Targeting 5-Hydroxytryptamine Receptor 1A in the Portal Vein to Decrease Portal Hypertension.

BACKGROUND & AIMS: Portal hypertension (PH) is one of the most frequent complications of chronic liver disease. The peripheral 5-hydroxytryptamine (5-HT) level was increased in cirrhotic patients. We aimed to elucidate the function and mechanism of 5-HT receptor 1A (HTR1A) in the portal vein (PV) on PH. METHODS: PH models were induced by thioacetamide injection, bile duct ligation, or partial PV ligation. HTR1A expression was detected using real-time polymerase chain reaction, in situ hybridization, and immunofluorescence staining. In situ intraportal infusion was used to assess the effects of 5-HT, the HTR1A agonist 8-OH-DPAT, and the HTR1A antagonist WAY-100635 on portal pressure (PP). Htr1a-knockout (Htr1a-/-) rats and vascular smooth muscle cell (VSMC)-specific Htr1a-knockout (Htr1aΔVSMC) mice were used to confirm the regulatory role of HTR1A on PP. RESULTS: HTR1A expression was significantly increased in the hypertensive PV of PH model rats and cirrhotic patients. Additionally, 8-OH-DPAT increased, but WAY-100635 decreased, the PP in rats without affecting liver fibrosis and systemic hemodynamics. Furthermore, 5-HT or 8-OH-DPAT directly induced the contraction of isolated PVs. Genetic deletion of Htr1a in rats and VSMC-specific Htr1a knockout in mice prevented the development of PH. Moreover, 5-HT triggered adenosine 3',5'-cyclic monophosphate pathway-mediated PV smooth muscle cell contraction via HTR1A in the PV. We also confirmed alverine as an HTR1A antagonist and demonstrated its capacity to decrease PP in rats with thioacetamide-, bile duct ligation-, and partial PV ligation-induced PH. CONCLUSIONS: Our findings reveal that 5-HT promotes PH by inducing the contraction of the PV and identify HTR1A as a promising therapeutic target for attenuating PH. As an HTR1A antagonist, alverine is expected to become a candidate for clinical PH treatment.

Effect of liberal or conservative oxygen therapy on the prognosis for mechanically ventilated intensive care unit patients: a meta-analysis

ABSTRACT BACKGROUND: For critically ill patients, physicians tend to administer sufficient or even excessive oxygen to maintain oxygen saturation at a high level. However, the credibility of the evidence for this practice is unclear. OBJECTIVE: To determine the effects of different oxygen therapy strategies on the outcomes of mechanically ventilated intensive care unit (ICU) patients. DESIGN AND SETTING: Systematic review of the literature and meta-analysis conducted at Jiangxi Provincial People's Hospital, Affiliated to Nanchang University, Nanchang, China. METHODS: We systematically searched electronic databases such as PubMed and Embase for relevant articles and performed meta-analyses on the effects of different oxygen therapy strategies on the outcomes of mechanically ventilated ICU patients. RESULTS: A total of 1802 patients from five studies were included. There were equal numbers of patients in the conservative and liberal groups (n = 910 in each group). There was no significant difference between the conservative and liberal groups with regard to 28-day mortality (risk ratio, RR = 0.88; 95% confidence interval, CI = 0.59-1.32; P = 0.55; I2 = 63%). Ninety-day mortality, infection rates, ICU length of stay, mechanical ventilation-free days up to day 28 and vasopressor-free days up to day 28 were comparable between the two strategies. CONCLUSIONS: It is not necessary to use liberal oxygen therapy strategies to pursue a higher level of peripheral oxygen saturation for mechanically ventilated ICU patients. Conservative oxygen therapy was not associated with any statistically significant reduction in mortality.

The Monocyte-Derived Exosomal CLMAT3 Activates the CtBP2-p300-NF-κB Transcriptional Complex to Induce Proinflammatory Cytokines in ALI.

Monocytes and macrophages are the two major cell types involved in innate immunity. Exosomes act as signaling molecules to regulate cell-to-cell communication by releasing proteins, mRNAs, microRNAs (miRNAs), and long noncoding RNAs (lncRNAs). However, it is still unclear whether monocyte-derived exosomes are involved in the communication between monocytes and macrophages. In this study, we analyzed the differentially expressed lncRNA profiles in monocytes isolated from blood samples of healthy controls and acute lung injury (ALI) patients. We focused our study on investigating the signaling downstream of CLMAT3 (colorectal liver metastasis-associated transcript 3), a lncRNA that regulated proinflammatory cytokine genes. We revealed that CLMAT3 specifically targeted CtBP2 (C-terminal binding protein 2) and repressed its expression. Elevated CtBP2 acted as a coactivator to assemble a transcriptional complex with histone acetyltransferase p300 and NF-κB (nuclear factor κB) subunits. In vitro coculture and in vivo injection of ALI monocyte-derived exosomes increased the production of proinflammatory cytokines. Importantly, the administration of two CtBP2 inhibitors, NSC95397 and MTOB, could significantly reverse CtBP2-mediated transactivation. Collectively, our results support a model in which monocyte-derived exosomal CLMAT3 activates the CtBP2-p300-NF-κB complex to induce proinflammatory cytokines, thus contributing to the pathogenesis of ALI.

Two-layer regulation of TRAF6 mediated by both TLR4/NF-kB signaling and miR-589-5p increases proinflammatory cytokines in the pathology of severe acute pancreatitis.

Inflammation is a leading cause of severe acute pancreatitis (SAP). MicroRNAs (miRNAs) are emerging as important regulators involved in the pathogenesis of many diseases including pancreatitis. To identify miRNAs that contribute to the pathology of SAP, we carried out a miRNA-specific microarray analysis using the biopsies donated by SAP patients. We totally obtained 50 differentially expressed miRNAs, including 20 upregulated and 30 downregulated miRNAs, respectively. We focused our current study on revealing the downstream target and the upstream regulatory mechanism of miR-589-5p, the most downregulated miRNA in our candidate lists. Our prediction results indicated that miR-589-5p might target TRAF6 (tumor necrosis factor receptor-associated factor 6), a critical member of the TLR4/NF-kB (Toll-like receptor 4/nuclear transcription factor-kB) pathway. Using different strategies such as in vitro overexpression or downregulation of miR-589-5p and treatment with lipopolysaccharide (LPS), we found that the expression of TRAF6 was regulated by two-layer mechanisms. On the one hand, TRAF6 was transcriptionally controlled by a DNA methylation mediated downregulation of miR-589-5p. On the other hand, the activation of TLR4/NF-kB signaling also could increase the protein level of TRAF6. The increased TRAF6 aggravated the downstream signaling and caused the translocation of NF-kB subunits from the cytoplasm to the nucleus, where NF-kB transcription factors induced the expression of proinflammatory cytokine genes. The maturation and production of proinflammatory cytokines induced inflammatory response and caused the occurrence of SAP.

Application of side-hole catheter technique for transradial arterial chemoembolization in patients with hepatocellular carcinoma.

PURPOSE: The purpose of this study was to retrospectively evaluate the efficacy and safety of side-hole catheter technique for transarterial chemoembolization (TACE) via transradial artery access (TRA) in patients with hepatocellular carcinoma. MATERIALS AND METHODS: From November 2015 to August 2017, a total of 1040 TACE procedures were performed via TRA for hepatocellular carcinoma. In 10 (1%) of these 1040 TACE procedures via TRA, conventional microcatheter technique (CMT) failed and side-hole catheter technique was attempted. RESULTS: Ten procedures of selective catheterizations by CMT failed due to the poor stability of the angiographic catheters or the target artery arising from the very proximal portion of the parent artery. These arteries included the right inferior phrenic artery in eight patients, one left gastric artery, and one right renal capsular artery. Cobra or MPA catheter with the microcatheter through the side-hole yielded a technical success rate of 100%. No procedure-related complications were observed. The mean time required to catheterize the target artery with the side-hole catheter was 9.5 min (5-15 min). CONCLUSION: Side-hole catheter technique may enable the completion of chemoembolization in cases that a potential tumor-feeding vessel cannot be catheterized by means of CMT for TACE via TRA.

Risk scores for predicting dysphagia in critically ill patients after cardiac surgery.

BACKGROUND: This study aimed at developing and validating a scoring model to stratify critically ill patients after cardiac surgery based on risk for dysphagia, a common but often neglected complication. METHODS: Data were prospectively collected and analyzed from January 2016 to June 2017 from 395 consecutive post cardiac surgery patients at the cardiac care unit (CCU) at a single center; 103 (26.1%) developed dysphagia. Univariate and multivariate logistic analyses were used to identify independent predictors for dysphagia. The survival nomogram was developed on the basis of a multivariable Cox model, which allowed us to obtain survival probability estimations. The predictive performance of the nomogram was verified for discrimination and calibration. Areas under receiver operating characteristic curve analysis were used to illustrate and evaluate the diagnostic performance of the novel model. RESULTS: The final novel scoring model, named SSG-OD, consists of three independent factors: gastric intubation (OR = 1.024, 95% CI 1.015-1.033), sedative drug use duration (OR = 1.031, 95% CI 1.001-1.063) and stroke or not (OR = 6.182, 95% CI 3.028-12.617). SSG-OD identified patients at risk for dysphagia with sensitivity of 68.5% and specificity of 89.0% (OR = 0.833, 95% CI: 0.782-0.884). The positive and negative likelihood ratios were 6.22 and 0.35. CONCLUSIONS: The novel SSG-OD scoring system to risk stratify CCU patients for dysphagia is an easy-to-use bedside prognostication aid with good predictive performance and the potential to reduce aspiration incidence and accelerate recovery.

Dynamic contrast-enhanced MRI for the assessment of spinal tumor vascularity: correlation with angiography.

PURPOSE: To determine if dynamic contrast-enhanced MRI (DCE-MRI) could correlate well with invasive angiography in the characterization of spinal tumor vascularity. METHODS: Totally 40 patients with untreated spinal tumors underwent MRI before preoperative angiography and embolization. Tumors were assigned to hypervascular, moderate, or hypovascular groups based on angiographic appearance. Tumor vascularity was also evaluated with enhancement degree on standard MR and with DCE-MRI parameters via ROI analysis of enhanced tumor area. The Spearman correlation coefficient was calculated to determine the correlation between the degree of angiographic vascularity and enhancement on MRI and DCE-MRI parameters. ROC analysis was conducted to assess the appropriate cut-off value. RESULTS: There were 12 hypervascular, 12 moderate, and 16 hypovascular tumors, respectively. The Spearman correlation coefficient between DCE-MRI parameter and the degree of angiographic vascularity was 0.899 (RSlopemax), 0.847 (Slopemax), 0.697 (E max), 0.694 (ERmax), and -0.587 (TTP), respectively, which showed excellent-to-moderate relationships. The RSlopemax cut-off value of 1.325 provided the highest specificity of 100 % and sensitivity of 87.5 % in predicting hypovascular tumors and the value of 1.85 provided the highest sensitivity of 100 % and specificity of 96.4 % in characterizing hypervascular ones. CONCLUSIONS: DCE-MRI is an accurate technique for the assessment of spinal tumor vascularity, which may have a potential value in the decision-making of preoperative embolization.

Deep sequencing identifies deregulation of microRNAs involved with vincristine drug-resistance of colon cancer cells.

BACKGROUND: Vincristine (VCR) is a chemical that is widely used in tumor therapy. While long-term use can make tumor cells resistant to VCR, the underlying mechanisms of this resistance are still unclear. OBJECTIVE: This study aimed at investigating the role of microRNA (miRNA) in colon cancer drug resistance. METHODS: HCT-8 colon carcinoma cells were cultured and treated with different VCR concentrations to establish an HCT-8/VCR resistant cell line. Whole-genome screens, HiSeq 2500 sequencing, and bioinformatics methods were used to detect and analyze differences in miRNA expression between the drug-resistant HCT-8/VCR cells and non-resistant HCT-8 cells. Differential expression profiles of miRNAs were constructed based on sequencing result. RESULTS: The HCT-8/VCR resistant colon carcinoma cell line was established. With regard to the difference in drug resistance between HCT-8/VCR and HCT-8 cells, 24 miRNAs showed statistically significant differences in their expression (fold change > 4), of which 17 were up-regulated. Seven miRNAs were down-regulated. CONCLUSION: As abnormal expression of miRNAs was associated with VCR resistance of colon carcinoma cells, differences in miRNA expression may play a key role in VCR resistance of colon cancer cells.

Prognostic value of tissue inhibitor of metalloproteinase-2 expression in patients with non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Tissue inhibitor of metalloproteinase-2 (TIMP-2) is a small secretory glycoprotein with anti-matrix metalloproteinase activity. Data on the value of TIMP-2 as a prognostic factor in non-small cell lung cancer (NSCLC) are discordant and remain controversial. A systematic review and meta-analysis was performed to explore this issue. METHODS: We identified the relevant literature by searching the PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, SinoMed, and Wanfang Data databases (search terms: "non-small cell lung cancer" or "NSCLC" or "Lung Carcinoma, Non-Small-Cell", "Tissue Inhibitor of Metalloproteinase-2" or "TIMP-2", and "prognosis" or "prognostic" or "survive") for updates prior to March 1, 2014. The pooled hazard ratio (HR) of overall survival with a 95% confidence interval (95% CI) was used to evaluate the strength of the association between positive TIMP-2 expression and survival in patients with NSCLC. RESULTS: We included 12 studies in our systematic review; five studies involving 399 patients with NSCLC were meta-analyzed. The pooled HR of all included patients was 0.57 (95% CI: 0.43-0.77), and the HRs of subgroup analysis according to stage (I-IV), testing method (immunohistochemistry) and high TIMP-2 expression percentage (<50%) were 0.63 (95% CI: 0.43-0.92), 0.55 (95% CI: 0.41-0.74), and 0.50 (95% CI: 0.28-0.88), respectively. These data suggested that high TIMP-2 expression is associated with favorable prognosis in NSCLC. The meta-analysis did not reveal heterogeneity or publication bias. CONCLUSIONS: TIMP-2 expression indicates favorable prognosis in patients with NSCLC; as a protective factor, it could help predict outcome and may guide clinical therapy in the future.

Association between reduced folate carrier G80A polymorphism and methotrexate toxicity in childhood acute lymphoblastic leukemia: a meta-analysis.

Abstract Methotrexate (MTX) is a key component of chemotherapeutic regimens for childhood acute lymphoblastic leukemia (ALL), and enters the cell via active transport mediated by the reduced folate carrier (RFC1). A major single-nucleotide polymorphism of the RFC1 gene, G80A, which affects the activity of RFC1, may influence MTX toxicity in pediatric ALL. We collected all studies that investigated the association of RFC1 G80A polymorphism and MTX toxicity in pediatric ALL, and found inconsistency among their results. The aim of this meta-analysis was to summarize all of these studies in order to clarify the correlation between the RFC1 G80A polymorphism and MTX toxicity in pediatric ALL. A recessive model demonstrated no influence of the RFC1 G80A genotype on MTX toxicity. In conclusion, the RFC1 G80A polymorphism does not seem to be a good marker of MTX-related toxicity in pediatric ALL.

Comparison of lung lesion biopsies between low-dose CT-guided and conventional CT-guided techniques.

BACKGROUND: The low-dose computed tomography (CT) technique has been widely used because it decreases the potential risk of radiation exposure, as well as enabling low-dose CT-guided lung lesion biopsy. However, uncertainties remain regarding diagnostic accuracy, radiation dose, complication rate, and image quality. PURPOSE: To compare the diagnostic accuracy, radiation dose, complication rate, and image quality of lung lesion biopsy between conventional CT-guided and low-dose CT-guided techniques. MATERIAL AND METHODS: A total of 90 patients were prospectively enrolled and randomized into two groups (group A: 120 kv; 200 mA; thickness, 2.0 mm; pitch, 16 mm/rot; n = 44; group B: 120 kv;10 mA; thickness, 2.0 mm; pitch, 23 mm/rot; n = 46). Sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), radiation dose, image quality, and complication rate were compared. All variables between the two groups were analyzed using chi-square and Student's t tests. A P value of < 0.05 was considered statistically significant. RESULTS: The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) for diagnosing lung lesions were 96.88%, 100%, 97.5%, 100%, and 88.89% in group A, respectively. In group B, the values were 96.67%, 100%, 97.5%, 100%, and 90.91%, respectively (P > 0.05). The mean weighted CT dose index (CTDIw) and dose-length product (DLP) were 29.29 ± 3.93 mGy and 211.74 ± 37.89 mGy*cm in group A and 1.55 ± 0.15 mGy and 10.98 ± 1.56 mGy*cm in group B (P < 0.001). Image quality satisfied the need for a coaxial biopsy. Complications in group A and group B were observed in 27.28% and 23.91% of the patients, respectively (P > 0.05). CONCLUSION: Compared to conventional CT-guided biopsies, lung lesion biopsies guided by the low-dose CT biopsy protocol showed dramatically lower CTDIw and DLP levels. In contrast, the diagnostic yield of the procedures did not differ significantly, which is a recommended technique in certain populations.

[Absorption and transportation characteristics of scutellarin and scutellarein across Caco-2 monolayer model].

OBJECTIVE: To investigate the absorption and transepithelial transport characteristics of scutellarin and scutellarein in the human colonic adenocarcinoma cell (Caco-2) monolayer model. The influence factors on these two compounds' absorption were investigated, such as buffer solution, duration of culture, and inhibitors of multidrug resistance-associated protein 2 (MRP(2)), breast cancer drug resistance protein (BCRP) and P-glycoprotein (P-gp). METHODS: By using Caco-2 monolayer as an intestinal epithelial cell model, the transport process was studied from apical (AP) side to basolateral (BL) side or from BL to AP. The two compounds were determined by high-performance liquid chromatography coupled with diode-array-detector detection. Transport parameters and apparent permeability coeffients (P(app)) were calculated. RESULTS: The P(app) values of scutellarin and scutellarein were different in two buffer solutions, respectively. In phosphate buffered saline, scutellarin had no absorption from AP to BL, while its P(app) value was 0.74×10(-6) to 1.58×10(-6) cm/s from BL to AP. The P(app) values of scutellarein were 4.33×10(-6) to 6.79×10(-6) cm/s and 1.32×10(-6) to 2.56×10(-6) cm/s from AP to BL and from BL to AP, respectively. The P(app) value gradually decreased with time. The absorption of scutellarein was better than that of scutellarin. The scutellarin absorption was improved by verapamil, MK-571 and reserpine. The scutellarein absorption was improved by verapamil whereas its excretion was improved by MK-571. CONCLUSION: Absorption of scutellarin is difficult in Caco-2 monolayer cells, which contributes to its low bioavailability. Scutellarein absorption is better than scutellarin absorption. Scutellarein transepithelial transport is passive diffusion. The inhibitor of P-gp can improve scutellarin and scutellarein transportation. The inhibitors of MRP(2) and BCRP can promote transportation of scutellarin. The inhibitor of MRP(2) can promote efflux of scutellarein. The multidrug resistance-associated protein may be the second reason for low bioavailability of scutellarin.

[Study on cadmium absorption in pumpkin by atomic absorption spectrophotometry].

A study was carried out on the characteristic of cadmium absorption in pumpkin by atomic absorption spectrophotometer. The results show that the cadmium absorption amount in pumpkin increased with the increase in cadmium concentration. Meanwhile the cadmium absorption amount in pumpkin increased with time. Eight hours after being cultured in the liquid, the cadmium absorption amount became saturated. The cadmium absorption rate reached the peak after 2 hours, then the absorption rate gradually reduced. The cadmium absorption amount in pumpkin is less in acid or alkali compared with neutral condition. And the absorption amount became minimum in pH 3, while maximum in pH 7.