[Prevalence and intervention effect of arteriovenous graft stenosis].

Objective: To evaluate the prevalence, intervention methods and effect of arteriovenous graft (AVG) stenosis. Methods: The clinical data of patients who received AVG in the Blood Purification Center, the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2022 were retrospectively analyzed. The patency rate, prevalence and intervention effect of AVG stenosis were analyzed. Results: A total of 475 patients aged (55.5±11.8) years were included, and there were 193 male cases (40.6%) and 282 female cases (59.4%). The patients were followed up for [M (Q1, Q3)] 19 (12, 30) months, and the primary, assisted primary and secondary patency were 14 (5, 27), 27 (13, 55), and 59 (33, 65) months, respectively. There were 799 access events which needed intervention, with a total standardized intervention rate of 0.90 per patient-year. Totally, 431(53.9%, 431/799) stenosis events occurred in 207 AVG. Among 422 AVG stenosis events with complete clinical data, 57.8% (244/422) were multi-site stenosis and 42.2% (178/422) were single-site stenosis. The most common sites of stenosis were graft-vein anastomosis (47.6%, 340/715), venous outflows (22.7%, 162/715), and puncture zone (20.0%, 143/715). In the 414 stenosis with intact follow-up data, 90.8% (376/414) were treated by balloon angioplasty, 8.5% (35/414) received covered stent insertion, and 0.7% (3/414) were intervened by open surgery. Clinical success rate was 98.1% (406/414). The primary patency time after endovascular treatment was 6 (4, 12) months. Covered stent significantly increased post-intervention primary patency time compared withballoon angioplasty [6 (3, 7) months vs 3 (1, 4) months, P=0.020]. Conclusions: Stenosis is the most common complication of AVG, and the most common sites are graft-vein anastomosis, venous outflows, and puncture zone. Intervention of AVG stenosis has a high clinical success rate, and a relatively low post-intervention patency. Covered stent insertion improves the post-intervention patency of AVG, which has a poor effect using balloon expansion.

[Risk factors for the development of liver cancer in patients with hepatitis B-related liver cirrhosis treated with long-term nucleos(t)ide analogues].

Objective: To retrospectively analyze the risk factors for the development of liver cancer in patients with hepatitis B-related liver cirrhosis (LC) treated and fully managed with long-term nucleos(t)ide analogues (NAs). Methods: The study subjects were derived from the follow-up cohort of chronic hepatitis B and liver cirrhosis who received antiviral therapy in the Department of Infectious Diseases of the First Affiliated Hospital of Guangxi Medical University from February 2004 to September 2019. LC patients who met the inclusion criteria were enrolled. The life-table method was used to calculate the incidence of liver cancer. Multivariable Cox regression model was used to analyze the risk factors that may affect the development of liver cancer in patients with LC. A subgroup analysis was conducted in liver cirrhotic patients who developed liver cancer to evaluate the effectiveness of antiviral treatment compliance. The (2) test was used for rate comparison. Results: The median follow-up time of 198 LC cases treated with NAs was 6.0 years (1.0-15.3 years). By the end of the visit: (1) 16.2% (32/198) of LC patients had developed liver cancer, and the cumulative incidence of liver cancer in 1, 3, 5, 7, and 9 years were 0, 8.9%, 14.3%, 18.6%, and 23.4%, respectively, with an average annual incidence of 3.1%. Among the 32 cases with liver cancer, 68.7% had developed small liver cancer (22/32). (2) Univariate Cox model analysis showed that the development of liver cancer was related to four factors, i.e., the presence or absence of LC nodules, whether the baseline was first-line medication, the family history of liver cancer, and patient compliance. The results of multivariate Cox model analysis showed that poor patient compliance and baseline non-first-line medication were risk factors for liver cancer. (3) The results of log-rank test subgroup analysis showed that the 5-year cumulative incidence of liver cancer in patients with hardened nodules was significantly higher than that of patients without hardened nodules (21.7% vs. 11.5%, P = 0.029). The 5-year cumulative incidence of liver cancer in patients with non-first-line drugs was significantly higher than that of patients with first-line drugs (22.0% vs.8.2%, P = 0.003). The 5-year cumulative incidence of liver cancer in patients with poor compliance was significantly higher than that of patients with good compliance (21.3% vs. 12.7%, P = 0.014). The 5-year cumulative incidence of liver cancer in patients with a family history of liver cancer was significantly higher than that of patients without a family history of liver cancer (22.3% vs. 8.1%, P = 0.006). (4) Compared with patients with poor compliance, patients with good compliance had higher HBV DNA negative serconversion rate (98.7% vs. 87.8%, P = 0.005), and a lower virological breakthrough rate (12.1% vs. 29.3%, P = 0.007). Conclusion: The long-term NAs antiviral therapy can reduce the risk of liver cancer, but it cannot completely prevent the development of liver cancer, especially in patients with a family history of liver cancer and baseline hardened nodules (high risk of liver cancer). Furthermore, the complete management can improve patient compliance, ensure the efficacy of antiviral therapy, and reduce the risk of liver cancer development, so to achieve secondary prevention of liver cancer, i.e., early detection, diagnosis and treatment.

[Liver histological status and clinic outcome in HBeAg-negative chronic hepatitis B with low viral load].

Objective: To retrospectively analyze the serological, virological, biochemical, liver histological status and clinical outcomes in HBeAg-negative chronic hepatitis B (CHB) patients with low HBV viral load, and to explore the necessity of antiviral therapy for these patients. Methods: A total of 99 HBeAg-negative CHB patients with HBV DNA level < 4 lg copies/ml who performed liver biopsy at the baseline were enrolled from the follow-up cohort. Among them, 23 cases received the second liver biopsy during follow-up. The relationships among the degree of inflammation and fibrosis of liver tissues, the status of HBsAg and HBcAg, age, gender, family history, HBV DNA load, serological markers and other indicators were analyzed. The pathological differences between two liver biopsy examinations were compared. The effect of nucleos(t)ide analogues (NAs) treatment on patient's clinical outcomes were analyzed. For multivariate analysis, a binary logistic regression model was performed. Log-rank test was used to compare the cumulative incidence of hepatocellular carcinoma (HCC) in NAs-treated and non-NA streated patients. Results: Baseline liver histology status showed that 58.6% (58/99) patients had obvious liver tissue damage in their baseline liver tissue pathology (G≥2 and /or S≥2). Univariate logistic regression analysis showed that a liver cirrhosis (LC) family history, a HBsAg-positive family history, baseline alanine aminotransferase and aspartate aminotransferase levels were positively correlated factors for liver tissue damage. Multivariate logistic regression analysis showed that a LC family history was the main risk factor for liver tissue damage. Twenty-three cases had received a second liver biopsy after an interval of 4.5 years. In 10 untreated cases, the second liver biopsy results showed the rate of obvious liver tissue damage (G≥2 and/ or S≥2) increased from 50.0% to 90.0%. In the other 13 cases who received NAs treatment, the second liver biopsy showed improvement in liver histology, and the rate of obvious liver tissue damage decreased from 61.5% to 46.2%. The 5-year HCC cumulative incidence in non-NAs-treated patients was significantly higher than that of in NAs-treated patients (17.7% vs. 3.8%, P = 0.046). Conclusion: For most HBeAg-negative CHB patients with low viral load, liver tissue pathology result suggests that it meets the indications for antiviral therapy, especially in patients with a LC familial history. Without antiviral therapy, liver tissue damage for these patients will progressively worse with the high incidence of HCC. Therefore, it is suggested that antiviral therapy should be started as soon as possible for the HBeAg-negative CHB patients with low viral load regardless of the alanine aminotransferase level, especially in patients over 30 years-old with a LC or HCC family history.

Comparison of gene expression of Toll-like receptors and antimicrobial peptides in immune organs and tissues between Yorkshire and Tibetan pigs.

Toll-like receptors (TLRs), an important family of pattern-recognition receptors, and antimicrobial peptides (AMPs) contribute to the first line of innate protection of mammals against microbes. To compare characteristics of innate immunity between Tibetan and Yorkshire pigs, we investigated the mRNA abundance of TLR genes (TLR1-TLR9) and two AMP-encoding genes (PBD-1 and PR-39) in thymus, spleen, blood, palatine tonsils, and mesenteric and pulmonary hilar lymph nodes of the two breeds at ages of 6, 12 and 24 weeks using quantitative real-time PCR. Results showed that all mRNAs were detected in all tissues. Transcript levels of the major TLR genes of Tibetan pigs were significantly higher than those of Yorkshires in most tissues of the immune system, with a higher abundance of porcine (PBD-1) (beta-defensin-1) and PR-39 mRNA in lymphoid organs and tissues, especially blood, palatine tonsils, and mesenteric and pulmonary hilar lymph nodes. Our data suggest that Tibetan pigs have stronger innate immunity for triggering local and/or systemic immune responses to eliminate infections with pathogenic microorganisms.

An investigation of nickel cobalt oxide nanorings using transmission electron, scanning electron and helium ion microscopy.

Nickel cobalt oxide alloy nanorings have been synthesized using a wet chemistry method. Standard characterization techniques such as transmission electron microscopy (TEM) and scanning electron microscopy (SEM) have been used to characterize the nanorings. We, however, also examined the nanostructures in the helium ion microscope (HIM) and employed backscattered ion spectroscopy to determine thickness and composition of the nanostructure. The HIM provides complementary information of the nanostructures and the viability of using it as a tool for magnetic nanoparticle characterization was demonstrated by comparing the results from all three microscopes.

Poly(acrylic acid) modifying bentonite with in-situ polymerization for removing lead ions.

In this paper, a new kind of poly(acrylic acid) modified clay adsorbent, the poly(acrylic acid)/bentonite composite (PAA/HB) was prepared by in-situ polymerization, and utilized to remove lead(II) ions from solutions. The maximum adsorption of adsorbent is at pH 5 for metal ions, whereas the adsorption starts at pH 2. The effects of contact time (5-60 min), initial concentration of metal ions (200-1,000 mg/L) and adsorbent dosage (0.04-0.12 g/100 mL) have been reported in this article. The experimental data were investigated by means of kinetic and equilibrium adsorption isotherms. The kinetic data were analyzed by the pseudo-first-order and pseudo-second-order equation. The experimental data fitted the pseudo-second-order kinetic model very well. Langmuir and Freundlich isotherms were tried for the system to better understand the adsorption isotherm process. The maximal adsorption capacity of the lead(II) ions on the PAA/HB, as calculated from the Langmuir model, was 769.2 mg/g. The results in this study indicated that PAA/HB was an attractive candidate for removing lead(II) (99%).

Clinical application of flash spiral mode of high-pitch dual source CT in carotid, cardiac and cerebral vessels combined one-stop angiography.

OBJECTIVE: This study aims to evaluate the clinical application value of flash spiral mode of high-pitch dual source CT in carotid, cardiac and cerebral vessels combined one-stop imaging. PATIENTS AND METHODS: A total of 100 consecutive patients were given carotid, cardiac and cerebral vessels combined one-stop imaging at flash spiral mode of high-pitch dual source CT. 27 patients received DSA examination of carotid and cerebral vessels, and 38 patients received digital subtraction angiography (DSA) examination of the coronary artery at the same time. Carotid, cardiac and cerebral vessels combined one-stop imaging was compared with "golden standard", DSA image. RESULTS: The overall satisfaction rate of coronary arteries, extracranial segment of the carotid artery (CA-E), intracranial segment of the carotid artery (CA-I), and cerebral vessels (anterior, middle, and posterior cerebral artery) were 93%, 99%, 95% and 97% respectively, and the positive rate of hemadostenosis was consistent with DSA. The kappa value indicating consistency of cerebral, carotid and coronary artery vessels was 0.78382, 0.80654, 0.82398, respectively. CONCLUSIONS: The method of carotid, cardiac and cerebral vessels combined one-stop imaging by flash spiral mode of high-pitch dual source CT can provide high image quality. It comprehensively evaluates stenosis of carotid, cardiac and cerebral vessels, which is of great importance for early intervention in harmful events of the cardia and cerebrovascular disorder.

Preparation of xanthated bentonite and its removal behavior for Pb(II) ions.

Xanthate was successfully grafted onto bentonite by a relatively simple solution reaction. The obtained xanthated bentonite (XBent) was characterized by FT-IR spectrophotometer, thermogravimetric analysis (TG), particle size analysis, x-ray diffraction (XRD) and scanning electron microscopy (SEM). XBent acting as a type of environmentally friendly adsorbent was applied to remove lead ions from aqueous solutions. The optimum conditions were as follows: [Pb(2+)] = 500 mg L(-1), [XBent] = 2 g L(-1), pH = 5.0; oscillating 60 min under 200 rpm at 25 degrees C. The removal rate of lead was up to 99.9%. It was found that the lead(II) ions-XBent adsorption isotherm model fitted well to the Freundlich isotherm. The adsorption mechanism was also investigated by SEM and XRD, which concluded that lead ions were complexed or chelated with XBent. XBent appears to have potential to be used later in water treatment as a type of inorganic polymer reagent.

Preparation of solid composite polyferric sulfate and its flocculation behavior for wastewater containing high concentration organic compounds.

A new kind of inorganic polymer flocculant, the solid composite polyferric sulfate (SPFS) was prepared using ferrous sulfate and Na-Bentonite. The obtained SPFS was characterized by FT-IR spectra, thermogravimetric analysis (TG), scanning electron microscope (SEM) and X-ray Diffraction (XRD). It showed that SPFS was a kind of composite inorganic polymer, which was the complex of PFS and Na-Bent, not only a simple mixture of raw materials. The synthetic mechanism and surface structure of SPFS were also discussed. Acting as a kind of environment-friendly flocculating agent, the solid composite polyferric sulfate (SPFS) was applied in pretreatment of potato starch industry wastewater, a typical wastewater containing high concentration organic compounds, which COD was above 6,000 mg/L. The results showed that the COD removal value reached 4,070 mg/L with COD removal rates being 46.6%. Based on these results, it is suggested that the SPFS can be attractive pretreatment agent for the starch industry wastewater.

Fibroblast growth factor 23 mRNA expression profile in chickens and its response to dietary phosphorus.

In mammals, fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis in kidney by binding α-Klotho, a coreceptor of FGF23. FGF23 mRNA is highly expressed in bone and slightly expressed in liver, and is regulated by dietary phosphorus. Little is known about distribution and regulation of FGF23 mRNA in avian lineage. The expression of FGF23 and its coreceptor α-Klotho in chicken and embryo were investigated by real-time quantitative PCR. The effect of dietary phosphorus on FGF23 expression was measured. 36 laying hens at 25 wk were randomly assigned to three dietary available phosphorus (AP) treatments for 11 days: 0.15% AP (LP), 0.40% AP (MP), and 0.80% AP (HP). We first cloned the full coding sequence of FGF23 by the reverse transcription PCR from chicken liver and calvaria. Bioinformatics analysis indicated that the deduced amino acid sequence was 57-87% identical to FGF23 of other species. In adult chicken FGF23 mRNA was expressed at unexpected higher level in liver than other tissues evaluated, including calvaria, femur, tibia, medullary bone, brain, spleen, duodenum, jejunum, ileum, heart and kidney (P < 0.0001), and α-Klotho was expressed at highest level in kidney. However, in 18-d chicken embryos, FGF23 mRNA level was much higher in tibia than in liver, heart and jejunum (P < 0.0001). Chickens at 2, 25, 50 and 80 wk had higher FGF23 expression in liver than 18-d chicken embryos, whereas chickens at 25 wk had lower FGF23 expression in tibia than 18-d chicken embryos and 2-wk-old chickens. HP diets significantly increased serum inorganic phosphorus level (P < 0.001) and FGF23 expression (P < 0.05) in bone tissue compared with LP diets, however, FGF23 mRNA abundance in liver was not changed significantly (P > 0.05) by dietary phosphorus treatments. In conclusion, FGF23 mRNA expression pattern in chicken was clearly different from that in mammals and dietary phosphorus regulated the expression of FGF23 in a tissue-specific way.

Glucagon-like peptide-1 is a physiological incretin in rat.

Glucagon-like peptide-1 7-36 amide (GLP-1) has been postulated to be the primary hormonal mediator of the entero-insular axis but evidence has been indirect. The discovery of exendin (9-39), a GLP-1 receptor antagonist, allowed this to be further investigated. The IC50 for GLP-1 receptor binding, using RIN 5AH beta-cell membranes, was found to be 0.36 nmol/l for GLP-1 and 3.44 nmol/l for exendin (9-39). There was no competition by exendin (9-39) at binding sites for glucagon or related peptides. In the anaesthetized fasted rat, insulin release after four doses of GLP-1 (0.1, 0.2, 0.3, and 0.4 nmol/kg) was tested by a 2-min intravenous infusion. Exendin (9-39) (1.5, 3.0, and 4.5 nmol/kg) was administered with GLP-1 0.3 nmol/kg, or saline, and only the highest dose fully inhibited insulin release. Exendin (9-39) at 4.5 nmol/kg had no effect on glucose, arginine, vasoactive intestinal peptide or glucose-dependent insulinotropic peptide stimulated insulin secretion. Postprandial insulin release was studied in conditioned conscious rats after a standard meal. Exendin (9-39) (0.5 nmol/kg) considerably reduced postprandial insulin concentrations, for example by 48% at 15 min (431 +/- 21 pmol/l saline, 224 +/- 32 pmol/l exendin, P < 0.001). Thus, GLP-1 appears to play a major role in the entero-insular axis.

Possible evidence for endogenous production of a novel galanin-like peptide.

Galanin mRNA and peptide are not detectable in normal islets. We studied the effect of galanin antagonists on insulin secretion in the rat beta cell line, RIN5AH, and in perifused rat islets. In RIN cell membranes galanin and its antagonists showed high affinity for 125I-galanin binding sites [Kd: (galanin) 0.03+/-0.01; Ki for galanin antagonists: (C7) 0.12+/- 0.02, (M35) 0.21+/-0.04, and (M40) 0.22+/-0.03 nM, mean+/- SEM, n = 4]. Galanin (1 microM) inhibited glucose-induced insulin release in islets (control 21.2+/-1.5 vs. galanin 4.5+/-0.2 fmol/islet per min, P < 0.001, n = 6) and RIN5AH cells (control 0.26+/-0.01 vs. galanin 0.15+/-0.02 pmol/10(6) cells per h, P < 0.001, n = 9). In RIN5AH cells, all antagonists blocked the inhibitory effects of galanin and stimulated insulin release in the absence of galanin. C7 and M40 (1 microM) alone significantly stimulated glucose-induced insulin secretion. Purified porcine galanin antibody (GAb) enhanced glucose-induced insulin release from islets (control 100+/- 16.3% vs. GAb 806.1+/-10.4%, P < 0.001, n = 6), and RIN5AH cells (control 100+/-9.6% vs. GAb 149+/-6.8%, P < 0. 01, n = 6). Western blotting of dexamethasone-treated islet extracts using GAb showed a specific band of similar molecular weight to porcine galanin not detected using a rat specific galanin antibody. One possible explanation for these results is the presence of an endogenous galanin-like peptide.

Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice.

Obesity is associated with diabetes, and leptin is known to be elevated in obesity. To investigate whether leptin has a direct effect on insulin secretion, isolated rat and human islets and cultured insulinoma cells were studied. In all cases, mouse leptin inhibited insulin secretion at concentrations within the plasma range reported in humans. Insulin mRNA expression was also suppressed in the cultured cells and rat islets. The long form of the leptin receptor (OB-Rb) mRNA was present in the islets and insulinoma cell lines. To determine the significance of these findings in vivo, normal fed mice were injected with two doses of leptin. A significant decrease in plasma insulin and associated rise in glucose concentration were observed. Fasted normal and leptin receptor-deficient db/db mice showed no response to leptin. A dose of leptin, which mimicked that found in normal mice, was administered to leptin-deficient, hyperinsulinemic ob/ob mice. This caused a marked lowering of plasma insulin concentration and a doubling of plasma glucose. Thus, leptin has a powerful acute inhibitory effect on insulin secretion. These results suggest that the action of leptin may be one mechanism by which excess adipose tissue could acutely impair carbohydrate metabolism.

Augmentation of lymphokine-activated killer cell cytotoxicity by monoclonal antibodies against human small cell lung carcinoma.

This study examined the lymphokine-activated killer (LAK) cell cytotoxicity on monoclonal antibody (MoAb)-bound tumor cells from the human small cell lung carcinoma cell lines H69 and H128. LAK cells were generated from normal peripheral blood mononuclear cells by incubation with interleukin 2 for 3 or more days. Cells from the LAK culture were cytotoxic to natural killer-sensitive (K562, 84% cytotoxicity) and natural killer-resistant (Daudi, 85%; H69 and H128, 69% and 97%, respectively) cell lines, and to freshly excised human lung (49%) and breast (57%) tumors. LAK cytotoxicity to H69 or H128 cells was significantly augmented by target cell preincubation with the small cell lung carcinoma-reactive MoAbs 1096 (increases of up to 271%) or 5023 (up to 223%). SCLC 5023 or 1096 did not enhance LAK cytotoxicity to Daudi cells of lymphoblastoid origin. Pretreatment of LAK cells with an anti-Fc receptor antibody blocked MoAb augmentation by 1096 or 5023 (but not LAK cytotoxicity), suggesting that LAK-MoAb interaction may be mediated by Fc binding. LAK activity coincided with emergence of a large cell [interleukin 2-stimulated large mononuclear leukocyte (LML)] subset expressing the CD16 and NKH-1 surface determinants. Serial immunophenotyping of the LAK cell culture harvested at Days 3, 5, and 7 indicated that the level of LAK cytotoxicity, with or without MoAb augmentation, correlated with frequency of NKH-1-reactive LMLs. These observations support the hypothesis that LAK cytotoxicity is mediated by a NKH-1-reactive LML subpopulation. Antitumor cytotoxicity may be augmented by tumor-reactive MoAbs through Fc binding to this LML subset.

Elimination of chemoresistant multiple myeloma clonogenic colony-forming cells by combined treatment with a plasma cell-reactive monoclonal antibody and a P-glycoprotein-reactive monoclonal antibody.

Patients with multiple myeloma (MM) commonly become refractory to chemotherapy despite a favorable response to induction treatment. We examined the effectiveness of a previously characterized plasma cell-reactive monoclonal antibody, MM4, in eliminating MM clonogenic colony-forming cells (CCC) with a multidrug-resistant (MDR) phenotype. Experiments were performed using MM cell lines that exhibit 6 (RPMI 8226/DOX6)- and 40 (RPMI 8226/DOX40)-fold resistance to doxorubicin (DOX). Both lines were selected from the chemosensitive MM line RPMI 8226/S and were cross-resistant to mitoxantrone, acronycine, etoposide, and vincristine. Surface marker analysis conducted in this study showed that DOX6 and DOX40 overexpressed the MDR1 gene product p170. Both MDR lines remained reactive to the plasma cell-reactive monoclonal antibodies MM4 and PCA-1 and expressed the relevant cytoplasmic immunoglobulin light chain. Treatment with MM4 and rabbit complement (C') was equally cytotoxic to RPMI 8226/S [80 +/- 5.6% (SD)], DOX6 [74 +/- 8.5], and DOX40 cells [75 +/- 11.3%], based on short-term chromium release studies. Furthermore, MM4 + C' deleted up to 3 logs of CCC colonies from chemosensitive and MDR lines (RPMI 8226/S, 99.87 +/- 0.11%; DOX6, 99.91 +/- 0.08%; DOX40, 99.55 +/- 0.44%). By comparison, the P-glycoprotein-reactive monoclonal antibody MRK-16 and C' inhibited tumor colony formation of MDR cells (8226/DOX6, 95.71 +/- 2.51%; 8226/DOX40, 99.61 +/- 0.43%) but affected that of chemosensitive cells only slightly (8.9 +/- 17.8%). In an attempt to optimize the depletion of myeloma CCC, MM4 was used together with MRK-16. This approach resulted in uniform depletion of myeloma clonogenic colony-forming cells from the chemosensitive (98.32 +/- 1.53%, n = 4) and MDR lines (8226/DOX6, 98.83 +/- 0.08%, n = 4; 8226/DOX40 99.29 +/- 0.62, n = 7) but did not result in enhanced CCC depletion. When DOX40 cells were mixed with normal bone marrow (BM) in the ratio of 90:10 (BM:MM), either MM4 or MRK-16 and C' depleted MM colonies (98.8 +/- 0.71% and 98.10 +/- 1.0%, respectively) without affecting the majority of BM progenitor cells. These observations suggest that either MM4 or MRK-16 is useful for depleting MDR myeloma clonogenic colony-forming cells.

Dual inhibiting EGFR and VEGF pathways versus EGFR-TKIs alone in the treatment of advanced non-small-cell lung cancer: a meta-analysis of randomized controlled trials.

BACKGROUND: The strategy of dual inhibiting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways has been extensively investigated in advanced non-small-cell lung cancer (NSCLC), but the benefit-to-risk ratio of dual-targeted regimen versus EGFR-tyrosine kinase inhibitors (TKIs) alone is still unclear. We thus perform this meta-analysis to assess the efficacy and safety of this regimen versus EGFR-TKIs alone in those patients. METHODS: Databases from PubMed, Web of Science and the Cochrane Library up to March 31, 2015 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials (RCTs) evaluating dual inhibiting EGFR and VEGF pathways versus EGFR-TKIs alone in advanced NSCLC. The endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and grade 3 or 4 adverse events. Statistical analyses were conducted by using either random effects or fixed effect models according to the heterogeneity of included studies. RESULTS: A total of 1918 patients with advanced NSCLC from 4 RCTs were identified for the analysis. The pooled results demonstrated that dual inhibiting EGFR and VEGF pathways significantly improved the PFS (HR 0.71, 95 % CI 0.58-0.86, p < 0.001) and ORR (OR 1.54, 95 % CI 1.14-2.08, p = 0.005) in unselected NSCLC when compared to EGFR-TKIs alone, but it did not translate into OS benefit (HR 0.94, 95 % CI 0.84-1.05, p = 0.24). No evidence of publication bias was observed. CONCLUSIONS: Our study suggests that dual inhibition of EGFR and VEGF pathways significantly improves PFS and ORR, but it does not translate into survival benefit in unselected NSCLC patients. Prospective clinical trials investigating the role of this regimen in EGFR mutation-positive NSCLC are still warranted.

Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39.

Glucagon-like peptide 1(7-36) amide (GLP-1) is postulated to be the major physiological incretin in humans, but evidence is indirect. We report the first studies examining the physiological role of GLP-1 in the postprandial state in humans using the GLP-1 antagonist exendin 9-39. Exendin 9-39 completely blocked GLP-1-induced glucose-stimulated insulin release from perifused human islets of Langerhans. In healthy fasted volunteers, intravenous infusion of exendin 9-39 at 500 pmol x kg(-1) x min(-1) in the hyperglycemic state abolished the insulinotropic effect of a physiological dose of GLP-1 and fully reversed the glucose-lowering effect of GLP-1. Nine healthy subjects consumed a 150-g oral glucose tolerance test and were infused with 500 pmol x kg(-1) x min(-1) exendin 9-39 or saline. Exendin 9-39 increased the peak postprandial glucose level (exendin 9-39, 8.67 +/- 0.35 vs. saline, 7.67 +/- 0.35 mmol/l, P < or = 0.005) and increased postprandial plasma glucose incremental area under the curve by 35% (exendin 9-39, 152 +/- 19 vs. saline, 113 +/- 16 mmol x min x l(-1), P < or = 0.05). This could be explained as partly secondary to the blockade of glucose-induced suppression of glucagon and maybe also to an increased rate of gastric emptying. Thus, in humans exendin 9-39 acts as an antagonist of GLP-1 both in vitro and in vivo. When infused alone, exendin 9-39 causes a deterioration in postprandial glycemic control, suggesting that GLP-1 may be important for maintenance of normal postprandial glucose homeostasis in humans.

Evidence of a paracrine role of neuropeptide-Y in the regulation of insulin release from pancreatic islets of normal and dexamethasone-treated rats.

Recent evidence suggests that a number of a paracrine regulatory peptides, including neuropeptide-Y (NPY), are synthesized within pancreatic islets. We have, therefore, assessed the role of NPY on insulin release from isolated perifused rat islets. NPY release was detectable at 2.1 (95% confidence interval, 1.6-2.6) attomoles/islet.min from the perifused islets of control rats when the glucose concentration was 2.8 mM and decreased by 62% (P = 0.01) on changing to 20 mM glucose. The initial insulin release was 0.7 (0.3-1.6) fmol/islet.min, and it was increased 4-fold (P < 0.001) by high glucose. Simultaneously, pancreatic glucagon release was decreased 85% (P < 0.001), and somatostatin release was decreased 25% (P = 0.06). In contrast, in islets from rats given dexamethasone (4 mg/kg.day) for 10 days, NPY release was 6-fold increased by high glucose. NPY (100 nM) decreased insulin release by 44% (P < 0.001). To determine the influence of naturally present islet NPY on insulin release, immunoneutralization with NPY antiserum was employed. With control rat islets, insulin release was increased 3-fold with NPY antiserum (P = 0.02) in the presence of 2.8 mM glucose and elevated 2-fold at 8 mM glucose (P < 0.001). NPY immunoneutralization similarly increased insulin release from the perifused islets of rats treated with dexamethasone. Our results suggest that NPY is produced by pancreatic islets, and its expression is dependent on the prevailing endocrine environment. Islet NPY appears to constrain insulin release under a variety of conditions. NPY may be an important intraislet paracrine hormone.

Pyroglutamyl-phenylalanyl-proline amide attenuates thyrotropin-releasing hormone-stimulated insulin secretion in perifused rat islets and insulin-secreting clonal beta-cell lines.

TRH immunoreactivity has been detected in the pancreas of man and rat and localized to the islets of Langerhans. We studied the effect of synthetic TRH and the related tripeptide pyroglutamyl-phenylalanyl-proline amide (EFP) on isolated perifused rat islets and the glucose-responsive clonal cell lines HIT-T15 and RIN5AH. TRH at 10 nM potentiated [0.5 +/- 0.1 (control) vs. 0.8 +/- 0.1 (TRH) pmol/10(6) cells per 120 min; mean +/- SEM; n = 6; P < 0.001; n = 15], whereas EFP from 1 nM upwards suppressed glucose-stimulated insulin secretion [0.8 +/- 0.1 (control) vs. 0.5 +/- 0.1 (EFP) pmol/10(6) cells per 120 min; P < 0.001; n = 12) in the cell lines. Further, EFP reversed TRH-stimulated insulin release. Similar responses were observed in perifused isolated rat islets at the tested dose of 1 microM. Gel permeation chromatography of rat adult and neonatal whole pancreas, isolated islets, and HIT cell extracts demonstrated the elution of total TRH-like immunoreactivity (t-TRH-LI) in the same position as synthetic TRH. Cation exchange analysis of the t-TRH-LI from rat adult pancreas and HIT cell extracts showed that neutral TRH-like peptides corresponding to synthetic EFP were also present. Reverse-phase fast protein liquid chromatographic analysis of t-TRH-LI in the unbound fraction of these extracts subjected to anion exchange columns, also demonstrated peaks corresponding to synthetic EFP. We conclude that TRH potentiates, whereas EFP inhibits, glucose-stimulated insulin release in isolated perifused islets and the cell lines. In addition, EFP reversed the stimulatory effect of TRH. The presence of EFP-LI in rat adult and neonatal pancreas and HIT cell extracts suggests it may contribute in the modulation of pancreatic endocrine function.

Presence of neuropeptide Y and its messenger ribonucleic acid in human islets: evidence for a possible paracrine role.

Neuropeptide Y (NPY) has been shown to decrease insulin secretion from rodent islets. NPY messenger ribonucleic acid (mRNA) has been demonstrated in rat and mouse pancreatic islets. We, therefore, examined human islets for the presence of NPY-encoding mRNA and NPY-like immunoreactivity. Human pancreatic islets were obtained from cadaveric organ donors, using collagenase digestion and purification on BSA density gradients. Northern blot analysis, employing a human NPY riboprobe, revealed specific NPY-encoding mRNA in the islet. Compared to the islet, NPY message abundance was 9-fold higher in the caudate nucleus and 2.4-fold higher in the temporal lobe, but it was 75% lower in the adrenal gland. NPY-like immunoreactivity was present at 2.4 +/- 0.3 fmol/microgram protein in acid-ethanol extracts from the islets. On fast protein liquid chromatography with a reverse phase column, the majority of NPY-like immunoreactivity eluted as a peak with a retention time identical to that of porcine NPY standard. Added NPY (100 nmol/L) decreased (P = 0.001) glucose-stimulated (8 mmol/L) insulin release from the human islets by 45% in a perfusion system. Therefore, human islets synthesize substantial amounts of NPY, which could act as an intra-islet paracrine regulator.