo.

Liver flukes of animals are parasitic flatworms of major socioeconomic importance in many countries. Particularly, Fasciola gigantica is a leading cause of production losses to the livestock (mainly sheep and cattle) and meat industries due to clinical disease, reduced weight gain and milk production, and deaths. Immune responses induced by helminth have been extensively studied, but there is limited information on this aspect by F. gigantica, especially on macrophages induced with this parasite. Studies have shown that host immune responses induced by parasitic infection is greatly correlated with the macrophage polarization axis. In the present study, we used the murine model of F. gigantica to explore the interaction of host and F. gigantica. We found F. gigantica NEJs promoted pathology and fibrosis of mice liver, and the enlargement of mice spleen. We also showed that macrophages were recruited to mice peritoneal cavity at 5 days post infection. By evaluating the expression of genetic markers of M2 macrophages such as Arg-1, Ym1 and RELMɑ, and genetic marker of M1 macrophages iNOS, we showed that M2 macrophages were induced by F. gigantica. M2 macrophages are central to the immune response during helminth infection, and our findings in this study provided insight into the immune interaction between F. gigantica and host.

The Indirect Path From Mindful Parenting to Emotional Problems in Adolescents: The Role of Maternal Warmth and Adolescents' Mindfulness.

Mindfulness has been demonstrated to have positive effects on children's emotional functioning, and adaptive parenting practices are associated with fewer emotional problems. However, the association between mindful parenting and adolescent emotional problems has not been studied much. In the current study, the indirect path from mindful parenting to adolescent emotional problems was examined, with maternal warmth and adolescent dispositional mindfulness as potential mediators. A sample of 168 mother-child dyads participated in this study. A serial indirect effects model showed mother's mindful parenting could decrease adolescent emotional problems through adolescent's perceived maternal warmth and their dispositional mindfulness. Findings of this study imply that intervention in mindful parenting may have benefits for adolescents' emotional problems through enhancing maternal warmth and children's trait mindfulness.

NLRP3 Inflammasome as a Molecular Marker in Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM), a common consequence of longstanding diabetes mellitus, is initiated by death of cardiomyocyte. Hyperglycemia-induced reactive oxygen species (ROS) overproduction is a major contributor of the chronic low-grade inflammation that characterizes as the DCM. ROS may promote the activation of nucleotide-binding oligomerization domain like receptor (NLR) pyrin domain containing 3 (NLRP3) inflammasome, a novel regulator of inflammation and cell death, by nuclear factor-kB (NF-κB) and thioredoxin interacting/inhibiting protein (TXNIP). NLRP3 inflammasome regulates the death of cardiomyocyte and activation of fibroblast in DCM, which is involved in the structural and functional disorder of DCM. However, comprehensive understanding of molecular mechanisms linking NLRP3 inflammasome and disorder of cardiomyocyte and fibroblast in DCM is lacking. Here, we review the molecular mechanism(s) of NLRP3 inflammasome activation in response to hyperglycemia in DCM.

[A systematic review and meta-analysis on efficacy and safety of cardiac resynchronization therapy alone or in combination with implantable cardioversion defibrillation in patients with mild to severe heart failure].

OBJECTIVE: To evaluate the efficacy and safety of cardiac resynchronization therapy (CRT) alone or in combination with implantable cardioversion defibrillation (ICD) in patients with mild to severe heart failure. METHOD: Electronic searches of MEDLINE, EMBASE, CENTREN and affiliated clinical trial registration data center, US Food and Drug Administration reports, CBMdisc, VIP, and CNKI databases from establishment to Dec 2010, using the search terms "CRT, heart failure", "biventricular pacer, heart failure", "biventricular pacing, heart failure", and "biventricular pacemaker, heart failure", were performed to identify randomized controlled trials (RCTs). Meta-analysis was performed by using RevMan 5.0 software after the strict evaluation of the methodological quality of the included RCTs. RESULTS: A total of 23 trials including 8521 patients were included. In patients with New York Heart Association (NYHA) class I/II, CRT improved left ventricular ejection fraction (LVEF) [weighted mean difference (WMD) = 0.05, 95% CI 0.01 - 0.08], reduced heart failure hospitalizations [risk ratio (RR) = 0.70, 95%CI 0.61 - 0.81] and all-cause mortality (RR = 0.78, 95%CI 0.65 - 0.93) with increasing complications (RR = 1.74, 95%CI 1.42 - 2.13). In patients with NYHA class III/IV, CRT improved LVEF (WMD = 0.03, 95%CI 0.01 - 0.05), reduced both heart failure hospitalizations (RR = 0.64, 95%CI 0.55 - 0.73) and all-cause mortality (RR = 0.80, 95%CI 0.70 - 0.91) without increasing complications (RR = 1.01, 95%CI 0.91 - 1.12). Compared with ICD alone, CRT in combination with ICD significantly improved LVEF (WMD = 0.03, 95%CI 0.00 - 0.06), reduced heart failure hospitalizations (RR = 0.73, 95%CI 0.64 - 0.82) and all-cause mortality (RR = 0.82, 95%CI 0.72 - 0.95) without increasing complications (RR = 1.36, 95%CI 0.91 - 2.03) in patients with NYHA class I-IV symptoms. CONCLUSIONS: CRT offered additional benefits on top of standard medication for heart failure patients with ventricular dyssynchrony in terms of improving LV function, and reducing heart failure hospitalization and all-cause mortality, regardless of NYHA class. CRT offers also additional benefit in heart failure patients implanted with ICD. However, CRT is associated with more adverse events in patients with NYHA class I/II.