Ping Wang

Does Postoperative Complication Have a Negative Impact on Long-Term Outcomes Following Hepatic Resection for Colorectal Liver Metastasis?: A Meta-Analysis

BackgroundThe negative impact of postoperative complications (POCs) on long-term outcomes is well documented for several cancer surgeries, but conclusive evidence has yet to be provided on the influence of POCs on long-term oncological outcomes after hepatic resection for colorectal liver metastasis (CRLM).MethodsStudies published through February 2012 evaluating the oncological impact of POCs after hepatectomy for CRLM were identified by an electronic literature search. Finally, 4 studies were identified and included in the meta-analysis. The main outcome measures were 5-year disease-free survival (DFS) and overall survival (OS). A meta-analysis was performed using the DerSimonian-Laird random-effects models to compute odds ratio (OR) along with 95 % confidence intervals (95xa0% CI).ResultsThe outcomes of 2,280 patients were studied. Meta-analysis of 5-year DFS data extracted from three studies demonstrated a significant reduction in 5-year DFS after POCs, with an OR of 1.98 (95xa0% CIxa0=xa01.33–2.96; Pxa0=xa0.0008). Meta-analysis of 5-year OS data extracted from four studies demonstrated a significant reduction in 5-year OS after POCs, with an OR of 1.68 (95xa0% CIxa0=xa01.25–2.27; Pxa0=xa0.0006). No differences between study heterogeneity were observed in either the DFS or the OS analyses.ConclusionsThis study provides persuasive evidence that POCs following hepatic resection for CRLM have significant adverse oncological outcomes. These findings emphasize the need for meticulous surgical technique and careful perioperative management to minimize POCs.

Cold-inducible RNA-binding protein mediates neuroinflammation in cerebral ischemia.

BACKGROUNDnNeuroinflammation is a key cascade after cerebral ischemia. Excessive production of proinflammatory mediators in ischemia exacerbates brain injury. Cold-inducible RNA-binding protein (CIRP) is a newly discovered proinflammatory mediator that can be released into the circulation during hemorrhage or septic shock. Here, we examine the involvement of CIRP in brain injury during ischemic stroke.nnnMETHODSnStroke was induced by middle cerebral artery occlusion (MCAO). In vitro hypoxia was conducted in a hypoxia chamber containing 1% oxygen. CIRP and tumor necrosis factor-α (TNF-α) levels were assessed by RT-PCR and Western blot analysis.nnnRESULTSnCIRP is elevated along with an upregulation of TNF-α expression in mouse brain after MCAO. In CIRP-deficient mice, the brain infarct volume, induction of TNF-α, and activation of microglia are markedly reduced after MCAO. Using microglial BV2 cells, we demonstrate that hypoxia induces the expression, translocation, and release of CIRP, which is associated with an increase of TNF-α levels. Addition of recombinant murine (rm) CIRP directly induces TNF-α release from BV2 cells and such induction is inhibited by neutralizing antisera to CIRP. Moreover, rmCIRP activates the NF-κB signaling pathway in BV2 cells. The conditioned medium from BV2 cells exposed to hypoxia triggers the apoptotic cascade by increasing caspase activity and decreasing Bcl-2 expression in neural SH-SY5Y cells, which is inhibited by antisera to CIRP.nnnCONCLUSIONnExtracellular CIRP is a detrimental factor in stimulating inflammation to cause neuronal damage in cerebral ischemia.nnnGENERAL SIGNIFICANCEnDevelopment of an anti-CIRP therapy may benefit patients with brain ischemia.

The Effect of Intraoperative Rectal Washout on Local Recurrence after Rectal Cancer Surgery: A Meta-Analysis

BackgroundImplantation of exfoliated cancer cells has been suggested as a possible mechanism of local recurrence at the site of colorectal anastomosis. Intraoperative rectal washout has been suggested to eliminate free cancer cells; however, there is no conclusive evidence of a beneficial effect of intraoperative rectal washout on local recurrence after anterior resection of rectal cancer.MethodsStudies published through February 2012 evaluating the impact of intraoperative rectal washout for local recurrence or positive cytology from donuts wash were identified by an electronic literature search. A meta-analysis was performed using the DerSimonian-Laird random-effects models to compute risk ratio (RR) along with 95xa0% confidence intervals (CI).ResultsNine studies met the inclusion criteria, yielding a total of 5,395 patients. Eight studies evaluated overall local recurrence, including anastomotic recurrence, and five of the eight studies evaluated anastomotic recurrence separately. Two studies evaluated positive cytology from donuts wash. Local recurrence rate was 5.79xa0% in the washout group and 10.05xa0% in the no washout group—a difference that was statistically significant (RRxa0=xa00.57; 95xa0% CIxa0=xa00.46-0.71; Pxa0<xa00.00001). Rectal washout significantly reduced the risk of anastomotic recurrence (RRxa0=xa00.3; 95xa0% CIxa0=xa00.12-0.71; Pxa0=xa00.007). No influence of rectal washout was observed on positive cytology from donuts wash.ConclusionsFrom the results of this meta-analysis, it may be justified to recommend intraoperative rectal washout to prevent local recurrence in rectal cancer surgery.

Milk fat globule--EGF factor VIII ameliorates liver injury after hepatic ischemia-reperfusion.

BACKGROUNDnHepatic ischemia-reperfusion (I/R) injury is a serious clinical complication that may compromise liver function because of extensive hepatocyte loss. Therefore, thexa0development of novel and effective therapies for hepatic I/R is critical for the improvement of patient outcome. It has been previously shown that administration of milk fat globule-EGF factor VIII (MFG-E8), a membrane-associated secretory glycoprotein, exerts significant beneficial effects under acute inflammatory conditions through multiple physiological processes associated with tissue remodeling.nnnMETHODSnTo determine whether administration of recombinant human (rh) MFG-E8 attenuates liver injury in an animal model of hepatic I/R, male adult rats were subjected to 70% hepatic ischemia for 90 min, followed by reperfusion. At the beginning of reperfusion, rats were treated intravenously with normal saline (vehicle) or rhMFG-E8 (160xa0μg/kg) over a period of 30 min. MFG-E8 levels and various measurements were assessed 4 h after reperfusion. In addition, survival study was conducted in MFG-E8(-/-) and rhMFG-E8-treated wild-type (WT) mice using a total hepatic ischemia model.nnnRESULTSnLiver and plasma MFG-E8 protein levels were significantly decreased after hepatic I/R. Administration of rhMFG-E8 significantly improved liver injury, suppressed apoptosis, attenuated inflammation and oxidative stress, and downregulated NF-κB pathway. We also noticed that rhMFG-E8 treatment restored the downregulated PPAR-γ expression after hepatic I/R. MFG-E8(-/-) mice showed deterioration on survival and, in contrast, rhMFG-E8-treated WT mice showed a significant improvement of survival compared with vehicle-treated WT mice.nnnCONCLUSIONSnMFG-E8-mediated multiple physiological events may represent an effective therapeutic option in tissue injury following an episode of hepatic I/R.

Cold-Inducible RNA-Binding Protein Is an Important Mediator of Alcohol-Induced Brain Inflammation

Binge drinking has been associated with cerebral dysfunction. Ethanol induced microglial activation initiates an inflammatory process that causes upregulation of proinflammatory cytokines which in turn creates neuronal inflammation and damage. However, the molecular mechanism is not fully understood. We postulate that cold-inducible RNA-binding protein (CIRP), a novel proinflammatory molecule, can contribute to alcohol-induced neuroinflammation. To test this theory male wild-type (WT) mice were exposed to alcohol at concentrations consistent to binge drinking and blood and brain tissues were collected. At 5 h after alcohol, a significant increase of 53% in the brain of CIRP mRNA was observed and its expression remained elevated at 10 h and 15 h. Brain CIRP protein levels were increased by 184% at 10 h and remained high at 15 h. We then exposed male WT and CIRP knockout (CIRP−/−) mice to alcohol, and blood and brain tissues were collected at 15 h post-alcohol infusion. Serum levels of tissue injury markers (AST, ALT and LDH) were significantly elevated in alcohol-exposed WT mice while they were less increased in the CIRP−/− mice. Brain TNF-α mRNA and protein expressions along with IL-1β protein levels were significantly increased in WT mice, which was not seen in the CIRP−/− mice. In cultured BV2 cells (mouse microglia), ethanol at 100 mM showed an increase of CIRP mRNA by 274% and 408% at 24 h and 48 h respectively. Corresponding increases in TNF-α and IL-1β were also observed. CIRP protein levels were markedly increased in the medium, suggesting that CIRP was secreted by the BV2 cells. From this we conclude that alcohol exposure activates microglia to produce and secrete CIRP and possibly induce pro-inflammatory response and thereby causing neuroinflammation. CIRP could be a novel mediator of alcohol-induced brain inflammation.

Alcohol and hepatocyte-Kupffer cell interaction (Review)

Alcoholic liver disease accounts for 12,000 deaths per year in the United States and is the second leading indication for liver transplantation. It covers a spectrum of disease conditions ranging from steatosis and cirrhosis to hepatic malignancies. Epidemiological data clearly show a strong correlation between alcohol consumption and liver diseases. A large body of evidence has accumulated over the years in determining the molecular mediators of alcohol-induced liver injury. In this review, we provide an overview of such mediators, which include alcohol metabolites and reactive oxygen/nitrogen species, endotoxin via bacterial translocation from the gut and TNF-α, and highlight the role of the sympathetic nervous stimuli, norepinephrine and the α2A-adrenergic receptors in contributing to the deleterious effect observed in alcohol-induced hepatic dysfunction.

Association between insertion/deletion polymorphism in angiotensin-converting enzyme gene and acute lung injury/acute respiratory distress syndrome: a meta-analysis

BackgroundA previous meta-analysis reported a positive association between an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) and the risk of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Here, we updated this meta-analysis and additionally assessed the association of this polymorphism with ALI/ARDS mortality.MethodsWe searched electronic databases through October 2011 for the terms “angiotensin-converting enzyme gene”, “acute lung injury”, and “acute respiratory distress syndrome,” and reviewed all studies that reported the relationship of the I/D polymorphism in ACE with ALI/ARDS in humans. Seven studies met the inclusion criteria, comprising 532 ALI/ARDS patients, 3032 healthy controls, and 1432 patients without ALI/ARDS. We used three genetic models: the allele, dominant, and recessive models.ResultsThe ACE I/D polymorphism was not associated with susceptibility to ALI/ARDS for any genetic model. However, the ACE I/D polymorphism was associated with the mortality risk of ALI/ARDS in Asian subjects ( Palleleu2009<u20090.0001, Pdominantu2009=u20090.001, Precessiveu2009=u20090.002). This finding remained significant after correction for multiple comparisons.ConclusionsThere is a possible association between the ACE I/D polymorphism genotype and the mortality risk of ALI/ARDS in Asians.

The role of B-1 cells in inflammation

B-1 lymphocytes exhibit unique phenotypic, ontogenic, and functional characteristics that differ from the conventional B-2 cells. B-1 cells spontaneously secrete germline-like, repertoire-skewed polyreactive natural antibody, which acts as a first line of defense by neutralizing a wide range of pathogens before launching of the adaptive immune response. Immunomodulatory molecules such as interleukin-10, adenosine, granulocyte–macrophage colony-stimulating factor, interleukin-3, and interleukin-35 are also produced by B-1 cells in the presence or absence of stimulation, which regulate acute and chronic inflammatory diseases. Considerable progress has been made during the past three decades since the discovery of B-1 cells, which has improved not only our understanding of their phenotypic and ontogenic uniqueness but also their role in various inflammatory diseases including influenza, pneumonia, sepsis, atherosclerosis, inflammatory bowel disease, autoimmunity, obesity and diabetes mellitus. Recent identification of human B-1 cells widens the scope of this field, leading to novel innovations that can be implemented from bench to bedside. Among the vast number of studies on B-1 cells, we have carried out a literature review highlighting current trends in the study of B-1 cell involvement during inflammation, which may result in a paradigm shift toward sustainable therapeutics in various inflammatory diseases.

Recombinant human MFG-E8 ameliorates colon damage in DSS- and TNBS-induced colitis in mice.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the digestive system and typically requires lifelong medical care. Recombinant human MFG-E8 (rhMFG-E8) is a 364-amino acid protein, which promotes apoptotic cell clearance and reduces inflammation. This study investigates the therapeutic effect of rhMFG-E8 on two well-established mouse models of IBD. Acute mucosal injury leading to colitis was caused by exposing C57BL/6 mice to 4% dextran sodium sulfate (DSS) in the drinking water over 7 days, and BALB/c mice to a single intrarectal dose of 2.75u2009mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Upon clinical onset of colitis (day 2 in the DSS model and day 1 in the TNBS model), mice were treated with daily subcutaneous injections of rhMFG-E8 (60 or 120u2009μg/kg/day) or vehicle (saline) for 6 days. Treatment with rhMFG-E8 significantly attenuated colitis in both models in a dose-dependent way. Treatment of DSS-induced colitis with rhMFG-E8 (120u2009μg/kg/day) decreased weight loss by 59%, the colitis severity score by 71%, and colon shrinkage by 49% when compared with vehicle. Similarly, treatment of TNBS-induced colitis with rhMFG-E8 (120u2009μg/kg/day) decreased weight loss by 97%, the colitis severity score by 82%, and colon shrinkage by 62% when compared with vehicle. In both models, the colons of animals receiving rhMFG-E8 showed marked reduction in neutrophil infiltration, cytokine and chemokine expression, and apoptotic cell counts. In conclusion, rhMFG-E8 ameliorates DSS- and TNBS-induced colitis, suggesting that it has the potential to become a novel therapeutic agent for IBD.

BTG2 is an LXXLL-dependent co-repressor for androgen receptor transcriptional activity

The tumor suppressor gene, BTG2 has been down-regulated in prostate cancer and the ectopic expression of this gene has been shown to inhibit prostate cancer cell growth. Sequence analysis revealed that the BTG2 protein contains two leucine-rich motifs ((20)LxxLL(24) and (92)LxxLL(96)), which are usually found in nuclear receptor co-factors. Based on this, we postulated that there will be an association between BTG2 and AR. In this study, we discovered that BTG2 directly bound to the androgen receptor (AR) in the absence of 5α-dihydrotestosterone (DHT), and in the presence of the androgen, this interaction was increased. BTG2 bearing the mutant (20)LxxLL(24) motif bound to AR equally efficient as the wild-type BTG2, while BTG2 bearing the mutant (92)LxxLL(96) motif failed to interact with AR. Functional studies indicated that ectopic expression of BTG2 caused a significant inhibition of AR-mediated transcriptional activity and a decreased growth of prostate cancer cells. Androgen-induced promoter activation and expression of prostate-specific antigen (PSA) are significantly attenuated by BTG2. The intact (92)LxxLL(96) motif is required for these activities. These findings, for the first time, demonstrate that BTG2 complexes with AR via an LxxLL-dependent mechanism and may play a role in prostate cancer via modulating the AR signaling pathway.