Applications of Graphene Family Nanomaterials in Regenerative Medicine: Recent Advances, Challenges, and Future Perspectives.

Graphene family nanomaterials (GFNs) have attracted considerable attention in diverse fields from engineering and electronics to biomedical applications because of their distinctive physicochemical properties such as large specific surface area, high mechanical strength, and favorable hydrophilic nature. Moreover, GFNs have demonstrated the ability to create an anti-inflammatory environment and exhibit antibacterial effects. Consequently, these materials hold immense potential in facilitating cell adhesion, proliferation, and differentiation, further promoting the repair and regeneration of various tissues, including bone, nerve, oral, myocardial, and vascular tissues. Note that challenges still persist in current applications, including concerns regarding biosecurity risks, inadequate adhesion performance, and unsuitable degradability as matrix materials. This review provides a comprehensive overview of current advancements in the utilization of GFNs in regenerative medicine, as well as their molecular mechanism and signaling targets in facilitating tissue repair and regeneration. Future research prospects for GFNs, such as potential in promoting ocular tissue regeneration, are also discussed in details. We hope to offer a valuable reference for the clinical application of GFNs in the treatment of bone defects, nerve damage, periodontitis, and atherosclerosis.

Data-Driven Design of Triple-Targeted Protein Nanoprobes for Multiplexed Imaging of Cancer Lymphatic Metastasis.

Targeted imaging of cancer lymphatic metastasis remains challenging due to its highly heterogeneous molecular and phenotypic diversity. Herein, we introduced triple-targeted protein nanoprobes capable of specifically binding to three targets for imaging cancer lymphatic metastasis, through a data-driven design approach combined with a synthetic biology-based assembly strategy. Specifically, to address the diversity of metastatic lymph nodes (LNs), a combination of three targets, including C-X-C motif chemokine receptor 4 (CXCR4), transferrin receptor protein 1 (TfR1) and vascular endothelial growth factor receptor 3 (VEGFR3) was identified, leveraging machine leaning-based bioinformatics analysis and examination of lymphatic metastatic tissues from patients with gastric cancer. Using this identified target combination, ferritin nanocage-based nanoprobes capable of specifically binding to all three targets were designed through the self-assembly of genetically engineered ferritin subunits using a synthetic biology approach. Multiplexed imaging of heterogeneous metastatic LNs using these nanoprobes resulted in approximately 80% binding with heterogeneous tumor cells, which was 60% higher than that of single-targeted nanoprobes in a polyclonal lymphatic metastasis animal model. In 19 freshly resected human gastric specimens, the signal from the triple-targeted nanoprobes significantly differentiated metastatic LNs from benign LNs, in high accordance with pathological examination. This study not only provides an effective nanoprobe for imaging highly heterogeneous lymphatic metastasis but also proposes a potential strategy for guiding the design of targeted nanomedicines for cancer lymphatic metastasis. This article is protected by copyright. All rights reserved.

Type X collagen knockdown inactivate ITGB1/PI3K/AKT to suppress chronic unpredictable mild stress-stimulated triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer, has a poor prognosis and limited access to efficient targeted treatments. Chronic unpredictable mild stress (CUMS) is highly risk factor for TNBC occurrence and development. Type X collagen (COL10A1), a crucial protein component of the extracellular matrix, ranks second among all aberrantly expressed genes in TNBC, and it is significantly up-regulated under CUMS. Nevertheless, the impact of CUMS and COL10A1 on TNBC, along with the underlying mechanisms are still unclear. In this research, we studied the effect of CUMS-induced norepinephrine (NE) elevation on TNBC, and uncovered that it notably enhanced TNBC cell proliferation, migration, and invasion in vitro, and also fostering tumor growth and lung metastasis in vivo. Additionally, our investigation found that COL10A1 directly interacted with integrin subunit beta 1 (ITGB1), then activates the downstream PI3K/AKT signaling pathway, thereby promoting TNBC growth and metastasis, while it was reversed by knocking down of COL10A1 or ITGB1. Our study demonstrated that the TNBC could respond to CUMS, and advocate for COL10A1 as a pivotal therapeutic target in TNBC treatment.

Graphitized Carbon-Supported Co@Co3O4 for Ozone Decomposition over the Entire Humidity Range.

Ground-level ozone (O3) pollution has emerged as a significant concern due to its detrimental effects on human health and the ecosystem. Catalytic removal of O3 has proven to be the most efficient and cost-effective method. However, its practical application faces substantial challenges, particularly in relation to its effectiveness across the entire humidity range. Herein, we proposed a novel strategy termed "dual active sites" by employing graphitized carbon-loaded core-shell cobalt catalysts (Co@Co3O4-C). Co@Co3O4-C was synthesized via the pyrolysis of a Co-organic ligand as the precursor. By utilizing this approach, we achieved a nearly constant 100% working efficiency of the Co@Co3O4-C catalyst for catalyzing O3 decomposition across the entire humidity range. Physicochemical characterization coupled with density functional theory calculations elucidates that the presence of encapsulated metallic Co nanoparticles enhances the reactivity of the cobalt oxide capping layer. Additionally, the interface carbon atom, strongly influenced by adjacent metallic Co nuclei, functions as a secondary active site for the decomposition of O3 decomposition. The utilization of dual active sites effectively mitigates the competitive adsorption of H2O molecules, thus isolating them for adsorption in the cobalt oxide capping layer. This optimized configuration allows for the decomposition of O3 without interference from moisture. Furthermore, O3 decomposition monolithic catalysts were synthesized using a material extrusion-based three-dimensional (3D) printing technology, which demonstrated a low pressure drop and exceptional mechanical strength. This work provides a "dual active site" strategy for the O3 decomposition reaction, realizing O3 catalytic decomposition over the entire humidity range.

Energy use in residential buildings for sustainable development: The fifth Solar Decathlon Europe revelations.

This research focuses on achieving sustainable development in residential buildings with energy use. Under the influence of the energy crisis and related problems, research on residential buildings for less energy use has great potential. The literature review, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses, and including VOSviewer analysis, shows the research is increasing and meaningful. Solar Decathlon buildings are used as the main objects in this research. The fifth Solar Decathlon Europe energy use technologies are examined through onsite investigation and online searching. The Analytic Hierarchy Process method for multi-criteria decision analysis is used for sustainability assessment. Moreover, the Ladybug and ClimateStudio plugins simulated respectively the annual solar radiation and the best angle for receiving it. The main findings show that 34 kinds of technologies used in these buildings can be classified into two categories in three directions. Passive technologies should be applied and prioritized, but generating renewable energy is also important. Some infrequently used technologies are not insignificant. The research shows that the combination of technologies decides sustainability performance, but the quantity used does not. Furthermore, energy use also needs to be balanced and coordinated in combination with architectural aesthetics. This research on energy use in residential buildings is beneficial for achieving sustainable development.

Interleukin-19 in Bone Marrow Contributes to Bone Loss Via Suppressing Osteogenic Differentiation Potential of BMSCs in Old Mice.

BACKGROUND: Cellular senescence is an important process related to the pathogenic mechanism of different disorders, especially bone loss. During senescence, bone marrow stromal cells (BMSCs) lose their self-renewal and functional differentiation abilities. Therefore, finding signals opposing the osteogenic differentiation of BMSCs within bone marrow microenvironment is the important for elucidating these above-mentioned mechanisms. Inflammatory cytokines affect bone physiology and remodeling. However, the function of interleukin-19 (IL-19) in skeletal system remains unclear. METHODS: The mouse model of IL-19 knockout was established through embryonic stem cell injection for analyzing how IL-19 affected bone formation. Micro-CT examinations were performed to evaluate bone microstructures. We performed a three-point bending test to measure bone stiffness and the ultimate force. Antibody arrays were performed to detect interleukin family members in bone marrow aspirates. BMSCs were cultured and induced for osteogenic differentiation. RESULTS: According to our findings, there was increased IL-19 accumulation within bone marrow in old mice relative to that in their young counterparts, resulting in bone loss via the inhibition of BMSCs osteogenic differentiation. Among Wnt/ß-catenin pathway members, IL-19 strongly upregulated sFRP1 via STAT3 phosphorylation. The inhibition of STAT3 and sFRP1 abolished IL-19's inhibition against the BMSCs osteogenic differentiation. CONCLUSION: To sum up, IL-19 inhibited BMSCs osteogenic differentiation in old mice. Our findings shed novel lights on pathogenic mechanism underlying age-related bone loss and laid a foundation for further research on identifying novel targets to treat senile osteoporosis.

Gestational diabetes mellitus combined with fulminant type 1 diabetes mellitus, four cases of double diabetes: A case report.

BACKGROUND: Fulminant type 1 diabetes mellitus (FT1DM) that occurs during pregnancy or the perinatal period is known as pregnancy-related FT1DM (PF), always without history of abnormal glucose metabolism. Here, we present four patients who developed FT1DM during treatment but were first diagnosed with gestational diabetes mellitus (GDM). CASE SUMMARY: The clinical data of four patients with GDM combined with FT1DM admitted to our hospital between July 2018 and April 2021 were collected, and the patients and their infants were followed up. All patients were diagnosed with GDM during the second trimester and were treated. The blood glucose level elevated suddenly during the third trimester and then were diagnosed with FT1DM. Two patients had an insulin allergy, and two had symptoms of upper respiratory tract infection before onset. One patient developed ketoacidosis, and three developed ketosis. Two patients had cesarean section deliveries, and two had vaginal deliveries. The growth and development of the infants were normal. C-peptide levels were lower than those at onset, suggesting progressive impairment of islet function. The frequencies of the DRB1 09:01, DQB1 03: 03, DQA1 03:02, DPA1 01:03, DPA1 02:02, DPB1 05:01, DRB4 01:03, G 01:01, and G 01:04 human leukocyte antigen (HLA)-G alleles were high in the present study. CONCLUSION: In comparison with pregnancy-associated FT1DM (PF), patients with GDM combined with FT1DM had an older age of onset, higher body mass index, slower onset, fewer prodromal symptoms, and less acidosis. The pathogenesis may be due to various factors affecting the already fragile ß-cells of GDM patients with genetically susceptible class II HLA genotypes. We speculate that GDM combined with FT1DM during pregnancy, referred to as "double diabetes," is a subtype of PF with its own unique characteristics that should be investigated further.

Lactate/GPR81 recruits regulatory T cells by modulating CX3CL1 to promote immune resistance in a highly glycolytic gastric cancer.

Lactate plays an important role in shaping immune tolerance in tumor microenvironment (TME) and correlates with poor prognosis in various solid tumors. Overcoming the immune resistance in an acidic TME may improve the anti-tumor immunity. Here, this study elucidated that via G-protein-coupled receptor 81 (GPR81), lactate could modulate immune tolerance in TME by recruiting regulatory T cells (Tregs) in vitro and in vivo. A high concentration of lactate was detected in cell supernatant and tissues of gastric cancer (GC), which was modulated by lactic dehydrogenase A (LDHA). GPR81 was the natural receptor of lactate and was overexpressed in different GC cell lines and samples, which correlated with poor outcomes in GC patients. Lactate/GPR81 signaling could promote the infiltration of Tregs into TME by inducing the expression of chemokine CX3CL1. GPR81 deficiency could decrease the infiltration of Tregs into TME, thereby inhibiting GC progression by weakening the inhibition of CD8+T cell function in a humanized mouse model. In conclusion, targeting the lactate/GPR81 signaling may potentially serve as a critical process to overcome immune resistance in highly glycolytic GC.

Correction: MiR-4458-loaded gelatin nanospheres target COL11A1 for DDR2/SRC signaling pathway inactivation to suppress the progression of estrogen receptor-positive breast cancer.

Correction for 'MiR-4458-loaded gelatin nanospheres target COL11A1 for DDR2/SRC signaling pathway inactivation to suppress the progression of estrogen receptor-positive breast cancer' by Jie Liu et al., Biomater. Sci., 2022, 10, 4596-4611, https://doi.org/10.1039/D2BM00543C.

High-efficiency antibacterial calcium alginate/lysozyme/AgNPs composite sponge for wound healing.

Infection poses a significant barrier to effective wound repair, leading to increased inflammatory responses that ultimately result in incomplete and prolonged wound healing. To address this challenge, numerous antibacterial ingredients have been incorporated into dressings to inhibit wound infection. Our previous work demonstrated that lysozyme/silver nanoparticles (LYZ/AgNPs) complexes, prepared using an eco-friendly one-step aqueous method, exhibited excellent antibacterial efficacy with favorable biosafety. To further explore its potential application in advancing wound healing, calcium alginate (CA) with good porosity, water absorption, and water retention capacities was formulated with LYZ/AgNPs to prepare composite sponge (CA/LYZ/AgNPs). As expected, in vivo experiments involving full-thickness skin wound and scald wound healing experiments demonstrated that CA-LYZ-AgNPs composite sponges with excellent biocompatibility exhibited remarkable antibacterial activity against gram-positive bacteria, gram-negative bacteria and fungi, and outperformed the wound healing process efficacy of other commercially available AgNPs-loaded wound dressings. In summary, this work introduces a CA/LYZ/AgNPs sponge featuring exceptional antibacterial efficacy and biocompatibility, thus holding promising potential in wound care applications.

Influence of Smoking Habits on the Efficacy of EGFR-TKI Therapy in Patients with Advanced NSCLC: A Systematic Review and Meta-Analysis.

Background: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are considered as the first-line treatment for advanced EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to analyze the efficacy of EGFR-TKIs treatment in patients with advanced NSCLC of different smoking habits. Methods: We conducted a search for meta-analyses and systematic reviews on the PubMed, MEDLINE, Embase, and the Cochrane Library to address this knowledge gap. Patients were divided into 2 groups: (1) experimental group: treated with EGFR-TKIs or EGFR-TKIs combined with chemotherapy, immunotherapy, antiangiogenesis, radiotherapy and (2) control group: treated with chemotherapy. Progressive-free survival (PFS) and total survival (OS) were adopted for evaluating the efficacy of EGFR-TKIs between experimental group and control group. Results: Eleven studies including 6760 patients were included in the meta-analysis. The results showed that smoking (including previous and current smoking) significantly reduces the PFS and OS in comparison to non-smoking group in the treatment of NSCLC with EGFR-TKIs. In addition, EGFR-TKIs combined with anti-vascular endothelial growth factor therapy can reduce the risk of disease progression in smokers. Conclusions: Our study indicated that smoking significantly reduced the PFS and OS in comparison to non-smoking group in the treatment of NSCLC with EGFR-TKIs.

Complete genomic profiles of 1496 Taiwanese reveal curated medical insights.

INTRODUCTION: The population of Taiwan has a long history of ethno-cultural evolution. The Taiwanese population was isolated from other large populations such as the European, Han Chinese, and Japanese population. The Taiwan Biobank (TWB) project has built a nationwide database, particularly for personal whole-genome sequence (WGS) to facilitate basic and clinical collaboration nationally and internationally, making it one of the most valuable public datasets of the East Asian population. OBJECTIVES: This study provides comprehensive medical genomic findings from TWB WGS data, for better characterization of disease susceptibility and the choice of ideal treatment regimens in Taiwanese population. METHODS: We reanalyzed 1496 WGS using a PrecisionFDA Truth challenge winner method Sentieon DNAscope. Single nucleotide variants (SNV) and small insertions/deletions (INDEL) were benchmarked. We also analyzed pharmacogenomic (PGx) drug-associated alleles, and copy number variants (CNV). Multiple practicing clinicians reviewed and curated the clinically significant variants. Variant annotations can be browsed at TaiwanGenomes (https://genomes.tw). RESULTS: We found that each participant had an average of 6,870.7 globally novel variants and 75.3% (831/1103) of the participants harbored at least one PharmGKB-selected high evidence level human leukocyte antigen (HLA) risk allele. 54 PharmGKB-reported high-level instances of evidence of Cytochrome P450 variant-drug pairs, with a population frequency of over 13.2%. We also identified 23 variants in the ACMG secondary finding V3 gene list from 25 participants, suggesting that 1.67% (25/1496) of the population is harboring at least one medical actionable variant. Our carrier status analyses suggest that one in 25 couples (3.94%) would risk having offspring with at least one pathogenic variant, which is in line with rates found in Japan and Singapore. For pathogenic CNV, we detected 6.88% and 2.02% carrier rates for alpha thalassemia and spinal muscular atrophy, respectively. CONCLUSION: Our study highlights the overall medical insights of a complete Taiwanese genomic profile.

Interleukin-19 promotes bone resorption by suppressing osteoprotegerin expression in BMSCs in a lipopolysaccharide-induced bone loss mouse model.

Aims: Osteoporosis is characterized by decreased trabecular bone volume, and microarchitectural deterioration in the medullary cavity. Interleukin-19 (IL-19), a member of the IL-10 family, is an anti-inflammatory cytokine produced primarily by macrophages. The aim of our study was to investigate the effect of IL-19 on osteoporosis. Methods: Blood and femoral bone marrow suspension IL-19 levels were first measured in the lipopolysaccharide (LPS)-induced bone loss model. Small interfering RNA (siRNA) was applied to knock down IL-19 for further validation. Thereafter, osteoclast production was stimulated with IL-19 in combination with mouse macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). The effect of IL-19 was subsequently evaluated using tartrate-resistant acid phosphatase (TRAP) staining and quantitative real-time polymerase chain reaction (RT-qPCR). The effect of IL-19 on osteoprotegerin (OPG) was then assessed using in vitro recombinant IL-19 treatment of primary osteoblasts and MLO-Y4 osteoblast cell line. Finally, transient transfection experiments and chromatin immunoprecipitation (ChIP) experiments were used to examine the exact mechanism of action. Results: In the LPS-induced bone loss mouse model, the levels of IL-19 in peripheral blood serum and femoral bone marrow suspension were significantly increased. The in vivo results indicated that global IL-19 deletion had no significant effect on RANKL content in the serum and bone marrow, but could increase the content of OPG in serum and femoral bone marrow, suggesting that IL-19 inhibits OPG expression in bone marrow mesenchymal stem cells (BMSCs) and thus increases bone resorption. Conclusion: IL-19 promotes bone resorption by suppressing OPG expression in BMSCs in a LPS-induced bone loss mouse model, which highlights the potential benefits and side effects of IL-19 for future clinical applications.

Influence of Socioeconomic Gender Inequality on Sex Disparities in Prevention and Outcome of Cardiovascular Disease: Data From a Nationwide Population Cohort in China.

Background Knowledge gaps remain in how gender-related socioeconomic inequality affects sex disparities in cardiovascular diseases (CVD) prevention and outcome. Methods and Results Based on a nationwide population cohort, we enrolled 3 737 036 residents aged 35 to 75 years (2014-2021). Age-standardized sex differences and the effect of gender-related socioeconomic inequality (Gender Inequality Index) on sex disparities were explored in 9 CVD prevention indicators. Compared with men, women had seemingly better primary prevention (aspirin usage: relative risk [RR], 1.24 [95% CI, 1.18-1.31] and statin usage: RR, 1.48 [95% CI, 1.39-1.57]); however, women's status became insignificant or even worse when adjusted for metabolic factors. In secondary prevention, the sex disparities in usage of aspirin (RR, 0.65 [95% CI, 0.63-0.68]) and statin (RR, 0.63 [95% CI, 0.61-0.66]) were explicitly larger than disparities in usage of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (RR, 0.88 [95% CI, 0.84-0.91]) or ß blockers (RR, 0.67 [95% CI, 0.63-0.71]). Nevertheless, women had better hypertension awareness (RR, 1.09 [95% CI, 1.09-1.10]), similar hypertension control (RR, 1.01 [95% CI, 1.00-1.02]), and lower CVD mortality (hazard ratio, 0.46 [95% CI, 0.45-0.47]). Heterogeneities of sex disparities existed across all subgroups. Significant correlations existed between regional Gender Inequality Index values and sex disparities in usage of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (Spearman correlation coefficient, r=-0.57, P=0.0013), hypertension control (r=-0.62, P=0.0007), and CVD mortality (r=0.45, P=0.014), which remained significant after adjusting for economic factors. Conclusions Notable sex disparities remain in CVD prevention and outcomes, with large subgroup heterogeneities. Gendered socioeconomic factors could reinforce such disparities. A sex-specific perspective factoring in socioeconomic disadvantages could facilitate more targeted prevention policy making.

Andrias Davidianus Mucus-Based Bioadhesive with Enhanced Adhesion and Wound Healing Properties.

The skin secretion of Andrias davidianus (SSAD) is a novel biological adhesive raw material under development. This material exhibits robust adhesion while maintaining the flexibility of the wound. It also has the potential for large-scale production, making it promising for practical application explore. Hence, in-depth research on methods to fine-tune SSAD properties is of great importance to promote its practical applications. Herein, we aim to enhance the adhesive and healing properties of SSAD by incorporating functional components. To achieve this goal, we selected 3,4-dihydroxy-l-phenylalanine and vaccarin as the functional components and mixed them with SSAD, resulting in a new bioadhesive, namely, a formulation termed "enhanced SSAD" (ESSAD). We found that the ESSAD exhibited superior adhesive properties, and its adhesive strength was improved compared with the SSAD. Moreover, ESSAD demonstrated a remarkable ability to promote wound healing. This study presents an SSAD-based bioadhesive formulation with enhanced properties, affirming the feasibility of developing SSAD-based adhesive materials with excellent performance and providing new evidence for the application of SSAD. This study also aims to show that SSAD can be mixed with other substances, and addition of effective components to SSAD can be studied to further adjust or improve its performance.

Decoding SEC24 Homolog D, COPII coat complex component accuracy as a signature gene in three human cancers.

Although an increasing body of evidence supports the crucial role of the SEC24 Homolog D, COPII Coat Complex Component (SEC24D) gene in the initiation and progression of cancer, a comprehensive pan-cancer analysis of this gene is still lacking. In this study, we conducted an extensive investigation of SEC24D, aiming to elucidate its potential role and underlying mechanisms across multiple human tumors. Our analysis relied on data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. To validate our findings, we employed RNA sequencing (RNA-seq), targeted bisulfite sequencing (bisulfite-seq) molecular techniques. Our findings revealed elevated mRNA (Messenger RNA) and protein levels of SEC24D in different tumor tissues. However, the up-regulation of SEC24D was significantly correlated with shorter overall survival (OS), metastasis, and various clinical parameters in esophageal cancer (ESCA), lung adenocarcinoma (LUAD), and kidney renal papillary cell carcinoma (KIRP). Expression validation analysis via RNA-seq and targeted bisulfite-seq analyses, further confirmed the higher expression of SEC24D in LUAD cancer cell lines as compared to normal controls. The DNA methylation level of SEC24D was found to be decreased in ESCA, LUAD, and KIRP samples. DNA methylation analysis via bisulfite-seq analysis also validate the lower promoter methylation level of SE24D in LUAD cell lines relative to controls. Moreover, we observed a significant association between the elevated expression of SEC24D and the levels of infiltrating cells, such as B cells, neutrophils, macrophages, CD8+ T cells, and CD4+ T cells. Analysis of SEC24-related genes revealed that "Protein processing in endoplasmic reticulum, SNARE interaction in vesicular transport, Legionellosis, Pathogenic Escherichia coli infection" were mainly involved in the functional mechanism of SEC24D in ESCA, LUAD, and KIRP. Moreover, we also suggested a few valuable drugs (Acetaminophen, Acteoside, Cyclosporine, Polydatin, Estradiol, Estradiol, Quercetin) for treating ESCA, LUAD, and KIRP patients with respect to overexpressed SEC24D. To summarize, this comprehensive pan-cancer study investigated the association between SEC24D expression and clinical parameters in ESCA, LUAD, KIRP. The study provides valuable insights for further exploring the functional and therapeutic aspects of SEC24D and underscores its predictive significance in the carcinogenesis and prognosis of these specific cancer types.

HOXA11 promotes lymphatic metastasis of gastric cancer via transcriptional activation of TGFß1.

Most gastric cancer (GC) patients with early stage often have no lymph node (LN) metastases, while LN metastases appear in the advanced stage. However, there are some patients who present with early stage LN metastases and no LN metastases in the advanced stage. To explore the deeper molecular mechanisms involved, we collected clinical samples from early and advanced stage GC with and without LN metastases, as well as metastatic lymph nodes. Herein, we identified a key target, HOXA11, that was upregulated in GC tissues and closely associated with lymphatic metastases. HOXA11 transcriptionally regulates TGFß1 expression and activates the TGFß1/Smad2 pathway, which not only promotes EMT development but also induces VEGF-C secretion and lymphangiogenesis. These findings provide a plausible mechanism for HOXA11-modulated tumor in lymphatic metastasis and suggest that HOXA11 may represent a potential therapeutic target for clinical intervention in LN-metastatic gastric cancer.

Three dimension high definition manometry evaluated postoperative anal canal functions in children with congenital anorectal malformations.

Background: We aimed to evaluate the function of the reconstructed anal canal in postoperative anorectal malformations (ARMs) patients through three dimension (3D) high-definition anorectal manometry. Methods: From January 2015 to December 2019, 3D manometry was performed as a postoperative functional assessment of patients with ARMs divided into age subgroups based on the time of manometry. Manometric parameters, such as the length of the anorectal high-pressure zone (HPZ-length), the mean resting and squeeze pressure of HPZ (HPZ-rest and HPZ-sqze), recto-anal inhibitory reflex (RAIR), and strength distribution of the anal canal, were collected and compared with age-matched controls. Their functional outcomes were analyzed with SPSS 23.0 software for statistical analysis. Results: 171 manometric measurements were performed on 142 postoperative patients (3 months∼15 years). The HPZ-rest in all patients was significantly lower than in age-matched controls (p < 0.05). HPZ-sqze was notably decreased in patients older than 4 years, whereas other age groups were comparable to controls (p < 0.05). The proportions of asymmetric strength distribution and negative RAIR were higher in ARMs patients. The type of anorectal malformations and lower HPZ-rest were the impact factors affecting postoperative functional outcomes. Conclusions: The majority of the ARMs patients had acceptable functional outcomes. 3D manometry can objectively assess the reconstructed anal canal function. The patients with fecal incontinence had a high proportion of extremely low HPZ-rest and HPZ-sqze, negative RAIR, and asymmetric strength distribution. The manometric details will help the clinicians explore the causes of defecation complications and guide further management.

Cancer Immunotherapy Based on Cell Membrane-Coated Nanocomposites Augmenting cGAS/STING Activation by Efferocytosis Blockade.

Innate immunity triggered by the cGAS/STING pathway has the potential to improve cancer immunotherapy. Previously, the authors reported that double-stranded DNA (dsDNA) released by dying tumor cells can trigger the cGAS/STING pathway. However, owing to efferocytosis, dying tumor cells are engulfed and cleared before the damaged dsDNA is released; hence, immunologic tolerance and immune escape occur. Herein, a cancer-cell-membrane biomimetic nanocomposites that exhibit tumor-immunotherapeutic effects are synthesized by augmenting the cGAS/STING pathway and suppressing efferocytosis. Once internalized by cancer cells, a combined chemo/chemodynamic therapy would be triggered, which damages their nuclear and mitochondrial DNA. Furthermore, the releasing Annexin A5 protein could inhibit efferocytosis effect and promote immunostimulatory secondary necrosis by preventing phosphatidylserine exposure, resulting in the burst release of dsDNA. These dsDNA fragments, as molecular patterns to immunogenic damage, escape from the cancer cells, activate the cGAS/STING pathway, enhance cross-presentation inside dendritic cells, and promote M1-polarization of tumor-associated macrophages. In vivo experiments suggest that the proposed nanocomposite could recruit cytotoxic T-cells and facilitate long-term immunological memory. Moreover, when combined with immune-checkpoint blockades, it could augment the immune response. Therefore, this novel biomimetic nanocomposite is a promising strategy for generating adaptive antitumor immune responses.

Di-CNN: Domain-Knowledge-Informed Convolutional Neural Network for Manufacturing Quality Prediction.

In manufacturing, convolutional neural networks (CNNs) are widely used on image sensor data for data-driven process monitoring and quality prediction. However, as purely data-driven models, CNNs do not integrate physical measures or practical considerations into the model structure or training procedure. Consequently, CNNs' prediction accuracy can be limited, and model outputs may be hard to interpret practically. This study aims to leverage manufacturing domain knowledge to improve the accuracy and interpretability of CNNs in quality prediction. A novel CNN model, named Di-CNN, was developed that learns from both design-stage information (such as working condition and operational mode) and real-time sensor data, and adaptively weighs these data sources during model training. It exploits domain knowledge to guide model training, thus improving prediction accuracy and model interpretability. A case study on resistance spot welding, a popular lightweight metal-joining process for automotive manufacturing, compared the performance of (1) a Di-CNN with adaptive weights (the proposed model), (2) a Di-CNN without adaptive weights, and (3) a conventional CNN. The quality prediction results were measured with the mean squared error (MSE) over sixfold cross-validation. Model (1) achieved a mean MSE of 6.8866 and a median MSE of 6.1916, Model (2) achieved 13.6171 and 13.1343, and Model (3) achieved 27.2935 and 25.6117, demonstrating the superior performance of the proposed model.