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1.  Identification of six new susceptibility loci for invasive epithelial ovarian cancer 
Kuchenbaecker, Karoline B. | Ramus, Susan J. | Tyrer, Jonathan | Lee, Andrew | Shen, Howard C. | Beesley, Jonathan | Lawrenson, Kate | McGuffog, Lesley | Healey, Sue | Lee, Janet M. | Spindler, Tassja J. | Lin, Yvonne G. | Pejovic, Tanja | Bean, Yukie | Li, Qiyuan | Coetzee, Simon | Hazelett, Dennis | Miron, Alexander | Southey, Melissa | Terry, Mary Beth | Goldgar, David E. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Neuhausen, Susan L. | Ding, Yuan Chun | Hansen, Thomas V. O. | Jønson, Lars | Gerdes, Anne-Marie | Ejlertsen, Bent | Barrowdale, Daniel | Dennis, Joe | Benitez, Javier | Osorio, Ana | Garcia, Maria Jose | Komenaka, Ian | Weitzel, Jeffrey N. | Ganschow, Pamela | Peterlongo, Paolo | Bernard, Loris | Viel, Alessandra | Bonanni, Bernardo | Peissel, Bernard | Manoukian, Siranoush | Radice, Paolo | Papi, Laura | Ottini, Laura | Fostira, Florentia | Konstantopoulou, Irene | Garber, Judy | Frost, Debra | Perkins, Jo | Platte, Radka | Ellis, Steve | Godwin, Andrew K. | Schmutzler, Rita Katharina | Meindl, Alfons | Engel, Christoph | Sutter, Christian | Sinilnikova, Olga M. | Damiola, Francesca | Mazoyer, Sylvie | Stoppa-Lyonnet, Dominique | Claes, Kathleen | De Leeneer, Kim | Kirk, Judy | Rodriguez, Gustavo C. | Piedmonte, Marion | O'Malley, David M. | de la Hoya, Miguel | Caldes, Trinidad | Aittomäki, Kristiina | Nevanlinna, Heli | Collée, J. Margriet | Rookus, Matti A. | Oosterwijk, Jan C. | Tihomirova, Laima | Tung, Nadine | Hamann, Ute | Isaacs, Claudine | Tischkowitz, Marc | Imyanitov, Evgeny N. | Caligo, Maria A. | Campbell, Ian | Hogervorst, Frans B.L. | Olah, Edith | Diez, Orland | Blanco, Ignacio | Brunet, Joan | Lazaro, Conxi | Pujana, Miquel Angel | Jakubowska, Anna | Gronwald, Jacek | Lubinski, Jan | Sukiennicki, Grzegorz | Barkardottir, Rosa B. | Plante, Marie | Simard, Jacques | Soucy, Penny | Montagna, Marco | Tognazzo, Silvia | Teixeira, Manuel R. | Pankratz, Vernon S. | Wang, Xianshu | Lindor, Noralane | Szabo, Csilla I. | Kauff, Noah | Vijai, Joseph | Aghajanian, Carol A. | Pfeiler, Georg | Berger, Andreas | Singer, Christian F. | Tea, Muy-Kheng | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Rennert, Gad | Mulligan, Anna Marie | Tchatchou, Sandrine | Andrulis, Irene L. | Glendon, Gord | Toland, Amanda Ewart | Jensen, Uffe Birk | Kruse, Torben A. | Thomassen, Mads | Bojesen, Anders | Zidan, Jamal | Friedman, Eitan | Laitman, Yael | Soller, Maria | Liljegren, Annelie | Arver, Brita | Einbeigi, Zakaria | Stenmark-Askmalm, Marie | Olopade, Olufunmilayo I. | Nussbaum, Robert L. | Rebbeck, Timothy R. | Nathanson, Katherine L. | Domchek, Susan M. | Lu, Karen H. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Fasching, Peter A. | Lambrechts, Diether | Nieuwenhuysen, Els Van | Vergote, Ignace | Lambrechts, Sandrina | Dicks, Ed | Doherty, Jennifer A. | Wicklund, Kristine G. | Rossing, Mary Anne | Rudolph, Anja | Chang-Claude, Jenny | Wang-Gohrke, Shan | Eilber, Ursula | Moysich, Kirsten B. | Odunsi, Kunle | Sucheston-Campbell, Lara | Lele, Shashi | Wilkens, Lynne R. | Goodman, Marc T. | Thompson, Pamela J. | Shvetsov, Yurii B. | Runnebaum, Ingo B. | Dürst, Matthias | Hillemanns, Peter | Dörk, Thilo | Antonenkova, Natalia | Bogdanova, Natalia | Leminen, Arto | Pelttari, Liisa M. | Butzow, Ralf | Modugno, Francesmary | Kelley, Joseph L. | Edwards, Robert P. | Ness, Roberta B. | du Bois, Andreas | Heitz, Florian | Schwaab, Ira | Harter, Philipp | Matsuo, Keitaro | Hosono, Satoyo | Orsulic, Sandra | Jensen, Allan | Kjaer, Susanne Kruger | Hogdall, Estrid | Hasmad, Hanis Nazihah | Noor Azmi, Mat Adenan | Teo, Soo-Hwang | Woo, Yin-Ling | Fridley, Brooke L. | Goode, Ellen L. | Cunningham, Julie M. | Vierkant, Robert A. | Bruinsma, Fiona | Giles, Graham G. | Liang, Dong | Hildebrandt, Michelle A.T. | Wu, Xifeng | Levine, Douglas A. | Bisogna, Maria | Berchuck, Andrew | Iversen, Edwin S. | Schildkraut, Joellen M. | Concannon, Patrick | Weber, Rachel Palmieri | Cramer, Daniel W. | Terry, Kathryn L. | Poole, Elizabeth M. | Tworoger, Shelley S. | Bandera, Elisa V. | Orlow, Irene | Olson, Sara H. | Krakstad, Camilla | Salvesen, Helga B. | Tangen, Ingvild L. | Bjorge, Line | van Altena, Anne M. | Aben, Katja K.H. | Kiemeney, Lambertus A. | Massuger, Leon F.A.G. | Kellar, Melissa | Brooks-Wilson, Angela | Kelemen, Linda E. | Cook, Linda S. | Le, Nhu D. | Cybulski, Cezary | Yang, Hannah | Lissowska, Jolanta | Brinton, Louise A. | Wentzensen, Nicolas | Hogdall, Claus | Lundvall, Lene | Nedergaard, Lotte | Baker, Helen | Song, Honglin | Eccles, Diana | McNeish, Ian | Paul, James | Carty, Karen | Siddiqui, Nadeem | Glasspool, Rosalind | Whittemore, Alice S. | Rothstein, Joseph H. | McGuire, Valerie | Sieh, Weiva | Ji, Bu-Tian | Zheng, Wei | Shu, Xiao-Ou | Gao, Yu-Tang | Rosen, Barry | Risch, Harvey A. | McLaughlin, John R. | Narod, Steven A. | Monteiro, Alvaro N. | Chen, Ann | Lin, Hui-Yi | Permuth-Wey, Jenny | Sellers, Thomas A. | Tsai, Ya-Yu | Chen, Zhihua | Ziogas, Argyrios | Anton-Culver, Hoda | Gentry-Maharaj, Aleksandra | Menon, Usha | Harrington, Patricia | Lee, Alice W. | Wu, Anna H. | Pearce, Celeste L. | Coetzee, Gerhard A. | Pike, Malcolm C. | Dansonka-Mieszkowska, Agnieszka | Timorek, Agnieszka | Rzepecka, Iwona K. | Kupryjanczyk, Jolanta | Freedman, Matt | Noushmehr, Houtan | Easton, Douglas F. | Offit, Kenneth | Couch, Fergus J. | Gayther, Simon | Pharoah, Paul P. | Antoniou, Antonis C. | Chenevix-Trench, Georgia
Nature genetics  2015;47(2):164-171.
doi:10.1038/ng.3185
PMCID: PMC4445140  PMID: 25581431
2.  Navigating Longitudinal Clinical Notes with an Automated Method for Detecting New Information 
Automated methods to detect new information in clinical notes may be valuable for navigating and using information in these documents for patient care. Statistical language models were evaluated as a means to quantify new information over longitudinal clinical notes for a given patient. The new information proportion (NIP) in target notes decreased logarithmically with increasing numbers of previous notes to create the language model. For a given patient, the amount of new information had cyclic patterns. Higher NIP scores correlated with notes having more new information often with clinically significant events, and lower NIP scores indicated notes with less new information. Our analysis also revealed “copying and pasting” to be widely used in generating clinical notes by copying information from the most recent historical clinical notes forward. These methods can potentially aid clinicians in finding notes with more clinically relevant new information and in reviewing notes more purposefully which may increase the efficiency of clinicians in delivering patient care.
PMCID: PMC4495914  PMID: 23920658
Electronic Health Records; Natural Language Processing; Text Mining; Information Storage and Retrieval
3.  Molecular Analysis of Mixed Endometrioid and Serous Adenocarcinoma of the Endometrium 
PLoS ONE  2015;10(7):e0130909.
Background
The molecular biology and cellular origins of mixed type endometrial carcinomas (MT-ECs) are poorly understood, and a Type II component of 10 percent or less may confer poorer prognoses.
Methodology/Principal Findings
We studied 10 cases of MT-EC (containing endometrioid and serous differentiation), 5 pure low-grade endometrioid adenocarcinoma (EAC) and 5 pure uterine serous carcinoma (USC). Endometrioid and serous components of the MT-ECs were macrodissected and the expression of 60 candidate genes compared between MT-EC, pure USC and pure EAC. We found that four genes were differentially expressed when MT-ECs were compared to pure low-grade EAC: CDKN2A (P = 0.006), H19 (P = 0.010), HOMER2 (P = 0.009) and TNNT1 (P = 0.006). Also while we found that even though MT-ECs closely resembled the molecular profiles of pure USCs, they also exhibit lower expression of PAX8 compared to all pure cases combined (P = 0.035).
Conclusion
Our data suggest that MT-EC exhibits the closest molecular and epidemiological similarities to pure USC and supports clinical observations that suggest patients with MT-EC should receive the same treatment as patients with pure serous carcinoma. Novel specific markers of MT-EC could be of diagnostic utility and could represent novel therapeutic targets in the future.
doi:10.1371/journal.pone.0130909
PMCID: PMC4488511  PMID: 26132201
4.  A placebo-controlled study of sertraline’s effect on cortisol response to the dexamethasone/corticotropin-releasing hormone test in healthy adults 
Psychopharmacology  2011;218(2):371-379.
Rationale
The dexamethasone/corticotropin-releasing hormone (Dex/CRH) test is a neuroendocrine probe involving serial blood sampling of cortisol during a standardized pharmacological challenge without inducing psychological distress in humans. Some past studies in depressed patients have shown a “normalization” or decrease in cortisol response to the Dex/CRH test following successful treatment with an antidepressant. Studies in nondepressed healthy adult samples have also shown aberrant cortisol reactivity to be associated with depression risk factors. These findings prompted research into the use of the Dex/CRH test as a tool for developing antidepressant drugs.
Objectives
In this study, the Dex/CRH test was evaluated with regard to its potential utility for drug development in nonclinical samples.
Methods
The Dex/CRH test was administered before and after 6 weeks of blinded treatment with either sertraline 100 mg/day or matching placebo in 22 healthy adults (13 women, nine men).
Results
Cortisol response to the Dex/CRH test increased following treatment with standard doses of sertraline, compared to placebo, after controlling for age and sex.
Conclusions
The observed pattern of change contrasts with results from published studies in depressed patients and with our initial hypothesis.
doi:10.1007/s00213-011-2336-y
PMCID: PMC4467780  PMID: 21617914
Sertraline; Dex/CRH test; Cortisol; HPA axis
5.  PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis 
Although aging is a known risk factor for idiopathic pulmonary fibrosis (IPF), the pathogenic mechanisms that underlie the effects of advancing age remain largely unexplained. Some age-related neurodegenerative diseases have an etiology that is related to mitochondrial dysfunction. Here, we found that alveolar type II cells (AECIIs) in the lungs of IPF patients exhibit marked accumulation of dysmorphic and dysfunctional mitochondria. These mitochondrial abnormalities in AECIIs of IPF lungs were associated with upregulation of ER stress markers and were recapitulated in normal mice with advancing age in response to stimulation of ER stress. We found that impaired mitochondria in IPF and aging lungs were associated with low expression of PTEN-induced putative kinase 1 (PINK1). Knockdown of PINK1 expression in lung epithelial cells resulted in mitochondria depolarization and expression of profibrotic factors. Moreover, young PINK1-deficient mice developed similarly dysmorphic, dysfunctional mitochondria in the AECIIs and were vulnerable to apoptosis and development of lung fibrosis. Our data indicate that PINK1 deficiency results in swollen, dysfunctional mitochondria and defective mitophagy, and promotes fibrosis in the aging lung.
doi:10.1172/JCI74942
PMCID: PMC4319413  PMID: 25562319
6.  Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study 
Annals of the Rheumatic Diseases  2013;74(4):694-702.
Objectives
The interleukin-6 receptor (IL-6R) blocker tocilizumab (TCZ) reduces inflammatory disease activity in rheumatoid arthritis (RA) but elevates lipid concentrations in some patients. We aimed to characterise the impact of IL-6R inhibition on established and novel risk factors in active RA.
Methods
Randomised, multicentre, two-part, phase III trial (24-week double-blind, 80-week open-label), MEASURE, evaluated lipid and lipoprotein levels, high-density lipoprotein (HDL) particle composition, markers of coagulation, thrombosis and vascular function by pulse wave velocity (PWV) in 132 patients with RA who received TCZ or placebo.
Results
Median total-cholesterol, low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels increased in TCZ versus placebo recipients by week 12 (12.6% vs 1.7%, 28.1% vs 2.2%, 10.6% vs −1.9%, respectively; all p<0.01). There were no significant differences in mean small LDL, mean oxidised LDL or total HDL-C concentrations. However, HDL-associated serum amyloid A content decreased in TCZ recipients. TCZ also induced reductions (>30%) in secretory phospholipase A2-IIA, lipoprotein(a), fibrinogen and D-dimers and elevation of paraoxonase (all p<0.0001 vs placebo). The ApoB/ApoA1 ratio remained stable over time in both groups. PWV decreases were greater with placebo than TCZ at 12 weeks (adjusted mean difference 0.79 m/s (95% CI 0.22 to 1.35; p=0.0067)).
Conclusions
These data provide the first detailed evidence for the modulation of lipoprotein particles and other surrogates of vascular risk with IL-6R inhibition. When compared with placebo, TCZ induced elevations in LDL-C but altered HDL particles towards an anti-inflammatory composition and favourably modified most, but not all, measured vascular risk surrogates. The net effect of such changes for cardiovascular risk requires determination.
doi:10.1136/annrheumdis-2013-204345
PMCID: PMC4392313  PMID: 24368514
Cardiovascular Disease; Lipids; Inflammation; Rheumatoid Arthritis; DMARDs (biologic)
7.  Duffy Antigen Facilitates Movement of Chemokine Across the Endothelium In Vitro and Promotes Neutrophil Transmigration In Vitro and In Vivo1 
The Duffy Ag expressed on RBCs, capillaries, and postcapillary venular endothelial cells binds selective CXC and CC chemokines with high affinity. Cells transfected with the Duffy Ag internalize but do not degrade chemokine ligand. It has been proposed that Duffy Ag transports chemokines across the endothelium. We hypothesized that Duffy Ag participates in the movement of chemokines across the endothelium and, by doing so, modifies neutrophil transmigration. We found that the Duffy Ag transfected into human endothelial cells facilitates movement of the radiolabeled CXC chemokine, growth related oncogene-α/CXC chemokine ligand 1 (GRO-α/CXCL1), across an endothelial monolayer. In addition, neutrophil migration toward GRO-α/CXCL1 and IL-8 (IL-8/CXCL8) was enhanced across an endothelial monolayer expressing the Duffy Ag. Furthermore, GRO-α/CXCL1 stimulation of endothelial cells expressing the Duffy Ag did not affect gene expression by oligonucleotide microarray analysis. These in vitro observations are supported by the finding that IL-8/CXCL8-driven neutrophil recruitment into the lungs was markedly attenuated in transgenic mice lacking the Duffy Ag. We conclude that Duffy Ag has a role in enhancing leukocyte recruitment to sites of inflammation by facilitating movement of chemokines across the endothelium.
PMCID: PMC4357319  PMID: 12734373
8.  Using Language Models to Identify Relevant New Information in Inpatient Clinical Notes 
AMIA Annual Symposium Proceedings  2014;2014:1268-1276.
Redundant information in clinical notes within electronic health record (EHR) systems is ubiquitous and may negatively impact the use of these notes by clinicians, and, potentially, the efficiency of patient care delivery. Automated methods to identify redundant versus relevant new information may provide a valuable tool for clinicians to better synthesize patient information and navigate to clinically important details. In this study, we investigated the use of language models for identification of new information in inpatient notes, and evaluated our methods using expert-derived reference standards. The best method achieved precision of 0.743, recall of 0.832 and F1-measure of 0.784. The average proportion of redundant information was similar between inpatient and outpatient progress notes (76.6% (SD=17.3%) and 76.7% (SD=14.0%), respectively). Advanced practice providers tended to have higher rates of redundancy in their notes compared to physicians. Future investigation includes the addition of semantic components and visualization of new information.
PMCID: PMC4419897  PMID: 25954438
9.  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.
Background
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.
Objective
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
Design
Prospective, randomized controlled experimental murine study. Observational clinical cohort analysis.
Setting
University research laboratory. Eight ICUs at a tertiary care center.
Patients
870 septic ICU patients.
Subjects
C57BL/6 and CaMKK−/− mice.
Interventions
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).
Conclusions
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.
doi:10.1097/CCM.0b013e31828cf436
PMCID: PMC3812408  PMID: 23887235
calcium; sepsis; infection; inflammation; calcium/calmodulin-dependent protein kinase; mortality; organ failure
10.  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
11.  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.
doi:10.1038/mi.2013.63
PMCID: PMC3945733  PMID: 24045574
Thrombospondin-1; Injury Resolution
12.  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.
doi:10.2337/db12-1093
PMCID: PMC3712060  PMID: 23434931
13.  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.
doi:10.4251/wjgo.v6.i6.184
PMCID: PMC4058726  PMID: 24936229
Rectal cancer; Robotics; Minimal invasive surgery; Systematic review; Rectal surgery
14.  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.
doi:10.4049/jimmunol.1102975
PMCID: PMC3608723  PMID: 23447692
15.  Red blood cell microparticles show altered inflammatory chemokine binding and release ligand upon interaction with platelets 
Transfusion  2010;51(3):610-621.
BACKGROUND
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.
STUDY DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSION
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.
doi:10.1111/j.1537-2995.2010.02861.x
PMCID: PMC3963470  PMID: 20738825
16.  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.
doi:10.4049/jimmunol.1003221
PMCID: PMC3912553  PMID: 21278339
17.  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.
doi:10.4161/cc.23308
PMCID: PMC3587445  PMID: 23324348
mesenchymal stem/stromal cells; transdifferentiation; cyclin-dependent kinase 4; neural cells; glial cells; cell cycle arrest; neurodegenerative disease
18.  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.
Background
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.
Conclusions
The results of these studies suggest new mechanisms for endothelial injury and impaired vascular function associated with the most fundamental of storage lesions, hemolysis.
doi:10.1161/CIRCULATIONAHA.110.008698
PMCID: PMC3891836  PMID: 21747051
Hemoglobin; microparticles; nitric oxide; blood transfusion; storage lesion; reactive oxygen species
19.  Effect of tocilizumab on haematological markers implicates interleukin-6 signalling in the anaemia of rheumatoid arthritis 
Arthritis Research & Therapy  2013;15(6):R204.
Introduction
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/ar4397
PMCID: PMC3978585  PMID: 24295403
20.  Neuroendocrine Predictors of Emotional and Behavioral Adjustment in Boys: Longitudinal Follow-Up of a Community Sample 
Psychoneuroendocrinology  2012;37(12):2042-2046.
Background
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.
Method
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.
Results
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.
Conclusion
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.
doi:10.1016/j.psyneuen.2012.04.004
PMCID: PMC3458171  PMID: 22575356
children; adolescents; boys; depression; cortisol; anxiety; HPA axis; stress reactivity; longitudinal; prospective
21.  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.
doi:10.1371/journal.pone.0081903
PMCID: PMC3842245  PMID: 24312378
22.  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.
doi:10.1155/2013/631028
PMCID: PMC3836296  PMID: 24307961
23.  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.
doi:10.1159/000337434
PMCID: PMC3804221  PMID: 22572241
chemokines; macrophages; pattern recognition receptors
24.  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.
doi:10.12688/f1000research.2-216.v1
PMCID: PMC3886788  PMID: 24555104
25.  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.
doi:10.1038/ng.2564
PMCID: PMC3693183  PMID: 23535730

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