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Objective: To investigate the characteristics of three-dimensional distribution of subchondral fracture lines on the surface of the osteonecrosis femoral head, and to discuss the underlying mechanisms that contribute to its collapse. Methods: We retrospectively analyzed computed tomography (CT) images from 75 patients (comprising a total of 77 femoral heads) diagnosed with Association Research Circulation Osseous (ARCO) stage IIIA or IIIB femoral head necrosis. The three-dimensional structures of both the femoral head and the subchondral fracture line were reconstructed and subsequently fitted into normal femoral head model. A heat map of fracture line was generated to visualize its spatial distribution across the femoral heads surface.to observe its distribution. In addition to that, the femoral head was partitioned into four zones, and the frequency of each fracture line traversing different zones was calculated and analysed. Results: Highest and lowest density of subchondral fracture lines was demonstrated in anterolateral and posterolateral zone respectively. and most sparse in posterolateral. Furthermore, the three-dimensional heat map of fracture lines highlighted their most frequent occurrence in the anterolateral area, particularly near the junction of the femoral head and neck. One fracture line may pass through multiple areas, passage frequencies for fracture lines was observed in zones I, II, III and IV for 66 times (85.7 %), 52 times (67.5 %), 25 times (32.5 %) and 46 times (59.7 %), respectively, with a significant difference between zone I and other zones (P

Purpose Develop an albumin nanoparticle-based nanoprobe for targeted glioblastoma (GBM) diagnosis and treatment, utilizing Angopep-2 for low-density lipoprotein receptor-related protein (LRP) targeting. Methods Combined albumin-coated superparamagnetic iron oxide (SPIO), Carmustine (BCNU), and indocyanine green (ICG). Assessed morphology, size, Zeta potential, fluorescence, and drug encapsulation. Conducted in vitro fluorescence/MRI imaging and cell viability assays, and in vivo nanoprobe accumulation evaluation in brain tumors. Results ANG-BSA/BCNU/ICG MNPs exhibited superior targeting and cytotoxicity against GBM cells in vitro. In vivo, enhanced brain tumor accumulation during imaging was observed. Conclusion This targeted imaging and drug delivery system holds promise for efficient GBM therapy and intraoperative localization, addressing Blood-brain barrier (BBB) limitations with precise drug delivery and imaging capabilities.

Abstract Emodin, a natural anthraquinone derivative, possesses anti-proliferative and anti-inflammatory properties in skin diseases. However, little information is available on the efficacy of emodin in treating acne vulgaris (acne). This study aims to investigate the protective effects and potential mechanisms of emodin as an anti-acne agent. In vitro, SZ95 sebocytes was chose to establish an acneigenic cellular model. We found that emodin effectively inhibited proliferation, induced cell cycle arrest and apoptosis of SZ95 sebocytes in a dose-dependent manner. To evaluate the lipid-lowering potential of emodin, we examined the levels of lipid contents and lipogenic transcription factors, and found that both lipid production and protein expression of PPARγ, LXR α/β, and SREBP-1 were decreased after treatment with emodin. Furthermore, our results revealed that emodin inhibited sebaceous lipogenesis induced by insulin-like growth factor 1 (IGF-1), which was accompanied by a potent inhibition of the phosphoinositide-3-kinase (PI3K)/Akt/forkhead box protein O1 (FoxO1) pathway. In detail, emodin augmented the inhibitory effect of isotretinoin and PI3K inhibitor LY294002, while attenuating the activation of IGF-1 on PI3K/Akt/FoxO1 pathway. In addition, emodin could decrease the secretion of pro-inflammatory cytokines IL-6 and IL-8, and suppress the expression of NLRP3, capase-1, IL-1β, and IL-18 in SZ95 sebocytes exposed to Cutibacterium acnes. Overall, our study provides preliminary evidence supporting the anti-growth, anti-lipogenic and anti-inflammatory properties of emodin, indicating the potential therapeutic application of emodin for acne treatment.

Two 3D Zn(II) and Cd(II) coordination polymers, [Zn2(µ4-dppa)(µ-dpe)(µ-H2O)]n·nH2O (1) and [Cd2(µ8-dppa)(µ-dpe)(H2O)]n (2), have been constructed hydrothermally using 4-(3,5-dicarboxyphenoxy)phthalic acid (H4dppa), 1,2-di(4-pyridyl)ethylene (dpe), and zinc or cadmium chlorides. Both compounds feature 3D network structures. Their structure and topology, thermal stability, catalytic, and anti-wear properties were investigated. Particularly, excellent catalytic performance was displayed by zinc(II)-polymer 1 in the Knoevenagel condensation reaction at room temperature.

CD4+ cytotoxic T lymphocytes (CTLs) were recently implicated in immune-mediated inflammation and fibrosis progression of Graves’ orbitopathy (GO). However, little is known about therapeutic targeting of CD4+ CTLs. Herein, we studied the effect of rapamycin, an approved mTOR complex 1 (mTORC1) inhibitor, in a GO mouse model, in vitro, and in patients with refractory GO. In the adenovirus-induced model, rapamycin significantly decreased the incidence of GO. This was accompanied by the reduction of both CD4+ CTLs and the reduction of orbital inflammation, adipogenesis, and fibrosis. CD4+ CTLs from patients with active GO showed upregulation of the mTOR pathway, while rapamycin decreased their proportions and cytotoxic function. Low-dose rapamycin treatment substantially improved diplopia and the clinical activity score in steroid-refractory patients with GO. Single-cell RNA-Seq revealed that eye motility improvement was closely related to suppression of inflammation and chemotaxis in CD4+ CTLs. In conclusion, rapamycin is a promising treatment for CD4+ CTL-mediated inflammation and fibrosis in GO.

Dysregulation of the microRNA machinery has crucial roles in cancer development. Here the authors show that inactivation of proteins involved in microRNA-mediated gene silencing, such as ANKRD52 or AGO2, confers resistance to T cell-mediated immune response in a preclinical cancer model.

Abstract Background Whereas there are many pharmacological interventions prescribed for patients with advanced anaplastic lymphoma kinase (ALK)- rearranged non-small cell lung cancer (NSCLC), comparative data between novel generation ALK-tyrosine kinase inhibitors (TKIs) remain scant. Here, we indirectly compared the efficacy and safety of first-line systemic therapeutic options used for the treatment of ALK-rearranged NSCLC. Methods We included all phase 2 and 3 randomised controlled trials (RCTs) comparing any two or three treatment options. Eligible studies reported at least one of the following outcomes: progression free survival (PFS), overall survival (OS), objective response rate (ORR), or adverse events of grade 3 or higher (Grade ≥ 3 AEs). Subgroup analysis was conducted according to central nervous system (CNS) metastases. Results A total of 9 RCTs consisting of 2484 patients with 8 treatment options were included in the systematic review. Our analysis showed that alectinib (300 mg and 600 mg), brigatinib, lorlatinib and ensartinib yielded the most favorable PFS. Whereas there was no significant OS or ORR difference among the ALK-TKIs. According to Bayesian ranking profiles, lorlatinib, alectinib 600 mg and alectinib 300 mg had the best PFS (63.7%), OS (35.9%) and ORR (37%), respectively. On the other hand, ceritinib showed the highest rate of severe adverse events (60%). Conclusion Our analysis indicated that alectinib and lorlatinib might be associated with the best therapeutic efficacy in first-line treatment for major population of advanced NSCLC patients with ALK-rearrangement. However, since there is little comparative evidence on the treatment options, there is need for relative trials to fully determine the best treatment options as well as the rapidly evolving treatment landscape.

Objective To investigate the efficacy and safety of core decompression (CD) with local administration of zoledronate and enriched bone marrow mononuclear cells (BMMCS) for the treatment of non‐traumatic osteonecrosis of femoral head (ONFH). Methods A total of 17 patients (30 hips) diagnosed with stage II and III ONFH according to the 2019 revised Association for Research on Osseous Circulation (ARCO) staging criteria from 2012 to 2014 were retrospectively reviewed. The patients received the following therapy: the BMMCs and zoledronate were injected into the necrotic zone, respectively, along with CD. The mean age of the patients was 36.8 years; 14 were men and three were women. All patients included had non‐traumatic ONFH and a minimum follow‐up of 5 years, which ended when total hip arthroplasty (THA) was performed. Imaging modalities, including plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI) were taken pre‐ and postoperatively. Harris hip score (HHS) was used to evaluate the functional outcomes of femoral head necrosis. Kaplan–Meier analysis was adopted to determine the probability of survivorship with THA as the end point in this series of patients. The correlation between radiological progression or THA and related risk factors were further analyzed. All complications were recorded. Results With THA as the follow‐up endpoint, All patients were followed up for an average of 69.1 ± 20.5 months (range, 18–95 months). Preoperative imaging found six hips (20%) at ARCO stage II, 14 hips (46.7%) at stage IIIA, 10 hips (33.3%) at stage IIIB. Fourteen hips (46.7%) shown progression radiologically, while six hips (20%) underwent TKA among these patients with hip preservation. The cumulative survival was 80% (95% CI, 0.608–905) at 5 years with THA as the end point. HHS improved from 63.3 ± 8.7 preoperatively to 74.6 ± 20.6 postoperatively (P = 0.000). Radiological progression was found to be associated with ARCO stage, Japanese Investigation Committee (JIC) type, and corticosteroid exposure (P = 0.047; P = 0.012; P = 0.031). However, no correlation was found between conversion to THA and the known risk factors. No major complication was reported, with only four patients complaining about general weakness and muscle soreness, and all disappeared within 2–3 days. Conclusions The novel treatment modality could relieve pain, delay the progression of collapse, which might be an effective and safe method for hip preservation of early and mid‐term ONFH. However, the effect of this method may be related to ARCO stage, JIC type, and corticosteroid exposure.

Objective To investigate the methods and outcomes of hip arthroscopy for hip labrum calcification, and to discuss the clinical, imaging, and intraoperative findings of hip labrum calcification. Methods This is a therapeutic case series study. From January 2015 to June 2018, 15 patients who met the inclusion and exclusion criteria were followed up for at least 2 years for an analysis on the outcomes of arthroscopy in the treatment of hip labrum calcification and the clinical, imaging, and intraoperative findings of the patients. There were eight males and seven females, with an average age of 38.9 ± 8.8 years (range, 23–50 years). The visual analog scale (VAS), the modified Harris hip score (mHSS), and the international hip outcome tool (iHOT‐12) were used to evaluate the outcomes of surgery. Results A total of 15 patients were followed up for at least 2 years (28.1 ± 2.9 months). The average calcified volume was 118.0 mm3 (range, 19.4–609.2 mm3) and calcified volume was related to the preoperative hip function score. Thirteen patients had pain in the groin area (86.7%). Labrum calcifications were located (according to the clock distribution) as follows: 14 patients were anterior and superior (11:00–3:00); 12 cases of femoroacetabular impingement (FAI) were observed during operation, including five cases of pincer type, two cases of cam type, and five cases of mixed type. VAS pain score means were 7.73 ± 1.28 before surgery, decreasing to 2.0 ± 0.89 and 1.73 ± 0.79 at 1 and 2 years post‐surgery, respectively. mHSS scores were 57.40 ± 6.23 before surgery and 82.10 ± 4.76 and 83.18 ± 4.07, 1 and 2 years post‐surgery, respectively; iHOT‐12 mean score pre‐surgery was 37.67 ± 4.85, increasing to 67.64 ± 5.30 and 72.18 ± 4.49, 1 and 2 years post‐surgery, respectively. Compared with preoperative values, postoperative VAS, mHSS, and iHOT‐12 scores were significantly improved (P

Background: The progression of liver disorders is frequently associated with inflammatory bowel disease through the gut-liver axis. However, no direct evidence showed the mechanisms of ulcerative colitis (UC) in the development of liver fibrosis per se. Thus, this study aimed to evaluate the effects of UC on liver fibrosis and its potential mechanism in the experimental model.Methods: Male C57BL/6 mice were allocated into five groups (n = 10 per group) to receive either drinking water (control), 2% dextran sulfate sodium (DSS), olive oil, carbon tetrachloride (CCl4) or DSS + CCl4 for 4 cycles. Blood was collected for biochemical analysis. Colons were excised for the evaluation of colon length and morphological score. Liver, colon, and mesenteric lymph nodes (MLNs) were collected for histopathological staining, expression analysis, and bacterial translocation assay to evaluate the inflammation, fibrosis, the activation of hepatic stellate cells (HSCs), and gut barrier function.Results: DSS caused severe colitis in mice treated or treated with CCl4, as evident from the elevation of disease activity index (DAI), histological abnormalities, and increased pro-inflammatory cytokines (TNF-α, IFN-γ, and IL-17A). Histopathological staining revealed that DSS treatment aggravated the CCl4-induced extracellular matrix deposition, liver fibrosis, and inflammation in mice. Additionally, biochemical and expression analysis indicated the DSS treatment caused the increase of hydroxyproline and pro-inflammatory cytokines, as well as the abnormal liver function indexes in CCl4-induced mice. Gut barrier function was impaired in DSS- and DSS + CCl4-treated mice, manifesting as the increase in bacterial translocation and lipopolysaccharide level, and the reduction in tight junction proteins (occluding, claudin-1 and ZO-1) expression. Further, the activations of HSCs and TLR4 signaling pathway were observed after DSS + CCl4 treatment, presenting with the increase in expression of α-SMA, vimentin, TGF-β, collagen type I, collagen type II, TIMP-2, TLR4, TRAF6, and NF-κB p65, and a decrease in GFAP and MMP-2 expression.Conclusion: The present study verified that UC aggravated CCl4-induced liver injury, inflammation, and fibrosis in mice through the gut-liver axis. Gut barrier dysfunction in UC leads to bacterial translocation and elevated lipopolysaccharide, which may promote the activation of TLR4 signaling and HSCs in the liver.

Proteomic profiling of extracellular vesicles (EVs) represents a promising approach for early detection and therapeutic monitoring of diseases such as cancer. The focus of this study was to apply robust EV isolation and subsequent data-independent acquisition mass spectrometry (DIA-MS) for urinary EV proteomics of prostate cancer and prostate inflammation patients. Urinary EVs were isolated by functionalized magnetic beads through chemical affinity on an automatic station, and EV proteins were analyzed by integrating three library-base analyses (Direct-DIA, GPF-DIA, and Fractionated DDA-base DIA) to improve the coverage and quantitation. We assessed the levels of urinary EV-associated proteins based on 40 samples consisting of 20 cases and 20 controls, where 18 EV proteins were identified to be differentiated in prostate cancer outcome, of which three (i.e., SERPINA3, LRG1, and SCGB3A1) were shown to be consistently upregulated. We also observed 6 out of the 18 (33%) EV proteins that had been developed as drug targets, while some of them showed protein-protein interactions. Moreover, the potential mechanistic pathways of 18 significantly different EV proteins were enriched in metabolic, immune, and inflammatory activities. These results showed consistency in an independent cohort with 20 participants. Using a random forest algorithm for classification assessment, including the identified EV proteins, we found that SERPINA3, LRG1, or SCGB3A1 add predictable value in addition to age, prostate size, body mass index (BMI), and prostate-specific antigen (PSA). In summary, the current study demonstrates a translational workflow to identify EV proteins as molecular markers to improve the clinical diagnosis of prostate cancer.

Abstract Background Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease. The dysregulated immune system plays an important role in the pathogenesis of AS. Myeloid-derived suppressor cells (MDSCs) play a key immunoregulatory role in autoimmune arthritis. The aim of this study was to clarify the underlying immunoregulatory mechanism of MDSCs in patients with AS. Methods Flow cytometry was used to analyze the phenotype of MDSCs among peripheral blood mononuclear cells (PBMCs) from 46 patients with AS and 46 healthy control subjects. The correlation between MDSC frequency and the disease index of patients with AS was evaluated. A T cell proliferation experiment was used to evaluate the immunosuppressive function of MDSCs. Results Polymorphonuclear (PMN) and monocytic (M)-MDSCs were significantly elevated in the PBMCs of patients with AS, when compared with levels in healthy controls. Additionally, M-MDSC levels correlated positively with the clinical index of AS, including the Bath ankylosing spondylitis disease activity index (BASDAI) score, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. M-MDSCs derived from patients with AS suppressed T cell responses, and this effect was dependent on the induction of arginase-I. Furthermore, AS-derived M-MDSCs showed high levels of phosphorylated STAT3. Stattic, a STAT3-specific inhibitor, and STAT3-targeted siRNA abrogated the immunosuppressive function of M-MDSCs. Inhibition of STAT3 signaling also resulted in decreased arginase-I activity. Conclusions STAT3/arginase-I signaling plays an important role in both the expansion and activation of M-MDSCs in patients with AS. This information may be beneficial in developing novel therapeutic strategies for preventing AS.

Summary: The bone marrow niche plays a critical role in controlling the fate of hematopoietic stem cells (HSCs) by integrating intrinsic and extrinsic signals. However, the molecular events in the HSC niche remain to be investigated. Here, we report that intercellular adhesion molecule-1 (ICAM-1) maintains HSC quiescence and repopulation capacity in the niche. ICAM-1-deficient mice (ICAM-1−/−) displayed significant expansion of phenotypic long-term HSCs with impaired quiescence, as well as favoring myeloid cell expansion. ICAM-1-deficient HSCs presented normal reconstitution capacity during serial transplantation; however, reciprocal transplantation experiments showed that ICAM-1 deficiency in the niche impaired HSC quiescence and repopulation capacity. In addition, ICAM-1 deletion caused failure to retain HSCs in the bone marrow and changed the expression profile of stroma cell-derived factors, possibly representing the mechanism for defective HSCs in ICAM-1−/− mice. Collectively, these observations identify ICAM-1 as a regulator in the bone marrow niche. : In this article, Jie Zhou and colleagues show that ICAM-1 expression in bone marrow niche contributes to the quiescence and repopulation capacity of HSCs. ICAM-1 deficiency changes the expression profile of stroma-derived factors, thus causing failure of HSC retention in the bone marrow. Clinical data indicate that ICAM-1 might participate in the progression of myelocytic leukemia. Keywords: hematopoietic stem cells, homeostasis, intercellular adhesion molecule-1, bone marrow niche

Abstract The interaction of paeoniflorin with human serum albumin (HSA) was investigated using fluorescence, UV–vis absorption, circular dichroism (CD) spectra and molecular docking techniques under simulative physiological conditions. The results clarified that the fluorescence quenching of HSA by paeoniflorin was a static quenching process and energy transfer as a result of a newly formed complex (1:1). Paeoniflorin spontaneously bound to HSA in site I (subdomain IIA), which was primarily driven by hydrophobic forces and hydrogen bonds (ΔH° = − 9.98 kJ mol−1, ΔS° = 28.18 J mol−1 K−1). The binding constant was calculated to be 1.909 × 103 L mol−1 at 288 K and it decreased with the increase of the temperature. The binding distance was estimated to be 1.74 nm at 288 K, showing the occurrence of fluorescence energy transfer. The results of CD and three-dimensional fluorescence spectra showed that paeoniflorin induced the conformational changes of HSA. Meanwhile, the study of molecular docking also indicated that paeoniflorin could bind to the site I of HSA mainly by hydrophobic and hydrogen bond interactions.

Various graph-based algorithms for semi-supervised learning have been proposed in recent literatures. How-ever, although classification on homogeneous networks has been studied for decades, classification on heterogeneous networks has not been explored until recently. The semi-supervised classification problem on query-document heteroge-neous information network which incorporate the bipartite graph with the content information from both sides is consid-ered. In order to strengthen the network structure, class information of sample nodes is introduced. A semi-supervised learning algorithm based on two frameworks including the novel graph-based regularization framework and the iterative framework is investigated. In the regularization framework, a new cost function to consider the direct relationship be-tween two entity sets and the content information from both sides which leads to a significant improvement over the baseline methods is developed. Experimental results demonstrate that proposed method achieves the best performance with consistent and promising improvements.

The aim of this study is to develop a set of functional finite mixture regression models with functional predictors in the framework of the reproducing kernel Hilbert space. First, we show the consistency of a penalized likelihood model order estimator for the true model order, denoted as q*. We further show that the penalty of order q 2r / (2r + 1) n 1 / (2r + 1) log(n) yields a strong consistent estimator of q*, where n and q are the sample size and the model order, respectively, and r is the eigenvalue decay rate of an operator determined jointly by the reproducing and covariance kernels. Second, we establish the minimax rate of convergence for the estimation risk. We show that the optimal rate is determined by the alignment of the reproducing kernel and the covariance kernel and the true model order q*. An efficient algorithm is also developed to estimate all unknown components of the functional finite mixture model. Simulation studies and a real-data analysis illustrate the merits of the proposed method. [ABSTRACT FROM AUTHOR]