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1.  Calcium supplementation during sepsis exacerbates organ failure and mortality via calcium/calmodulin-dependent protein kinase kinase (CaMKK) signaling 
Critical care medicine  2013;41(11):10.1097/CCM.0b013e31828cf436.
Calcium plays an essential role in nearly all cellular processes. As such, cellular and systemic calcium concentrations are tightly regulated. During sepsis derangements in such tight regulation frequently occur, and treating hypocalcemia with parenteral calcium administration remains the current practice guideline.
We investigated whether calcium administration worsens mortality and organ dysfunction using an experimental murine model of sepsis and explored the mechanistic role of the family of calcium/calmodulin-dependent protein kinases in mediating these physiologic effects. To highlight the biological relevance of these observations, we conducted a translational study of the association between calcium administration, organ dysfunction and mortality among a cohort of critically ill septic ICU patients
Prospective, randomized controlled experimental murine study. Observational clinical cohort analysis.
University research laboratory. Eight ICUs at a tertiary care center.
870 septic ICU patients.
C57BL/6 and CaMKK−/− mice.
Mice underwent cecal ligation and puncture polymicrobial sepsis and were administered calcium chloride (0.25 or 0.25 mg/kg) or normal saline.
Measurements and Main Results
Administering calcium chloride to septic C57BL/6 mice heightened systemic inflammation and vascular leak, exacerbated hepatic and renal dysfunction, and increased mortality. These events were significantly attenuated in CaMKK−/− mice. In a risk–adjusted analysis of septic patients, calcium administration was associated with an increased risk of death, OR 1.92 (95% CI 1.00–3.68, p=0.049), a significant increase in the risk of renal dysfunction, OR 4.74 (95% CI 2.48–9.08, p<0.001), and a significant reduction in ventilator free days, mean decrease 3.29 days (0.50–6.08 days, p=0.02).
Derangements in calcium homeostasis occur during sepsis that are sensitive to calcium administration. This altered calcium signaling, transduced by the CaMKK cascade, mediates heightened inflammation and vascular leak that culminates in elevated organ dysfunction and mortality. In the clinical management of septic patients calcium supplementation provides no benefit and may impose harm.
PMCID: PMC3812408  PMID: 23887235
calcium; sepsis; infection; inflammation; calcium/calmodulin-dependent protein kinase; mortality; organ failure
2.  The Changing Face of Hypophosphatemic Disorders in the FGF-23 Era 
In the past decade, research in genetic disorders of hypophosphatemia has significantly expanded our understanding of phosphate metabolism. X-linked hypophosphatemia (XLH) is the most common inherited form of rickets due to renal phosphate wasting. Recent understanding of the mechanisms of disease and role of fibroblast growth factor 23 (FGF-23) in XLH and other hypophosphatemic disorders have opened new potential therapeutic avenues. We will discuss the current standard of treatment for XLH as well as promising future directions under study.
PMCID: PMC4170520  PMID: 23858620
X-linked hypophosphatemia; phosphate; FGF-23; 1,25(OH)2D
3.  Thrombospondin-1 triggers macrophage IL-10 production and promotes resolution of experimental lung injury 
Mucosal immunology  2013;7(2):440-448.
Mononuclear phagocyte recognition of apoptotic cells triggering suppressive cytokine signaling is a key event in inflammation resolution from injury. Mice deficient in thrombospondin-1 (thbs1−/−), an extracellular matrix glycoprotein that bridges cell-cell interactions, are prone to LPS-induced lung injury and show defective macrophage IL-10 production during the resolution phase of inflammation. Reconstitution of IL-10 rescues thbs1−/− mice from persistent neutrophilic lung inflammation and injury and thbs1−/− alveolar macrophages show defective IL-10 production following intratracheal instillation of apoptotic neutrophils despite intact efferocytosis. Following co-culture with apoptotic neutrophils, thbs1−/− macrophages show a selective defect in IL-10 production whereas PGE2 and TGF-β1 responses remain intact. Full macrophage IL-10 responses require the engagement of thrombospondin-1 structural repeat 2 domain and the macrophage scavenger receptor CD36 LIMP-II Emp sequence homology (CLESH) domain in vitro. Although TSP-1 is not essential for macrophage engulfment of apoptotic neutrophils in vivo, TSP-1 aids in the curtailment of inflammatory responses during the resolution phase of injury in the lungs by providing a means by which apoptotic cells are recognized and trigger optimal IL-10 production by macrophages.
PMCID: PMC3945733  PMID: 24045574
Thrombospondin-1; Injury Resolution
4.  TCF7L2 Variation and Proliferative Diabetic Retinopathy 
Diabetes  2013;62(7):2613-2617.
Proliferative diabetic retinopathy (PDR) is the most severe vision-threatening complication of diabetes. For investigation of genetic association between TCF7L2 and PDR in Caucasian type 2 diabetes mellitus (T2DM) and its functional consequences, 383 T2DM patients with PDR (T2DM-PDR) and 756 T2DM patients without diabetic retinopathy (T2DM–no DR) were genotyped with rs7903146 in TCF7L2. We found that risk allele (T) frequency of rs7903146 was significantly higher in T2DM-PDR patients (allelic P = 2.52E-04). In lymphoblastoid cells induced to undergo endoplasmic reticulum (ER) stress by treatment of tunicamycin, higher fold change of TCF7L2 and VEGFA mRNA levels were observed in rs7903146-TT cells than in rs7903146-CC cells (P = 0.02 for TCF7L2; P = 0.004 for VEGFA), suggesting that ER stress plays a role in PDR pathogenesis. Silencing TCF7L2 resulted in decreased mRNA levels of both TCF7L2 and VEGFA (P < 0.001). Retinas of oxygen-induced retinopathy mice (a model for PDR) had higher TCF7L2 and VEGFA mRNA levels than those of controls (P = 2.9E-04 for TCF7L2; P = 1.9E-07 for VEGFA). Together, data from our study show that TCF7L2-rs7903146 is associated with PDR in Caucasian T2DM and suggest that TCF7L2 promotes pathological retinal neovascularization via ER stress–dependent upregulation of VEGFA.
PMCID: PMC3712060  PMID: 23434931
5.  Robotic surgery for rectal cancer: A systematic review of current practice 
AIM: To give a comprehensive review of current literature on robotic rectal cancer surgery.
METHODS: A systematic review of current literature via PubMed and Embase search engines was performed to identify relevant articles from january 2007 to november 2013. The keywords used were: “robotic surgery”, “surgical robotics”, “laparoscopic computer-assisted surgery”, “colectomy” and “rectal resection”.
RESULTS: After the initial screen of 380 articles, 20 papers were selected for review. A total of 1062 patients (male 64.0%) with a mean age of 61.1 years and body mass index of 24.9 kg/m2 were included in the review. Out of 1062 robotic-assisted operations, 831 (78.2%) anterior and low anterior resections, 132 (12.4%) intersphincteric resection with coloanal anastomosis, 98 (9.3%) abdominoperineal resections and 1 (0.1%) Hartmann’s operation were included in the review. Robotic rectal surgery was associated with longer operative time but with comparable oncological results and anastomotic leak rate when compared with laparoscopic rectal surgery.
CONCLUSION: Robotic colorectal surgery has continued to evolve to its current state with promising results; feasible surgical option with low conversion rate and comparable short-term oncological results. The challenges faced with robotic surgery are for more high quality studies to justify its cost.
PMCID: PMC4058726  PMID: 24936229
Rectal cancer; Robotics; Minimal invasive surgery; Systematic review; Rectal surgery
6.  CaMKIα regulates AMPK-dependent, TORC-1 independent autophagy during LPS-induced acute lung neutrophilic inflammation1,2 
Autophagy is an evolutionarily conserved cytoplasmic process regulated by the energy rheostats mTOR and AMPK that recycles damaged or unused proteins and organelles. It has been described as an important effector arm of immune cells. We have shown that the cytoplasmically oriented calcium/calmodulin-dependent protein kinase I α (CaMKIα) regulates the inflammatory phenotype of the macrophage (Mφ). Here, we hypothesize that CaMKIα mediates Mφ autophagy. LPS induced autophagy in RAW 264.7 cells and murine peritoneal Mφ that was attenuated with biochemical CaMK inhibition or CaMKIα siRNA. Inhibition of CaMKIα reduced LPS-induced p-Thr172AMPK and TORC1 activity, and expression of a constitutively active CaMKIα but not a kinase-deficient mutant induced p-Thr172AMPK and autophagy that was attenuated by the AMPK inhibitor Compound C. Co-immunoprecipitation and in vitro kinase assays demonstrated that CaMKIα activates AMPK, thereby inducing ATG7, which also localizes to this CaMKIα-AMPK complex. During LPS-induced lung inflammation, C57Bl/6 mice receiving CaMKIαsiRNA displayed reduced lung and bronchoalveolar immune cell autophagy that correlated with reduced neutrophil recruitment, myeloperoxidase activity, and air space cytokine concentration. Independently inhibiting autophagy, using siRNA targeting the PI3 kinase VPS34, yielded similar reductions in lung autophagy and neutrophil recruitment. Thus, a novel CaMKIα-AMPK pathway is rapidly activated in Mφ exposed to LPS and regulates an early autophagic response, independent of TORC1 inhibition. These mechanisms appear to be operant in vivo in orchestrating LPS-induced lung neutrophil recruitment and inflammation.
PMCID: PMC3608723  PMID: 23447692
7.  Red blood cell microparticles show altered inflammatory chemokine binding and release ligand upon interaction with platelets 
Transfusion  2010;51(3):610-621.
Storage of red blood cells (RBCs) under standard blood bank conditions results in reduced structural integrity leading to membrane budding and release of microparticles. Microparticles express the blood group Duffy antigen known to bind multiple inflammatory chemokines, but the functional chemokine binding properties of microparticles are not known.
We determined whether storage-induced microparticles show inflammatory chemokine binding through the expression of the Duffy antigen, comparing the binding properties to intact RBCs, and assessed microparticle interactions with platelets (PLTs) that release chemokines upon activation.
Intact RBCs retained similar equilibrium dissociation constants for CCL2 (Kd = 7.4 ± 0.9 nmol/L), CXCL8 (Kd = 7.9 ± 1.0 nmol/L), and CXCL1 (Kd = 4.4 ± 1.0 nmol/L) throughout storage. In contrast, microparticles increased in relative counts with storage, showed higher percentages of surface phosphatidylserine, and demonstrated impaired Duffy-dependent chemokine binding affinity with wider variability in dissociation constant for CXCL1(Kd = 362 ± 328 nmol/L; range, 0.6–2000 nmol/L). The altered chemokine binding affinity of RBC microparticles was associated with a propensity to release ligand upon incubation with PLTs. Relative quantification of microparticles, based on criteria of glycophorin A expression and size, underestimated particle numbers with functional chemokine binding, suggesting that glycophorin A–negative particles and nanoparticles contribute to overall chemokine binding capacity.
Microparticle burden in transfusates, as determined by functional chemokine binding, is considerable. Altered membrane properties of RBC microparticles enhance PLT interactions to increase inflammatory chemokine bioavailability in vitro.
PMCID: PMC3963470  PMID: 20738825
8.  CX3CR1+ Lung Mononuclear Phagocytes Spatially Confined to the Interstitium Produce TNF-α and IL-6 and Promote Cigarette Smoke-Induced Emphysema 
Increased numbers of macrophages are found in the lungs of smokers and those with chronic obstructive pulmonary disease. Experimental evidence shows the central role of macrophages in elaboration of inflammatory mediators such as TNF-a and the progression toward cigarette smoke-induced emphysema. We investigated the role of CX3CR1 in recruitment of mononuclear phagocytes, inflammatory cytokine responses, and tissue destruction in the lungs after cigarette smoke exposure. Using mice in which egfp is expressed at the locus of the cx3cr1 gene, we show that alveolar macrophages increased transmembrane ligand CX3CL1 expression and soluble CX3CL1 was detectable in the airspaces, but cx3cr1GFP/GFP and cx3cr1GFP/+ mice failed to show recruitment of CX3CR1+ cells into the airspaces with cigarette smoke. In contrast, cigarette smoke increased the accumulation of CX3CR1+CD11b+ mononuclear phagocytes that were spatially confined to the lung interstitium and heterogenous in their expression of CD11c, MHC class II, and autofluorescent property. Although an intact CX3CL1–CX3CR1 pathway amplified the percentage of CX3CR1+CD11b+ mononuclear phagocytes in the lungs, it was not essential for recruitment. Rather, functional CX3CR1 was required for a subset of tissue-bound mononuclear phagocytes to produce TNF-α and IL-6 in response to cigarette smoke, and the absence of functional CX3CR1 protected mice from developing tissue-destructive emphysema. Thus, CX3CR1+ “tissue resident” mononuclear phagocytes initiate an innate immune response to cigarette smoke by producing TNF-α and IL-6 and are capable of promoting emphysema.
PMCID: PMC3912553  PMID: 21278339
9.  Cyclin-dependent kinase 4 signaling acts as a molecular switch between syngenic differentiation and neural transdifferentiation in human mesenchymal stem cells 
Cell Cycle  2013;12(3):442-451.
Multipotent mesenchymal stem/stromal cells (MSCs) are capable of differentiating into a variety of cell types from different germ layers. However, the molecular and biochemical mechanisms underlying the transdifferentiation of MSCs into specific cell types still need to be elucidated. In this study, we unexpectedly found that treatment of human adipose- and bone marrow-derived MSCs with cyclin-dependent kinase (CDK) inhibitor, in particular CDK4 inhibitor, selectively led to transdifferentiation into neural cells with a high frequency. Specifically, targeted inhibition of CDK4 expression using recombinant adenovial shRNA induced the neural transdifferentiation of human MSCs. However, the inhibition of CDK4 activity attenuated the syngenic differentiation of human adipose-derived MSCs. Importantly, the forced regulation of CDK4 activity showed reciprocal reversibility between neural differentiation and dedifferentiation of human MSCs. Together, these results provide novel molecular evidence underlying the neural transdifferentiation of human MSCs; in addition, CDK4 signaling appears to act as a molecular switch from syngenic differentiation to neural transdifferentiation of human MSCs.
PMCID: PMC3587445  PMID: 23324348
mesenchymal stem/stromal cells; transdifferentiation; cyclin-dependent kinase 4; neural cells; glial cells; cell cycle arrest; neurodegenerative disease
10.  Nitric Oxide Scavenging by Red Cell Microparticles and Cell Free Hemoglobin as a Mechanism for the Red Cell Storage Lesion 
Circulation  2011;124(4):465-476.
Intravascular red cell hemolysis impairs NO-redox homeostasis, producing endothelial dysfunction, platelet activation and vasculopathy. Red blood cell storage under standard conditions results in reduced integrity of the erythrocyte membrane, with formation of exocytic microvesicles or “microparticles” and hemolysis, which we hypothesized could impair vascular function and contribute to the putative “storage lesion” of banked blood.
Methods and Results
We now find that storage of human red blood cells under standard blood banking conditions results in the accumulation of cell free and microparticle-encapsulated hemoglobin which, despite 39 days of storage, remains in the reduced ferrous oxyhemoglobin redox state and stoichiometrically reacts with and scavenges the vasodilator nitric oxide (NO). Using stopped-flow spectroscopy and laser triggered NO release from a caged NO compound we found that both free hemoglobin and microparticles react with NO about 1000 times faster than with intact erythrocytes. In complementary in vivo studies we show that hemoglobin, even at concentrations below 10 μM (in heme), produces potent vasoconstriction when infused into the rat circulation, while controlled infusions of methemoglobin and cyanomethemoglobin, which do not consume NO, have substantially reduced vasoconstrictor effects. Infusion of the plasma from stored human red cell units into the rat circulation produces significant vasoconstriction related to the magnitude of storage related hemolysis.
The results of these studies suggest new mechanisms for endothelial injury and impaired vascular function associated with the most fundamental of storage lesions, hemolysis.
PMCID: PMC3891836  PMID: 21747051
Hemoglobin; microparticles; nitric oxide; blood transfusion; storage lesion; reactive oxygen species
11.  Effect of tocilizumab on haematological markers implicates interleukin-6 signalling in the anaemia of rheumatoid arthritis 
Arthritis Research & Therapy  2013;15(6):R204.
Our objective was to determine the interrelationships of interleukin (IL)-6 receptor inhibition with haemoglobin, acute-phase reactants and iron metabolism markers (including hepcidin) in patients with rheumatoid arthritis (RA).
Data of patients receiving tocilizumab or placebo in the MEASURE study were analysed. We investigated associations at baseline and during tocilizumab treatment among haemoglobin, parameters of haemoglobin and iron homeostasis [ferritin, total iron-binding capacity (TIBC), hepcidin, haptoglobin], IL-6 and acute-phase reactants [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)] to identify statistical correlates of rise in haemoglobin level.
At baseline, CRP and haptoglobin were inversely correlated (modestly) with haemoglobin levels. After treatment with tocilizumab, CRP, hepcidin, ferritin and haptoglobin levels fell alongside increases in TIBC and haemoglobin. The falls in CRP, hepcidin and haptoglobin levels in the first 2 weeks correlated with a week 12 rise in TIBC and haemoglobin.
Inflammatory anaemia improves in patients with RA treated with tocilizumab. This improvement correlates with the degree of suppression of systemic inflammation, reduction in hepcidin and haptoglobin and increase in iron-binding capacity. These clinical data provide evidence of a role for IL-6 signalling in the inflammatory anaemia of RA.
PMCID: PMC3978585  PMID: 24295403
12.  Neuroendocrine Predictors of Emotional and Behavioral Adjustment in Boys: Longitudinal Follow-Up of a Community Sample 
Psychoneuroendocrinology  2012;37(12):2042-2046.
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been observed in adults and children with mood and anxiety disorders and is thought to be involved in the pathogenesis of these disorders. We recently studied a diverse community sample of boys and found associations of behavioral problems, including symptoms of depression and anxiety, with basal and stress-induced cortisol concentrations. Here we examine cortisol-emotional/behavioral associations at a two-year follow-up and test whether initial cortisol is predictive of worsening of emotional/behavioral problems two years later.
Seventy-eight 10–14 year-old boys and their mothers completed a battery of psychosocial assessments, provided morning and afternoon saliva samples, and participated in a home visit involving mildly stressful tasks and saliva collection for cortisol assay during a two-year follow-up assessment.
Consistent with the findings from our time 1 assessment, greater declines in cortisol across the home-visit challenge task were significantly associated with internalizing and externalizing behaviors as well as attention problems and social problems at the two-year follow-up. In addition, morning and afternoon cortisol concentrations at the initial assessment were significant positive predictors of the later development of child depressive symptoms at follow-up after controlling for initial depressive symptoms.
These findings demonstrate that children in the community with internalizing and externalizing behavior problems have altered patterns of HPA axis stress reactivity. In addition, our prospective findings suggest that elevated cortisol concentrations may influence the later development of emotional/behavioral problems in boys.
PMCID: PMC3458171  PMID: 22575356
children; adolescents; boys; depression; cortisol; anxiety; HPA axis; stress reactivity; longitudinal; prospective
13.  Caveolae-Dependent and -Independent Uptake of Albumin in Cultured Rodent Pulmonary Endothelial Cells 
PLoS ONE  2013;8(11):e81903.
Although a critical role for caveolae-mediated albumin transcytosis in pulmonary endothelium is well established, considerably less is known about caveolae-independent pathways. In this current study, we confirmed that cultured rat pulmonary microvascular (RPMEC) and pulmonary artery (RPAEC) endothelium endocytosed Alexa488-labeled albumin in a saturable, temperature-sensitive mode and internalization resulted in co-localization by fluorescence microscopy with cholera B toxin and caveolin-1. Although siRNA to caveolin-1 (cav-1) in RPAEC significantly inhibited albumin uptake, a remnant portion of albumin uptake was cav-1-independent, suggesting alternative pathways for albumin uptake. Thus, we isolated and cultured mouse lung endothelial cells (MLEC) from wild type and cav-1-/- mice and noted that ~ 65% of albumin uptake, as determined by confocal imaging or live cell total internal reflectance fluorescence microscopy (TIRF), persisted in total absence of cav-1. Uptake of colloidal gold labeled albumin was evaluated by electron microscopy and demonstrated that albumin uptake in MLEC from cav-1-/- mice was through caveolae-independent pathway(s) including clathrin-coated pits that resulted in endosomal accumulation of albumin. Finally, we noted that albumin uptake in RPMEC was in part sensitive to pharmacological agents (amiloride [sodium transport inhibitor], Gö6976 [protein kinase C inhibitor], and cytochalasin D [inhibitor of actin polymerization]) consistent with a macropinocytosis-like process. The amiloride sensitivity accounting for macropinocytosis also exists in albumin uptake by both wild type and cav-1-/- MLEC. We conclude from these studies that in addition to the well described caveolar-dependent pulmonary endothelial cell endocytosis of albumin, a portion of overall uptake in pulmonary endothelial cells is cav-1 insensitive and appears to involve clathrin-mediated endocytosis and macropinocytosis-like process.
PMCID: PMC3842245  PMID: 24312378
14.  Hypofractionated Stereotactic Radiosurgery in a Large Bilateral Thalamic and Basal Ganglia Arteriovenous Malformation 
Purpose. Arteriovenous malformations (AVMs) in the basal ganglia and thalamus have a more aggressive natural history with a higher morbidity and mortality than AVMs in other locations. Optimal treatment—complete obliteration without new neurological deficits—is often challenging. We present a patient with a large bilateral basal ganglia and thalamic AVM successfully treated with hypofractionated stereotactic radiosurgery (HFSRS) with intensity modulated radiotherapy (IMRT). Methods. The patient was treated with hypofractionated stereotactic radiosurgery to 30 Gy at margin in 5 fractions of 9 static fields with a minimultileaf collimator and intensity modulated radiotherapy. Results. At 10 months following treatment, digital subtraction angiography showed complete obliteration of the AVM. Conclusions. Large bilateral thalamic and basal ganglia AVMs can be successfully treated with complete obliteration by HFSRS with IMRT with relatively limited toxicity. Appropriate caution is recommended.
PMCID: PMC3836296  PMID: 24307961
15.  Heterogeneity of Lung Mononuclear Phagocytes in Chronic Obstructive Pulmonary Disease 
Journal of innate immunity  2012;4(0):489-497.
Chronic Obstructive Pulmonary Disease (COPD) is a disease defined by an aberrant inflammatory response to inhaled cigarette smoke and other noxious particles. The factors triggered in the lungs that drive inflammation and lung tissue destruction are not fully understood, but mononuclear phagocytes play a central role by releasing mediators that promote both inflammation and tissue destructive emphysema. Although conflicting studies in alveolar macrophages exist regarding chronic cigarette smoke exposure and its effects on macrophage polarization patterns, we have recently identified a cell-type in mice defined by CX3CR1 expression whose population expands in the lungs and elaborates M1 signature cytokines in response to cigarette smoke exposure in vivo. In addition, the absence of functional CX3CR1 provides protection from tissue-destructive emphysema in a murine model of chronic cigarette smoke exposure. The heterogeneity and plasticity of discrete macrophage subsets, in terms of immuno-phenotype and function, may explain the seemingly disparate findings showing a suppressed inflammatory profile on the one hand and heightened inflammatory response on the other. This review proposes to examine the evidence that discrete mononuclear phagocyte subsets develop in response to cigarette smoke exposure, and the spatial cues provided by the lung tissue microenvironment in which the mononuclear phagocyte resides may influence the distribution and function of these subsets.
PMCID: PMC3804221  PMID: 22572241
chemokines; macrophages; pattern recognition receptors
16.  Buffering the pH of the culture medium does not extend yeast replicative lifespan 
F1000Research  2013;2:216.
During chronological aging of budding yeast cells, the culture medium can become acidified, and this acidification limits cell survival.  As a consequence, buffering the culture medium to pH 6 significantly extends chronological life span under standard conditions in synthetic medium.  In this study, we assessed whether a similar process occurs during replicative aging of yeast cells.  We find no evidence that buffering the pH of the culture medium to pH levels either higher or lower than the initial pH of the medium is able to significantly extend replicative lifespan.  Thus, we conclude that, unlike chronological life span, replicative life span is not limited by acidification of the culture medium or by changes in the pH of the environment.
PMCID: PMC3886788  PMID: 24555104
17.  GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer 
Pharoah, Paul D. P. | Tsai, Ya-Yu | Ramus, Susan J. | Phelan, Catherine M. | Goode, Ellen L. | Lawrenson, Kate | Price, Melissa | Fridley, Brooke L. | Tyrer, Jonathan P. | Shen, Howard | Weber, Rachel | Karevan, Rod | Larson, Melissa C. | Song, Honglin | Tessier, Daniel C. | Bacot, François | Vincent, Daniel | Cunningham, Julie M. | Dennis, Joe | Dicks, Ed | Aben, Katja K. | Anton-Culver, Hoda | Antonenkova, Natalia | Armasu, Sebastian M. | Baglietto, Laura | Bandera, Elisa V. | Beckmann, Matthias W. | Birrer, Michael J. | Bloom, Greg | Bogdanova, Natalia | Brenton, James D. | Brinton, Louise A. | Brooks-Wilson, Angela | Brown, Robert | Butzow, Ralf | Campbell, Ian | Carney, Michael E | Carvalho, Renato S. | Chang-Claude, Jenny | Chen, Y. Anne | Chen, Zhihua | Chow, Wong-Ho | Cicek, Mine S. | Coetzee, Gerhard | Cook, Linda S. | Cramer, Daniel W. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | Despierre, Evelyn | Doherty, Jennifer A | Dörk, Thilo | du Bois, Andreas | Dürst, Matthias | Eccles, Diana | Edwards, Robert | Ekici, Arif B. | Fasching, Peter A. | Fenstermacher, David | Flanagan, James | Gao, Yu-Tang | Garcia-Closas, Montserrat | Gentry-Maharaj, Aleksandra | Giles, Graham | Gjyshi, Anxhela | Gore, Martin | Gronwald, Jacek | Guo, Qi | Halle, Mari K | Harter, Philipp | Hein, Alexander | Heitz, Florian | Hillemanns, Peter | Hoatlin, Maureen | Høgdall, Estrid | Høgdall, Claus K. | Hosono, Satoyo | Jakubowska, Anna | Jensen, Allan | Kalli, Kimberly R. | Karlan, Beth Y. | Kelemen, Linda E. | Kiemeney, Lambertus A. | Kjaer, Susanne Krüger | Konecny, Gottfried E. | Krakstad, Camilla | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Nathan | Lee, Janet | Leminen, Arto | Lim, Boon Kiong | Lissowska, Jolanta | Lubiński, Jan | Lundvall, Lene | Lurie, Galina | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R | Menon, Usha | Modugno, Francesmary | Moysich, Kirsten B. | Nakanishi, Toru | Narod, Steven A. | Ness, Roberta B. | Nevanlinna, Heli | Nickels, Stefan | Noushmehr, Houtan | Odunsi, Kunle | Olson, Sara | Orlow, Irene | Paul, James | Pejovic, Tanja | Pelttari, Liisa M | Permuth-Wey, Jenny | Pike, Malcolm C | Poole, Elizabeth M | Qu, Xiaotao | Risch, Harvey A. | Rodriguez-Rodriguez, Lorna | Rossing, Mary Anne | Rudolph, Anja | Runnebaum, Ingo | Rzepecka, Iwona K | Salvesen, Helga B. | Schwaab, Ira | Severi, Gianluca | Shen, Hui | Shridhar, Vijayalakshmi | Shu, Xiao-Ou | Sieh, Weiva | Southey, Melissa C. | Spellman, Paul | Tajima, Kazuo | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J | Timorek, Agnieszka | Tworoger, Shelley S. | van Altena, Anne M. | Berg, David Van Den | Vergote, Ignace | Vierkant, Robert A. | Vitonis, Allison F. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wik, Elisabeth | Winterhoff, Boris | Woo, Yin Ling | Wu, Anna H | Yang, Hannah P. | Zheng, Wei | Ziogas, Argyrios | Zulkifli, Famida | Goodman, Marc T. | Hall, Per | Easton, Douglas F | Pearce, Celeste L | Berchuck, Andrew | Chenevix-Trench, Georgia | Iversen, Edwin | Monteiro, Alvaro N.A. | Gayther, Simon A. | Schildkraut, Joellen M. | Sellers, Thomas A.
Nature genetics  2013;45(4):362-370e2.
Genome wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC) with another two loci being close to genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the United Kingdom. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. Follow-up genotyping was carried out in 18,174 cases and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 previously near genome-wide significance and identified three novel loci associated with risk; two loci associated with all EOC subtypes, at 8q21 (rs11782652, P=5.5×10-9) and 10p12 (rs1243180; P=1.8×10-8), and another locus specific to the serous subtype at 17q12 (rs757210; P=8.1×10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility that implicates CHMP4C in the pathogenesis of ovarian cancer.
PMCID: PMC3693183  PMID: 23535730
18.  Developing and Testing the Effectiveness of a Novel Health Qigong for Frail Elders in Hong Kong: A Preliminary Study 
Eight-Section Brocades and Yijin Jing consist of some routine movements that are too difficult for frail elders. A novel health qigong protocol was developed and its effectiveness for frail elders was examined using a randomized clinical trial (RCT). An expert panel performed functional anatomy analysis and safety field test prior to the RCT. The experimental group (n = 61, 83 ± 6 yr) was given a 12-week qigong exercise program, while the comparison group (n = 55, 84 ± 6 yr) participated in a newspaper reading program with the same duration and frequency. Pre-, mid-, post-, and follow-up assessments were conducted. At 12 weeks, the qigong group had significant improvements in thinking operations (F = 4.05, P = .02) and significant reduction of resting heart rate (F = 3.14, P = .045) as compared to the newspaper reading group. A trend of improvements in grip strength and a decreasing trend of depression levels were observed among the qigong group. Significant perceived improvements in physical health (F = 13.01, P = .001), activities of daily living (F = 5.32, P = .03), and overall health status (F = 15.26, P = .0001) were found. There are improvements in some aspects of psychosocial, cognitive, physical, and physiological domains. Clinical applications and possibilities for further research are discussed.
PMCID: PMC3784263  PMID: 24109493
19.  CXCL5 Regulates Chemokine Scavenging and Pulmonary Host Defense to Bacterial Infection 
Immunity  2010;33(1):106-117.
The chemokine sink hypothesis pertaining to erythrocyte Duffy Antigen Receptor for Chemokines (DARC) during inflammation has received considerable attention, but lacks direct in vivo evidence. Here we demonstrate, using mice with a targeted deletion in CXCL5, that CXCL5 bound erythrocyte DARC and impaired its chemokine scavenging in blood. CXCL5 increased the plasma concentrations of CXCL1 and CXCL2 in part through inhibiting chemokine scavenging, impairing chemokine gradients and desensitizing CXCR2, which led to decreased neutrophil influx to the lung, increased lung bacterial burden and mortality in an Escherichia coli pneumonia model. In contrast, CXCL5 exerted a predominant role in mediating neutrophil influx to the lung during inflammation after LPS inhalation. Platelets and lung resident cells were the sources of homeostatic CXCL5 in blood and inflammatory CXCL5 in the lung respectively. This study presents a paradigm whereby platelets and red cells alter chemokine scavenging and neutrophil-chemokine interaction during inflammation.
PMCID: PMC3748840  PMID: 20643340
20.  Quality of life after laparoscopic vs open sphincter-preserving resection for rectal cancer 
AIM: To compare quality of life (QoL) outcomes in Chinese patients after curative laparoscopic vs open surgery for rectal cancer.
METHODS: Eligible Chinese patients with rectal cancer undergoing curative laparoscopic or open sphincter-preserving resection between July 2006 and July 2008 were enrolled in this prospective study. The QoL outcomes were assessed longitudinally using the validated Chinese versions of the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires before surgery and at 4, 8, and 12 mo after surgery. The QoL scores at the different time points were compared between the laparoscopic and open groups. A higher score on a functional scale indicated better functioning, whereas a higher score on a symptom scale indicated a higher degree of symptoms.
RESULTS: Seventy-four patients (49 laparoscopic and 25 open) were enrolled. The two groups of patients were comparable in terms of sociodemographic data, types of surgery, tumor staging, and baseline mean QoL scores. There was no significant decrease from baseline in global QoL for the laparoscopic group at different time points, whereas the global QoL was worse compared to baseline beginning at 4 mo but returned to baseline by 12 mo for the open group (P = 0.019, Friedman test). Compared to the open group, the laparoscopic group had significantly better physical (89.9 ± 1.4 vs 79.2 ± 3.7, P = 0.016), role (85.0 ± 3.4 vs 63.3 ± 6.9, P = 0.005), and cognitive (73.5 ± 3.4 vs 50.7 ± 6.2, P = 0.002) functioning at 8 mo, fewer micturition problems at 4-8 mo (4 mo: 32.3 ± 4.7 vs 54.7 ± 7.1, P = 0.011; 8 mo: 22.8 ± 4.0 vs 40.7 ± 6.9, P = 0.020), and fewer male sexual problems from 8 mo onward (20.0 ± 8.5 vs 76.7 ± 14.5, P = 0.013). At 12 mo after surgery, no significant differences were observed in any functional or symptom scale between the two groups, with the exception of male sexual problems, which remained worse in the open group (29.2 ± 11.3 vs 80.0 ± 9.7, P = 0.026).
CONCLUSION: Laparoscopic sphincter-preserving resection for rectal cancer is associated with better preservation of QoL and fewer male sexual problems when compared with open surgery in Chinese patients. These findings, however, should be interpreted with caution because of the small sample size of the study.
PMCID: PMC3732850  PMID: 23922475
Quality of life; Rectal cancer; Laparoscopic surgery; Sphincter-preserving surgery; European Organization for Research and Treatment of Cancer QLQ-C30; European Organization for Research and Treatment of Cancer QLQ-CR38
21.  Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31 
Permuth-Wey, Jennifer | Lawrenson, Kate | Shen, Howard C. | Velkova, Aneliya | Tyrer, Jonathan P. | Chen, Zhihua | Lin, Hui-Yi | Chen, Y. Ann | Tsai, Ya-Yu | Qu, Xiaotao | Ramus, Susan J. | Karevan, Rod | Lee, Janet | Lee, Nathan | Larson, Melissa C. | Aben, Katja K. | Anton-Culver, Hoda | Antonenkova, Natalia | Antoniou, Antonis | Armasu, Sebastian M. | Bacot, François | Baglietto, Laura | Bandera, Elisa V. | Barnholtz-Sloan, Jill | Beckmann, Matthias W. | Birrer, Michael J. | Bloom, Greg | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Brown, Robert | Butzow, Ralf | Cai, Qiuyin | Campbell, Ian | Chang-Claude, Jenny | Chanock, Stephen | Chenevix-Trench, Georgia | Cheng, Jin Q. | Cicek, Mine S. | Coetzee, Gerhard A. | Cook, Linda S. | Couch, Fergus J. | Cramer, Daniel W. | Cunningham, Julie M. | Dansonka-Mieszkowska, Agnieszka | Despierre, Evelyn | Doherty, Jennifer A | Dörk, Thilo | du Bois, Andreas | Dürst, Matthias | Easton, Douglas F | Eccles, Diana | Edwards, Robert | Ekici, Arif B. | Fasching, Peter A. | Fenstermacher, David A. | Flanagan, James M. | Garcia-Closas, Montserrat | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind M. | Gonzalez-Bosquet, Jesus | Goodman, Marc T. | Gore, Martin | Górski, Bohdan | Gronwald, Jacek | Hall, Per | Halle, Mari K. | Harter, Philipp | Heitz, Florian | Hillemanns, Peter | Hoatlin, Maureen | Høgdall, Claus K. | Høgdall, Estrid | Hosono, Satoyo | Jakubowska, Anna | Jensen, Allan | Jim, Heather | Kalli, Kimberly R. | Karlan, Beth Y. | Kaye, Stanley B. | Kelemen, Linda E. | Kiemeney, Lambertus A. | Kikkawa, Fumitaka | Konecny, Gottfried E. | Krakstad, Camilla | Kjaer, Susanne Krüger | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Lancaster, Johnathan M. | Le, Nhu D. | Leminen, Arto | Levine, Douglas A. | Liang, Dong | Lim, Boon Kiong | Lin, Jie | Lissowska, Jolanta | Lu, Karen H. | Lubiński, Jan | Lurie, Galina | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R | Menon, Usha | Modugno, Francesmary | Moysich, Kirsten B. | Nakanishi, Toru | Narod, Steven A. | Nedergaard, Lotte | Ness, Roberta B. | Nevanlinna, Heli | Nickels, Stefan | Noushmehr, Houtan | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Paul, James | Pearce, Celeste L | Pejovic, Tanja | Pelttari, Liisa M. | Pike, Malcolm C. | Poole, Elizabeth M. | Raska, Paola | Renner, Stefan P. | Risch, Harvey A. | Rodriguez-Rodriguez, Lorna | Rossing, Mary Anne | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schwaab, Ira | Severi, Gianluca | Shridhar, Vijayalakshmi | Shu, Xiao-Ou | Shvetsov, Yurii B. | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Spiewankiewicz, Beata | Stram, Daniel | Sutphen, Rebecca | Teo, Soo-Hwang | Terry, Kathryn L. | Tessier, Daniel C. | Thompson, Pamela J. | Tworoger, Shelley S. | van Altena, Anne M. | Vergote, Ignace | Vierkant, Robert A. | Vincent, Daniel | Vitonis, Allison F. | Wang-Gohrke, Shan | Weber, Rachel Palmieri | Wentzensen, Nicolas | Whittemore, Alice S. | Wik, Elisabeth | Wilkens, Lynne R. | Winterhoff, Boris | Woo, Yin Ling | Wu, Anna H. | Xiang, Yong-Bing | Yang, Hannah P. | Zheng, Wei | Ziogas, Argyrios | Zulkifli, Famida | Phelan, Catherine M. | Iversen, Edwin | Schildkraut, Joellen M. | Berchuck, Andrew | Fridley, Brooke L. | Goode, Ellen L. | Pharoah, Paul D. P. | Monteiro, Alvaro N.A. | Sellers, Thomas A. | Gayther, Simon A.
Nature communications  2013;4:1627.
Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3′ untranslated region at putative microRNA (miRNA) binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA binding site single nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (OR=1.12, P=10−8) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10−10). Variation at 17q21.31 associates with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.
PMCID: PMC3709460  PMID: 23535648
22.  STAT1-Regulated Lung MDSC-like Cells Produce IL-10 and Efferocytose Apoptotic Neutrophils With Relevance In Resolution of Bacterial Pneumonia 
Mucosal immunology  2012;6(1):189-199.
Bacterial pneumonia remains a significant burden worldwide. Although an inflammatory response in the lung is required to fight the causative agent, persistent tissue-resident neutrophils in non-resolving pneumonia can induce collateral tissue damage and precipitate acute lung injury. However, little is known about mechanisms orchestrated in the lung tissue that remove apoptotic neutrophils to restore tissue homeostasis. In mice infected with Klebsiella pneumoniae, a bacterium commonly associated with hospital-acquired pneumonia, we show that interleukin-10 is essential for resolution of lung inflammation and recovery of mice after infection. Although IL-10−/− mice cleared bacteria, they displayed increased morbidity with progressive weight loss and persistent lung inflammation in the later phase after infection. A source of tissue IL-10 was found to be resident CD11b+Gr1intF4/80+ cells resembling myeloid-derived suppressor cells that appeared with a delayed kinetics after infection. These cells efficiently efferocytosed apoptotic neutrophils, which was aided by IL-10. The lung neutrophil burden was attenuated in infected STAT1−/− mice with concomitant increase in the frequency of the MDSC-like cells and lung IL-10 levels. Thus, inhibiting STAT1 in combination with antibiotics may be a novel therapeutic strategy to address inefficient resolution of bacterial pneumonia.
PMCID: PMC3505806  PMID: 22785228
23.  Persistence of elevated plasma CXCL8 concentrations following red blood cell transfusion in a trauma cohort 
Shock (Augusta, Ga.)  2012;37(4):373-377.
Red blood cell (RBC) transfusion is associated with alterations in systemic concentrations of IL-8/CXCL8 functional homologues in a murine model. Whether RBC transfusion alters systemic neutrophil chemokine concentrations in individuals sustaining traumatic injury is not known. We conducted a retrospective, single-center study of severely injured trauma patients presenting within 12 h of injury with a base deficit > 6 and hypotension in the field. Plasma concentrations of twenty-five chemokines, cytokines, and growth factors were obtained from both transfused (N=22) and non-transfused (N=33) groups in the first 48 h following admission. The transfused group (mean RBC units ± SD: 2.7 ±1.7) tended to be older (49.9 ±21.1 versus 40.4 ±19.9 years, p=0.10), with a higher percentage of females (40.9% versus 18.2%, p=0.06), and a higher injury severity score (ISS) (27.1 ±12.7 versus 21.4 ±10.2, p=0.07). In univariate and multivariate analyses, transfusion was associated with increased hospital and ICU length of stay but not ventilator-free days. Plasma CXCL8 concentrations were higher in the transfused (mean ±SD: 84 ±88 pg/mL) than the non-transfused group (31 ±21 pg/mL, p=0.003). Using a linear prediction model to calculate bioanalyte concentrations standardized for age, gender, ISS, and admission SBP, we observed that CXCL8 concentrations diverged within 12 hours following injury, with the transfused group showing persistently elevated CXCL8 concentrations by contrast to the decay observed in the non-transfused group. Other bioanalytes showed no differences across time. RBC transfusion is associated with persistently elevated neutrophil chemokine CXCL8 concentrations following traumatic injury.
PMCID: PMC3346279  PMID: 22293598
Chemokines; RBC transfusion; Inflammation; trauma
24.  Acute exacerbation of subclinical pulmonary fibrosis following red cell transfusion: a case report 
Transfusion  2011;52(3):589-594.
Red cell transfusion is associated with lung injury in susceptible hosts, although many cases do not meet criteria for transfusion related acute lung injury. Patients with underlying pulmonary fibrosis can exhibit precipitous deteriorations in respiratory status of unknown etiology defined as acute exacerbations due to superimposed lung injury syndrome. It is unclear whether red cell transfusion is associated with acute exacerbation of underlying pulmonary fibrosis.
Case Report
We describe a patient who underwent an uneventful elective left total hip replacement but developed anemia post-operatively. Twenty-four hours following transfusion of her fifth non-leukoreduced AS-5 red cell unit, she developed new bilateral airspace infiltrates associated with progressive hypoxemia. These RBC units were 35-38 days old. Despite supportive care and diuresis, patient remained profoundly hypoxemic with infiltrates that progressed to fibrosis.
The patient had mild sub-clinical lower-lobe predominant interstitial pulmonary fibrosis but developed diffuse bilateral ground glass opacities with areas of consolidation 24 h after receiving her last RBC unit. Transbronchial biopsy of the right lower lobe showed active organizing pneumonia and underlying interstitial fibrosis, supporting the clinical diagnosis of acute exacerbation of pulmonary fibrosis. The bronchoalveolar lavage showed progressive bloody effluent, consistent with diffuse alveolar hemorrhage, a marker of lung injury. There was no evidence of viral inclusions, fungal elements, pneumocystis, or bacterial organisms.
Transfusion of multiple units of aged RBCs was temporally associated with an acute exacerbation and rapid progression of underlying sub-clinical pulmonary fibrosis.
PMCID: PMC3214228  PMID: 21827507
transfusion; acute exacerbation; pulmonary fibrosis; lung injury; red blood cells
25.  Acupuncture transcutaneous electrical nerve stimulation reduces discomfort associated with barostat-induced rectal distension: A randomized-controlled study 
AIM: To explore the effectiveness of acupuncture transcutaneous electrical nerve stimulation (Acu-TENS), a non-invasive modality in reduction of rectal discomfort during barostat-induced rectal distension.
METHODS: Forty healthy subjects were randomized to receive 45 min of either Acu-TENS or placebo-TENS (no electrical output) over acupuncture points Hegu (large-intestine 4), Neiguan (pericardium 6) and Zusanli (stomach 36). A balloon catheter attached to a dual-drive barostat machine was then inserted into the subjects’ rectum. A step-wise (4 mmHg) increase in balloon pressure was induced until maximal tolerable or 48 mmHg. Visual analogue scale and a 5-point subjective discomfort scale (no perception, first perception of distension, urge to defecate, discomfort/pain and extreme pain) were used to assess rectal discomfort at each distension pressure. Blood beta-endorphin levels were measured before, immediately after intervention, at 24 mmHg and at maximal tolerable distension pressure.
RESULTS: There was no difference in the demographic data and baseline plasma beta-endorphin levels between the two groups. Perception threshold levels were higher in the Acu-TENS group when compared to the placebo group, but the difference reached statistical significance only at the sensations “urge to defecate” and “pain”. The distension pressures recorded at the “urge to defecate” sensation for the Acu-TENS and placebo-TENS groups were 28.0 ± 4.5 mmHg and 24.6 ± 5.7 mmHg, respectively (P = 0.043); and the pressures recorded for the “pain” sensation for these two groups were 36.0 ± 4.2 mmHg and 30.5 ± 4.3 mmHg respectively (P = 0.002). Compared to the placebo group, a higher number of participants in the Acu-TENS group tolerated higher distension pressures (> 40 mmHg) (65% in Acu-TENS vs 25% in placebo, P = 0.02). The plasma beta-endorphin levels of the Acu-TENS group were significantly higher than that of the placebo group at barostat inflation pressure of 24 mmHg (1.31 ± 0.40 ng/mL vs 1.04 ± 0.43 ng/mL, P = 0.044) and at maximal inflation pressure (1.46 ± 0.53 ng/mL vs 0.95 ± 0.38 ng/mL, P = 0.003).
CONCLUSION: Acu-TENS reduced rectal discomfort during barostat-induced rectal distension and concurrently associated with a rise in beta-endorphin level.
PMCID: PMC3554823  PMID: 23372361
Colonoscopy; Rectal discomfort; Transcutaneous electrical nerve stimulation; Acupuncture; Visceral pain

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