LRG1 Contributes to the Pathogenesis of Multiple Kidney Diseases: A Comprehensive Review.

Background: The increasing prevalence of kidney diseases has become a significant public health issue, with a global prevalence exceeding 10%. In order to accurately identify biochemical changes and treatment outcomes associated with kidney diseases, novel methods targeting specific genes have been discovered. Among these genes, leucine-rich α-2 glycoprotein 1 (LRG1) has been identified to function as a multifunctional pathogenic signaling molecule in multiple diseases, including kidney diseases. This study aims to provide a comprehensive overview of the current evidence regarding the roles of LRG1 in different types of kidney diseases. Summary: Based on a comprehensive review, it was found that LRG1 was upregulated in the urine, serum, or renal tissues of patients or experimental animal models with multiple kidney diseases, such as diabetic nephropathy, kidney injury, IgA nephropathy, chronic kidney diseases, clear cell renal cell carcinoma, end-stage renal disease, canine leishmaniosis-induced kidney disease, kidney fibrosis, and aristolochic acid nephropathy. Mechanistically, the role of LRG1 in kidney diseases is believed to be detrimental, potentially through its regulation of various genes and signaling cascades, i.e., fibronectin 1, GPR56, vascular endothelial growth factor (VEGF), VEGFR-2, death receptor 5, GDF15, HIF-1α, SPP1, activin receptor-like kinase 1-Smad1/5/8, NLRP3-IL-1b, and transforming growth factor ß pathway. Key Messages: Further research is needed to fully comprehend the molecular mechanisms by which LRG1 contributes to the pathogenesis and pathophysiology of kidney diseases. It is anticipated that targeted treatments focusing on LRG1 will be utilized in clinical trials and implemented in clinical practice in the future.

Large-scale genome-wide association studies reveal the genetic causal etiology between air pollutants and autoimmune diseases.

BACKGROUND: Epidemiological evidence links a close correlation between long-term exposure to air pollutants and autoimmune diseases, while the causality remained unknown. METHODS: Two-sample Mendelian randomization (TSMR) was used to investigate the role of PM10, PM2.5, NO2, and NOX (N = 423,796-456,380) in 15 autoimmune diseases (N = 14,890-314,995) using data from large European GWASs including UKB, FINNGEN, IMSGC, and IPSCSG. Multivariable Mendelian randomization (MVMR) was conducted to investigate the direct effect of each air pollutant and the mediating role of common factors, including body mass index (BMI), alcohol consumption, smoking status, and household income. Transcriptome-wide association studies (TWAS), two-step MR, and colocalization analyses were performed to explore underlying mechanisms between air pollution and autoimmune diseases. RESULTS: In TSMR, after correction of multiple testing, hypothyroidism was causally associated with higher exposure to NO2 [odds ratio (OR): 1.37, p = 9.08 × 10-4] and NOX [OR: 1.34, p = 2.86 × 10-3], ulcerative colitis (UC) was causally associated with higher exposure to NOX [OR: 2.24, p = 1.23 × 10-2] and PM2.5 [OR: 2.60, p = 5.96 × 10-3], rheumatoid arthritis was causally associated with higher exposure to NOX [OR: 1.72, p = 1.50 × 10-2], systemic lupus erythematosus was causally associated with higher exposure to NOX [OR: 4.92, p = 6.89 × 10-3], celiac disease was causally associated with lower exposure to NOX [OR: 0.14, p = 6.74 × 10-4] and PM2.5 [OR: 0.17, p = 3.18 × 10-3]. The risky effects of PM2.5 on UC remained significant in MVMR analyses after adjusting for other air pollutants. MVMR revealed several common mediators between air pollutants and autoimmune diseases. Transcriptional analysis identified specific gene transcripts and pathways interconnecting air pollutants and autoimmune diseases. Two-step MR revealed that POR, HSPA1B, and BRD2 might mediate from air pollutants to autoimmune diseases. POR pQTL (rs59882870, PPH4=1.00) strongly colocalized with autoimmune diseases. CONCLUSION: This research underscores the necessity of rigorous air pollutant surveillance within public health studies to curb the prevalence of autoimmune diseases.

A novel intraoperative acetabular reaming center locating method in total hip arthroplasty for Crowe type IV developmental dysplasia of the hip: a retrospective cohort study.

PURPOSE: Although the principles of hip reconstruction are consistent, due to lack of reliable anatomical landmarks, how to decide the acetabular cup reaming centre intraoperatively in Crowe IV patients with developmental dysplasia of the hip (DDH) remains unclear. This study aims to address this question. METHODS: Fifty-eight Crowe IV patients were enrolled from 2017 to 2019. By examining our previous clinical data, we analyzed the anatomical morphology of Crowe IV acetabulum and proposed a method of locating intraoperative reaming centering for implantation of a standard-sized acetabular cup, which is the upper two thirds of the posterior border of the true acetabulum. All patients included in this study were reamed according to this method. The average postoperative follow-up was 4.1 years (3-5 years). The position of the centre of rotation (COR), cup coverage (CC), and optimal range of joint motion (ROM) were examined by 3D computer simulation measurement. Postoperative complications and hip Harris score were collected and analyzed. RESULTS: The morphology of the type IV DDH true acetabulum was mostly triangular. The intraoperative reaming centre were centered on the upper two thirds of the posterior border of the true acetabulum. The postoperative 3D CC was 80.20% ± 7.63% (64.68-90.24%, 44-48-mm cup size). The patients' mean Harris score improved from 39.7 ± 20.4 preoperatively to 91.5 ± 8.12 at the last follow-up. CONCLUSION: Our study demonstrated that satisfactory CC and clinical results could be achieved by implanting a standard-sized cup with the reaming centre on the upper two thirds of the posterior border of the true acetabulum.

METTL3 orchestrates glycolysis by stabilizing the c-Myc/WDR5 complex in triple-negative breast cancer.

BACKGROUND: The carcinogenic transcription factor c-Myc is the most aggressive oncogene, which drive malignant transformation and dissemination of triple-negative breast cancer (TNBC). Recruitment of many cofactors, especially WDR5, a protein that nucleates H3K4me chromatin modifying complexes, play a pivotal role in regulating c-Myc-dependent gene transcription, a critical process for c-Myc signaling to function in a variety of biological and pathological contexts. For this reason, interrupting the interaction between c-Myc and the transcription cofactor WDR5 may become the most promising new strategy for treating c-Myc driven TNBC. METHODS: Immunoprecipitation and mass spectrometry (IP-MS) is used to screen proteins that bind c-Myc/WDR5 interactions. The interaction of METTL3 with c-Myc/WDR5 in breast cancer tissues and TNBC cells was detected by Co-IP and immunofluorescence. Subsequently, we further analyzed the influence of METTL3 expression on c-Myc/WDR5 protein expression and its interaction stability by Western blot and Co-IP. The correlation between METTL3 and c-Myc pathway was analyzed by ChIP-seq sequencing and METTL3 knockdown transcriptome data. The effect of METTL3 expression on c-Myc transcriptional activity was detected by ChIP-qPCR and Dual Luciferase Reporter. At the same time, the overexpression vector METTL3-MUT (m6A) was constructed, which mutated the methyltransferase active site (Aa395-398, DPPW/APPA), and further explored whether the interaction between METTL3 and c-Myc/WDR5 was independent of methyltransferase activity. In addition, we also detected the changes of METTL3 expression on TNBC's sensitivity to small molecule inhibitors such as JQ1 and OICR9429 by CCK8, Transwell and clonal formation assays. Finally, we further verified our conclusions in spontaneous tumor formation mouse MMTV-PyMT and nude mouse orthotopic transplantation tumor models. RESULTS: METTL3 was found to bind mainly to c-Myc/WDR5 protein in the nucleus. It enhances the stability of c-Myc/WDR5 interaction through its methyltransferase independent mechanism, thereby enhancing the transcriptional activity of c-Myc on downstream glucose metabolism genes. Notably, the study also confirmed that METTL3 can directly participate in the transcription of glucose metabolism genes as a transcription factor, and knockdown METTL3 enhances the drug sensitivity of breast cancer cells to small molecule inhibitors JQ1 and OICR9429. The study was further confirmed by spontaneous tumor formation mouse MMTV-PyMT and nude mouse orthotopic transplantation tumor models. CONCLUSION: METTL3 binds to the c-Myc/WDR5 protein complex and promotes glycolysis, which plays a powerful role in promoting TNBC progression. Our findings further broaden our understanding of the role and mechanism of action of METTL3, and may open up new therapeutic avenues for effective treatment of TNBC with high c-Myc expression.

A New Method to Predict Postoperative Stem Anteversion in Total Hip Arthroplasty for Developmental Dysplasia of the Hip.

BACKGROUND: Preoperative evaluation of femoral anteversion to predict postoperative stem anteversion aids the selection of an appropriate prosthesis and optimizes the combined anteversion in total hip arthroplasty (THA) for developmental dysplasia of the hip (DDH). The conventional prediction methods are based on the femoral anteversion measurement at the location of the femoral head and/or neck. However, varied differences between femoral anteversion and postoperative stem anteversion were demonstrated. This study investigated the predictive role of a new method based on the principle of sagittal three-point fixation. METHODS: From January 2017 to December 2018, a total of 133 DDH hips that underwent THA were retrospectively analyzed. There were 76 Crowe type I, 27 type II, and 30 type III hips. The single-wedge stem was used in 49 hips, and the double-wedge stem was used in 84 hips. Preoperative native femoral anteversion at the femoral head-neck junction, anterior cortex anteversion at 2 levels of the lesser trochanter, posterior cortex anteversion at 5 levels of the femoral neck, and postoperative stem anteversion were measured using two-dimensional computed tomography. Predictive anteversion by the new method was calculated as the average anteversion formed by the anterior cortex at the lesser trochanter and the posterior cortex at the femoral neck. RESULTS: For hips with different neck heights, different Crowe types, different stem types, or different femoral anteversions, native femoral anteversion showed widely varied differences and correlations with stem anteversion, with differences ranging from -1.27 ± 8.33° to -13.67 ± 9.47° and correlations ranging from 0.122 (p = 0.705, no correlation) to 0.813. Predictive anteversion formed by the anterior cortex at the lesser trochanter proximal base and posterior cortex 10 mm above the lesser trochanter proximal base showed no significant difference with stem anteversion, with less varied differences (0.92 ± 7.52°) and good to excellent correlations (r = 0.826). CONCLUSION: Adopting our new method, predictive anteversion, measured as the average anteversion of the anterior cortex at the lesser trochanter proximal base and posterior cortex 10 mm above the lesser trochanter proximal base, predicted postoperative stem anteversion more reliably than native femoral anteversion.

Consolidation chemotherapy after definitive concurrent chemoradiotherapy in patients with inoperable esophageal squamous cell carcinoma: a multicenter non-inferiority phase III randomized clinical trial.

BACKGROUND: Definitive concurrent chemoradiotherapy (dCCRT) is the gold standard for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). However, the potential benefits of consolidation chemotherapy after dCCRT in patients with esophageal cancer remain debatable. Prospective randomized controlled trials comparing the outcomes of dCCRT with or without consolidation chemotherapy in patients with ESCC are lacking. In this study, we aim to generate evidence regarding consolidation chemotherapy efficacy in patients with locally advanced, inoperable ESCC. METHODS: This is a multicenter, prospective, open-label, phase-III randomized controlled trial comparing non-inferiority of dCCRT alone to consolidation chemotherapy following dCCRT. In total, 600 patients will be enrolled and randomly assigned in a 1:1 ratio to receive either consolidation chemotherapy after dCCRT (Arm A) or dCCRT alone (Arm B). Overall survival will be the primary endpoint, whereas progression-free survival, locoregional progression-free survival, distant metastasis-free survival, and treatment-related toxicity will be the secondary endpoints. DISCUSSION: This study aid in further understanding the effects of consolidation chemotherapy after dCCRT in patients with locally advanced, inoperable ESCC. TRIAL REGISTRATION: ChiCTR1800017646.

Co-Intercalation-Free Graphite Anode Enabled by an Additive Regulated Interphase in an Ether-Based Electrolyte for Low-Temperature Lithium-Ion Batteries.

Graphite (Gr) anode, which is endowed with high electronic conductivity and low volume expansion after Li-ion intercalation, establishes the basis for the success of rocking-chair Li-ion batteries (LIBs). However, due to the high barrier of the Li-ion desolvation process, sluggish transport of Li ions through the solid electrolyte interphase (SEI) and the high freezing points of electrolytes, the Gr anode still suffers from great loss of capacity and severe polarization at low temperature. Here, 1,2-diethoxyethane (DEE) with an intrinsically wide liquid region and weak solvation ability is applied as an electrolyte solvent for LIBs. By rationally designing the additives of electrolytes, an intact SEI with fast Li-ion conductivity is constructed, enabling the co-intercalation-free Gr anode with long-term stability (91.8% after 500 cycles) and impressive low-temperature characteristics (82.6% capacity retention at -20 °C). Coupled with LiFePO4 and LiNi0.8Mn0.1Co0.1O2 cathodes, the optimized electrolyte also demonstrates low polarization under -20 °C. Our work offers a feasible approach to enable ether-based electrolytes for low-temperature LIBs.

Attention De-sparsification Matters: Inducing diversity in digital pathology representation learning.

We propose DiRL, a Diversity-inducing Representation Learning technique for histopathology imaging. Self-supervised learning (SSL) techniques, such as contrastive and non-contrastive approaches, have been shown to learn rich and effective representations of digitized tissue samples with limited pathologist supervision. Our analysis of vanilla SSL-pretrained models' attention distribution reveals an insightful observation: sparsity in attention, i.e, models tends to localize most of their attention to some prominent patterns in the image. Although attention sparsity can be beneficial in natural images due to these prominent patterns being the object of interest itself, this can be sub-optimal in digital pathology; this is because, unlike natural images, digital pathology scans are not object-centric, but rather a complex phenotype of various spatially intermixed biological components. Inadequate diversification of attention in these complex images could result in crucial information loss. To address this, we leverage cell segmentation to densely extract multiple histopathology-specific representations, and then propose a prior-guided dense pretext task, designed to match the multiple corresponding representations between the views. Through this, the model learns to attend to various components more closely and evenly, thus inducing adequate diversification in attention for capturing context-rich representations. Through quantitative and qualitative analysis on multiple tasks across cancer types, we demonstrate the efficacy of our method and observe that the attention is more globally distributed.

Effects of starch hydration properties on the batter properties and oil absorption of fried crust and battered ham sausages.

Water plays an important role in deep-frying. To assess the effects of water on oil absorption by fried crust and battered ham sausages (FCBHSs), we selected four starch types with different hydration properties: tapioca starch (TS), freeze-thawed tapioca starch (FTS), carboxymethyl tapioca starch (CMTS), and carboxymethyl freeze-thawed tapioca starch (CM-FTS). CMTS had the best hydration properties, followed by CM-FTS, FTS, and TS, respectively. CM-FTS with its medium hydration properties strengthened batter properties which reduced FCBHSs oil absorption. Low-field nuclear magnetic resonance analysis revealed that CM-FTS increased the percentages of bound and semi-bound water in the batter, thereby enhancing water retention and delaying water loss during deep-frying. Analyses of protein particle size distribution, zeta potential, disulfide bonding and microstructure revealed that CM-FTS promotes protein aggregation and the formation of a protein network structure, leading to a denser internal structure, which inhibits oil absorption. Additionally, differential scanning calorimetry analysis indicated that CM-FTS enhances the batter's thermal stability of batter, thereby rendering it more resistant to frying. However, the use of CMTS, with its strong hydration properties increased FCBHSs oil absorption. In conclusion, we propose that suitable modification of starch's hydration properties can aid in preparing deep-fried battered food characterized by low oil absorption.

A multicenter single-arm trial of neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2-positive breast cancer.

The objective of this multicenter, single-arm trial (ChiCTR1900022293) was to explore the efficacy and safety of neoadjuvant therapy with epirubicin, cyclophosphamide, and pyrotinib followed by docetaxel, trastuzumab, and pyrotinib (ECPy-THPy) in the treatment of patients with stage II-III HER2-positive breast cancer. The present study enrolled patients with stage II-III HER2-positive breast cancer. Epirubicin and cyclophosphamide were administrated for four 21-day cycles, followed by four cycles of docetaxel and trastuzumab. Pyrotinib was taken orally once per day throughout the treatment period. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0) rate in the modified intention-to-treat (mITT) population. In total, 175 patients were included. The tpCR rate was 68.6% (95% CI, 60.7-75.8%), while the objective response rate was 89.1%. In the post-hoc subgroup analysis, no association between clinical characteristics and the tpCR rate was observed. The most common grade ≥3 adverse events were diarrhea (54.3%), followed by white blood cell count decreased (5.1%), and neutrophil count decreased (4.6%). In conclusion, the neoadjuvant regimen with ECPy-THPy showed promising pathological response and clinical benefits with an acceptable safety profile in patients with stage II-III HER2-positive breast cancer.

Machine Learning-Assisted Automatically Electrochemical Addressable Cytosensing Arrays for Anticancer Drug Screening.

The high-throughput and accurate screening of anticancer drugs is crucial to the preclinical assessment of candidate drugs and remains challenging. Herein, an automatically electrochemical addressable cytosensor (AEAC) for the efficient screening of anticancer drugs is reported. This sensor consists of sectionalized laser-induced graphene arrays decorated by the rhombohedral TiO2 and spherical Pt nanoparticles (LIG-TiO2-Pt) with high electrocatalytic activity for H2O2 and a homemade Ag/Pt electrode couple fixed onto the robot arm. The immobilization of laminin on the surface of LIG-TiO2-Pt can promote its biocompatibility for the growth and proliferation of various tumor cells, which empowers the in situ monitoring of H2O2 directly released from these live cells for drug screening. A machine learning (ML) algorithm is employed to eliminate the possible random or systematic errors of AEAC, realizing rapid, high-throughput, and accurate prediction of different types of anticancer drugs. This ML-assisted AEAC provides a powerful approach to accelerate the evolution of sensing-served tumor therapy.

Large-scale genome-wide association study to identify causal relationships and potential mediators between education and autoimmune diseases.

Objectives: Epidemiological studies suggested a potential connection between education and autoimmune disorders. This study investigated the possible cause-and-effect relationship using a Mendelian randomization approach. Methods: We explored the causality between four education traits (n = 257,841~1,131,881) and 22 autoimmune diseases. The mediating role of smoking (632,802 individuals), BMI (681,275 individuals), alcohol (335,394 individuals), and income (397,751 individuals) was also investigated. Transcriptome-wide association study (TWAS) and enriched signaling pathways analysis were used to investigate the underlying biological mechanisms. Results: Especially, higher cognitive performance was protective for psoriasis (odds ratio (OR) = 0.69, 95% confidence interval (CI) = 0.60-0.79, p = 6.12×10-8), rheumatoid arthritis (RA) (OR = 0.75, 95% CI = 0.67-0.83, p = 4.62×10-6), and hypothyroidism (OR = 0.83, 95% CI = 0.77-0.90, p = 9.82×10-6). Higher levels of educational attainment decreased risks of psoriasis (OR = 0.61, 95% CI = 0.52-0.72, p = 1.12×10-9), RA (OR = 0.68, 95% CI = 0.59-0.79, p = 1.56×10-7), and hypothyroidism (OR = 0.80, 95% CI = 0.72-0.88, p = 5.00×10-6). The completion of highest-level math class genetically downregulates the incidence of psoriasis (OR = 0.66, 95% CI = 0.58-0.76, p = 2.47×10-9), RA (OR = 0.71, 95% CI = 0.63-0.81, p = 5.28×10-8), and hypothyroidism (OR = 0.85, 95% CI = 0.79-0.92, p = 8.88×10-5). Higher self-reported math ability showed protective effects on Crohn's disease (CD) (OR = 0.67, 95% CI = 0.55-0.81, p = 4.96×10-5), RA (OR = 0.76, 95% CI = 0.67-0.87, p = 5.21×10-5), and psoriasis (OR = 0.76, 95% CI = 0.65-0.88, p = 4.08×10-4). Protein modification and localization, response to arsenic-containing substances may participate in the genetic association of cognitive performance on UC, RA, psoriasis, and hypothyroidism. According to mediation analyses, BMI, smoking, and income served as significant mediators in the causal connection between educational traits and autoimmune diseases. Conclusion: Higher levels of education-related factors have a protective effect on the risk of several autoimmune disorders. Reducing smoking and BMI and promoting income equality can mitigate health risks associated with low education levels.

Shape-memory sawtooth-arm embracing clamp used in complex femoral revision hip arthroplasty for stem stability: average 9-year follow-up study.

BACKGROUND: Nickel-Titanium shape-memory sawtooth-arm embracing clamps (SSECs) have been used in revision total hip arthroplasties (rTHAs) to protect stem stability. This study was to introduce this technique and report its mid to long-term clinical and radiographic outcomes. METHODS: We retrospectively reviewed all patients implanted with SSECs in our department from January 2008 to December 2015. 41 patients (41 hips) were finally included. Radiographs and Harris hip scores (HHS) were collected. Radiographs were blindly analyzed for evidence of loosening, subsidence and stress shielding. HHS were compared to previous records by student's t tests. The average follow-up period was 9.3 years. RESULTS: All stems were stably fixed with no signs of loosening. The mean stem subsidence was 0.9 mm (range, 0 to 3 mm). Only one patient (2.4%) demonstrated the fourth degree of stress shielding, with the others none or minor bone resorption. The mean HHS at the final follow-up was 84.2 (range, 81 to 91), which was improved from 17.4 (range, 0 to 37) before surgery. No implant failures or re-revisions occurred. Dislocation occurred in 1 case during the follow-up period. CONCLUSIONS: The SSEC protected stem fixation and achieved favorable clinical and radiographic outcomes in this 9-year follow-up study. It offered an additional extramedullary fixation option for surgeons to choose from in treating complex femoral revision arthroplasties.

The apex of the deep cartilage is a stable landmark to position the femoral tunnel during remnant-preserving anterior cruciate ligament reconstruction.

PURPOSE: The aim of this retrospective cohort study was to investigate whether the apex of the deep cartilage (ADC) could help surgeons position the femoral tunnel accurately in remnant-preserving anterior cruciate ligament (ACL) reconstruction (ACLR). METHODS: In the current retrospective cohort study, a total of 134 patients who underwent ACLR between 2016 and 2020 were included. The femoral tunnel position was located using ADC as the landmark. The patients were divided into two groups: the remnant-preserving group (RP group, n = 68) underwent remnant-preserving ACLR, and the nonremnant group (NRP group, n = 66) underwent traditional ACLR with remnant removal. Postoperatively, the femoral tunnel position was evaluated on 3D-CT. The length from the ADC to the shallow cartilage margin (L) and to the centre of the femoral tunnel (l) and the length from the centre of the femoral tunnel to a low cartilage ratio in the direction from high to low (H) were measured. RESULTS: The l/L values of the RP and NRP groups were both 0.4 ± 0.1 after rounding (n.s.), and the H values were 9.3 ± 1.6 mm and 9.3 ± 1.7 mm, respectively (n.s.). There was no significant difference in l/L or H between the two groups. The estimation plot also showed high consistency of H and l/L of the two groups. The inter- and intraobserver reliability of I, L, l/L, and H were almost perfect. CONCLUSIONS: The apex of the deep cartilage is a good landmark for positioning the femoral tunnel in remnant-preserving ACL reconstruction. LEVEL OF EVIDENCE: Level III.

A multi-branch network to detect post-operative complications following hip arthroplasty on X-ray images.

Background: Postoperative complications following total hip arthroplasty (THA) often require revision surgery. X-rays are usually used to detect such complications, but manually identifying the location of the problem and making an accurate assessment can be subjective and time-consuming. Therefore, in this study, we propose a multi-branch network to automatically detect postoperative complications on X-ray images. Methods: We developed a multi-branch network using ResNet as the backbone and two additional branches with a global feature stream and a channel feature stream for extracting features of interest. Additionally, inspired by our domain knowledge, we designed a multi-coefficient class-specific residual attention block to learn the correlations between different complications to improve the performance of the system. Results: Our proposed method achieved state-of-the-art (SOTA) performance in detecting multiple complications, with mean average precision (mAP) and F1 scores of 0.346 and 0.429, respectively. The network also showed excellent performance at identifying aseptic loosening, with recall and precision rates of 0.929 and 0.897, respectively. Ablation experiments were conducted on detecting multiple complications and single complications, as well as internal and external datasets, demonstrating the effectiveness of our proposed modules. Conclusion: Our deep learning method provides an accurate end-to-end solution for detecting postoperative complications following THA.

Nano Self-Assemblies of Caffeic Acid-Fibronectin Mimic a Peptide Conjugate for the Treatment of Corneal Epithelial Injury.

Rapid corneal re-epithelialization is important for corneal wound healing. Corneal epithelial cell motility and oxidative stress are important targets for therapeutic intervention. In this study, we covalently conjugated the antioxidant caffeic acid (CA) with a bioactive peptide sequence (PHSRN) to generate a CA-PHSRN amphiphile, which was formulated into nanoparticular eye drops with an average size of 43.21 ± 16 nm. CA-PHSRN caused minimal cytotoxicity against human corneal epithelial cells (HCECs) and RAW264.7 cells, exhibited an excellent free radical scavenging ability, and remarkably attenuated reactive oxygen species (ROS) levels in H2O2-stimulated HCECs. The antioxidant and anti-inflammatory activities of CA-PHSRN were assessed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The results show that CA-PHSRN treatment effectively prevented LPS-induced DNA damage and significantly reduced the levels of LPS-induced pro-inflammatory cytochemokines (i.e., iNOS, NO, TNF-α, IL-6, and COX-2) in a dose-dependent manner. Moreover, using a rabbit corneal epithelial ex vivo migration assay, we demonstrated that the proposed CA-PHSRN accelerated corneal epithelial cell migration and exhibited high ocular tolerance and ocular bioavailability after topical instillation. Taken together, the proposed CA-PHSRN nanoparticular eye drops are a promising therapeutic formulation for the treatment of corneal epithelial injury.

Translational Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Oxaliplatin and Irinotecan in Colorectal Cancer.

Despite the recent advances in this field, there are limited methods for translating organoid-based study results to clinical response. The goal of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model to facilitate the translation, using oxaliplatin and irinotecan treatments with colorectal cancer (CRC) as examples. The PK models were developed using qualified oxaliplatin and irinotecan PK data from the literature. The PD models were developed based on antitumor efficacy data of SN-38 and oxaliplatin evaluated in vitro using tumor organoids. To predict the clinical response, translational scaling of the models was established by incorporating predicted ultrafiltration platinum in plasma or SN-38 in tumors to PD models as the driver of efficacy. The final PK/PD model can predict PK profiles and responses following treatments with oxaliplatin or irinotecan. After generation of virtual patient cohorts, this model simulated their tumor shrinkages following treatments, which were used in analyzing the efficacies of the two treatments. Consistent with the published clinical trials, the model simulation suggested similar patient responses following the treatments of oxaliplatin and irinotecan with regards to the probabilities of progression-free survival (HR = 1.05, 95%CI [0.97;1.15]) and the objective response rate (OR = 1.15, 95%CI [1.00;1.32]). This proposed translational PK/PD modeling approach provides a significant tool for predicting clinical responses of different agents, which may help decision-making in drug development and guide clinical trial design.

IGF2BP2-modified UBE2D1 interacts with Smad2/3 to promote the progression of breast cancer.

Recent studies have suggested that ubiquitin-conjugating enzyme E2D1 (UBE2D1) is involved in tumor progression. In this study, we found that UBE2D1 expression was upregulated in breast cancer (BC) and was related to the prognosis of BC patients. Through in vitro and in vivo experiments, we demonstrated the aberrant expression of UBE2D1 promoted the proliferation and migration of BC cells, and the IGF2BP2-mediated N6-methyladenosine (m6A) modification increased the stability of UBE2D1 mRNA. Mechanistically, UBE2D1 expression regulated the activity of TGF-ß signaling through modulating the expression and the phosphorylation level of Smad2/3. Furthermore, UBE2D1 directly bound to Smad2/3 and affected the subsequent binding of Smad2 and Smad3, which is a necessary step for TGF-ß signaling activation. Thus, our study reveals a pro-oncogenic role of UBE2D1 in the progression of BC and may provide novel strategies for BC treatment.

Mettl3 synergistically regulates TGF-ß/SMAD2/3 to promote proliferation and metastasis of gastric cancer.

Transforming Growth factor-ß (TGF-ß)/Smad signaling is a complex regulatory network that both inhibits and promotes tumorigenesis. However, the mechanisms underlying the function of TGF-ß/Smad signaling pathway remain to be fully elucidated. As a methyltransferase, METTL3 is closely related to tumor development, but the role of METTL3 in the proliferation and metastasis of TGF-ß/Smad-activated gastric cancer (GC) is unclear. In this study, we identified TGF-ß/Smad2/3 axis as an important carcinogenic pathway in GC, which significantly promoted the proliferation and metastasis of GC. Furthermore, we found that Smad3 mRNA could be modified by m6A, which was subsequently recognized and stabilized by IGF2BP2, thereby enhancing Smad3 protein expression and promoting the activation of TGF-ß/Smad pathway. Importantly, we also found that METTL3 could combine with p-Smad3 to regulate the transcription of downstream target genes. Therefore, this study revealed a novel mechanism by which METTL3 synergistically regulates TGF-ß/Smad2/3 signaling and provide a new potential therapeutic target for the treatment of GC.