The hepatocellular carcinoma risk in patients with HBV-related cirrhosis: a competing risk nomogram based on a 4-year retrospective cohort study.

Objective: The study aimed to build and validate a competitive risk nomogram to predict the cumulative incidence of hepatocellular carcinoma (HCC) for patients with hepatitis B virus (HBV)-related cirrhosis. Methods: A total of 1401 HBV-related cirrhosis patients were retrospectively enrolled from January 1, 2011 to December 31, 2014. Application of 20 times imputation dealt with missing data using multiple imputation by chained equations (MICE). The patients were randomly divided into a training set (n = 1017) and a validation set (n = 384) at a ratio of 3:1. A prediction study was carried out using a competing risk model, where the event of interest was HCC and the competing events were death and liver transplantation, and subdistribution hazard ratios (sHRs) with 95% CIs were reported. The multivariate competing risk model was constructed and validated. Results: There was a negligible difference between the original database and the 20 imputed datasets. At the end of follow-up, the median follow-up time was 69.9 months (interquartile range: 43.8-86.6). There were 31.5% (442/1401) of the patients who developed HCC, with a 5-year cumulative incidence of 22.9 (95%CI, 20.8%-25.2%). The univariate and multivariate competing risk regression and construction of the nomogram were performed in 20 imputed training datasets. Age, sex, antiviral therapy history, hepatitis B e antigen, alcohol drinking history, and alpha-fetoprotein levels were included in the nomogram. The area under receiver operating characteristic curve values at 12, 24, 36, 60, and 96 months were 0.68, 0.69, 0.70, 0.68, and 0.80, and the Brier scores were 0.30, 0.25, 0.23, 0.21, and 0.20 in the validation set. According to the cumulative incidence function, the nomogram effectively screened out high-risk HCC patients from low-risk patients in the presence of competing events (Fine-Gray test p < 0.001). Conclusion: The competitive risk nomogram was allowed to be used for predicting HCC risk in individual patients with liver cirrhosis, taking into account both the association between risk factors and HCC and the modifying effect of competition events on this association.

Clinicopathological and molecular genetic analysis of 13 cases of primary retroperitoneal Ewing sarcoma.

Retroperitoneal Ewing sarcomas (RES) are very rare and mostly described in case reports. The purpose of this study was to retrospectively analyze the clinicopathology, molecular characteristics, biological behavior, and therapeutic information of 13 cases of primary RES with immunohistochemical staining, fluorescence in situ hybridization, RT-PCR and NGS sequencing detection techniques. The thirteen patients included eight males and five females with a mean age of 34 years. Morphologically, the tumors were comprised of small round or epithelial-like cells with vacuolated cytoplasm (6/13,46 %) arranged in diffuse, nested (8/13,62 %) and perivascular (7/13,54 %) patterns. Unusual morphologic patterns, such as meningioma-like swirling structures and sieve-like structures were relatively novel findings. Immunohistochemical studies showed CD99 (12/13; 92 %), CD56 (11/13; 85 %), NKX2.2 (9/13; 69 %), PAX7 (10/11;91 %) and CD117(6/9;67 %) to be positive.12 cases (92 %) demonstrated EWSR1 rearrangement and 3 cases displayed EWSR1::FLI1 fusion by FISH. ERCC4 splice-site variant, a novel pathogenic variant, was discovered for the first time via RNA sequencing. With a median follow-up duration of 14 months (6 to 79 months), 8/13 (62 %) patients died, while 5/13(38 %) survived. Three cases recurred, and five patients developed metastasis to the liver (2 cases), lung (2 cases) and bone (1 case). RES is an aggressive, high-grade tumor, prone to multiple recurrences and metastases, with distinctive morphologic, immunohistochemical, and molecular genetic features. ERCC4 splicing mutation, which is a novel pathogenic variant discovered for the first time, with possible significance for understanding the disease, as well as the development of targeted drugs.

BDNF mimetics recover palmitic acid-induced injury in cardiomyocytes by ameliorating Akt-dependent mitochondrial impairments.

Cardiac lipotoxicity is a prevalent consequence of lipid metabolism disorders occurring in cardiomyocytes, which in turn precipitates the onset of heart failure. Mimetics of brain-derived neurotrophic factor (BDNF), such as 7,8-dihydroxyflavone (DHF) and 7,8,3'-trihydroxyflavone (THF), have demonstrated significant cardioprotective effects. However, it remains unclear whether these mimetics can protect cardiomyocytes against lipotoxicity. The aim of this study was to examine the impact of DHF and THF on the lipotoxic effects induced by palmitic acid (PA), as well as the concurrent mitochondrial dysfunction. H9c2 cells were subjected to treatment with PA alone or in conjunction with DHF or THF. Various factors such as cell viability, lactate dehydrogenase (LDH) release, death ratio, and mitochondrial function including mitochondrial membrane potential (MMP), mitochondrial-derived reactive oxygen species (mito-SOX) production, and mitochondrial respiration were assessed. PA dose-dependently reduced cell viability, which was restored by DHF or THF. Additionally, both DHF and THF decreased LDH content, death ratio, and mito-SOX production, while increasing MMP and regulating mitochondrial oxidative phosphorylation in cardiomyocytes. Moreover, DHF and THF specifically activated Akt signaling. The protective effects of DHF and THF were abolished when an Akt inhibitor was used. In conclusion, BDNF mimetics attenuate PA-induced injury in cardiomyocytes by alleviating mitochondrial impairments through the activation of Akt signaling.

Compressed Sensitivity Encoding Artificial Intelligence Accelerates Brain Metastasis Imaging by Optimizing Image Quality and Reducing Scan Time.

BACKGROUND AND PURPOSE: Accelerating the image acquisition speed of MR imaging without compromising the image quality is challenging. This study aimed to evaluate the feasibility of contrast-enhanced (CE) 3D T1WI and CE 3D-FLAIR sequences reconstructed with compressed sensitivity encoding artificial intelligence (CS-AI) for detecting brain metastases (BM) and explore the optimal acceleration factor (AF) for clinical BM imaging. MATERIALS AND METHODS: Fifty-one patients with cancer with suspected BM were included. Fifty participants underwent different customized CE 3D-T1WI or CE 3D-FLAIR sequence scans. Compressed SENSE encoding acceleration 6 (CS6), a commercially available standard sequence, was used as the reference standard. Quantitative and qualitative methods were used to evaluate image quality. The SNR and contrast-to-noise ratio (CNR) were calculated, and qualitative evaluations were independently conducted by 2 neuroradiologists. After exploring the optimal AF, sample images were obtained from 1 patient by using both optimized sequences. RESULTS: Quantitatively, the CNR of the CS-AI protocol for CE 3D-T1WI and CE 3D-FLAIR sequences was superior to that of the CS protocol under the same AF (P < .05). Compared with reference CS6, the CS-AI groups had higher CNR values (all P < .05), with the CS-AI10 scan having the highest value. The SNR of the CS-AI group was better than that of the reference for both CE 3D-T1WI and CE 3D-FLAIR sequences (all P < .05). Qualitatively, the CS-AI protocol produced higher image quality scores than did the CS protocol with the same AF (all P < .05). In contrast to the reference CS6, the CS-AI group showed good image quality scores until an AF of up to 10 (all P < .05). The CS-AI10 scan provided the optimal images, improving the delineation of normal gray-white matter boundaries and lesion areas (P < .05). Compared with the reference, CS-AI10 showed reductions in scan time of 39.25% and 39.93% for CE 3D-T1WI and CE 3D-FLAIR sequences, respectively. CONCLUSIONS: CE 3D-T1WI and CE 3D-FLAIR sequences reconstructed with CS-AI for the detection of BM may provide a more effective alternative reconstruction approach than CS. CS-AI10 is suitable for clinical applications, providing optimal image quality and a shortened scan time.

Development and validation of a deep learning model for predicting postoperative survival of patients with gastric cancer.

BACKGROUND: Deep learning (DL), a specialized form of machine learning (ML), is valuable for forecasting survival in various diseases. Its clinical applicability in real-world patients with gastric cancer (GC) has yet to be extensively validated. METHODS: A combined cohort of 11,414 GC patients from the Surveillance, Epidemiology and End Results (SEER) database and 2,846 patients from a Chinese dataset were utilized. The internal validation of different algorithms, including DL model, traditional ML models, and American Joint Committee on Cancer (AJCC) stage model, was conducted by training and testing sets on the SEER database, followed by external validation on the Chinese dataset. The performance of the algorithms was assessed using the area under the receiver operating characteristic curve, decision curve, and calibration curve. RESULTS: DL model demonstrated superior performance in terms of the area under the curve (AUC) at 1, 3, and, 5 years post-surgery across both datasets, surpassing other ML models and AJCC stage model, with AUCs of 0.77, 0.80, and 0.82 in the SEER dataset and 0.77, 0.76, and 0.75 in the Chinese dataset, respectively. Furthermore, decision curve analysis revealed that the DL model yielded greater net gains at 3 years than other ML models and AJCC stage model, and calibration plots at 3 years indicated a favorable level of consistency between the ML and actual observations during external validation. CONCLUSIONS: DL-based model was established to accurately predict the survival rate of postoperative patients with GC.

[The correlation between preoperative neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio and postoperative recurrence of chronic rhinosinusitis].

Objective:Neutrophil-to-lymphocyte ratio （NLR） and platelet-to-lymphocyte ratio （PLR） play important roles in the poor prognosis of different inflammatory and neoplastic diseases, but their effects on postoperative recurrence of chronic rhinosinusitis（CRS） are unknown. The aim of this study was to investigate the correlation between preoperative NLR and PLR and the risk of postoperative recurrence in CRS. Methods:Clinical data were collected from patients with CRS who underwent initial functional endoscopic sinus surgery from October 2018 to February 2022 at our institution. Follow-up was until February 2023, and the study endpoint was defined as patient postoperative recurrence or follow-up time up to date. The optimal preoperative NLR and PLR threshold values were obtained based on subject work curve analysis, and they were divided into high and low level subgroups, respectively, and the clinical characteristics and postoperative recurrence rates of patients were compared between groups; patients were divided into non-recurrent CRS and recurrent CRS according to their postoperative recurrence, and Kaplan-Meier survival curves and logistic regression analysis were performed to explore the correlation between NLR and PLR and CRS The correlation between NLR and PLR and postoperative recurrence was investigated by Kaplan-Meier survival curve and logistic regression analysis. Results:A total of 630 patients with CRS were included, including 382 and 140 patients with high NLR and high PLR, respectively. The postoperative recurrence rates of CRS patients in the high NLR and high PLR groups were significantly higher than those in the low NLR and low PLR groups（P<0.05）. The recurrent CRS had higher NLR and PLR levels and higher proportion of high NLR and high PLR than the non-recurrent CRS（P<0.05）, and similarly the duration of recurrent CRS and the rate of allergic rhinitis with recurrence were significantly higher than the non-recurrent CRS（P<0.05）. Kaplan-Meier survival curves showed that postoperative CRS was significantly higher in the high NLR and high PLR groups compared with the low NLR and low PLR groups. recurrence was significantly higher（P<0.05）. In addition, logistic regression analysis showed that high NLR, high PLR, disease duration, and combined allergic rhinitis were significantly associated with an increased risk of postoperative recurrence of CRS（P<0.05）. Conclusion:Both high preoperative NLR and high PLR are independent risk factors for postoperative recurrence of CRS, and they are expected to be new indicators for postoperative prognostic assessment and risk stratification of CRS patients. In addition, disease duration and comorbid allergic rhinitis were significantly associated with the risk of postoperative recurrence of CRS.

Multi-omics landscape to decrypt the distinct flavonoid biosynthesis of Scutellaria baicalensis across multiple tissues.

Scutellaria baicalensis Georgi, also known as huang-qin in traditional Chinese medicine, is a widely used herbal remedy due to its anticancer, antivirus, and hepatoprotective properties. The S. baicalensis genome was sequenced many years ago; by contrast, the proteome as the executer of most biological processes of S. baicalensis in the aerial parts, as well as the secondary structure of the roots (xylem, phloem, and periderm), is far less comprehensively characterized. Here we attempt to depict the molecular landscape of the non-model plant S. baicalensis through a multi-omics approach, with the goal of constructing a highly informative and valuable reference dataset. Furthermore, we provide an in-depth characterization dissection to explain the two distinct flavonoid biosynthesis pathways that exist in the aerial parts and root, at the protein and phosphorylated protein levels. Our study provides detailed spatial proteomic and phosphoproteomic information in the context of secondary structures, with implications for the molecular profiling of secondary metabolite biosynthesis in non-model medicinal plants.

[Role of macrophage polarization in hypertension and traditional Chinese medicine intervention: a review].

Hypertension is known to be a chronic inflammatory state and a key risk factor for heart failure, coronary heart disease, and atherosclerosis. Macrophages in the circulatory system are the main cell group that constitutes the immune system and participates in the inflammatory response. Depending on the local microenvironment, macrophages can be polarized into pro-inflammatory(M1) and anti-inflammatory(M2) phenotypes. When blood pressure is elevated, M1 macrophages can release pro-inflammatory cytokines and chemokines to generate an immune response. However, an excessive immune response can lead to tissue damage, and M2 macrophages release anti-inflammatory cytokines to promote the repair of wounds and tissue damage. It is clear that the dynamic balance between M1 and M2 macrophages resembles the traditional Chinese medicine(TCM) theory of Yin and Yang. That is, when Yin and Yang are imbalanced, the human body will exhibit pathological states, e.g., altered blood pressure rhythms. Studies have confirmed that TCM can produce positive therapeutic effects on hypertension by regulating macrophage polarization. Therefore, this study reviews the studies about the TCM regulation of macrophage polarization and summarized the mechanisms of TCM intervention in hypertension, with the aim of providing evidence for clinical treatment and ideas for scientific research design.

Liquiritin targeting Th17 cells differentiation and abnormal proliferation of keratinocytes alleviates psoriasis via NF-κB and AP-1 pathway.

Psoriasis is a common immune-mediated inflammatory skin disease, caused by disturbed interactions between keratinocytes and immune cells. Chinese medicine shows potential clinical application for its treatment. Liquiritin is a flavone compound extracted from licorice and shows potential antitussive, antioxidant and antiinflammatory effects, and therefore may have potential as a psoriasis therapeutic. The aim of this work was to examine the possible roles that liquiritin may have in treating psoriasis. HaCaT cells were stimulated by TNF-α with or without liquiritin, harvested for analysis by western blots and RT-qPCR, and the cellular supernatants were collected and analyzed by ELISA for cytokines. In addition, 4 groups of mice were examined: Normal, Vehicle, LQ-L and LQ-H. The mice were sacrificed after 6 days and analyzed using IHC, ELISA, RT-qPCR and flow cytometry. The results showed that liquiritin could significantly inhibit the progression of psoriasis both in vitro and in vivo. Liquiritin strongly suppressed the proliferation of HaCaT keratinocytes but did not affect cell viability. Moreover, liquiritin alleviated imiquimod-induced psoriasis-like skin inflammation and accumulation of Th17 cells and DCs in vivo. In TNF-α-induced HaCaT keratinocytes, both protein and mRNA expression levels of inflammatory cytokines were sharply decreased. In imiquimod-induced mice, the activation of NF-κB and AP-1 was reduced after treatment with liquiritin. Collectively, our results show that liquiritin might act as a pivotal regulator of psoriasis via modulating NF-κB and AP-1 signal pathways.

Demographics and Clinical Characteristics of Patients with Neurocysticercosis: A Retrospective Study from Dali, China.

Background: Neurocysticercosis (NCC), a predominant parasitic disease that affects the central nervous system and presents with diverse clinical manifestations, is a major contributor to acquired epilepsy worldwide, particularly in low-, middle-, and upper middle-income nations, such as China. In China, the Yunnan Province bears a significant burden of this disease. Objective: To describe the demographic, clinical, and radiological features as well as serum and cerebrospinal fluid antibodies to cysticercus in patients with NCC from Dali, Yunnan Province, China. Materials and Methods: This retrospective study included patients who were diagnosed with NCC at The First Affiliated Hospital of Dali University between January 2018 and May 2023 and were residing in Dali, Yunnan Province, China. Results: A total of 552 patients with NCC were included, of which 33.3% belonged to Bai ethnicity. The clinical presentation of NCC exhibited variability that was influenced by factors such as the number, location, and stage of the parasites. Epilepsy/seizure (49.9%) was the most prevalent symptom, with higher occurrence in the degenerative stage of cysts (P < 0.001). Compared with other locations, cysticerci located in the brain parenchyma are more likely to lead to seizures/epilepsy (OR = 17.45, 95% CI: 7.96-38.25) and headaches (OR = 3.02, 95% CI: 1.23-7.41). Seizures/epilepsy are more likely in patients with cysts in the vesicular (OR = 2.71, 95% CI: 1.12-6.61) and degenerative (OR = 102.38, 95% CI: 28.36-369.60) stages than those in the calcified stage. Seizures was not dependent on the number of lesions. All NCC patients underwent anthelminthic therapy, with the majority receiving albendazole (79.7%). Conclusion: This study provides valuable clinical insights into NCC patients in Dali and underscores the significance of NCC as a leading preventable cause of epilepsy.

Angiotensin-(1-7) Improves Islet ß-cell Dedifferentiation by Activating PI3K/Akt/FoxO1 Pathway.

BACKGROUND: Islet ß-cell dedifferentiation may be the main cause of reduced insulin secretion. Angiotensin-(1-7) [Ang-(1-7)] can attenuate high glucose-induced apoptosis and dedifferentiation of pancreatic ß-cell, but the specific signal transduction pathway and mechanism are not yet clear. OBJECTIVES: This study aimed to investigate the effects of Ang-(1-7) on high glucose-induced islet ß-cell dedifferentiation by activating the phosphatidylinositol-3-kinase/Protein kinase B/ Forkhead box transcription factor O1 (PI3K/Akt/FoxO1) signaling pathway. METHODS: The mouse islet ß-cell line MIN6 cells were passaged and cultured and randomly divided into five groups: control (Con) group, high glucose (HG) group, HG with Ang-(1-7) group, HG with Ang-(1-7) and specific MasR antagonist A-779 group, and HG with Ang-(1-7) and PI3K inhibitor LY294002 group. After 48 hours, glucose-stimulated insulin secretion (GSIS) was detected by Enzyme-Linked Immunosorbent Assay (ELISA). The mRNA and protein expression levels of ß-cell-specific factors (Pancreatic duodenal homeobox-1 (Pdx1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A(MafA)) and endocrine progenitor cell-specific factors (Octamer binding transcription factor 4(Oct4), Nanog) were measured by Real Time-PCR and Western blot. The factors of protein expression levels of PI3K/Akt/FoxO1 signaling pathway (Akt, p-Akt, Fox- O1, p-FoxO1) were determined by Western blot. RESULTS: We observed for the first time that high glucotoxicity can induce dedifferentiation of pancreatic islet ß-cell, causing a decrease in insulin secretion levels and expression of Pdx1, MafA, p-- FoxO1, and p-Akt and an increase in expression of Oct4 and Nanog. After Ang-(1-7) intervention, insulin secretion levels and expression of Pdx1, MafA, p-FoxO1 and p-Akt were increased, and the levels of Oct4 and Nanog were reduced. However, A-779 and LY294002 could reverse this effect. During these processes, the total Akt and total FoxO1 expression did not change significantly. CONCLUSION: Ang-(1-7) may prevent high glucose-induced pathological dedifferentiation of pancreatic ß-cell by activating the PI3K/Akt/FoxO1 signaling pathway.

Primary lipoblastic nerve sheath tumor in an inguinal lymph node mimicking metastatic tumor: a case report and literature review.

Lipoblastic nerve sheath tumors of soft tissue are characterized as schwannoma tumors that exhibit adipose tissue and lipoblast-like cells with signet-ring morphology. They have been documented to arise in various anatomic locations, including the thigh, groin, shoulder, and retroperitoneum. However, to our knowledge, this tumor has not been previously reported as a lymph node primary. We present herein the first case of a benign primary lipoblastic nerve sheath tumor arising in an inguinal lymph node in a 69-year-old man. Microscopic examination revealed a multinodular tumor comprising fascicles of spindle cells, as well as adipocytic and lipoblast-like signet-ring cell component in the context of schwannoma. Despite the presence of some bizarre cells with nuclear atypia, no obvious mitotic activity or necrosis was observed. Immunohistochemical analysis showed strong and diffuse expression of S-100, SOX10, CD56, and NSE in the spindle cells as well as in the signet-ring lipoblast-like cells and the mature adipocytes. Sequencing analysis of the neoplasm identified six non-synonymous single nucleotide variant genes, specifically NF1, BRAF, ECE1, AMPD3, CRYAB, and NPHS1, as well as four nonsense mutation genes including MRE11A, CEP290, OTOA, and ALOXE3. The patient remained alive and well with no evidence of recurrence over a period of ten-year follow-up.

7,8,3'-Trihydroxyflavone prevents doxorubicin-induced cardiotoxicity and mitochondrial dysfunction via activating Akt signaling pathway in H9c2 cells.

Clinical application of the widely used chemotherapeutic agent, doxorubicin (DOX), is limited by its cardiotoxicity. Mitochondrial dysfunction has been revealed as a crucial factor in DOX-induced cardiotoxicity. 7,8,3'-Trihydroxyflavone (THF) is a mimetic brain-derived neurotrophic factor with neuroprotective effects. However, the potential effects of THF on DOX-induced cardiomyocyte damage and mitochondrial disorders remain unclear. H9c2 cardiomyoblasts were exposed to DOX and/or THF at different concentrations. Cardiomyocyte injury was evaluated using lactate dehydrogenase (LDH) assay and Live/Dead cytotoxicity kit. Meanwhile, mitochondrial membrane potential (MMP), morphology, mitochondrial reactive oxygen species (mito-ROS) production, and the oxygen consumption rate of cardiomyocytes were measured. The protein levels of key mitochondria-related factors such as adenosine monophosphate-activated protein kinase (AMPK), mitofusin 2 (Mfn2), dynamin-related protein 1 (Drp1), and optic atrophy protein 1 (OPA1) were examined. We found that THF reduced LDH content and death ratio of DOX-treated cardiomyocytes in a concentration-dependent manner, while increasing MMP without significantly affecting the routine and maximum capacity of mitochondrial respiration. Mechanistically, THF increased the activity of Akt and protein levels of Mfn2 and heme oxygenase 1 (HO-1). Moreover, inhibition of Akt reversed the protective role of THF, increased mito-ROS levels, and repressed Mfn2 and HO-1 expression. Therefore, we conclude, THF relieves DOX-induced cardiotoxicity and improves mitochondrial function by activating Akt-mediated Mfn2 and HO-1 pathways. This finding provides promising therapeutic insights for DOX-induced cardiac dysfunction.

Sexual health problems of patients with cancer: A bibliometrics study and visualization analysis via CiteSpace.

Purpose: This study aimed to conduct a bibliometric analysis of the data acquired and clarified the current research status of sexual health problems in patients with cancer, to provide a comprehensive visual perspective suitable as a reference for subsequent research. Methods: We searched the Web of Science Core Collection (WoSCC) up to April 30, 2023 to identify studies associated with sexual health problems in patients with cancer. CiteSpace was used to create visualization networks for countries, institutions, authors, and journals. Results: A total of 3183 publications related to sexual health problems in patients with cancer were collected from the WoSCC. In terms of volume, the USA (1259 papers) was the leading country, the Memorial Sloan Kettering Cancer Center (119 papers) was the leading institution, and Carter (39 papers) was the author with the most publications. The top-cited references and keywords were related to quality of life. The top five clusters of reference cocitation were 'brachytherapy', 'prostate cancer', 'radical prostatectomy', 'hypogonadism', and 'breast cancer'. Meanwhile, the top five clusters of keyword cocitation were 'breast cancer', 'prostate cancer', 'rectal cancer', 'testicular cancer', and 'sexual function'. The analysis of the top 25 references and keywords with the strongest citation bursts of published papers on sexual health problems in patients with cancer to reveal the research hotspots and trends. Conclusions: Research on sexual health among patients with cancer is constantly developing. The current research focuses on the impact of different treatment options for sexual health and quality of life of patients with breast, rectal, and genitourinary neoplasms. Exploring the long-term changing regularities of sexual function among cancer survivors and formulating sexual health interventions toward patient-reported outcomes and needs are key research directions.

Co-expression of IL-4/IL-15-based inverted cytokine receptor in CAR-T cells overcomes IL-4 signaling in immunosuppressive pancreatic tumor microenvironment.

The efficacy of CAR-T cell therapy has been hindered by several factors that are intrinsic to the tumor microenvironment. Many strategies are being employed to overcome these barriers and improve immunotherapies efficacy. Interleukin (IL)- 4 is a cytokine released by tumor cells inside the tumor microenvironment and it can oppose T cell effector functions via engagement with the IL-4 receptor on the surface of T cells. To overcome IL-4-mediated immunosuppressive signals, we designed a novel inverted cytokine receptor (ICR). Our novel CAR construct (4/15NKG2D-CAR), consisted of an NKG2D-based chimeric antigen receptor, co-expressing IL-4R as an extracellular domain and IL-15R as a transmembrane and intracellular domain. In this way, IL-4R inhibitory signals were converted into IL-15R activation signals downstream. This strategy increased the efficacy of NKG2D-CAR-T cells in the pancreatic tumor microenvironment in vitro and in vivo. 4/15NKG2D-CAR-T cells exhibited increased activation, degranulation, cytokine release, and cytotoxic ability of NKG2D-CAR-T cells against IL-4+ pancreatic cell lines. Furthermore, 4/15NKG2D-CAR-T cells exhibited more expansion, less exhaustion, and an increased percentage of less differentiated T cell phenotypes in vitro when compared with NKG2D-CAR-T cells. That is why IL-4R/IL-15R-modified CAR-T cells eradicated more tumors in vivo and outperformed NKG2D-CAR-T cells. Thus, we report here a novel NKG2D-CAR-T cells that could overcome IL-4-mediated immunosuppression in solid tumors.

Dynamic Changes of Cytokine Profiles and Their Correlation With Tumor Recurrence Following Thermal Ablation in Hepatocellular Carcinoma.

The 5-year recurrence rate of thermal ablation for hepatocellular carcinoma (HCC) is high, and whether this treatment strategy induces systemic immune response remains elusive. This study aimed to investigate the effects of thermal ablation on HCC patients' cytokine profiles and to explore the correlation of cytokine profiles with tumor recurrence after ablation. A total of 22 HCC patients were included in this prospective study. The levels of 27 cytokines in the peripheral blood of HCC patients were measured before ablation (baseline), week 1, and week 4 after ablation using a Bio-Plex Pro Human Cytokine 27-plex Assay kit. Cytokines showed different dynamic changing trends after ablation treatment. It was found that the level of IL-6 was significantly elevated at week 1 and returned to the baseline level at week 4 after ablation. The level of IL-10 was slightly reduced at week 1 and significantly decreased at week 4. The levels of MCP-1, macrophage inflammatory protein-1ß (MIP-1ß), and TNF-α were similarly reduced at week 1 and increased at week 4. The levels of IL-17, platelet-derived growth factor-BB (PDGF-BB), and regulated upon activation, normal T cell expressed and secreted (RANTES) showed little to no change at week 1 while an observable increase at week 4. Patients with a high IL-10 level (2.99 pg/ml) at baseline and low levels of TNF-α (20.4 pg/ml), PDGF-BB (107.78 pg/ml), and RANTES (2303.94 pg/ml) at week 4 were at risk of tumor recurrence during 1-year follow-up. The results suggested that thermal ablation activated systemic immune responses by changing the levels of cytokines. The results also demonstrated that measurement of IL-10 at baseline, TNF-α, PDGF-BB, and RANTES at week 4 after ablation might predict the risk of tumor recurrence.

Detection of various fusion genes by one-step RT-PCR and the association with clinicopathological features in 242 cases of soft tissue tumor.

Introduction: Over the past decades, an increasing number of chromosomal translocations have been found in different STSs, which not only has value for clinical diagnosis but also suggests the pathogenesis of STS. Fusion genes can be detected by FISH, RT-PCR, and next-generation sequencing. One-step RT-PCR is a convenient method to detect fusion genes with higher sensitivity and lower cost. Method: In this study, 242 cases of soft tissue tumors were included, which were detected by one-step RT-PCR in multicenter with seven types of tumors: rhabdomyosarcoma (RMS), peripheral primitive neuroectodermal tumor (pPNET), synovial sarcoma (SS), myxoid liposarcomas (MLPS), alveolar soft part sarcoma (ASPS), dermatofibrosarcoma protuberans (DFSP), and soft tissue angiofibroma (AFST). 18 cases detected by one-step RT-PCR were further tested by FISH. One case with novel fusion gene detected by RNA-sequencing was further validated by one-step RT-PCR. Results: The total positive rate of fusion genes was 60% (133/213) in the 242 samples detected by one-step RT-PCR, in which 29 samples could not be evaluated because of poor RNA quality. The positive rate of PAX3-FOXO1 was 88.6% (31/35) in alveolar rhabdomyosarcoma, EWSR1-FLI1 was 63% (17/27) in pPNET, SYT-SSX was 95.4% in SS (62/65), ASPSCR1-TFE3 was 100% in ASPS (10/10), FUS-DDIT3 was 80% in MLPS (4/5), and COL1A1-PDGFB was 66.7% in DFSP (8/12). For clinicopathological parameters, fusion gene status was correlated with age and location in 213 cases. The PAX3-FOXO1 fusion gene status was correlated with lymph node metastasis and distant metastasis in RMS. Furthermore, RMS patients with positive PAX3-FOXO1 fusion gene had a significantly shorter overall survival time than those patients with the negative fusion gene. Among them, the FISH result of 18 cases was concordant with one-step RT-PCR. As detected as the most common fusion types of AHRR-NCOA2 in one case of AFST were detected as negative by one-step RT-PCR. RNA-sequencing was used to determine the fusion genes, and a novel fusion gene PTCH1-PLAG1 was found. Moreover, the fusion gene was confirmed by one-step RT-PCR. Conclusion: Our study indicates that one-step RT-PCR displays a reliable tool to detect fusion genes with the advantage of high accuracy and low cost. Moreover, it is a great tool to identify novel fusion genes. Overall, it provides useful information for molecular pathological diagnosis and improves the diagnosis rate of STSs.

Individual surveillance by competing risk model for patients with hepatocellular carcinoma occurrence in all-cause cirrhosis.

PURPOSE: It was of great significance to identify someone with a high risk of hepatocellular carcinoma (HCC) occurrence and make a diagnosis as early as possible. Therefore, we aimed to develop and validate a new, objective, and accurate prediction model, and convert it into a nomogram to make a personalized prediction of cancer occurrence in cirrhotic patients with different etiologies. METHODS: The present study included 938 patients with cirrhosis from January 1, 2011, to December 31, 2012. Patients were prospectively followed-up until January 1, 2018. We used a competing risk model and the Fine-Gray test to develop and validate the prediction model and to plot a nomogram based on the model established. RESULTS: At the end of follow-up, 202 (21.5%) patients developed HCC, with a 5-year incidence of 19.0% (corrected for competing risk model). Based on the competing risk regression method, we built a prediction model including age, gender, etiology, lymphocyte, and A/G ratio. Three groups with different risks were generated on account of tertiles of the 5-year risk predicted by the model. The cumulative 1-, 3-, and 5-year incidences of HCC were 2.0%, 20.8%, and 42.3% in high-risk group, 0.9%, 10.1%, and 17.7% in medium-risk group, and 0%, 2.0%, 8.5% in low-risk group (P < 0.001). The model showed excellent discrimination and calibration in predicting the risk of HCC occurrence in patients with all-cause cirrhosis. CONCLUSION: The model could make an individual prediction of cancer occurrence and stratify patients based on predicted risk, regardless of the causes of cirrhosis.

Benzoylaconitine Alleviates Progression of Psoriasis via Suppressing STAT3 Phosphorylation in Keratinocytes.

Psoriasis is a chronic and multifactorial skin disease which is caused by inflammatory infiltrates, keratinocyte hyperproliferation, and accumulation of immune cells. As part of the Aconitum species, Benzoylaconitine (BAC) shows potential antiviral, anti-tumor, and anti-inflammatory effects. In this study, we investigated the effects and mechanisms of BAC on tumor necrosis factor-alpha (TNF-α)/LPS-induced HaCaT keratinocytes in a imiquimod(IMQ)-induced mice model. The results showed that BAC could relieve the symptoms of psoriasis by inhibiting cell proliferation, the release of inflammatory factors, and the accumulation of Th17 cells, while no obvious effect on cell viability and safety was observed both in vitro and in vivo. Additionally, BAC can markedly inhibit the protein and mRNA levels of inflammatory cytokines in TNF-α/LPS-induced HaCaT keratinocytes by inhibiting the phosphorylation of STAT3. In brief, our data indicated that BAC could alleviate the progression of psoriasis and may be a potential therapeutic agent for treating psoriasis in clinical practice.