Sophora alopecuroide - Taraxacum decoction (STD) inhibits non-small cell lung cancer via inducing ferroptosis and modulating tumor immune microenvironment.

The Sophora alopecuroide - Taraxacum Decoction (STD) is a traditional Chinese herbal formulation that has demonstrated significant potential in combating tumors. Despite its apparent effectiveness, the specific mechanisms through which STD exerts its anti-tumor properties remain largely unexplored and are yet to be fully understood. In our study, we provided evidence that STD effectively inhibits cellular growth and movement, as well as halting the cell cycle at the G2/M checkpoint. Furthermore, our pharmacological network analysis indicated that STD might induce cell death through a process known as ferroptosis. This hypothesis was substantiated by observing important biochemical changes associated with ferroptosis, including a decrease in glutathione (GSH) levels, an increase in iron accumulation, and elevated levels of reactive oxygen species (ROS) and lipid peroxidation. Additionally, we noted a significant rise in the expression of pro-ferroptosis genes such as Keap1, Nrf2, and HO-1, further supporting our findings. Significantly, and in line with the in vitro results, STD also showed a strong ability to inhibit tumor growth by inducing ferroptosis in a subcutaneous tumor model. Additionally, STD treatment changed the tumor immune microenvironment (TIME), as seen by an increase in CD107a+ CD8 and NK cells within the tumor. These findings demonstrate that STD induces ferroptosis and alters TIME to combat tumors, suggesting that STD may be a viable alternative treatment for patients with NSCLC.

Aloperine Suppresses Cancer Progression by Interacting with VPS4A to Inhibit Autophagosome-lysosome Fusion in NSCLC.

Aloperine (ALO), a quinolizidine-type alkaloid isolated from a natural Chinese herb, has shown promising antitumor effects. Nevertheless, its common mechanism of action and specific target remain elusive. Here, it is demonstrated that ALO inhibits the proliferation and migration of non-small cell lung cancer cell lines in vitro and the tumor development in several mouse tumor models in vivo. Mechanistically, ALO inhibits the fusion of autophagosomes with lysosomes and the autophagic flux, leading to the accumulation of sequestosome-1 (SQSTM1) and production of reactive oxygen species (ROS), thereby inducing tumor cell apoptosis and preventing tumor growth. Knockdown of SQSTM1 in cells inhibits ROS production and reverses ALO-induced cell apoptosis. Furthermore, VPS4A is identified as a direct target of ALO, and the amino acids F153 and D263 of VPS4A are confirmed as the binding sites for ALO. Knockout of VPS4A in H1299 cells demonstrates a similar biological effect as ALO treatment. Additionally, ALO enhances the efficacy of the anti-PD-L1/TGF-ß bispecific antibody in inhibiting LLC-derived subcutaneous tumor models. Thus, ALO is first identified as a novel late-stage autophagy inhibitor that triggers tumor cell death by targeting VPS4A.

Role of lens in early refractive development: evidence from a large cohort of Chinese children.

AIMS: To document longitudinal changes in spherical equivalent refraction (SER) and related biometric factors during early refractive development. METHODS: This was a prospective cohort study of Chinese children, starting in 2018 with annual follow-ups. At each visit, children received cycloplegic autorefraction and ocular biometry measurements. Lens power (LP) was calculated using Bennett's formula. Children were divided into eight groups based on baseline age: the 3-year-old (n=426, 49.77% girls), 4-year-old (n=834, 47.36% girls), 6-year-old (n=292, 46.58% girls), 7-year-old (n=964, 43.46% girls), 9-year-old (n=981, 46.18% girls), 10-year-old (n=1181, 46.32% girls), 12-year-old (n=504, 49.01%) and 13-year-old (n=644, 42.70%) age groups. RESULTS: This study included right-eye data from 5826 children. The 3-year-old and 4-year-old age groups demonstrated an inflection point in longitudinal SER changes at a mild hyperopic baseline SER (+1 to +2 D), with children with more myopic SER showing hyperopic refractive shifts while those with more hyperopic SER showing myopic shifts. The hyperopic shift in SER was mainly attributed to rapid LP loss and was rarely seen in the older age groups. Axial elongation accelerated in the premyopia stage, accompanied by a partially counter-balancing acceleration of LP loss. For children aged 3-7 years, those with annual SER changes <0.25 D were all mildly hyperopic at baseline (mean: 1.23 D, 95% CI 1.20 to 1.27 D). CONCLUSION: Our findings suggest that during early refractive development, refractions cluster around or above +1.00 D. There is a pushback process in which increases in the rate of LP occur in parallel with increases in axial elongation.

Construction of the underlying circRNA-miRNA-mRNA regulatory network and a new diagnostic model in ulcerative colitis by bioinformatics analysis.

BACKGROUND: Circular RNAs (circRNAs) are involved in the pathogenesis of many diseases through competing endogenous RNA (ceRNA) regulatory mechanisms. AIM: To investigate a circRNA-related ceRNA regulatory network and a new predictive model by circRNA to understand the diagnostic mechanism of circRNAs in ulcerative colitis (UC). METHODS: We obtained gene expression profiles of circRNAs, miRNAs, and mRNAs in UC from the Gene Expression Omnibus dataset. The circRNA-miRNA-mRNA network was constructed based on circRNA-miRNA and miRNA-mRNA interactions. Functional enrichment analysis was performed to identify the biological mechanisms involved in circRNAs. We identified the most relevant differential circRNAs for diagnosing UC and constructed a new predictive nomogram, whose efficacy was tested with the C-index, receiver operating characteristic curve (ROC), and decision curve analysis (DCA). RESULTS: A circRNA-miRNA-mRNA regulatory network was obtained, containing 12 circRNAs, three miRNAs, and 38 mRNAs. Two optimal prognostic-related differentially expressed circRNAs, hsa_circ_0085323 and hsa_circ_0036906, were included to construct a predictive nomogram. The model showed good discrimination, with a C-index of 1(> 0.9, high accuracy). ROC and DCA suggested that the nomogram had a beneficial diagnostic ability. CONCLUSION: This novel predictive nomogram incorporating hsa_circ_0085323 and hsa_circ_0036906 can be conveniently used to predict the risk of UC. The circRNa-miRNA-mRNA network in UC could be more clinically significant.

Antagomir of miR-31-5p modulates macrophage polarization via the AMPK/SIRT1/NLRP3 signaling pathway to protect against DSS-induced colitis in mice.

Macrophage-driven immune dysfunction of the intestinal mucosa is involved in the pathophysiology of ulcerative colitis (UC). Emerging evidence indicates that there is an elevation in miR-31-5p levels in UC, which is accompanied by a downregulation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) expression. Nevertheless, the precise influence of miR-31-5p on macrophage polarization and the integrity of the intestinal epithelial barrier in UC remains to be fully elucidated. This study explored the role of miR-31-5p and AMPK in UC through a bioinformatics investigation. It investigated the potential of miR-31-5p antagomir to shift macrophages from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype and enhance the intestinal mucosal barrier in DSS-induced UC mice. Additionally, RAW264.7 cells stimulated with LPS were employed to confirm the reversal of miR-31-5p antagomir's therapeutic effect under AMPK inhibition. The findings demonstrated that miR-31-5p antagomir penetrated colonic tissues and ameliorated DSS-induced experimental colitis. Transformation of spleen and mesenteric lymph node macrophages from M1 to M2 type was seen in the DSS+miR-31-5p antagomir group. AMPK/Sirt1 expression increased while NLRP3 expression decreased. Expression of M2-related genes and proteins was enhanced and that of the M1 phenotype suppressed. Tight junction proteins, ZO-1 and occludin, were increased. The therapeutic effects of miR-31-5p antagomir transfection into RAW264.7 cells were repressed when AMPK expression was inhibited. Therefore, our results suggest that suppression of miR-31-5p expression transformed macrophages from M1 to M2, ameliorated inflammation and repaired the intestinal epithelium to alleviate DSS-induced colitis. AMPK/Sirt1/NLRP3 was involved.

The combination of Tanshinone IIA and Astragaloside IV attenuates myocardial ischemia-reperfusion injury by inhibiting the STING pathway.

BACKGROUND: Astragaloside IV (As-IV) and Tanshinone IIA (Ta-IIA) are the main ingredients of traditional Chinese medicinal Astragalus membranaceus (Fisch.) Bunge and Salvia miltiorrhiza Bunge, respectively, both of which have been employed in the treatment of cardiovascular diseases. Nevertheless, the efficacy of the combination (Co) of Ta-IIA and As-IV for cardiovascular diseases remain unclear and warrant further investigation. This study aimed to investigate the efficacy and the underlying molecular mechanism of Co in treating myocardial ischemia-reperfusion injury (MIRI). METHODS: In order to assess the efficacy of Co, an in vivo MIRI mouse model was created by temporarily blocking the coronary arteries for 30 min and then releasing the blockage. Parameters such as blood myocardial enzymes, infarct size, and ventricular function were measured. Additionally, in vitro experiments were conducted using HL1 cells in both hypoxia-reoxygenation model and oxidative stress models. The apoptosis rate, expression levels of apoptosis-related proteins, oxidative stress indexes, and release of inflammatory factors were detected. Furthermore, molecular docking was applied to examine the binding properties of Ta-IIA and As-IV to STING, and western blotting was performed to analyze protein expression of the STING pathway. Additionally, the protective effect of Ta-IIA, As-IV and Co via inhibiting STING was further confirmed in models of knockdown STING by siRNA and adding STING agonist. RESULTS: Both in vitro and in vivo data demonstrated that, compared to Ta-IIA or As-IV alone, the Co exhibited superior efficacy in reducing the area of myocardial infarction, lowering myocardial enzyme levels, and promoting the recovery of myocardial contractility. Furthermore, the Co showed more potent anti-apoptosis, antioxidant, and anti-inflammation effects. Additionally, the Co enhanced the inhibitory effects of Ta-IIA and As-IV on STING phosphorylation and the activation of STING signaling pathway. However, the administration of a STING agonist attenuated the protective effects of the Co, Ta-IIA, and As-IV by compromising their anti-apoptotic, antioxidant, and anti-inflammatory effects in MIRI. CONCLUSION: Compared to the individual administration of Ta-IIA or As-IV, the combined treatment demonstrated more potent ability in inhibiting apoptosis, oxidative stress, inflammation, and the STING signaling pathway in the context of MIRI, indicating a more powerful protective effect against MIRI.

Effect of Extracurricular After-School Physical Activities on Academic Performance of Schoolchildren: A Cluster Randomized Clinical Trial.

Importance: The beneficial effects of increasing outdoor physical activity time on children's myopia onset and physical well-being are widely acknowledged. However, in countries with competitive educational systems, such as China, parents and school administrators may be relatively reluctant to increase the extracurricular physical activity time for children due to concerns that this action will compromise children's academic performance. Objective: To investigate whether additional extracurricular physical activity time after school compromises the academic performance of schoolchildren. Design, Setting, and Participants: This cluster randomized clinical trial was conducted from October 2020 to June 2021 in Yudu, Jiangxi, China. Eligible children in grades 3 and 4 from 24 elementary schools were randomized to the intervention or control group. Primary analysis was conducted in the full sample using the intention-to-treat principle. Interventions: The intervention group received 2 hours of after-school physical activity time outdoors on school days. The control group was free to arrange their after-school activity. Main Outcomes and Measures: The primary outcome was the between-group mean difference in mathematics test scores at the end of 1 academic year, with a noninferiority margin of -3.3 points. Standardized mathematics tests, physical fitness assessments (in reference to the 2018 National Physical Fitness Survey Monitoring Programme in China), and cycloplegic autorefraction were performed at baseline and the end of 1 academic year. Myopia was defined as a cycloplegic spherical equivalent refraction of -0.5 diopters or less in either eye. Results: A total of 2032 children (mean [SD] age, 9.22 [0.62] years; 1040 girls [51.2%]) from 24 schools were randomized to the intervention group (12 schools; 1012 children) or control group (12 schools; 1020 children). The mean (SD) mathematics score at the end of 1 academic year was 78.01 (17.56) points in the intervention group and 77.70 (17.29) points in the control group. The adjusted between-group mean difference was 0.65 points (95% CI, -2.85 to 4.15). The adjusted between-group mean difference in physical fitness score was 4.95 points (95% CI, 3.56-6.34; P < .001) and -1.90% (95% CI, -18.72% to 14.91%; P > .99) in myopia incidence. Conclusions and Relevance: Results of this trial indicate that, compared with the control practice of free play after school, adding 2 hours of extracurricular physical activity outdoors after school was noninferior in academic performance and had superior efficacy in improving physical fitness. Trial Registration: ClinicalTrials.gov Identifier: NCT04587765.

Structural Network Topology Reveals Higher Brain Resilience in Individuals with Preclinical Alzheimer's Disease.

Introduction: The diagnosis of Alzheimer's disease (AD) requires the presence of amyloid and tau pathology, but it remains unclear how they affect the structural network in the pre-clinical stage. We aimed to assess differences in topological properties in cognitively normal (CN) individuals with varying levels of amyloid and tau pathology, as well as their association with AD pathology burden. Methods: A total of 68 CN individuals were included and stratified by normal/abnormal (-/+) amyloid (A) and tau (T) status based on positron emission tomography results, yielding three groups: A-T- (n = 19), A+T- (n = 28), and A+T+ (n = 21). Topological properties were measured from structural connectivity. Group differences and correlations with A and T were evaluated. Results: Compared with the A-T- group, the A+T+ group exhibited changes in the structural network topology. At the global level, higher assortativity was shown in the A+T+ group and was correlated with greater tau burden (r = 0.29, p = 0.02), while no difference in global efficiency was found across the three groups. At the local level, the A+T+ group showed disrupted topological properties in the left hippocampus compared with the A-T- group, characterized by lower local efficiency (p < 0.01) and a lower clustering coefficient (p = 0.014). Conclusions: The increased linkage in the higher level architecture of the white matter network reflected by assortativity may indicate increased brain resilience in the early pathological state. Our results encourage further investigation of the topological properties of the structural network in pre-clinical AD.

Application of fluorescence endoscopy with methylene blue dye and indocyanine green dual-tracer method in sentinel lymph node biopsy for women with breast cancer.

Background: Indocyanine green (ICG) allows for the real-time visualization of lymphatic drainage and provides favorable performance for sentinel lymph node (SLN) mapping. However, the limited ability of tissue penetration of the near-infrared fluorescence of ICG may lead to the failure of lymph node detection in the traditional open approach of sentinel lymph node biopsy (SLNB) for breast cancer, especially in overweight or obese patients. To accurately and quickly detect SLNs, we applied fluorescence endoscopy with a dual-tracer method using ICG and methylene blue dye (MBD) in SLNB for breast cancer. We conducted this study to assess the feasibility and application value of this method in minimally invasive surgery. Methods: A total of 117 patients who received dual-tracer injection of ICG and MBD prior to endoscopic SLNB from November 2020 to September 2021 were examined in this study. The number of SLNs identified, the SLN identification rate, the time to identify the first SLN, the procedure duration, and the postoperative morbidity were analyzed. Results: Biopsied SLNs could be identified in 116 patients (99.15%) with an average number of 5.12±1.87 per patient. Blue-stained SLNs were found in 99 patients (84.62%) and fluorescent SLNs in 112 patients (95.73%). A total of 34 patients (29.06%) had positive SLNs. In 6 cases (5.13%), the positive SLNs were only stained with ICG fluorescence. In 1 case (0.85%), the positive SLNs were only blue-stained with no fluorescence staining. The mean durations for the identification of the first SLN and endoscopic SLNB were 7.14±6.31 and 37.75±16.94 min, respectively. Upper-limb lymphoedema was observed 5 cases (4.27%) during a median follow-up period of 10 months. Conclusions: The fluorescence endoscopy method assisted by dual tracer facilitates SLN detection with a comparatively short procedure duration and low complication rate. This approach could serve as a new method for SLNB for patients with breast cancer.

Timosaponin AIII promotes non-small-cell lung cancer ferroptosis through targeting and facilitating HSP90 mediated GPX4 ubiquitination and degradation.

Timosaponin AIII (Tim-AIII), a steroid saponin, exhibits strong anticancer activity in a variety of cancers, especially breast cancer and liver cancer. However, the underlying mechanism of the effects of Tim-AIII-mediated anti-lung cancer effects remain obscure. In this study, we showed that Tim-AIII suppressed cell proliferation and migration, induced G2/M phase arrest and ultimately triggered cell death of non-small cell lung cancer (NSCLC) cell lines accompanied by the release of reactive oxygen species (ROS) and iron accumulation, malondialdehyde (MDA) production, and glutathione (GSH) depletion. Interestingly, we found that Tim-AIII-mediated cell death was reversed by ferroptosis inhibitor ferrostatin-1 (Fer-1). Meanwhile, the heat shock protein 90 (HSP90) was predicted and verified as the direct binding target of Tim-AIII by SwissTargetPrediction (STP) and surface plasmon resonance (SPR) assay. Further study showed that Tim-AIII promoted HSP90 expression and Tim-AIII induced cell death was blocked by the HSP90 inhibitor tanespimycin, indicating that HSP90 was the main target of Tim-AIII to further trigger intracellular events. Mechanical analysis revealed that the Tim-AIII-HSP90 complex further targeted and degraded glutathione peroxidase 4 (GPX4), and promoted the ubiquitination of GPX4, as shown by an immunoprecipitation, degradation and in vitro ubiquitination assay. In addition, Tim-AIII inhibited cell proliferation, induced cell death, led to ROS and iron accumulation, MDA production, GSH depletion, as well as GPX4 ubiquitination and degradation, were markedly abrogated when HSP90 was knockdown by HSP90-shRNA transfection. Importantly, Tim-AIII also showed a strong capacity of preventing tumor growth by promoting ferroptosis in a subcutaneous xenograft tumor model, whether C57BL/6J or BALB/c-nu/nu nude mice. Together, HSP90 was identified as a new target of Tim-AIII. Tim-AIII, by binding and forming a complex with HSP90, further targeted and degraded GPX4, ultimately induced ferroptosis in NSCLC. These findings provided solid evidence that Tim-AIII can serve as a potential candidate for NSCLC treatment.

Fabrication of Centimeter-Scale Plasmonic Nanoparticle Arrays with Ultranarrow Surface Lattice Resonances.

Plasmonic surface lattice resonances (SLRs) supported by metallic nanoparticle (NP) arrays show diverse applications including nanolasers, sensors, photocatalysis, and nonlinear optics. However, to rationally fabricate high-quality plasmonic NP arrays with ultranarrow SLR line widths over large areas remains challenging. This article describes a general approach for the efficient fabrication of centimeter-scale inorganic NP arrays with precisely controlled NP size, composition, position, and lattice geometry. This method combines the processes of solvent-assisted soft lithography and in situ site-specific NP growth to reproducibly create many replicates of NP arrays without utilizing cleanroom and specialized equipment. For demonstration, we show that Au NP arrays exhibit ultranarrow SLRs with a line width of 4 nm and a quality factor of 218 toward the theoretical limit.

Diffusion Changes in Hippocampal Cingulum in Early Biologically Defined Alzheimer's Disease.

BACKGROUND: Diagnosis of Alzheimer's disease (AD) was recently shifted from clinical to biological construct to reflect underlying neuropathological status, where amyloid deposition designated patients to the Alzheimer's continuum, and additional tau positivity represented AD. OBJECTIVE: To investigate white matter (WM) alteration in the brain of patients in the Alzheimer's continuum. METHODS: A total of 236 subjects across the clinical and biological spectra of AD were included and stratified by normal/abnormal (-/+) amyloid (A) and tau (T) status based on positron emission tomography results, yielding five groups: A-T-cognitively normal (CN), A+T-CN, A+T+ CN, A+T+ mild cognitive impairment, and A+T+ AD. WM alteration was measured by diffusion tensor imaging (DTI). Group differences, correlation of DTI measures with amyloid and tau, and diagnostic performance of such measures were evaluated. RESULTS: Compared with A-T-CN, widespread WM alteration was observed in the Alzheimer's continuum, including hippocampal cingulum (CGH), cingulum of the cingulate gyrus, and uncinate fasciculus. Diffusion changes measured by regional mean fractional anisotropy (FA) in the bilateral CGH were first detected in the A+T+ CN group and associated with tau burden in the Alzheimer's continuum (p < 0.001). For discrimination between A+T+ CN and A-T-CN groups, CGH FA achieved accuracy, sensitivity, and specificity of 74%, 58%, and 78% for right CGH and 57%, 83%, and 47% respectively for left CGH. CONCLUSION: WM alteration is widespread in the Alzheimer's continuum. Diffusion alteration in CGH occurred early and was correlated with tau pathology, thus may be a promising biomarker in preclinical AD.

Adjuvant chemotherapy benefits on patients with elevated carcinoembryonic antigen in stage IIA colon cancer: a SEER-based analysis.

OBJECTIVE: Indications for adjuvant chemotherapy in stage IIA (T3N0M0) colon cancer are still controversial. The purpose of this study was to evaluate the prognostic value of elevated carcinoembryonic antigen (CEA) levels for cancer-specific survival (CSS) and overall survival (OS) in patients with stage IIA colon cancer. We aimed to examine the impact of adjuvant chemotherapy on OS in stage IIA colon cancer patients with elevated CEA levels. METHODS: Patients with stage IIA colon cancer (N = 3477) diagnosed between 2010 and 2015 were identified using the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier and Cox proportional hazards regression models were used to assess the prognostic effect of CEA on CSS and OS. RESULTS: Cox regression analysis demonstrated that CEA was an independent risk factor for CSS and OS in patients with stage IIA colon cancer (CSS: HR = 2.001, 95% CI 1.603-2.499, P < 0.001; OS: HR = 1.530, 95% CI 1.335-1.752, P < 0.001). In the subgroup with elevated CEA, patients received adjuvant chemotherapy had a better OS compared with those did not (χ2 = 10.585, p = 0.001). CONCLUSION: CEA was an independent risk factor for CSS and OS in patients with stage IIA colon cancer. Patients with stage IIA colon cancer with an elevated CEA level might benefit from adjuvant chemotherapy.

Longitudinal Changes in Lens Thickness and Lens Power Among Persistent Non-Myopic and Myopic Children.

Purpose: To assess the longitudinal changes in crystalline lens in persistent non-myopic and myopic children. Methods: Four cohorts of children were recruited from Guangzhou, China, from first year of kindergarten (G0, n = 1129), first year of primary school (G1, n = 1324), fourth year of primary school (G4, n = 1854), and first year of junior high school (G7, n = 867) in 2018 and followed up annually for 2 years. All children received cycloplegic autorefraction and ocular biometry measurement. Children were classified into categories of persistent non-myopia (PNM; spherical equivalent refraction [SER] ≥-0.5 diopter [D] at baseline and during follow-up), persistent myopia (PM; SER <-0.5 D at baseline and during follow-up), or newly developed myopia (NDM: SER ≥-0.5 D at baseline and <-0.5 D during follow-up). Results: The mean (SD) age was 3.69 (0.34) years for children in G0, 6.79 (0.35) years in G1, 9.52 (0.42) years in G4, and 12.56 (0.38) years in G7. A LOWESS plot showed a three-stage pattern of change in lens thickness (LT) in PNM children including a rapid decrease from 3 to 7 years of age and a slower decrease from 7 to 11 years, followed by an increase thereafter. Similar trends were observed in the PM and NDM groups, although there was less change in LT. In contrast, lens power (LP) decreased consistently in all cohorts during the follow-up. No significant changes in LT or LP were observed around myopia onset. Conclusions: The lens showed a three-stage pattern of change in LT, whereas there was continuous loss of LP in children ages 3 to 15 years.

Patient-Derived Organoid Facilitating Personalized Medicine in Gastrointestinal Stromal Tumor With Liver Metastasis: A Case Report.

The gastrointestinal stromal tumors (GIST) are a rare gastrointestinal tract malignancy. The two primary mutation sites are found in KIT and platelet-derived growth factor receptor-α (PDGFR-α) genes. The current study reports on a point mutation within the exon 11 of KIT, named KIT p.V560E. Patient-derived organoids (PDOs) are potential 3D in vitro models of tissues that can be used to identify sensitivity toward specific targets in patients with tumors and allow for personalized medicine when drugs specific for newly identified genetic locus mutations are not yet available. This study describes a 68-year-old patient who complained of diffused abdominal pain and intermittent melena lasting more than 10 days. He has no other gastrointestinal abnormalities, prior abdominal surgery, or related family history. Surgery was conducted first to remove the lesions and ascertain the disease through histology and immunohistochemical stains of the mass. Immunohistochemistry revealed that the tumor was positive for CD117 and Dog-1. Based on the above findings, he was diagnosed with GISTs. Gene detection analysis and organoid culture were then performed to verify clinical decisions. KIT p.V560E and the reduced number of RB1 copies were identified as two obvious mutations, so the patient was administrated first-line treatment of imatinib 400 mg/d. However, progressive disease prompted us to switch to sunitinib, and his condition gradually improved. Meanwhile, organoid culture showed sensitivity to sunitinib and tolerance to imatinib with half-maximal inhibitory concentration (IC50) values of 0.89 and >20, respectively. In summary, to the best of our knowledge, this is the first time that the established organoid culture indicated that the GISTs organoid could identify the sensitivity to target therapies and facilitate individual-based treatment.

Extracellular vesicles produced by bone marrow mesenchymal stem cells overexpressing programmed death-ligand 1 ameliorate dextran sodium sulfate-induced ulcerative colitis in rats by regulating Th17/Treg cell balance through PTEN/PI3K/AKT/mTOR axis.

BACKGROUND AND AIM: Programmed death-ligand 1 (PD-L1) was involved in regulating Th17/Treg cell balance in ulcerative colitis (UC). Extracellular vesicles (EVs) from genetically modified bone marrow mesenchymal stem cells (BMSCs) can serve as a stable delivery system to overexpress PD-L1. The study was designed to evaluate the therapeutic mechanism of BMSC-EVs overexpressing PD-L1 (PD-L1-EVs) on ulcerative colitis. METHODS: Experimental model of UC was established in rats by drinking 5% dextran sulfate sodium (DSS). Apoptosis-related proteins, inflammatory response-related factors and oxidative stress related mediators were detected. Westernblot was used to detecte key proteins in the PI3K/AKT signaling pathway and its downstream effectors. The CD4+ Foxp3+ Treg cells and CD4+ IL-17A+ Th17 cells in spleen and mesenteric lymph nodes (MLNs) was detected by flow cytometry. RESULTS: PD-L1-EVs significantly alleviated the manifestations and pathological damage of UC rats by inhibiting the expression of IFN-γ, IL-1ß, IL-8, IL-6, IL-2, BAX, NF-κB, TNF-α, MPO, and MDA, and up-regulating the expression of IL-4, BCL-2, SOD, and GSH. Furthermore, the proportions of Th17 cells were decreased and that of Treg cells were upregulated by PD-L1-EVs treatment. PTEN inhibitors (bpv) partially abolished the inhibitory effect of PD-L1-EVs on PI3K-AKT signaling and impaired the therapeutic efficacy of PD-L1-EVs. CONCLUSIONS: PD-L1-EVs mitigated colonal inflammation, apoptosis and oxidative stress through blocking the activation of PI3K/Akt/mTOR pathway and regulating the balance of Th17/Treg cells.

JMJD3/H3K27me3 epigenetic modification regulates Th17/Treg cell differentiation in ulcerative colitis.

Ulcerative colitis (UC) is a chronic nonspecific inflammatory bowel disease characterized by chronic inflammation and ulceration of the colonic mucosa, frequent relapse, and cancerization that is difficult to cure. In recent years, the incidence of UC has increased. However, its etiology and pathogenesis are still not completely clear. In this study, dextran sodium sulfate (DSS) was used to induce the model, and GSK-J1 and dexamethasone were administered to the mice. A variety of molecular biology and immunological techniques, such as immunofluorescence, PCR and chromatin immunoprecipitation (ChIP), were used to examine JMJD3/H3K27me3-mediated regulation of Th17/Treg cell differentiation in UC by targeting histone modification. This study will provide an important theoretical basis for understanding the pathogenesis and potential therapeutic targets of UC.

Axial Growth Driven by Physical Development and Myopia among Children: A Two Year Cohort Study.

Background: The physical process of axial length growth among children and its role in the occurrence of myopia remain insufficiently explored. In this study, we investigate the patterns of ocular axial growth among persistent myopia (PM) and persistent non-myopia (PNM) children aged 3 to 15 years. Methods: A group of 6353 children aged 3 to 15 years, selected from rural schools in China, were followed up annually for 2 years. Biometric measurements including axial length (AL) and spherical equivalent refraction (SER) were obtained. Body height was recorded. Children were divided into two groups: PM group defined as SER of −0.50 D or less; PNM group defined as −0.50 D < SER < +3.0 D during follow-up. Results: Annual AL growth was fairly consistent for PNM eyes of children aged 3 to 11 years and then reduced significantly (independent t test, p < 0.001) for children aged 12 years and older. This pattern of AL changes was similar for PM children, although the AL growth was greater among them. Among children aged 6 and older, body height change was concomitant to AL growth (p < 0.01) and SER myopic shift (p < 0.001) until reaching 12 years old (p = 0.308 and p = 0.679, respectively). Conclusions: Stature growth and AL growth are both remarkable and consistent and concomitant but start to attenuate when the children reach 10 to 12 years old among emmetropic children. This observation suggests that AL growth is driven by physical development until 12 years old, whereas its excessive growth is dominated by myopia development.

Lower Posterior Cingulate N-Acetylaspartate to Creatine Level in Early Detection of Biologically Defined Alzheimer's Disease.

Alzheimer's disease (AD) was recently defined as a biological construct to reflect neuropathologic status, and both abnormal amyloid and tau are required for a diagnosis of AD. We aimed to determine the proton MR spectroscopic (1H-MRS) patterns of the posterior cingulate in biologically defined AD. A total of 68 participants were included in this study, comprising 37 controls, 16 early AD, and 15 late AD, who were classified according to their amyloid and tau status and presence of hippocampal atrophy. Compared with controls, early AD showed lower N-acetylaspartate (NAA)/creatine (Cr) (p = 0.003), whereas late AD showed lower NAA/Cr and higher myoInositol (mI)/Cr (all with p < 0.05). Lower NAA/Cr correlated with a greater global amyloid load (r = −0.47, p < 0.001) and tau load (r = −0.51, p < 0.001) and allowed a discrimination of early AD from controls (p < 0.001). Subgroup analysis showed that NAA/Cr also allowed a differentiation of early AD from controls in the cognitively unimpaired subjects, with an area under the receiver operating characteristics curve, sensitivity, and specificity of 0.96, 100%, and 83.8%, respectively. Lower posterior cingulate NAA levels may help to inform underlying neuropathologic changes in the early stage of AD.

Statistical changes of lung morphology in patients with adolescent idiopathic scoliosis after spinal fusion surgery-a prospective nonrandomized study based on low-dose biplanar X-ray imaging.

Background: Adolescent idiopathic scoliosis (AIS) patients suffer from restrictive impairment of pulmonary function (PF) as a consequence of spinal and ribcage deformity. Statistic modelling of scoliotic geometry has been well-established based on low-dose biplanar X-ray device (EOS) imaging. However, the postoperative lung morphology change derived from EOS has not yet been studied adequately till now. Methods: Twenty-five female AIS patients with severe right-sided major thoracic curve (aged 13-31 years; Cobb angle 45°-92°) underwent posterior spinal fusion (PSF) were prospectively recruited for standing EOS imaging at preoperative, postoperative, and 1-year follow-up (1Y-FU) stages. EOS-based lung morphology at frontal and lateral view was measured respectively to assess serial statistical changes in area and height. Results: At frontal view, left lung area significantly increased postoperatively (104.7 vs. 125.1 cm2; P<0.001) but without continuous increase at 1Y-FU (125.1 vs. 124.5 cm2; P=0.084), whereas right lung area showed a slight but insignificant interval increase (median: 143.8, 146.5, 148.4 cm2 at preoperative, postoperative, 1Y-FU stage, respectively; all P>0.05). At lateral view, the increase in left lung area was slight without statistically difference (median: 175.8, 178.4, 182.5 cm2 at preoperative, postoperative, 1Y-FU stage, respectively; all P>0.05), while right lung area did not significantly change postoperatively (median: 209.9, 206.7, 212.4 cm2 at preoperative, postoperative, 1Y-FU stage, respectively; all P>0.05). At both frontal and lateral view, left lung height significantly improved at both postoperative and 1Y-FU stage (all P<0.05), while preoperative right lung height was not significantly different from postoperative and 1Y-FU value (all P>0.05). Conclusions: EOS imaging demonstrates that left lung area in severe AIS may improve after PSF surgery. EOS may provide useful information about lung morphology change after PSF in severe AIS.