Assessment of Endoscopy-Based Scoring Systems for Prognostication in Ulcerative Colitis: A Comparative Analysis.

BACKGROUND AND OBJECTIVE: Endoscopy-based scoring systems, including Mayo Endoscopic Score (MES), Modified Mayo Endoscopic Score (MMES), and Degree of Ulcerative Colitis Burden of Luminal Inflammation (DUBLIN) Score, have been introduced to evaluate UC prognosis. This study aims to compare their predictive capacity for clinical outcomes in UC patients. METHODS: Consecutive UC patients from a tertiary hospital were included. The primary outcome was acute severe ulcerative colitis (ASUC), and secondary outcomes were UC-related admission, medication treatment escalation, disease extension and surgery. Predictive performance was assessed using receiver operating characteristic (ROC) curves. RESULTS: Among 300 patients, 15.3% developed ASUC. Robust correlations were observed among the three scoring systems and were with elevated serum inflammatory markers. The DUBLIN score exhibited superior predictive ability for UC-related admission (AUC 0.751; 95%CI 0.698-0.799) and medication treatment escalation (AUC 0.735; 95% CI 0.681-0.784). No statistical differences were found among three scoring systems for predicting ASUC, disease extension, and surgery. Employing respective cut-offs of 2, 11.25, and 3, higher MES (HR = 3.859, 95% CI 1.636-9.107, p = 0.002), MMES (HR = 3.352, 95% CI 1.879-5.980, p < 0.001), and DUBLIN score (HR = 5.619, 95% CI 2.378-13.277, p < 0.001) were associated with an increased risk of developing ASUC. CONCLUSION: The DUBLIN score, assessing the overall inflammatory burden of the intestinal tract, outperforms the MMES in predicting admission and medication treatment escalation related to UC. Its integration into clinical practice has the potential to enhance risk stratification for patients with UC.

Osteopontin interacts with dendritic cells and macrophages in pulp inflammation: Comprehensive transcriptomic analysis and laboratory investigations.

AIM: To investigate novel diagnostic markers for pulpitis and validate by clinical samples from normal and inflamed pulp. To explore the relationship between diagnostic markers and immune cells or their phenotypes during pulp inflammation. METHODOLOGY: Two microarray datasets, GSE77459 and GSE92681, and identified differential expression genes were integrated. To understand immune features, gene functions, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Disease Ontology (DO) and ImmuneSigDB Gene Set Enrichment Analysis (GSEA) were analysed. For predictive purposes, machine learning techniques were applied to detect diagnostic markers. Immune infiltration in inflamed pulp was studied using CIBERSORT. The relationship between diagnostic markers and immune cells was investigated and validated their gene expression in clinical samples from the normal or inflamed pulp by qRT-PCR. Finally, the correlation between one marker, secreted phosphoprotein 1 (SPP1), encoding osteopontin (OPN), and dendritic cells (DCs)/macrophages was identified via HE staining and multiplex immunohistochemistry. An in vitro inflammatory dental pulp microenvironment model of THP-1 macrophages cocultured with dental pulp cells derived conditioned media (DPCs-CM) to investigate OPN production and macrophage phenotypes was established. RESULTS: Analysis revealed unique immunologic features in inflamed pulp. Three diagnostic markers for pulpitis: endothelin-1 (EDN1), SPP1, and purine nucleoside phosphorylase (PNP), and validated them using qRT-PCR were predicted. Multiplex immunohistochemistry demonstrated OPN co-localized with activated DCs and M2 macrophages during pulp inflammation. In vitro experiments showed that THP-1 macrophages produced the highest levels of OPN when stimulated with DPCs-CM derived from the 20 µg/mL LPS pre-conditioned group, suggesting an M2b-like phenotype by increasing surface marker CD86 and expression of IL6, TNFα, IL10, and CCL1 but not CCL17 and MerTK. Levels of CCL1 and IL10 elevated significantly in the macrophages' supernatant from the 20 µg/mL LPS pre-conditioned CM group. OPN was proven co-localizing with CD86 in the inflamed pulp by immunofluorescence. CONCLUSIONS: The current findings suggest that OPN can serve as a promising biomarker for pulpitis, correlated with DCs and macrophages. OPN+ macrophages in the inflamed pulp are associated with M2b-like phenotypes. These insights offer the potential for improved diagnosis and targeted therapy.

Dispersive solid phase extraction based on cross-linked hydroxypropyl ß-cyclodextrin polymers for simultaneous enantiomeric determination of three chiral triazole fungicides in water.

An efficient method is presented for simultaneous enantioselective determination of three chiral triazole fungicides (namely paclobutrazol, hexaconazole, and diniconazole) in water samples by DSPE-HPLC-UV. The perfect chiral separation of the enantiomers was achieved on a Chiralpak IH column within 15 min. In order to adsorb and enrich the analytes from water matrices, a cross-linked hydroxypropyl ß-cyclodextrin polymer was synthesized. The prepared material exhibited good adsorption capacity, which was assessed by adsorption kinetic and adsorption thermodynamic experiments. One-variable-at-a-time and the response surface methodology were used to optimize the extraction parameters. Under the optimum sample preparation conditions, good linearity (2.0 ~ 800 µg L-1, R2 ≥ 0.9978), detection limits (0.6 to 1.0 µg L-1), quantitation limits (2.0 to 3.2 µg L-1), recoveries (86.7 ~ 105.8%), and the relative standard deviation (intra-day RSD ≤ 3.7%, inter-day RSD ≤ 5.1%) were obtained, satisfying the requirements of pesticides residues determination. These results demonstrated that the proposed method was applicable for routine determination of chiral triazole fungicide residues in water samples.

deepMDDI: A deep graph convolutional network framework for multi-label prediction of drug-drug interactions.

It is crucial to identify DDIs and explore their underlying mechanism (e.g., DDIs types) for polypharmacy safety. However, the detection of DDIs in assays is still time-consuming and costly, due to the need for experimental search over a large space of drug combinations. Thus, many computational methods have been developed to predict DDIs, most of them focusing on whether a drug interacts with another or not. And a few deep learning-based methods address a more realistic screening task for identifying various DDI types, but they assume a DDI only triggers one pharmacological effect, while a DDI can trigger more types of pharmacological effects. Thus, here we proposed a novel end-to-end deep learning-based method (called deepMDDI) for the Multi-label prediction of Drug-Drug Interactions. deepMDDI contains an encoder derived from relational graph convolutional networks and a tensor-like decoder to uniformly model interactions. deepMDDI is not only efficient for DDI transductive prediction, but also inductive prediction. The experimental results show that our model is superior to other state-of-the-art deep learning-based methods. We also validated the power of deepMDDI in the DDIs multi-label prediction and found several new valid DDIs in the case study. In conclusion, deepMDDI is beneficial to uncover the mechanism and regularity of DDIs.

Intraperitoneal siRNA Nanoparticles for Augmentation of Gemcitabine Efficacy in the Treatment of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma is a deadly disease with limited treatment options due to late diagnosis and resistance to conventional chemotherapy. Among emerging therapeutic targets, the CXCR4 chemokine receptor and polo-like kinase 1 (PLK1) play critical roles in the progression, metastasis, and chemoresistance of pancreatic cancer. Here, we tested the hypothesis that combining CXCR4 inhibition by a polymeric CXCR4 antagonist PAMD-CHOL with PLK1 knockdown by siRNA will enhance the therapeutic effect of gemcitabine (GEM) in the orthotopic model of metastatic pancreatic cancer. We formulated nanoparticles with cholesterol-modified PAMD and siPLK1 and found strong synergism when combined with GEM treatment in vitro in both murine and human pancreatic cancer cell lines. The biodistribution of the nanoparticles in orthotopic pancreatic cancer models revealed strong accumulation in primary and metastatic tumors, with limited hepatic disposition. The cholesterol-containing nanoparticles showed not only increased tumor accumulation than the cholesterol-lacking control but also deeper penetration into the tumors. In a therapeutic study in vivo, the triple combination of PAMD-CHOL/siPLK1 and GEM showed superior anticancer activity when compared with single and dual combination controls. In conclusion, PAMD-CHOL/siPLK1 nanoparticles synergistically enhance anticancer activity of GEM in pancreatic cancer and represent a promising addition to the treatment arsenal.

Abnormal Acoustic Features Following Pharyngeal Flap Surgery in Patients Aged Six Years and Older.

In our study, older velopharyngeal insufficiency (posterior velopharyngeal insufficiency) patients were defined as those older than 6 years of age. This study aimed to evaluate the abnormal acoustic features of older velopharyngeal insufficiency patients before and after posterior pharyngeal flap surgery. A retrospective medical record review was conducted for patients aged 6 years and older, who underwent posterior pharyngeal flap surgery between November 2011 and March 2015. The audio records of patients were evaluated before and after surgery. Spectral analysis was conducted by the Computer Speech Lab (CSL)-4150B acoustic system with the following input data: The vowel /i/, unaspirated plosive /b/, aspirated plosives /p/, aspirated fricatives /s/ and /x/, unaspirated affricates /j/ and /z/, and aspirated affricates /c/ and /q/. The patients were followed up for 3 months. Speech outcome was evaluated by comparing the postoperatively phonetic data with preoperative data. Subjective and objective analyses showed significant differences in the sonogram, formant, and speech articulation before and after the posterior pharyngeal flap surgery. However, the sampled patients could not be considered to have a high speech articulation (<85%) as the normal value was above or equal to 96%. Our results showed that pharyngeal flap surgery could correct the speech function of older patients with posterior velopharyngeal insufficiency to some extent. Owing to the original errors in pronunciation patterns, pathological speech articulation still existed, and speech treatment is required in the future.

Fluorometric Detection of Thiamine Based on Hemoglobin-Cu3(PO4)2 Nanoflowers (NFs) with Peroxidase Mimetic Activity.

Component analysis plays an important role in food production, pharmaceutics and agriculture. Nanozymes have attracted wide attention in analytical applications for their enzyme-like properties. In this work, a fluorometric method is described for the determination of thiamine (TH) (vitamin B1) based on hemoglobin-Cu3(PO4)2 nanoflowers (Hb-Cu3(PO4)2 NFs) with peroxidase-like properties. The Hb-Cu3(PO4)2 NFs catalyzed the decomposition of H2O2 into ·OH radicals in an alkaline solution that could efficiently react with nonfluorescent thiamine to fluoresce thiochrome. The fluorescence of thiochrome was further enhanced with a nonionic surfactant, Tween 80. Under optimal reaction conditions, the linear range for thiamine was from 5 × 10-8 to 5 × 10-5 mol/L. The correlation coefficient for the calibration curve and the limit of detection (LOD) were 0.9972 and 4.8 × 10-8 mol/L, respectively. The other vitamins did not bring about any obvious changes in fluorescence. The developed method based on hybrid nanoflowers is specific, pragmatically simple and sensitive, and has potential for application in thiamine detection.

Safflower polysaccharide inhibits the development of tongue squamous cell carcinoma.

BACKGROUND: Safflower polysaccharide (SPS) is one of the most important active components of safflower (Carthamus tinctorius L.), which has been confirmed to have the immune-regulatory function and antitumor effect. This study aimed to explore the effects of safflower polysaccharide (SPS) on tongue squamous cell carcinoma (TSCC). METHODS: HN-6 cells were treated with 5 µg/mL cisplatin and various concentrations of SPS (0, 0.02, 0.04, 0.08, 0.16, 0.32, 0.64, and 1.28 mg/mL), and cell proliferation was measured. After treatment with 5 µg/mL cisplatin and 0.64 mg/mL SPS, the induction of apoptosis and the protein and mRNA expression of Bax, Bcl-2, COX-2, and cleaved caspase-3 in HN-6 cells were quantified. In addition, HN-6 cells were implanted into mice to establish an in vivo tumor xenograft model. Animals were randomly assigned to three groups: SPS treatment, cisplatin treatment, and the model group (no treatment). The body weight, tumor volume, and tumor weight were measured, and the expression of the above molecules was determined. RESULTS: SPS treatment (0.02-0.64 mg/mL) for 24-72 h inhibited HN-6 cell proliferation. In addition, 0.64 mg/mL SFP markedly induced apoptosis in HN-6 cells and arrested the cell cycle at the G0/G1 phase. Compared with the control group, the expression of Bcl-2 and COX-2 was markedly reduced by SPS treatment, whereas the expression of Bax and cleaved caspase-3 was increased. Moreover, SPS significantly inhibited the growth of the tumor xenograft, with similar changes in the expression of Bcl-2, COX-2, Bax, and cleaved caspase-3 in the tumor xenograft to the in vitro analysis. CONCLUSIONS: Our results indicated that SPS may inhibit TSCC development through regulation of Bcl-2, COX-2, Bax, and cleaved caspase-3 expression.

AdversaFlow: Visual Red Teaming for Large Language Models with Multi-Level Adversarial Flow.

Large Language Models (LLMs) are powerful but also raise significant security concerns, particularly regarding the harm they can cause, such as generating fake news that manipulates public opinion on social media and providing responses to unethical activities. Traditional red teaming approaches for identifying AI vulnerabilities rely on manual prompt construction and expertise. This paper introduces AdversaFlow, a novel visual analytics system designed to enhance LLM security against adversarial attacks through human-AI collaboration. AdversaFlow involves adversarial training between a target model and a red model, featuring unique multi-level adversarial flow and fluctuation path visualizations. These features provide insights into adversarial dynamics and LLM robustness, enabling experts to identify and mitigate vulnerabilities effectively. We present quantitative evaluations and case studies validating our system's utility and offering insights for future AI security solutions. Our method can enhance LLM security, supporting downstream scenarios like social media regulation by enabling more effective detection, monitoring, and mitigation of harmful content and behaviors.

The important role of the Wnt/ß-catenin signaling pathway in small molecules mediated gingival mesenchymal stem cells transdifferentiate into neuron-like cells.

OBJECTIVE: Given their neural crest origin, gingival mesenchymal stem cells (GMSCs) possess high neurogenic potential, which makes them suitable for cell replacement therapy against neurodegenerative diseases. This study investigated whether GMSCs can be transdifferentiated into neurons in vitro using a protocol involving small molecules VCRFY (VPA, CHIR99021, Repsox, Forskolin, and Y-27632). The regulatory mechanisms of key signaling pathways were also investigated. METHODS: Neuronal induction of GMSCs was conducted using a small molecules-based protocol over 7 days, which included the evaluation of cell morphology, proliferation, expressions of neurogenic markers, and intracellular calcium oscillation. The activation of canonical the Wnt signaling pathway was assessed by examining the protein content and subcellular localization of ß-catenin. RESULTS: Small molecules-treated GMSCs displayed neuronal morphology and increased expression of neurogenic markers, including class III beta-tubulin (TUJ1), neuron-specific enolase (NSE), microtube-associated protein 2 (MAP2), and neurofilament medium (NFM), verified through RT-qPCR, western blotting, and immunocytochemistry. Based on the results of Fluo-4 AM calcium flux assay, small molecules-treated GMSCs exhibited enhanced electrophysiological activity. GMSC proliferation halted after 2 days of treatment. Among the small molecules, CHIR99021 exhibited the highest neuronal induction efficiency. Furthermore, activation of the Wnt/ß-catenin signaling pathway augmented neuronal differentiation. CONCLUSIONS: Small molecule-based cellular reprogramming can efficiently generate neurons from GMSCs, with Wnt/ß-catenin signaling to play a critical role in neuronal induction.

Establishment and application of TaqMan real-time PCR method for detection of Theileria annulata resistant to buparvaquone.

Tropical theileriosis is a tick-borne disease that caused by Theileria annulata, and leads to substantial economic impact in endemic area. Distinguishes to other piroplasms, Theileria is the only eukaryotic parasite could transform mammalian leukocytes. At present, buparvaquone is the most effective drug used for treatment of Theileria infection. However, frequently reported of failure treatment with buparvaquone for some T. annulata isolates. Mutation of TaPIN1 was reported to be the direct reason for failure of buparvaquone treatment. Through in vitro culture, a T. annulata isolate with a TaPIN1 mutation that is similar to the reported strain was recently identified in China. In order to understand the distribution of Theileria with mutation of TaPIN1 in China, here we developed a TaqMan probe-based real-time PCR technology to detect the mutated TaPIN1 gene. The specificity, sensitivity and reproducibility of the established TaqMan Real-time PCR method were evaluated, and field cattle blood samples collected from Xinjiang Uyghur Autonomous Region were used to test its application. Among 1683 samples, 335 samples were confirmed positive for T. annulata by traditional PCR method and 34 samples were positive for buparvaquone-resistant. The TaPIN1 gene of those 34 samples was sequenced and analyzed with the published gene sequences from NCBI database. The results showed that the sequence obtained from the present study has good consistency with those published sequences. In conclusion, the TaqMan probe-based real-time PCR targeting T. annulata mutated TaPIN1 gene was successfully established and can be used to detect clinical samples to investigation of buparvaquone-resistant parasites in Xinjiang region quickly and accurately, which will be useful for guiding clinical medicine application.

IL-21-armored B7H3 CAR-iNKT cells exert potent antitumor effects.

CD1d-restricted invariant NKT (iNKT) cells play a critical role in tumor immunity. However, the scarcity and limited persistence restricts their development and clinical application. Here, we demonstrated that iNKT cells could be efficiently expanded using modified cytokines combination from peripheral blood mononuclear cells. Introduction of IL-21 significantly increased the frequency of CD62L-positive memory-like iNKT cells. iNKT cells armoring with B7H3-targeting second generation CAR and IL-21 showed potent tumor cell killing activity. Moreover, co-expression of IL-21 promoted the activation of Stat3 signaling and reduced the expression of exhaustion markers in CAR-iNKT cells in vitro. Most importantly, IL-21-arming significantly prolonged B7H3 CAR-iNKT cell proliferation and survival in vivo, thus improving their therapeutic efficacy in mouse renal cancer xerograph models without observed cytokine-related adverse events. In summary, these results suggest that B7H3 CAR-iNKT armored with IL-21 is a promising therapeutic strategy for cancer treatment.

Developing a Machine-Learning Prediction Model for Infliximab Response in Crohn's Disease: Integrating Clinical Characteristics and Longitudinal Laboratory Trends.

BACKGROUND: Achieving long-term clinical remission in Crohn's disease (CD) with antitumor necrosis factor α (anti-TNF-α) agents remains challenging. AIMS: This study aims to establish a prediction model based on patients' clinical characteristics using a machine-learning approach to predict the long-term efficacy of infliximab (IFX). METHODS: Three cohorts comprising 746 patients with CD were included from 3 inflammatory bowel disease (IBD) centers between June 2013 and January 2022. Clinical records were collected from baseline, 14-, 30-, and 52-week post-IFX treatment. Three machine-learning approaches were employed to develop predictive models based on 23 baseline predictors. The SHapley Additive exPlanations (SHAP) algorithm was used to dissect underlying predictors, and latent class mixed model (LCMM) was applied for trajectory analysis of the longitudinal change of blood routine tests along with long-term IFX therapy. RESULTS: The XGBoost model exhibited the best discrimination between long-term responders and nonresponders. In the internal training and testing set, the model achieved an AUC of 0.91 (95% CI, 0.86-0.95) and 0.71 (95% CI, 0.66-0.87), respectively. Moreover, it achieved a moderate predictive performance in the independent external cohort, with an AUC of 0.68 (95% CI, 0.59-0.77). The SHAP algorithm revealed disease-relevant laboratory measurements, notably hemoglobin (HB), white blood cells (WBC), erythrocyte sedimentation rate (ESR), albumin (ALB), and platelets (PLT), alongside age at diagnosis and the Montreal classification, as the most influential predictors. Furthermore, 2 distinct patient clusters based on dynamic laboratory tests were identified for monitoring the long-term remission. CONCLUSIONS: The established prediction model demonstrated remarkable discriminatory power in distinguishing long-term responders from nonresponders to IFX therapy. The identification of distinct patient clusters further emphasizes the need for tailored therapeutic approaches in CD management.

The study developed a machine-learning model using clinical data to predict long-term efficacy of IFX in Crohn's disease. The XGBoost model demonstrated strong discriminatory power, revealing influential predictors and distinct patient clusters, emphasizing the importance of tailored therapeutic approaches in CD management.

Targeting immunosenescence for improved tumor immunotherapy.

Tumor immunotherapy has significantly transformed the field of oncology over the past decade. An optimal tumor immunotherapy would ideally elicit robust innate and adaptive immune responses within tumor immune microenvironment (TIME). Unfortunately, immune system experiences functional decline with chronological age, a process termed "immunosenescence," which contributes to impaired immune responses against pathogens, suboptimal vaccination outcomes, and heightened vulnerability to various diseases, including cancer. In this context, we will elucidate hallmarks and molecular mechanisms underlying immunosenescence, detailing alterations in immunosenescence at molecular, cellular, organ, and disease levels. The role of immunosenescence in tumorigenesis and senescence-related extracellular matrix (ECM) has also been addressed. Recognizing that immunosenescence is a dynamic process influenced by various factors, we will evaluate treatment strategies targeting hallmarks and molecular mechanisms, as well as methods for immune cell, organ restoration, and present emerging approaches in immunosenescence for tumor immunotherapy. The overarching goal of immunosenescence research is to prevent tumor development, recurrence, and metastasis, ultimately improving patient prognosis. Our review aims to reveal latest advancements and prospective directions in the field of immunosenescence research, offering a theoretical basis for development of practical anti-immunosenescence and anti-tumor strategies.

Deterministic full-scenario analysis for maximum credible earthquake hazards.

Great earthquakes are one of the major threats to modern society due to their great destructive power and unpredictability. The maximum credible earthquake (MCE) for a specific fault, i.e., the largest magnitude earthquake that may occur there, has numerous potential scenarios with different source processes, making the future seismic hazard highly uncertain. We propose a full-scenario analysis method to evaluate the MCE hazards with deterministic broadband simulations of numerous scenarios. The full-scenario analysis is achieved by considering all uncertainties of potential future earthquakes with sufficient scenarios. Here we show an application of this method in the seismic hazard analysis for the Xiluodu dam in China by simulating 22,000,000 MCE scenarios in 0-10 Hz. The proposed method can provide arbitrary intensity measures, ground-motion time series, and spatial ground-motion fields for all hazard levels, which enables more realistic and accurate MCE hazard evaluations, and thus has great application potential in earthquake engineering.

Methyl jasmonate and selenium synergistically mitigative cadmium toxicity in hot pepper (Capsicum annuum L.) plants by improving antioxidase activities and reducing Cd accumulation.

Methyl jasmonate (MeJA) or selenium (Se)-mediated response to cadmium (Cd) stress in plant has been widely reported, but the combined effects both on plant growth in response to Cd stress and the underlying mechanisms remain obscure. Here, we showed the combined effects of MeJA (2.5 µM) and Se (7 µM) on hot pepper growth under Cd stress (CdCl2, 5 µM). The results showed Cd suppressed the accumulation of total chlorophyll and carotenoid and reduced the photosynthesis, while it increased the content of endogenous signaling molecules, e.g. nitric oxide (NO) and hydrogen peroxide (H2O2), as well as Cd content in leaves. The combined application of MeJA and Se significantly decreased the malondialdehyde (MDA) accumulation and improved the activities of antioxidant enzymes (AOEs, e.g. SOD and CAT) and defense-related enzymes (DREs, POD and PAL). Additionally, the synergistic application of MeJA and Se also obviously improved photosynthesis in hot pepper plants under Cd stress compared with those treated with MeJA or Se respectively or not. Moreover, the treatment of MeJA associated with Se also effectively reduced the Cd accumulation in hot pepper leaves under Cd stress compared with the plants treated with MeJA or Se separately, which implied a potentially synergistic role of MeJA and Se in alleviating Cd toxicity in hot pepper plants. This study provides a theoretical reference for the further analysis of the molecular mechanism of MeJA and Se in jointly mediating the response to heavy metals in plants.

Gastrointestinal injury induced by immunomodulators: A review article.

An increasing number of immunomodulators, either anti-inflammatory or immunity-enhancing, have brought about a revolutionary effect in the management of a variety of autoimmune disorders and malignancies. However, their ability to cause gastrointestinal (GI) injury and induce GI symptoms has been increasingly and unexpectedly recognized. GI injury associated with immunomodulators may demonstrate various histologic and endoscopic patterns. Optimal diagnosis and treatment require a multidisciplinary approach. This review aims to provide an overview of the literature on its pathogenesis, the clinical, endoscopic, and histologic features, and suggested approaches to manage these newly recognized immunomodulator-induced GI adverse effects (AEs). We also reviewed current biomarkers predictive of GI toxicity and potential risk factors to identify susceptible patients. In addition, these immune-mediated AEs were compared with inflammatory bowel disease, a well-documented form of inflammation-driven GI injury. We hope this review will raise awareness and vigilance among clinicians of these entities to increase early diagnosis and rapid referral to specialist care.

A boronate-based modular assembly nanosystem to block the undesirable crosstalk between hepatic stellate cells and Kupffer cells.

Crosstalk between Kupffer cells (KCs) and hepatic stellate cells (HSCs) plays an important role in multiple liver disease conditions, including the formation of liver fibrosis in alcohol-associated liver disease (AALD). Therapeutic targeting of the KC-HSC crosstalk is a prime target for therapeutic interventions. Herein, a novel modular nanosystem was designed and prepared through the self-assembly utilizing boric acid and catechol interactions to prepare polymers modified with a CXCR4-inhibiting moieties. The polymers were used to encapsulate anti-miR-155 and to block the undesirable crosstalk between HSCs and KCs by downregulating miR-155 expression in KCs with the parallel inhibition of CXCR4 signaling in activated HSCs. The combined inhibition of miR-155 and CXCR4 at two different liver cell types achieved improved antifibrosis effects in a mouse model of AALD fibrosis. Our finding highlights the key role that blocking the undesirable crosstalk between HSCs and KCs plays in reversing AALD fibrosis as well as demonstrates a proof-of-concept approach for designing and constructing multifunctional delivery nanosystems using orthogonal functional modules based on the understanding of disease mechanisms.

Enhanced electron beam and X-ray beam therapy by applying nanoparticle heterojunctions: A Monte Carlo simulation.

Cancer has become one of the major diseases that seriously threaten human health. In order to improve the therapeutic gain ratio (TGF) of conventional X-ray and electron beams, we studied the dose enhancement effect and secondary electrons emission of Au-Fe nanoparticle heterostructures by Monte Carlo method. Under the irradiation of 6 MeV photon and 6 MeV electron beams, the Au-Fe mixture has a dose enhancement effect. For this reason, we explored the secondary electrons production that leads to dose enhancement. For 6 MeV electron beam irradiation, Au-Fe nanoparticle heterojunctions have an higher electrons emission than Au and Fe nanoparticles. When cubic, spherical and cylindrical heterogeneous structures are considered, the electron emission of the columnar Au-Fe nanoparticles is the highest, with a maximum value of 0.00024. For 6 MV X-ray beam irradiation, Au nanoparticle and Au-Fe nanoparticle heterojunction have similar electrons emission, while Fe nanoparticle has the lowest one. When cubic, spherical and cylindrical heterogeneous structures are considered, the electron emission of the columnar Au-Fe nanoparticles is the highest, with a maximum value of 0.000118. This study contributes to improve the tumor-killing effect of conventional X-ray radiotherapy treatment and has guiding significance for the research of new nanoparticles.

980 nm Photobiomodulation Promotes Osteo/Odontogenic Differentiation of the Stem Cells from Human Exfoliated Deciduous Teeth Via the Cross talk Between BMP/Smad and Wnt/ß-Catenin Signaling Pathways.

Increasing evidence suggests stem cells from human exfoliated deciduous teeth (SHEDs) serve as desirable sources of dentin regeneration. Photobiomodulation (PBM) has shown great potential in enhancing the proliferation and osteogenesis of human bone marrow mesenchymal stem cells (hBMMSCs). However, the specific role of PBM in odontogenic differentiation of SHEDs is little know, and we further investigated potential mechanism of PBM osteo/odontogenisis. A 980 nm diode laser with different energy densities of (0.5, 5, 10 J cm-2 ) in a 100-mW continuous wave was used for irradiation every 24 h. Osteo/odontogenic differentiation of SHEDs was achieved by performing alkaline phosphatase (ALP) and alizarin red staining (ARS) and osteo/odontogenic markers were also evaluated by qRT-PCR and western blotting. Additionally, western blot and immunohistochemical staining were performed to evaluate the levels of BMP/Smad and Wnt/ß-catenin signaling-related proteins. We found that PBM at 5 J cm-1 increased mineral deposition and upregulated the expression of related osteo/odontogenic markers along with the elevated expression of ß-catenin and phosphorylation level of Smad1/5/9. Furthermore, Wnt signaling inhibition using DKK1 and BMP signaling inhibition using noggin inhibited PBM-induced osteo/odontogenic marker expression when used individually or jointly. In conclusion, PBM induces the osteo/odontogenic differentiation of SHEDs through cross talk between BMP/Smad and Wnt/ß-catenin signaling pathways.