The Application Value of Using Semiquantitative and Quantitative Parameters in Multimodal Ultrasound to Distinguish Between Benign and Malignant BI-RADS 4 Lesions.

ABSTRACT: This study aims to explore the value of real-time strain elastography (RTE) and contrast-enhanced ultrasonography (CEUS) in the diagnosis of breast BI-RADS 4 lesions. It collected 85 cases (totaling 85 lesions) diagnosed with breast BI-RADS 4 through routine ultrasound from October 2020 to December 2022 in Huangshan City People's Hospital. All lesions underwent RTE and CEUS examination before surgery, and the ImageJ software was used to measure the periphery of lesion images in the enhancement peak mode and grayscale mode to calculate the contrast-enhanced ultrasound area ratio. The diagnostic capabilities of single-modal and multimodal ultrasound examination for the malignancy of breast BI-RADS 4 lesions were compared using the receiver operating characteristic curve; the Spearman correlation analysis was adopted to evaluate the correlation between multimodal ultrasound and CEUS area ratio. As a result, among the 85 lesions, 51 were benign, and 34 were malignant. The areas under the curve (AUCs) of routine ultrasound (US), US + RTE, US + CEUS, and US + RTE + CEUS were 0.816, 0.928, 0.953, and 0.967, respectively, with the combined method showing a higher AUC than the single application. The AUC of the CEUS area ratio diagnosing breast lesions was 0.888. There was a strong positive correlation (r = 0.819, P < 0.001) between the diagnostic performance of US + RTE + CEUS and the CEUS area ratio. In conclusion, based on routine ultrasound, the combination of RTE and CEUS can further improve the differential diagnosis of benign and malignant lesions in breast BI-RADS 4.

Magnetic fibrin nanofiber hydrogel delivering iron oxide magnetic nanoparticles promotes peripheral nerve regeneration.

Peripheral nerve injury is a debilitating condition that have a profound impact on the overall quality of an individual's life. The repair of peripheral nerve defects continues to present significant challenges in the field. Iron oxide magnetic nanoparticles (IONPs) have been recognized as potent nanotools for promoting the regeneration of peripheral nerves due to their capability as biological carriers and their ability to template the hydrogel structure under an external magnetic field. This research used a fibrin nanofiber hydrogel loaded with IONPs (IONPs/fibrin) to promote the regeneration of peripheral nerves in rats. In vitro examination of PC12 cells on various concentrations of IONPs/fibrin hydrogels revealed a remarkable increase in NGF and VEGF expression at 2% IONPs concentration. The biocompatibility and degradation of 2% IONPs/fibrin hydrogel were assessed using the in vivo imaging system, demonstrating subcutaneous degradation within a week without immediate inflammation. Bridging a 10-mm sciatic nerve gap in Sprague Dawley rats with 2% IONPs/fibrin hydrogel led to satisfactory morphological recovery of myelinated nerve fibers. And motor functional recovery in the 2% IONPs/fibrin group was comparable to autografts at 6, 9 and 12 weeks postoperatively. Hence, the composite fibrin hydrogel incorporating 2% IONPs exhibits potential for peripheral nerve regeneration.

The ubiquitin-like protein UBTD1 promotes colorectal cancer progression by stabilizing c-Myc to upregulate glycolysis.

Dysfunction of the ubiquitin-proteasome system (UPS) is involved in the pathogenesis of various malignancies including colorectal cancer (CRC). Ubiquitin domain containing 1 (UBTD1), a ubiquitin-like protein, regulates UPS-mediated protein degradation and tumor progression in some cancer types. However, the biological function and mechanism of UBTD1 are far from being well elucidated, and its role in CRC has not been explored yet. In our study, we analyzed CRC patients' clinical information and UBTD1 expression data, and found that the expression of UBTD1 in cancer tissue was significantly higher than that in adjacent normal tissue. Higher UBTD1 expression was significantly associated with poorer survival and more lymph node metastasis. Overexpression of UBTD1 could facilitate, while knockdown could inhibit CRC cell proliferation and migration, respectively. RNA-seq and proteomics indicated that c-Myc is an important downstream target of UBTD1. Metabolomics showed the products of the glycolysis pathway were significantly increased in UBTD1 overexpression cells. In vitro, we verified UBTD1 upregulating c-Myc protein and promoting CRC cell proliferation and migration via regulating c-Myc. UBTD1 promoted CRC cells' glycolysis, evidenced by the increased lactate production and glucose uptake following UBTD1 overexpression. Mechanistically, UBTD1 prolonged the half-life of the c-Myc protein by binding to E3 ligase ß-transducin repeat-containing protein (ß-TrCP), thereby upregulated the expression of glycolysis rate-limiting enzyme hexokinase II (HK2), and enhanced glycolysis and promoted CRC progression. In conclusion, our study revealed that UBTD1 promotes CRC progression by upregulating glycolysis via the ß-TrCP/c-Myc/HK2 pathway, suggesting its potential as a prognostic biomarker and therapeutic target in CRC.

Association of plasma sphingosine-1-phosphate levels with disease severity and prognosis after intracerebral hemorrhage.

Purpose: Sphingosine-1-phosphate (S1P) is a signaling lipid involved in many biological processes, including inflammatory and immune regulatory responses. The study aimed to determine whether admission S1P levels are associated with disease severity and prognosis after spontaneous intracerebral hemorrhage (ICH). Methods: Data of 134 patients with spontaneous ICH and 120 healthy controls were obtained from Biological Resource Sample Database of Intracerebral Hemorrhage at the First Affiliated Hospital of Zhengzhou University. Plasma S1P levels were measured. Regression analyses were used to analyze the association between S1P levels and admission and 90-day modified Rankin scale (mRS) scores. Receiver operating characteristic (ROC) curves assessed the predictive value of S1P levels for ICH severity and prognosis. Results: Patients with ICH exhibited elevated plasma S1P levels compared to the control group (median 286.95 vs. 239.80 ng/mL, p < 0.001). When divided patients into mild-to-moderate and severe groups according to their mRS scores both at admission and discharge, S1P levels were significantly elevated in the severe group compared to the mild-to-moderate group (admission 259.30 vs. 300.54, p < 0.001; 90-day 275.24 vs. 303.25, p < 0.001). The patients were divided into three groups with different concentration gradients, which showed significant statistical differences in admission mRS scores (3 vs. 4 vs. 5, p < 0.001), 90-day mRS scores (2.5 vs. 3 vs. 4, p < 0.001), consciousness disorders (45.5% vs. 68.2% vs. 69.6%, p = 0.033), ICU admission (29.5% vs. 59.1% vs. 89.1%, p < 0.001), surgery (15.9% vs. 47.7% vs. 82.6%, p < 0.001), intraventricular hemorrhages (27.3% vs. 61.4% vs. 65.2%, p < 0.001) and pulmonary infection (25% vs. 47.7% vs. 84.8%, p < 0.001). Multivariate analysis displayed that S1P level was an independent risk factor for disease severity (OR = 1.037, 95% CI = 1.020-1.054, p < 0.001) and prognosis (OR = 1.018, 95% CI = 1.006-1.030, p = 0.003). ROC curves revealed a predictive value of S1P levels with an area under the curve of 0.7952 (95% CI = 0.7144-0.8759, p < 0.001) for disease severity and 0.7105 (95% CI = 0.6227-0.7983, p < 0.001) for prognosis. Conclusion: Higher admission S1P is associated with worse initial disease severity and 90-day functional outcomes in intracerebral hemorrhage.

Enhanced Reactivities of Iron(IV)-Oxo Porphyrin Species in Oxidation Reactions Promoted by Intramolecular Hydrogen-Bonding.

High-valent iron-oxo species are one of the common intermediates in both biological and biomimetic catalytic oxidation reactions. Recently, hydrogen-bonding (H-bonding) has been proved to be critical in determining the selectivity and reactivity. However, few examples have been established for mechanistic insights into the H-bonding effect. Moreover, intramolecular H-bonding effect on both C-H activation and oxygen atom transfer (OAT) reactions in synthetic porphyrin model system has not been investigated yet. In this study, a series of heme-containing iron(IV)-oxo porphyrin species with or without intramolecular H-bonding are synthesized and characterized. Kinetic studies revealed that intramolecular H-bonding can significantly enhance the reactivity of iron(IV)-oxo species in OAT, C-H activation, and electron-transfer reactions. This unprecedented unified H-bonding effect is elucidated by theoretical calculations, which showed that intramolecular H-bonding interactions lower the energy of the anti-bonding orbital of iron(IV)-oxo porphyrin species, resulting in the enhanced reactivities in oxidation reactions irrespective of the reaction type. To the best of the knowledge, this is the first extensive investigation on the intramolecular H-bonding effect in heme system. The results show that H-bonding interactions have a unified effect with iron(IV)-oxo porphyrin species in all three investigated reactions.

Blocking cerebral lymphatic system reduces central and peripheral inflammatory response in ischemic stroke.

Reduced blood supply to the brain activates the intracranial inflammatory response, a key contributor to secondary brain damage in ischemic stroke. Post-stroke, activation of peripheral immune cells leads to systemic inflammatory responses. Usingin vivo approaches, we investigated meningeal lymphatics' role in central immune cell infiltration and peripheral immune cell activation. The bilateral deep cervical lymph nodes (dCLNs) were removed 7 days before right middle cerebral artery occlusion in Sprague Dawley (SD) rats. At 3, 24, and 72 h post-intervention, brain immune cell infiltration and microglial and astrocyte activation were measured, while immune cells were classified in the spleen and blood. Inflammatory factor levels in peripheral blood were analyzed. Simultaneously, reverse verification was conducted by injecting AAV-vascular endothelial growth factor C (AAV-VEGFC) adenovirus into the lateral ventricle 14 days before middle cerebral artery occlusion (MCAO) induction to enhance meningeal lymph function. Blocking meningeal LVs in MCAO rats significantly reduced infarct area and infiltration, and inhibited microglia and pro-inflammatory astrocytes activation. After removing dCLNs, CD4+ T lymphocytes, CD8+ T lymphocytes, B lymphocytes, macrophages, and neutrophils in the spleen and blood of MCAO rats decreased significantly at different time points. The levels of inflammatory factors IL-6, IL-10, IL-1ß, and TNF-α in plasma decreased significantly. Tests confirmed the results, and AAV-VEGFC-induced MCAO rats provided reverse validation.

Amyloid and Tau as cerebrospinal fluid biomarkers in anti-N-Methyl-D-aspartate receptor encephalitis.

INTRODUCTION: Neuroinfection is associated with the deposition of amyloid-beta (Aß) peptides, and subsequent decrease in cerebrospinal fluid (CSF) amyloid levels. However, whether autoimmune encephalitis involves extracellular deposition of Aß peptides in the brain is unreported. METHODS: We examined CSF amyloid and tau values in adults with anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E). Forty-two patients with NMDAR-E, 35 patients with viral and bacterial neuroinfections, and 16 controls were included. We measured CSF Aß1-42 (cAß1-42), Aß1-40 (cAß1-40), t-Tau (ct-Tau), and p-Tau181 (cp-Tau181) levels and assessed their efficacies regarding differential diagnosis and predicting prognosis. RESULTS: NMDAR-E patients had lower cAß1-42 levels; however, they were higher than those of patients with bacterial meningitis. ct-Tau levels in NMDAR-E patients were lower than those in patients with neuroinfections. No changes were observed in controls. cAß1-42 and ct-Tau were combined as an excellent marker to distinguish NMDAR-E from neuroinfections. cAß1-42 levels in NMDAR-E patients were positively correlated with Montreal Cognitive Assessment scores. We observed an inverse relationship between cAß1-42 levels and modified Rankin Scale scores. Patients with poor outcomes exhibited low cAß1-42 levels and high levels of several blood parameters. cAß1-42 was the highest quality biomarker for assessing NMDAR-E prognosis. Correlations were found between cAß1-42 and some inflammatory indicators. CONCLUSION: cAß1-42 was decreased in NMDAR-E patients. cAß1-42 levels indicated NMDAR-E severity and acted as a biomarker for its prognosis. Combining cAß1-42 and ct-Tau levels could serve as a novel differential diagnostic marker for NMDAR-E.

A liquid biopsy signature of circulating extracellular vesicles-derived RNAs predicts response to first line chemotherapy in patients with metastatic colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most threatening tumors in the world, and chemotherapy remains dominant in the treatment of metastatic CRC (mCRC) patients. The purpose of this study was to develop a biomarker panel to predict the response of the first line chemotherapy in mCRC patients. METHODS: Totally 190 mCRC patients treated with FOLFOX or XEOLX chemotherapy in 3 different institutions were included. We extracted the plasma extracellular vesicle (EV) RNA, performed RNA sequencing, constructed a model and generated a signature through shrinking the number of variables by the random forest algorithm and the least absolute shrinkage and selection operator (LASSO) algorithm in the training cohort (n = 80). We validated it in an internal validation cohort (n = 62) and a prospective external validation cohort (n = 48). RESULTS: We established a signature consisted of 22 EV RNAs which could identify responders, and the area under the receiver operating characteristic curve (AUC) values was 0.986, 0.821, and 0.816 in the training, internal validation, and external validation cohort respectively. The signature could also identify the progression-free survival (PFS) and overall survival (OS). Besides, we constructed a 7-gene signature which could predict tumor response to first-line oxaliplatin-containing chemotherapy and simultaneously resistance to second-line irinotecan-containing chemotherapy. CONCLUSIONS: The study was first to develop a signature of EV-derived RNAs to predict the response of the first line chemotherapy in mCRC with high accuracy using a non-invasive approach, indicating that the signature could help to select the optimal regimen for mCRC patients.

CircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications.

Osteoarthritis is a prevalent age-related disease characterized by dysregulation of extracellular matrix metabolism, lipid metabolism, and upregulation of senescence-associated secretory phenotypes. Herein, we clarify that CircRREB1 is highly expressed in secondary generation chondrocytes and its deficiency can alleviate FASN related senescent phenotypes and osteoarthritis progression. CircRREB1 impedes proteasome-mediated degradation of FASN by inhibiting acetylation-mediated ubiquitination. Meanwhile, CircRREB1 induces RanBP2-mediated SUMOylation of FASN and enhances its protein stability. CircRREB1-FASN axis inhibits FGF18 and FGFR3 mediated PI3K-AKT signal transduction, then increased p21 expression. Intra-articular injection of adenovirus-CircRreb1 reverses the protective effects in CircRreb1 deficiency mice. Further therapeutic interventions could have beneficial effects in identifying CircRREB1 as a potential prognostic and therapeutic target for age-related OA.

Positive Feedback Regulation of Circular RNA Hsa_circ_0000566 and HIF-1α promotes Osteosarcoma Progression and Glycolysis Metabolism.

Hypoxia is an indispensable factor for cancer progression and is closely associated with the Warburg effect. Circular RNAs (CircRNA) have garnered considerable attention in molecular malignancy therapy as they are potentially important modulators. However, the roles of circRNAs and hypoxia in osteosarcoma (OS) progression have not yet been elucidated. This study reveals the hypoxia-sensitive circRNA, Hsa_circ_0000566, that plays a crucial role in OS progression and energy metabolism under hypoxic stress. Hsa_circ_0000566 is regulated by hypoxia-inducible factor-1α (HIF-1α) and directly binds to it as well as to the Von Hippel-Lindau (VHL) E3 ubiquitin ligase protein. Consequentially, binding between VHL and HIF-1α is impeded. Furthermore, Hsa_circ_0000566 contributes to OS progression by binding to HIF-1α (while competing with VHL) and by confers protection against HIF-1α against VHL-mediated ubiquitin degradation. These findings demonstrate the existence of a positive feedback loop formed by HIF-1α and Hsa_circ_0000566 and the key role they play in OS glycolysis. Taken together, these data indicate the significance of Hsa_circ_0000566 in the Warburg effect and suggest that Hsa_circ_0000566 could be a potential therapeutic target to combat OS progression.

Exosomes from bone marrow mesenchymal stem cells are a potential treatment for ischemic stroke.

Exosomes derived from human bone marrow mesenchymal stem cells (MSC-Exo) are characterized by easy expansion and storage, low risk of tumor formation, low immunogenicity, and anti-inflammatory effects. The therapeutic effects of MSC-Exo on ischemic stroke have been widely explored. However, the underlying mechanism remains unclear. In this study, we established a mouse model of ischemic brain injury induced by occlusion of the middle cerebral artery using the thread bolt method and injected MSC-Exo into the tail vein. We found that administration of MSC-Exo reduced the volume of cerebral infarction in the ischemic brain injury mouse model, increased the levels of interleukin-33 (IL-33) and suppression of tumorigenicity 2 receptor (ST2) in the penumbra of cerebral infarction, and improved neurological function. In vitro results showed that astrocyte-conditioned medium of cells deprived of both oxygen and glucose, to simulate ischemia conditions, combined with MSC-Exo increased the survival rate of primary cortical neurons. However, after transfection by IL-33 siRNA or ST2 siRNA, the survival rate of primary cortical neurons was markedly decreased. These results indicated that MSC-Exo inhibited neuronal death induced by oxygen and glucose deprivation through the IL-33/ST2 signaling pathway in astrocytes. These findings suggest that MSC-Exo may reduce ischemia-induced brain injury through regulating the IL-33/ST2 signaling pathway. Therefore, MSC-Exo may be a potential therapeutic method for ischemic stroke.

A novel circular RNA circRBMS3 regulates proliferation and metastasis of osteosarcoma by targeting miR-424-eIF4B/YRDC axis.

Circular RNAs (circRNAs) have been demonstrated to have critical regulatory roles in tumorigenesis. However, the contribution of circRNAs to OS (osteosarcoma) remains largely unknown. circRNA deep sequencing was performed to the expression of circRNAs between OS and chondroma tissues. The regulatory and functional role of circRBMS3 (a circRNA derived from exons 7 to 10 of the RBMS3 gene, hsa_circ_0064644) upregulation was examined in OS and was validated in vitro and in vivo, upstream regulator and downstream target of circRBMS3 were both explored. RNA pull down, a luciferase reporter assay, biotin-coupled microRNA capture and fluorescence in situ hybridization were used to evaluate the interaction between circRBMS3 and micro (mi)-R-424-5p. For in vivo tumorigenesis experiments, Subcutaneous and Orthotopic xenograft OS mouse models were built. Expression of circRBMS3 was higher in OS tissues due to the regulation of adenosine deaminase 1-acting on RNA (ADAR1), an abundant RNA editing enzyme. Our in vitro data indicated that ShcircRBMS3 inhibits the proliferation and migration of osteosarcoma cells. Mechanistically, we showed that circRBMS3 could regulate eIF4B and YRDC, through 'sponging' miR-424-5p. Furthermore, knockdown of circRBMS3 inhibited malignant phenotypes and bone destruction of OS in vivo. Our results reveal an important role for a novel circRBMS3 in the growth and metastasis of malignant tumor cells and offer a fresh perspective on circRNAs in OS progression.

LncRNA LINC01094 Promotes Cells Proliferation and Metastasis through the PTEN/AKT Pathway by Targeting AZGP1 in Gastric Cancer.

Long noncoding RNAs (lncRNAs) were recently reported to play an essential role in multiple cancer types. Herein, through next-generation sequencing, we screened metastasis-driving molecules by using tissues from early-stage gastric cancer (GC) patients with lymph node metastasis, and we identified a lncRNA LINC01094, which was associated with the metastasis of GC. According to the clinical data from the TCGA, GSE15459, and GSE62254 cohorts, the high expression of LINC01094 was associated with an unfavorable prognosis. Moreover, 106 clinical GC and paired normal samples were collected, and the qRT-PCR results showed that the high expression of LINC01094 was associated with high T and N stages and a poor prognosis. We found that LINC01094 promotes the proliferation and metastasis of GC in vitro and in vivo. AZGP1 was found as the protein-binding partner of LINC01094 by using RNA pulldown and RNA-binding protein immunoprecipitation (RIP) assays. LINC01094 antagonizes the function of AZGP1, downregulates the expression of PTEN, and further upregulates the AKT pathway. Collectively, our results suggested that LINC01094 might predict the prognosis of GC patients and become the therapy target for GC.

The altered functional connectivity density related to cognitive impairment in alcoholics.

Alcohol use disorder (AUD) is one of the most common substance use disorders contributing to both behavioral and cognitive impairments in patients with AUD. Recent neuroimaging studies point out that AUD is a typical disorder featured by altered functional connectivity. However, the details about how voxel-wise functional coordination remain unknown. Here, we adopted a newly proposed method named functional connectivity density (FCD) to depict altered voxel-wise functional coordination in AUD. The novel functional imaging technique, FCD, provides a comprehensive analytical method for brain's "scale-free" networks. We applied resting-state functional MRI (rs-fMRI) toward subjects to obtain their FCD, including global FCD (gFCD), local FCD (lFCD), and long-range FCD (lrFCD). Sixty-one patients with AUD and 29 healthy controls (HC) were recruited, and patients with AUD were further divided into alcohol-related cognitive impairment group (ARCI, n = 11) and non-cognitive impairment group (AUD-NCI, n = 50). All subjects were asked to stay stationary during the scan in order to calculate the resting-state gFCD, lFCD, and lrFCD values, and further investigate the abnormal connectivity alterations among AUD-NCI, ARCI, and HC. Compared to HC, both AUD groups exhibited significantly altered gFCD in the left inferior occipital lobe, left calcarine, altered lFCD in right lingual, and altered lrFCD in ventromedial frontal gyrus (VMPFC). It is notable that gFCD of the ARCI group was found to be significantly deviated from AUD-NCI and HC in left medial frontal gyrus, which changes probably contributed by the impairment in cognition. In addition, no significant differences in gFCD were found between ARCI and HC in left parahippocampal, while ARCI and HC were profoundly deviated from AUD-NCI, possibly reflecting a compensation of cognition impairment. Further analysis showed that within patients with AUD, gFCD values in left medial frontal gyrus are negatively correlated with MMSE scores, while lFCD values in left inferior occipital lobe are positively related to ADS scores. In conclusion, patients with AUD exhibited significantly altered functional connectivity patterns mainly in several left hemisphere brain regions, while patients with AUD with or without cognitive impairment also demonstrated intergroup FCD differences which correlated with symptom severity, and patients with AUD cognitive impairment would suffer less severe alcohol dependence. This difference in symptom severity probably served as a compensation for cognitive impairment, suggesting a difference in pathological pathways. These findings assisted future AUD studies by providing insight into possible pathological mechanisms.

Fully connected autoencoder and convolutional neural network with attention-based method for inferring disease-related lncRNAs.

Since abnormal expression of long noncoding RNAs (lncRNAs) is often closely related to various human diseases, identification of disease-associated lncRNAs is helpful for exploring the complex pathogenesis. Most of recent methods concentrate on exploiting multiple kinds of data related to lncRNAs and diseases for predicting candidate disease-related lncRNAs. These methods, however, failed to deeply integrate the topology information from the meta-paths that are composed of lncRNA, disease and microRNA (miRNA) nodes. We proposed a new method based on fully connected autoencoders and convolutional neural networks, called ACLDA, for inferring potential disease-related lncRNA candidates. A heterogeneous graph that consists of lncRNA, disease and miRNA nodes were firstly constructed to integrate similarities, associations and interactions among them. Fully connected autoencoder-based module was established to extract the low-dimensional features of lncRNA, disease and miRNA nodes in the heterogeneous graph. We designed the attention mechanisms at the node feature level and at the meta-path level to learn more informative features and meta-paths. A module based on convolutional neural networks was constructed to encode the local topologies of lncRNA and disease nodes from multiple meta-path perspectives. The comprehensive experimental results demonstrated ACLDA achieves superior performance than several state-of-the-art prediction methods. Case studies on breast, lung and colon cancers demonstrated that ACLDA is able to discover the potential disease-related lncRNAs.

Integrated DNA and RNA sequencing reveals early drivers involved in metastasis of gastric cancer.

Gastric cancer (GC) is the second cause of cancer-related death and metastasis is an important cause of death. Considering difficulties in searching for metastatic driver mutations, we tried a novel strategy here. We conducted an integrative genomic analysis on GC and identified early drivers lead to metastasis. Whole-exome sequencing (WES), transcriptomes sequencing and targeted-exome sequencing (TES) were performed on tumors and matched normal tissues from 432 Chinese GC patients, especially the comparative analysis between higher metastatic-potential (HMP) group with T1 stage and lymph-node metastasis, and lower metastatic-potential (LMP) group without lymph-nodes or distant metastasis. HMP group presented higher mutation load and heterogeneity, enrichment in immunosuppressive signaling, more immune cell infiltration than LMP group. An integrated mRNA-lncRNA signature based on differentially expressed genes was constructed and its prognostic value was better than traditional TNM stage. We identified 176 candidate prometastatic mutations by WES and selected 8 genes for following TES. Mutated TP53 and MADCAM1 were significantly associated with poor metastasis-free survival. We further demonstrated that mutated MADCAM1 could not only directly promote cancer cells migration, but also could trigger tumor metastasis by establishing immunosuppressive microenvironment, including promoting PD-L1-mediated immune escape and reprogramming tumor-associated macrophages by regulating CCL2 through Akt/mTOR axis. In conclusion, GCs with different metastatic-potential are distinguishable at the genetic level and we revealed a number of potential metastatic driver mutations. Driver mutations in early-onset metastatic GC could promote metastasis by establishing an immunosuppressive microenvironment. This study provided possibility for future target therapy of GC.

Stem cell-homing hydrogel-based miR-29b-5p delivery promotes cartilage regeneration by suppressing senescence in an osteoarthritis rat model.

Osteoarthritis (OA) is a common joint disease characterized by progressive loss of cartilage and reduction in lubricating synovial fluid, which lacks effective treatments currently. Here, we propose a hydrogel-based miRNA delivery strategy to rejuvenate impaired cartilage by creating a regenerative microenvironment to mitigate chondrocyte senescence that mainly contributes to cartilage breakdown during OA development. An aging-related miRNA, miR-29b-5p, was first found to be markedly down-regulated in OA cartilage, and their up-regulation suppressed the expression of matrix metalloproteinases and senescence-associated genes (P16INK4a/P21) via ten-eleven-translocation enzyme 1 (TET1). An injectable bioactive self-assembling peptide nanofiber hydrogel was applied to deliver agomir-29b-5p, which was functionalized by conjugating a stem cell-homing peptide SKPPGTSS for endogenous synovial stem cell recruitment simultaneously. Sustained miR-29b-5p delivery and recruitment of synovial stem cells and their subsequent differentiation into chondrocytes led to successful cartilage repair and chondrocyte rejuvenation. This strategy enables miRNA-based therapeutic modality to become a viable alternative for surgery in OA treatment.

Altered Global Signal Topography in Alcohol Use Disorders.

The most common symptom of patients with alcohol use disorders (AUD) is cognitive impairment that negatively affects abstinence. Presently, there is a lack of indicators for early diagnosis of alcohol-related cognitive impairment (ARCI). We aimed to assess the cognitive deficits in AUD patients with the help of a specific imaging marker for ARCI. Data-driven dynamic and static global signal topography (GST) methods were applied to explore the cross-talks between local and global neuronal activities in the AUD brain. Twenty-six ARCI, 54 AUD without cognitive impairment (AUD-NCI), and gender/age-matched 40 healthy control (HC) subjects were recruited for this study. We found that there was no significant difference with respect to voxel-based morphometry (VBM) and static GST between AUD-NCI and ARCI groups. And in dynamic GST measurements, the AUD-NCI patients had the highest coefficient of variation (CV) at the right insula, followed by ARCI and the HC subjects. In precuneus, the order was reversed. There was no significant correlation between the dynamic GST and behavioral scores or alcohol consumption. These results suggested that dynamic GST might have potential implications in understanding AUD pathogenesis and disease management.

XELOX doublet regimen versus EOX triplet regimen as first-line treatment for advanced gastric cancer: An open-labeled, multicenter, randomized, prospective phase III trial (EXELOX).

BACKGROUND: There is no consensus on whether triplet regimen is better than doublet regimen in the first-line treatment of advanced gastric cancer (AGC). We aimed to compare the efficacy and safety of oxaliplatin plus capecitabine (XELOX) and epirubicin, oxaliplatin, plus capecitabine (EOX) regimens in treating AGC. METHODS: This phase III trial enrolled previously untreated patients with AGC who were randomly assigned to receive the XELOX or EOX regimen. The primary endpoint was non-inferiority in progression-free survival (PFS) for XELOX as compared with EOX on an intention-to-treat basis. RESULTS: Between April 10, 2015 and August 20, 2020, 448 AGC patients were randomized to receive XELOX (n = 222) or EOX (n = 226). The median PFS (mPFS) was 5.0 months (95% confidence interval [CI] = 4.5-6.0 months) in the XELOX arm and 5.5 months (95% CI = 5.0-6.0 months) in the EOX arm (hazard ratio [HR] = 0.989, 95% CI = 0.812-1.203; Pnon-inferiority = 0.003). There was no significant difference in median overall survival (mOS) (12.0 vs. 12.0 months, P = 0.384) or objective response rate (37.4% vs. 45.1%, P = 0.291) between the two groups. In patients with poorly differentiated adenocarcinoma and liver metastasis, the EOX arm had a significantly longer mOS (P = 0.021) and a trend of longer mPFS (P = 0.073) than the XELOX arm. The rate of grade 3/4 adverse events (AEs) was 42.2% (90/213) in the XELOX arm and 72.5% (156/215) in the EOX arm (P = 0.001). The global health-related quality of life (QoL) score was significantly higher in the XELOX arm than in the EOX arm during chemotherapy. CONCLUSIONS: This non-inferiority trial demonstrated that the doublet regimen was as effective as the triplet regimen and had a better safety profile and QoL as a first-line treatment for AGC patients. However, the triplet regimen might have a survival advantage in patients with poorly differentiated adenocarcinoma and liver metastasis.

Exosomes derived from bone marrow mesenchymal stem cells protect the injured spinal cord by inhibiting pericyte pyroptosis.

Mesenchymal stem cell (MSC) transplantation is a promising treatment strategy for spinal cord injury, but immunological rejection and possible tumor formation limit its application. The therapeutic effects of MSCs mainly depend on their release of soluble paracrine factors. Exosomes are essential for the secretion of these paracrine effectors. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-EXOs) can be substituted for BMSCs in cell transplantation. However, the underlying mechanisms remain unclear. In this study, a rat model of T10 spinal cord injury was established using the impact method. Then, 30 minutes and 1 day after spinal cord injury, the rats were administered 200 µL exosomes via the tail vein (200 µg/mL; approximately 1 × 106 BMSCs). Treatment with BMSC-EXOs greatly reduced neuronal cell death, improved myelin arrangement and reduced myelin loss, increased pericyte/endothelial cell coverage on the vascular wall, decreased blood-spinal cord barrier leakage, reduced caspase 1 expression, inhibited interleukin-1ß release, and accelerated locomotor functional recovery in rats with spinal cord injury. In the cell culture experiment, pericytes were treated with interferon-γ and tumor necrosis factor-α. Then, Lipofectamine 3000 was used to deliver lipopolysaccharide into the cells, and the cells were co-incubated with adenosine triphosphate to simulate injury in vitro. Pre-treatment with BMSC-EXOs for 8 hours greatly reduced pericyte pyroptosis and increased pericyte survival rate. These findings suggest that BMSC-EXOs may protect pericytes by inhibiting pyroptosis and by improving blood-spinal cord barrier integrity, thereby promoting the survival of neurons and the extension of nerve fibers, and ultimately improving motor function in rats with spinal cord injury. All protocols were conducted with the approval of the Animal Ethics Committee of Zhengzhou University on March 16, 2019.