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Two HER2-specific mAbs, trastuzumab and pertuzumab (T+P), combined with chemotherapy comprise standard-of-care treatment for advanced HER2+ breast cancers (BC). While this antibody combination is highly effective, its synergistic mechanism-of-action (MOA) remains incompletely understood. Past studies have suggested that the synergy underlying this combination occurs through the different mechanisms elicited by these antibodies, with pertuzumab suppressing HER2 heterodimerization and trastuzumab inducing antitumor immunity. However, in vivo evidence for this synergy is lacking. In this study, we found that the therapeutic efficacy elicited by their combination occurs through their joint ability to activate the classical complement pathway, resulting in both complement-dependent cytotoxicity and complement-dependent cellular phagocytosis of HER2+ tumors. We also demonstrate that tumor C1q expression is positively associated with survival outcome in HER2+ BC patients and that complement regulators CD55 and CD59 were inversely correlated with outcome, suggesting the clinical importance of complement activity. Accordingly, inhibition of C1q in mice abolished the synergistic therapeutic activity of T+P therapy, whereas knockdown of CD55 and CD59 expression enhanced T+P efficacy. In summary, our study identifies classical complement activation as a significant antitumor MOA for T+P therapy that may be functionally enhanced to potentially augment clinical therapeutic efficacy.

Erectile dysfunction (ED), as a common male disease, can seriously reduce the life quality of men and their partners. With the improvement of human living standards, ED is considered to be an important health issue that plagues men. However, it is difficult for existing therapeutic approaches to meet the needs of all patients, so it is necessary to develop novel treatment strategies. Exosomes, as a class of vesicles secreted by cells with bilayer membrane structure, are involved in various physiological and pathological processes in human body and considered to have great therapeutic potentials. This review summarizes the recent advances on exosome therapy with animal models of ED, and proposes the prospect of future research in order to provide a basis for clinical trials and clinical translation. [ABSTRACT FROM AUTHOR]

Despite advances in the diagnosis and treatment of ischemic heart disease (IHD), it remains the leading cause of death globally. Thus, there is a need to investigate the underlying pathophysiology and develop new therapies for the prevention and treatment of IHD. Murine models are widely used in IHD research because they are readily available, relatively inexpensive, and can be genetically modified to explore mechanistic questions. Ischemia-reperfusion (I/R)-induced myocardial infarction in mice is produced by the blockage followed by reperfusion of the left anterior descending branch (LAD) to imitate human IHD disease and its treatment. This I/R model can be widely used to investigate the potential reparative effect of putative treatments in the setting of reperfusion. However, the surgical technique is demanding and can produce an inconsistent amount of damage, which can make identification of treatment effects challenging. Therefore, determining which hearts have been significantly damaged by I/R is an important consideration in studies designed to either explore the mechanisms of disrupted function or test possible therapies. Noninvasive echocardiography (ECHO) is often used to determine structural and functional changes in the mouse heart following injury. In the present study, we determined that ECHO performed 3 days post I/R surgery could predict the permanent injury produced by the ischemic insult. [ABSTRACT FROM AUTHOR]

Radix Codonopsis has been used in traditional Chinese medicine for strengthening the immune system, improving poor gastrointestinal function, treating gastric ulcers and chronic gastritis and so on. In the present study, an inulin-type fructan CP-A was obtained from the roots of Codonopsis pilosula (Franch.) Nannf. and its structure was confirmed by MS and NMR as (2 → 1) linked-β-D-fructofuranose. The protective effects of CP-A against ethanol-induced acute gastric ulcer in rats were intensively investigated. A Lacy assay demonstrated that CP-A-treated group (50 mg/kg) showed the gastric damage level 1, which was similar to the positive control group, while the model group exhibited the gastric damage level 3. The Guth assay demonstrated that the mucosa ulcer index for CP-A groups at the doses of 50 mg/kg and 25 mg/kg significantly decreased compared with that in the model group (p < 0.05). Meanwhile, CP-A significantly increased the activities of SOD and GSH-Px, and decreased the contents of MDA and NO, and the activity of MPO in gastric tissue in a dose-dependent manner (p < 0.05). The present research reported for the first time that inulin-type fructan CP-A were likely the potential component in Radix Codonopsis for treatment of acute gastric ulcers. [ABSTRACT FROM AUTHOR]

Background: inhibition of acetylcholinesterase (AChE) has been a effective treatment for Alzheimer's disease (AD). Octohydroaminoacridine, a new AChE inhibitor, is a potential treatment for AD. Method: we conducted a multicenter, randomised, double blind, placebo-controlled, parallel-group Phase II clinical trial to investigate the effects of octohydroaminoacridine in patients with mild-to-moderate AD. Patients were randomised to receive placebo thrice daily, octohydroaminoacridine 1 mg/thrice daily (TID) (low-dose group), 2 mg/TID (middle-dose group) or 4 mg/TID (high-dose group). Doses in the middle-dose and high-dose group were titrated over 2-4 weeks. Changes from baseline to Week 16 were assessed with the AD Assessment Scale-Cognitive Subscale (ADAS-cog), Clinician's Interview-Based Impression of Change Plus (CIBIC+), activities of daily living (ADL) and the neuropsychiatric inventory (NPI). ADAS-cog was the primary end point of the study. A two-way analysis of covariance and least squares mean t-test were used. Results: at Week 16, the changes from baseline in ADAS-cog were 1.4, -2.1, -2.2 and -4.2 for placebo, low-, middle- and high-dose groups, respectively. Patients in the high-dose group had better performance in CIBIC+ and ADL scores at the end of the study. There was no significant difference in the change in NPI score among the groups. The effects of octohydroaminoacridine were dose dependent, and were effective within 16 weeks of treatment. No evidence was found for more adverse events that occurred in different drug groups than placebo group. Conclusions: octohydroaminoacridine significantly improved cognitive function and behaviour in patients with mild-tomoderate AD and this effect was dose dependent. [ABSTRACT FROM AUTHOR]

Objective: Xingnaojing injection (XNJ) is derived from An-Gong-Niu-Huang pill, a wellknown traditional Chinese patent medicine, which is widely used for stroke. To evaluate the therapeutic effect of XNJ on cerebral infarction, an extensive meta-analysis was used. Methods: Six major electronic databases including the Chinese Biomedical Database (CBM), Wanfang, the VIP medicine information system (VMIS) and the China National Knowledge Infrastructure (CNKI), PubMed, Embase, and the Cochrane Library were examined to retrieve randomized controlled trials designed to evaluate the clinical efficacy of XNJ in treating CI before November 26, 2016. Results: There were 53 randomized controlled trials with 4915 participants in this study. The results reflected that compared with the conventional therapy (CT) alone, XNJ could significantly improve the overall response rate (OR D 3.56, 95% CI [2.94, 4.32], P < 0.00001), and clinical symptom (including increasing activities of daily living (ADL, MD D 10.23, 95% CI [9.47, 10.99], P < 0.00001), and reduce infarction size (MD D -1.83, 95% CI [-2.49, -1.16], P < 0.00001)). However, there was no significant difference between the XNJ treatment and conventional therapy in Glasgow Coma Scale (GCS, P D 0.32). Neurological deficit score demonstrated that XNJ could significantly reduce the score in two different evaluation criterions as National Institutes of Health Stroke Scale (NIHSS, MD D -3.44, 95% CI [-4.52, -2.36], P < 0.00001), and the Chinese Stroke Scale (CSS, MD D -5.72, 95% CI [-6.94, -4.50], P < 0.00001). Additionally, serum MMPs, including MMP-2 and MMP-9 were significantly reduced by XNJ treatment compared with conventional therapy (MD D -11.24, 95% CI [-20.83, -1.65], P D 0.02; MD D -25.08, 95% CI [-35.49, -14.67], P < 0.00001, respectively). Moreover, XNJ was able to improve hemorrheology in reducing whole blood viscosity, plasma viscosity, and hematocrit (MD D -1.44, 95% CI [-2.18, 0.70], P D 0.001; MD D -0.22, 95% CI [-0.37, -0.07], P D 0.003; MD D -3.63, 95% CI [-6.23, -1.03], P D 0.006, respectively). The therapeutic efficacy of XNJ was found associated with improving hemodynamics (increasing peak-flow rate, and average velocity) (MD D 12.66, 95% CI [10.50, 14.81], P < 0.00001; MD D 9.90, 95% CI [8.63, 11.17], P < 0.00001). XNJ was also related to reducing cholesterol and triglyceride (MD D -1.06, 95% CI [-1.21, -0.92], P < 0.00001; MD D -1.05, 95% CI [-1.12, -0.97], P < 0.00001). Conclusion: Despite the sample size and the poor quality of the included studies of this review, the results of the research showed that XNJ might be a beneficial therapeutic method for the treatment of cerebral infarction. [ABSTRACT FROM AUTHOR]

The molecular mechanisms underlying protection and pathogenesis in spinal degenerative diseases remain unclear. Tumor necrosis factor-α (TNF-α) has been demonstrated to induce apoptosis of inte rvertebral disc (IVD) cells during IVD degeneration, and 17β-estradiol (17β-E2) has a protective effect against IVD cell apoptosis. However, the underlying molecular mechanism by which 17β-E2 protects nucleus pulposus (NP) cells remains to be investigated. The aim of the present study was to evaluate whether 17β-E2 modulates apoptosis of human NP cells induced by TNF-α. In addition, the concentration-response effect of 17β-E2 on human NP cells was investigated. Human NP cells were cultured in complete medium, which was replaced every three days until the culture was ~80% confluent. Cells were treated with 100 ng/ml TNF-α for 48 h, with or without pretreatment with various concentrations of 17β-E2, and ICI 182,780, for 30 min. Morphologic alterations characteristic of apoptosis were observed by inverted phase-contrast microscopy and Hoechst 33258 staining; the apoptosis rate was analyzed by flow cytometry. A Cell Counting kit-8 assay was used to assess cell proliferation. Furthermore, caspase-3 activity was determined and proteins associated with apoptosis were analyzed by western blotting. The level of apoptosis and caspase-3 activity in human NP cells increased, whereas proliferation and the expression of poly ADP-ribose polymerase decreased following TNF-α treatment. These effects of TNF-α were abolished by pretreatment with 17β-E2 in a concentration-dependent manner. The results of the present study indicated that 17β-E2 serves a critical role in the survival of degenerative human NP cells. [ABSTRACT FROM AUTHOR]

More than 200 medications can induce taste disorders in patients. They not only reduce quality of life for those affected, but can lead to malnutrition, severe dehydration and difficulty in maintaining a therapeutic regimen. Nevertheless, the impact of drug candidates on taste is rarely evaluated in preclinical toxicology studies during the early stage of drug development. Moreover, knowledge about how to investigate these adverse effects is scarce in the toxicology field. Here, we discuss the clinical status of drug-induced taste disorders in patients, with the goal of providing toxicologists with a broad understanding of its prevalence, and how stressful and even dangerous it can be to affected patients. Because taste, smell, and oral trigeminal sensation are highly interdependent, we also address drug-induced changes in olfactory and oral somatosensory perceptions. We then review the biology of the gustatory system (including anatomy and histology), and the latest developments about how taste contributes to flavor perception. Finally, we feature recently optimized preclinical approaches to investigate drug-induced taste change in animal models, including morphological evaluation of taste buds and taste cells, gustatory nerve recording, and behavioral testing. Our goals are to raise awareness of drug-induced taste disorders among toxicologists, share an overview of new approaches and key studies that can be used to identify druginduced gustatory system toxicity early in the drug development process, and to stimulate further research at this emerging interface of chemosensory disorders with toxicology. [ABSTRACT FROM AUTHOR]

Hypertrophic scars (HS) area fibroproliferative disorder of the skin, which causes aesthetic and functional impairment. However, the molecular pathogenesis of this disease remains largely unknown and currently no efficient treatment exists. MicroRNAs (miRNAs) are involved in a variety of pathophysiological processes, however the role of miRNAs in HS development remains unclear. To investigate the miRNA expression signature of HS, microarray analysis was performed and 152 miRNAs were observed to be differentially expressed in HS tissue compared with normal skin tissues. Of the miRNAs identified, miRNA-21 (miR-21) was significantly increased in HS tissues and hypertrophic scar fibroblasts (HSFBs) as determined by reverse transcription-quantitative polymerase chain reaction analysis. It was also observed that, when miR-21 in HSFBs was blocked through use of an antagomir, the phenotype of fibrotic fibroblasts in vitro was reversed, as demonstrated by growth inhibition, induction of apoptosis and suppressed expression of fibrosis-associated genes collagen type I ɑ 1 chain (COL1A1), COL1A2 and fibronectin. Furthermore, miR-21 antagomir administration significantly reduced the severity of HS formation and decreased collagen deposition in a rabbit ear HS model. The total scar area and scar elevation index were calculated and were demonstrated to be significantly decreased in the treatment group compared with control rabbits. These results indicated that the miR-21 antagomir has a therapeutic effect on HS and suggests that targeting miRNAs may be a successful and novel therapeutic strategy in the treatment of fibrotic diseases that are difficult to treat with existing methods. [ABSTRACT FROM AUTHOR]

Calcium oxalate stones account for >80% of urinary stones, however the mechanisms underlying their formation remains to be elucidated. Hyperoxaluria serves an important role in the pathophysiological process of stone formation. In the present study, differences in the miRNA expression profiles between experimental hyperoxaluric rats and normal rats were analyzed, in order to identify target genes and signaling pathways involved in the pathogenesis of hyperoxaluria. Ethylene glycol and ammonium chloride was fed to male hyperoxaluric rats (EXP) and normal age-matched male rats (CON). The oxalate concentration in the urine of each experimental rat was collected every 24 h and measured on day 14. Three rats exhibiting the highest concentrations were selected for microarray analysis. Microarray analysis was performed to evaluate differences in the expression of microRNA (miRNA) in the kidney tissues from EXP and CON groups, and miRNAs that exhibited a >2-fold or a <0.5-fold alteration in expression between these groups were screened for differential expression patterns according to the threshold P-values. Reverse transcription-quantitative polymerase chain reaction analysis was employed to confirm the microarray results. In order to predict the potential role of miRNAs in pathophysiological processes, gene ontology (GO), pathway and target prediction analyses were conducted. A total of 28 miRNAs were observed to be differentially expressed (>2-fold change) between EXP and CON groups. Among these miRNAs, 20 were upregulated and 8 were downregulated. GO and pathway analyses revealed that the insulin resistance and phosphatidylinositol-bisphosphonate 3-kinase/AKT serine threonine kinase signaling pathways were potentially associated with miRNA regulation in this setting. In conclusion, the results of the present study identified differentially expressed miRNAs in hyperoxaluric rats, and provided a novel perspective for the role of miRNAs in the formation of calcium oxalate stones. [ABSTRACT FROM AUTHOR]

Objective: To retrospectively analyze the results of surgical resection in patients with pulmonary hamartoma (PH) in the Peoples Liberation Army (PLA) General Hospital during the past 30 years.Materials and Methods: We retrospectively enrolled 226 patients with PH who underwent surgical resection in the PLA General Hospital between January 1980 and January 2010, including tumors of pulmonary parenchyma (n = 216) and endobronchial tumors (n = 10). The type of operation include tumor enucleation (n = 103), wedge resection (n = 103), and lobectomy (n = 20). The postoperative follow-up time was 5-22 years.Results: Only one postoperative death occurred. The intraoperative blood loss and the drainage volume within 24 postoperative hours were significantly less in patients underwent lateral thoracotomy or video-assisted thoracic surgery (VATS) than those of patients underwent conventional incision. None of the patients experienced regional recurrence.Conclusion: We recommended lateral thoracotomy or VATS for the patients whose PH could not be confirmed preoperatively, and tumor enucleation or wedge resection was recommended. [ABSTRACT FROM AUTHOR]

Pyrazinamide (PZA) is an indispensable first-line drug used for the treatment of tuberculosis which may cause serious hepatotoxicity; however, the mechanisms underlying these toxicities are poorly understood. Cholestasis plays an important role in drug-induced liver injury. Since there were no previous published works reported cholestasis and PZA hepatotoxicity relationship, this study aimed to identify whether PZA can induce liver injury with characterized evidences of cholestasis and to clarify expression changes of proteins related to both bile acid synthesis and transport in PZA-induced liver injury. PZA (2 g/kg) was administered for 7 consecutive days by oral gavage. Results showed there were 2-fold elevation in both ALT and AST serum levels in PZA-treated rats. In addition, a 10-fold increment in serum total bile acid was observed after PZA administration. The mRNA and protein expressions of bile acid synthesis and transport parameters were markedly altered, in which FXR, Bsep, Mrp2, Mdr2, Osta/b, Oatp1a1, Oatp1b2, and Cyp8b1 were decreased (P<.05), while Mrp3, Ntcp, Oatp1a4, and Cyp7a1 were increased (P<.05). Moreover, treatment with the FXR agonist obeticholic acid (OCA) generated obvious reductions in serum ALT, AST, and TBA levels in PZA-treated rats. Those effects were due to transcriptional regulation of pre-mentioned target genes by OCA. Taken together, these results suggested that PZA-induced cholestatic liver injury was related to FXR inhibition, leading to the dysfunction in bile acid synthesis and transport. [ABSTRACT FROM AUTHOR]

Many kinds of endocrine-disrupting chemicals (EDCs), for example, the environmental estrogens bisphenol A and nonylphenol, may regulate the activity of estrogen receptor α (ERα) and therefore induce potential disruption of normal endocrine function. However, the involvement of EDCs in human cancers, especially in endocrine-related cancer neuroblastoma regulation, is not very clear. In this work, results showed that upon bisphenol A or nonylphenol treatment, the transcription factor activity of ERα was significantly increased in neuroblastoma cell line SH-SY5Y. Bisphenol A and nonylphenol could enhance ERα activity via recruiting it to the target gene promoter. Furthermore, treatment of bisphenol A and nonylphenol enhanced the in vitro proliferation, invasion, and migration ability of neuroblastoma cells. By investigating the role of EDC-induced ERα upregulation, our data extend the understanding of the function of EDCs and further suggest that ERα might be a potential therapeutic target in human neuroblastoma treatment. [ABSTRACT FROM AUTHOR]

Objective: To evaluate tofacitinib's effect upon pneumococcal and influenza vaccine immunogenicity.Methods: We conducted two studies in patients with rheumatoid arthritis using the 23-valent pneumococcal polysaccharide vaccine (PPSV-23) and the 2011-2012 trivalent influenza vaccine. In study A, tofacitinib-naive patients were randomised to tofacitinib 10 mg twice daily or placebo, stratified by background methotrexate and vaccinated 4 weeks later. In study B, patients already receiving tofacitinib 10 mg twice daily (with or without methotrexate) were randomised into two groups: those continuing ('continuous') or interrupting ('withdrawn') tofacitinib for 2 weeks, and then vaccinated 1 week after randomisation. In both studies, titres were measured 35 days after vaccination. Primary endpoints were the proportion of patients achieving a satisfactory response to pneumococcus (twofold or more titre increase against six or more of 12 pneumococcal serotypes) and influenza (fourfold or more titre increase against two or more of three influenza antigens).Results: In study A (N=200), fewer tofacitinib patients (45.1%) developed satisfactory pneumococcal responses versus placebo (68.4%), and pneumococcal titres were lower with tofacitinib (particularly with methotrexate). Similar proportions of tofacitinib-treated and placebo-treated patients developed satisfactory influenza responses (56.9% and 62.2%, respectively), although fewer tofacitinib patients (76.5%) developed protective influenza titres (≥1:40 in two or more of three antigens) versus placebo (91.8%). In study B (N=183), similar proportions of continuous and withdrawn patients had satisfactory responses to PPSV-23 (75.0% and 84.6%, respectively) and influenza (66.3% and 63.7%, respectively).Conclusions: Among patients starting tofacitinib, diminished responsiveness to PPSV-23, but not influenza, was observed, particularly in those taking concomitant methotrexate. Among existing tofacitinib users, temporary drug discontinuation had limited effect upon influenza or PPSV-23 vaccine responses.Trial Registration Numbers: NCT01359150, NCT00413699. [ABSTRACT FROM AUTHOR]

BACKGROUND: Various vascular risk factors such as smoking, obesity, and diabetes mellitus are associated with hyperviscosity and lumbar disc herniation (LDH). However, the changes of viscosity in LDH have not been examined. AIMS: The present study was to elucidate 1) the rheological parameter levels in patients with LDH, 2) the risk factors that were related to rheological parameters. METHODS: Our study evaluated the rheological parameters in 307 cases with LDH and in 307 control subjects. Multiple linear regression analysis was conducted to assess the significant factors for whole blood viscosity (WBV) at low shear rate. RESULTS: LDH patients had markedly lower physical activity and significantly higher WBV3 s-1 compared with non-LDH subjects (p < 0.001). Moreover, WBV (3 s-1) tended to increase as physical activity decreased. Multiple linear regression analysis revealed that reduced physical activity was a significant factor contributing to elevated WBV (3 s-1). CONCLUSIONS: WBV (3 s-1) is elevated in patients with LDH. In addition, reduced physical activity is a significant factor for WBV (3 s-1). Further studies are warranted to determine the role of WBV (3 s-1) in LDH. [ABSTRACT FROM AUTHOR]

Triptolide, a diterpenoid isolated from the plant Tripterygium wilfordii Hook. f., exerts a unique bioactive spectrum of anti-inflammatory and anticancer activities. However, triptolide's clinical applications are limited due to its severe toxicities. Fatty liver toxicity occurs in response to triptolide, and this toxic response significantly differs between males and females. This report investigated the pathogenesis underlying the sex-related differences in the dyslipidosis induced by triptolide in rats. Wistar rats were administered 0, 150, 300, or 450 μg triptolide/kg/day by gavage for 28 days. Ultrastructural examination revealed that more lipid droplets were present in female triptolide-treated rats than in male triptolide-treated rats. Furthermore, liver triglyceride, total bile acid and free fatty acid levels were significantly increased in female rats in the 300 and 450 μg/kg dose groups. The expression of liver X receptor α (LXRα) and its target genes, cholesterol 7α-hydroxylase (CYP7A1) and Sterol regulatory element-binding transcription factor 1(SREBP-1), increased following triptolide treatment in both male and female rats; however, the female rats were more sensitive to triptolide than the male rats. In addition, the expression of acetyl-CoA carboxylase 1(ACC1), a target gene of SREBP-1, increased in the female rats treated with 450 μg triptolide/kg/day, and ACC1 expression contributed to the sex-related differences in the triptolide-induced dysfunction of lipid metabolism. Our results demonstrate that the sex-related differences in LXR/SREBP-1-mediated regulation of gene expression in rats are responsible for the sex-related differences in lipid metabolism induced by triptolide, which likely underlie the sex-related differences in triptolide hepatotoxicity. This study will be important for predicting sex-related effects on the pharmacokinetics and toxicity of triptolide and for improving its safety. [ABSTRACT FROM AUTHOR]

Malignant mesothelioma is a rare type of cancer, most commonly associated with exposure to asbestos. Mesothelioma of the peritoneum, the membrane lining the abdominal cavity, is extremely rare. The current study reports the case of a 60-year-old female who presented with intestinal fistula, recurrent incisional hernia and abdominal infection, with no history of asbestos exposure, and was diagnosed with clear cell MPM. Computed tomography scans of the abdomen revealed extensive small bowel adhesions and massive peritoneal effusion. Histological examination of biopsy specimens indicated a diagnosis of malignant peritoneal mesothelioma with clear cell morphology. A laparotomy was performed, with subsequent resection of the bowel with fistula. Follow-up examination performed at 1-year post-surgery revealed that the patient was alive and in generally good health. [ABSTRACT FROM AUTHOR]

Background: Portal hypertension (PHT) requires invasive measures to prevent rupture and bleeding of esophagogastric varices; however, the long-term results of subtotal splenectomy plus fixation of the retrosternal omentum majus (SSFROM) have not been reported. Specifically, the advantages and disadvantages of surgery that preserves the spleen and the long-term hematologic effects have not been described. Study design: Our studies relating to SSFROM commenced in February 1999. As of April 2014 we have performed 256 subtotal splenectomies The records of 65 patients with PHT who underwent SSFROM were reviewed retrospectively. Results: Four patients died within 4 years of surgery, with a 4-year survival rate of 94 %; the 11-year survival rate was 60 %. Eleven patients (17 %) had re-bleeding from esophagogastric varices. The white blood cell and platelet counts were higher 6 and 11 years post-operatively compared with pre-operative values (P < 0.01). Portal venous diameter, portal venous flow volume, splenic artery flow volume, as well as splenic length, thickness, and average cross-sectional areas were shown to be significantly constricted or decreased (P < 0.01). The proportion of serum CD3+ T cells, CD4+ T cells, and CD8+ T cells was increased (P < 0.01), while the serum levels of macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor were significantly decreased (P < 0.01). There was no significant change in the serum levels of IgA, IgM, IgG, and Tuftsin (P > 0.05). DSA demonstrated that 15 cases formed collateral circulations between the portal vein and superior vena cava. Conclusion: SSFROM provide long-term hemostasis for esophagogastric variceal bleeding in PHT and corrected hypersplenism. SSFROM is an effective treatment for patients with PHT in whom long-term survival is expected. [ABSTRACT FROM AUTHOR]

Background It has been demonstrated that platycodin D (PD) exhibits anti-cancer activities. This study aims to investigate the anti-proliferative effects of the combination of PD and doxorubicin (DOX) on human breast cancer cells (MCF-7 and MDA-MB-231 cells). Methods The anti-proliferative effects of different dosages of PD, DOX, and PD + DOX on MCF-7 and MDA-MB-231 cells were determined by the MTT assay. The 10 μM PD, 5 μM DOX, and 10 μM PD + 5 μM DOX induced-protein expression of apoptosis-related molecules on MCF-7 and MDA-MB-231 cells were detected by western blot. The 10 μM PD, 5 μM DOX and 10 μM PD + 5 μM DOX-induced mitochondrial membrane potential changes on MCF-7 and MDA-MB-231 cells were stained with JC-1 before visual determination. The intracellular accumulations of DOX, induced by 10 μM PD, 5 μM DOX and 10 μM PD + 5 μM DOX, were detected by flow cytometry. Results PD enhanced anti-cancer activities of DOX were observed in both MCF-7 and MDA-MB- 231 cell lines. Compared with mono treatment, the combined treatment increased the protein expression of cleaved poly (ADP-ribose) polymerase and decreased the mitochondrial membrane potential. The combined treatment with PD did not obviously increase the accumulation of DOX in MCF-7 cells (1.66 ± 0.13 in DOX-treated group, and 1.69 ± 0.06 in PD + DOX-treated group, P = 0.76), but it significantly increased the accumulation of DOX in MDA-MB-231 cells (1.76 ± 0.17 in DOX-treated group, 2.09 ± 0.02 in PD + DOX-treated group, P = 0.027). Conclusion The combined treatment of DOX and PD exhibited stronger anti-proliferative effects on MCF-7 and MDA-MB-231 cells than DOX and PD treatment did. [ABSTRACT FROM AUTHOR]

The anti-oxidative stress effect of heme oxygenase-1 (HO-1) expression is being increasingly studied. However, few studies regarding HO-1 have been conducted in patients with gestational diabetes mellitus (GDM). In the present study, HO-1 expression was compared in peripheral blood mononuclear cells at 24-28 weeks of pregnancy in patients with GDM and healthy females, to investigate the correlation between HO-1 and oxidative stress by calculation of MDA content in the peripheral blood serum (thiobarbituric acid method), tested ROS (flow cytometry method), HO-1mRNA (RT-PCR method), and HO-1 protein (western blotting method) of Mononuclear cells. The results show that the levels of serum malonaldehyde (MDA), reactive oxygen species (ROS), HO1 mRNA and HO-1 protein expression in peripheral blood mononuclear cells were higher in the GDM group than in the control group. Correlation analysis showed that the expression levels of HO-1 protein were positively correlated with the HO1 mRNA expression levels (r=0.680; P=0.000), and the levels of ROS (r=0.572; P=0.000) and MDA (r=0.614; P=0.000). HO1 mRNA expression levels were found to positively correlate with the levels of MDA (r=0.451; P=0.010) and fasting plasma glucose (FPG; r=0.337; P=0.039). Partial correlation analysis demonstrated that, after removing the effects of body mass index, FPG and 2-h plasma glucose, HO-1 protein expression levels were positively correlated with the levels of HO1 mRNA expression (r=0.611; P=0.005), ROS (r=0.526; P=0.021) and MDA (r=0.519; P=0.015). These findings indicate that pregnant females with GDM may be protected against oxidative injury due to the induction of adaptive and compensatory expression of HO-1 to guard against oxidative stress induced by high glucose levels. [ABSTRACT FROM AUTHOR]

The importance of human leukocyte anti-gen (HLA) matching In unrelated donor transplantation for nonmalignant dis-eases (NMD) has yet to be defined. We analyzed data from 663 unrelated marrow and peripheral blood stem cell trans-plants performed from 1995 to 2007 for treatment of NMD. Transplantation from a donor mismatched at the HLA-A, -B, -C, or -DRB1, but not -DQB1 or -DPB1, loci was associated with higher mortality in multi-variate analyses (P = .002). The hazard ratio for mortality for single (7/8) and double mismatched (6/8) transplants was 1.29 (0.97-1.72; P = .079) and 1.82 (1.30-2.55; P = .0004), respectively, compared with 8/8 matched transplants. HLA mis-matches were not associated with acute or chronic GVHD, but were strongly asso-ciated with graft failure. After adjustment for other factors, the odds ratio for graft failure for 7/8 and 6/8 (allele and/or antigen) matched pairs compared with 8/8 matched transplants was 2.81 (1.74-4.54; P﹤ .0001) and 2.22 (1.26-3.97; P= .006), respectively. Patients with NMD should receive trans-plants from allele matched (8/8) donors if possible. Unlike the case with malignancies, HLA mismatching in NMD is associated with graft failure rather than GVHD. [ABSTRACT FROM AUTHOR]

We investigated whether plasma long-chain sphingoid base (LCSB) concentrations are altered by transient cardiac ischemia during percutaneous coronary intervention (PCI) in humans and examined the signaling through the sphingosine-1-phosphate (S1P) cascade as a mechanism underlying the S1P cardioprotective effect in cardiac myocytes. Venous samples were collected from either the coronary sinus (n = 7) or femoral vein (n = 24) of 31 patients at 1 and 5 min and 12 h, following induction of transient myocardial ischemia during elective PCI. Coronary sinus levels of LCSB were increased by 1,072% at 1 min and 941% at 5 min (n = 7), while peripheral blood levels of LCSB were increased by 579% at 1 min, 617% at 5 min, and 436% at 12 h (n = 24). In cultured cardiac myocytes, S1P, sphingosine (SPH), and FTY720, a sphingolipid drug candidate, showed protective effects against CoCl induced hypoxia/ischemic cell injury by reducing lactate dehydrogenase activity. Twenty-five nanomolars of FTY720 significantly increased phospho-Pak1 and phospho-Akt levels by 56 and 65.6% in cells treated with this drug for 15 min. Further experiments demonstrated that FTY720 triggered nitric oxide release from cardiac myocytes is through pertussis toxin-sensitive phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase signaling. In ex vivo hearts, ischemic preconditioning was cardioprotective in wild-type control mice (Pak1f/f), but this protection appeared to be ineffective in cardiomyocyte-specific Pak1 knockout (Pak1cko) hearts. The present study provides the first direct evidence of the behavior of plasma sphingolipids following transient cardiac ischemia with dramatic and early increases in LCSB in humans. We also demonstrated that S1P, SPH, and FTY720 have protective effects against hypoxic/ischemic cell injury, likely a Pak1/Akt1 signaling cascade and nitric oxide release. Further study on a mouse model of cardiac specific deletion of Pak1 demonstrates a crucial role of Pak1 in cardiac protection against ischemia/reperfusion injury. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the potential therapeutic effect of cholecystokinin octapeptide (CCK-8) on collagen-induced arthritis (CIA), an accepted murine experimental disease model with diverse histopathological features similar to human rheumatoid arthritis (RA). CIA was induced in DBA/1J mice by immunization with chicken collagen type II (CII). CCK-8 at different doses was intraperitoneally administered daily for 1 week. Mice treated with CCK-8 at doses of 5 and 10 nmol but not 1 nmol displayed much delayed onset of CIA and significantly lower incidence and decreased severity of arthritis. CCK-8 treatment significantly reduced the production of cytokines (IL-17, IL-23, IL-6 and TNF-α) and chemokines monocyte chemoattractant protein 1 in the joints of arthritic mice or in synovial cell culture supernatant, and increased the levels of IFN-γ and TGF-β. T cells from CCK-8 treated mice proliferated much less, produced low level of IL-17 and high levels of IFN-γ and TGF-β. Moreover, CCK-8 treated mice showed lower levels of CII-specific IgG, particularly that of IgG2a, in sera than those from control mice. These results indicate that CCK-8 is effective in suppressing both inflammatory and Th17 responses in CIA. CCK-8 may represent a new therapeutic modality for rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

VEGF (vascular endothelial growth factor) is a potent proangiogenic cytokine, and vascular change is one of the characteristic features of airway remodelling. Since the glucocorticoids have shown antifibrosis properties, we sought to investigate whether budesonide, a widely used glucocorticoid in clinical practice, could attenuate TGF-β1 (transforming growth factor-β1)-induced VEGF production by HFL-1 (human lung fibroblasts). HFL-1 fibroblasts were treated with various concentrations of budesonide (10-11 M, 10-9 M and 10-7 M) in the absence or presence of TGF-β1. Postculture media were collected for ELISA of VEGF at the indicated times. The cell lysates were subjected to Western blotting analysis to test TGF-β1/Smad and MAP (mitogen-activated protein) kinase signalling activation, respectively. The results suggested that budesonide pretreatment reduced the significant increase of VEGF release induced by TGF-β1 in HFL-1 fibroblasts in a dose-dependent manner, and suppressed the increase of phospho-Smad3 and phosphor-ERK (extracellular signalregulated kinase) protein levels. In conclusion, budesonide may reduce TGF-β1-induced VEGF production in the lung, probably through the Smad/ERK signalling pathway and, thus, may provide new sight into the molecular mechanism underlying glucocorticoid therapy for airway inflammatory diseases. [ABSTRACT FROM AUTHOR]

Azaindole derivatives derived from the screening lead 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1) were prepared and characterized to assess their potential as inhibitors of HIV-1 attachment. Systematic replacement of each of the unfused carbon atoms in the phenyl ring of the indole moiety by a nitrogen atom provided four different azaindole derivatives that displayed a clear SAR for antiviral activity and all of which displayed marked improvements in pharmaceutical properties. Optimization of these azaindole leads resulted in the identification of two compounds that were advanced to clinical studies: (R)-1-(4-benzoyl-2-methylpiperazin-1-yl)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione (BMS-377806, 3) and 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043, 4). In a preliminary clinical study, 4administered as monotherapy for 8 days, reduced viremia in HIV-1-infected subjects, providing proof of concept for this mechanistic class. [ABSTRACT FROM AUTHOR]

Adenocarcinoma of the prostate remains a significant public health problem and a prevalent cancer in men. Prostate-specific antigen used as a biomarker has established a clear migration of patients towards earlier-stage disease at presentation. However, in spite of process improvements in traditional therapies including surgery, radiation therapy, and hormone management, there remains a significant cohort of patients with intermediate- to high-risk features for poor outcome in spite of optimal use of traditional management. This paper focuses on future treatment strategies integrating new therapeutic options with traditional management, specifically to pinpoint new radiation therapy strategies. [ABSTRACT FROM AUTHOR]

Vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). Studies have shown a link between single-nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase (eNOS) gene and the incidence of coronary spasm and aneurysms. Alterations in the eNOS T-786 SNP may lead to an increased risk of post-aSAH cerebral vasospasm. In this prospective clinical study, 77 aSAH patients provided genetic material and were followed for the occurrence of vasospasm. In multivariate logistic regression analysis, genotype was the only factor predictive of vasospasm. The odds ratio (OR) for symptomatic vasospasm in patients with one T allele was 3.3 (95% confidence interval (CI): 1.1 to 10.0, P=0.034) and 10.9 for TT. Patients with angiographic spasm were 3.6 times more likely to have a T allele (95% CI: 1.3 to 9.6, P=0.013; for TT: OR 12.6). Patients with severe vasospasm requiring endovascular therapy were more likely to have a T allele (OR 3.5, 95% CI: 1.3 to 9.5, P=0.016; for TT: OR 12.0). Patients with the T allele of the eNOS gene are more likely to have severe vasospasm. Presence of this genotype may allow the identification of individuals at high risk for post-aSAH vasospasm and lead to early treatment and improved outcome.Journal of Cerebral Blood Flow & Metabolism (2008) 28, 1204–1211; doi:10.1038/jcbfm.2008.11; published online 5 March 2008 [ABSTRACT FROM AUTHOR]

Background/Aims: Evaluating the peritoneal fluid kinetics is of clinical importance in peritoneal dialysis treatment. We have previously developed a simple way to evaluate the peritoneal fluid transport characteristics in continuous ambulatory peritoneal dialysis patients which, however, cannot be applied to those patients on a fixed dialysis schedule. Therefore, in the present study, we tested the possibility to vary the peritoneal dwell time and tried to develop a more patient-friendly ultrafiltration (UF) collection protocol. Methods: The patients’ UF volume was recorded for 10 days. All patients recruited were asked to perform their usual dialysis exchanges with, however, a special UF data collection protocol to improve the accuracy of computer simulation: at least one dwell of 2–4 h, one of 4–7 h, and one of more than 7 h. The fluid transport model was applied to the pooled UF volume for fluid kinetics simulation, and the data from the following day’s UF records using the same glucose concentration and dwell time were used to evaluate reliability and accuracy of the simulated UF value. Results: Fifty-two chronic peritoneal dialysis patients were included in the present study. All of the UF data could be used in the computer simulation, and there was a significant negative correlation between fluid absorption rate (Ke; see text) and actual UF volume on the following day using a glucose concentration of 1.5% and a dwell time of 4 h (r = –0.336, p < 0.05). The estimated UF values correlated significantly with the actually measured UF values. The variability of the results, expressed by the width between the 95% limits of agreement, fell within –139.2 to 131.9 ml, while the mean difference was –3.7 ml. Conclusions: Our present study showed that varying the peritoneal dwell time was a patient-friendly UF data collection protocol for continuous ambulatory peritoneal dialysis patients on a fixed dialysis schedule. Applying the fluid transport model and nonlinear least squares regression analysis to pooled UF values might be a good and simple way to predict the peritoneal UF capacity. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: To investigate the anti-tumor effect of microRNA-194 (miR-194) and possible relationship with profilin 2. Methods: The expressions of miR-194 and profilin 2 were investigated via bioinformatic analysis and were further verified using quantitative real-time polymerase chain reaction (qRT-PCR) in both normal and non-small cell lung cancer (NSCLC) cells. Dual luciferase reporter assay, together with transfection, was applied to determine the effect of miR-194 and profilin 2 on proliferation, migration and invasion, and its underlying mechanisms. Results: Relatively low expression of miR-194 and high expression of profilin 2 in cancerous lung tissue were found through bioinformatic analysis and further confirmed by qRT-PCR on normal and NSCLC cell lines. Profilin 2 was the direct target of miR-194. Also, miR-194 overexpression inhibited the proliferation, migration and invasion of NSCLC cells, and this suppressive effect was partially reversed by transfection of pcDNA3.1-PFN2 plasmid. Conclusion: The results show that miR-194 plays a tumor suppressor role in NSCLC development. It inhibits the proliferation, migration and invasion of NSCLC cells via profilin 2 suppression. Interventions targeting the miR-194/profilin 2 axis may therefore serve as a clinical strategy for the prevention and treatment of NSCLC metastases. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus-1 (HIV-1) infection currently requires lifelong therapy with drugs that are used in combination to control viremia. The indole-3-glyoxamide 6 was discovered as an inhibitor of HIV-1 infectivity using a phenotypic screen and derivatives of this compound were found to interfere with the HIV-1 entry process by stabilizing a conformation of the virus gp120 protein not recognized by the host cell CD4 receptor. An extensive optimization program led to the identification of temsavir (31), which exhibited an improved antiviral and pharmacokinetic profile compared to 6 and was explored in phase 3 clinical trials as the phosphonooxymethyl derivative fostemsavir (35), a prodrug designed to address dissolution- and solubility-limited absorption issues. In this drug annotation, we summarize the structure-activity and structure-liability studies leading to the discovery of 31 and the clinical studies conducted with 35 that entailed the development of an extended release formulation suitable for phase 3 clinical trials. [ABSTRACT FROM AUTHOR]

To improve the selectivity, delivery, and activity of ferric (Fe) anticancer agents, we design prodrugs based on N-donor residues of the human serum albumin (HSA) carrier IIA subdomain. We synthesized six Fe(III) compounds derived from 2-hydroxy-1-naphthaldehyde thiosemicarbazone (7-12). HSA complex structure revealed that Fe compound binds to the hydrophobic cavity in the HSA IIA subdomain. Lys199 and His242 of HSA replace the two Cl atoms of Fe compound, coordinating with Fe3+. In vivo data revealed that compound 12 and HSA-12 complex inhibit the growth of the liver tumor and that the HSA-12 complex has stronger targeting ability and therapeutic efficacy than compound 12 alone. In addition, our results have shown that compound 12 and HSA-12 complex induce Bel-7402 cell death possible by several mechanisms. [ABSTRACT FROM AUTHOR]

AbstractA Chinese herbal preparation, Qing'E formula (QEF), has been used clinically for treating osteoporosis in postmenopausal women by virtue of its kidney-invigorating function; however, no evidence base links QEF to estrogen replacement therapy. In this study, we undertake a characterization of estrogenic activity of QEF using an in vivomodel of ovariectomized (OVX) mice together with in vitrostudies with the MCF-7 cells for further molecular characterization. OVX mice were treated intragastrically with QEF at doses of 0.85, 1.7, and 3.4 g/kg per day for 4 weeks. QEF treatments restored the estrus cycle and demonstrated significant estrogenic activity, as indicated by reversal of uterine atrophy (six-fold increase in uterine weight), reduction in rectal temperature, and increased expression (1.6-fold) of estrogen receptors (ERs) in the uterus. Notably, the largest changes in these three parameters were found at the lowest dose. At the highest dose of QEF, significant changes were found in adrenal gland weight (30% increase), serum estradiol (E2) (60% increase), and luteinizing hormone (LH) (17% decrease) compared with untreated OVX controls. The data suggest estrogenic responses induced by QEF show tissue variation that reflects different affinities of ERs for QEF components. QEF could significantly induce luciferase expression (2.7-fold compared with control) from an estrogen response element luciferase reporter and induced expression of ERα and ERβ (1.2-fold and 1.7-fold respectively) in MCF-7 cells. Both activities were inhibited 80–90% by the estrogen antagonist ICI 182,780. This study demonstrates that QEF activity is mediated through estrogenic components and provides an evidence base for QEF treatment of postmenopausal symptoms. [ABSTRACT FROM AUTHOR]