Tertiary lymphoid structures: Associated multiple immune cells and analysis their formation in hepatocellular carcinoma.

The prognostic value of immune cells in tertiary lymphoid structures (TLSs) remains unclear in hepatocellular carcinoma (HCC). Here, 59 of 145 patients had TLSs in training set, 48 of 120 patients had TLSs in testing set. Immunohistochemistry (IHC) were used to label CD3+ T cells, CD20+ B cells, CD8+ T cells, CD208+ dendritic cells, and CD21+ follicular dendritic cells in TLSs. High CD20+, CD208+, and CD8+ cell densities were favorable prognostic factors for overall survival (OS). High CD3+, CD20+, CD208+, and CD8+ cell densities were significantly associated with reduced early recurrence. TLSs were divided into three grades (A, B, and C) based on immune cell density. Patients with grade C or B had significantly improved OS. Patients with grade C had the lowest recurrence rate, followed by those with grade B, while patients with grade A had the highest recurrence rate. The stromal, immune, and ESTIMATE scores derived from the ESTIMATE package were significantly higher and tumor purity was significantly lower in patients with TLSs. Patients with TLSs had significantly higher relative numbers of memory B cells, plasma cells, CD8+ T cells, NK cells, and dendritic cells and lower relative numbers of Treg cells, macrophages, and M2 macrophages according to the CIBERSORT assessment. Bioinformatics analysis and experiments confirmed that KLRK1 and GZMA expression are associated TLSs formation and can predict TLSs existence. Grade B and grade C were favorable prognostic factors for OS and recurrence and could represent immune-active tumors.

Impact of Decreased Visibility of Deep Medullary Veins on White Matter Integrity in Patients with Cerebral Small Vessel Disease.

BACKGROUND: Based on susceptibility-weighted imaging (SWI) visibility, deep medullary vein (DMV) scores are related to white matter damage (WMD) in patients with cerebral small vessel disease (CSVD). However, whether mechanisms are associated with DMV changes is unclear. We examined extracellular fluid (ECF) roles in white matter associations between DMV scores and white matter integrity (WMI) in patients with CSVD. METHODS: We examined magnetic resonance imaging (MRI) and clinical data from 140 patients with CSVD. DMV scores (0-18) were assigned on SWI according to DMV anatomic regions and signal continuity/visibility. WMI and ECF volumes were evaluated using free water (FW) and fractional anisotropy (FA) values by diffusion tensor imaging (DTI). RESULTS: DMV scores were independently associated with FA after adjusting for vascular risk factors, age, white matter hyperintensity (WMH) volume, and CSVD burden [ß (95% confidence interval (CI)): -0.219 (-0.375, -0.061), p = 0.006]. We also observed a significant indirect effect of DMV scores on FA in white matter (mediated by FW in white matter) after controlling for age, vascular risk factors, WMH volume, and CSVD burden. CONCLUSIONS: DMV scores were independently related to WMI and mediated by ECF in the white matter of patients with CSVD.

BMI differences among in-hospital management and outcomes in patients with atrial fibrillation: findings from the Care for Cardiovascular Disease project in China.

BACKGROUND: Underweight or obese status influences the prognosis of atrial fibrillation (AF). However, the association between stratification of body mass index (BMI) and in-hospital outcomes in patients with AF, remains lacking in China. METHODS: Using data from the Improving Care for Cardiovascular Disease in China-AF project, which was launched in February 2015 and recruited 150 hospitals in China, we compared characteristics, in-hospital treatments and clinical outcomes among the stratifications of BMI for Asians. RESULTS: A total of 15,867 AF patients with AF were enrolled, including 830 (5.23%) underweight, 4965 (31.29%) with normal weight, 3716 (23.42%) overweight, 5263 (33.17%) obese class I and 1093 (6.89%) obese class II participants. Compared with normal weight patients, underweight, overweight, and obese patients showed increased percentages of CHADS2 scores (3-6) and CHA2DS2-VASc scores (5-9). During hospitalization, overweight or obese patients showed greater use of rhythm control medications, anticoagulant drugs, and intervention therapies than underweight-normal weight patients. In adjusted logistic models, BMI was a strong predictor of in-hospital mortality. Especially, underweight BMI was associated with higher incidence of in-hospital mortality, with an adjusted odds ratio of 2.08 (95% confidence interval, 1.56-4.46; p = 0.04) than overweight and obese BMI. CONCLUSIONS: Asian patients with AF and high BMI received more medical treatments and presented less adverse in-hospital outcomes compared with those with underweight-normal weight. Although low BMI may be associated with other comorbidities and advanced age, underweight BMI retained a negative correlation with all-cause mortality in the patients with AF during hospitalization.

Role of Kir2.1 in human monocyte-derived foam cell maturation.

The role of K(+) channels in macrophage immunomodulation has been well-established. However, it remains unclear whether K(+) channels are involved in the lipid uptake of macrophages. The expression and function of the inward rectifier potassium channel (Kir2.1, KCNJ2) in Human acute monocytic leukemia cell line (THP-1) cells and human monocytes derived macrophages (HMDMs) were investigated using RT-PCR and western blotting, and patch clamp technique. The expression of scavenger receptors in THP-1-derived macrophages was detected using western blotting. Expressions of Kir2.1 mRNA and protein in HMDMs were significantly decreased by 60% (P < 0.05) and 90% (P < 0.001) on macrophage maturation, but overexpressed by approximately 1.3 (P > 0.05) and 3.8 times (P = 0.001) after foam cell formation respectively. Concurrently, the Kir2.1 peak current density in HMDMs, mature macrophages and foam cells, measured at -150 mV, were -22.61 ± 2.1 pA/pF, -7.88 ± 0.60 pA/pF and -13.39 ± 0.80 pA/pF respectively (P < 0.05). In association with an up-regulation of Kir2.1 in foam cells, the SR-A protein level was significantly increased by over 1.5 times compared with macrophages (P < 0.05). THP-1 cells contained much less lipids upon Kir2.1 knockdown and cholesterol ester/total cholesterol ratio was 29.46 ± 2.01% (P < 0.05), and the SR-BI protein level was increased by over 6.2 times, compared to that of macrophages (P < 0.001). Kir2.1 may participate in macrophage maturation and differentiation, and play a key role in lipid uptake and foam cell formation through modulating the expression of scavenger receptors.

Effect of MTHFR Gene Polymorphism Impact on Atherosclerosis via Genome-Wide Methylation.

BACKGROUND: Atherosclerosis seriously threats human health. Homocysteine is an independent risk factor closely related to DNA methylation. MTHFR C667T loci polymorphism is closely associated with homocysteine level. This study aimed to investigate the relationship among MTHFR C667T loci polymorphism, genome-wide methylation, and atherosclerosis. MATERIAL/METHODS: Blood sample was collected from 105 patients with coronary atherosclerosis and 105 healthy controls. Pyrosequencing methylation was used to detect LINE-1 methylation level. Polymerase chain reaction-restriction enzyme fragment length polymorphism (PCR-RFLP) was used to test MTHFR. RESULTS: LINE-1 methylation level in the patient group was significantly lower than in the controls (t=5.007, P<0.001). MTHFR C667T genotype distribution presented marked differences in the 2 groups. TT genotype carriers had significantly increased risk of atherosclerosis (OR=3.56, P=0.009). Three different genotypes of MTHFR C667T loci showed different LINE-1 methylation level between the 2 groups (P<0.01). LINE-1 methylation level in TT and CT genotype carriers was obviously lower than in CC genotype carriers (P<0.05). CONCLUSIONS: MTHFR C667T loci polymorphism may affect atherosclerosis by regulating genome methylation level.

Deep vein diameters and perivascular space scores are associated with deep medullary vein hypo-visibility in patients with white matter hyperintensity.

Background: Deep medullary vein (DMV) hypo-visibility is correlated with white matter hyperintensity (WMH), but the underlying causes remain unclear. This study aimed to explore the relationship between deep vein diameters and perivascular space (PVS) scores, and DMV hypo-visibility in the presence of WMH. Methods: This cross-sectional study prospectively analyzed the clinical and imaging data of 190 cerebral small vessel disease patients with WMH and 40 healthy controls from the Lishui Hospital of Traditional Chinese Medicine affiliated with Zhejiang Chinese Medical University. PVS scores ranging from 0 to 4 were determined according to the PVS counts in the basal ganglia area on T2-weighted magnetic resonance images; high-grade PVS was defined as a PVS score >1. The diameters of the deep cerebral veins, including the bilateral septal veins (SVs), thalamostriate veins (TSVs), lateral ventricular veins (LVVs), and internal cerebral veins, were measured using susceptibility weighted imaging (SWI). Left and right DMV scores, ranging from 0 to 9, were calculated based on the visibility of the DMV on SWI in the ipsilateral frontal, parietal, and occipital lobes. Results: The deep cerebral vein diameters, left and right DMV scores, and high-grade PVS differed between the healthy controls and WMH patients (P<0.05). Left DMV scores were independently associated with age {ß [95% confidence interval (CI)]: 0.050 (0.018, 0.082)}, high-grade PVS [ß (95% CI): 0.998 (0.262, 1.737)], and the diameters of the ipsilateral SVs [ß (95% CI): -1.114 (-1.754, -0.475)], SVs [ß (95% CI): -0.734 (-1.191, -0.277)], and LVVs [ß (95% CI): -0.921 (-1.567, -0.275)] [all false discovery rate (FDR)-corrected P<0.05]. Right DMV scores were independently associated with age [ß (95% CI): 0.071 (0.037, 0.105)], high-grade PVS [ß (95% CI): 0.873 (0.111, 1.635)], and the diameters of the ipsilateral SVs [ß (95% CI): -0.837 (-1.386, -0.289)], TSVs [ß (95% CI): -0.875 (-1.331, -0.419)], and LVVs [ß (95% CI): -1.813 (-2.484, -1.142)] (all FDR-corrected P<0.05). Conclusions: Decreased hypo-visibility of DMVs on SWI was associated with a higher age, the presence of high-grade PVS, and smaller diameters of the ipsilateral deep cerebral veins in individuals with WMH. Our findings provide novel insights into the probable mechanisms leading to high DMV scores.

Association between "weekend warrior" physical activity and the incidence of neurodegenerative diseases.

While guidelines recommend 150 â€‹min of moderate to vigorous physical activity (MVPA) weekly to enhance health, it remains unclear whether concentrating these activities into 1-2 days of the week, "weekend warrior" (WW) pattern, has the same benefit for neurodegenerative diseases (NDDs). This study aimed to evaluate the associations of WW pattern and the risk of NDDs. This prospective study was conducted using accelerometer-based physical activity data for a full week from June 2013 to December 2015 in the UK Biobank. These individuals were categorized into distinct physical activity patterns, including the WW pattern (i.e., over 50% or 75% of recommended MVPA achieved over 1-2 days), regular pattern, and inactive pattern. Cox proportional hazards model was used to evaluate the association between physical activity patterns and outcomes. Compared to inactive group, WW pattern and regular pattern was similarly linked to a reduced risk of all-cause dementia (WW: Hazard Ratio [HR]: 0.68, 95% Confidence Interval [CI]: 0.56-0.84; regular: HR: 0.86, 95% CI: 0.67-1.1) and all-cause Parkinsonism (WW: HR: 0.47, 95% CI: 0.35-0.63; regular: HR: 0.69, 95% CI: 0.5-0.95). When the exercise threshold was increased to 75% of MVPA, both patterns still were associated with decreased risk of incident all-cause dementia (WW: HR: 0.61, 95% CI: 0.41-0.91; regular: HR: 0.76, 95% CI: 0.63-0.92) and all-cause Parkinsonism (WW: HR: 0.22, 95% CI: 0.10-0.47; regular: HR: 0.59, 95% CI: 0.46-0.75). Concentrating recommended physical activities into 1-2 days per week is associated with a lower incidence of NDDs.

Cardioprotective Effects of Atorvastatin plus Trimetazidine in Percutaneous Coronary Intervention.

OBJECTIVE: To explore the effects of preoperative administration of conventional doses of atorvastatin plus trimetazidine on the myocardial injury of patients during the perioperative period of percutaneous coronary intervention (PCI). METHODOLOGY: 475 cases of acute coronary syndrome patients before PCI were randomly divided into the control group (238 cases) and experimental group (237 cases).The control group was treated with conventional doses of atorvastatin calcium (20 mg each time, once a night), and the experimental group was treated with conventional doses of atorvastatin calcium plus trimetazidine hydrochloride (20 mg each time, tid) for 3 d. After PCI, preoperative and postoperative 24 h concentrations of serum creatine kinase MB isoenzyme (CK-MB), cardiac troponin I (cTnI) and high sensitivity C-reactive protein (hs-CRP) as well as activity of myeloperoxidase (MPO) were investigated. Left ventricular ejection fractions of the patients were then examined 4 weeks later. RESULTS: Postoperative 24 h cTnI concentration and elevated MPO activity of the experimental group were significantly lower than those of the control group (P <0 05). CK-MB activities and hs-CRP concentrations of the two groups did not differ significantly (P> 0 05). CONCLUSION: The administration of conventional doses of atorvastatin plus trimetazidine three days before PCI is able to protect the perioperative patients from myocardial injury.

Revealing Prognostic and Immunotherapy-Sensitive Characteristics of a Novel Cuproptosis-Related LncRNA Model in Hepatocellular Carcinoma Patients by Genomic Analysis.

Immunotherapy has shown strong anti-tumor activity in a subset of patients. However, many patients do not benefit from the treatment, and there is no effective method to identify sensitive immunotherapy patients. Cuproptosis as a non-apoptotic programmed cell death caused by excess copper, whether it is related to tumor immunity has attracted our attention. In the study, we constructed the prognostic model of 9 cuproptosis-related LncRNAs (crLncRNAs) and assessed its predictive capability, preliminarily explored the potential mechanism causing treatment sensitivity difference between the high-/low-risk group. Our results revealed that the risk score was more effective than traditional clinical features in predicting the survival of HCC patients (AUC = 0.828). The low-risk group had more infiltration of immune cells (B cells, CD8+ T cells, CD4+ T cells), mainly with anti-tumor immune function (p < 0.05). It showed higher sensitivity to immune checkpoint inhibitors (ICIs) treatment (p < 0.001) which may exert the effect through the AL365361.1/hsa-miR-17-5p/NLRP3 axis. In addition, NLRP3 mutation-sensitive drugs (VNLG/124, sunitinib, linifanib) may have better clinical benefits in the high-risk group. All in all, the crLncRNAs model has excellent specificity and sensitivity, which can be used for classifying the therapy-sensitive population and predicting the prognosis of HCC patients.

Peritumor tertiary lymphoid structures are associated with infiltrating neutrophils and inferior prognosis in hepatocellular carcinoma.

BACKGROUND: The positive prediction of prognosis and immunotherapy within tertiary lymphoid structure (TLS) in cancerous tissue has been well demonstrated, including liver cancer. However, the relationship between TLS and prognosis in the peritumoral region of hepatocellular carcinoma (HCC) has received less attention. Few studies on whether TLS, as a typical representative of acquired immune cell groups, is associated with innate immune cells. The aim of this paper was to identify the prognostic role of peritumor TLS in HCC and to simply explore the relationship with neutrophils infiltration. METHODS: This study included cancerous and paracancerous tissue from 170 patients after surgical resection of HCC. TLS was examined and identified by pathological H&E examination, and the impact on prognosis was further classified by determination of total TLS area. Immunohistochemical staining of CD15+ neutrophils was also performed on half of the cases. The obtained results were validated by external public database, as TLS has been widely shown to be tagged with 12 chemokines. RESULTS: In peritumoral tissue, the TLS- group had better overall survival (OS) and disease-free survival (DFS) outcomes compared with the TLS+ group. On the contrary, the intratumor TLS+ group showed better DFS outcomes. When further investigating the relationship between TLS area distribution and DFS, progressively worse prognosis was only found in the peritumor region with increasing TLS density (TLS- vs. TLSL vs. TLSH ). In addition, neutrophil infiltration increased in parallel with TLS density in the peritumoral region, which was not observed in the intratumoral region. CONCLUSIONS: TLS might have a dual prognostic role in different regions of HCC. The abundance of peritumoral TLS is an independent influence of DFS. The inconsistent correlation between neutrophils and corresponding TLS in different regions may indicate different pathways of immune aggregation and may serve as an explanation for the different prognosis of TLS, which needs to be specifically explored.

Role of NLRP3 inflammasome activation in HCC cell progression.

Hepatocellular carcinoma (HCC) is a globally prevalent and fatal malignancy worldwide, and identifying therapeutic strategies is time-consuming. Numerous reports have suggested the involvement of the NLRP3 inflammasome in the progression of various cancers. However, the detailed mechanisms underlying the role of NLRP3 inflammasome in HCC progression remain unclear. In this study, we observed low expression levels of the NLRP3 inflammasome in a subset of HCC cells. Furthermore, we demonstrated that the NLRP3 inflammasome can be activated by LPS + ATP through the nuclear factor kappa B signaling pathway, as confirmed by western blotting and immunofluorescence staining. To assess the impact of NLRP3 inflammasome activation on HCC cell behavior, we employed Edu staining, cell cycle assay, Annexin V/PI staining, and wound healing assay. Our results revealed that NLRP3 inflammasome activation inhibited the proliferation of Bel-7402 and SMMC-7721 cells, arrested the cell cycle at the G1 phase, and suppressed cell migration, while apoptosis remained unaffected. In summary, our findings suggest that targeting the NLRP3 inflammasome could have therapeutic potential for HCC.

Vibration and Trajectory Tracking Control of Engineering Mechanical Arm Based on Neural Network.

We offer a neural network-based control method to control the vibration of the engineering mechanical arm and the trajectory in order to solve the problem of large errors in tracking the path when the engineering mechanical arm is unstable and under the influence of the outside world. A mechanical arm network is used to perform tasks related to learning the unknown dynamic properties of a engineering mechanical arms keyboard without the need for prior learning. Given the dynamic equations of the engineering mechanical arm, the dynamic properties of the mechanical arm were studied using a positive feedback network. The adaptive neural network management system was developed, and the stability and integrity of the closed-loop system were proved by Lyapunov's function. Engineering mechanical arm motion trajectory control errors were modeled and validated in the Matlab/Simulink environment. The simulation results show that the management of the adaptive neural network is able to better control the desired path of the engineering mechanical arm in the presence of external interference, and the fluctuation range of input torque is small. The PID control has a large error in the expected trajectory tracking of the engineering mechanical arm, the fluctuation range of the input torque is as high as 20, and the jitter phenomenon is more serious. The use of detailed comparisons and adaptive neural network monitoring can perform well in manipulating the trajectory of the engineering mechanical arm. The engineering mechanical arm uses an adaptive neural network control method, in which the control precision of engineering mechanical arm motion trajectory can be improved and the out-of-control phenomenon of mechanical arm motion can be reduced.

Guidezilla™ guide extension catheter I for transradial coronary intervention.

Background: Percutaneous coronary intervention (PCI) is the preferred treatment method for coronary artery diseases (CAD). This study aimed to evaluate the effectiveness and complications of the Guidezilla™ guide extension catheter I (GGEC I) in transradial coronary intervention (TRI). Methods: This case series study included patients with CAD who underwent TRI using the GGEC I between August 2016 and January 2019 at the First Affiliated Hospital of Xi'an Jiaotong University. Results: A total of 221 patients aged 65.1 ± 9.26 years were included. Coronary angiography results indicated that most patients (77.8%) had triple-vessel lesions, including 47.5% with chronic total occlusion (CTO). A total of 237 target lesions were treated, most being type C lesions (95.8%). The most common indication for GGEC I use was heavy calcification (67%), followed by extreme tortuosity (12.2%), extreme tortuosity and heavy calcification (10.9%), distally located lesion (4.5%), picking up the retrograde wire (3.2%), anomalous vessel origin (1.8%), and releasing the burr incarceration (0.4%). The mean operation time was 58 min, and the overall success rate was 94.1%. Four patients received a drug-coated balloon. No significant differences were found in operation time and success rate among the low (<23), intermediate (23-32), and severe (>32) CAD groups based on SYNTAX score stratification (P > 0.05). Two subacute thrombosis cases each were reported perioperatively, during hospitalization, and at the 1-month follow-up. Conclusion: The GGEC I might have advantages for TRI and is unaffected by SYNTAX score stratification.

New insights in addressing cerebral small vessel disease: Associated with extracellular fluid in white matter.

Objective: To explore the role of extracellular fluid, assessed by diffusion tensor imaging (DTI) metrics of free water (FW), in the white matter of patients with cerebral small vessel disease (CSVD). Materials and methods: The baseline clinical and imaging data of 129 patients with CSVD were collected and reviewed. CSVD MR markers, including periventricular white matter hyperintensity (PWMH), deep white matter hyperintensity (DWMH), cerebral microbleed (CMB), enlarged perivascular space (PVS), and lacunar infarction (LI), were identified, and CSVD burden was calculated. According to total CSVD MR marker score, cases were classified as mild, moderate, or severe. The mean FW and fractional anisotropy (FA) values were calculated using DTI images. Results: The mean white matter FW was associated with the CSVD MR markers, including PWMH, DWMH, LI and PVS (P < 0.05). Moreover, age, hypertension, diabetes mellitus, and FW value were associated with total CSVD MR marker score (P < 0.05). Ordinal logistic regression analysis revealed that FW and age were independently associated with CSVD burden (P < 0.05). Finally, FW in white matter was associated with FA (r = -0.334, P < 0.001). Conclusion: Extracellular fluid changes, assessed by DTI metrics of FW in white matter, were associated with CSVD markers and burden. An increased extracellular fluid volume in the white matter was associated with lower FA.

Efficacy and safety of drug-coated balloon combined with cutting balloon for side branch of true coronary bifurcation lesions: Study protocol for a multicenter, prospective, randomized controlled trial.

Background: Coronary bifurcation lesions are common of percutaneous coronary intervention (PCI), and the optimal interventional therapy strategy is still a matter of debate and remains a challenge for interventional cardiologists. The provisional stenting technique is still a preferred method for most bifurcation lesions, but restenosis of the side branch (SB) occurs in approximately 17-19% of cases. Therefore, the dilemma of reducing SB restenosis still exists, and further research on strategies to reduce restenosis for SB is necessary. Drug-coated balloon (DCB) can reduce clinical events in small vessel disease and in-stent restenosis. The efficacy and safety of DCB for SB of true coronary bifurcation lesions have not been fully investigated. A randomized comparison of DCB combined with cutting balloon angioplasty vs. cutting balloon angioplasty for SB has never been published. Methods and design: The purpose of this study is to explore the superiority of DCB combined with cutting balloon vs. cutting balloon angioplasty for SB after main vessel (MV) drug-eluting stent implantation of true coronary bifurcation lesions. This study is a multicenter, prospective, randomized controlled trial including 140 patients with true coronary bifurcation lesions. Patients will be randomized in a 1:1 manner to receive either DCB combined with cutting balloon or cutting balloon angioplasty for SB after MV drug-eluting stent implantation. The primary endpoint is the evaluation of late lumen loss (LLL) of SB at the 9-month follow-up. The secondary endpoints include procedural success during initial hospitalization, LLL of MV at the 9-month follow-up, binary angiographic restenosis in MV and SB at the 9-month follow-up, the proportion of patients with a final post-PCI quantitative flow ratio result ≤ 0.80 for SB at the 9-month follow-up, and major adverse cardiac events during the 24-month follow-up. Conclusions: This clinical trial will provide evidence as to whether DCB combined with cutting balloon for SB of true coronary bifurcation lesions is a superior treatment approach. Trial Registration Number: ChiCTR2000040475. Dissemination: The results of this clinical trial will be published in a peer-reviewed journal.

Circular RNA circ_0001006 aggravates cardiac hypertrophy via miR-214-3p/PAK6 axis.

AIM: Circular RNAs (circRNAs) control gene expression in a series of physiological and pathological processes, but their role in heart disease is unknown. This research illustrates the role and potential mechanism of circRNA in cardiac hypertrophy. METHODS AND RESULTS: In this report, we found that circular RNA hsa_circ_0001006 (circ_0001006) was upregulated in cardiac hypertrophy mice and cardiomyocytes treated with angiotensin II (Ang II). Next, we noticed that gain of function circ_0001006 could induce cardiomyocyte hypertrophy; oppositely, knockdown of circ_0001006 remitted Ang II-induced cardiomyocyte hypertrophy. Biotin-coupled miRNA and RNA-pull down assays showed that miR-214-3p could bind with circ_0001006 and gain the function of miR-214-3p abrogated the pro-hypertrophy effect of circ_0001006. Furthermore, Further, dual-luciferase reporter assay showed that miR-214-3p could interact with 3'UTRs of the PAK6 gene, and circRNA_0001006 could block the above interactions. Additionally, PAK6 expression is inhibited by miR-214-3p mimic in cardiomyocytes but enhanced by over-expression of circRNA_000203 in vitro. CONCLUSIONS: Our data demonstrated that circRNA_0001006 exacerbates cardiac hypertrophy via suppressing miR-214-3p leading to enhanced PAK6 levels.

Protective effect of tertiary lymphoid structures against hepatocellular carcinoma: New findings from a genetic perspective.

Background: Tertiary lymphoid structures (TLS) have an effect on hepatocellular carcinoma (HCC), but the underlying mechanism remains to be elucidated. Methods: Intratumoral TLS (iTLS) was classified in the Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort using pathological sections from the Cancer Digital Slide Archive. Univariate and multivariate Cox regression analyses were performed to validate the effect of iTLS on overall survival (OS), relapse-free survival (RFS), and disease-free survival (DFS). The genes differentially expressed between the iTLS-negative and iTLS-positive groups were analyzed in combination with sequencing data. Gene set enrichment analysis (GSEA) was used to explore the signaling pathways affected by these differentially expressed genes. The random forest algorithm was used to identify genes with the highest correlation with the iTLS in the training set. Multivariate logistic regression was used to build a model to predict iTLS in tissue samples. Spearman's correlation was used to analyze the relationship between TLS-associated chemokines and signature genes, and CIBERSORT was used to calculate immune infiltration scores. Copy number variation and its relationship with immune cell infiltration and signature genes were assessed using the gene set cancer analysis (GSCA). The Correlation R package was used for gene ontology (GO), disease ontology (DO), and gene mutation analyses. The GSCA was used for drug sensitivity analysis. LASSO regression was used to build prognostic models, and external data were used to validate the models. Results: There were 218 positive and 146 negative samples for iTLS. iTLS was significantly associated with better RFS and DFS according to Cox regression analysis. Twenty signature genes that were highly associated with iTLS positivity were identified. GO and mutation analyses revealed that the signature genes were associated with immunity. Most signature genes were sensitive to immune checkpoint inhibitors. Risk scores calculated using a characteristic gene-based prognostic model were found to be an independent prognostic factor for OS. Conclusions: The improvement of RFS in HCC by iTLS was not limited to the early period as previously reported. iTLS improved DFS in patients. Characteristic genes are closely related to the formation of iTLS and TLS chemokines in HCC. These genes are closely related to immunity in terms of cellular infiltration, biological functions, and signaling pathways. Most are sensitive to immune checkpoint inhibitors, and their expression levels can affect prognosis.

Tertiary Lymphatic Structures in Primary Hepatic Carcinoma: Controversy Cannot Overshadow Hope.

Tertiary lymphoid structures (TLSs) are organized aggregates of immune cells found in the tumor microenvironment. TLS can influence primary hepatic carcinoma (PHC) occurrence and have an active role in cancer. TLS can promote or inhibit the growth of PHC depending on their location, and although available findings are controversial, they suggest that TLS have a protective role in PHC tissues and a non-protective role in paracancerous tissues. In addition, the cellular composition of TLS can also influence the outcome of PHC. As an immunity marker, TLS can act as a marker of immunotherapy to predict its effect and help to identify patients who will respond well to immunotherapy. Modulation of TLS formation through the use of chemokines/cytokines, immunotherapy, or induction of high endothelial vein to interfere with tumor growth has been studied extensively in PHC and other cancers. In addition, new tools such as genetic interventions, cellular crosstalk, preoperative radiotherapy, and advances in materials science have been shown to influence the prognosis of malignant tumors by modulating TLS production. These can also be used to develop PHC treatment.

Elevated Lipoprotein-Associated Phospholipase A2 is Valuable in Prediction of Coronary Slow Flow in Non-ST-Segment Elevation Myocardial Infarction Patients.

Background Coronary flow is a determinative factor of non-ST-segment elevation myocardial infarction (NSTEMI) patients. Lipoprotein-Associated Phospholipase A2(Lp-PLA2) as a vascular specific inflammatory cytokine might relate to coronary slow flow in these patients. Methods 105 NSTEMI patients and 83 UAP patients were enrolled. Another group division was made by Lp-PLA2 tertile data. Corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC) was adopted to represent coronary flow condition. Correlation analysis was made between CTFC and other clinical indicators. Multivariable regression analysis was used to identify the influential factors of coronary flow in NSTEMI patients. ROC curve was used to determine the diagnostic value of Lp-PLA2 with coronary slow flow (CSF). Results High sensitive C reactive protein (hsCRP, P < 0.01), Lp-PLA2(P < 0.01), N-terminal pro-brain natriuretic peptide (NT-proBNP, P < 0.05), mean platelet volume (MPV, P<0.05), CTFC(P < 0.05) was higher in NSTEMI than UAP patients. hsCRP(P < 0.01), MPV(P < 0.01), NT-proBNP(P < 0.01) CTFC(P < 0.01) was higher in high-Lp-PLA2 group. Lp-PLA2 and hsCRP (r = 0.22, P < 0.01), MPV (r = 0.21, P < 0.05), CTFC (r = 0.69, P < 0.01) had a positive correlation in NSTEMI group. Multivariable regression analysis showed that Lp-PLA2 could explain most part changes of CTFC in NSTEMI patients, CTFC = 0.55*Lp-PLA2+0.03*hsCRP+0.005*NT-proBNP+15.843. Lp-PLA2 was specific and sensitive in diagnosis of CSF in NSTEMI group, AUC = 0.851(95% confidence interval (CI): 0.771-0.924, P < 0.01), Cutoff=196.96ng/ml, sensitivity = 84%, specificity = 81%. Conclusions Lp-PLA2 is closely correlated with coronary flow in NSTEMI patients. Lp-PLA2 over 196.96ng/ml could be used to predict CSF in NSTEMI patients.

A Novel Nine-lncRNA Risk Signature Correlates With Immunotherapy in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma is one of the most common malignant tumors with a very high mortality rate. The emergence of immunotherapy has brought hope for the cure of hepatocellular carcinoma. Only a small number of patients respond to immune checkpoint inhibitors, and ferroptosis and tertiary lymphoid structure contribute to the increased response rate of immune checkpoint inhibitors; thus, we first need to identify those who are sensitive to immunotherapy and then develop different methods to improve sensitivity for different groups. METHODS: The sequencing data of hepatocellular carcinoma from The Cancer Genome Atlas and Gene Expression Omnibus was downloaded to identify the immune-related long non-coding RNAs (lncRNAs). LncRNAs related to survival data were screened out, and a risk signature was established using Cox proportional hazard regression model. R software was used to calculate the riskScore of each patient, and the patients were divided into high- and low-risk groups. The prognostic value of riskScore and its application in clinical chemotherapeutic drugs were confirmed. The relationship between riskScore and immune checkpoint genes, ferroptosis genes, and genes related to tertiary lymphoid structure formation was analyzed by Spearman method. TIMER, CIBERSORT, ssGSEA, and ImmuCellAI were used to evaluate the relative number of lymphocytes in tumor. The Wilcoxon signed-rank test confirmed differences in immunophenoscore between the high- and low-risk groups. RESULTS: Data analysis revealed that our signature could well predict the 1-, 2-, 3-, and 5-year survival rates of hepatocellular carcinoma and to predict susceptible populations with Sorafenib. The risk signature were significantly correlated with immune checkpoint genes, ferroptosis genes, and tertiary lymphoid structure-forming genes, and predicted tumor-infiltrating lymphocyte status. There was a significant difference in IPS scores between the low-risk group and the high-risk group, while the low-risk group had higher scores. CONCLUSION: The riskScore obtained from an immune-related lncRNA signature could successfully predict the survival time and reflect the efficacy of immune checkpoint inhibitors. More importantly, it is possible to select different treatments for different hepatocellular carcinoma patients that increase the response rate of immune checkpoint inhibitors and will help improve the individualized treatment of hepatocellular carcinoma.