The value of the malignant subregion-based texture analysis in predicting the Ki-67 status in breast cancer.

Objective: To evaluate the value of the malignant subregion-based texture analysis in predicting Ki-67 status in breast cancer. Materials and methods: The dynamic contrast-enhanced magnetic resonance imaging data of 119 histopathologically confirmed breast cancer patients (81 patients with high Ki-67 expression status) from January 2018 to February 2023 in our hospital were retrospectively collected. According to the enhancement curve of each voxel within the tumor, three subregions were divided: washout subregion, plateau subregion, and persistent subregion. The washout subregion and the plateau subregion were merged as the malignant subregion. The texture features of the malignant subregion were extracted using Pyradiomics software for texture analysis. The differences in texture features were compared between the low and high Ki-67 expression cohorts and then the receiver operating characteristic (ROC) curve analysis to evaluate the predictive performance of texture features on Ki-67 expression. Finally, a support vector machine (SVM) classifier was constructed based on differential features to predict the expression level of Ki-67, the performance of the classifier was evaluated using ROC analysis and confirmed using 10-fold cross-validation. Results: Through comparative analysis, 51 features exhibited significant differences between the low and high Ki-67 expression cohorts. Following feature reduction, 5 features were selected to build the SVM classifier, which achieved an area under the ROC curve (AUC) of 0.77 (0.68-0.87) for predicting the Ki-67 expression status. The accuracy, sensitivity, and specificity were 0.76, 0.80, and 0.68, respectively. The average AUC from the 10-fold cross-validation was 0.72 ± 0.14. Conclusion: The texture features of the malignant subregion in breast cancer were potential biomarkers for predicting Ki-67 expression level in breast cancer, which might be used to precisely diagnose and guide the treatment of breast cancer.

Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

A newly evolved rice-specific gene JAUP1 regulates jasmonate biosynthesis and signalling to promote root development and multi-stress tolerance.

Root architecture and function are critical for plants to secure water and nutrient supply from the soil, but environmental stresses alter root development. The phytohormone jasmonic acid (JA) regulates plant growth and responses to wounding and other stresses, but its role in root development for adaptation to environmental challenges had not been well investigated. We discovered a novel JA Upregulated Protein 1 gene (JAUP1) that has recently evolved in rice and is specific to modern rice accessions. JAUP1 regulates a self-perpetuating feed-forward loop to activate the expression of genes involved in JA biosynthesis and signalling that confers tolerance to abiotic stresses and regulates auxin-dependent root development. Ectopic expression of JAUP1 alleviates abscisic acid- and salt-mediated suppression of lateral root (LR) growth. JAUP1 is primarily expressed in the root cap and epidermal cells (EPCs) that protect the meristematic stem cells and emerging LRs. Wound-activated JA/JAUP1 signalling promotes crosstalk between the root cap of LR and parental root EPCs, as well as induces cell wall remodelling in EPCs overlaying the emerging LR, thereby facilitating LR emergence even under ABA-suppressive conditions. Elevated expression of JAUP1 in transgenic rice or natural rice accessions enhances abiotic stress tolerance and reduces grain yield loss under a limited water supply. We reveal a hitherto unappreciated role for wound-induced JA in LR development under abiotic stress and suggest that JAUP1 can be used in biotechnology and as a molecular marker for breeding rice adapted to extreme environmental challenges and for the conservation of water resources.

Arterial chemotherapy for hepatocellular carcinoma in China: consensus recommendations.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer-related deaths globally. Hepatic arterial infusion chemotherapy (HAIC) treatment is widely accepted as one of the alternative therapeutic modalities for HCC owing to its local control effect and low systemic toxicity. Nevertheless, although accumulating high-quality evidence has displayed the superior survival advantages of HAIC of oxaliplatin, fluorouracil, and leucovorin (HAIC-FOLFOX) compared with standard first-line treatment in different scenarios, the lack of standardization for HAIC procedure and remained controversy limited the proper and safe performance of HAIC treatment in HCC. Therefore, an expert consensus conference was held on March 2023 in Guangzhou, China to review current practices regarding HAIC treatment in patients with HCC and develop widely accepted statements and recommendations. In this article, the latest evidence of HAIC was systematically summarized and the final 22 expert recommendations were proposed, which incorporate the assessment of candidates for HAIC treatment, procedural technique details, therapeutic outcomes, the HAIC-related complications and corresponding treatments, and therapeutic scheme management.

A prediction model for osteonecrosis of femoral head after internal fixation with multiple cannulated compression screws for adult femoral neck fractures.

OBJECTIVES: This study aims to investigate the high-risk factors for osteonecrosis of the femoral head (ONFH) after internal fixation with multiple cannulated compression screws for adult femoral neck fractures and to construct a prediction model. PATIENTS AND METHODS: Between from January 2012 and December 2020, a total of 268 patients (138 males, 130 females; mean age: 53±10 years; range, 23 to 70 years) with ONFH who had complete follow-up data were included. Closed reduction in combination with open reduction were performed. All patients received internal fixation with multiple cannulated compression screws and were assigned to ONFH and non-ONFH groups. Logistic regression model was utilized to identify independent risk factors for postoperative ONFH, followed by constructing a nomogram prediction model. The predictive ability of the model was evaluated by receiver operating characteristic curve, Hosmer-Lemeshow test, and calibration curve. RESULTS: Multivariate analysis revealed that older age (odds ratio [OR]: 2.307, 95% confidence interval [CI]: 1.295-4.108], Charlson Comorbidity Index (CCI) ≥2 (OR: 2.214, 95% CI: 1.035-4.739), fracture displacement (OR: 2.426, 95% CI: 1.122-5.247), unsatisfactory reduction (OR: 2.629, 95% CI: 1.275-5.423), postoperative removal of internal fixation implant (OR: 2.200, 95% CI: 1.051-4.604) were independent risk factors for postoperative ONFH (p<0.05). The nomogram prediction model constructed based on these clinical characteristics showed high predictive value (AUC=0.807) and consistency (p>0.05). CONCLUSION: Age, comorbidity index, fracture type, reduction quality and postoperative removal of internal fixation implant are of utmost importance for postoperative ONFH in patients with femoral neck fractures. The established nomogram prediction model can accurately predict the occurrence of postoperative ONFH.

Identification of (E)-1-((1H-indol-3-yl)methylene)-4-substitute-thiosemicarbazones as potential anti-hepatic fibrosis agents.

Liver fibrosis remains a global health challenge due to its rapidly rising prevalence and limited treatment options. The orphan nuclear receptor Nur77 has been implicated in regulation of autophagy and liver fibrosis. Targeting Nur77-mediated autophagic flux may thus be a new promising strategy against hepatic fibrosis. In this study, we synthesized four types of Nur77-based thiourea derivatives to determine their anti-hepatic fibrosis activity. Among the synthesized thiourea derivatives, 9e was the most potent inhibitor of hepatic stellate cells (HSCs) proliferation and activation. This compound could directly bind to Nur77 and inhibit TGF-ß1-induced α-SMA and COLA1 expression in a Nur77-dependent manner. In vivo, 9e significantly reduced CCl4-mediated hepatic inflammation response and extracellular matrix (ECM) production, revealing that 9e is capable of blocking the progression of hepatic fibrosis. Mechanistically, 9e induced Nur77 expression and enhanced autophagic flux by inhibiting the mTORC1 signaling pathway in vitro and in vivo. Thus, the Nur77-targeted lead 9e may serve as a promising candidate for treatment of chronic liver fibrosis.

Spinosin inhibits activated hepatic stellate cell to attenuate liver fibrosis by targeting Nur77/ASK1/p38 MAPK signaling pathway.

AIM: Liver fibrosis remains a great challenge in the world. Spinosin (SPI), a natural flavonoid-C-glycoside, possesses various pharmacological activities including anti-inflammatory and anti-myocardial fibrosis effects. In this study, we investigate whether SPI can be a potential lead for the treatment of liver fibrosis and explore whether the orphan nuclear receptor Nur77, a negative regulator of liver fibrosis development, plays a critical role in SPI's action. METHODS: A dual luciferase reporter system of α-SMA was established to evaluate the effect of SPI on hepatic stellate cell (HSC) activation in LX2 and HSC-T6 cells. A mouse model of CCl4-induced liver fibrosis was used to test the efficacy of SPI against liver fibrosis. The expression levels of Nur77, inflammatory cytokines and collagen were determined by Western blotting and qPCR. Potential kinase pathways involved were also analyzed. The affinity of Nur77 with SPI was documented by fluorescence titration. RESULTS: SPI can strongly suppress TGF-ß1-mediated activation of both LX2 and HSC-T6 cells in a dose-dependent manner. SPI increases the expression of Nur77 and reduces TGF-ß1-mediated phosphorylation levels of ASK1 and p38 MAPK, which can be reversed by knocking out of Nur77. SPI strongly inhibits collagen deposition (COLA1) and reduces inflammatory cytokines (IL-6 and IL-1ß), which is followed by improved liver function in the CCl4-induced mouse model. SPI can directly bind to R515 and R563 in the Nur77-LBD pocket with a Kd of 2.14 µM. CONCLUSION: Spinosin is the major pharmacological active component of Ziziphus jujuba Mill. var. spinosa which has been frequently prescribed in traditional Chinese medicine. We demonstrate here for the first time that spinosin is a new therapeutic lead for treatment of liver fibrosis by targeting Nur77 and blocking the ASK1/p38 MAPK signaling pathway.

A case report of dermatomyositis mimicking myasthenia gravis.

RATIONALE: Patients who have myasthenia gravis or dermatomyositis show clinical signs of muscular weakening. Ocular muscle involvement is uncommon, and symmetrical proximal limb weakness is the typical presentation of dermatomyositis. However, the earliest and most noticeable sign in those with myasthenia gravis is extraocular muscular paralysis. Dermatomyositis is frequently complicated by malignancy, and the common malignancies associated with dermatomyositis vary by region and ethnicity, while thymoma is relatively rare. About 10% to 15% of people with myasthenia gravis have thymoma, which is involved in the etiology of the disease. PATIENT CONCERNS: A 68-year-old female presented with ocular muscle weakness for 10 days that manifested as bilateral blepharoptosis with the phenomenon of "light in the morning and heavy in the evening." Imaging examination showed anterior mediastinal thymic tumor with metastasis. DIAGNOSES: After a thorough physical examination, we discovered bilateral upper limbs with grade IV muscle strength and the typical rash of dermatomyositis. In combination with elevated serum kinase levels and electromyography suggesting myogenic damage, the patient was finally diagnosed as dermatomyositis with multiple metastases of thymoma. INTERVENTIONS: The patient received oral hydroxychloroquine sulfate, topical corticosteroids, and tacrolimus ointment, but these did not work very well. Subsequently, the patient underwent surgery combined with radiotherapy for the thymoma. OUTCOMES: Muscle weakness in the patient improved after effective treatment of tumor, and the rash mostly disappeared. CONCLUSION: Ocular muscle weakness and thymoma are more common in myasthenia gravis, but we cannot ignore the possibility of dermatomyositis. To further establish the diagnosis, a thorough physical examination and laboratory findings are required. Further tumor screening should be performed for patients with dermatomyositis. Early detection and management of possible tumors are essential to the treatment of dermatomyositis linked to malignancies.

High precision measurements of lithium isotopic composition at sub-nanogram by MC-ICP-MS with membrane desolvation.

The geochemistry of Li and Li isotopes is a promising tracer of chemical weathering processes for both modern and ancient times. Therefore, accurate and precise determination of the isotopic composition of Li is required for a large variety of complex geological samples with different Li concentrations and matrix/Li ratios. Especially, geochemical studies of precious geological samples with ultra-low lithium content and high matrix. In this study, the accuracy and the precision corresponding to Li isotopic measurements of low-level samples using multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS) with membrane desolvation introduction system was evaluated. The method of MC-ICP-MS with membrane desolvation and a high-sensitivity X-skimmer cone, together with a simple one-step column separation enabled the high-precision isotopic analysis of Li quantities as small as 2 ng. The long-term instrumental external reproducibility of δ7Li values for the L-SVEC and SPEX-Li were 0.0 ± 0.1‰ (n = 20) and 12.1 ± 0.4‰ (n = 20), respectively. Based on the measurements on a series of international reference materials over the last two years. The measured δ7Li values for the standards with a variety of matrices, including BHVO-2, AGV-2 and seawater (NASS-6). The δ7Li values of BHVO-2 (4.58 ± 0.35‰), AGV-2 (6.85 ± 0.40‰) and NASS-6 (30.88 ± 0.20‰) are in agreement with the published data within the uncertainty. We also present analytical results for South China Sea surface seawater water, meteorite, limestones and rain water. These results demonstrate the validity of the method for obtaining highly precise and accurate outcomes.

Design, synthesis, and biological evaluation of carbonyl-hydrazine-1-carboxamide derivatives as anti-hepatic fibrosis agents targeting Nur77.

Hepatic fibrosis remains a great challenge clinically. The orphan nuclear receptor Nur77 is recently suggested as the critical regulator of transforming growth factor-ß (TGF-ß) signaling, which plays a central role in multi-organic fibrosis. Herein, we optimized our previously reported Nur77-targeted compound 9 h for attempting to develop effective and safe anti-hepatic fibrosis agents. The critical pharmacophore scaffold of pyridine-carbonyl-hydrazine-1-carboxamide was retained, while the naphthalene ring was replaced with an aromatic ring containing pyridyl or indole groups. Four series of derivatives were thus generated, among which the compound 16f had excellent binding activity toward Nur77-LBD (KD = 470 nM) with the best inhibitory activity against the TGF- ß 1 activation of hepatic stellate cells (HSCs) and low cytotoxicity to normal mice liver AML-12 cells (IC50 > 80 µM). In mice, 16f displayed potent activity against CCl4-induced liver fibrosis with improved liver function. Mechanistically, 16f-mediated inactivation of HSC and suppression of liver fibrosis were associated with its enhancement of autophagic flux in a Nur77-dependent manner. Together, 16f was identified as a potential anti-liver fibrosis agent. Our study suggests that Nur77 may serve as a critical anti-hepatic fibrosis target.

Cultural differences in intertemporal decision making: A comparison between Chile and China.

A cross-cultural comparison is made of delay discounting in samples of participants from Chile and China. Comparisons are made based on previous literature that suggests that individuals from an Asian culture should be willing to postpone delayed rewards more than are individuals from a Latin American culture. To test the cross-cultural validity of a hyperbolic discounting model, the model was fitted to both data sets. Additionally, a self-enhancement measure was evaluated as a potential mediator between culture of origin and delay discounting. Seventy-eight college students from China and 120 college students from Chile, with similar demographic backgrounds, discounted hypothetical monetary outcomes using an adjusting-amount titration procedure. Additionally, participants completed a self-enhancement measure. Age, academic major, gender, and grade point average were controlled. Chilean participants discounted much more steeply than Chinese nationals did. No support was obtained for the mediation of self-enhancement between culture of origin and degree of delay discounting. In both samples, delay discounting was better described by a hyperboloid than an exponential function, the only exception being the $10,000 condition in which the medians for Chilean participants' present subjective value were equally well explained by a hyperboloid and an exponential function.

Synergistic effect of porous carbon shell confinement and catalytic conversion of nickel nanoparticle cores for improved lithium-sulfur batteries.

Lithium-sulfur batteries (LSBs) are some of the most promising energy storage systems to break the ceiling of Li-ion batteries. However, the notorious shuttle effect and slow redox kinetics give rise to low sulfur utilization and discharge capacity, poor rate performance, and fast capacity decay. It is proved that the reasonable design of the electrocatalyst is one of the important ways to improve the electrochemical performance of LSBs. Here, a core-shell structure with gradient adsorption capacity for reactants and sulfur products was designed. The Ni nanoparticles core coated with graphite carbon shell was prepared by one-step pyrolysis of Ni-MOF precursors. The design takes advantage of the principle that the adsorption capacity decreases from the core to the shell, and the Ni core with strong adsorption capacity is easy to attract and capture soluble lithium polysulfide (LiPS) during the discharge/charging process. This trapping mechanism prevents the diffusion of LiPSs to the outer shell and effectively inhibits the shuttle effect. In addition, the Ni nanoparticles within the porous carbon, as the active center, expose most of the inherent active sites to the surface area, thus achieving a rapid transformation of LiPSs, significantly reducing the reaction polarization, and improving the cyclic stability and reaction kinetics of LSB. Therefore, the S/Ni@PC composites exhibited excellent cycle stability (a capacity of 417.4 mA h g-1 for 500 cycles at 1C with a fading rate of 0.11%) and outstanding rate performance (1014.6 mA h g-1 at 2C). This study provides a promising design solution of Ni nanoparticles embedded in porous carbon for high-performance, safe and reliable LSB.

Remote Sensing Image Characteristics and Typical Area Analysis of Taiyuan Xishan Ecological Restoration Area.

The Taiyuan Xishan Ecological Restoration Zone is located in the west of Taiyuan City and belongs to the Xishan Coalfield. Due to the resource development activity of coal mining, which is caused by coal gangue accumulation, surface vegetation degradation, bare surfaces, and other phenomena, it is most common in this area. These have an impact on the surface ecology; however, after ecological restoration, the surface ecology has been greatly improved. There are many extraction models of vegetation coverage based on pixel dichotomology combined with multispectral vegetation index, but we believe that the combination of visible light vegetation index to construct models is relatively unexplored. The main problem of how to use the RGB image data in order to quickly and accurately extract vegetation coverage information is still under investigation and needs researchers' attention. In this paper, through selecting the vegetation coverage as the evaluation index of ecological restoration effect, a new RGB vegetation coverage CIVE calculation model is innovatively proposed to solve the above problem, and on the basis of this model, the vegetation cover change analysis is carried out in the Xishan ecological restoration area of Taiyuan. According to the analysis of vegetation coverage change, relevant paper data, and the characteristics of multiple historical remote sensing images, the ecological restoration area of Taiyuan Xishan is divided into six typical areas. Through empirical evaluation, we summarize and analyze these six typical areas, which can provide typical demonstration roles for other ecological restoration areas. Our findings suggest that the proposed CIVE model realizes the extraction of vegetation cover information and long-term series dynamic monitoring of vegetation coverage.

Orphan Nuclear Receptor Nur77 Mediates the Lethal Endoplasmic Reticulum Stress and Therapeutic Efficacy of Cryptomeridiol in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) commonly possesses chronical elevation of IRE1α-ASK1 signaling. Orphan nuclear receptor Nur77, a promising therapeutic target in various cancer types, is frequently silenced in HCC. In this study, we show that cryptomeridiol (Bkh126), a naturally occurring sesquiterpenoid derivative isolated from traditional Chinese medicine Magnolia officinalis, has therapeutic efficacy in HCC by aggravating the pre-activated UPR and activating the silenced Nur77. Mechanistically, Nur77 is induced to sense IRE1α-ASK1-JNK signaling and translocate to the mitochondria, which leads to the loss of mitochondrial membrane potential (Δψm). The Bkh126-induced aggravation of ER stress and mitochondrial dysfunction result in increased cytotoxic product of reactive oxygen species (ROS). The in vivo anti-HCC activity of Bkh126 is superior to that of sorafenib, currently used to treat advanced HCC. Our study shows that Bkh126 induces Nur77 to connect ER stress to mitochondria-mediated cell killing. The identification of Nur77 as a molecular target of Bhk126 provides a basis for improving the leads for the further development of anti-HCC drugs.

The Oncogenic and Diagnostic Potential of Stanniocalcin 2 in Hepatocellular Carcinoma.

Purpose: Early detection and prognostic prediction of hepatocellular carcinoma (HCC) remain a great challenge. In this study, we explored the role and diagnostic significance of stanniocalcin 2 (STC2), recently identified as a secretory protein, in HCC. Methods: STC2 mRNA and protein in HCC tissues were examined by qRT-PCR and immunohistochemistry. The regulatory role of HCC growth by STC2 was evaluated in vitro and in vivo. Serum STC2 levels were determined in HCC patients and compared to those with liver cirrhosis (LC) and normal controls (NC). The difference and significance of STC2 levels between groups were analyzed by Mann-Whitney U-test. The diagnostic value of serum STC2 in detecting early HCC was assayed with receiver operating characteristics (ROC). The association of STC2 with overall survival (OS) was determined with Kaplan-Meier method. Results: STC2 was elevated in about 77.1% HCC patients and correlated with advanced tumor progression. Overexpression or knockdown of STC2 stimulated or suppressed HCC colony formation and xenograft tumor growth. AKT activation played a critical role in tumor-promoting effect of STC2. The median level of serum STC2 in HCC patients (n = 98, 2086.6 ng/L) was 2.6-fold and 4.2-fold that in LC patients (n = 42, 801.9 ng/L) and NC (n = 26, 496.9 ng/L), respectively. A cut-off value 1493 ng/L for STC2 could distinguish early HCC from LC with a sensitivity of 76.9% and a specificity of 76.2%, both of which were superior to AFP at 20 µg/L (sensitivity 69.2%, specificity 52.4%). STC2 was positive in 77.8% (14/18) AFP-negative patients. High STC2 level was correlated with poor overall and disease specific survival. Conclusion: STC2 is upregulated in both tumor and serum of HCC patients, and its overexpression promotes HCC via AKT pathway. STC2 possesses a diagnostic significance and may serve as an auxiliary biomarker of AFP for detecting early HCC.

Blood routine risk factors for coronary artery aneurysm in infants younger than 8 months with Kawasaki disease.

OBJECTIVE: The aims of this study were to characterize the evolution of routine blood values within the first 10 days of illness and coronary artery outcome in infants < 8 months with Kawasaki disease (KD) and to identify risk factors for coronary artery aneurysm (CAA). METHODS: Laboratory data, clinical features and coronary artery outcomes from 78 infants < 8 months old and 86 patients between 8 months and 7 years old were retrospectively analyzed. Logistic regression analysis was conducted to evaluate the potential risk factors for CAA. RESULTS: Infants < 8 months old were more likely to present with incomplete KD (37.2% vs 4.7%, P < 0.001), erythema and induration at the BCG inoculation site (24.4% vs 3.5%, P < 0.001) and CAA (47.4% vs 15.1%, P < 0.001) even with timely diagnosis and treatment with intravenous immunoglobulin (IVIG) compared with patients ≥8 months old. Clinical feature related to diagnostic criteria for KD including bilateral conjunctival injection, oral changes, unilateral cervical lymphadenopathy and extremity changes were less common in the younger group. During the acute phase, the percentage neutrophils and neutrophil to lymphocyte ratio [NLR] peaked on median illness day 3, followed by white blood cell (WBC) and CRP on median illness day 4, hemoglobin on median illness day 7 and platelet count on median illness day 9. CAA occurred on median illness day 6 and regressed on median illness day 28. Multivariate logistic regression analysis revealed that the peak percentage neutrophils (odds ratio [OR] per 0.1: 1.597, 95% confidence interval [CI]: 1.041-2.452, P = 0.032) and the peak platelet count (OR per 10 × 109/L: 1.029, 95% CI: 1.004-1.055, P = 0.024) were independent risk factors for CAA. Hemoglobin on the 5th day was associated with persistent CAA at 1 year after KD onset. CONCLUSION: Factors associated with CAA include a high peak percentage neutrophils, increased peak platelet count, and reduced hemoglobin within 4-6 days during the acute phase of KD. Therefore, this population should receive primary therapy with IVIG and adjunctive anti-inflammatory medications.

Topical Transplantation of Bone Marrow Mesenchymal Stem Cells Made Deeper Skin Wounds Regeneration.

Current wound healing models generally employ full-thickness or irregular split wounds. Consequently, assessing the type of healing at varying wound depths and determining the deepest level at which wounds can regenerate has been a challenge. We describe a wound model that allows assessment of the healing process over a continuous gradient of wound depth, from epidermal to full-thickness dermal loss. Further, we investigate whether green fluorescent protein-labeled bone marrow mesenchymal stem cells (BM-MSCs/GFP) transplantation could regenerate deeper wounds that might otherwise lead to scar formation. A wound gradient was created on the back of 120 Sprague Dawley rats, which were randomized into the BM-MSCs/GFP and control group. These were further subdivided into 6 groups where terminal biopsies of the healing wounds were taken at days 1, 3, 5, 7, 14, and 21 post-operatively. At each observed time point, the experimental animals were anesthetized and photographed, and depending on the group, the animals euthanized and skin taken for rapid freezing, haemotoxylin and eosin staining, and vascular endothelial growth factor (VEGF) immunohistochemistry. We found the deepest layer to regenerate in the control group was at the level of the infundibulum apex, while in the BM-MSCs/GFP group this was deeper, at the opening site of sebaceous duct at hair follicle in which had the appearance of normal skin and less wound contraction than the control group (P value less than .05). The expression of VEGF in BM-MSCs/GFP group was higher than that in control group (P value less than .05). The number of vessels increased from 2.5 ± 0.2/phf of control group to 5.0 ± 0.3/phf of BM-MSCs/GFP (P value less than .05). The progressively deepening wound model we described can identify the type of wound repair at increasing depths. Further, topical transplantation of BM-MSCs/GFP significantly improved regeneration of deeper wounds from infundibulum apex (maximum depth of control group regeneration) to the opening site of sebaceous duct at hair follicle level.

Les modèles actuels de cicatrisation des plaies font généralement appel à des plaies pleine épaisseur ou de forme irrégulière. Il est donc difficile d'évaluer le type de cicatrisation à diverses profondeurs et de déterminer la profondeur maximale à laquelle les plaies se régénèrent. Les auteurs décrivent un modèle de plaie qui permet d'évaluer le processus de cicatrisation d'après un gradient continu de la profondeur de plaie, entre la perte épidermique et la perte dermique pleine épaisseur. Ils ont également examiné si la transplantation de cellules souches mésenchymateuses marquées de protéines fluorescentes vertes (BM-MSCs/GFP) peut régénérer des plaies plus profondes qui formeraient autrement des cicatrices. Les chercheurs ont créé un gradient de plaie sur le dos de 120 rats Sprague-Dawley divisés de manière aléatoire entre le groupe BM-MSCs/GFP et le groupe témoin. Ils ont ensuite subdivisé ces deux groupes en six groupes, dans lesquels ils ont prélevé des biopsies terminales des plaies en voie de cicatrisation les 1er, 3e, 5e, 7e, 14e et 21e journées après l'opération. À chaque journée d'observation, ils ont anesthésié et photographié les animaux expérimentaux et, selon le groupe, les ont euthanasiés et en ont prélevé la peau en vue de leur congélation rapide, de leur coloration HE et de l'immunohistochimie VEGF. Les chercheurs ont découvert que l'apex infundibulum était la couche la plus profonde à se régénérer dans le groupe témoin, mais que dans le groupe BM-MSCs/GFP, la régénération était plus profonde, à l'entrée du follicule pileux dans la glande sébacée, a repris l'apparence de la peau normale et se contractait moins que dans le groupe témoin (p<0,05). L'expression du VEGF dans le groupe BM-MSCs/GFP était plus élevée que dans le groupe témoin (valeur p inférieure à 0,05). Le nombre de vaisseaux observé était de 2,5±0,2/phf dans le groupe témoin et de 5,0±0,3/phf dans le groupe BM-MSCs/GFP (p<0,05). Le modèle de plaie de plus en plus profonde peut déterminer le type de réparation selon la profondeur. De plus, la transplantation topique de BM-MSCs/GFP améliore considérablement la régénération des plaies plus profondes, qui passe de l'apex de l'infundibulum (profondeur de régénération maximale dans le groupe témoin) à l'entrée du follicule pileux dans la glande sébacée.

The Ginsenoside Compound K Suppresses Stem-Cell-like Properties and Colorectal Cancer Metastasis by Targeting Hypoxia-Driven Nur77-Akt Feed-Forward Signaling.

Hypoxia reprograms cancer stem cells. Nur77, an orphan nuclear receptor, highly expresses and facilitates colorectal cancer (CRC) stemness and metastasis under a hypoxic microenvironment. However, safe and effective small molecules that target Nur77 for CSC depletion remain unexplored. Here, we report our identification of the ginsenoside compound K (CK) as a new ligand of Nur77. CK strongly inhibits hypoxia-induced CRC sphere formation and CSC phenotypes in a Nur77-dependent manner. Hypoxia induces an intriguing Nur77-Akt feed-forward loop, resulting in reinforced PI3K/Akt signaling that is druggable by targeting Nur77. CK directly binds and modulates Nur77 phosphorylation to block the Nur77-Akt activation loop by disassociating Nur77 from the p63-bound Dicer promoter. The transcription of Dicer that is silenced under a hypoxia microenvironment is thus reactivated by CK. Consequently, the expression and processing capability of microRNA let-7i-5p are significantly increased, which targets PIK3CA mRNA for decay. The in vivo results showed that CK suppresses cancer stemness and metastasis without causing significant adverse effects. Given that the majority of FDA-approved and currently clinically tested PI3K/Akt inhibitors are reversible ATP-competitive kinase antagonists, targeting Nur77 for PI3K/Akt inactivation may provide an alternative strategy to overcoming concerns about drug selectivity and safety. The mechanistic target identification provides a basis for exploring CK as a promising nutraceutical against CRC.

α-Mangostin Induces Apoptosis and Inhibits Metastasis of Breast Cancer Cells via Regulating RXRα-AKT Signaling Pathway.

Mangostin, which has the function of anti-inflammatory, antioxidant, and anticancer, etc, is one of the main active ingredients of the hull of the mangosteen. The main objective of the study was to elucidate its anti-cancer function and possible mechanism. α-Mangostin was separated and structurally confirmed. MTT method was used to check the effect of mangostin on breast cancer cell proliferation. Then the effect of α-Mangostin on the transcriptional activity of RXRα was tested by dual-luciferase reporter gene assay. And Western blot (WB) was used to detect the expression of apoptosis-related proteins or cell cycle-associated proteins after treatment. Also, this study was to observe the effects of α-Mangostin on the invasion of breast cancer cell line MDA-MB-231. α-Mangostin regulates the downstream effectors of the PI3K/AKT signaling pathway by degrading RXRα/tRXRα. α-Mangostin can trigger PARP cleavage and induce apoptosis, which may be related to the induction of upregulated BAX expression and downregulation of BAD and cleaved caspase-3 expression in MDA-MB-231 cells through blockade of AKT signaling. The experiments verify that α-Mangostin have evident inhibition effects of invasion and metastasis of MDA-MB-231 cells. Cyclin D1 was involved in the anticancer effects of α-Mangostin on the cell cycle in MDA-MB-231 cells. α-Mangostin induces apoptosis, suppresses the migration and invasion of breast cancer cells through the PI3K/AKT signaling pathway by targeting RXRα, and cyclin D1 has involved in this process.