The Role of Immune Cells in DKD: Mechanisms and Targeted Therapies.

Diabetic kidney disease (DKD), is a common microvascular complication and a major cause of death in patients with diabetes. Disorders of immune cells and immune cytokines can accelerate DKD development of in a number of ways. As the kidney is composed of complex and highly differentiated cells, the interactions among different cell types and immune cells play important regulatory roles in disease development. Here, we summarize the latest research into the molecular mechanisms underlying the interactions among various immune and renal cells in DKD. In addition, we discuss the most recent studies related to single cell technology and bioinformatics analysis in the field of DKD. The aims of our review were to explore immune cells as potential therapeutic targets in DKD and provide some guidance for future clinical treatments.

Artificial dermis combined with negative pressure wound therapy and platelet-rich plasma to treat traumatic wounds: a retrospective study.

OBJECTIVE: The reconstruction of complex soft tissue defects with exposure of bones and tendons represents an increasing challenge in wound care, especially in large extremity wounds. The aim of this study was to detect the clinical efficacy of combined use of negative pressure wound therapy (NPWT), artificial dermis (ADM), platelet-rich plasma (PRP) and split-thickness skin grafting (STSG) in the reconstruction of large traumatic extremity skin defects. METHOD: In this study, eight cases were treated with combined therapies for repairing complex extremity wounds and the results were reviewed retrospectively. After surgical debridement, all wounds received ADM, PRP and delayed STSG, which were all aided with NPWT. RESULTS: The patients consisted of five males and three females, with a mean age of 44 years. A total of six lower extremity wounds were located at the foot/ankle, with exposed tendon in five, bone exposure in three and both in two. Of the group, two patients had exposed tendon on arm/hand wounds. The size of wounds and ADM averaged 126cm2 and 42.3cm2, respectively. ADM was used to cover the exposed bone or tendon, the granulation and muscular tissue were covered with vacuum sealing drainage (VSD) directly, for NPWT. The survival rate of ADM averaged 98.9%. The average time for survival of ADM was 12.8 days and the mean uptake of autologous skin graft was 93.5%. Only one patient received repeated skin grafts. All patients achieved successful healing and reported no complications. The mean length of hospital stay was 36.1 days. CONCLUSION: Our study revealed that ADM in conjunction with NPWT, PRP and STSG could be used for repairing large traumatic extremity wounds. Wound closure was achieved without flaps, the aesthetic and functional outcomes were acceptable, and only one patient developed a 35% loss of skin graft. DECLARATION OF INTEREST: This work was supported by grants from the Natural Science Foundation of Hubei Province (grant no. 2020CFB464) and Youth Foundation of Wuhan Municipal Health Commission (grant no. WX20Q15). The authors have no conflicts of interest to declare.

Filamentous prophage Pf4 promotes genetic exchange in Pseudomonas aeruginosa.

Filamentous prophages are widespread among bacteria and play crucial functions in virulence, antibiotic resistance, and biofilm structures. The filamentous Pf4 particles, extruded by an important pathogen Pseudomonas aeruginosa, can protect producing cells from adverse conditions. Contrary to the conventional belief that the Pf4-encoding cells resist reinfection, we herein report that the Pf4 prophage is reciprocally and commonly exchanged within P. aeruginosa colonies, which can repair defective Pf4 within the community. By labeling the Pf4 locus with antibiotic resistance and fluorescence markers, we demonstrate that the Pf4 locus is frequently exchanged within colony biofilms, in artificial sputum media, and in infected mouse lungs. We further show that Pf4 trafficking is a rapid process and capable of rescuing Pf4-defective mutants. The Pf4 phage is highly adaptable and can package additional DNA doubling its genome size. We also report that two clinical P. aeruginosa isolates are susceptible to the Pf4-mediated exchange, and the Pf5 prophage can be exchanged between cells as well. These findings suggest that the genetic exchanging interactions by filamentous prophages may facilitate defect rescue and the sharing of prophage-dependent benefits and costs within the P. aeruginosa community.

A few-shot link prediction framework to drug repurposing using multi-level attention network.

Drug repurposing is a strategy aiming at uncovering novel medical indications of approved drugs. This process of discovery can be effectively represented as a link prediction task within a medical knowledge graph by predicting the missing relation between the disease entity and the drug entity. Typically, the links to be predicted pertain to rare types, thereby necessitating the task of few-shot link prediction. However, the sparsity of neighborhood information and weak triplet interactions result in less effective representations, which brings great challenges to the few-shot link prediction. Therefore, in this paper, we proposed a meta-learning framework based on a multi-level attention network (MLAN) to capture valuable information in the few-shot scenario for drug repurposing. First, the proposed method utilized a gating mechanism and a graph attention network to effectively filter noise information and highlight the valuable neighborhood information, respectively. Second, the proposed commonality relation learner, employing a set transformer, effectively captured triplet-level interactions while remaining insensitive to the size of the support set. Finally, a model-agnostic meta-learning training strategy was employed to optimize the model quickly on each meta task. We conducted validation of the proposed method on two datasets specifically designed for few-shot link prediction in medical field: COVID19-One and BIOKG-One. Experimental results showed that the proposed model had significant advantages over state-of-the-art few-shot link prediction methods. Results also highlighted the valuable insights of the proposed method, which successfully integrated the components within a unified meta-learning framework for drug repurposing.

Biodentine as a pulpotomy medicament for primary molars: a retrospective chart review.

This retrospective chart review study investigates the long-term clinical outcome of Biodentine® (Tricalcium silicate) as a medicament for pulpotomy in primary molars. Data in this retrospective study was collected from the dental records of all patients that had at least one primary molar receive pulpotomy treatment (CDT code: D3221) between 01 July 2012 and 01 July 2015. This data includes child's age, medical history, dental history, dental radiographs, pulpotomy procedure details and follow-up clinical notes. Kaplan-Meier Estimate was used to measure the fraction of successful pulpotomy procedures for up to 24 months. A total of 1758 pulpotomy procedures were performed on 1032 patients in our institute in the three-year period and 21.4% of them (N = 376) had follow-up dental records that qualified for the study. Eleven teeth out of 376 teeth were excluded from the statistical analysis due to loss of/broken stainless steel crowns (3.1%). Seventeen pulpotomy failures were identified out of the remaining 365 procedures. The survival probablity of using Biodentine® as a pulpotomy medicament is 96.3% for 18-month follow-up and 95.4% for 24-month follow-up. Biodentine®, a tricalcium silicate formulation, used as a pulpotomy medicament demonstrates a high clinical success rate (95.4%) over a 24-month peroid in primary molars.

Hyperglycemia-induced STING signaling activation leads to aortic endothelial injury in diabetes.

Hyperglycaemia-induced endothelial dysfunction is a key factor in the pathogenesis of diabetic microangiopathy and macroangiopathy. STING, which is a newly discovered regulator of innate immunity, has also been reported to play an important role in various metabolic diseases. However, the role of STING in diabetes-induced endothelial cell dysfunction is unknown. In this study, we established a diabetic macroangiopathy mouse model by streptozotocin (STZ) injection combined with high-fat diet (HFD) feeding and a glucotoxicity cell model in high glucose (HG)-treated rat aortic endothelial cells (RAECs). We found that STING expression was specifically increased in the endothelial cells of diabetic arteries, as well as in HG-treated RAECs. Moreover, genetic deletion of STING significantly ameliorated diabetes-induced endothelial cell dysfunction and apoptosis in vivo. Likewise, STING inhibition by C-176 reversed HG-induced migration dysfunction and apoptosis in RAECs, whereas STING activation by DMXAA resulted in migration dysfunction and apoptosis. Mechanistically, hyperglycaemia-induced oxidative stress promoted endothelial mitochondrial dysfunction and mtDNA release, which subsequently activated the cGAS-STING system and the cGAS-STING-dependent IRF3/NF-kB pathway, ultimately resulting in inflammation and apoptosis. In conclusion, our study identified a novel role of STING in diabetes-induced aortic endothelial cell injury and suggested that STING inhibition was a potential new therapeutic strategy for the treatment of diabetic macroangiopathy. Video Abstract.

[Corrigendum] Fully human VEGFR2 monoclonal antibody BC001 attenuates tumor angiogenesis and inhibits tumor growth.

Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that, for the scratch wound assay experiments shown in Fig. 1 on p. 2413, the panels showing the '0 h' experiments for the respective incubations with VEGF or BC001 were apparently identical. The authors were able to re­examine their original data files, and realized that this figure had been inadverently assembled incorrectly. The revised version of Fig. 1, containing the correct data for the '0 h / BC001' panel, is shown below. Note that the revisions made to this figure do not affect the overall conclusions reported in the paper. The authors are grateful to the Editor of International Journal of Oncology for allowing them the opportunity to publish this Corrigendum, and apologize to the readership for any inconvenience caused. [International Journal of Oncology 45: 2411­2420, 2014; DOI: 10.3892/ijo.2014.2690].

PARSE: A personalized clinical time-series representation learning framework via abnormal offsets analysis.

BACKGROUND AND OBJECTIVE: Clinical risk prediction of patients is an important research issue in the field of healthcare, which is of great significance for the diagnosis, treatment and prevention of diseases. In recent years, a large number of deep learning-based methods have been proposed for clinical prediction by mining relevant features of patients' health condition from historical Electronic Health Records (EHRs) data. However, most of these existing methods only focus on discovering the time series characteristics of physiological indexes such as laboratory tests and physical examinations, and fail to comprehensively consider the deviation degree of these physiological indexes from the normal range and their stability, thus greatly limiting the prediction performance. METHODS: We propose a personalized clinical time-series representation learning framework via abnormal offsets analysis named PARSE for clinical risk prediction. In PARSE, while extracting relevant temporal features from the original EHR data, we further capture relevant features of abnormal condition as complementary information from the absolute offset of each physiological index's observed values from its normal value and the relative offset between each physiological index's observed values in two adjacent time steps. Finally, an adaptive fusion module is introduced to effectively integrate the above features to obtain the personalized patient's representations for clinical risk prediction. RESULTS: We conduct an in-hospital mortality prediction task on two public real-world datasets. PARSE achieves the highest F1 scores of 48.1% and 40.3%, outperforming the state-of-the-art methods with a boost of 2.4% and 6.2% on two datasets respectively. Furthermore, the results of ablation experiments demonstrate that the two abnormal offsets and the proposed adaptive fusion method are contributing. CONCLUSIONS: PARSE can better extract the risk-related information from the EHRs data and improve the personalization of the patients' representations. Each part of PARSE improves the final prediction performance independently.

Nitrogen removal from dewatering liquid of landfill sludge by partial nitrification and denitrification.

Two pilot-scale two-stage anoxic/oxic membrane bioreactors were operated at different dissolved oxygen (DO) levels to evaluate nitrogen removal performances for treating landfill sludge dewatering liquid. Under either high (5.0-6.0 mg/L) or conventional DO (2.0-3.0 mg/L) conditions, partial nitrification (PN)-denitrification was both achieved, and high-concentration free ammonia (FA) ensured stable PN. The high DO system exhibited higher nitrite accumulation (98.5 %) and nitrogen removal (98.0 %), and its nitrogen removal was mainly ascribed to PN-denitrification (53.8 %). Kinetic inhibition tests and microbial sequencing results demonstrated that high DO condition improved the abundance and ability of ammonia-oxidizing bacteria (AOB) rather than nitrite-oxidizing bacteria under the FA inhibition. Pseudomonas, Thauera, and Soehngenia were characteristic genus in the high DO system, and Nitrosomonas was only AOB. Metagenomic analysis confirmed the important role of PN on nitrogen removal in high DO system. This provides valuable references for the efficient and economic treatment of ammonia-rich wastewater.

The role of oxidative stress in diabetes mellitus-induced vascular endothelial dysfunction.

Diabetes mellitus is a metabolic disease characterized by long-term hyperglycaemia, which leads to microangiopathy and macroangiopathy and ultimately increases the mortality of diabetic patients. Endothelial dysfunction, which has been recognized as a key factor in the pathogenesis of diabetic microangiopathy and macroangiopathy, is characterized by a reduction in NO bioavailability. Oxidative stress, which is the main pathogenic factor in diabetes, is one of the major triggers of endothelial dysfunction through the reduction in NO. In this review, we summarize the four sources of ROS in the diabetic vasculature and the underlying molecular mechanisms by which the pathogenic factors hyperglycaemia, hyperlipidaemia, adipokines and insulin resistance induce oxidative stress in endothelial cells in the context of diabetes. In addition, we discuss oxidative stress-targeted interventions, including hypoglycaemic drugs, antioxidants and lifestyle interventions, and their effects on diabetes-induced endothelial dysfunction. In summary, our review provides comprehensive insight into the roles of oxidative stress in diabetes-induced endothelial dysfunction.

SPBERE: Boosting span-based pipeline biomedical entity and relation extraction via entity information.

Triplet extraction is one of the fundamental tasks in biomedical text mining. Compared with traditional pipeline approaches, joint methods can alleviate the error propagation problem from entity recognition to relation classification. However, existing methods face challenges in detecting overlapping entities and overlapping relations, which are ubiquitous in biomedical texts. In this work, we propose a novel pipeline method of end-to-end biomedical triplet extraction. In particular, a span-based detection strategy is used to detect the overlapping triplets by enumerating possible candidate spans and entity pairs. The strategy is further used to capture different contextualized representations via an entity model and a relation model, respectively. Furthermore, to enhance interrelation between spans, entity information from the output of the entity model is used to construct the input for the relation model without utilizing any external knowledge. Our approach is evaluated on the drug-drug interaction (DDI) and chemical-protein interaction (CHEMPROT) datasets, exhibiting improvement of the absolute F1-score in relation extraction by 3.5%-3.7% compared prior work. The experimental results highlight the importance of overlapping triplet detection using the span-based approach, acquisition of various contextualized representations via different in-domain pre-trained language models, and early fusion of entity information in the relation model.

Comparative transcriptomic analysis reveals the underlying molecular mechanism in high-fat diet-induced islet dysfunction.

Obesity, characterized by accumulation of adipose, is usually accompanied by hyperlipidemia and abnormal glucose metabolism, which destroys the function and structure of islet ß cells. However, the exact mechanism of islet deterioration caused by obesity has not yet been fully elucidated. Here, we fed C57BL/6 mice with a high-fat diet (HFD) for 2 (2M group) and 6 months (6M group) to construct obesity mouse models. Then, RNA-based sequencing was used to identify the molecular mechanisms in HFD-induced islet dysfunction. Compared with the control diet, a total of 262 and 428 differentially expressed genes (DEGs) were identified from islets of the 2M and 6M groups, respectively. GO and KEGG enrichment analysis revealed that the DEGs up-regulated in both the 2M and 6M groups are mainly enriched in response to endoplasmic reticulum stress and the pancreatic secretion pathway. DEGs down-regulated in both the 2M and 6M groups are mainly enriched in the neuronal cell body and protein digestion and absorption pathway. Notably, along with the HFD feeding, mRNA expression of islet cell markers was significantly down-regulated, such as Ins1, Pdx1, MafA (ß cell), Gcg, Arx (α cell), Sst (δcell), and Ppy (PP cell). In contrast, mRNA expression of acinar cell markers was remarkably up-regulated, such as Amy1, Prss2, and Pnlip. Besides, a large number of collagen genes were down-regulated, such as Col1a1, Col6a6, and Col9a2. Overall, our study provides a full-scale DEG map regarding HFD-induced islet dysfunction, which was helpful to understand the underlying molecular mechanism of islet deterioration further.

LGTRL-DE: Local and Global Temporal Representation Learning with Demographic Embedding for in-hospital mortality prediction.

Predicting the patient's in-hospital mortality from the historical Electronic Medical Records (EMRs) can assist physicians to make clinical decisions and assign medical resources. In recent years, researchers proposed many deep learning methods to predict in-hospital mortality by learning patient representations. However, most of these methods fail to comprehensively learn the temporal representations and do not sufficiently mine the contextual knowledge of demographic information. We propose a novel end-to-end approach based on Local and Global Temporal Representation Learning with Demographic Embedding (LGTRL-DE) to address the current issues for in-hospital mortality prediction. LGTRL-DE is enabled by (1) a local temporal representation learning module that captures the temporal information and analyzes the health status from a local perspective through a recurrent neural network with the demographic initialization and the local attention mechanism; (2) a Transformer-based global temporal representation learning module that extracts the interaction dependencies among clinical events; (3) a multi-view representation fusion module that fuses temporal and static information and generates the final patient's health representations. We evaluate our proposed LGTRL-DE on two public real-world clinical datasets (MIMIC-III and e-ICU). Experimental results show that LGTRL-DE achieves area under receiver operating characteristic curve of 0.8685 and 0.8733 on the MIMIC-III and e-ICU datasets, respectively, outperforming several state-of-the-art approaches.

NADPH-dependent ROS accumulation contributes to the impaired osteogenic differentiation of periodontal ligament stem cells under high glucose conditions.

Diabetes mellitus is an established risk factor for periodontal disease that can aggravate the severity of periodontal inflammation and accelerate periodontal destruction. The chronic high glucose condition is a hallmark of diabetes-related pathogenesis, and has been demonstrated to impair the osteogenic differentiation of periodontal ligament stem cells (PDLSCs), leading to delayed recovery of periodontal defects in diabetic patients. Reactive oxygen species (ROS) are small molecules that can influence cell fate determination and the direction of cell differentiation. Although excessive accumulation of ROS has been found to be associated with high glucose-induced cell damage, the underlying mechanisms remain unclear. Nicotinamide adenine dinucleotide phosphate (NADPH) is an important electron donor and functions as a critical ROS scavenger in antioxidant systems. It has been identified as a key mediator of various biological processes, including energy metabolism and cell differentiation. However, whether NADPH is involved in the dysregulation of ROS and further compromise of PDLSC osteogenic differentiation under high glucose conditions is still not known. In the present study, we found that PDLSCs incubated under high glucose conditions showed impaired osteogenic differentiation, excessive ROS accumulation and increased NADPH production. Furthermore, after inhibiting the synthesis of NADPH, the osteogenic differentiation of PDLSCs was significantly enhanced, accompanied by reduced cellular ROS accumulation. Our findings demonstrated the crucial role of NADPH in regulating cellular osteogenic differentiation under high glucose conditions and suggested a new target for rescuing high glucose-induced cell dysfunction and promoting tissue regeneration in the future.

Xinkeshu tablets promote angiogenesis in zebrafish embryos and human umbilical vein endothelial cells through multiple signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Angiogenesis is particularly important in ischemic cardiovascular diseases such as coronary heart disease (CHD). Xinkeshu tablets (XKS) are a commonly used Chinese patent medicine for CHD with a defined clinical effect. However, the proangiogenic effect of XKS remains unknown. AIM OF THE STUDY: We attempted to investigate the chemical composition and proangiogenic effect of XKS, as well as its underlying mechanisms. MATERIALS AND METHODS: The chemical composition of a XKS methanol extract was analyzed using a UPLC-Q-Orbitrap-MS system. The compound's proangiogenic effects were evaluated in zebrafish embryos and human umbilical vein endothelial cells (HUVECs). Furthermore, the underlying mechanisms were investigated using transcriptome assays and real-time quantitative PCR validation. RESULTS: We identified 116 chemical constituents of XKS. XKS significantly stimulated subintestinal vessel plexus (SIVs) growth and rescued tyrosine kinase inhibitor (PTK787)-induced intersegmental vessels (ISVs) injury in zebrafish in a concentration-dependent manner. XKS significantly rescued the proliferation, migration capacity and tube formation of Recombinant VEGFR tyrosine kinase inhibitor II (VRI)-injured HUVECs. XKS promoted angiogenesis through multiple signaling pathways, including metabolic pathways, the PPAR signaling pathway, the AGE-RAGE signaling pathway, the NOD-like receptor signaling pathway, the VEGF signaling pathway, and the PI3K/Akt signaling pathway. CONCLUSION: Herein, we identified 116 chemical constituents of XKS for the first time and demonstrated that XKS may regulate angiogenesis through multiple signaling pathways to treat CHD.

High glucose-induced endothelial STING activation inhibits diabetic wound healing through impairment of angiogenesis.

Chronic hyperglycemia-induced impairment of angiogenesis is important in diabetic foot ulcer (DFU). Additionally, the stimulator of interferon gene (STING), which is a key protein in innate immunity, mediates palmitic acid-induced lipotoxicity in metabolic diseases through oxidative stress-induced STING activation. However, the role of STING in DFU is unknown. In this study, we established a DFU mouse model with streptozotocin (STZ) injection and found that the expression of STING was significantly increased in the vascular endothelial cells of wound tissues from diabetic patients and in the STZ-induced diabetic mouse model. We further established high glucose (HG)-induced endothelial dysfunction with rat vascular endothelial cells and found that the expression of STING was also increased by high-glucose treatment. Moreover, the STING inhibitor, C176, promoted diabetic wound healing, whereas the STING activator, DMXAA, inhibited diabetic wound healing. Consistently, STING inhibition reversed the HG-induced reduction of CD31 and vascular endothelial growth factor (VEGF), inhibited apoptosis, and promoted migration of endothelial cells. Notably, DMXAA treatment alone was sufficient to induce endothelial cell dysfunction as a high-glucose treatment. Mechanistically, STING mediated HG-induced vascular endothelial cell dysfunction by activating the interferon regulatory factor 3/nuclear factor kappa B pathway. In conclusion, our study reveals an endothelial STING activation-mediated molecular mechanism in the pathogenesis of DFU and identifies STING as a novel potential therapeutic target for DFU.

Knockdown of miR-19a suppresses gastrointestinal dysmotility diarrhea after TBI by regulating VIP expression.

BACKGROUND AND AIMS: Traumatic brain injury (TBI) is the main cause of death and can lead to a variety of physiological complications, including gastrointestinal dysfunction. The present study aimed to confirm the miR-19a-mediated suppression of diarrhea after TBI through the regulation of VIP expression. METHODS: A rat model of TBI induced by controlled cortical injury was used to observe gastrointestinal morphology by opening the abdomen after TBI. After 72 h of injury, the fecal water content of the rats was measured. The end ileal segments were removed, and HE staining was used to observe the histopathological changes in the intestine. The levels of serum miR-19a and VIP mRNA were detected by qRT-PCR. ELISA was performed to detect VIP levels in serum. Immunohistochemistry was used to detect the level of VIP in ileal tissues, and immunofluorescence was used to detect c-kit expression in ileal tissue. CCK-8 assay was used to detect the cell viability of interstitial cells of Cajal (ICCs), and TUNEL assay was used to detect apoptosis of ICCs. RESULTS: miR-19a and VIP were highly expressed in the serum of TBI rats, and the knockdown of miR-19a alleviated TBI-induced diarrhea. In addition, the overexpression of miR-19a or VIP inhibited the proliferation of ICCs, promoted apoptosis, and suppressed intracellular Ca2+ levels, whereas miR-19a suppression had the opposite effects. A nonselective nitric oxide synthase inhibitor (L-NA), PKG inhibitors (KT-5823 and RP-8CPT-cGMPS), and a guanylate cyclase inhibitor (ODQ) restored the inhibitory effects of VIP on ICC proliferation, anti-apoptosis effects, and Ca2+ concentrations. CONCLUSION: Knockdown of miR-19a inhibits activation of the VIP-NO-cGMP-PKG pathway through suppression of VIP expression, which in turn inhibits diarrhea after TBI.

Unraveling roles of the intermediate settler in a microaerobic hydrolysis sludge in situ reduction process.

The roles of the intermediate settler in the sludge process reduction activated sludge process (SPRAS), and the influences of its hydraulic retention time (HRTST) on pollutant removal and sludge reduction were investigated. Prolonging HRTST from 3.0 to 4.5 and 6.0 h resulted in sludge reduction efficiencies increased from 46.8% to 61.5% and 62.7%. The sludge accumulation in the intermediate settler formed an anaerobic zone but inhibited methane production, and the alternating microaerobic and anaerobic environment in the sludge process reduction (SPR) module increased the microbial diversity and enriched the hydrolytic and fermentative bacteria. Prolonging HRTST accelerated dissolved organic matter release and elevated the degradation of refractory fraction, and improved the sludge properties of the SPRAS. Metagenomic analysis showed that the SPR module enhanced the glycolysis pathway and decoupling metabolism for sludge reduction. The results revealed that the intermediate settler plays dual roles in solid-liquid separation and sludge reduction metabolism.

An epithelial-mesenchymal transition-related mRNA signature associated with the prognosis, immune infiltration and therapeutic response of colon adenocarcinoma.

Background: Epithelial-mesenchymal transition (EMT) is closely associated with cancer cell metastasis. Colon adenocarcinoma (COAD) is one of the most common malignancies in the world, and its metastasis leading to poor prognosis remains a challenge for clinicians. The purpose of this study was to explore the prognostic value of EMT-related genes (EMTRGs) by bioinformatics analysis and to develop a new EMTRGs prognostic signature for COAD. Methods: The TCGA-COAD dataset was downloaded from the TCGA portal as the training cohort, and the GSE17538 and GSE29621 datasets were obtained from the GEO database as the validation cohort. The best EMTRGs prognostic signature was constructed by differential expression analysis, Cox, and LASSO regression analysis. Gene set enrichment analysis (GSEA) is used to reveal pathways that are enriched in high-risk and low-risk groups. Differences in tumor immune cell levels were analyzed using microenvironmental cell population counter and single sample gene set enrichment analysis. Subclass mapping analysis and Genomics of Drug Sensitivity in Cancer were applied for prediction of immunotherapy response and chemotherapy response, respectively. Results: A total of 77 differentially expressed EMTRGs were identified in the TCGA-COAD cohort, and they were significantly associated with functions and pathways related to cancer cell metastasis, proliferation, and apoptosis. We constructed EMTRGs prognostic signature with COMP, MYL9, PCOLCE2, SCG2, and TIMP1 as new COAD prognostic biomarkers. The high-risk group had a poorer prognosis with enhanced immune cell infiltration. The GSEA demonstrated that the high-risk group was involved in "ECM Receptor Interaction," "WNT Signaling Pathway" and "Colorectal Cancer." Furthermore, patients with high risk scores may respond to anti-CTLA4 therapy and may be more resistant to targeted therapy agents BI 2536 and ABT-888. Conclusion: Together, we developed a new EMTRGs prognostic signature that can be an independent prognostic factor for COAD. This study has guiding implications for individualized counseling and treatment of COAD patients.

Crosslinked albumin-manganese nanoaggregates with sensitized T1 relaxivity and indocyanine green loading for multimodal imaging and cancer phototherapy.

Albumin-manganese-based nanocomposites (AMNs) characterized by simple preparation and good biocompatibility have been widely used for in vivo T1-weighted magnetic resonance imaging (MRI) and cancer theranostics. Herein, an aggregation and crosslinking assembly strategy was proposed to achieve the sensitization to T1 relaxivity of the albumin-manganese nanocomposite. At a relatively low Mn content (0.35%), the aggregation and crosslinking of bovine serum albumin-MnO2 (BM) resulted in a dramatic increase of T1 relaxivity from 5.49 to 67.2 mM-1 s-1. Upon the loading of indocyanine green (ICG) into the crosslinked BM nanoaggregates (C-BM), the T1 relaxivity of the C-BM/ICG nanocomposite (C-BM/I) was further increased to 97.3 mM-1 s-1, which was much higher than those reported previously even at high Mn contents. Moreover, the presence of C-BM greatly enhanced the photoacoustic (PA) and photothermal effects of ICG at 830 and 808 nm, respectively, and the second near infrared fluorescence (NIR-II FL) of ICG also showed better stability. Therefore, the synthesized C-BM/ICG nanocomposite exhibited remarkable performance in in vivo multimodal imaging of tumors, such as T1-weighted MRI, NIR-II FL imaging and PA imaging, and cancer phototherapy with little side effects. This work provided a highly efficient and promising multifunctional nanoprobe for breaking through the limits of cancer theranostics, and opened a new avenue for the development of high-relaxivity AMNs and multimodal imaging methodology.