S-Adenosylmethionine attenuates lipopolysaccharide-induced liver injury by downregulating the Toll-like receptor 4 signal in Kupffer cells

Purpose

S-Adenosylmethionine (SAM) is beneficial for lipopolysaccharide (LPS)-induced liver injury, but its molecular basis is not fully understood. The present study was carried out to investigate the effects of SAM on LPS signal transduction and its possible mechanism.

Methods

An animal model of LPS-induced liver injury was established by intraperitoneally injecting mice with 10 mg/kg LPS pretreatment with or without SAM (170 μmol/kg body weight). Toll-like receptor 4 (TLR4) protein expression in liver tissues and the tumor necrosis factor alpha (TNF-α) secretion level in serum were detected by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. Then, Kupffer cells (KCs) were isolated and challenged with LPS, with or without SAM pretreatment (1,000 μM), and the expressions of TLR4 and myeloid differentiation primary response protein (MYD88) were assayed at the mRNA and protein levels. The activities of nuclear factor-kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) were also analyzed using Western blotting.

Results

SAM significantly improved the survival rate of endotoxemic mice (p < 0.05) and decreased TNF-α levels in serum (p < 0.05). Simultaneously, SAM also attenuated LPS-induced liver injury and expression of TLR4 and MYD88 in the hepatic sinusoid. Moreover, TLR4 and MYD88 gene and protein expressions were downregulated by SAM pretreatment in LPS-stimulated KCs. Finally, SAM did not affect NF-κB-p65 translocation into the nucleus (p > 0.05), but significantly inhibited p38 MAPK activation (p < 0.05).

Conclusions

SAM attenuated liver injury and improved the survival rate in endotoxemic mice by decreasing the TNF-α expression. The downregulative effect of SAM on TNF-α was mediated by suppressing activation of the TLR4/MAPK signaling pathway.     

A Randomized,Double-Blind,Placebo-Controlled Study of Rebamipide for Gastric Mucosal Injury Taking Aspirin With or Without Clopidogrel

Introduction

Antithrombotic drugs, such as low-dose aspirin (LDA) and clopidogrel, can cause upper gastrointestinal complications.

Aim

The goal of the present study was to investigate whether a mucosal-protective agent, rebamipide, could prevent gastric mucosal injuries induced by LDA with or without clopidogrel in healthy subjects.

Materials and Methods

A randomized, double-blind, placebo-controlled trial was performed with 32 healthy male volunteers. Subjects were randomly assigned to a 14-day course of one of the following regimens: group A, placebo (tid) + LDA; group B, rebamipide (100 mg tid) + LDA (100 mg once-daily); group C, placebo + LDA + clopidogrel (75 mg once-daily); or group D, rebamipide + LDA + clopidogrel. The grade of gastric mucosal injuries was evaluated by esophagogastroduodenoscopy before and after dosing (on day 0 and day 14), and the grade of gastric mucosal injury was assessed according to the modified Lanza score. Subjective symptoms were assessed using the Gastrointestinal Symptom Rating Scale (GSRS). A rapid urease test was performed on day 0, and blood tests were performed on day 0 and day 14.

Results

Rebamipide significantly inhibited gastric mucosal injury induced by LDA alone or by LDA plus clopidogrel when compared with placebo in healthy subjects. GSRS score and hemoglobin level were not significantly different among the four groups.

Conclusions

Rebamipide is useful for the primary prevention of gastric mucosal injury induced by LDA alone or by LDA plus clopidogrel in healthy subjects.     

Epigallocatechin Gallate Does Not Accelerate the Early Phase of Liver Regeneration After Partial Hepatectomy in Rats

Background

Two-thirds partial hepatectomy (PHx) is an established model for the study of liver regeneration after resection. This process is accompanied by oxidative stress.

Aims

In our study, we tested the effect of epigallocatechin gallate (EGCG), a green tea antioxidant, on the early phase of liver regeneration after PHx.

Methods

Male Wistar rats were divided into five groups: (I) laparotomy + water for intraperitoneal injections, (II) laparotomy + EGCG 50 mg/kg body weight, (III) PHx + water for injections, (IV) PHx + EGCG 20 mg/kg and (V) PHx + EGCG 50 mg/kg, for 3 consecutive days. The rats were killed 24 h after surgery. Biochemical analysis of rat sera was performed. Histological samples were stained with hematoxylin & eosin and bromodeoxyuridine (BrdU). In hepatectomized rats, we also measured plasma malondialdehyde, tissue malondialdehyde, glutathione and cytokines levels, the activity of caspases 3/7, expression of Nqo-1 and HO-1 genes at the mRNA level, and expression of p21, p-p27 and p-p53 genes at the protein level.

Results

We observed lower accumulation of BrdU in group V when compared to groups III and IV. The activity of caspases 3/7 and expression of p-p53 were lower in group V than in groups III and IV. Tissue levels of IL-6 were lower in group V when compared to group III. Significant differences were not noted in other parameters.

Conclusions

Administration of EGCG did not stimulate early phase liver regeneration in rats after PHx. There was even lower DNA synthesis in the group treated with a high dose of EGCG.     

Clinicopathologic characteristics and molecular subtypes of invasive papillary carcinoma of the breast: a large case study

Purpose

Although patients with invasive papillary carcinoma (IPC) often have favorable prognoses, it remains unclear whether this special type of breast cancer represents a distinct morphological entity with its own biological features and clinical behavior distinct from those of invasive ductal carcinoma (IDC) and whether its four molecular subtypes are associated with different prognoses.

Methods

The study is a retrospective analysis of a large patient cohort from a single institution. 284 IPC samples were collected from January 2000 to May 2011. 300 IDC cases were selected randomly from 13,428 cases of IDC during the same periods. We assessed the clinicopathologic characteristics, molecular features, and prognostic value of IPC (n = 284) and compared them to those of IDC (n = 300). Clinicopathologic features and survival status of the four subtypes of IPC were also evaluated.

Results

IPC differed from IDC with respect to age upon diagnosis, tumor grade, lymph node status, and menopausal status (P < 0.05). IPC was associated with a better 5-year overall survival rate (OS) (92.77 vs. 87.95 %) and disease-free survival rate (DFS) (87.95 vs. 80.72 %) than IDC. Tumors of the luminal A subtype had a better 5-year OS (97.78 %) and DFS (95.56 %) than other subtypes.

Conclusions

The biologic behavior of IPC is more favorable to patient outcome than that of IDC. The chance of pure IPC causing death without an intervening event of a different histologic type is exceptionally low. Luminal A subtypes have better outcomes when compared to the other subtypes.     

The Caspase 1 Inhibitor VX-765 Protects the Isolated Rat Heart via the RISK Pathway

Purpose

Protecting the heart from ischaemia-reperfusion (IR) injury is a major goal in patients presenting with an acute myocardial infarction. Pyroptosis is a novel form of cell death in which caspase 1 is activated and cleaves interleukin 1β. VX-785 is a highly selective, prodrug caspase 1 inhibitor that is also clinically available. It has been shown to be protective against acute IR in vivo rat model, and therefore might be a promising possibility for future cardioprotective therapy. However, it is not known whether protection by VX-765 involves the reperfusion injury salvage kinase (RISK) pathway. We therefore investigated whether VX-765 protects the isolated, perfused rat heart via the PI3K/Akt pathway and whether protection was additive with ischaemic preconditioning (IPC).

Methods

Langendorff-perfused rat hearts were subject to ischaemia and reperfusion injury in the presence of 30 μM VX-765, with precedent IPC, or the combination of VX-765 and IPC.

Results

VX-765 reduced infarct size (28 vs 48% control; P?<?0.05) to a similar extent as IPC (30%; P?<?0.05). The PI3 kinase inhibitor, wortmannin, abolished the protective effect of VX-765. Importantly in the model used, we were unable to show additive protection with VX-765 + IPC.

Conclusions

The caspase 1 inhibitor, VX-765, was able to reduce myocardial infarction in a model of IR injury. However, the addition of IPC did not demonstrate any further protection.

     

Angiotensin Converting Enzyme-Inhibitor Reduces Colitis Severity in an IL-10 Knockout Model

Background

We previously demonstrated angiotensin converting enzymes (ACE) over-expression in a dextran-sodium sulfate colitis model; ACE inhibitor (ACE-I) treatment reduced colitis severity in this model. However, ACE-I has not been tested in more immunologically relevant colitis models.

Aim

We hypothesized that ACE-I would decrease disease severity in an IL-10 knockout (?/?) colitis model.

Methods

Colitis was induced by giving 10-week old IL-10?/? mice piroxicam (P.O.) for 14 days. The ACE-I enalaprilat was given transanally at a dose of 6.25 mg/kg for 21 days. Prednisolone (PSL) with or without enalaprilat were used as therapeutic, comparative groups. All groups were compared to a placebo treated group. Outcome measures were clinical course, histology, abundance of pro-inflammatory cytokines/chemokines, and epithelial barrier function.

Results

Enalaprilat exhibited better survival (91 %) versus other treatment groups (PSL: 85.7 %, PSL + ACE-I: 71.4 %, placebo: 66.6 %). The ACE-I and PSL + ACE-I groups showed significantly better histological scores versus placebo mice. ACE-I and the PSL groups significantly reduced several pro-inflammatory cytokines versus placebo mice. FITC-dextran permeability was reduced in the ACE-I and PSL + ACE-I groups. Blood pressure was not affected in ACE-I treated mice compared to placebo mice.

Conclusions

ACE-I was effective in reducing severity of colitis in an IL-10?/? model. The addition of prednisolone minimally augmented this effect. The findings suggest that appropriately dosed ACE-I with or without steroids may be a new therapeutic agent for colitis.     

Probucol Ameliorates the Development of Nonalcoholic Steatohepatitis in Rats Fed High-Fat Diets

Aims

We sought to evaluate the effects of probucol on steatohepatitis and associated molecular mechanisms in a rat model of nonalcoholic steatohepatitis (NASH) induced by high-fat diet (HFD).

Methods

Forty male rats weighing 100–120 g were randomly assigned to the following treatments (n = 10 for each treatment): standard diet + normal saline (NC group), standard diet + 500 mg/kg/day probucol (NP group), HFD + normal saline (HD group), and HFD + 500 mg/kg/day probucol (HP group). All animals received the above treatments for 15 weeks. Lipid metabolism and steatohepatitis were assessed. Systemic insulin resistance, oxidative stress status, serum tumor necrosis factor-alpha (TNF-α) and adiponectin levels, and gene expression were examined.

Results

High-fat feeding resulted in macrovesicular steatosis, lobular inflammation, and hepatocellular ballooning degeneration in the liver, coupled with increased concentrations of serum aspartate aminotransferase and alanine aminotransferase. Probucol exposure attenuated the biochemical and histological changes comparable with NASH. Moreover, probucol treatment significantly prevented the elevations of serum total cholesterol, low-density lipoprotein, and high-density lipoprotein and the increase in the expression of numerous lipid metabolism-related genes in HFD-fed rats. There were increased insulin sensitivity and serum adiponectin levels and enhanced hepatic AMP-activated protein kinase phosphorylation in the HP group. Probucol lessened the HFD-induced elevation of serum TNF-α and hepatic malondialdehyde and reduced antioxidant enzymatic activities.

Conclusions

Probucol shows beneficial effects on HFD-induced steatohepatitis by improving insulin resistance and attenuating oxidative stress and systemic inflammation.     

Dipeptidyl Peptidase IV Inhibition Prevents the Formation and Promotes the Healing of Indomethacin-Induced Intestinal Ulcers in Rats

Backgrounds and Aims

We studied the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) as a possible therapy for non-steroidal anti-inflammatory drug (NSAID)-induced intestinal ulcers. Luminal nutrients release endogenous GLP-2 from enteroendocrine L cells. Since GLP-2 is degraded by dipeptidyl peptidase IV (DPPIV), we hypothesized that DPPIV inhibition combined with luminal administration of nutrients potentiates the effects of endogenous GLP-2 on intestinal injury.

Methods

Intestinal injury was induced by indomethacin (10 mg/kg, sc) in fed rats. The long-acting DPPIV inhibitor K579 was given intragastrically (ig) or intraperitoneally (ip) before or after indomethacin treatment. l-Alanine (l-Ala) and inosine 5′-monophosphate (IMP) were co-administered ig after the treatment.

Results

Indomethacin treatment induced intestinal ulcers that gradually healed after treatment. Pretreatment with ig or ip K579 given at 1 mg/kg reduced total ulcer length, whereas K579 at 3 mg/kg had no effect. Exogenous GLP-2 also reduced intestinal ulcers. The preventive effect of K579 was dose-dependently inhibited by a GLP-2 receptor antagonist. Daily treatment with K579 (1 mg/kg), GLP-2, or l-Ala + IMP after indomethacin treatment reduced total ulcer length. Co-administration (ig) of K579 and l-Ala + IMP further accelerated intestinal ulcer healing.

Conclusion

DPPIV inhibition and exogenous GLP-2 prevented the formation and promoted the healing of indomethacin-induced intestinal ulcers, although high-dose DPPIV inhibition reversed the preventive effect. Umami receptor agonists also enhanced the healing effects of the DPPIV inhibitor. The combination of DPPIV inhibition and luminal nutrient-induced GLP-2 release may be a useful therapeutic tool for the treatment of NSAIDs-induced intestinal ulcers.     

Tetradecylthioacetic Acid Attenuates Inflammation and Has Antioxidative Potential During Experimental Colitis in Rats

Background

The fatty acid analogue tetradecylthioacetic acid (TTA) is a moderate pan-activator of peroxisome proliferator-activated receptors (PPARs), and has in previous studies showed potential as an antioxidant and anti-inflammatory agent, both through PPAR and non-PPAR mediated mechanisms.

Aims

This study aimed to determine whether TTA could alleviate dextran sulfate sodium (DSS)-induced colitis in rats.

Methods

Male Wistar rats were fed a control diet (control- and DSS-group) or a diet supplemented with 0.4 % TTA (TTA + DSS-group) for 30 days, and DSS was added to the drinking water the last 7 days. Ultrasound measurements were performed at day 29. At day 30, rats were sacrificed and the distal colon was removed for histological evaluation and measurement of cytokine levels, oxidative damage, and gene expression.

Results

The disease activity index was not improved in the TTA + DSS-group compared to the DSS-group. However, ultrasound measurements showed a significantly reduced colonic wall thickening in the TTA + DSS-group. TNF-α, IL-1β, and IL-6 were reduced at the protein and mRNA level in the TTA + DSS-group. Moreover, TTA-treated rats demonstrated reduced colonic oxidative damage, while inducible nitric oxide synthase 2 mRNA expression was elevated in both the DSS- and TTA + DSS-groups. PPARγ signaling may be involved in the anti-inflammatory response to TTA, as Pparg mRNA expression was significantly upregulated in colon.

Conclusions

This study demonstrated that the pan-PPAR agonist TTA reduced colonic oxidative damage and cytokine levels in a rat model of colitis, and its potential to ameliorate colitis should be further explored.     

Peritoneal metastases of lower gastrointestinal tract origin: a comparative study of patient outcomes following cytoreduction and intraperitoneal chemotherapy

Background

Cytoreductive surgery (CS) combined with intraperitoneal chemotherapy (IPC) is a multimodal approach to the treatment of peritoneal metastases (PM) of lower gastrointestinal origin. This study examines patient outcomes and critically evaluates its patterns of recurrences relative to the site of metastatic origin.

Methods

Patients treated with CS/IPC from 2000 to 2012 where PM arose from a primary tumour of the appendix, colon and rectum were identified from a prospective database for retrospective evaluation. The primary end points were survival (overall and disease-free), and secondary end points include patterns of recurrence and prognostic factors associated with overall outcomes.

Results

Two hundred and eleven patients were followed up for a median of 23.3 months (range 1–156). Overall median survival was 46.8 months, and the 1-, 3-, 5-year survival rates were 87, 56 and 42 %, respectively. The 5-year survival of patients with appendiceal, colonic and rectal PM was 55, 33 and 20 %, respectively. Tumour origin was the only independent prognostic factor associated with overall survival (p = 0.03). Recurrences were more common in patients of colorectal origin over appendiceal origin (p < 0.001) and were more likely to be of a systemic nature (p = 0.05).

Conclusion

CS/IPC provides an option for improved survival in patients with PM of lower gastrointestinal origin and appears to be most promising in patients with disease of appendiceal origin.     

Transcriptional Profiling of Peripheral Blood in Pancreatic Adenocarcinoma Patients Identifies Diagnostic Biomarkers

Background

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with poor survival rates. Fast detection of PDAC appears to be the most relevant strategy to improve the long-term survival of patients.

Aims

Our objective was to identify new markers in peripheral blood that differentiates between PDAC patients and healthy controls.

Methods

Peripheral blood samples from PDAC patients (n = 18) and controls (n = 18) were analyzed by whole genome cDNA microarray hybridization. The most relevant genes were validated by quantitative real-time PCR (RT-qPCR) in the same set of samples. Finally, our gene prediction set was tested in a blinded set of new peripheral blood samples (n = 30).

Results

Microarray studies identified 87 genes differentially expressed in peripheral blood samples from PDAC patients. Four of these genes were selected for analysis by RT-qPCR, which confirmed the previously observed changes. In our blinded validation study, the combination of CLEC4D and IRAK3 predicted the diagnosis of PDAC with 93 % accuracy, with a sensitivity of 86 % and specificity of 100 %.

Conclusions

Peripheral blood gene expression profiling is an useful tool for the diagnosis of PDAC. We present a validated four-gene predictor set (ANKRD22, CLEC4D, VNN1, and IRAK3) that may be useful in PDAC diagnosis.     

Remote Cardioprotection by Transfer of Coronary Effluent from Ischemic Preconditioned Rabbit Heart Preserves Mitochondrial Integrity and Function via Adenosine Receptor Activation

Background

Coronary effluent from an isolated perfused heart undergoing ischemic preconditioning can be transferred to precondition another naïve isolated heart. We investigated the effects of this effluent on mitochondrial integrity and function following a global infarct model of ischemia/reperfusion and the role of adenosine in this model of remote preconditioning.

Methods and Results

Coronary effluent from isolated perfused rabbit hearts was collected prior to (control effluent) and during three cycles of 5-min ischemia and 10-min reperfusion (IPC effluent). Adenosine concentration was significantly increased in IPC effluent (2.6?±?1.1 μM) versus control effluent (0.21?±?0.06 μM, P?<?0.01). Infarct size (% necrotic LV mass) after 30-min global ischemia and 90-min reperfusion was significantly reduced in hearts preconditioned with IPC effluent (IPC_eff, 23?±?7 %) and control effluent supplemented with 2.5 μM exogenous adenosine (C_eff + 2.5 μM ADO, 25?±?10 %) when compared to control effluent perfused hearts (C_eff, 41?±?8 %, P?<?0.05). Compared to C_eff mitochondria, IPC_eff mitochondria had preserved complex I/State3 and complex IV/State 3 respiration and outer membrane integrity, and reduced cytochrome c release. In contrast, C_eff + 2.5 μM ADO mitochondria had improved state 2 respiration and coupling to oxidative phosphorylation, reduced reactive oxygen species production and preserved outer membrane integrity. Administration of adenosine receptor blocker 8-(p-sulfophenyl)theophylline abolished the infarct limiting effect (46?±?7 %) and the mitochondrial integrity and function preservation of IPC effluent.

Conclusion

Remote cardioprotection by IPC effluent preserves mitochondrial integrity and function in an adenosine receptor dependent mechanism, and although infarct size reduction can be mimicked by adenosine, IPC effluent contains additional factor(s) contributing to modulation of the mitochondrial response to ischemia/reperfusion injury.     

The importance of gender in patients with peritoneal metastases of appendiceal origin treated by cytoreduction and intraperitoneal chemotherapy: an analysis of 257 consecutive patients from an Australian centre

Background and objectives

In the setting of colorectal cancer, female gender has been associated with superior long-term outcomes. Our aim is to investigate the gender differences for metastatic epithelial neoplasms of the appendix treated by cytoreductive surgery (CS) and intraperitoneal chemotherapy (IPC).

Methods

The survival outcomes of patients treated with CS/IPC from 1996 to 2013 at St. George Hospital, Sydney, Australia, for peritoneal metastases of appendiceal origin were retrospectively analysed.

Results

Two hundred and fifty-seven consecutive patients were followed for a median of 35.3 months. Baseline characteristics between genders were comparable, including age (p = 0.13) and peritoneal cancer index (p = 0.94). Median overall survival (OS) and progression-free survival (PFS) was not reached (NR) and 44.4 months, with a 3-, 5- and 10-year survival of 82, 74 and 64 %. OS and PFS for females was NR and 50.7 months, compared to NR (p = 0.007) and 31.5 months for males (p = 0.07). Three-, 5- and 10-year survival rates for females were 88, 84 and 72 % compared to 74, 61 and 53 % for males.

Conclusion

Observed gender differences for neoplasms of the appendix may direct future research in gender-specific tumour markers and the development of adjuvant therapies to improve patient outcomes.     

Losartan Supports Liver Regrowth via Distinct Boost of Portal Vein Pressure in Rodents with 90 % Portal Branch Ligation

Objectives

The study used a model of 90 % portal branch ligation (PBL) in rats to study the effect of losartan on portal vein pressure (PVP) and liver regeneration in rats after PBL.

Methods

A total of 144 male Sprague–Dawley rats were arbitrarily designated into three treatment method groups: a sham operation group (Sham), a PBL treatment group (PBL), and a PBL plus losartan treatment group (PBL + L). Losartan (2 mg/day) was intragastrically gavaged 3 days before the PBL or sham operation to time points of study.

Results

Both the PBL and PBL + L groups showed an intense surge in PVP after PBL treatment, peaking at 12 h postsurgery, then lessening progressively afterwards. PVP was substantially greater in these two groups compared with the Sham group at 6–72 h postsurgery (p < 0.01). Compared with the PBL group, the PBL + L group showed a noticeable reduction in PVP 6–48 h postsurgery (p < 0.05); the PBL group showed considerably raised levels of plasma ALT and AST 6–72 h postsurgery (p < 0.01). Compared to the PBL group, the PBL + L group showed drastically reduced plasma ALT and AST levels 12–72 h postsurgery (p < 0.05).

Conclusions

Losartan supports liver regeneration in 90 % of rats that underwent PBL. The mechanism may be related to losartan’s ability to regulate PVP and increase serum hepatocyte growth factor levels.     

A Rapid and Accurate Method to Detect Active Small Bowel Gastrointestinal Bleeding on Video Capsule Endoscopy

Background

Video capsule endoscopy (VCE) is indicated to evaluate for suspected small bowel bleeding, but “standard view” (SV) evaluation is time-consuming. Rapid Reader 6.0 software (Given Imaging, Duluth GA) contains two computer algorithmic systems: (1) “Quickview” (QV) which automatically skips similar images and (2) a pixel analysis program that identifies suspected blood (SBI). Combining the two modalities (QV + SBI) may provide a faster modality to assess for active small bowel bleeding.

Aims

This study was designed to assess the accuracy of QV + SBI for small bowel bleeding compared to SV findings.

Methods

This is a retrospective, case–control study at a single tertiary care referral hospital including all patients with VCE performed for suspected small bowel bleeding from 4/2007 to 3/2011. All studies were previously read using SV by one of two experienced faculty (CS, DR). The primary outcome was diagnostic accuracy of QV + SBI in assessing for active small bowel bleeding compared to SV.

Results

A total of 116 VCE were included, 28 with active small bowel bleeding identified by original SV. Using QV + SBI, all 28 VCEs with active small bowel bleeding were identified. The sensitivity of QV + SBI to detect active bleeding was 100 %, while the specificity was 93–94 %. The mean time to identify landmarks and read the entire study was 3 min 20 s.

Conclusions

The QV + SBI reading format of VCE is an efficient, highly sensitive modality to assess for potential small bowel bleeding.     

Elevation of KL-6 serum levels in clinical trials of tumor necrosis factor inhibitors in patients with rheumatoid arthritis: a report from the Japan College of Rheumatology Ad Hoc Committee for Safety of Biological DMARDs

Objective

The associations between elevated levels of serum Krebs von den Lungen-6 (KL-6) and treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF) inhibitors were investigated in five Japanese clinical trials.

Methods

Percentages and incidence rates were calculated for elevated serum KL-6 levels. Adverse events associated with elevated levels of serum KL-6 were investigated.

Results

In RISING, a clinical trial for infliximab, 15.6 % of the enrolled patients met criterion B (KL-6 ≥500 U/ml and >1.5-fold increase over the baseline value) by week 54. In HIKARI, 7.8 % of the certolizumab pegol (CZP) group and 0 % of the placebo group met criterion B during the double-blind (DB) period (p = 0.003). In J-RAPID, 8.4 % of the methotrexate (MTX) + CZP and 3.9 % of the MTX + placebo groups met criterion B during the DB period. In GO-MONO, 1.8 % of the golimumab (GLM) and 1.3 % of the placebo groups met criterion B during the DB period. In GO-FORTH, 7.1 % of the MTX + GLM and 0 % of the MTX + placebo groups met criteron B during the DB period (p = 0.017). No adverse events accompanied the elevation of serum KL-6 levels in 95.7 % of these patients.

Conclusion

Serum KL-6 levels may increase during anti-TNF therapy without significant clinical events. In these patients, continuing treatment with TNF inhibitors under careful observation is a reasonable option.     

Elevated circulating levels of tissue factor-positive microvesicles are associated with distant metastasis in lung cancer

Purpose

Microvesicles (MV) in the blood stream are associated with distant metastasis in cancer. Platelet or endothelial cell-related MV actively participate in thrombogenesis, which is an important step in cancer metastasis. This study investigated the correlations between MV levels of platelet-poor plasma and distant metastasis in lung cancer.

Methods

Platelet-poor plasma from 44 treatment-naive lung cancer (23 with distant metastasis) and 19 normal subjects was used to determine the levels of glycoprotein Iβ (CD42) + platelet MV (PMV), P-selectin (CD62P) + PMV, VE-cadherin (CD144) + endothelial MV (EMV), tissue factor (CD142) + MV, thrombin-antithrombin complex and vascular endothelial growth factor (VEGF).

Results

The level of CD142 + MV was significant (odds ratio 5.86, 95 % confidence interval 1.31–38.3) in predicting distant metastasis in lung cancer, and a cutoff value of 2.668 (after logarithm transformation) in the ROC curve had a specificity of 90 % and a sensitivity of 59 %. The presence of distant metastasis showed a significant correlation between CD144 + EMV and VEGF, but not between CD144 + EMV and CD42 + PMV or CD62P + PMV in lung cancer subjects.

Conclusions

The finding of CD142 + MV in platelet-poor plasma may be useful for suggesting distant metastasis in lung cancer. In addition to thrombogenesis, interaction between VE-cadherin and VEGF may be needed for successful metastasis in lung cancer.     

Role of inducible nitric oxide synthase in myocardial ischemia-reperfusion injury in sleep-deprived rats

Introduction

REM sleep deprivation (SD) decreases tolerance of the rat heart to ischemia-reperfusion (IR) injury; the underlying mechanisms, however, are unknown. This study aimed at determining whether changes in iNOS, Bax, and Bcl-2 gene expression are involved in this detrimental effect.

Method

SD was induced by flowerpot technique for a period of 4 days. This method is simple and able to induce sleep fragmentation which occurs as one of the sleep disorder symptoms in clinical conditions. The hearts of control and SD rats were perfused in Langendorff apparatus and subjected to 30 min ischemia, followed by 90 min reperfusion. The hemodynamic parameters (left ventricular developed pressure (LVDP), and ± dp/dt), NOx (nitrite + nitrate) level, infarct size, and mRNA expression of iNOS, Bax, and Bcl-2 were measured after IR.

Results

SD rats had lower recovery of post-ischemic LVDP (32.8 ± 2.5 vs. 51.5 ± 2.1 mmHg; P < 0.05), + dp/dt (1555 ± 66 vs. 1119.5 ± 87 mmHg/s; P < 0.05) and ? dp/dt (1437 ± 65 vs. 888 ± 162 mmHg/s; P < 0.05). SD rats also had higher NOx levels (41.4 ± 3.1 vs. 22.4 ± 3.6 μmol/L; P < 0.05) and infarct size (64.3 ± 2.3 vs. 38.3 ± 1.6%; P < 0.05) after IR, which along with LVDP, ± dp/dt restored to near normal status in the presence of aminoguanidine, a selective iNOS inhibitor. Following IR, expression of iNOS and Bax increased and Bcl-2 decreased (502, 372, and 54%, respectively) in SD rats; whereas in the presence of aminoguanidine, expression of iNOS and Bax significantly decreased and Bcl-2 increased (165, 168, and 19%, respectively).

Conclusion

Higher expression of iNOS and subsequent increase in apoptosis in the hearts after IR may contribute to less tolerance to myocardial IR injury in SD rats.

     

Different sequential approaches of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in treating ovarian cancer with malignant ascites

Background and objectives

Treatment for malignant ascites in advanced ovarian cancer (OC) patients remains controversial. The objective of this study was to investigate the efficacy of combined continuous circulatory hyperthermic intraperitoneal chemotherapy (HIPEC) preceded or followed by cytoreductive surgery (CRS) for malignant ascites in OC patients.

Methods

Female OC patients (n = 32) with malignant ascites were divided based on stable (n = 17) or unstable (n = 15) vital signs. Stable patients were treated with CRS immediately followed by HIPEC (CRS + HIPEC). Unstable patients were treated using B-mode ultrasound-guided HIPEC followed by delayed CRS upon vital sign stability (HIPEC + dCRS). All patients were followed up until death or until December 2012.

Results

Median follow-up was 29 months. All patients showed ascite regression [objective remission rates (ORR) = 100 %]. Among stable patients, CRS + HIPEC was successful in 14/17 (83.4 %). Among unstable patients, HIPEC + dCRS was successful in 13/15 (86.7 %). Median survival times were 19 and 17 months in the stable and unstable groups, respectively. No significant differences in CRS rates, ascites ORR, Karnofsky performance status scores, or survival rates were observed between groups (P > 0.05).

Conclusion

Cytoreductive surgery with immediate HIPEC and HIPEC with dCRS, determined by vital sign stability, may lead to similar outcomes in OC patients with malignant ascites.