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Reconstructive phase transitions involving breaking and reconstruction of primary chemical bonds are ubiquitous and important for many technological applications. In contrast to displacive phase transitions, the dynamics of reconstructive phase transitions are usually slow due to the large energy barrier. Nevertheless, the reconstructive phase transformation from ß- to λ-Ti3O5 exhibits an ultrafast and reversible behavior. Despite extensive studies, the underlying microscopic mechanism remains unclear. Here, we discover a kinetically favorable in-plane nucleated layer-by-layer transformation mechanism through metadynamics and large-scale molecular dynamics simulations. This is enabled by developing an efficient machine learning potential with near first-principles accuracy through an on-the-fly active learning method and an advanced sampling technique. Our results reveal that the ß-λ phase transformation initiates with the formation of two-dimensional nuclei in the ab-plane and then proceeds layer-by-layer through a multistep barrier-lowering kinetic process via intermediate metastable phases. Our work not only provides important insight into the ultrafast and reversible nature of the ß-λ transition, but also presents useful strategies and methods for tackling other complex structural phase transitions.
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BACKGROUND: We previously treated small gastric submucosal tumors originating from the muscularis propria layer by precutting endoscopic band ligation but lacked precise pathological results. Then, precutting endoscopic band ligation was modified by additional snare resection after ligation to obtain tumor specimens, termed precutting endoscopic band ligation-assisted resection. AIMS: In this study, we aimed to explore the safety, feasibility, and efficacy of precutting endoscopic band ligation-assisted resection. METHODS: From 2021 to 2022, a total of 16 consecutive patients underwent precutting endoscopic band ligation-assisted resection to treat small gastric submucosal tumors originating from the muscularis propria. The clinical demography, perioperative data, and follow-up outcomes were retrospectively collected. RESULTS: With a mean operative time of 21.3 min, all lesions were successfully and completely resected, and no severe adverse events or local recurrences occurred postoperatively. More importantly, en bloc and R0 resection were achieved in all 16 patients. CONCLUSION: Precutting endoscopic band ligation-assisted resection is a safe, effective, and time-saving endoscopic technique for managing gastric small gastric submucosal tumors originating from the muscularis propria for both diagnosis and eradication.
Subject(s)
Gastric Mucosa , Stomach Neoplasms , Humans , Stomach Neoplasms/surgery , Stomach Neoplasms/pathology , Male , Female , Ligation/methods , Middle Aged , Retrospective Studies , Gastric Mucosa/surgery , Gastric Mucosa/pathology , Aged , Adult , Treatment Outcome , Endoscopic Mucosal Resection/methods , Endoscopic Mucosal Resection/adverse effects , Operative Time , Gastroscopy/methods , Feasibility StudiesABSTRACT
BACKGROUND: Imatinib is the first-line treatment for gastrointestinal stromal tumors; however, the clinical prognosis and adverse reactions of patients vary owing to individualized discrepancies in plasma exposure. METHODS: To determine the safe interval for steady-state plasma trough concentrations (C min ) of imatinib and its active metabolite, N-demethyl imatinib (NDI), 328 plasma samples from 273 patients treated with imatinib were retrospectively analyzed. Imatinib C min and NDI C min were tested, and adverse reactions were recorded. The association between imatinib C min , NDI C min , and serious adverse reactions was evaluated. RESULTS: The C min range of imatinib was 209.5-4950.0 ng/mL, with the mean value and SD of 1491.8 ± 731.4 ng/mL. The C min range of NDI was 80.0-2390.0 ng/mL with the mean value and SD of 610.8 ± 281.5 ng/mL. NDI C min was positively correlated with imatinib C min , whereas the ratio of NDI C min to imatinib C min (NDI C min /imatinib C min ) was negatively correlated with imatinib C min . Univariate logistic regression analysis demonstrated that the treatment objective, daily dose, imatinib C min , NDI C min , and imatinib C min + NDI C min were significantly associated with serious adverse reactions. Multivariate logistic regression analysis showed that NDI C min was an independent risk factor for serious adverse reactions, with a threshold of 665 ng/mL. CONCLUSIONS: NDI C min was an independent risk factor for serious adverse reactions, with a threshold of 665 ng/mL. Monitoring NDI C min was beneficial for the rational application of imatinib and individualized treatment of patients with gastrointestinal stromal tumors.
Subject(s)
Antineoplastic Agents , Gastrointestinal Neoplasms , Gastrointestinal Stromal Tumors , Imatinib Mesylate , Humans , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Stromal Tumors/blood , Imatinib Mesylate/therapeutic use , Imatinib Mesylate/pharmacokinetics , Imatinib Mesylate/adverse effects , Imatinib Mesylate/blood , Retrospective Studies , Male , Female , Middle Aged , Aged , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Adult , Gastrointestinal Neoplasms/drug therapy , Aged, 80 and over , Cohort Studies , Drug Monitoring/methods , Young AdultABSTRACT
BACKGROUND: The management of small gastric submucosal tumors (SMTs) originating from the muscularis propria layer (SMT-MPs) remains a subject of debate. Endoscopic submucosal dissection (ESD) is currently considered the optimal treatment for resection. However, high expenses, complex procedures, and the risk of complications have limited its application. Our previously proposed novel operation, precutting endoscopic band ligation (precutting EBL), has been demonstrated in a long-term, single-arm study to be an effective and safe technique for removing small gastric SMTs. However, the absence of a pathological examination and the potential for delayed perforation have raised concerns. Thus, we modified the precutting EBL by adding endoscopic resection to the snare after ligation and closure, yielding the precutting endoscopic band ligation-assisted resection (precutting EBLR). Moreover, the initial pilot study confirmed the safety and efficacy of the proposed approach and we planned a randomized controlled trial (RCT) to further validate its clinical feasibility. METHODS: This was a prospective, single-center, open-label, parallel group, and randomized controlled trial. Approximately 40 patients with SMT-MPs will be included in this trial. The patients included were allocated to two groups: ESD and precutting EBLR. The basic clinical data of the patients were collected in detail. To better quantify the difference between ESD and precutting EBLR, the primary outcome was set as the operation duration. The secondary outcomes included total operation cost and hospitalization, intraoperative adverse events, and postoperative recurrence. The primary outcome was tested for superiority, while the secondary outcomes were tested for noninferiority. SPSS is commonly used for statistical analysis. DISCUSSION: This study was designed to validate the feasibility of a novel operation for removing gastric SMT-MPs. To intuitively assess this phenomenon, the operation durations of precutting EBLR and ESD were compared, and other outcomes were also recorded comprehensively. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200065473 . Registered on November 5, 2022.
Subject(s)
Endoscopic Mucosal Resection , Stomach Neoplasms , Humans , Endoscopic Mucosal Resection/adverse effects , Ligation , Randomized Controlled Trials as Topic , Stomach Neoplasms/surgery , Stomach Neoplasms/pathology , Treatment OutcomeABSTRACT
BACKGROUND AND OBJECTIVE: Imatinib is primarily transported into the liver by organic cation transporter 1 (OCT1), organic anion transporting polypeptide 1B3 (OATP1B3), and novel organic cation transporter 2 (OCTN2), which is the first step in the metabolic and elimination of imatinib. Patients taking imatinib may concurrently take metformin, a substrate for OCT1. Drug-drug interactions (DDI) may occur between imatinib and metformin, affecting the clinical efficacy of imatinib. This experiment aimed to investigate the pharmacokinetic effects of metformin on imatinib and its active metabolism of N-desmethyl imatinib in rats. METHODS: Twenty healthy Sprague-Dawley rats were selected and randomly divided into control and experimental groups (10 rats per group). The control group was orally administered imatinib (30 mg/kg) for 14 days, and the experimental group was orally co-administered imatinib (30 mg/kg) and metformin (200 mg/kg) for 14 days. The plasma concentrations of imatinib and N-desmethyl imatinib in rats were determined by ultra-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by DAS2.0 software. RESULTS: After single-dose co-administration of imatinib and metformin on day 1, the AUC0-24 (area under the plasma concentration-time curve) and Cmax (maximum concentration) of imatinib and the MRT (mean residence time) and Cmax of N-desmethyl imatinib in the experimental group were significantly decreased compared with the control group (P < 0.05). After multiple-dose co-administration of imatinib and metformin for 14 days, the AUC0-24 and Cmax of both imatinib and N-desmethyl imatinib were significantly decreased in the experimental group (P < 0.05). CONCLUSION: With both single and multiple co-administration doses, metformin significantly changed the pharmacokinetic parameters of imatinib and N-desmethyl imatinib. The results suggest that care should be taken when metformin and imatinib are co-administered.
Subject(s)
Metformin , Humans , Rats , Animals , Imatinib Mesylate , Metformin/pharmacokinetics , Rats, Sprague-Dawley , Drug Interactions , Biological TransportABSTRACT
Deep-ultraviolet (DUV) nonlinear optical (NLO) materials play a crucial role in cutting-edge laser technology. In order to solve the serious layered growth tendency of the sole commercial DUV NLO crystal KBe2BO3F2 (KBBF), developing alternative systems of compounds with bulk crystal habits has become an urgent task for practical applications. Herein, a novel strategy was developed by applying non-centrosymmetric (NCS) cancrinite (CAN)-type zincophosphates {Na6(OH)2(H2O)2}Cs2[ZnPO4]6 with bulk-crystal habits as the prototype to design new DUV NLO crystals. Two new anhydrous alkali zincophosphates, namely, {(Li6 -xNaxO)A2}[(ZnPO4)6] (A = Cs, Rb; x = 2-3) crystallizing in the NCS hexagonal space group P63 (no. 173) with a CAN-type framework, were successfully synthesized via a modified fluoro-solvo-hydrothermal method by applying triethylamine (TEA) and concentrated NaF solution as a co-solvent. Interestingly, the rigidity of the NCS CAN-type framework acting as the host ensures the non-centrosymmetry of the resulting new compounds. Meanwhile, the replacement of water molecules by guest cationic species in the channels or cages can greatly improve the thermal stability of the resultant crystal and tune its NLO properties. The synergetic effect of the host framework and the guest species makes the two compounds transparent down to the DUV region (<200 nm) and exhibit SHG effects. Therefore, the proposed rational design strategy of applying the known zeotype NCS frameworks as prototypes together with the modified fluoro-solvo-hydrothermal method opens a great avenue for highly effectively exploring new DUV NLO materials.
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Developing strategies to rational design noncentrosymmetric structure still attract much interest for their applications in nonlinear optical and piezoelectric materials. Two noncentrosymmetric (NCS) alkaline earth metal bismuth phosphates have been successfully achieved via partial replacement of Bi3+ with Ca2+ or Sr2+ ions. BiCa(H0.5PO4)2 (designated as CaBiPO) and BiSr(H0.5PO4)2 (designated as SrBiPO), together with their solid solution Bi(Sr1-xCax)(H0.5PO4)2 (0 < x ≤ 0.5), crystallize in the NCS space group C2. Both CaBiPO and SrBiPO exhibit ultraviolet nonlinear optical (NLO) properties, and their second-harmonic generation effects belong to type-II phase matching. Meanwhile, they could also act as photoluminescence hosts in which the Eu3+-doping samples SrBiPO:xEu3+ (x = 0.02-0.2) emit orange light. The effect of different radius ions on the derivative structures and the structure-NLO property relationship has also been discussed in detail.
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BACKGROUND: Traumatic brain injury (TBI) is a leading cause of long-term disability in young adults and induces complex neuropathological processes. Cellular autonomous and intercellular changes during the subacute phase contribute substantially to the neuropathology of TBI. However, the underlying mechanisms remain elusive. In this study, we explored the dysregulated cellular signaling during the subacute phase of TBI. METHODS: Single-cell RNA-sequencing data (GSE160763) of TBI were analyzed to explore the cell-cell communication in the subacute phase of TBI. Upregulated neurotrophic factor signaling was validated in a mouse model of TBI. Primary cell cultures and cell lines were used as in vitro models to examine the potential mechanisms affecting signaling. RESULTS: Single-cell RNA-sequencing analysis revealed that microglia and astrocytes were the most affected cells during the subacute phase of TBI. Cell-cell communication analysis demonstrated that signaling mediated by the non-canonical neurotrophic factors midkine (MDK), pleiotrophin (PTN), and prosaposin (PSAP) in the microglia/astrocytes was upregulated in the subacute phase of TBI. Time-course profiling showed that MDK, PTN, and PSAP expression was primarily upregulated in the subacute phase of TBI, and astrocytes were the major source of MDK and PTN after TBI. In vitro studies revealed that the expression of MDK, PTN, and PSAP in astrocytes was enhanced by activated microglia. Moreover, MDK and PTN promoted the proliferation of neural progenitors derived from human-induced pluripotent stem cells (iPSCs) and neurite growth in iPSC-derived neurons, whereas PSAP exclusively stimulated neurite growth. CONCLUSION: The non-canonical neurotrophic factors MDK, PTN, and PSAP were upregulated in the subacute phase of TBI and played a crucial role in neuroregeneration.
Subject(s)
Brain Injuries, Traumatic , Nerve Growth Factors , Animals , Humans , Mice , Brain Injuries, Traumatic/genetics , Brain Injuries, Traumatic/metabolism , Brain Injuries, Traumatic/pathology , Cytokines/metabolism , Nerve Growth Factors/genetics , Nerve Growth Factors/metabolism , Neurons/metabolism , RNA , Signal TransductionABSTRACT
BACKGROUND: Reptiles exhibit a wide variety of skin colors, which serve essential roles in survival and reproduction. However, the molecular basis of these conspicuous colors remains unresolved. RESULTS: We investigate color morph-enriched Asian vine snakes (Ahaetulla prasina), to explore the mechanism underpinning color variations. Transmission electron microscopy imaging and metabolomics analysis indicates that chromatophore morphology (mainly iridophores) is the main basis for differences in skin color. Additionally, we assemble a 1.77-Gb high-quality chromosome-anchored genome of the snake. Genome-wide association study and RNA sequencing reveal a conservative amino acid substitution (p.P20S) in SMARCE1, which may be involved in the regulation of chromatophore development initiated from neural crest cells. SMARCE1 knockdown in zebrafish and immunofluorescence verify the interactions among SMARCE1, iridophores, and tfec, which may determine color variations in the Asian vine snake. CONCLUSIONS: This study reveals the genetic associations of color variation in Asian vine snakes, providing insights and important resources for a deeper understanding of the molecular and genetic mechanisms related to reptilian coloration.
Subject(s)
Chromatophores , Genome-Wide Association Study , Animals , Zebrafish/genetics , Skin Pigmentation , Snakes/genetics , Color , Zebrafish Proteins , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/geneticsABSTRACT
The determination of sudden cardiac death (SCD) is one of the difficult tasks in the forensic practice, especially in the absence of specific morphological changes in the autopsies and histological investigations. In this study, we combined the metabolic characteristics from corpse specimens of cardiac blood and cardiac muscle to predict SCD. Firstly, ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-HRMS)-based untargeted metabolomics was applied to obtain the metabolomic profiles of the specimens, and 18 and 16 differential metabolites were identified in the cardiac blood and cardiac muscle from the corpses of those who died of SCD, respectively. Several possible metabolic pathways were proposed to explain these metabolic alterations, including the metabolism of energy, amino acids, and lipids. Then, we validated the capability of these combinations of differential metabolites to distinguish between SCD and non-SCD through multiple machine learning algorithms. The results showed that stacking model integrated differential metabolites featured from the specimens showed the best performance with 92.31% accuracy, 93.08% precision, 92.31% recall, 91.96% F1 score, and 0.92 AUC. Our results revealed that the SCD metabolic signature identified by metabolomics and ensemble learning in cardiac blood and cardiac muscle has potential in SCD post-mortem diagnosis and metabolic mechanism investigations.
Subject(s)
Metabolome , Metabolomics , Humans , Metabolomics/methods , Mass Spectrometry/methods , Chromatography, High Pressure Liquid , Death, Sudden, CardiacABSTRACT
Blood concentration monitoring plays an important role in the rational use of norvancomycin. However, the reference interval for the norvancomycin plasma concentration in the treatment of infections in hemodialysis patients with end stage kidney disease is undefined. To determine the safe and effective interval for the norvancomycin plasma trough concentration, 39 patients treated with hemodialysis and norvancomycin were analyzed retrospectively. The norvancomycin plasma concentration before hemodialysis was tested as the trough concentration. The associations of the norvancomycin trough concentration with efficacy and adverse reactions were evaluated. No norvancomycin concentration above 20 µg/mL was detected. The trough concentration, but not the dose, had a significant effect on the anti-infectious efficacy. Compared with the low norvancomycin trough concentration group (<9.30 µg/mL), the high concentration group (9.30-20.0 µg/mL) had improved efficacy (OR = 15.45, p < 0.01) with similar side effects (OR = 0.5417, p = 0.4069). It is beneficial to maintain the norvancomycin trough concentration at 9.30-20.0 µg/mL to achieve a good anti-infectious effect in hemodialysis patients with end stage kidney disease. Plasma concentration monitoring provides a data basis for the individual treatment of infections with norvancomycin in hemodialysis patients.
Subject(s)
Anti-Bacterial Agents , Kidney Failure, Chronic , Humans , Retrospective Studies , Renal DialysisABSTRACT
(1) Background: Accurate diagnosis of wound age is crucial for investigating violent cases in forensic practice. However, effective biomarkers and forecast methods are lacking. (2) Methods: Samples were collected from rats divided randomly into control and contusion groups at 0, 4, 8, 12, 16, 20, and 24 h post-injury. The characteristics of concern were nine mRNA expression levels. Internal validation data were used to train different machine learning algorithms, namely random forest (RF), support vector machine (SVM), multilayer perceptron (MLP), gradient boosting (GB), and stochastic gradient descent (SGD), to predict wound age. These models were considered the base learners, which were then applied to developing 26 stacking ensemble models combining two, three, four, or five base learners. The best-performing stacking model and base learner were evaluated through external validation data. (3) Results: The best results were obtained using a stacking model of RF + SVM + MLP (accuracy = 92.85%, area under the receiver operating characteristic curve (AUROC) = 0.93, root-mean-square-error (RMSE) = 1.06 h). The wound age prediction performance of the stacking models was also confirmed for another independent dataset. (4) Conclusions: We illustrate that machine learning techniques, especially ensemble algorithms, have a high potential to be used to predict wound age. According to the results, the strategy can be applied to other types of forensic forecasts.
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This work reports new analytic free in-plane vibration solutions for orthotropic non-Lévy-type rectangular plates, i.e., those without two opposite edges simply supported, by the symplectic superposition method (SSM), which has never been applied to in-plane elasticity problems in any existing works. Such analytic solutions are not accessible through conventional analytic methods as seeking analytic solutions that meet both the governing partial differential equations and various non-Lévy-type boundary conditions is an acknowledged challenge in mechanical analysis of plates. The clamped and free plates are considered as two most representative cases of non-Lévy-type plates. The SSM is implemented in the Hamiltonian system-based symplectic space, where the separation of variables and the symplectic eigen expansion prove to be well-grounded. These two mathematical treatments are adopted to first gain the analytic solutions of two elementary problems. The final analytic free in-plane vibration solutions are obtained by superposition of the two elementary problems. Comprehensive new natural frequencies and vibration modes are studied and validated by reference solutions from the finite element method or other approaches. The rigorous solution procedure, fast convergence, and highly accurate results render the present framework capable of serving as benchmarks for future comparison and applicable to analytic investigation of more plate problems.
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Autism spectrum disorder (ASD) affects 1-2% of all children and poses a great social and economic challenge for the globe. As a highly heterogeneous neurodevelopmental disorder, the development of its treatment is extremely challenging. Multiple pathways have been linked to the pathogenesis of ASD, including signaling involved in synaptic function, oxytocinergic activities, immune homeostasis, chromatin modifications, and mitochondrial functions. Here, we identify secretagogin (SCGN), a regulator of synaptic transmission, as a new risk gene for ASD. Two heterozygous loss-of-function mutations in SCGN are presented in ASD probands. Deletion of Scgn in zebrafish or mice leads to autism-like behaviors and impairs brain development. Mechanistically, Scgn deficiency disrupts the oxytocin signaling and abnormally activates inflammation in both animal models. Both ASD probands carrying Scgn mutations also show reduced oxytocin levels. Importantly, we demonstrate that the administration of oxytocin and anti-inflammatory drugs can attenuate ASD-associated defects caused by SCGN deficiency. Altogether, we identify a convergence between a potential autism genetic risk factor SCGN, and the pathological deregulation in oxytocinergic signaling and immune responses, providing potential treatment for ASD patients suffering from SCGN deficiency. Our study also indicates that it is critical to identify and stratify ASD patient populations based on their disease mechanisms, which could greatly enhance therapeutic success.
Subject(s)
Autism Spectrum Disorder , Secretagogins , Animals , Mice , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/metabolism , Oxytocin/genetics , Oxytocin/metabolism , Risk Factors , Secretagogins/genetics , Secretagogins/metabolism , Zebrafish/metabolism , HumansABSTRACT
Tissue culture technology is the main method for the commercial propagation of blueberry plants, but blueberry plantlets grow slowly and have long growth cycles under in vitro propagation, resulting in low propagation efficiency. In addition, the long culturing time can also result in reduced nutrient content in the culture medium, and the accumulation of toxic and harmful substances that can lead to weak growth for the plantlets or browning and vitrification, which ultimately can seriously reduce the quality of the plantlets. Gamma-aminobutyric acid (GABA) is a four-carbon non-protein amino acid that can improve plant resistance to various stresses and promote plant growth, but the effects of its application and mechanism in tissue culture are still unclear. In this study, the effects of GABA on the growth of in vitro blueberry plantlets were analyzed following the treatment of the plantlets with GABA. In addition, the GABA-treated plantlets were also subjected to a comparative transcriptomic and metabolomic analysis. The exogenous application of GABA significantly promoted growth and improved the quality of the blueberry plantlets. In total, 2,626 differentially expressed genes (DEGs) and 377 differentially accumulated metabolites (DAMs) were detected by comparison of the control and GABA-treated plantlets. Most of the DEGs and DAMs were involved in carbohydrate metabolism and biosynthesis of secondary metabolites. The comprehensive analysis results indicated that GABA may promote the growth of blueberry plantlets by promoting carbon metabolism and nitrogen assimilation, as well as increasing the accumulation of secondary metabolites such as flavonoids, steroids and terpenes.
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Despite the high prevalence of Down syndrome (DS) and early identification of the cause (trisomy 21), its molecular pathogenesis has been poorly understood and specific treatments have consequently been practically unavailable. A number of medical conditions throughout the body associated with DS have prompted us to investigate its molecular etiology from the viewpoint of the embryonic organizer, which can steer the development of surrounding cells into specific organs and tissues. We established a DS zebrafish model by overexpressing the human DYRK1A gene, a highly haploinsufficient gene located at the "critical region" within 21q22. We found that both embryonic organizer and body axis were significantly impaired during early embryogenesis, producing abnormalities of the nervous, heart, visceral, and blood systems, similar to those observed with DS. Quantitative phosphoproteome analysis and related assays demonstrated that the DYRK1A-overexpressed zebrafish embryos had anomalous phosphorylation of ß-catenin and Hsp90ab1, resulting in Wnt signaling enhancement and TGF-ß inhibition. We found an uncovered ectopic molecular mechanism present in amniocytes from fetuses diagnosed with DS and isolated hematopoietic stem cells (HSCs) of DS patients. Importantly, the abnormal proliferation of DS HSCs could be recovered by switching the balance between Wnt and TGF-ß signaling in vitro. Our findings provide a novel molecular pathogenic mechanism in which ectopic Wnt and TGF-ß lead to DS physical dysplasia, suggesting potential targeted therapies for DS.
Subject(s)
Down Syndrome , Animals , Humans , Down Syndrome/pathology , Zebrafish , Organizers, Embryonic/pathology , Wnt Signaling Pathway , Transforming Growth Factor betaABSTRACT
Background: The role of cystic fibrosis transmembrane conductance regulator (CFTR) in hematopoiesis and adult leukemia has been demonstrated using a zebrafish model and leukemia cell lines in our previous works. Here, we continue to explore the association between CFTR and human childhood B-cell acute lymphoblastic leukemia (B-ALL). Methods: We continued to collect the peripheral blood and bone marrows of human childhood patients diagnosed with primary B-ALL as well as non-leukemia controls and isolated lymphocytes for analysis using western blotting and quantitative real-time polymerase chain reaction (qPCR) assay. Then, we used immunofluorescence, co-immunoprecipitation, western blotting, luciferase, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assays to identify the interaction of CFTR with Wnt signaling in B-ALL. Finally, we established B-ALL xenograft model in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice using SUP-B15 cells, and examined whether the CFTR inhibitor CFTR-inh172 could active against SUP-B15-Dependent B-ALL in vivo. Results: Highly expressed CFTR protein and mRNA are associated with primary childhood B-ALL patients. Aberrantly upregulated CFTR and Wnt signaling, our previously reported CFTR-Dvl2-ß-catenin pathway, is found in human childhood B-ALL patients. Interference with CFTR in B-ALL cell lines induces the downregulation of DVL2/ß-catenin and Wnt downstream target accompanied by a reduction of cell proliferation. Furthermore, B-ALL cell lines SUP-B15 cell-transplanted NOD/SCID mice treated with CFTR inhibitor CFTRinh-172 had significantly longer survival and slower leukemia progression compared with mice treated with vehicle dimethyl sulfoxide (DMSO). Conclusions: These findings demonstrate that highly expressed CFTR is associated with human childhood B-ALL and the potential of CFTR inhibitor CFTR-inh172 for the treatment of human B-ALL.
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Refining grains to the nanoscale can greatly enhance the strength of metals. But the engineering applications of nanostructured metals are limited by their complex manufacturing technology and poor microstructural stability. Here we report a facile "Eutectoid element alloyingâ Quenchingâ Hot deformation" (EQD) strategy, which enables the mass production of a Ti6Al4V5Cu (wt.%) alloy with α-Ti grain size of 95 ± 32 nm. In addition, rapid co-precipitation of Ti2Cu and ß phases forms a "dual-phase honeycomb shell" (DPHS) structure along the grain boundaries and effectively stabilizes the α-grains. The instability temperature of the nanostructured Ti6Al4V5Cu alloy reaches 973 K (0.55Tm). The room temperature tensile strength approaches 1.52 ± 0.03 GPa, which is 60% higher than the Ti6Al4V counterpart without sacrificing its ductility. Furthermore, the tensile elongation at 923 K exceeds 1000%. The aforementioned strategy paves a new pathway to develop manufacture-friendly nanostructured materials and it also has great potential for application in other alloy systems.
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The management of hemorrhagic diseases and other commonly refractory diseases (including gout, inflammatory diseases, cancer, pain of various forms and causes) are very challenging in clinical practice. Charcoal medicine is a frequently used complementary and alternative drug therapy for hemorrhagic diseases. However, studies (other than those assessing effects on hemostasis) on charcoal-processed medicines are limited. Carbon dots (CDs) are quasi-spherical nanoparticles that are biocompatible and have high stability, low toxicity, unique optical properties. Currently, there are various studies carried out to evaluate their efficacy and safety. The exploration of using traditional Chinese medicine (TCM) -based CDs for the treatment of common diseases has received great attention. This review summarizes the literatures on medicinal herbs-derived CDs for the treatment of the difficult-to-treat diseases, and explored the possible mechanisms involved in the process of treatment.