Radioactive iodine therapy for thyroid cancer coexisting with hashimoto's thyroiditis: a systematic review and meta-analysis.

OBJECTIVES: To investigate the clinical character of differentiated thyroid cancer (DTC) coexisting with Hashimoto's thyroiditis (HT) and provide state-of-art evidence for personalized RAIT for patients coexisting with HT. METHODS: From January 2000 to January 2023, PubMed, Embase, Web of Science databases were searched for relevant original articles that published in English on the RAIT efficacy for DTC with HT. Revman 5.4 and Stata 17.0 were used for date analysis. RESULTS: Eleven studies involved 16,605 DTC patients (3,321 with HT) were included. HT were more frequent in female (OR: 2.90, 95% CI: 1.77 to 4.76, P < 0.00001). The size of tumor (MD: -0.20, 95% CI: -0.30 to -0.11), extrathyroidal extension rate (OR: 0.77, 95% CI: 0.67 to 0.90) and metastasis rate (OR: 0.18, 95% CI: 0.08 to 0.41) were less in HT, but TNM stage had no significant difference among HT and non-HT group. DFS rate (OR: 1.96, 95% CI : 1.57 to 2.44, P < 0.00001), 5-year and 10-year DFS (OR: 1.73, 95% CI: 1.04 to 2.89, P = 0.04; OR: 1.56, 95% CI: 1.17 to 2.09, P = 0.003, respectively) were higher in HT group. The recurrent (OR: 0.62, 95% CI: 0.45 to 0.83, P = 0.002), RAIT dosage (MD=-38.71, 95% CI: -60.86 to -16.56, P = 0.0006) and treatment (MD: -0.13, 95% CI: -0.22 to -0.03, P = 0.008) were less in HT group. CONCLUSIONS: DTC coexisting with HT was associated with less invasion. DFS of HT group was higher than non-HT group after RAIT. Low dose treatment did not impair the efficacy of RAIT in DTC with HT. ADVANCES IN KNOWLEDGE: Hashimoto's thyroiditis is a risk for DTC, but it minimalizes the progression of cancer and enhance the efficacy of RAIT, which should be considered in personalizing RAIT.

A novel small-molecule PCSK9 inhibitor E28362 ameliorates hyperlipidemia and atherosclerosis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 µM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 µM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg-1·d-1, i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE-/- mice (20, 60 mg·kg-1·d-1, i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg-1·d-1, i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis.

Innate and Adaptive Immune Parameters following mRNA Vaccination in Mice.

The COVID-19 pandemic has raised the standard regarding the current vaccine development pace, as several messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccines have proved their ability to induce strong immunogenicity and protective efficacy. We developed 1-methylpseudouridine-containing mRNA-LNP vaccines, expressing either the more conserved SARS-CoV-2 nucleoprotein (mRNA-N) or spike protein (mRNA-S), both based on the prototypic viral sequences. When combining both mRNA-S and mRNA-N together (mRNA-S+N), the vaccine showed high immunogenicity and broad protection against different SARS-CoV-2 variants, including wildtype, Delta, BA.1, BA.5, and BQ.1. To better understand the mechanisms behind this broad protection obtained by mRNA-S+N, we analyzed innate and adaptive immune parameters following vaccination in mice. Compared to either mRNA-S or mRNA-N alone, mice vaccinated with mRNA-S+N exhibited an increase in the innate immune response, as depicted by the higher cytokine (IL-6 and chemokine (MCP-1) levels. In addition, lymph node immunophenotyping showed the maturation and activation of dendritic cells and natural killer cells, respectively. To understand the adaptive immune response, RNA-Seq analyses of the lung and spleen samples of the vaccinated mice were performed in parallel and revealed a stronger immune gene-expression profile in the lung than that in the spleen. Compared to mRNA-S alone, mRNA-S+N vaccination elicited higher levels of expression for genes involved in multiple immune pathways, including T cells, cytokine signaling, antigen presentation, B cells, and innate immunity. Together, our studies provide immunological insights into the mechanisms of broad protection conferred by dual mRNA vaccination against SARS-CoV-2 variants.

Dependency-aware deep generative models for multitasking analysis of spatial omics data.

Spatially resolved transcriptomics (SRT) technologies have significantly advanced biomedical research, but their data analysis remains challenging due to the discrete nature of the data and the high levels of noise, compounded by complex spatial dependencies. Here, we propose spaVAE, a dependency-aware, deep generative spatial variational autoencoder model that probabilistically characterizes count data while capturing spatial correlations. spaVAE introduces a hybrid embedding combining a Gaussian process prior with a Gaussian prior to explicitly capture spatial correlations among spots. It then optimizes the parameters of deep neural networks to approximate the distributions underlying the SRT data. With the approximated distributions, spaVAE can contribute to several analytical tasks that are essential for SRT data analysis, including dimensionality reduction, visualization, clustering, batch integration, denoising, differential expression, spatial interpolation, resolution enhancement and identification of spatially variable genes. Moreover, we have extended spaVAE to spaPeakVAE and spaMultiVAE to characterize spatial ATAC-seq (assay for transposase-accessible chromatin using sequencing) data and spatial multi-omics data, respectively.

Hem-o-lok clip migration to duodenal bulb post-cholecystectomy: A case report.

BACKGROUND: Hem-o-lok clips are typically used to control the cystic duct and vessels during laparoscopic cholecystectomy (LC) and common bile duct exploration for stones in the bile duct and gallbladder. Here, we report a unique example of Hem-o-lok clip movement towards the duodenal bulb after LC, appearing as a submucosal tumor (SMT). Additionally, we provide initial evidence of gradual and evolving endoscopic manifestations of Hem-o-lok clip migration to the duodenal bulb wall and review the available literature. CASE SUMMARY: A 72-year-old man underwent LC for gallstones, and Hem-o-lok clips were used to ligate both the cystic duct and cystic artery. Esophagogastroduodenoscopy (EGD) 2 years later revealed an SMT-like lesion in the duodenal bulb. Due to the symptomatology, the clinical examination did not reveal any major abnormalities, and the patient was followed up as an outpatient. A repeat EGD performed 5 months later revealed an SMT-like lesion in the duodenal bulb with raised edges and a central depression. A third EGD was conducted, during which a Hem-o-lok clip was discovered connected to the front side of the duodenum. The clip was extracted easily using biopsy forceps, and no complications occurred. Two months after the fourth EGD, the scar was surrounded by normal mucosa. CONCLUSION: Clinicians should be aware of potential post-LC complications. Hem-o-lok clips should be removed if symptomatic.

Gene Co-Expression and miRNA Regulation: A Path to Early Intervention in Colorectal Cancer.

Early diagnosis and intervention are pivotal in reducing colorectal cancer (CRC) incidence and enhancing patient outcomes. In this study, we focused on three genes, AQP8, GUCA2B, and SPIB, which exhibit high co-expression and play crucial roles in suppressing early-stage CRC. Our objective was to identify key miRNAs that can mitigate CRC tumorigenesis and modulate the co-expression network involving these genes. We conducted a comprehensive analysis using large-scale tissue mRNA data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus to validate the co-expression of AQP8, GUCA2B, and SPIB, and to assess their diagnostic and prognostic significance in CRC. mRNA-miRNA interactions were examined using MiRNet and the Encyclopedia of RNA Interactomes. Furthermore, using various molecular techniques, we conducted miRNA inhibitor transfection experiments in HCT116 cells to evaluate their effects on cell growth, migration, and gene/protein expression. Our findings revealed that, compared to normal tissues, AQP8, GUCA2B, and SPIB exhibited high co-expression and were downregulated in CRC, particularly during tumorigenesis. OncoMirs, hsa-miR-182-5p, and hsa-miR-27a-3p, were predicted to regulate these genes. MiRNA inhibition experiments in HCT116 cells demonstrated the inhibitory effects of miR-27a-3p and miR-182-5p on GUCA2B mRNA and protein expression. These miRNAs promoted the proliferation of CRC cells, possibly through their involvement in the GUCA2B-GUCY2C axis, which is known to promote tumor growth. While the expressions of AQP8 and SPIB were barely detectable, their regulatory relationship with hsa-miR-182-5p remained inconclusive. Our study confirms that hsa-miR-27a-3p and hsa-miR-182-5p are oncomiRs in CRC. These miRNAs may contribute to GUCY2C dysregulation by downregulating GUCA2B, which encodes uroguanylin. Consequently, hsa-miR-182-5p and hsa-miR-27a-3p show promise as potential targets for early intervention and treatment in the early stages of CRC.

A safety and efficacy study of allogeneic haematopoietic stem cell transplantation for refractory and relapsed T-cell acute lymphoblastic leukaemia/lymphoblastic lymphoma patients who achieved complete remission after autologous CD7 chimeric antigen receptor T-cell therapy.

CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T-ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy. These were compared with 124 consecutive T-ALL/LBL patients who received allo-HSCT in CR following chemotherapy. The study revealed that both the CAR-T and chemotherapy cohorts exhibited comparable 2-year overall survival (OS) (61.9% [95% CI, 44.1-78.1] vs. 67.6% [95% CI, 57.5-76.9], p = 0.210), leukaemia-free survival (LFS) (62.3% [95% CI, 44.6-78.4] vs. 62.0% [95% CI, 51.8-71.7], p = 0.548), non-relapse mortality (NRM) rates (32.0% [95% CI, 19.0-54.0] vs. 25.3% [95% CI, 17.9-35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0-26.0] vs. 15.8% [95% CI, 9.8-25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR-T group achieved high 2-year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR-T therapy followed by allo-HSCT is not only effective and safe for r/r T-ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM.

Anti-aging effects of icariin and the underlying mechanisms: A mini-review.

Aging is an extremely intricate and progressive phenomenon that is implicated in many physiological and pathological conditions. Icariin (ICA) is the main active ingredient of Epimedium and has exhibited multiple bioactivities, such as anti-tumor, neuroprotective, antioxidant, anti-inflammatory, and anti-aging properties. ICA could extend healthspan in both invertebrate and vertebrate models. In this review, the roles of ICA in protection from declined reproductive function, neurodegeneration, osteoporosis, aging intestinal microecology, and senescence of cardiovascular system will be summarized. Furthermore, the underlying mechanisms of ICA-mediated anti-aging effects will be introduced. Finally, we will discuss some key aspects that constrain the usage of ICA in clinical practice and the corresponding strategies to solve these issues.

Early gastric cancer detection and lesion segmentation based on deep learning and gastroscopic images.

Gastric cancer is a highly prevalent disease that poses a serious threat to public health. In clinical practice, gastroscopy is frequently used by medical practitioners to screen for gastric cancer. However, the symptoms of gastric cancer at different stages of advancement vary significantly, particularly in the case of early gastric cancer (EGC). The manifestations of EGC are often indistinct, leading to a detection rate of less than 10%. In recent years, researchers have focused on leveraging deep learning algorithms to assist medical professionals in detecting EGC and thereby improve detection rates. To enhance the ability of deep learning to detect EGC and segment lesions in gastroscopic images, an Improved Mask R-CNN (IMR-CNN) model was proposed. This model incorporates a "Bi-directional feature extraction and fusion module" and a "Purification module for feature channel and space" based on the Mask R-CNN (MR-CNN). Our study includes a dataset of 1120 images of EGC for training and validation of the models. The experimental results indicate that the IMR-CNN model outperforms the original MR-CNN model, with Precision, Recall, Accuracy, Specificity and F1-Score values of 92.9%, 95.3%, 93.9%, 92.5% and 94.1%, respectively. Therefore, our proposed IMR-CNN model has superior detection and lesion segmentation capabilities and can effectively aid doctors in diagnosing EGC from gastroscopic images.

Platelet-inspired targeting delivery for coronary heart disease.

Platelets play a pivotal role in many physiological and pathological processes, with their special targeting/adhering properties towards infarcted myocardium, injured or dysfunctional endothelium, and growing thrombus. Leveraging the site-targeting/adhering property, a variety of platelet-inspired targeting delivery（PITD）designs have been developed, the majority of which are reached by hitchhiking live platelets, cloaking nanoparticles with platelet membranes and mimicking platelet functions. With PITD, drugs or regenerative cells can directly reach targeted sites with minimized systematical distribution thus being of great clinical benefits. Coronary heart disease (CHD) is a major health burden worldwide. Plenty of PITD designs have shown promising outcomes for the treatment of CHD in preclinical models, especially in thrombolysis and post-percutaneous coronary intervention (post-PCI) anti-restenosis. Besides, PITD applications in cardiac protection and atherosclerotic plaque imaging are also under investigation. What's more, the potential benefits of PITD in the field of cell-based therapy are also attracting growing attention since it may resolve the problem of low arriving and retention efficiency, which are also particularly discussed in this review. In brief, our focus is putting on PITD strategies designed for the treatment of CHD, which hopefully can facilitate further optimization of this direction.

Rapid Screening of 34 Emerging Contaminants in Surface Water by UHPLC-Q-TOF-MS.

OBJECTIVES: To establish a rapid screening method for 34 emerging contaminants in surface water by ultra-high performance liquid chromatography-quadrupole-time of flight mass spectrometry (UHPLC-Q-TOF-MS). METHODS: The pretreatment conditions of solid phase extraction (SPE) were optimized by orthogonal experimental design and the surface water samples were concentrated and extracted by Oasis® HLB and Oasis® MCX SPE columns in series. The extracts were separated by Kinetex® EVO C18 column, with gradient elution of 0.1% formic acid aqueous solution and 0.1% formic acid methanol solution. Q-TOF-MS 'fullscan' and 'targeted MS/MS' modes were used to detect 34 emerging contaminants and to establish a database with 34 emerging contaminants precursor ion, product ion and retention times. RESULTS: The 34 emerging contaminants exhibited good linearity in the concentration range respectively and the correlation coefficients (r) were higher than 0.97. The limit of detection was 0.2-10 ng/L and the recoveries were 81.2%-119.2%. The intra-day precision was 0.78%-18.70%. The method was applied to analyze multiple surface water samples and 6 emerging contaminants were detected, with a concentration range of 1.93-157.71 ng/L. CONCLUSIONS: The method is simple and rapid for screening various emerging contaminants at the trace level in surface water.

Toxicokinetics of MDMA and Its Metabolite MDA in Rats.

OBJECTIVES: To investigate the toxicokinetic differences of 3,4-methylenedioxy-N-methylamphetamine (MDMA) and its metabolite 4,5-methylene dioxy amphetamine (MDA) in rats after single and continuous administration of MDMA, providing reference data for the forensic identification of MDMA. METHODS: A total of 24 rats in the single administration group were randomly divided into 5, 10 and 20 mg/kg experimental groups and the control group, with 6 rats in each group. The experimental group was given intraperitoneal injection of MDMA, and the control group was given intraperitoneal injection of the same volume of normal saline as the experimental group. The amount of 0.5 mL blood was collected from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. In the continuous administration group, 24 rats were randomly divided into the experimental group (18 rats) and the control group (6 rats). The experimental group was given MDMA 7 d by continuous intraperitoneal injection in increments of 5, 7, 9, 11, 13, 15, 17 mg/kg per day, respectively, while the control group was given the same volume of normal saline as the experimental group by intraperitoneal injection. On the eighth day, the experimental rats were randomly divided into 5, 10 and 20 mg/kg dose groups, with 6 rats in each group. MDMA was injected intraperitoneally, and the control group was injected intraperitoneally with the same volume of normal saline as the experimental group. On the eighth day, 0.5 mL of blood was taken from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. Liquid chromatography-triple quadrupole tandem mass spectrometry was used to detect MDMA and MDA levels, and statistical software was employed for data analysis. RESULTS: In the single-administration group, peak concentrations of MDMA and MDA were reached at 5 min and 1 h after administration, respectively, with the largest detection time limit of 12 h. In the continuous administration group, peak concentrations were reached at 30 min and 1.5 h after administration, respectively, with the largest detection time limit of 10 h. Nonlinear fitting equations for the concentration ratio of MDMA and MDA in plasma and administration time in the single-administration group and continuous administration group were as follows: T=10.362C-1.183, R2=0.974 6; T=7.397 3C-0.694, R2=0.961 5 (T: injection time; C: concentration ratio of MDMA to MDA in plasma). CONCLUSIONS: The toxicokinetic data of MDMA and its metabolite MDA in rats, obtained through single and continuous administration, including peak concentration, peak time, detection time limit, and the relationship between concentration ratio and administration time, provide a theoretical and data foundation for relevant forensic identification.

Targeted Delivery of Mesenchymal Stem Cell-Derived Bioinspired Exosome-Mimetic Nanovesicles with Platelet Membrane Fusion for Atherosclerotic Treatment.

Purpose: Accumulating evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes hold significant potential for the treatment of atherosclerosis. However, large-scale production and organ-specific targeting of exosomes are still challenges for further clinical applications. This study aims to explore the targeted efficiency and therapeutic potential of biomimetic platelet membrane-coated exosome-mimetic nanovesicles (P-ENVs) in atherosclerosis. Methods: To produce exosome-mimetic nanovesicles (ENVs), MSCs were successively extruded through polycarbonate porous membranes. P-ENVs were engineered by fusing MSC-derived ENVs with platelet membranes and characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. The stability and safety of P-ENVs were also assessed. The targeted efficacy of P-ENVs was evaluated using an in vivo imaging system (IVIS) spectrum imaging system and immunofluorescence. Histological analyses, Oil Red O (ORO) staining, and Western blot were used to investigate the anti-atherosclerotic effectiveness of P-ENVs. Results: Both ENVs and P-ENVs exhibited similar characteristics to exosomes. Subsequent miRNA sequencing of P-ENVs revealed their potential to mitigate atherosclerosis by influencing biological processes related to cholesterol metabolism. In an ApoE-/- mice model, the intravenous administration of P-ENVs exhibited enhanced targeting of atherosclerotic plaques, resulting in a significant reduction in lipid deposition and necrotic core area. Our in vitro experiments showed that P-ENVs promoted cholesterol efflux and reduced total cholesterol content in foam cells. Further analysis revealed that P-ENVs attenuated intracellular cholesterol accumulation by upregulating the expression of the critical cholesterol transporters ABCA1 and ABCG1. Conclusion: This study highlighted the potential of P-ENVs as a novel nano-drug delivery platform for enhancing drug delivery efficiency while concurrently mitigating adverse reactions in atherosclerotic therapy.

Identification and Functional Characterization of an Omega-Class Glutathione S-Transferase Gene PcGSTO1 Associated with Cyetpyrafen Resistance in Panonychus citri (McGregor).

Cyetpyrafen is a recently developed acaricide. The citrus red mite, Panonychus citri (McGregor), has developed significant resistance to cyetpyrafen. However, the molecular mechanism underlying the cyetpyrafen resistance in P. citri remains unclear. Glutathione S-transferases (GSTs) play a critical role in arthropod pesticide resistance. This study showed that GSTs were potentially related to the resistance of P. citri to cyetpyrafen through synergistic experiments and enzyme activity analysis. An omega-family GST gene, PcGSTO1, was significantly up-regulated in the egg, nymph, and adult stages of the cyetpyrafen-resistant strain. Additionally, silencing of PcGSTO1 significantly increased the mortality of P. citri to cyetpyrafen and recombinant PcGSTO1 demonstrated the ability to metabolize cyetpyrafen. Our results indicated that the overexpression of PcGSTO1 is associated with cyetpyrafen resistance in P. citri, and they also provided valuable information for managing resistance in P. citri.

Preparation of Matrix Product States with Log-Depth Quantum Circuits.

We consider the preparation of matrix product states (MPS) on quantum devices via quantum circuits of local gates. We first prove that faithfully preparing translation-invariant normal MPS of N sites requires a circuit depth T=Ω(logN). We then introduce an algorithm based on the renormalization-group transformation to prepare normal MPS with an error ε in depth T=O[log(N/ε)], which is optimal. We also show that measurement and feedback leads to an exponential speedup of the algorithm to T=O[loglog(N/ε)]. Measurements also allow one to prepare arbitrary translation-invariant MPS, including long-range non-normal ones, in the same depth. Finally, the algorithm naturally extends to inhomogeneous MPS.

Air-Stable Self-Driven UV Photodetectors on Controllable Lead-Free CsCu2I3 Microwire Arrays.

The rapid evolution of the Internet of Things has engendered increased requirements for low-cost, self-powered UV photodetectors. Herein, high-performance self-driven UV photodetectors are fabricated by designing asymmetric metal-semiconductor-metal structures on the high-quality large-area CsCu2I3 microwire arrays. The asymmetrical depletion region doubles the photocurrent and response speed compared to the symmetric structure device, leading to a high responsivity of 233 mA/W to 355 nm radiation. Notably, at 0 V bias, the asymmetric device produces an open-circuit voltage of 356 mV and drives to a short-circuit current of 372 pA; meanwhile, the switch ratio (Iph/Idark) reaches up to 103, indicating its excellent potential for detecting weak light. Furthermore, the device maintains stable responses throughout 10000 UV-light switch cycles, with negligible degradation even after 90-day storage in air. Our work establishes that CsCu2I3 is a good candidate for self-powered UV detection and thoroughly demonstrates its potential as a passive device.

Initial arch wires used in orthodontic treatment with fixed appliances.

BACKGROUND: Initial arch wires are the first arch wires inserted into fixed appliance at the beginning of orthodontic treatment. With a number of different types of orthodontic arch wires available for initial tooth alignment, it is important to understand which are most efficient and which cause the least amount of root resorption and pain during the initial aligning stage of treatment. This is the third update of a Cochrane review first published in 2010. OBJECTIVES: To assess the effects of initial arch wires for the alignment of teeth with fixed orthodontic braces, in terms of the rate of tooth alignment, amount of root resorption accompanying tooth movement, and intensity of pain experienced by patients during the initial alignment stage of treatment. SEARCH METHODS: We searched Cochrane Oral Health's Trials Register, CENTRAL, MEDLINE, Embase, and two ongoing trials registries on 4 July 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of different initial arch wires used to align teeth with fixed orthodontic braces. We included people with full-arch fixed orthodontic appliances on the upper arch, lower arch, or both arches. DATA COLLECTION AND ANALYSIS: Two independent review authors were responsible for study selection, data extraction, and assessment of risk of bias in included studies. We contacted corresponding authors of included studies to obtain missing information. We resolved disagreements by discussion between the review authors. Our main outcomes were alignment rate (movement of teeth in mm), root resorption, time to alignment, and intensity of pain measured on a 100-mm visual analogue scale (VAS). We pooled data from studies with similar interventions and outcomes using random-effects models. We reported mean differences (MDs) with 95% confidence intervals (CIs) for continuous data, risk ratios (RRs) with 95% CIs for dichotomous data, and alignment rate ratios with 95% CIs for time-to-event data. Two independent review authors assessed the certainty of evidence. We resolved disagreements by discussion between the review authors. MAIN RESULTS: We included 29 RCTs with 1915 participants (2581 arches) in this review. Studies were generally small (sample sizes ranged from 14 to 200 participants). Duration of follow-up varied between three days and six months. Eleven studies received funding, six received no funding, and 12 provided no information about funding sources. We judged eight studies at high risk of bias, nine at low risk, and 12 at unclear risk. We grouped the studies into six main comparisons. Multistrand stainless steel wires versus wires composed of other materials Six studies with 409 participants (545 arches) evaluated multistrand stainless steel (StSt) wires versus wires composed of other materials. We are very uncertain about the effect of multistrand StSt wires versus other wires on alignment rate (4 studies, 281 participants, 417 arches; very low-certainty evidence). There may be little to no difference between multistrand StSt wires and other wires in terms of intensity of pain (MD -2.68 mm, 95% CI -6.75 to 1.38; 2 studies, 127 participants, 127 arches; low-certainty evidence). Conventional nickel-titanium wires versus superelastic nickel-titanium wires Four studies with 266 participants (274 arches) evaluated conventional nickel-titanium (NiTi) wires versus superelastic NiTi wires. There may be little to no difference between the different wire types in terms of alignment rate (124 participants, 124 arches, 2 studies; low-certainty evidence) and intensity of pain (MD -0.29 mm, 95% CI -1.10 to 0.52; 2 studies, 142 participants, 150 arches; low-certainty evidence). Conventional nickel-titanium wires versus thermoelastic copper-nickel-titanium wires Three studies with 210 participants (210 arches) evaluated conventional Ni-Ti versus thermoelastic copper-nickel-titanium (CuNiTi) wires. We are very uncertain about the effects of the different arch wires on alignment rate (1 study, 66 participants, 66 arches; very low-certainty evidence). There may be little to no difference between conventional NiTi wires and thermoelastic CuNiTi wires in terms of time to alignment (alignment rate ratio 1.30, 95% CI 0.68 to 2.50; 1 study, 60 participants, 60 arches; low-certainty evidence). Superelastic nickel-titanium wires versus thermoelastic nickel-titanium wires Twelve studies with 703 participants (936 arches) evaluated superelastic NiTi versus thermoelastic NiTi wires. There may be little to no difference between superelastic NiTi wires and thermoelastic NiTi wires in alignment rate at four weeks (MD -0.28 mm, 95% CI 0.62 to 0.06; 5 studies, 183 participants, 183 arches; low-certainty evidence). We are very uncertain about the effects of the different wires on root resorption (2 studies, 52 participants, 312 teeth; very low-certainty evidence). Superelastic NiTi wires compared with thermoelastic NiTi wires may result in a slight increase in time to alignment (MD 0.5 months, 95% CI 0.21 to 0.79; 1 study, 32 participants, 32 arches; low-certainty evidence) but are probably associated with a slight increase in intensity of pain (MD 6.96 mm, 95% CI 1.82 to 12.10; 3 studies, 94 participants, 138 arches, moderate-certainty evidence). Single-strand superelastic nickel-titanium wires versus coaxial superelastic nickel-titanium wires Three studies with 104 participants (104 arches) evaluated single-strand superelastic NiTi versus coaxial superelastic NiTi wires. Use of single-strand superelastic NiTi wires compared with coaxial superelastic NiTi wires probably results in a slight reduction in alignment rate at four weeks (MD -2.64 mm, 95% CI -4.61 to -0.67; 2 studies, 64 participants, 64 arches, moderate-certainty evidence). Different sizes of nickel-titanium wires Two studies with 149 participants (232 arches) compared different types of NiTi wires. There may be little to no difference between different sizes of NiTi wires in terms of pain (low-certainty evidence). AUTHORS' CONCLUSIONS: Superelastic NiTi wires probably produce slightly more pain after one day than thermoelastic NiTi wires, and single-strand superelastic NiTi wires probably have a lower alignment rate over four weeks compared with coaxial superelastic NiTi wires. All other evidence on alignment rate, root resorption, time to alignment, and pain is of low or very low certainty in all comparisons. Therefore, there is insufficient evidence to determine whether any particular arch wire material or size is superior to any other. The findings of this review are imprecise and unreliable; well-designed larger studies are needed to give better estimates of the benefits and harms of different arch wires. Orthodontists should exercise caution when interpreting the findings of this review and be prepared to adapt their treatment plans based on individual patient needs.

Ntsr1 contributes to pulmonary hypertension by enhancing endoplasmic reticulum stress via JAK2-STAT3-Thbs1 signaling.

Pulmonary hypertension (PH) is a severe clinical syndrome with pulmonary vascular remodeling and poor long-term prognosis. Neurotensin receptor 1 (Ntsr1), serve as one of the G protein-coupled receptors (GPCRs), implicates in various biological processes, but the potential effects of Ntsr1 in PH development are unclear. The Sugen/Hypoxia (SuHx) or monocrotaline (MCT) induced rat PH model was used in our study and the PH rats showed aggravated pulmonary artery remodeling and increased right ventricular systolic pressure (RVSP). Our results revealed that Ntsr1 induced endoplasmic reticulum (ER) stress response via ATF6 activation contributed to the development of PH. Moreover, RNA-sequencing (RNA-seq) and phosphoproteomics were performed and the Ntsr1-JAK2-STAT3-thrombospondin 1 (Thbs1)-ATF6 signaling was distinguished as the key pathway. In vitro, pulmonary artery smooth muscle cells (PASMCs) under hypoxia condition showed enhanced proliferation and migration properties, which could be inhibited by Ntsr1 knockdown, JAK2 inhibitor (Fedratinib) treatment, STAT3 inhibitior (Stattic) treatment, Thbs1 knockdown or ATF6 knockdown. In addition, adeno-associated virus 1 (AAV1) were used to knockdown the expression of Ntsr1, Thbs1 or ATF6 in rats and reversed the phenotype of PH. In summary, our results reveal that Ntsr1-JAK2-STAT3-Thbs1 pathway can induce enhanced ER stress via ATF6 activation and increased PASMC proliferation and migration capacities, which can be mechanism of the pulmonary artery remodeling and PH. Targeting Ntsr1 might be a novel therapeutic strategy to ameliorate PH.