Myocardial infarction (MI) is the leading cause of cardiovascular disease-related death worldwide. Nonetheless, existing therapeutic approaches for MI are hampered by issues such as reliance on pharmacological agents and suboptimal patient adherence. Caffeic acid (CA) is a bioactive polyphenolic compound with important anti-inflammatory, anti-bacterial and anti-oxidant functions. Still, its specific role and mechanism in treating cardiovascular disease remain to be further studied. In recent years, a large number of studies have shown that the kelch-like ECH-associated protein 1/nuclear factor erythroid 2 related factor 2 (Keap1/Nrf2) pathway is a key factor in the occurrence and development of cardiovascular diseases. In this study, H₂O₂-induced oxidative stress model of H9c2 cells and left anterior descending branch (LAD) conjunctival induced acute myocardial infarction reperfusion (AMI/R) model were used to evaluate the protective effect of CA on the heart. The interaction between CA and Keap1 was analyzed by CA-labeled fluorescence probe, target fishing, isothermal titration calorimetry (ITC), protein crystallography and surface plasmon resonance (SPR). Our results suggested that CA binds Keap1 and degrades Keap1 in a p62-dependent manner, further promoting nuclear transcription of Nrf2 and thus effectively reducing oxidative stress. In addition, based on the three-dimensional eutectic structure, it was confirmed that CA directly targets Keap1 protein by interacting with residues M550 and N532, inducing conformation changes in Keap1 protein. We also found that the CA analog chlorogenic acid (GCA) can bind Keap1. In conclusion, this study elucidates a novel molecular mechanism and structural basis for the protective effects of CA against oxidative damage via the Keap1-Nrf2 pathway.

Background::In the clinic, practitioners encounter many patients with an abnormal pattern of dense punctate magnetic resonance imaging (MRI) signal in the basal ganglia, a phenomenon known as "cheese sign". This sign is reported as common in cerebrovascular diseases, dementia, and old age. Recently, cheese sign has been speculated to consist of dense perivascular space (PVS). This study aimed to assess the lesion types of cheese sign and analyze the correlation between this sign and vascular disease risk factors.Methods::A total of 812 patients from Peking Union Medical College Hospital (PUMCH) dementia cohort were enrolled. We analyzed the relationship between cheese sign and vascular risk. For assessing cheese sign and defining its degree, the abnormal punctate signals were classified into basal ganglia hyperintensity (BGH), PVS, lacunae/infarctions and microbleeds, and counted separately. Each type of lesion was rated on a four-level scale, and then the sum was calculated; this total was defined as the cheese sign score. Fazekas and Age-Related White Matter Changes (ARWMC) scores were used to evaluate the paraventricular, deep, and subcortical gray/white matter hyperintensities.Results::A total of 118 patients (14.5%) in this dementia cohort were found to have cheese sign. Age (odds ratio [OR]: 1.090, 95% confidence interval [CI]: 1.064-1.120, P <0.001), hypertension (OR: 1.828, 95% CI: 1.123-2.983, P = 0.014), and stroke (OR: 1.901, 95% CI: 1.092-3.259, P = 0.025) were risk factors for cheese sign. There was no significant relationship between diabetes, hyperlipidemia, and cheese sign. The main components of cheese sign were BGH, PVS, and lacunae/infarction. The proportion of PVS increased with cheese sign severity. Conclusions::The risk factors for cheese sign were hypertension, age, and stroke. Cheese sign consists of BGH, PVS, and lacunae/infarction.

The pathogenesis of attention deficit and hyperactive disorder(ADHD)remains unclear.Evidence from epidemiological,biomarker,and genetic studies indicates that inflammation may play a crucial role in ADHD development.Inflammation can influence the onset and progression of ADHD through various mechanisms,such as activation of the hypothalamic-pituitary-adrenal(HPA)axis,alterations in neurotransmitter metabolism,maternal immune activation,disruption of the blood-brain barrier integrity,and impacts on neurodevelopment.A deeper understanding of the relationship between inflammation and ADHD could provide valuable insights into the pathophysiological mechanisms of ADHD and open new perspectives for clinical diagnosis and treatment.

Hepatocellular carcinoma is one of the most common malignant tumors in the world, which is a serious threat to human health. HBV infection is one of the most common causes of hepatocellular carcinoma.The diagnosis of most hepatocellular carcinoma has progressed to the middle and late stage, and the prognosis is poor. Early detection, diagnosis and treatment are important supports to improve the clinical outcome of hepatocellular carcinoma. In recent years, scholars at home and abroad have established various hepatocellular carcinoma risk prediction models, which are conducive to improving the early diagnosis rate of hepatocellular carcinoma and reducing the mortality rate. This article reviews the risk factors and risk prediction models of chronic hepatitis B associated hepatocellular carcinoma, in order to provide reference for HBV-associated liver cancer risk monitoring and management decision.

Objective:To investigate the changes of T lymphocyte subsets in peripheral blood of patients with diffuse large B-cell lymphoma (DLBCL) and its clinical significance.Methods:The clinical data of 99 DLBCL patients admitted to the First Affiliated Hospital of Xiamen University from January 2022 to January 2023 were retrospectively analyzed. T lymphocyte subsets in peripheral blood before and after treatment were detected by using flow cytometry. According to the disease status at the time of blood collection and detection, the patients were divided into the newly-diagnosed DLBCL group (28 cases), and the newly-treated remission DLBCL group (71 cases); and 40 healthy volunteers undergoing the physical examination during the same period were selected as the healthy control group. The proportion and absolute count differences of T lymphocytes and the related subsets in 3 groups were compared. Besides, the correlation among T lymphocyte subsets, the correlation of each subset with international prognostic index (IPI) score and treatment response in newly-diagnosed DLBCL patients were further analyzed.Results:The proportion of CD3 + T cells in newly-diagnosed DLBCL group was decreased compared with that in the healthy control group [(58±14)% vs. (67±7)%, P < 0.05]. The absolute count of CD3 + T cells in both newly-diagnosed group and the newly-treated remission group was reduced compared with that in the healthy control group [(875±483) /μl and (808±553) /μl vs. (1 374±279) /μl, P < 0.001]. The absolute count of CD4 + and CD8 + T cells in newly-diagnosed group was decreased compared with that in the healthy control group [(478±313) /μl vs. (695±154) /μl, (316±181) /μl vs. (525±193) /μl, all P < 0.001]. Both the proportion and absolute count of CD4 + T cells in the newly-treated remission DLBCL group were decreased compared with those in the newly-diagnosed DLBCL group and the healthy control group [(40±14)% vs. (53±14)% and (51±9)%, (313±247) /μl vs. (478±313) /μl and (695±154) /μl, all P < 0.05]. The porportion of CD8 + T cells was increased compared with that in the other two groups [(51±15)% vs. (37±12)% and (38±9)%, all P < 0.001]. Compared with the healthy control group, the effect/memory subsets proportion of regulatory T cell (Treg) and conventional T cell (Tcon) were increased in both newly-diagnosed DLBCL group and the newly-treated remission DLBCL group [(79±16)% and (84±12)% vs. (71±11)%,(72±16)% and (76±14)% vs. (62±13)%, all P < 0.05], and the proportion of CD127 + memory Tcon and CD8 + T cell subsets was reduced [(73±14)% and (66±20)% vs. (85±8)%,(39±15)% and (25±21)% vs. (62±16)%, all P < 0.05]. In newly-diagnosed DLBCL group, the absolute counts of CD3 + T and CD4 + T cells were negatively correlated with the proportion of effector Treg ( r = -0.379, P = 0.049; r = -0.384, P = 0.040, respectively). IPI score of DLBCL patients was correlated with the proportion of CD8 + T cells ( Eta2 = 0.15, P = 0.038). The proportion of CD127 + memory Tcon in patients with non-complete remission was increased compared with that in patients with complete remission after treatment ( P = 0.020). Conclusions:The proportion and absolute count of T lymphocyte cells in peripheral blood of newly-diagnosed DLBCL patients is decreased, and the differentiation state of T lymphocyte cells shows change trend, which is related to the clinical characteristics and treatment response of DLBCL patients. Even if DLBCL patients have achieved treatment remission, T lymphocyte cells are not completely return to the normal.

Objective:To investigate the diagnostic accuracy of serological indicators and evaluate the diagnostic value of a new established combined serological model on identifying the minimal hepatic encephalopathy (MHE) in patients with compensated cirrhosis.Methods:This prospective multicenter study enrolled 263 compensated cirrhotic patients from 23 hospitals in 15 provinces, autonomous regions and municipalities of China between October 2021 and August 2022. Clinical data and laboratory test results were collected, and the model for end-stage liver disease (MELD) score was calculated. Ammonia level was corrected to the upper limit of normal (AMM-ULN) by the baseline blood ammonia measurements/upper limit of the normal reference value. MHE was diagnosed by combined abnormal number connection test-A and abnormal digit symbol test as suggested by Guidelines on the management of hepatic encephalopathy in cirrhosis. The patients were randomly divided (7∶3) into training set ( n=185) and validation set ( n=78) based on caret package of R language. Logistic regression was used to establish a combined model of MHE diagnosis. The diagnostic performance was evaluated by the area under the curve (AUC) of receiver operating characteristic curve, Hosmer-Lemeshow test and calibration curve. The internal verification was carried out by the Bootstrap method ( n=200). AUC comparisons were achieved using the Delong test. Results:In the training set, prevalence of MHE was 37.8% (70/185). There were statistically significant differences in AMM-ULN, albumin, platelet, alkaline phosphatase, international normalized ratio, MELD score and education between non-MHE group and MHE group (all P<0.05). Multivariate Logistic regression analysis showed that AMM-ULN [odds ratio ( OR)=1.78, 95% confidence interval ( CI) 1.05-3.14, P=0.038] and MELD score ( OR=1.11, 95% CI 1.04-1.20, P=0.002) were independent risk factors for MHE, and the AUC for predicting MHE were 0.663, 0.625, respectively. Compared with the use of blood AMM-ULN and MELD score alone, the AUC of the combined model of AMM-ULN, MELD score and education exhibited better predictive performance in determining the presence of MHE was 0.755, the specificity and sensitivity was 85.2% and 55.7%, respectively. Hosmer-Lemeshow test and calibration curve showed that the model had good calibration ( P=0.733). The AUC for internal validation of the combined model for diagnosing MHE was 0.752. In the validation set, the AUC of the combined model for diagnosing MHE was 0.794, and Hosmer-Lemeshow test showed good calibration ( P=0.841). Conclusion:Use of the combined model including AMM-ULN, MELD score and education could improve the predictive efficiency of MHE among patients with compensated cirrhosis.

Due to the lack of understanding of the concept of staging of survivors, clinical nurses pay different attention to the symptom burden of colorectal cancer survivors in different stages, resulting in different levels of symptom burden, compliance, and quality of life. This article starts from the definition and stages of survivors, introduces the current situation of the symptom burden of colorectal cancer survivors under different stages, analyzes and compares the main evaluation tools, and combs the influencing factors of the symptom burden of colorectal cancer survivors from various aspects. On this basis, this article puts forward the shortcomings and enlightenment of existing research, aiming to help doctors and nurses understand the staging of survivors, accurately grasp the level of symptom burden of colorectal cancer survivors, and provide reference for further clinical research.

Acidosis, regardless of hypoxia involvement, is recognized as a chronic and harsh tumor microenvironment (TME) that educates malignant cells to thrive and metastasize. Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression, the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy. Here, chemical-induced and transgenic mouse models for colon, liver and lung cancer were established, respectively. miR-7 and TGF-β2 expressions were examined in clinical tissues (n = 184). RNA-seq, miRNA-seq, proteomics, biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis. Our data show that lung cancer is sensitive to the increased acidification of TME, and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5p. TGF-β2 is a direct target of miR-7-5p. The reduced expression of miR-7-5p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung cancer. Indeed, overexpression of miR-7-5p reduces the acidic pH-enhanced lung cancer metastasis. Furthermore, the human lung tumor samples also show a reduced miR-7-5p expression but an elevated level of activated TGF-β2; the expressions of both miR-7-5p and TGF-β2 are correlated with patients' survival. We are the first to identify the role of the miR-7/TGF-β2 axis in acidic pH-enhanced lung cancer metastasis. Our study not only delineates how acidification directly affects tumorigenesis, but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer (NSCLC) treatment. Our study opens an avenue to explore the pH-sensitive subcellular components as novel therapeutic targets for cancer treatment.

Inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) is one of important kinases in inflammation to phosphorylate inhibitor of nuclear factor kappa-B (IκBα) and then activate nuclear factor kappa-B (NF-κB). Inhibition of IKKβ has been a therapeutic strategy for inflammatory and autoimmune diseases. Here we report that IKKβ is constitutively activated in healthy donors and healthy Ikkβ ^C46A (cysteine 46 mutated to alanine) knock-in mice although they possess intensive IKKβ-IκBα-NF-κB signaling activation. These indicate that IKKβ activation probably plays homeostatic role instead of causing inflammation. Compared to Ikkβ ^WT littermates, lipopolysaccharides (LPS) could induce high mortality rate in Ikkβ ^C46A mice which is correlated to breaking the homeostasis by intensively activating p-IκBα-NF-κB signaling and inhibiting phosphorylation of 5' adenosine monophosphate-activated protein kinase (p-AMPK) expression. We then demonstrated that IKKβ kinase domain (KD) phosphorylates AMPKα1 via interacting with residues Thr183, Ser184, and Thr388, while IKKβ helix-loop-helix motifs is essential to phosphorylate IκBα according to the previous reports. Kinase assay further demonstrated that IKKβ simultaneously catalyzes phosphorylation of AMPK and IκBα to mediate homeostasis. Accordingly, activation of AMPK rather than inhibition of IKKβ could substantially rescue LPS-induced mortality in Ikkβ ^C46A mice by rebuilding the homeostasis. We conclude that IKKβ activates AMPK to restrict inflammation and IKKβ mediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα.