CRKL dictates anti-PD-1 resistance by mediating tumor-associated neutrophil infiltration in hepatocellular carcinoma.

BACKGROUND & AIMS: The effectiveness of immune checkpoint inhibitor (ICI) therapy for hepatocellular carcinoma (HCC) is limited by treatment resistance. However, the mechanisms underlying immunotherapy resistance remain elusive. We aimed to identify the role of CT10 regulator of kinase-like (CRKL) in resistance to anti-PD-1 therapy in HCC. METHODS: Gene expression in HCC specimens from 10 patients receiving anti-PD-1 therapy was identified by RNA-sequencing. A total of 404 HCC samples from tissue microarrays were analyzed by immunohistochemistry. Transgenic mice (Alb-Cre/Trp53fl/fl) received hydrodynamic tail vein injections of a CRKL-overexpressing vector. Mass cytometry by time of flight was used to profile the proportion and status of different immune cell lineages in the mouse tumor tissues. RESULTS: CRKL was identified as a candidate anti-PD-1-resistance gene using a pooled genetic screen. CRKL overexpression nullifies anti-PD-1 treatment efficacy by mobilizing tumor-associated neutrophils (TANs), which block the infiltration and function of CD8+ T cells. PD-L1+ TANs were found to be an essential subset of TANs that were regulated by CRKL expression and display an immunosuppressive phenotype. Mechanistically, CRKL inhibits APC (adenomatous polyposis coli)-mediated proteasomal degradation of ß-catenin by competitively decreasing Axin1 binding, and thus promotes VEGFα and CXCL1 expression. Using human HCC samples, we verified the positive correlations of CRKL/ß-catenin/VEGFα and CXCL1. Targeting CRKL using CRISPR-Cas9 gene editing (CRKL knockout) or its downstream regulators effectively restored the efficacy of anti-PD-1 therapy in an orthotopic mouse model and a patient-derived organotypic tumor spheroid model. CONCLUSIONS: Activation of the CRKL/ß-catenin/VEGFα and CXCL1 axis is a critical obstacle to successful anti-PD-1 therapy. Therefore, CRKL inhibitors combined with anti-PD-1 could be useful for the treatment of HCC. IMPACT AND IMPLICATIONS: Here, we found that CRKL was overexpressed in anti-PD-1-resistant hepatocellular carcinoma (HCC) and that CRKL upregulation promotes anti-PD-1 resistance in HCC. We identified that upregulation of the CRKL/ß-catenin/VEGFα and CXCL1 axis contributes to anti-PD-1 tolerance by promoting infiltration of tumor-associated neutrophils. These findings support the strategy of bevacizumab-based immune checkpoint inhibitor combination therapy, and CRKL inhibitors combined with anti-PD-1 therapy may be developed for the treatment of HCC.

Early predictors of severe left main and/or three-vessel disease in patients with non-ST-segment elevation myocardial infarction: A dual-center retrospective study.

BACKGROUND: Early detection of patients concomitant with left main and/or three-vessel disease (LM/3VD) and high SYNTAX score (SS) is crucial for determining the most effective revascularization options regarding the use of antiplatelet medications and prognosis risk stratification. However, there is a lack of study for predictors of LM/3VD with SS in patients with non-ST-segment elevation myocardial infarction (NSTEMI). We aimed to identify potential factors that could predict LM/3VD with high SS (SS > 22) in patients with NSTEMI. METHODS: This dual-center retrospective study included a total of 481 patients diagnosed with NSTEMI who performed coronary angiography procedures. Clinical factors on admission were collected. The patients were divided into non-LM/3VD, Nonsevere LM/3VD (SS ≤ 22), and Severe LM/3VD (SS > 22) groups. To identify independent predictors, Univariate and logistic regression analyses were conducted on the clinical parameters. RESULTS: A total of 481 patients were included, with an average age of 60.9 years and 75.9% being male. Among these patients, 108 individuals had severe LM/3VD. Based on the findings of a multivariate logistic regression analysis, the extent of ST-segment elevation observed in lead aVR (OR: 7.431, 95% CI: 3.862-14.301, p < .001) and age (OR: 1.050, 95% CI: 1.029-1.071, p < .001) were identified as independent predictors of severe LM/3VD. CONCLUSION: This study indicated that the age of patients and the extent of ST-segment elevation observed in lead aVR on initial electrocardiogram were the independent predictive factors of LM/3VD with high SS in patients with NSTEMI.

A new magnetic resonance imaging tumour response grading scheme for locally advanced rectal cancer.

BACKGROUND: The potential of using magnetic resonance image tumour-regression grading (MRI-TRG) system to predict pathological TRG is debatable for locally advanced rectal cancer treated by neoadjuvant radiochemotherapy. METHODS: Referring to the American Joint Committee on Cancer/College of American Pathologists (AJCC/CAP) TRG classification scheme, a new four-category MRI-TRG system based on the volumetric analysis of the residual tumour and radiochemotherapy induced anorectal fibrosis was established. The agreement between them was evaluated by Kendall's tau-b test, while Kaplan-Meier analysis was used to calculate survival outcomes. RESULTS: In total, 1033 patients were included. Good agreement between MRI-TRG and AJCC/CAP TRG classifications was observed (k = 0.671). Particularly, as compared with other pairs, MRI-TRG 0 displayed the highest sensitivity [90.1% (95% CI: 84.3-93.9)] and specificity [92.8% (95% CI: 90.4-94.7)] in identifying AJCC/CAP TRG 0 category patients. Except for the survival ratios that were comparable between the MRI-TRG 0 and MRI-TRG 1 categories, any two of the four categories had distinguished 3-year prognosis (all P < 0.05). Cox regression analysis further proved that the MRI-TRG system was an independent prognostic factor (all P < 0.05). CONCLUSION: The new MRI-TRG system might be a surrogate for AJCC/CAP TRG classification scheme. Importantly, the system is a reliable and non-invasive way to identify patients with complete pathological responses.

Tumor-derived PD1 and PD-L1 could promote hepatocellular carcinoma growth through autophagy induction in vitro.

BACKGROUNDS: Autophagy in tumor was also found to influence immune microenvironment. The relation between autophagy and cancer intrinsic PD1 and PD-L1 expression was not clear. METHODS: With data from TCGA and GTEx databases, mRNA expression levels of autophagy-related genes were compared between tumor samples and normal tissues, which were also correlated with survival status. Expression of autophagy-related genes were also associated with clinical traits in datasets of GSE14520 and ICGC LIRI. Single sample gene set enrichment analysis (ssGSEA) was used to calculate autophagy scores in tumor samples, using signatures from MSigDB database. Lentivirus (PD1 and PD-L1), siRNA (ATG13) and plasmids (LC3A/B) were used to target specific genes in tumor cells; Western blot was used to examine protein expression accordingly. Co-immunoprecipitation was performed to find PD1 or PD-L1 interacting proteins; colony formation and EdU analysis were used to evaluate tumor cell growth abilities. RESULTS: mRNA levels of autophagy markers were increased in tumor and correlated with worse survival of cancer patients. In hepatocellular carcinoma (HCC), high mRNA expression of autophagy markers was related to poor clinical status; increasing LC3 expression in HCC cell lines could promote tumor growth. Tumor intrinsic PD1 or PD-L1 were related to higher autophagy levels in specific tumor types; over-expression of PD1 or PD-L1 could increase autophagy in tumor cells through ATG13 interaction. CONCLUSION: Autophagy could promote tumor growth in specific cancer types. Tumor intrinsic PD1 or PD-L1 could both increase autophagy through ATG13 interaction.

The deubiquitinase OTUB1 fosters papillary thyroid carcinoma growth through EYA1 stabilization.

Deubiquitinating enzyme OTU domain-containing ubiquitin aldehyde-binding proteins 1 (OTUB1) has been shown to have an essential role in multiple carcinomas. However, the function of OTUB1 in papillary thyroid cancer (PTC) and the underlying mechanisms regulating PTC cells proliferation remain poorly understood. In this study, OTUB1 was significantly upregulated in papillary thyroid carcinoma tissues and cells. Through in vitro and in vivo experiments, knockdown of OTUB1 suppressed PTC cells growth whereas OTUB1 overexpression enhanced the proliferation ability of PTC cells. Moreover, the eyes absent homologue 1 (EYA1) was recognized as a potential target of OTUB1 through mass spectrometry analysis, and we further verified that EYA1 protein level was positively correlated with OTUB1 expression in PTC cells and clinical samples. Mechanistically, OTUB1 could interact with EYA1 directly and deubiquitinate EYA1 to stabilize it. At last, EYA1 was found to play an essential role in OTUB1-derived PTC cells growth. Overall, our investigation reveals that OTUB1 is a previously unrecognized oncogenic factor in PTC cells proliferation and suggests that OTUB1 might be a novel therapeutic target in PTC.

Radiomic signature of the FOWARC trial predicts pathological response to neoadjuvant treatment in rectal cancer.

BACKGROUND: We aimed to develop a radiomic model based on pre-treatment computed tomography (CT) to predict the pathological complete response (pCR) in patients with rectal cancer after neoadjuvant treatment and tried to integrate our model with magnetic resonance imaging (MRI)-based radiomic signature. METHODS: This was a secondary analysis of the FOWARC randomized controlled trial. Radiomic features were extracted from pre-treatment portal venous-phase contrast-enhanced CT images of 177 patients with rectal cancer. Patients were randomly allocated to the primary and validation cohort. The least absolute shrinkage and selection operator regression was applied to select predictive features to build a radiomic signature for pCR prediction (rad-score). This CT-based rad-score was integrated with clinicopathological variables using gradient boosting machine (GBM) or MRI-based rad-score to construct comprehensive models for pCR prediction. The performance of CT-based model was evaluated and compared by receiver operator characteristic (ROC) curve analysis. The LR (likelihood ratio) test and AIC (Akaike information criterion) were applied to compare CT-based rad-score, MRI-based rad-score and the combined rad-score. RESULTS: We developed a CT-based rad-score for pCR prediction and a gradient boosting machine (GBM) model was built after clinicopathological variables were incorporated, with improved AUCs of 0.997 [95% CI 0.990-1.000] and 0.822 [95% CI 0.649-0.995] in the primary and validation cohort, respectively. Moreover, we constructed a combined model of CT- and MRI-based radiomic signatures that achieve better AIC (75.49 vs. 81.34 vs.82.39) than CT-based rad-score (P = 0.005) and MRI-based rad-score (P = 0.003) alone did. CONCLUSIONS: The CT-based radiomic models we constructed may provide a useful and reliable tool to predict pCR after neoadjuvant treatment, identify patients that are appropriate for a 'watch and wait' approach, and thus avoid overtreatment. Moreover, the CT-based radiomic signature may add predictive value to the MRI-based models for clinical decision making.

Tumor response as defined by iRECIST in gastrointestinal malignancies treated with PD-1 and PD-L1 inhibitors and correlation with survival.

BACKGROUND: Atypical tumor response patterns during immune checkpoint inhibitor therapy pose a challenge to clinicians and investigators in immuno-oncology practice. This study evaluated tumor burden dynamics to identify imaging biomarkers for treatment response and overall survival (OS) in advanced gastrointestinal malignancies treated with PD-1/PD-L1 inhibitors. METHODS: This retrospective study enrolled a total of 198 target lesions in 75 patients with advanced gastrointestinal malignancies treated with PD-1/PD-L1 inhibitors between January 2017 and March 2021. Tumor diameter changes as defined by immunotherapy Response Evaluation Criteria in Solid Tumors (iRECIST) were studied to determine treatment response and association with OS. RESULTS: Based on the best overall response, the tumor diameter ranged from - 100 to + 135.3% (median: - 9.6%). The overall response rate was 32.0% (24/75), and the rate of durable disease control for at least 6 months was 30.7% (23/75, one (iCR, immune complete response) or 20 iPR (immune partial response), or 2iSD (immune stable disease). Using univariate analysis, patients with a tumor diameter maintaining a < 20% increase (48/75, 64.0%) from baseline had longer OS than those with ≥20% increase (27/75, 36.0%) and, a reduced risk of death (median OS: 80 months vs. 48 months, HR = 0.22, P = 0.034). The differences in age (HR = 1.09, P = 0.01), combined surgery (HR = 0.15, P = 0.01) and cancer type (HR = 0.23, P = 0.001) were significant. In multivariable analysis, patients with a tumor diameter with a < 20% increase had notably reduced hazards of death (HR = 0.15, P = 0.01) after adjusting for age, combined surgery, KRAS status, cancer type, mismatch repair (MMR) status, treatment course and cancer differentiation. Two patients (2.7%) showed pseudoprogression. CONCLUSIONS: Tumor diameter with a < 20% increase from baseline during therapy in gastrointestinal malignancies was associated with therapeutic benefit and longer OS and may serve as a practical imaging marker for treatment response, clinical outcome and treatment decision making.

PRMT2 accelerates tumorigenesis of hepatocellular carcinoma by activating Bcl2 via histone H3R8 methylation.

Protein arginine methyltransferases (PRMTs) have been implicated in the development of various cancers. PRMT2, a member of the type I PRMT family, is overexpressed in multiple tumors. However, the expression and role of PRMT2 in hepatocellular carcinoma (HCC) have not been studied. Here, we discovered that PRMT2 expression is elevated in HCC tissues compared to the corresponding non-tumor tissues, and PRMT2 overexpression is an independent predictor of poor prognosis in HCC patients. Depletion of PRMT2 in HCC cell lines inhibited their cell growth and induced apoptosis. Mechanistic investigations showed that PRMT2 is responsible for H3R8 asymmetric methylation (H3R8me2a). H3R8me2a enrichment at the Bcl2 promoter increases its accessibility to STAT3, promoting Bcl2 gene expression. In addition, our results confirmed that the catalytically inactive mutant of PRMT2 or the type I PRMT inhibitor MS023 impaired the pro-tumorigenic functions of PRMT2 in HCC cells. Overall, our findings showed that PRMT2 functions as an oncogenic gene in HCC, revealing its potential as a novel therapeutic target in HCC.

miR-6718-5p and miR-4329 can be used as potential biomarkers for acute myocardial infarction.

BACKGROUND: The prevention and prognosis of the onset or recurrence of acute myocardial infarction (AMI) is a difficult problem in contemporary research. METHODS: In this study, peripheral blood samples were collected from seven patients with AMI and nine healthy adults, and exosome microRNAs (miRNAs) were extracted. The miRNA differential expression profiles of serum exosomes in patients with AMI were obtained by using the next-generation sequencing technology combined with bioinformatics analysis. Reverse-transcriptase polymerase chain reaction (RT-PCR) was used to verify the primary screening of differential exosome miRNAs to reveal the possible mechanism of their action on AMI. RESULTS: Compared with healthy individuals, 544 miRNAs were upregulated and 518 miRNAs were downregulated in AMI patients preoperatively. Among these miRNAs, we selected miR-6718 and miR-4329 for qPCR verification. The expression of miR6718 and miR-4329 in patients with myocardial infarction was significantly lower than that in normal controls.

[A Survey of Patient Monitoring Alarms in Cardiac Care Units].

OBJECTIVE: The patient monitors were used to explore the alarm fatigue in a cardiac care unit and to investigate the awareness and reaction of nurse to alarms. METHODS: A semi-structured survey was taken to acquire nurses' feeling and knowledge about monitoring alarm. Three full-time researchers were scheduled to track the alarms with annotations, and analyze the alarm data of 12 patient monitors using central monitoring system. RESULTS: A total of 72 310 unique alarms occurred in the 67-day study period. About 75.7% of them were physiological alarms and less than 10% of medium-low alarms were false positives. The average alarm rate was 128 alarms/patient-day. CONCLUSIONS: There remains alarm fatigue in CCU, the alarm accuracy has improved than the past by applying new technologies. In some cases, clinicians will pay more attention to trend alarm and combination alarm.

Preoperative radiomic signature based on multiparametric magnetic resonance imaging for noninvasive evaluation of biological characteristics in rectal cancer.

OBJECTIVES: To develop and validate radiomic models in evaluating biological characteristics of rectal cancer based on multiparametric magnetic resonance imaging (MP-MRI). METHODS: This study consisted of 345 patients with rectal cancer who underwent MP-MRI. We focused on evaluating five postoperative confirmed characteristics: lymph node (LN) metastasis, tumor differentiation, fraction of Ki-67-positive tumor cells, human epidermal growth factor receptor 2 (HER-2), and KRAS-2 gene mutation status. Data from 197 patients were used to develop the biological characteristics evaluation models. Radiomic features were extracted from MP-MRI and then refined for reproducibility and redundancy. The refined features were investigated for usefulness in building radiomic signatures by using two feature-ranking methods (MRMR and WLCX) and three classifiers (RF, SVM, and LASSO). Multivariable logistic regression was used to build an integrated evaluation model combining radiomic signatures and clinical characteristics. The performance was evaluated using an independent validation dataset comprising 148 patients. RESULTS: The MRMR and LASSO regression produced the best-performing radiomic signatures for evaluating HER-2, LN metastasis, tumor differentiation, and KRAS-2 gene status, with AUC values of 0.696 (95% CI, 0.610-0.782), 0.677 (95% CI, 0.591-0.763), 0.720 (95% CI, 0.621-0.819), and 0.651 (95% CI, 0.539-0.763), respectively. The best-performing signatures for evaluating Ki-67 produced an AUC value of 0.699 (95% CI, 0.611-0.786), and it was developed by WLCX and RF algorithm. The integrated evaluation model incorporating radiomic signature and MRI-reported LN status had improved AUC of 0.697 (95% CI, 0.612-0.781). CONCLUSION: Radiomic signatures based on MP-MRI have potential to noninvasively evaluate the biological characteristics of rectal cancer. KEY POINTS: • Radiomic features were extracted from MP-MRI images of the rectal tumor. • The proposed radiomic signatures demonstrated discrimination ability in identifying the histopathological, immunohistochemical, and genetic characteristics of rectal cancer. • All MRI sequences were important and could provide complementary information in radiomic analysis.

Generation of functional hepatocyte-like cells from human bone marrow mesenchymal stem cells by overexpression of transcription factor HNF4α and FOXA2.

BACKGROUND: Our previous study showed that overexpression of hepatocyte nuclear factor 4α (HNF4α) could directly promote mesenchymal stem cells (MSCs) to differentiate into hepatocyte-like cells. However, the efficiency of hepatic differentiation remains low. The purpose of our study was to establish an MSC cell line that overexpressed HNF4α and FOXA2 genes to obtain an increased hepatic differentiation efficiency and hepatocyte-like cells with more mature hepatocyte functions. METHODS: Successful establishment of high-level HNF4α and FOXA2 co-overexpression in human induced hepatocyte-like cells (hiHep cells) was verified by flow cytometry, immunofluorescence and RT-PCR. Measurements of albumin (ALB), urea, glucose, indocyanine green (ICG) uptake and release, cytochrome P450 (CYP) activity and gene expression were used to analyze mature hepatic functions of hiHep cells. RESULTS: hiHep cells efficiently express HNF4α and FOXA2 genes and proteins, exhibit typical epithelial morphology and acquire mature hepatocyte-like cell functions, including ALB secretion, urea production, ICG uptake and release, and glycogen storage. hiHep cells can be activated by CYP inducers. The percentage of both ALB and α-1-antitrypsin (AAT)-positive cells was approximately 72.6%. The expression levels of hepatocyte-specific genes (ALB, AAT, and CYP1A1) and liver drug transport-related genes (ABCB1, ABCG2, and SLC22A18) in hiHep cells were significantly higher than those in MSCs-Vector cells. The hiHep cells did not form tumors after subcutaneous xenograft in BALB/c nude mice after 2 months. CONCLUSION: This study provides an accessible, feasible and efficient strategy to generate hiHep cells from MSCs.

Contemporary Epidemiology, Management, and Outcomes of Patients Hospitalized for Heart Failure in China: Results From the China Heart Failure (China-HF) Registry.

BACKGROUND: Contemporary data on the epidemiology of heart failure (HF) in China are scarce. The China-HF Registry was designed to investigate clinical characteristics, management, and outcomes of patients hospitalized for HF in China. METHODS AND RESULTS: Data were collected prospectively on 13,687 patients with a primary discharge diagnosis of HF who were enrolled from 132 participating hospitals from January 2012 to September 2015. Data from the China-HF Registry was compared with previously published literature. The mean age was 65 ± 15 years, 59.1% were male, and 36.0% had preserved ejection fraction. Age, body mass index, and systolic blood pressure were lower than in high-income countries. Common comorbidities included hypertension (50.9%), coronary heart disease (49.6%), and atrial fibrillation (24.4%). The overall use of diuretics, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB), and ß-blockers at admission was 30.1%, 27.0%, and 25.6%, respectively, which was lower than in other registries. For patients discharged alive, ACEI/ARB, ß-blocker, and mineralocorticoid receptor antagonist use in patients with reduced ejection fraction was 67.5%, 70.0%, and 74.1%, respectively; device use was much lower. The median length of hospital stay was 10 (range 7-15) days, and in-hospital mortality was 4.1 ± 0.3%. Predictors of mortality included low systolic blood pressure, acute myocardial infarction, infection, right bundle branch block, and elevated total bilirubin and blood urea nitrogen level. CONCLUSIONS: Several important findings in patient profile and treatment patterns among Chinese patients with HF were noted compared with published literature. These data underscore the need for regional characterization of HF for global clinical trials and for the identification of several quality improvement opportunities.

Direct induction of hepatocyte-like cells from immortalized human bone marrow mesenchymal stem cells by overexpression of HNF4α.

Hepatocytes from human bone marrow-derived mesenchymal stem cells (hBM-MSCs) are expected to be a useful source for cell transplantation. However, relatively low efficiency and repeatability of hepatic differentiation of human BM-MSCs remains an obstacle for clinical translation. Hepatocyte nuclear factor 4 alpha (HNF4α), a critical transcription factor, plays an essential role in the entire process of liver development. In this study, immortalized hBM-MSCs, UE7T-13 cells were transduced with a lentiviral vector containing HNF4α. The typical fibroblast-like morphology of the MSCs changed, and polygonal, epithelioid cells grew out after HNF4α transduction. In hepatocyte culture medium, HNF4α-transduced MSCs (E7-hHNF4α cells) strongly expressed the albumin (ALB), CYP2B6, alpha-1 antitrypsin (AAT), and FOXA2 mRNA and exhibited morphology markedly similar to that of mature hepatocytes. The E7-hHNF4α cells showed hepatic functions such as Indocyanine green (ICG) uptake and release, glycogen storage, urea production and ALB secretion. Approximately 28% of E7-hHNF4α cells expressed both ALB and AAT. Furthermore, these E7-hHNF4α cells via superior mesenteric vein (SMV) injection expressed human ALB in mouse chronic injured liver. In conclusion, this study represents a novel strategy by directly inducing hepatocyte-like cells from MSCs.

Recurrent syncope due to ischemia with non-obstructive coronary artery disease: a case report.

BACKGROUND: Ischemia with non-obstructive coronary artery disease is a prevalent form of ischemic heart disease. The majority of ischemia with non-obstructive coronary artery disease cases are attributed to underlying factors such as coronary microvascular dysfunction (CMD) and/or coronary artery spasm. Ischemia with non-obstructive coronary artery disease can present with various clinical manifestations. Recurrent syncope is an atypical complaint in patients with ischemia with non-obstructive coronary artery disease. CASE PRESENTATION: This case report describes the presentation of a 58-year-old Chinese male patient who experienced repeated episodes of syncope. The syncope was found to be caused by concomitant coronary artery spasm and presumptive coronary microvascular dysfunctionc suggested by "slow flow" on coronary angiography. The patient was prescribed diltiazem sustained-release capsules, nicorandil, and atorvastatin. During the three-month follow-up conducted on our outpatient basis, the patient did not experience a recurrence of syncope. CONCLUSION: This study highlights the importance of considering ischemia with non-obstructive coronary artery disease as a potential cause of syncope in the differential diagnosis. It emphasizes the need for early diagnosis of ischemia with non-obstructive coronary artery disease to facilitate more effective management strategies.

Residual abnormalities on CTE predict adverse outcomes in Crohn's disease with endoscopic healing.

BACKGROUND: Residual abnormalities on computed tomography enterography (CTE) in Crohn's disease (CD) with endoscopic healing (EH) may have prognostic implications and affect therapeutic strategy. METHODS: CD patients with EH who underwent CTE between March 2015 and June 2022 were enrolled. CTE findings of the terminal ileum and the most severe segment of colon at the time of EH were assessed respectively for each patient. Cox regression analysis and Kaplan-Meier curves were used to evaluate the association between residual abnormalities and adverse outcomes. RESULTS: A total of 140 patients (217 digestive segments) were included. Mesenteric edema (hazard ratio [HR] = 3.61, 95% CI = 1.81-7.20, P<0.001), fibrofatty proliferation (HR = 3.40, 95% CI = 1.97-5.85, P<0.001) and active small bowel inflammation (HR = 2.74, 95% CI = 1.59-4.71, P<0.001) were risk factors for clinical relapse. Furthermore, we built a scoring system using the three parameters. Radiologic score ≥ 1 was the best threshold to predict clinical relapse (HR = 4.56, 95% CI = 2.54-8.19, P<0.001) and it was validated in different outcomes. CONCLUSION: The scoring system based on three residual abnormalities on CTE can predict adverse outcomes in CD patients with EH.

Diagnostic CT of colorectal cancer with artificial intelligence iterative reconstruction: A clinical evaluation.

OBJECTIVES: To investigate the clinical value of a novel deep-learning based CT reconstruction algorithm, artificial intelligence iterative reconstruction (AIIR), in diagnostic imaging of colorectal cancer (CRC). METHODS: This study retrospectively enrolled 217 patients with pathologically confirmed CRC. CT images were reconstructed with the AIIR algorithm and compared with those originally obtained with hybrid iterative reconstruction (HIR). Objective image quality was evaluated in terms of the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). Subjective image quality was graded on the conspicuity of tumor margin and enhancement pattern as well as the certainty in diagnosing organ invasion and regional lymphadenopathy. In patients with surgical pathology (n = 116), the performance of diagnosing visceral peritoneum invasion was characterized using receiver operating characteristic (ROC) analysis. Changes of diagnostic thinking in diagnosing hepatic metastases were assessed through lesion classification confidence. RESULTS: The SNRs and CNRs on AIIR images were significantly higher than those on HIR images (all p < 0.001). The AIIR was scored higher for all subjective metrics (all p < 0.001) except for the certainty of diagnosing regional lymphadenopathy (p = 0.467). In diagnosing visceral peritoneum invasion, higher area under curve (AUC) of the ROC was found for AIIR than HIR (0.87 vs 0.77, p = 0.001). In assessing hepatic metastases, AIIR was found capable of correcting the misdiagnosis and improving the diagnostic confidence provided by HIR (p = 0.01). CONCLUSIONS: Compared to HIR, AIIR offers better image quality, improves the diagnostic performance regarding CRC, and thus has the potential for application in routine abdominal CT.

Kruppel-like factor 2 regulates dendritic cell activation in patients with acute coronary syndrome.

OBJECTIVE: Dendritic cells (DCs) activation is important in atherosclerosis and coronary heart disease, but the mechanisms regulating activation of dendritic cells remain largely unclear. The aim of this study was to evaluate the effect of transcription factor Kruppel-like factor 2 (KLF2) in the proinflammatory activation of DCs in acute coronary syndrome. METHODS AND RESULTS: In this study, the expression of CD80 and KLF2 was detected in DCs in normal health controls, patients with stable angina (SA), and acute coronary syndrome (ACS). Our study found that compared with normal control and SA, KLF2 expression in DCs is reduced in patients with ACS. Moreover, the surface expression of CD80 was increased in ACS. In vitro experiment, we found that ox-LDL could increase CD80 expression and decrease KLF2 expression. Furthermore, down-regulated KLF2 could in turn increase CD80 expression via NF-κB pathway. CONCLUSIONS: These observations identify KLF2 as a novel negative regulator of DC function and it may play an essential role in DC activation in ACS.

Prognostic value of the ratio of pretreatment carcinoembryonic antigen to tumor volume in rectal cancer.

Background: As a commonly used biomarker in rectal cancer (RC), the prognostic value of carcinoembryonic antigen (CEA) remains underexplored. This study aims to evaluate the prognostic value of pretreatment CEA/tumor volume in RC. Methods: This retrospective study included patients who underwent pretreatment magnetic resonance imaging (MRI) with histologically confirmed primary rectal adenocarcinoma from November 2012 to April 2018. Patients were divided into high-risk and low-risk groups according to the median values of CEA/Diapath (CEA to pathological diameter), CEA/DiaMRI (CEA to MRI tumor diameter), and CEA/VolMRI (CEA to MRI tumor volume). Cox regression analysis was utilized to determine the prognostic value of CEA, CEA/Diapath, CEA/DiaMRI, and CEA/VolMRI. Stepwise regression was used to establish nomograms for predicting disease-free survival (DFS) and overall survival (OS). Predictive performance was estimated by using the concordance index (C-index) and area under curve receiver operating characteristic (AUC). Results: A total of 343 patients [median age 58.99 years, 206 (60.06%) males] were included. After adjusting for patient-related and tumor-related factors, CEA/VolMRI was superior to CEA, CEA/Diapath, and CEA/DiaMRI in distinguishing high-risk from low-risk patients in terms of DFS [hazard ratio (HR) =1.83; P=0.010] and OS (HR =1.67; P=0.048). Subanalysis revealed that CEA/VolMRI stratified high death risk in CEA-negative individuals (HR =2.50; P=0.038), and also stratified low recurrence risk in CEA-positive individuals (HR =2.06; P=0.024). In the subanalysis of stage II or III cases, the highest HRs and the smallest P values were observed in distinguishing high-risk from low-risk patients according to CEA/VolMRI in terms of DFS (HR =2.44; P=0.046 or HR =2.41; P=0.001) and OS (HR =1.96; P=0.130 or HR =2.22; P=0.008). The nomograms incorporating CEA/VolMRI showed good performance, with a C-index of 0.72 [95% confidence interval (CI): 0.68-0.79] for DFS and 0.73 (95% CI: 0.68-0.80) for OS. Conclusions: Higher CEA/VolMRI was associated with worse DFS and OS. CEA/VolMRI was superior to CEA, CEA/Diapath, and CEA/DiaMRI in predicting DFS and OS. Pretreatment CEA/VolMRI may facilitate risk stratification and treatment decision-making.

Improving prognosis and assessing adjuvant chemotherapy benefit in locally advanced rectal cancer with deep learning for MRI: A retrospective, multi-cohort study.

PURPOSE: Adjuvant therapy is recommended to minimize the risk of distant metastasis (DM) and local recurrence (LR) in patients with locally advanced rectal cancer (LARC). However, its role is controversial. We aimed to develop a pretreatment MRI-based deep learning model to predict LR, DM, and overall survival (OS) over 5 years after surgery and to identify patients benefitting from adjuvant chemotherapy (AC). MATERIALS AND METHODS: The multi-survival tasks network (MuST) model was developed in a primary cohort (n = 308) and validated using two external cohorts (n = 247, 245). An AC decision tree integrating the MuST-DM score, perineural invasion (PNI), and preoperative carbohydrate antigen 19-9 (CA19-9) was constructed to assess chemotherapy benefits and aid personalized treatment of patients. We also quantified the prognostic improvement of the decision tree. RESULTS: The MuST network demonstrated high prognostic accuracy in the primary and two external cohorts for the prediction of three different survival tasks. Within the stratified analysis and decision tree, patients with CA19-9 levels > 37 U/mL and high MuST-DM scores exhibited favorable chemotherapy efficacy. Similar results were observed in PNI-positive patients with low MuST-DM scores. PNI-negative patients with low MuST-DM scores exhibited poor chemotherapy efficacy. Based on the decision tree, 14 additional patients benefiting from AC and 391 patients who received over-treatment were identified in this retrospective study. CONCLUSION: The MuST model accurately and non-invasively predicted OS, DM, and LR. A specific and direct tool linking chemotherapy decisions and benefit quantification has also been provided.