Transarterial Chemoembolization Combined With Apatinib Plus PD-1 Inhibitors for Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Multicenter Retrospective Study.

INTRODUCTION: The aim of this study was to compare transarterial chemoembolization (TACE) combined with apatinib and PD-1 inhibitors (TACE-AP) with TACE combined with apatinib alone (TACE-A) in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) and to explore the prognostic factors affecting the survival of patients. METHODS: This retrospective study analyzed data of patients with HCC with PVTT who were treated with TACE-AP or TACE-A between December 2018 and June 2021. The primary end points of the study were progression-free survival (PFS) and overall survival (OS), and the secondary end points were objective response rate (ORR) and adverse events (AEs). Propensity score matching (PSM) and stabilized inverse probability weighting (sIPTW) analyses were used to reduce patient selection bias, and Cox regression analysis was used to analyze prognostic factors affecting patient survival. RESULTS: Sixty-nine and 40 patients were included in the TACE-A and TACE-AP groups, respectively. After PSM and IPTW analyses, the median PFS and median OS in the TACE-AP group were significantly higher than those in the TACE-A group (PFS: after PSM, 6.9 vs 4.0 months, P < 0.001, after IPTW, 6.5 vs 5.1 months, P < 0.001; OS: after PSM, 14.6 vs 8.5 months P < 0.001, after IPTW, 16.1 vs 10.5 months, P < 0.001). After PSM and IPTW analyses, the tumor ORR in the TACE-AP group was significantly higher than that in the TACE-A group (PSM, 53.6% vs 17.9%, P = 0.005; IPTW, 52.5% vs 28.6%, P = 0.013). All treatment-related AEs were observed to be tolerated. Multivariate Cox regression analysis showed that the main prognostic factors affecting the survival of patients were tumor number, PVTT type, alpha-fetoprotein, and treatment mode. DISCUSSION: In the treatment of patients with HCC with PVTT, TACE-AP significantly improved PFS, OS, and ORR, and the AEs were safe and controllable.

Correlation of Serum Chemokine Ligand 14 with Barcelona Clinic Liver Cancer Stage, Lymphocyte Profile, and Response to Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma.

PURPOSE: To investigate the clinical relevance of serum chemokine ligand 14 (sCCL14) in patients with hepatocellular carcinoma (HCC) and the effect of transarterial chemoembolization (TACE) on the expression level of sCCL14 and the immune microenvironment. MATERIALS AND METHODS: In this prospective single-center observational study, 52 patients with HCC were recruited from January 2019 to December 2021, their clinical data and blood samples were collected, and the relationship between sCCL14 and progression-free survival (PFS) and TACE treatment response was analyzed. RESULTS: Among the 52 patients with HCC (Barcelona Clinic Liver Cancer [BCLC] Stage A, 25.0%; BCLC Stage B, 44.2%; and BCLC Stage C, 30.8%), patients with BCLC Stage C HCC had significantly lower sCCL14 levels than those of patients with BCLC Stages A and B HCC (P = .001). sCCL14 levels were significantly higher in the first week after treatment than before TACE treatment (P = .024). Baseline sCCL14 levels in patients who showed complete response after TACE treatment were significantly higher than those in other groups, and lower baseline sCCL14 values were associated with shorter PFS times. Multivariate Cox regression analysis showed that sCCL14 level (hazard ratio, 1.855; 95% CI, 1.039-3.311; P = .037) was an independent prognostic factor of PFS. sCCL14 levels negatively correlated with the proportion of B lymphocytes and regulatory T cells in circulating blood and positively correlated with the absolute T-lymphocyte count. CONCLUSIONS: sCCL14 may be a predictive biomarker of TACE effectiveness. Further studies are needed to validate and outline the role of combination immunotherapy.

The role of miRNAs in T helper cell development, activation, fate decisions and tumor immunity.

T helper (Th) cells are central members of adaptive immunity and comprise the last line of defense against pathogen infection and malignant cell invasion by secreting specific cytokines. These cytokines then attract or induce the activation and differentiation of other immune cells, including antibody-producing B cells and cytotoxic CD8+ T cells. Therefore, the bidirectional communication between Th cells and tumor cells and their positioning within the tumor microenvironment (TME), especially the tumor immune microenvironment (TIME), sculpt the tumor immune landscape, which affects disease initiation and progression. The type, number, and condition of Th cells in the TME and TIME strongly affect tumor immunity, which is precisely regulated by key effectors, such as granzymes, perforins, cytokines, and chemokines. Moreover, microRNAs (miRNAs) have emerged as important regulators of Th cells. In this review, we discuss the role of miRNAs in regulating Th cell mediated adaptive immunity, focusing on the development, activation, fate decisions, and tumor immunity.

Proteoglycan-4 predicts good prognosis in patients with hepatocellular carcinoma receiving transcatheter arterial chemoembolization and inhibits cancer cell migration in vitro.

Purpose: To search for adaptive response molecules that affect the efficacy of transcatheter arterial chemoembolization (TACE), analyze their clinical correlation with and prognostic value for hepatocellular carcinoma (HCC), and explore their impact on cell biological behavior and their mechanisms of action. Methods: HCC tissue gene sequencing was used to identify differentially expressed genes. The expression of proteoglycan 4 (PRG4) in the serum of 117 patients with HCC who received TACE was detected by enzyme-linked immunosorbent assay. Serum-free medium mimicked TACE-induced nutrient deprivation. Cells with stable knockdown of PRG4 (shPRG4) were constructed to verify the effect and mechanism of PRG4 on the biological behavior of HCC cells in vitro. Results: The expression of PRG4 was significantly elevated under TACE-induced starvation conditions. Low PRG4 expression was associated with worse response to TACE treatment, shorter survival time, and stronger HCC migration ability. Furthermore, in vitro experiments showed that knockdown of PRG4 promoted HCC cell migration by enhancing epithelial-mesenchymal transition (EMT) while did not affect proliferation. When PRG4 expression was low, starvation treatment impaired the migratory ability of HCC cells and reduced the chemosensitivity of HCC cells to epirubicin. Conclusions: PRG4 expression predicts survival and TACE treatment response in patients with HCC. Furthermore, knockdown of PRG4 enhanced EMT, leading to HCC cell migration. PRG4 may serve as a biomarker for HCC patients receiving TACE.

Transarterial chemoembolization combined with apatinib with or without PD-1 inhibitors in BCLC stage C hepatocellular carcinoma: A multicenter retrospective study.

Objective: We evaluated the efficacy and safety of transarterial chemoembolization (TACE) combined with apatinib plus PD-1 inhibitors (TACE-AP) compared with TACE combined with apatinib (TACE-A) in patients with advanced hepatocellular carcinoma (HCC) and to explore the prognostic factors affecting patient survival. Methods: Data from patients with unresectable HCC who received TACE-AP or TACE-A from December 2018 to June 2021 were collected retrospectively. The main outcome of the study was overall survival (OS) and prognostic factors affecting survival, while the secondary outcomes were progression-free survival (PFS), the objective response rate (ORR), and treatment-related adverse events (TRAEs). Propensity score matching (PSM) analysis was used to reduce patient selection bias, and the random survival forest (RF) model was employed to explore prognostic factors affecting patient survival. Results: We enrolled 216 patients, including 148 and 68 patients in the TACE-A and TACE-AP groups, respectively. A total of 59 pairs of patients were matched using PSM analysis. Before and after PSM, the OS, PFS, and ORR in the TACE-AP group were significantly higher than in the TACE-A group (before, OS: 22.5 months vs. 12.8 months, P < 0.001; PFS: 6.7 months vs. 4.3 months, P < 0.001; ORR: 63.2% vs. 34.5%, P < 0.001; after, OS: 22.5 months vs. 12.0 months, P < 0.001; PFS: 6.7 months vs. 4.3 months, P < 0.001; ORR: 62.7% vs. 30.5%, P = 0.003). Multivariate Cox regression and RF models before and after PSM analysis revealed that the main prognostic factors affecting survival were tumor number, portal vein tumor thrombus (PVTT) invasion, alpha-fetoprotein (AFP) levels, total bilirubin (TBIL) level, and treatment. There was no significant difference in TRAEs between the two groups (P > 0.05). Conclusion: Compared with TACE-A, TACE-AP significantly improved OS, PFS, and ORR in patients with advanced HCC. The number of tumors, PVTT invasion, AFP levels, TBIL level, and treatment were significant prognostic factors associated with patient survival. All observed TRAEs were mild and controllable.

Plasma arginase-1 as a predictive marker for early transarterial chemoembolization refractoriness in unresectable hepatocellular carcinoma.

Objective: To explore the relationship between plasma arginase-1 (ARG1) and early transarterial chemoembolization (TACE) refractoriness in patients with hepatocellular carcinoma (HCC) and develop nomograms for predicting early TACE refractoriness. Methods: A total of 200 patients with HCC, treated with TACE, were included in the study, including 120 in the training set and 80 in the validation set. Pre-treatment enzyme-linked immunosorbent assay was used to detected the plasma ARG1 levels of the patient, and independent predictors of early TACE refractoriness were determined using a multivariate logistic regression model, based on which a predictive model was developed using a nomogram. Results: Risk of early TACE refractoriness was negatively correlated with plasma ARG1 levels, and multivariate logistic analysis showed tumour size (OR = 1.138, 95% CI = 1.006-1.288, P = 0.041), multiple tumors (OR=4.374, 95% CI = 1.189-16.089, P = 0.026), platelet count (OR = 0.990, 95% CI = 0.980-0.999, P = 0.036), and plasma ARG1 levels (OR = 0.209, 95% CI = 0.079-0.551, P = 0.002) to be independent prognostic factors for early TACE refractoriness.The AUC value for the nomogram of the training cohort was 0.786 (95% CI = 0.702-0.870), and the validation set AUC value was 0.833 (95% CI = 0.791-0.875).The decision curve analysis suggested that the nomogram had good clinical utility. Conclusion: High plasma ARG1 expression was associated with a lower incidence of early TACE refractoriness. The nomogram constructed based on four independent prognostic factors could facilitate an individualised prediction of the incidence of early TACE refractoriness.

Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development.

Liver development is a highly complex process that is regulated by the orchestrated interplay of epigenetic regulators, transcription factors, and microRNAs (miRNAs). Owing to the lack of global in vivo targets of all miRNAs during liver development, the mechanisms underlying the dynamic control of hepatocyte differentiation by miRNAs remain elusive. Here, using Argonaute (Ago) high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) in the mouse liver at different developmental stages, we characterized massive Ago-binding RNAs and obtained a genome-wide map of liver miRNA-mRNA interactions. The dynamic changes of five clusters of miRNAs and their potential targets were identified to be differentially involved at specific stages, a dozen of high abundant miRNAs and their epigenetic regulation by super-enhancer were found during liver development. Remarkably, miR-122, a liver-specific and most abundant miRNA in newborn and adult livers, was found by its targetome and pathway reporter analyses to regulate the Hippo pathway, which is crucial for liver size control and homeostasis. Mechanistically, we further demonstrated that miR-122 negatively regulates the outcomes of the Hippo pathway transcription factor TEAD by directly targeting a number of hippo pathway regulators, including the coactivator TAZ and a key factor of the phosphatase complex PPP1CC, which contributes to the dephosphorylation of YAP, another coactivator downstream of the Hippo pathway. This study identifies for the first time the genome-wide miRNA targetomes during mouse liver development and demonstrates a novel mechanism of terminal differentiation of hepatocytes regulated by the miR-122/Hippo pathway in a coordinated manner. As the Hippo pathway plays important roles in cell proliferation and liver pathological processes like inflammation, fibrosis, and hepatocellular carcinoma (HCC), our study could also provide a new insight into the function of miR-122 in liver pathology.

Localized Photothermal Ablation Therapy of Obstructive Rectal Cancer Using a Nanofunctionalized Stent in a Mouse Model.

The self-expanding metal stent (SEMS) is a versatile, palliative treatment method for unresectable, malignant, non-vascular strictures. Colorectal cancer (CRC) is one of the candidates for the application of the SEMS, in combination with the photothermal ablation (PTA) technique that enhances its therapeutic efficacy. The objective of this study was to investigate the efficacy of stent-mediated PTA therapy in an endoscopy-guided, orthotopic rectal cancer model. A total of 30 of 40 mice with the tumor size of grade 4 were included and were divided into three groups of 10 mice each. Group A underwent a gold nanoparticle (AuNP)-coated SEMS but no near-infrared (NIR) irradiation, group B received an uncoated control SEMS with NIR irradiation, and group C received a AuNP-coated SEMS and NIR irradiation together. Colonoscopy and in vivo imaging, immunohistochemical analysis, and quantitative reverse-transcription polymerase chain reaction of major tumor markers were performed. Stent placement and PTA were technically successful using colonoscopy. The tumor grade reduction after PTA is significant in group C, compared with groups A or B (p < 0.001). Molecular analysis validated this observation with a significantly reduced Mapk1 proliferation marker or increased Jnk expression. Histological analysis confirmed the localized PTA therapy using AuNP-coated SEMS profoundly ablated tumor outgrowth through the stent. Our results indicate that this novel strategy of localized PTA therapy could be a promising option for palliative treatment of CRC and to support prolonged stent patency with a decreased tumor volume.

Risk factors for acute kidney injury following coronary artery bypass graft surgery in a Chinese population and development of a prediction model.

BACKGROUND: Acute kidney injury (AKI) after coronary artery bypass graft (CABG) surgery is associated with significant morbidity and mortality. This retrospective study aimed to establish a risk score for postoperative AKI in a Chinese population. METHODS: A total of 1138 patients undergoing CABG were collected from September 2018 to May 2020 and divided into a derivation and validation cohort. AKI was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Multivariable logistic regression analysis was used to determine the independent predictors of AKI, and the predictive ability of the model was determined using a receiver operating characteristic (ROC) curve. RESULTS: The incidence of cardiac surgery-associated acute kidney injury (CSA-AKI) was 24.17%, and 0.53% of AKI patients required dialysis (AKI-D). Among the derivation cohort, multivariable logistic regression showed that age ≥ 70 years, body mass index (BMI) ≥ 25 kg/m2, estimated glomerular filtration rate (eGFR) ≤ 60 mL/min per 1.73 m2, ejection fraction (EF) ≤ 45%, use of statins, red blood cell transfusion, use of adrenaline, intra-aortic balloon pump (IABP) implantation, postoperative low cardiac output syndrome (LCOS) and reoperation for bleeding were independent predictors. The predictive model was scored from 0 to 32 points with three risk categories. The AKI frequencies were as follows: 0-8 points (15.9%), 9-17points (36.5%) and ≥ 18 points (90.4%). The area under of the ROC curve was 0.730 (95% CI: 0.691-0.768) in the derivation cohort. The predictive index had good discrimination in the validation cohort, with an area under the curve of 0.735 (95% CI: 0.655-0.815). The model was well calibrated according to the Hosmer-Lemeshow test (P = 0.372). CONCLUSION: The performance of the prediction model was valid and accurate in predicting KDIGO-AKI after CABG surgery in Chinese patients, and could improve the early prognosis and clinical interventions.

The Establishment of a Fast and Safe Orthotopic Colon Cancer Model Using a Tissue Adhesive Technique.

PURPOSE: We aimed to develop a novel method for orthotopic colon cancer model, using tissue adhesive in place of conventional surgical method. MATERIALS AND METHODS: RFP HCT 116 cell line were used to establish the colon cancer model. Fresh tumor tissue harvested from a subcutaneous injection was grafted into twenty nude mice, divided into group A (suture method) and group B (tissue adhesive method). For the group A, we fixed the tissue on the serosa layer of proximal colon by 8-0 surgical suture. For the group B, tissue adhesive (10 µL) was used to fix the tumor. The mortality, tumor implantation success, tumor metastasis, primary tumor size, and operation time were compared between the two groups. Dissected tumor tissue was analyzed for the histology and immunohistochemistry. Also, we performed tumor marker analysis. RESULTS: We observed 30% increase in graft success and 20% decrease in mortality, by using tissue adhesive method, respectively. The median colon tumor size was significantly increased by 4 mm and operation time was shortened by 6.5 minutes. The H&E showed similar tumor structure between the two groups. The immunohistochemistry staining for cancer antigen 19-9, carcinoembryonic antigen, cytokeratin 20, and Ki-67 showed comparable intensities in both groups. Real-time quantitative reverse transcription analysis showed eight out of nine tumor markers are unchanged in the tissue adhesive group. Western blot indicated the tissue adhesive group expressed less p-JNK (apototic marker) and more p-MEK/p-p38 (proliferation marker) levels. CONCLUSION: We concluded the tissue adhesive method is a quick and safe way to generate orthotopic, colon cancer model.

Clinical characteristics and risk factors for fatal outcome of patients receiving Sun's procedure after previous cardiac surgery.

BACKGROUND: Cardiac reoperation has always been a difficult problem in clinical practice. Because of the difficulty of operation, the incidence of complications and mortality rate is high. Secondary aortic surgery, especially the reoperation involving arch, has higher risk and is more difficult for patients with renal failure. Sun's operation (total arch replacement + stent elephant nose) has achieved good results in the treatment of diseases involving aortic arch, and occupies an important position in the treatment of patients with secondary arch lesions after cardiac surgery. METHODS: A total of 395 patients with a history of cardiac surgery were recorded in our center from January 1, 2009 to December 31, 2017, among whom 118 (30.1%) patients underwent aortic reoperation via the original incision using Sun's aortic procedure owing to postoperative great vessel disease. We analyzed the clinical data and survival time, and used Cox regression to analyze the risk factors for 30-day mortality as well as long term mortality. RESULTS: The interval between the last operation and the present operation was 0.08-19 years. Sixteen patients died within 30 days after operation and the average mortality rate was 13.6%. During the follow-up period, 28 patients died, with the mortality rate of 23.7%. As of December 31, 2017, the longest survival time was 9.36 years, and the survival time of 70 patients was more than 3.05 years. The main risk factor associated with the 30-day survival was cardiopulmonary bypass (CPB) time. The longer the CPB time was, the greater the risk of death was. The main risk factors associated with the long-term survival were CPB time and 24-h bleeding volume. The longer the CPB time was, the more the 24-h bleeding volume was, the higher long-term mortality rate was. CONCLUSION: The second Sun's operation, as a surgical treatment after cardiac surgery, showed a high survival rate, with long survival time and good curative effect. CPB is the main risk factor for the 30-day survival state after operation, and CPB time and 24-h bleeding volume are the main risk factors for the long-term survival state after operation.

Prophylactic intra-aortic balloon pump in patients with left main disease undergoing off-pump coronary artery bypass grafting.

BACKGROUND: Preventive intra-aortic balloon pump (IABP) for high-risk patients with stable hemodynamics is controversial, and its definition of high-risk is still unclear. This study aimed to investigate the effect of prophylactic IABP on the early outcome of left main disease (LMD) patients receiving off-pump coronary artery bypass grafting (OPCABG) with stable hemodynamics. METHODS: From January 2013 to April 2020, 257 consecutive patients who underwent OPCABG through sternotomy were enrolled in this study. All LMD patients (greater than 70%) had stable hemodynamics (BP>100 mmHg without vasoconstrictor substance infusion). Early outcomes of 125 patients with prophylactic IABP (IABP group) and 132 patients without IABP (Control group) were compared in this study. RESULTS: IABP did not show favorable effect on the conversion to CPB (RR 0.63, 95%CI 0.05-7.89, P = 0.7211), perioperative MI (RR 0.69, 95%CI 0.22-2.12, P = 0.5163), mortality (RR 0.65, 95%CI 0.04-10.25, P = 0.7608) or the composite end of the conversion, MI and mortality (RR 0.63, 95%CI 0.23-1.74, P = 0.3747). There was greater incidence of prolonged ventilation in IABP after adjustment (RR2.16, 95%CI 1.12-4.18, P = 0.0221). There was no IABP-related mortality or limb ischemia. CONCLUSION: No significant difference in early outcomes was observed in hemodynamically stable patients with LMD between prophylactic IABP group and control group. Prophylactic IABP may be unnecessary in patients with LMD undergoing OPCABG.

Does preoperative serum creatinine affect the early surgical outcomes of acute Stanford type A aortic dissection?

BACKGROUND: Acute Stanford type A aortic dissection is a lethal disease requiring surgery. Evidence regarding the effects of preoperative creatinine in mortality is limited, and few studies have evaluated the effect of postoperative dialysis treatment on it. METHODS: In this cohort study, we continuously recruited 632 surgical patients who were treated for acute type A aortic dissection in our hospital between January 2015 and May 2017. The preoperative level of serum creatinine was measured. All patients were followed up after surgery for 30 days to determine early mortality. RESULTS: The 30-day mortality after surgery increased with elevated levels of preoperative serum creatinine. Median (interquartile range) serum creatinine levels in survivors were 9.61 µmol/dL (7.28-12.62 µmol/dL) versus 13.41 µmol/dL (10.28-20.63 µmol/dL) in death (p < 0.01). Adjusted odds ratios for increasing per µmol/dL serum creatinine were 1.09 (95% confidence interval, 1.03-1.15). We also found that the effect of preoperative creatinine on 30-day mortality was diminished by dialysis treatment after surgery. CONCLUSION: Preoperative serum creatinine predicts outcome in patients undergoing surgery for Stanford type A aortic dissection, and postoperative dialysis treatment can reduce its hazard.

The Role of miRNAs in Immune Cell Development, Immune Cell Activation, and Tumor Immunity: With a Focus on Macrophages and Natural Killer Cells.

The tumor microenvironment (TME) is the primary arena where tumor cells and the host immune system interact. Bidirectional communication between tumor cells and the associated stromal cell types within the TME influences disease initiation and progression, as well as tumor immunity. Macrophages and natural killer (NK) cells are crucial components of the stromal compartment and display either pro- or anti-tumor properties, depending on the expression of key regulators. MicroRNAs (miRNAs) are emerging as such regulators. They affect several immune cell functions closely related to tumor evasion of the immune system. This review discusses the role of miRNAs in the differentiation, maturation, and activation of immune cells as well as tumor immunity, focusing particularly on macrophages and NK cells.

MicroRNA-122 supports robust innate immunity in hepatocytes by targeting the RTKs/STAT3 signaling pathway.

MicroRNA-122 (miR-122) is the most abundant microRNA in hepatocytes and a central player in liver biology and disease. Herein, we report a previously unknown role for miR-122 in hepatocyte intrinsic innate immunity. Restoration of miR-122 levels in hepatoma cells markedly enhanced the activation of interferons (IFNs) in response to a variety of viral nucleic acids or simulations, especially in response to hepatitis C virus RNA and poly (I:C). Mechanistically, miR-122 downregulated the phosphorylation (Tyr705) of STAT3, thereby removing the negative regulation of STAT3 on IFN-signaling. STAT3 represses IFN expression by inhibiting interferon regulatory factor 1 (IRF1), whereas miR-122 targets MERTK, FGFR1 and IGF1R, three receptor tyrosine kinases (RTKs) that directly promote STAT3 phosphorylation. This work identifies a miR-122-RTKs/STAT3-IRF1-IFNs regulatory circuitry, which may play a pivotal role in regulating hepatocyte innate immunity. These findings renewed our knowledge of miR-122's function and have important implications for the treatment of hepatitis viruses.

Ascending aortic dilation in adult patients with congenital ventricular septal defect: An observational study.

Many adult patients with congenital ventricular septal defect (VSD) also developed ascending aortic dilation, but few report the clinical features and surgical management of these patients. This study was designed to study ascending aortic dilation in adult patients with congenital VSD, and summarized the treatment experience and prognosis.To assess the clinical features and surgical management, we performed a retrospective analysis on preoperative data, intraoperative data, and postoperative data from the adult patients with congenital VSD who developed ascending aortic dilation in our institution from February 2010 to December 2016.From February 2010 to December 2016, we operated on 13 adult patients (12 males, 92.31%) with VSD who developed ascending aortic dilation. Median age was 37 (interquartile range 14) years. All patients suffered from perimembranous VSD and received surgical treatment. Their symptoms were all improved after surgery, no deaths occurred.Surgery is feasible for the ascending aortic dilation in adult patients with congenital VSD. Both proper perioperative treatment and close monitoring are required for the successful surgery.

[Effect of Baihu Guizhi decoction on characteristic methylation genes expression of pyretic arthralgia rat model].

To investigate the characteristic methylation genes of pyretic arthralgia model in hot and dampness environment and the regulation effect of Baihu Guizhi decoction on this characteristic methylation genes. Plantar injection of CFA was used in hot and dampness environment to induce the pyretic arthralgia rat models. From 15th day after modeling, Baihu Guizhi decoction was given for 30 days. Foot volume was detected every 4 days after modeling, and HE staining was used to detect the histopathology of all rats' ankle joint at day 45.MeDIP-Seq sequencing method was used to detect the methylation level of knee joint synovial, and the method of difference sets was used to screen the characteristic methylation genesinpyretic arthralgia models.The contents of IL-1ß, IL-17, TNF-α, EGF, IL-12p70, IL-4, IL-6 and IFN-γ in serum were measured by using suspension chips. The mRNA expression level of characteristic methylation genes was measured by qRT-PCR. The results suggested that as compared with adjuvant arthritis rat models(AA), the foot swelling and histopathology inpyretic arthralgia models (PA) were only slightly increased. As compared with normal group (NG), the wholegenome CpG island in both AA and PA groups was kept in a lower methylation state, furthermore, the methylation level was lowest in PA group; with 705 difference methylation genes in AA group and 2 418 difference methylation genes in PA group. As compared with AA, there were 1 287 difference methylation genes, including 974 down-regulated methylation genesand 313 up-regulated methylation genes. This difference methylation genes were mostly enriched in 32 KEGG pathways. Moreover, there were 52 characteristic methylation genes of PA models in promoter region, including 36 down-regulatedmethylation genes and 16 up-regulatedmethylation genes. After drug intervention, Baihu Guizhi decoction improved the foot swelling and pathological injury in PA models, significantly decreased the levels of IL-1ß, TNF-α, EGF, VEGF, IL-17, IL-12p70, inhibited the mRNA expression levels of down-regulated methylation genes AHCY and RPL3, and promoted the mRNA expression levels of up-regulated methylation gene Agxt. In conclusion, unique methylation changes of synovial genes were present in PA models, and Baihu Guizhi decoction may adjust the methylation level of PA's characteristic methylation genes to achieve the therapeutic effect of pyretic arthralgia.

Serum Resistin Levels May Contribute to an Increased Risk of Acute Cerebral Infarction.

The objective of this study was to investigate the association between serum resistin levels and acute cerebral infarction (ACI). PubMed, SpringerLink, Wiley, EBSCO, Ovid, Web of Science, Wanfang, China National Knowledge Infrastructure, and VIP databases (last updated search in October 2014) were exhaustively searched, and data from the eligible studies were extracted and analyzed to assess the association between serum resistin levels and ACI. STATA software (version 12.0, Stata Corporation, College Station, TX, USA) was utilized for data analysis. Ten studies including 1829 ACI patients and 1557 healthy controls were eligible for inclusion in the meta-analysis. Our major result revealed that ACI patients exhibited higher serum resistin levels compared with healthy controls. Asubgroup analysis based on ethnicity showed a significant association between serum resistin levels and ACI in Asians, but surprisingly not in Caucasians. The results of our meta-analysis suggest that serum resistin levels are associated with an increased risk of ACI.

[Effects of Tongluo Xingnao effervescent tablets on blood rheology, iNOS, VEGF and LDH-5 in MID rats].

The study was to explore effects of Tongluo Xingnao effervescent tablets on the blood rheology, iNOS, VEGF and LDH-5 in multi-infarct dementia(MID) model rats. Establish MID model rats were induced by microthrombosis, from which 50 successful model rats were randomly divided into five groups, such as the model control group, the dihydroergotoxine mesylate tablets(hydergine) group(0.7 mg•kg⁻¹), Tongluo Xingnao effervescent tablets high-dose, medium-dose and low-dose groups(7.56, 3.78, 1.89 g•kg⁻¹). Another ten rats in the sham group were randomly selected as the parallel control group. Each group was orally administered with drugs for 90 days. The learning and memory ability was evaluated with the Morris water maze test, while the whole blood viscosity and the erythrocyte aggregation index derived from abdominal aorta were measured in different shear rates. In addition, the levels of VEGF and iNOS in the serum were determined by ELISA kits. The expression of LDH-5 in hippocampus of rats was measured with immunohistochemistry and image quantitative analysis. The result showed that Tongluo Xingnao effervescent tablets notably decreased the escape latency of MID model rats, increased times of entering into the escape platform and prolonged retention time in medium ring, meanwhile the whole blood viscosity in MID model rats was also notably reduced in four shear rates, i.e. 1, 5, 30, 200 S⁻¹, erythrocyte aggregation index, serum VEGF and iNOS, and average optical density value of LDH-5, with a statistically significant differences compared with the model control group (P<0.05). In conclusion, Tongluo Xingnao effervescent tablets could improve the ability of learning and memory of MID model rats and the blood rheology, reduce the level of iNOS, VEGF and the expression of LDH-5, and then improved the brain energy supply.

[Effect of Tongluo Xingnao effervescent tablets on learning and memory dysfunction in rats with chronic cerebral ischemia].

OBJECTIVE: To study the effect of Tongluo Xingnao effervescent tablets on learning and memory capacity and expression of Na(+)-K(+)-ATPase in hippocampus of rats with chronic cerebral ischemia-induced learning and memory dysfunction model. METHOD: The 2-VO method was used to establish sd rat model learning and memory dysfunction induced by chronic cerebral ischemia. The 50 rats in the successfully established model were randomly divided into the model control group, the Dihydroergotoxine Mesylate tablets group (0.7 mg x kg(-1), Tongluo Xingnao effervescent tablets high dose (7.56 g x kg(-1)), middle dose (3.78 g x kg(-1)) and low dose (1.59 g x kg(-1)) groups and the sham operation group (n = 10) as the control group. The groups were orally given 10 ml x kg(-1) x d(-1) drugs for consecutively 90 days. On the 86th day, Morris water maze was adopted for them. On the 90th day, a leaning and memory capacity test was held. The brain tissues were fixed with 10% formaldehyde and observed for pathomorphism after routine slide preparation and staining. The expression of hippocampal Na(+)-K(+)-ATPase was detected with immunohistochemistry and image quantitative analysis. RESULT: Compared with the model group, all of Tongluo Xingnao effervescent tablets groups showed significant decrease in the escape latency at the 5th day in the Morris water maze, and notable increase in the frequency of the first quadrant dwell, the frequency passing the escape platform and the frequency entering effective area (p < 0.05). According to the pathomorphological detection, the control group showed a significantly higher pathological score than the sham operation group (p < 0.01), the middle dose group showed a significantly lower pathological score than the model group (p < 0.05). According to the immunohistochemistical detection, the model control group showed a remarkably lower mean OD value of Na(+)-K(+)-ATPase than the sham operation group (p < 0.05), high and middle dose groups showed a significantly higher mean od value than the model control group (p < 0.01). CONCLUSION: Tongluo Xingnao effervescent tablets can improve the learning and memory capacity, reduce pathological changes of hippocampal tissues of rats with chronic cerebral ischemia-induced learning and memory dysfunction model, and promote the expression of Na(+)-K(+)-ATPase in hippocampus.