The prognostic value and potential immunotherapeutic efficacy of ACVR1 in treating gastric cancer.

Background: The discovery of biomarkers has facilitated the treatment of cancer. At present, the relationship between activin A receptor type-1 (ACVR1) and gastric cancer is gradually discovered. The aim of this study was to explore the expression of ACVR1 in gastric cancer and its clinical significance, to study the relationship between ACVR1 and tumor microenvironment (TME) for the prognosis of gastric cancer, and to further identify new targets for immunotherapy in gastric cancer. Methods: ACVR1 was first selected as a study gene according to several cancer and gastric cancer public datasets. Its pancancer expression was explored using the UCSC Xena database. The expression level, prognosis, and clinicopathological features of ACVR1 in gastric cancer were analyzed using The Cancer Genome Atlas (TCGA) database. Immunohistochemistry (IHC)-based experiments were conducted to study the expression of ACVR1 at the protein level. The IHC data were analyzed for correlations between ACVR1 expression and various clinicopathological factors and prognosis. The correlation of this gene with the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, immune infiltration, immune checkpoints, drug therapy, tumor mutation burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR) system was analyzed using R software. Results: TCGA data showed that the expression of ACVR1 was higher in gastric cancer tissues than in paracancerous tissues. Moreover, the IHC experiments indicated that ACVR1 was upregulated in gastric cancer tissues at the protein level. Both univariate Cox and multivariate Cox results showed that the increase of ACVR1 was closely associated with tumor stage, size, lymph node metastasis, and age. High ACVR1 expression was linked to a poor prognosis of gastric cancer. The results also revealed that ACVR1 was closely related to suppressive immune cells and pathways. Analyses of immune checkpoints, antitumor drug, TMB, and immune microenvironment indicated that ACVR1 had an antitumor immune effect, promoting gastric cancer development and leading to poor immunotherapy. Conclusions: High ACVR1 expression can be used as an independent prognostic factor to predict the prognostic survival of patients with gastric cancer. ACVR1 expression in gastric cancer tissues was significantly correlated with immune infiltration and may thus serve as a potential therapeutic target for gastric cancer immunotherapy.

Adenoid cystic carcinoma of head and neck: Summary and review of imaging findings.

Purpose: Current reports of adenoid cystic carcinoma of the head and neck (ACC) are all case reports, and there is no basilar summary of its imaging findings. This study aims to summarise ACC's computed tomography (CT) and magnetic resonance imaging (MRI) findings to improve radiologists' knowledge of this disease. Methods: We collected clinical and imaging data of patients with ACC during the last decade, and two radiologists retrospectively analysed the imaging characteristics. Results: Of the 16 patients included, six were able to self-perceive bulkiness, and 11 had regional pain. Tumour morphology was regular in six cases, with clear borders in 11 cases, invasion of the surrounding bony mass in 12 cases, and invasion of peripheral nerves in 15 cases. CT mostly shows an irregular soft-tissue density mass with mild-to-moderate enhancement after contrast medium administration. On MRI, the ACC showed isointense or hypointense signals on T1-weighted images (T1WI) and hyperintense or slightly hyperintense signals on T2-weighted images (T2WI). All signals were markedly enhanced after gadolinium enhancement. Conclusions: ACC often has an irregular morphology, sometimes with a cystic component, enhancement on enhancement scans, easy destruction of adjacent bone, and invasion of peripheral nerves. The diagnosis should be considered when these features are encountered in clinical practice.

MRI features of neuronal intranuclear inclusion disease, combining visual and quantitative imaging investigations.

OBJECTIVE: To observe the radiological characteristics of Neuronal Intranuclear Inclusion Disease (NIID) on lesion locations and diffusion property using quantitative imaging analysis. METHODS: Visual inspection and quantitative analyses were performed on MRI data from 31 retrospectively included patients with NIID. Frequency heatmaps of lesion locations on T2WI and DWI were generated using voxel-wise analysis. Gray matter volume (GMV), white matter volume (WMV) and diffusion property of apparent diffusion coefficient (ADC) values of patients were voxel-wisely compared with healthy controls. Moreover, the ADC values within the DWI-detected lesion were compared with those within the adjacent cortical gray matter and white matter. Voxel-based lesion symptom mapping (VLSM) techniques, were used to determine the relationship between DWI lesion location and disease durations. RESULTS: By visual inspection on the imaging findings, we proposed an "cockscomb flower sign" for describing the radiological feature of DWI hyperintensity within the corticomedullary junction. A "T2WI-DWI mismatch of spatial distribution" pattern was also revealed with visual inspection and frequency heatmaps, for describing the feature of a wider lesion distribution covering white matter shown on T2WI than that on DWI. Voxel-based morphometry comparison revealed that wildly reduced GMV and WMV, both the lesion areas detected by DWI and T2WI demonstrated ADC increase in patients. Furthermore, the ADC values within the DWI-detected lesion were intermediate between the adjacent cortex and the deep white matter with highest ADC. VLSM analysis revealed that frontal lobe, parietal lobe and internal capsule damage were associated with higher NIID durations. CONCLUSION: NIID features with "cockscomb flower-like" DWI hyperintensity in area of corticomedullary junction, based on a "T2WI-DWI mismatch of spatial distribution" of lesion locations. The pathological substrate of corticomedullary junction hyperintensity on DWI, can not be explained as diffusion restriction. These typical radiological features of brain MRI would be helpful for diagnosis of NIID.

Global, but not chondrocyte-specific, MT1-MMP deficiency in adult mice causes inflammatory arthritis.

Membrane-type I metalloproteinase (MT1-MMP/MMP14) plays a key role in various pathophysiological processes, indicating an unaddressed need for a targeted therapeutic approach. However, mice genetically deficient in Mmp14 show severe defects in development and growth. To investigate the possibility of MT1-MMP inhibition as a safe treatment in adults, we generated global Mmp14 tamoxifen-induced conditional knockout (Mmp14kd) mice and found that MT1-MMP deficiency in adult mice resulted in severe inflammatory arthritis. Mmp14kd mice started to show noticeably swollen joints two weeks after tamoxifen administration, which progressed rapidly. Mmp14kd mice reached a humane endpoint 6 to 8 weeks after tamoxifen administration due to severe arthritis. Plasma TNF-α levels were also significantly increased in Mmp14kd mice. Detailed analysis revealed chondrocyte hypertrophy, synovial fibrosis, and subchondral bone remodeling in the joints of Mmp14kd mice. However, global conditional knockout of MT1-MMP in adult mice did not affect body weight, blood glucose, or plasma cholesterol and triglyceride levels. Furthermore, we observed substantial expression of MT1-MMP in the articular cartilage of patients with osteoarthritis. We then developed chondrocyte-specific Mmp14 tamoxifen-induced conditional knockout (Mmp14chkd) mice. Chondrocyte MT1-MMP deficiency in adult mice also caused apparent chondrocyte hypertrophy. However, Mmp14chkd mice did not exhibit synovial hyperplasia or noticeable arthritis, suggesting that chondrocyte MT1-MMP is not solely responsible for the onset of severe arthritis observed in Mmp14kd mice. Our findings also suggest that highly cell-type specific inhibition of MT1-MMP is required for its potential therapeutic use.

Extracellular matrix turnover: phytochemicals target and modulate the dual role of matrix metalloproteinases (MMPs) in liver fibrosis.

Extracellular matrix (ECM) resolution by matrix metalloproteinases (MMPs) is a well-documented mechanism. MMPs play a dual and complex role in modulating ECM degradation at different stages of liver fibrosis, depending on the timing and levels of their expression. Increased MMP-1 combats disease progression by cleaving the fibrillar ECM. Activated hepatic stellate cells (HSCs) increase expression of MMP-2, -9, and -13 in different chemicals-induced animal models, which may alleviate or worsen disease progression based on animal models and the stage of liver fibrosis. In the early stage, elevated expression of certain MMPs may damage surrounding tissue and activate HSCs, promoting fibrosis progression. At the later stage, downregulation of MMPs can facilitate ECM accumulation and disease progression. A number of phytochemicals modulate MMP activity and ECM turnover, alleviating disease progression. However, the effects of phytochemicals on the expression of different MMPs are variable and may depend on the disease models and stage, and the dosage, timing and duration of phytochemicals used in each study. Here, we review the most recent advances in the role of MMPs in the effects of phytochemicals on liver fibrogenesis, which indicates that further studies are warranted to confirm and define the potential clinical efficacy of these phytochemicals.

Corrigendum: Loss of hepatic Surf4 depletes lipid droplets in the adrenal cortex but does not impair adrenal hormone production.

[This corrects the article DOI: 10.3389/fcvm.2021.764024.].

Physiological ischemic training improves cardiac function through the attenuation of cardiomyocyte apoptosis and the activation of the vagus nerve in chronic heart failure.

Purpose: This study investigated the functional outcomes of patients with chronic heart failure (CHF) after physiological ischemic training (PIT), identified the optimal PIT protocol, evaluated its cardioprotective effects and explored the underlying neural mechanisms. Methods: Patients with CHF were randomly divided into experimental group (n = 25, PIT intervention + regular treatment) and control group (n = 25, regular treatment). The outcomes included the left ventricular ejection fraction (LVEF), brain natriuretic peptide (BNP) and cardiopulmonary parameters. LVEF and cardiac biomarkers in CHF rats after various PIT treatments (different in intensity, frequency, and course of treatment) were measured to identify the optimal PIT protocol. The effect of PIT on cardiomyocyte programmed cell death was investigated by western blot, flow cytometry and fluorescent staining. The neural mechanism involved in PIT-induced cardioprotective effect was assessed by stimulation of the vagus nerve and muscarinic M2 receptor in CHF rats. Results: LVEF and VO2max increased while BNP decreased in patients subjected to PIT. The optimal PIT protocol in CHF rats was composed of five cycles of 5 min ischemia followed by 5 min reperfusion on remote limbs for 8 weeks. LVEF and cardiac biomarker levels were significantly improved, and cardiomyocyte apoptosis was inhibited. However, these cardioprotective effects disappeared after subjecting CHF rats to vagotomy or muscarinic M2 receptor inhibition. Conclusion: PIT improved functional outcomes in CHF patients. The optimal PIT protocol required appropriate intensity, reasonable frequency, and adequate treatment course. Under these conditions, improvement of cardiac function in CHF was confirmed through cardiomyocyte apoptosis reduction and vagus nerve activation.

ß-secretase 1 overexpression by AAV-mediated gene delivery prevents retina degeneration in a mouse model of age-related macular degeneration.

We reported previously that ß-site amyloid precursor protein cleaving enzyme (BACE1) is strongly expressed in the normal retina and that BACE1-/- mice develop pathological phenotypes associated with age-related macular degeneration (AMD). BACE1 expression is increased within the neural retina and retinal pigment epithelium (RPE) in AMD donor eyes suggesting that increased BACE1 is compensatory. We observed that AAV-mediated BACE1 overexpression in the RPE was maintained up to 6 months after AAV1-BACE1 administration. No significant changes in normal mouse visual function or retinal morphology were observed with low-dose vector while the high-dose vector demonstrated some early pathology which regressed with time. No increase in ß-amyloid was observed. BACE1 overexpression in the RPE of the superoxide dismutase 2 knockdown (SOD2 KD) mouse, which exhibits an AMD-like phenotype, prevented loss of retinal function and retinal pathology, and this was sustained out to 6 months. Furthermore, BACE1 overexpression was able to inhibit oxidative stress, microglial changes, and loss of RPE tight junction integrity (all features of AMD) in SOD2 KD mice. In conclusion, BACE1 plays a key role in retina/RPE homeostasis, and BACE1 overexpression offers a novel therapeutic target in the treatment of AMD.

Surf4 (Surfeit Locus Protein 4) Deficiency Reduces Intestinal Lipid Absorption and Secretion and Decreases Metabolism in Mice.

BACKGROUND: Postprandial dyslipidemia is a causative risk factor for cardiovascular disease. The majority of absorbed dietary lipids are packaged into chylomicron and then delivered to circulation. Previous studies showed that Surf4 (surfeit locus protein 4) mediates very low-density lipoprotein secretion from hepatocytes. Silencing hepatic Surf4 markedly reduces the development of atherosclerosis in different mouse models of atherosclerosis without causing hepatic steatosis. However, the role of Surf4 in chylomicron secretion is unknown. METHODS: We developed inducible intestinal-specific Surf4 knockdown mice (Surf4IKO) using Vil1Cre-ERT2 and Surf4flox mice. Metabolic cages were used to monitor mouse metabolism. Enzymatic kits were employed to measure serum and tissue lipid levels. The expression of target genes was detected by qRT-PCR and Western Blot. Transmission electron microscopy and radiolabeled oleic acid were used to assess the structure of enterocytes and intestinal lipid absorption and secretion, respectively. Proteomics was performed to determine changes in protein expression in serum and jejunum. RESULTS: Surf4IKO mice, especially male Surf4IKO mice, displayed significant body weight loss, increased mortality, and reduced metabolism. Surf4IKO mice exhibited lipid accumulation in enterocytes and impaired fat absorption and secretion. Lipid droplets and small lipid vacuoles were accumulated in the cytosol and the endoplasmic reticulum lumen of the enterocytes of Surf4IKO mice, respectively. Surf4 colocalized with apoB and co-immunoprecipitated with apoB48 in differentiated Caco-2 cells. Intestinal Surf4 deficiency also significantly reduced serum triglyceride, cholesterol, and free fatty acid levels in mice. Proteomics data revealed that diverse pathways were altered in Surf4IKO mice. In addition, Surf4IKO mice had mild liver damage, decreased liver size and weight, and reduced hepatic triglyceride levels. CONCLUSIONS: Our findings demonstrate that intestinal Surf4 plays an essential role in lipid absorption and chylomicron secretion and suggest that the therapeutic use of Surf4 inhibition requires highly cell/tissue-specific targeting.

The Value of Dual-Energy Computed Tomography Angiography-Derived Parameters in the Evaluation of Clot Composition.

OBJECTIVES: We aimed to assess the value of dual-energy computed tomography angiography (DE-CTA) derived parameters as a quantitative biomarker of thrombus composition in acute ischemic stroke (AIS). METHODS: AIS patients who underwent DE-CTA before thrombectomy between August 2016 and September 2022 were included in this study. We assessed the relative proportion of red blood cells (RBCs) and the fibrin/platelet ratio (F/P) of the retrieved clots and categorized the clots as RBC-dominant (RBCs > F/P) or F/P-dominant (F/P > RBCs). The thrombus based parameters were measured on polyenergetic images (PEI), virtual monoenergetic (VM), virtual non-contrast (VNC), iodine concentration (IC), and effective atomic number (Zeff) images respectively, and the slope of the spectral Hounsfield unit curve (λHU) was calculated. These parameters were compared in the DE-CTA images of RBC- and F/P-dominant thrombi. The diagnostic performance of the parameters was analyzed using the ROC curve. Correlations between thrombus composition and DE-CTA-derived parameters were assessed. RESULTS: The retrieved clots in 54 of 88 patients (61.36%) were RBC-dominant. The RBC-dominant thrombi showed significantly higher VNC values and lower IC, λHU, and Zeff values than the F/P-dominant thrombi (p < 0.05). The CT density measured on IC images showed the largest AUC value (AUC, 0.94; sensitivity, 77.78%; specificity, 100.00%). The Spearman rank-order correlation coefficient values showed that CT density measured on IC images of the thrombus showed the strongest association with the proportion of RBCs (r = -0.64, p < 0.001) and F/P (r = 0.65, p < 0.001). CONCLUSIONS: DE-CTA-derived parameters, especially the CT density measured on IC images, could be associated with thrombus composition and allow for personalized thrombectomy strategies.

CT-based radiomics nomogram for the pre-operative prediction of lymphovascular invasion in colorectal cancer: a multicenter study.

OBJECTIVE: To develop and externally validate a CT-based radiomics nomogram for the pre-operative prediction of lymphovascular invasion (LVI) in patients with colorectal cancer (CRC). METHODS: 357 patients derived from 2 centers with pathologically confirmed CRC were included in this retrospective study. Two-dimensional (2D) and three-dimensional (3D) radiomics features were extracted from portal venous phase CT images. The least absolute shrinkage and selection operator algorithm and logistic regression were used for constructing 2D and 3D radiomics models. The radiomics nomogram was developed by integrating the radiomics score (rad-score) and the clinical risk factor. RESULTS: The rad-score was significantly higher in the LVI+ group than in the LVI- group (p < 0.05). The area under the curve (AUC), accuracy, sensitivity and specificity of the 3D radiomics model were higher than those of the 2D radiomics model. The AUCs of 3D and 2D radiomics models in the training set were 0.82 (95% CI: 0.75-0.89) and 0.74 (95% CI: 0.66-0.82); in the internal validation set were 0.75 (95% CI: 0.65-0.85) and 0.67 (95% CI: 0.56-0.78); in the external validation set were 0.75 (95% CI: 0.64-0.86) and 0.57 (95% CI: 0.45-0.69); respectively. The AUCs of the nomogram integrating the optimal 3D rad-score and clinical risk factors (CT-reported T stage, CT-reported lymph node status) in the internal set and external validation set were 0.82 (95% CI: 0.73-0.91) and 0.80 (95% CI: 0.68-0.91), respectively. CONCLUSION: Both 2D and 3D radiomics models can predict LVI status of CRC. The nomogram combining the optimal 3D rad-score and clinical risk factors further improved predictive performance. ADVANCES IN KNOWLEDGE: This is the first study to compare the difference in performance of CT-based 2D and 3D radiomics models for the pre-operative prediction of LVI in CRC. The prediction of the nomogram could be improved by combining the 3D radiomics model with the imaging model, suggesting its potential for clinical application.

Surf4, cargo trafficking, lipid metabolism, and therapeutic implications.

Surfeit 4 is a polytopic transmembrane protein that primarily resides in the endoplasmic reticulum (ER) membrane. It is ubiquitously expressed and functions as a cargo receptor, mediating cargo transport from the ER to the Golgi apparatus via the canonical coat protein complex II (COPII)-coated vesicles or specific vesicles. It also participates in ER-Golgi protein trafficking through a tubular network. Meanwhile, it facilitates retrograde transportation of cargos from the Golgi apparatus to the ER through COPI-coated vesicles. Surf4 can selectively mediate export of diverse cargos, such as PCSK9 very low-density lipoprotein (VLDL), progranulin, α1-antitrypsin, STING, proinsulin, and erythropoietin. It has been implicated in facilitating VLDL secretion, promoting cell proliferation and migration, and increasing replication of positive-strand RNA viruses. Therefore, Surf4 plays a crucial role in various physiological and pathophysiological processes and emerges as a promising therapeutic target. However, the molecular mechanisms by which Surf4 selectively sorts diverse cargos for ER-Golgi protein trafficking remain elusive. Here, we summarize the most recent advances in Surf4, focusing on its role in lipid metabolism.

Liquiritin alleviates alpha-naphthylisothiocyanate-induced intrahepatic cholestasis through the Sirt1/FXR/Nrf2 pathway.

Liquiritin (LQ) is an important monomer active component in flavonoids of licorice. The objective of this study was to evaluate the hepatoprotective effects of LQ in cholestatic mice. LQ (40 or 80 mg/kg) was intragastrically administered to mice once daily for 6 days, and mice were treated intragastrically with a single dosage of ANIT (75 mg/kg) on the 5th day. On the 7th day, mice were sacrificed to collect blood and livers. The mRNA and protein levels were determined by qRT-PCR and western blot assay. We also conducted systematical assessments of miRNAs expression profiles in the liver. LQ ameliorated ANIT-induced cholestatic liver injury, as evidenced by reduced serum biochemical markers and attenuated pathological changes in liver. Pretreatment of LQ reduced the increase of malondialdehyde, TNF-α, and IL-1ß induced by ANIT. Moreover, ANIT suppressed the expression of Sirt1 and FXR in liver tissue, which was weakened in the LQ pre-treatment group. LQ enhanced the nuclear expression of Nrf2, which was increased in the ANIT group. LQ also increased the mRNA expressions of bile acid transporters Bsep, Ntcp, Mrp3, and Mrp4. Furthermore, a miRNA deep sequencing analysis revealed that LQ had a global regulatory effect on the hepatic miRNA expression. Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis showed that the differentially expressed miRNAs were mainly related to metabolic pathways, endocytosis, and MAPK signaling pathway. Collectively, LQ attenuated hepatotoxicity and cholestasis by regulating the expression of Sirt1/FXR/Nrf2 and the bile acid transporters, indicating that LQ might be an effective approach for cholestatic liver diseases.

Identification of amino acid residues in the MT-loop of MT1-MMP critical for its ability to cleave low-density lipoprotein receptor.

Low-density lipoprotein receptor (LDLR) mediates clearance of plasma LDL cholesterol, preventing the development of atherosclerosis. We previously demonstrated that membrane type 1-matrix metalloproteinase (MT1-MMP) cleaves LDLR and exacerbates the development of atherosclerosis. Here, we investigated determinants in LDLR and MT1-MMP that were critical for MT1-MMP-induced LDLR cleavage. We observed that deletion of various functional domains in LDLR or removal of each of the five predicted cleavage sites of MT1-MMP on LDLR did not affect MT1-MMP-induced cleavage of the receptor. Removal of the hemopexin domain or the C-terminal cytoplasmic tail of MT1-MMP also did not impair its ability to cleave LDLR. On the other hand, mutant MT1-MMP, in which the catalytic domain or the MT-loop was deleted, could not cleave LDLR. Further Ala-scanning analysis revealed an important role for Ile at position 167 of the MT-loop in MT1-MMP's action on LDLR. Replacement of Ile167 with Ala, Thr, Glu, or Lys resulted in a marked loss of the ability to cleave LDLR, whereas mutation of Ile167 to a non-polar amino acid residue, including Leu, Val, Met, and Phe, had no effect. Therefore, our studies indicate that MT1-MMP does not require a specific cleavage site on LDLR. In contrast, an amino acid residue with a hydrophobic side chain at position 167 in the MT-loop is critical for MT1-MMP-induced LDLR cleavage.

Comprehensive Curative Effect of Targeting PD-1 or Traditional Single-Agent Chemotherapy in Second-Line Therapy for Terminal or Metastatic Esophageal Cancer: A Systematic Review and Meta-Analysis.

The number of programmed cell death protein 1 (PD-1) inhibitors is gradually increasing; this study aimed to comprehensively and systematically evaluate the impact of PD-1 inhibitors as second-line therapy for terminal or metastatic esophageal cancer (EC) on patient survival and the occurrence of adverse events. Suitable randomized controlled trials (RCTs) were retrieved from PubMed, Web of Science, Embase, and Cochrane Library databases. Moreover, we searched for conference abstracts from the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) to compare the comprehensive curative effects of PD-1 inhibitors or single-agent therapy in terminal or metastatic EC. The primary outcome indicators were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Treatment-related adverse events (TRAEs) were the secondary outcome indicators. We compared the previously mentioned indicators of the two treatment modalities using Stata software (version 12.0). We compared the long-term survival rates of both treatment groups and analyzed the possible factors affecting OS. We selected five RCTs with 2197 patients as study subjects. Compared with conventional single-agent chemotherapy, PD-1 inhibitors greatly improved the patients' OS (HR = 0.77, 95% CI 0.70-0.85, P < 0.001), but PFS (HR = 0.93, 95% CI 0.77-1.12, P=0.431) and DCR (RR = 0.93, 95% CI 0.71-1.22, P=0.609) were not greatly improved. Moreover, PD-1 inhibitors improved ORR (RR = 1.83, 95% CI 1.16-2.89, P=0.009) and decreased TRAEs (RR = 0.76, 95% CI 0.61-0.95, P < 0.001) and serious TRAEs (RR = 0.40, 95% CI 0.32-0.49, P < 0.001). Further analysis demonstrated that OS was affected by age, sex, region, smoking history, and the number of organ and lymph node metastases. Compared with the traditional single chemotherapy drugs, PD-1 inhibitors can achieve higher OS and ORR, fewer and more serious TRAEs, and better efficacy and safety for second-line therapy of terminal or metastatic EC.

Computed tomography-based radiomics nomogram for the preoperative prediction of perineural invasion in colorectal cancer: a multicentre study.

PURPOSE: To develop and validate a computed tomography (CT) radiomics nomogram from multicentre datasets for preoperative prediction of perineural invasion (PNI) in colorectal cancer. METHODS: A total of 299 patients with histologically confirmed colorectal cancer from three hospitals were enrolled in this retrospective study. Radiomic features were extracted from the whole tumour volume. The least absolute shrinkage and selection operator logistic regression was applied for feature selection and radiomics signature construction. Finally, a radiomics nomogram combining the radiomics score and clinical predictors was established. The receiver operating characteristic curve and decision curve analysis (DCA) were used to evaluate the predictive performance of the radiomics nomogram in the training cohort, internal validation and external validation cohorts. RESULTS: Twelve radiomics features extracted from the whole tumour volume were used to construct the radiomics model. The area under the curve (AUC) values of the radiomics model in the training cohort, internal validation cohort, external validation cohort 1, and external validation cohort 2 were 0.82 (0.75-0.90), 0.77 (0.62-0.92), 0.71 (0.56-0.85), and 0.73 (0.60-0.85), respectively. The nomogram, which combined the radiomics score with T category and N category by CT, yielded better performance in the training cohort (AUC = 0.88), internal validation cohort (AUC = 0.80), external validation cohort 1 (AUC = 0.75), and external validation cohort 2 (AUC = 0.76). DCA confirmed the clinical utility of the nomogram. CONCLUSIONS: The CT-based radiomics nomogram has the potential to accurately predict PNI in patients with colorectal cancer.

Overexpression of Decay Accelerating Factor Mitigates Fibrotic Responses to Lung Injury.

CD55 or decay accelerating factor (DAF), a ubiquitously expressed glycosylphosphatidylinositol (GPI)-anchored protein, confers a protective threshold against complement dysregulation which is linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Since lung fibrosis is associated with downregulation of DAF, we hypothesize that overexpression of DAF in fibrosed lungs will limit fibrotic injury by restraining complement dysregulation. Normal primary human alveolar type II epithelial cells (AECs) exposed to exogenous complement 3a or 5a, and primary AECs purified from IPF lungs demonstrated decreased membrane-bound DAF expression with concurrent increase in the endoplasmic reticulum (ER) stress protein, ATF6. Increased loss of extracellular cleaved DAF fragments was detected in normal human AECs exposed to complement 3a or 5a, and in lungs of IPF patients. C3a-induced ATF6 expression and DAF loss was inhibited using pertussis toxin (an enzymatic inactivator of G-protein coupled receptors), in murine AECs. Treatment with soluble DAF abrogated tunicamycin-induced C3a secretion and ER stress (ATF6 and BiP expression) and restored epithelial cadherin. Bleomycin-injured fibrotic mice subjected to lentiviral overexpression of DAF demonstrated diminished levels of local collagen deposition and complement activation. Further analyses showed diminished release of DAF fragments, as well as reduction in apoptosis (TUNEL and caspase 3/7 activity), and ER stress-related transcripts. Loss-of-function studies using Daf1 siRNA demonstrated worsened lung fibrosis detected by higher mRNA levels of Col1a1 and epithelial injury-related Muc1 and Snai1, with exacerbated local deposition of C5b-9. Our studies provide a rationale for rescuing fibrotic lungs via DAF induction that will restrain complement dysregulation and lung injury.

The role of hepatic Surf4 in lipoprotein metabolism and the development of atherosclerosis in apoE-/- mice.

Elevated plasma levels of low-density lipoprotein-C (LDL-C) increase the risk of atherosclerotic cardiovascular disease. Circulating LDL is derived from very low-density lipoprotein (VLDL) metabolism and cleared by LDL receptor (LDLR). We have previously demonstrated that cargo receptor Surfeit 4 (Surf4) mediates VLDL secretion. Inhibition of hepatic Surf4 impairs VLDL secretion, significantly reduces plasma LDL-C levels, and markedly mitigates the development of atherosclerosis in LDLR knockout (Ldlr-/-) mice. Here, we investigated the role of Surf4 in lipoprotein metabolism and the development of atherosclerosis in another commonly used mouse model of atherosclerosis, apolipoprotein E knockout (apoE-/-) mice. Adeno-associated viral shRNA was used to silence Surf4 expression mainly in the liver of apoE-/- mice. In apoE-/- mice fed a regular chow diet, knockdown of Surf4 expression significantly reduced triglyceride secretion and plasma levels of non-HDL cholesterol and triglycerides without causing hepatic lipid accumulation or liver damage. When Surf4 was knocked down in apoE-/- mice fed the Western-type diet, we observed a significant reduction in plasma levels of non-HDL cholesterol, but not triglycerides. Knockdown of Surf4 did not increase hepatic cholesterol and triglyceride levels or cause liver damage, but significantly diminished atherosclerosis lesions. Therefore, our findings indicate the potential of hepatic Surf4 inhibition as a novel therapeutic strategy to reduce the risk of atherosclerotic cardiovascular disease.

A novel long excitation/emission wavelength fluorophore as platform utilized to construct NIR probes for bioimaging and biosensing.

Near-infrared (NIR) fluorophores, especially dicyano-based fluorophores and xanthene-based hemicyanines, have beenput high expectation in bioimaging application due to their excellent optical properties. However, they suffer from inherentshortagessuch as short excitation/emission wavelength (less than 700 nm) or small Stokes shift (20-50 nm). Herein, we constructed a novel NIR dicyano-based fluorophore (DCO-HBTN). Toourknowledge, it is the first reported dicyano-based fluorophore of which the excitation/emission wavelength is more than 650 nm and Stokes shift is more than 100 nm. To demonstrate the feasibility of our efforts, we developed two NIR fluorescent probes (Probe-Cys and Probe-H2S) based on the fluorophore, Probe-Cys displayed good selective and highly sensitive (LOD = 0.28 µM) recognition of Cys over Hcy and GSH, which was used to visualize endogenous Cys in tumor tissue. Probe-H2S exhibited an. excellent specific and sensitive (LOD = 0.11 µM) response to H2S, which was applied in monitoring H2S releasing from the prodrug in vitro and in vivo.