id
int64 37.5k
3.5M
| image
unknown | bboxes
sequence | tokens
sequence | ner_tags
sequence |
---|---|---|---|---|
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] | [
"SAGE-Hindawi",
"Access",
"to",
"Research",
"Veterinary",
"Medicine",
"International",
"Volume",
"2010,",
"Article",
"ID",
"485060,",
"5",
"pages",
"doi:10.4061/2010/485060",
"Research",
"Article",
"The",
"Immune",
"Enhancement",
"of",
"Sodium",
"Lauryl",
"Sulfoacetate",
"in",
"Chickens",
"DaRong",
"Cheng,1",
"ShanYuan",
"Zhu,2",
"and",
"HuaiChang",
"Sun1",
"1",
"College",
"of",
"Veterinary",
"Medicine,",
"Yangzhou",
"University,",
"Yangzhou",
"225009,",
"China",
"2",
"Department",
"of",
"Pharmacy,",
"Jiangsu",
"Animal",
"Husbandry",
"and",
"Veterinary",
"College,",
"Taizhou",
"225300,",
"China",
"Correspondence",
"should",
"be",
"addressed",
"to",
"DaRong",
"Cheng,",
"jsyzcdr@yahoo.com.cn",
"Received",
"27",
"August",
"2009;",
"Revised",
"10",
"January",
"2010;",
"Accepted",
"2",
"March",
"2010",
"Academic",
"Editor:",
"Maurice",
"Pensaert",
"Copyright",
"©",
"2010",
"DaRong",
"Cheng",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"The",
"purpose",
"of",
"this",
"study",
"is",
"to",
"investigate",
"feasibility",
"of",
"sodium",
"lauryl",
"sulfoacetate",
"(SLS)",
"as",
"an",
"immunoadjuvant",
"in",
"chickens.",
"After",
"treating",
"with",
"62.5,",
"125,",
"250,",
"or",
"500",
"μg/mL",
"SLS",
"in",
"vitro,",
"lymphocyte",
"proliferation",
"assay",
"of",
"chicken",
"peripheral",
"blood",
"mononuclear",
"cells",
"showed",
"that",
"the",
"OD570",
"values",
"of",
"all",
"experimental",
"groups,",
"as",
"well",
"as",
"Con",
"A-stimulated",
"group,",
"were",
"significantly",
"higher",
"than",
"that",
"of",
"the",
"untreated",
"control",
"group.",
"After",
"injection",
"with",
"1.0,",
"2.0,",
"or",
"4.0",
"mg/kg",
"of",
"SLS",
"for",
"3",
"consecutive",
"days,",
"chickens",
"were",
"vaccinated",
"with",
"an",
"attenuated",
"vaccine",
"against",
"Newcastle",
"disease",
"virus",
"(NDV),",
"and",
"the",
"immunoadjuvant",
"effects",
"of",
"SLS",
"were",
"evaluated",
"on",
"the",
"basis",
"of",
"immune",
"organ",
"index,",
"antibody",
"response,",
"and",
"CD4+/CD8+",
"T-cell",
"ratio.",
"The",
"results",
"confirmed",
"that",
"SLS",
"could",
"enhance",
"NDV-",
"specific",
"antibody",
"response",
"and",
"increase",
"CD4+/CD8+",
"T-cell",
"ratio",
"in",
"vivo.",
"Furthermore,",
"SLS",
"could",
"improve",
"NDV-specific",
"antibody",
"response",
"in",
"thiamphenicol-treated",
"chickens.",
"These",
"data",
"indicate",
"that",
"SLS",
"not",
"only",
"can",
"improve",
"humoral",
"immune",
"response",
"but",
"also",
"reverse",
"the",
"immunosuppressive",
"effect",
"of",
"thiamphenicol",
"in",
"chickens.",
"1.",
"Introduction",
"Houttuynia",
"cordata",
"thunb",
"(Saururaceae,",
"HC)",
"is",
"a",
"therapeutic",
"drug",
"which",
"has",
"been",
"used",
"for",
"the",
"treatment",
"of",
"infections,",
"allergy",
"and",
"cancers",
"[1–9].",
"The",
"major",
"active",
"component",
"of",
"the",
"herb",
"is",
"houttuynin,",
"which",
"is",
"present",
"in",
"the",
"fraction",
"of",
"volatile",
"oil",
"with",
"antimicrobial,",
"antioxidative,",
"antimuta-",
"genic,",
"and",
"immunoadjuvant",
"effects",
"[10–12].",
"The",
"modified",
"form",
"of",
"houttuynin,",
"called",
"sodium",
"houttuyfonate",
"(SH,",
"C12H23NaO5S,",
"MW",
"302.36),",
"has",
"potent",
"immunoadjuvant",
"effects",
"including",
"promotion",
"of",
"phagocytosis",
"and",
"secretion",
"of",
"lysozyme,",
"acidic",
"phosphatase",
"and",
"IL-1β",
"by",
"macrophages",
"[13–16].",
"To",
"reduce",
"the",
"cytotoxicitic",
"effect",
"of",
"SH,",
"sodium",
"lauryl",
"sulfoacetate",
"(SLS,",
"brand",
"name",
"is",
"sodium",
"new",
"houttuy-",
"fonate,",
"SNH,",
"C14H27NaO5S,",
"MW",
"330.4,",
"Figure",
"1)",
"has",
"been",
"generated",
"by",
"additive",
"reaction",
"with",
"houttuynin",
"and",
"sodium",
"bisulfite,",
"which",
"has",
"also",
"been",
"widely",
"used",
"for",
"the",
"treat-",
"ment",
"of",
"infections,",
"inflammation,",
"anaphylaxis,",
"and",
"cancers",
"[17,",
"18].",
"To",
"investigate",
"the",
"feasibility",
"of",
"SLS",
"as",
"an",
"immunoad-",
"juvant",
"for",
"chickens,",
"in",
"this",
"study",
"lymphocyte",
"prolifera-",
"tion",
"assay",
"was",
"performed",
"using",
"chicken",
"peripheral",
"blood",
"mononuclear",
"cells",
"(PBMCs)",
"in",
"the",
"presence",
"of",
"different",
"doses",
"of",
"SLS.",
"Then,",
"the",
"in",
"vivo",
"immunoadjuvant",
"effect",
"was",
"confirmed",
"according",
"to",
"the",
"immune",
"organ",
"index,",
"antibody",
"response,",
"and",
"CD4+/CD8+",
"T-cell",
"ratio",
"of",
"the",
"chickens",
"vaccinated",
"with",
"an",
"attenuated",
"vaccine",
"against",
"Newcastle",
"disease",
"virus",
"(NDV)",
"with",
"SLS",
"or",
"SLS",
"plus",
"thiamphenicol",
"treatment.",
"2.",
"Materials",
"and",
"Methods",
"2.1.",
"Materials",
"and",
"Animals.",
"11-day-old",
"unvaccinated",
"local",
"breed",
"Shanhuang",
"chickens",
"were",
"provided",
"by",
"the",
"Jiangsu",
"Institute",
"of",
"Poultry",
"Science.",
"0.2%",
"SLS",
"in",
"0.85%",
"sodium",
"chloride",
"solution",
"was",
"provided",
"by",
"the",
"Animal",
"Pharma-",
"ceutical",
"Center,",
"Jiangsu",
"Animal",
"Husbandry",
"and",
"Veteri-",
"nary",
"College.",
"Ficoll-paque",
"lymphocyte",
"separation",
"medium",
"(5.7%",
"(w/v)",
"ficoll",
"400,",
"9.0%",
"(w/v)",
"sodium",
"diatrizoate,",
"and",
"D",
"=",
"1.077",
"±",
"0.002)",
"was",
"from",
"Shanghai",
"Huajing",
"Bio-tech",
"Company",
"Limited.",
"RPMI",
"1640",
"medium",
"was",
"the",
"product",
"of",
"GIBCO",
"(USA).",
"Fetal",
"calf",
"serum",
"(FCS)",
"was",
"purchased",
"from",
"Hangzhou",
"Sijiqing",
"Biological",
"Engineer-",
"ing",
"Materials",
"Company",
"Limited.",
"Concanavalin",
"A",
"(Con",
"A),",
"methylthiazolyldiphenyl-tetrazolium",
"MTT",
"bromide,",
"and"
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] | [
"Three",
"Dimensional",
"Assessment",
"of",
"the",
"Pharyngeal",
"Airway",
"in",
"Individuals",
"with",
"Non-Syndromic",
"Cleft",
"Lip",
"and",
"Palate",
"Tracy",
"Cheung1,",
"Snehlata",
"Oberoi2*",
"1",
"University",
"of",
"California",
"Los",
"Angeles,",
"Los",
"Angeles,",
"California,",
"United",
"States",
"of",
"America,",
"2",
"Division",
"of",
"Orthodontics,",
"Department",
"of",
"Orofacial",
"Sciences,",
"School",
"of",
"Dentistry,",
"University",
"of",
"California",
"San",
"Francisco,",
"San",
"Francisco,",
"California,",
"United",
"States",
"of",
"America",
"Abstract",
"Introduction:",
"Children",
"with",
"cleft",
"lip",
"and",
"palate",
"(CLP)",
"are",
"known",
"to",
"have",
"airway",
"problems.",
"Previous",
"studies",
"have",
"shown",
"that",
"individuals",
"with",
"CLP",
"have",
"a",
"30%",
"reduction",
"in",
"nasal",
"airway",
"size",
"compared",
"to",
"non-cleft",
"controls.",
"No",
"reports",
"have",
"been",
"found",
"on",
"cross-sectional",
"area",
"and",
"volume",
"of",
"the",
"pharyngeal",
"airway",
"in",
"clefts.",
"Introduction",
"of",
"Cone-Beam",
"CT",
"(CBCT)",
"and",
"imaging",
"software",
"has",
"facilitated",
"generation",
"of",
"3D",
"images",
"for",
"assessment",
"of",
"the",
"cross-sectional",
"area",
"and",
"volume",
"of",
"the",
"airway.",
"Objective:",
"To",
"assess",
"the",
"pharyngeal",
"airway",
"in",
"individuals",
"with",
"CLP",
"using",
"CBCT",
"by",
"measuring",
"volume",
"and",
"smallest",
"cross-",
"sectional",
"areas",
"and",
"compare",
"with",
"19",
"age-",
"and",
"sex-matched",
"non-cleft",
"controls.",
"Methods:",
"Retrospective",
"study",
"of",
"CBCT",
"data",
"of",
"pre-adolescent",
"individuals",
"(N",
"=",
"19,",
"Mean",
"age",
"=",
"10.6,",
"7",
"females,",
"12",
"males,",
"UCLP",
"=",
"6,",
"BCLP",
"=",
"3)",
"from",
"the",
"Center",
"for",
"Craniofacial",
"Anomalies.",
"Volumetric",
"analysis",
"was",
"performed",
"using",
"image",
"segmentation",
"features",
"in",
"CB",
"Works",
"3.0.",
"Volume",
"and",
"smallest",
"cross-sectional",
"were",
"studied",
"in",
"both",
"groups.",
"Seven",
"measurements",
"were",
"repeated",
"to",
"verify",
"reliability",
"using",
"Pearson",
"correlation",
"coefficient.",
"Volume",
"and",
"cross-sectional",
"area",
"differences",
"were",
"analyzed",
"using",
"paired",
"t-tests.",
"Results:",
"The",
"method",
"was",
"found",
"to",
"be",
"reliable.",
"Individuals",
"with",
"CLP",
"did",
"not",
"exhibit",
"smaller",
"total",
"airway",
"volume",
"and",
"cross",
"sectional",
"area",
"than",
"non-CLP",
"controls.",
"Conclusion:",
"3D",
"imaging",
"using",
"CBCT",
"and",
"CB",
"Works",
"is",
"reliable",
"for",
"assessing",
"airway",
"volume.",
"Previous",
"studies",
"have",
"shown",
"that",
"the",
"nasal",
"airway",
"is",
"restricted",
"in",
"individuals",
"with",
"CLP.",
"In",
"our",
"study,",
"we",
"found",
"that",
"the",
"pharyngeal",
"airway",
"is",
"not",
"compromised",
"in",
"these",
"individuals.",
"Citation:",
"Cheung",
"T,",
"Oberoi",
"S",
"(2012)",
"Three",
"Dimensional",
"Assessment",
"of",
"the",
"Pharyngeal",
"Airway",
"in",
"Individuals",
"with",
"Non-Syndromic",
"Cleft",
"Lip",
"and",
"Palate.",
"PLoS",
"ONE",
"7(8):",
"e43405.",
"doi:10.1371/journal.pone.0043405",
"Editor:",
"Noam",
"A.",
"Cohen,",
"Hospital",
"of",
"the",
"University",
"of",
"Pennsylvania,",
"United",
"States",
"of",
"America",
"Received",
"March",
"21,",
"2012;",
"Accepted",
"July",
"20,",
"2012;",
"Published",
"August",
"29,",
"2012",
"Copyright:",
"2012",
"Cheung,",
"Oberoi.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"No",
"current",
"external",
"funding",
"sources",
"for",
"this",
"study.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"sneha.oberoi@ucsf.edu",
"Introduction",
"Birth",
"defects",
"affect",
"approximately",
"3%",
"of",
"all",
"births",
"and",
"contribute",
"substantially",
"to",
"childhood",
"morbidity",
"in",
"the",
"United",
"States",
"[1].",
"Orofacial",
"defects",
"like",
"cleft",
"lip",
"and/or",
"palate",
"(CLP)",
"occur",
"in",
"an",
"estimated",
"6,800",
"children",
"annually,",
"making",
"it",
"the",
"most",
"common",
"birth",
"defect",
"in",
"the",
"United",
"States",
"[2].",
"Anatomical",
"abnormalities",
"associated",
"with",
"CLP",
"increase",
"the",
"risk",
"of",
"airway",
"complications",
"[3].",
"CLP",
"are",
"frequently",
"associated",
"with",
"nasal",
"abnormalities",
"such",
"as",
"septal",
"deviation,",
"nostril",
"atresia,",
"turbinate",
"hypertrophy,",
"maxillary",
"constriction,",
"vomerine",
"spurs,",
"and",
"alar",
"constriction",
"[4,5,6,7,8].",
"These",
"abnormalities",
"are",
"attributed",
"in",
"part",
"to",
"the",
"congenital",
"defect",
"itself",
"and",
"partly",
"to",
"the",
"surgeries",
"done",
"to",
"repair",
"the",
"orofacial",
"defect",
"[9,10].",
"Collectively,",
"the",
"nasal",
"abnormalities",
"tend",
"to",
"reduce",
"the",
"dimensions",
"of",
"the",
"nasal",
"cavity",
"and",
"lower",
"airway",
"function",
"[6,11].",
"Airway",
"patency",
"has",
"been",
"evaluated",
"by",
"two-dimensional",
"(2D)",
"radiographic",
"imaging",
"such",
"as",
"lateral",
"and",
"anterior-posterior",
"cephalometric",
"films",
"and",
"functional",
"studies",
"such",
"as",
"rhinomano-",
"metry",
"and",
"plethysmography",
"[12,13,14,15].",
"A",
"rhinomanometry",
"study",
"showed",
"that",
"individuals",
"with",
"bilateral",
"CLP",
"had",
"a",
"41%",
"reduction",
"in",
"nasal",
"airway",
"compared",
"to",
"a",
"19%",
"reduction",
"in",
"individuals",
"with",
"unilateral",
"CLP",
"[15].",
"Plethysmography",
"showed",
"that",
"individuals",
"with",
"CLP",
"had",
"a",
"30%",
"reduction",
"in",
"the",
"nasal",
"airway",
"compared",
"to",
"non-cleft",
"controls",
"[12].",
"Lateral",
"cephalometric",
"films",
"of",
"children",
"with",
"CLP",
"were",
"compared",
"with",
"non-cleft",
"controls",
"and",
"showed",
"a",
"reduction",
"in",
"the",
"nasopharyngeal",
"bony",
"framework",
"and",
"pharyngeal",
"airway",
"[16].",
"Furthermore,",
"a",
"reduction",
"in",
"the",
"upper",
"airway",
"in",
"juveniles",
"with",
"CLP",
"was",
"found",
"when",
"compared",
"to",
"gender",
"and",
"age",
"matched",
"non-cleft",
"controls",
"and",
"were",
"found",
"to",
"persist",
"through",
"adolescence",
"when",
"lateral",
"cephalometric",
"films",
"were",
"compared",
"[13].",
"Until",
"recently,",
"diagnostic",
"imaging",
"of",
"the",
"airway",
"has",
"been",
"limited",
"to",
"2D",
"studies.",
"Two-dimensional",
"imaging",
"using",
"lateral",
"head",
"films",
"is",
"useful",
"for",
"analyzing",
"airway",
"size",
"in",
"the",
"sagittal",
"plane,",
"but",
"does",
"not",
"depict",
"the",
"three-dimensional",
"anatomy.",
"The",
"physiologi-",
"cally",
"most",
"relevant",
"information",
"is",
"obtained",
"from",
"axial",
"images",
"which",
"are",
"perpendicular",
"to",
"the",
"direction",
"of",
"airflow,",
"but",
"the",
"axial",
"plane",
"is",
"not",
"visualized",
"on",
"lateral",
"cephalograms",
"[17].",
"In",
"addition,",
"lateral",
"cephalometric",
"films",
"have",
"many",
"limitations,",
"such",
"as",
"image",
"enlargement",
"and",
"distortion,",
"structure",
"overlap,",
"limited",
"identifiable",
"landmarks,",
"and",
"positioning",
"problems",
"that",
"may",
"adversely",
"affect",
"PLOS",
"ONE",
"|",
"www.plosone.org",
"1",
"August",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"8",
"|",
"e43405"
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] | [
"Eur",
"Radiol",
"(2008)",
"18:",
"1431–1441",
"DOI",
"10.1007/s00330-008-0906-0",
"I",
"N",
"T",
"E",
"RV",
"E",
"N",
"T",
"I",
"O",
"N",
"A",
"L",
"A.",
"C.",
"Schmitz",
"D.",
"Gianfelice",
"B.",
"L.",
"Daniel",
"W.",
"P.",
"Th.",
"M.",
"Mali",
"M.",
"A.",
"A.",
"J.",
"van",
"den",
"Bosch",
"Image-guided",
"focused",
"ultrasound",
"ablation",
"of",
"breast",
"cancer:",
"current",
"status,",
"challenges,",
"and",
"future",
"directions",
"Received:",
"26",
"September",
"2007",
"Revised:",
"4",
"December",
"2007",
"Accepted:",
"15",
"January",
"2008",
"Published",
"online:",
"20",
"March",
"2008",
"#",
"The",
"Author(s)",
"2008",
"A.",
"C.",
"Schmitz",
".",
"W.",
"P.",
"T.",
"M.",
"Mali",
".",
"M.",
"A.",
"A.",
"J.",
"van",
"den",
"Bosch",
"Department",
"of",
"Radiology,",
"University",
"Medical",
"Center",
"Utrecht,",
"Utrecht,",
"The",
"Netherlands",
"D.",
"Gianfelice",
"Department",
"of",
"Radiology,",
"University",
"Health",
"Network",
"C/O",
"Toronto",
"General",
"Hospital,",
"Toronto,",
"Canada",
"B.",
"L.",
"Daniel",
".",
"M.",
"A.",
"A.",
"J.",
"van",
"den",
"Bosch",
"Department",
"of",
"Radiology,",
"Stanford",
"University,",
"Stanford,",
"CA,",
"USA",
"M.",
"A.",
"A.",
"J.",
"van",
"den",
"Bosch",
"(*)",
"Department",
"of",
"Radiology,",
"Lucas",
"MR",
"Imaging",
"Center,",
"1201",
"Welch",
"Road,",
"Stanford,",
"CA,",
"94305-5488,",
"USA",
"e-mail:",
"mbosch@stanford.edu",
"Tel.:",
"+1-650-4987550",
"Fax:",
"+1-650-7367925",
"Abstract",
"Image-guided",
"focussed",
"ul-",
"trasound",
"(FUS)",
"ablation",
"is",
"a",
"non-",
"invasive",
"procedure",
"that",
"has",
"been",
"used",
"for",
"treatment",
"of",
"benign",
"or",
"malignant",
"breast",
"tumours.",
"Image-guidance",
"dur-",
"ing",
"ablation",
"is",
"achieved",
"either",
"by",
"using",
"real-time",
"ultrasound",
"(US)",
"or",
"magnetic",
"resonance",
"imaging",
"(MRI).",
"The",
"past",
"decade",
"phase",
"I",
"studies",
"have",
"proven",
"MRI-guided",
"and",
"US-guided",
"FUS",
"ablation",
"of",
"breast",
"cancer",
"to",
"be",
"technically",
"feasible",
"and",
"safe.",
"We",
"provide",
"an",
"overview",
"of",
"studies",
"asses-",
"sing",
"the",
"efficacy",
"of",
"FUS",
"for",
"breast",
"tumour",
"ablation",
"as",
"measured",
"by",
"per-",
"centages",
"of",
"complete",
"tumour",
"necrosis.",
"Successful",
"ablation",
"ranged",
"from",
"20%",
"to",
"100%,",
"depending",
"on",
"FUS",
"system",
"type,",
"imaging",
"technique,",
"ablation",
"protocol,",
"and",
"patient",
"selection.",
"Spe-",
"cific",
"issues",
"related",
"to",
"FUS",
"ablation",
"of",
"breast",
"cancer,",
"such",
"as",
"increased",
"treat-",
"ment",
"time",
"for",
"larger",
"tumours,",
"size",
"of",
"ablation",
"margins,",
"methods",
"used",
"for",
"margin",
"assessment",
"and",
"residual",
"tu-",
"mour",
"detection",
"after",
"FUS",
"ablation,",
"and",
"impact",
"of",
"FUS",
"ablation",
"on",
"senti-",
"nel",
"node",
"procedure",
"are",
"presented.",
"Finally,",
"potential",
"future",
"applications",
"of",
"FUS",
"for",
"breast",
"cancer",
"treatment",
"such",
"as",
"FUS-induced",
"anti-tumour",
"im-",
"mune",
"response,",
"FUS-mediated",
"gene",
"transfer,",
"and",
"enhanced",
"drug",
"delivery",
"are",
"discussed.",
"Currently,",
"breast-",
"conserving",
"surgery",
"remains",
"the",
"gold",
"standard",
"for",
"breast",
"cancer",
"treatment.",
"Keywords",
"Image-guided",
"therapy",
".",
"Focussed",
"ultrasound",
".",
"Breast",
"cancer",
".",
"Tumour",
"ablation",
".",
"Magnetic",
"resonance",
"imaging",
"Evolution",
"of",
"breast",
"cancer",
"treatment",
"Breast",
"cancer",
"is",
"the",
"most",
"frequently",
"occurring",
"malignant",
"disease",
"and",
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] | [
"Original",
"Article",
"Clinics",
"in",
"Orthopedic",
"Surgery",
"2011;3:279-284",
"http://dx.doi.org/10.4055/cios.2011.3.4.279",
"Medial",
"Unicompartmental",
"Knee",
"Arthroplasty",
"in",
"Patients",
"with",
"Spontaneous",
"Osteonecrosis",
"of",
"the",
"Knee",
"Won-Sik",
"Choy,",
"MD,",
"Kap",
"Jung",
"Kim,",
"MD,",
"Sang",
"Ki",
"Lee,",
"MD,",
"Dae",
"Suk",
"Yang,",
"MD,",
"Choon",
"Myeon",
"Kim,",
"MD,",
"Ju",
"Sang",
"Park,",
"MD",
"Department",
"of",
"Orthopaedic",
"Surgery,",
"Eulji",
"University",
"School",
"of",
"Medicine,",
"Daejeon,",
"Korea",
"Background:",
"We",
"analyzed",
"the",
"clinical",
"and",
"radiologic",
"results",
"of",
"patients",
"with",
"spontaneous",
"osteonecrosis",
"of",
"the",
"knee",
"treated",
"by",
"minimally",
"invasive",
"medial",
"unicompartmental",
"arthroplasty",
"using",
"Oxford",
"Uni.",
"Methods:",
"We",
"reviewed",
"22",
"knees",
"in",
"21",
"patients",
"which",
"were",
"treated",
"for",
"spontaneous",
"osteonecrosis",
"between",
"2002",
"and",
"2006.",
"Pa-",
"tients",
"included",
"one",
"male",
"and",
"20",
"females.",
"The",
"mean",
"age",
"was",
"70.8",
"years",
"(range,",
"53",
"to",
"82",
"years).",
"The",
"mean",
"follow-up",
"period",
"was",
"70.3",
"months",
"(range,",
"48",
"to",
"93",
"months).",
"The",
"clinical",
"results",
"were",
"evaluated",
"using",
"the",
"Hospital",
"for",
"Special",
"Surgery",
"(HSS)",
"knee",
"score",
"and",
"the",
"range",
"of",
"motion",
"of",
"the",
"knee",
"preoperatively",
"and",
"at",
"the",
"final",
"follow-up.",
"Preoperative",
"plain",
"radiographs",
"and",
"magnetic",
"reso-",
"nance",
"images",
"were",
"analyzed",
"to",
"determine",
"the",
"size",
"and",
"stage",
"of",
"osteonecrotic",
"lesions.",
"Results:",
"The",
"mean",
"HSS",
"knee",
"score",
"was",
"64.3",
"(range,",
"54",
"to",
"75)",
"preoperatively",
"and",
"92.0",
"(range,",
"71",
"to",
"100)",
"at",
"the",
"final",
"follow-up.",
"The",
"mean",
"preoperative",
"flexion",
"contracture",
"was",
"8.9o",
"(range,",
"0",
"to",
"15o)",
"and",
"0.2o",
"(range,",
"0",
"to",
"5o)",
"at",
"the",
"final",
"follow-up.",
"The",
"mean",
"fur-",
"ther",
"flexion",
"increased",
"from",
"138.6o",
"(range,",
"100",
"to",
"145o)",
"preoperatively",
"to",
"145.6o",
"(range,",
"140",
"to",
"150o)",
"at",
"the",
"final",
"follow-up.",
"Active",
"full",
"flexion",
"was",
"possible",
"within",
"2",
"months",
"of",
"the",
"operation.",
"The",
"squatting",
"position",
"was",
"possible",
"in",
"16",
"patients",
"(84.2%)",
"out",
"of",
"19,",
"except",
"one",
"case",
"of",
"bronchiectasis",
"and",
"one",
"case",
"of",
"spine",
"fracture.",
"The",
"cross-leg",
"posture",
"was",
"possible",
"in",
"19",
"patients",
"(90.5%)",
"out",
"of",
"21.",
"The",
"mean",
"tibiofemoral",
"angle",
"was",
"improved",
"from",
"varus",
"0.98o",
"to",
"valgus",
"3.22o.",
"Meniscal",
"bearing",
"dislocation",
"occurred",
"in",
"2",
"cases",
"and",
"femoral",
"component",
"loosening",
"occurred",
"in",
"1",
"case.",
"Conclusions:",
"Unicompartmental",
"knee",
"arthroplasty",
"using",
"Oxford",
"Uni",
"could",
"be",
"an",
"alternative",
"treatment",
"option",
"in",
"spontaneous",
"os-",
"teonecrosis",
"of",
"the",
"knee.",
"Keywords:",
"Knee,",
"Spontaneous",
"osteonecrosis,",
"Unicompartmental",
"knee",
"arthroplasty",
"Spontaneous",
"osteonecrosis",
"of",
"the",
"knee",
"(SPONK)",
"was",
"first",
"reported",
"by",
"Ahlback",
"et",
"al.1)",
"in",
"1968.",
"Since",
"then,",
"the",
"terms",
"SPONK",
"and",
"Ahlback’s",
"disease",
"have",
"been",
"used",
"synony-",
"mously.1)",
"The",
"typical",
"SPONK",
"patient",
"is",
"fifty-five",
"years",
"of",
"age",
"or",
"older,",
"has",
"no",
"risk",
"factors,",
"has",
"unilateral",
"monoar-",
"ticular",
"pain,",
"has",
"limited",
"involvement",
"of",
"the",
"periarticular",
"Received",
"April",
"13,",
"2011;",
"Accepted",
"August",
"24,",
"2011",
"Correspondence",
"to:",
"Kap",
"Jung",
"Kim,",
"MD",
"Department",
"of",
"Orthopaedic",
"Surgery,",
"Eulji",
"University",
"School",
"of",
"Medicine,",
"1306",
"Dunsan-dong,",
"Seo-gu,",
"Daejeon",
"322-799,",
"Korea",
"Tel:",
"+82-42-611-3278,",
"Fax:",
"+82-42-259-1289",
"E-mail:",
"oskkj@eulji.ac.kr",
"bone,",
"and",
"is",
"involved",
"mainly",
"in",
"medial",
"femoral",
"condyle.2)",
"The",
"clinical",
"presentation",
"of",
"SPONK",
"commonly",
"includes",
"sudden",
"onset",
"of",
"acute",
"pain",
"which",
"is",
"frequently",
"worse",
"at",
"night.2)",
"The",
"sudden",
"acute",
"onset",
"of",
"pain",
"correlates",
"with",
"reports",
"in",
"the",
"literature",
"stating",
"that",
"insufficiency",
"fractures",
"with",
"natural",
"and",
"expected",
"surrounding",
"necrosis",
"of",
"bone",
"may",
"be",
"the",
"underlying",
"clinical",
"pathology",
"of",
"this",
"disorder.",
"However,",
"the",
"exact",
"pathogenesis",
"is",
"still",
"unknown.",
"The",
"treatment",
"options",
"of",
"SPONK",
"are",
"microfracture",
"technique,",
"high",
"tibial",
"osteotomy,",
"unicompartmental",
"knee",
"arthroplas-",
"ty,",
"or",
"total",
"knee",
"arthroplasty",
"depending",
"on",
"the",
"location,",
"size,",
"and",
"progression",
"of",
"lesion,",
"and",
"on",
"the",
"patient's",
"age",
"and",
"activity.",
"In",
"stages",
"described",
"as",
"advanced",
"by",
"Mont",
"clas-",
"Copyright",
"©",
"2011",
"by",
"The",
"Korean",
"Orthopaedic",
"Association",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/by-nc/3.0)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Clinics",
"in",
"Orthopedic",
"Surgery",
"pISSN",
"2005-291X",
"eISSN",
"2005-4408"
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] | [
"Critical",
"Care",
"June",
"2004",
"Vol",
"8",
"Suppl",
"2",
"Corwin",
"Review",
"Anemia",
"and",
"blood",
"transfusion",
"in",
"the",
"critically",
"ill",
"patient:",
"role",
"of",
"erythropoietin",
"Howard",
"L",
"Corwin",
"Professor",
"of",
"Medicine",
"and",
"Anesthesiology,",
"Dartmouth",
"Medical",
"School;",
"Section",
"Chief,",
"Critical",
"Care",
"Medicine;",
"Medical",
"Director,",
"Intensive",
"Care",
"Unit,",
"Dartmouth-Hitchcock",
"Medical",
"Center,",
"Lebanon,",
"New",
"Hampshire,",
"USA",
"Correspondence:",
"Howard",
"L",
"Corwin,",
"Howard.L.Corwin@Hitchcock.org",
"Published",
"online:",
"14",
"June",
"2004",
"This",
"article",
"is",
"online",
"at",
"http://ccforum.com/content/8/S2/S42",
"©",
"2004",
"BioMed",
"Central",
"Ltd",
"Critical",
"Care",
"2004,",
"8(Suppl",
"2):S42-S44",
"(DOI",
"10.1186/cc2411)",
"Abstract",
"Critically",
"ill",
"patients",
"receive",
"an",
"extraordinarily",
"large",
"number",
"of",
"blood",
"transfusions.",
"Between",
"40%",
"and",
"50%",
"of",
"all",
"patients",
"admitted",
"to",
"intensive",
"care",
"units",
"receive",
"at",
"least",
"1",
"red",
"blood",
"cell",
"(RBC)",
"unit",
"during",
"their",
"stay,",
"and",
"the",
"average",
"is",
"close",
"to",
"5",
"RBC",
"units.",
"RBC",
"transfusion",
"is",
"not",
"risk",
"free.",
"There",
"is",
"little",
"evidence",
"that",
"‘routine’",
"transfusion",
"of",
"stored",
"allogeneic",
"RBCs",
"is",
"beneficial",
"to",
"critically",
"ill",
"patients.",
"The",
"efficacy",
"of",
"perioperative",
"recombinant",
"human",
"erythropoietin",
"(rHuEPO)",
"has",
"been",
"demonstrated",
"in",
"a",
"variety",
"of",
"elective",
"surgical",
"settings.",
"Similarly,",
"in",
"critically",
"ill",
"patients",
"with",
"multiple",
"organ",
"failure,",
"rHuEPO",
"therapy",
"will",
"also",
"stimulate",
"erythropoiesis.",
"In",
"a",
"randomized,",
"placebo-controlled",
"trial,",
"therapy",
"with",
"rHuEPO",
"resulted",
"in",
"a",
"significant",
"reduction",
"in",
"RBC",
"transfusions.",
"Despite",
"receiving",
"fewer",
"RBC",
"transfusions,",
"patients",
"in",
"the",
"rHuEPO",
"group",
"had",
"a",
"significantly",
"greater",
"increase",
"in",
"hematocrit.",
"Strategies",
"to",
"increase",
"the",
"production",
"of",
"RBCs",
"are",
"complementary",
"to",
"other",
"approaches",
"to",
"reduce",
"blood",
"loss",
"in",
"the",
"intensive",
"care",
"unit,",
"and",
"they",
"decrease",
"the",
"transfusion",
"threshold",
"in",
"the",
"management",
"of",
"all",
"critically",
"ill",
"patients.",
"Keywords",
"anemia,",
"blood",
"transfusion,",
"critical",
"illness,",
"erythropoietin",
"Anemia",
"is",
"common",
"in",
"critically",
"ill",
"patients",
"and",
"appears",
"early",
"during",
"their",
"intensive",
"care",
"unit",
"(ICU)",
"course.",
"By",
"day",
"3",
"after",
"ICU",
"admission,",
"almost",
"95%",
"of",
"patients",
"are",
"anemic",
"[1–3].",
"The",
"anemia",
"in",
"these",
"critically",
"ill",
"patients",
"persists",
"throughout",
"their",
"ICU",
"and",
"hospital",
"stay,",
"with",
"or",
"without",
"red",
"blood",
"cell",
"(RBC)",
"transfusion",
"[3].",
"Historically,",
"the",
"anemia",
"observed",
"in",
"the",
"critically",
"ill",
"resulted",
"in",
"a",
"high",
"number",
"of",
"RBC",
"transfusions.",
"Studies",
"conducted",
"a",
"decade",
"ago",
"[4]",
"revealed",
"that",
"50%",
"of",
"all",
"patients",
"admitted",
"to",
"the",
"ICU",
"are",
"transfused",
"during",
"their",
"stay.",
"In",
"addition,",
"85%",
"of",
"patients",
"with",
"a",
"prolonged",
"ICU",
"stay",
"(>",
"1",
"week)",
"received",
"trans-",
"fusions",
"[5].",
"On",
"average,",
"these",
"latter",
"patients",
"were",
"transfused",
"9.5",
"RBC",
"units",
"during",
"their",
"ICU",
"stay.",
"These",
"transfusions",
"are",
"not",
"restricted",
"to",
"the",
"early",
"ICU",
"course;",
"rather,",
"patients",
"are",
"transfused",
"at",
"a",
"rate",
"of",
"2–3",
"units",
"per",
"week.",
"An",
"observational",
"study",
"of",
"4892",
"patients",
"admitted",
"to",
"ICUs",
"in",
"the",
"USA",
"throughout",
"2000",
"and",
"2001",
"[3]",
"found",
"that",
"almost",
"50%",
"of",
"patients",
"are",
"still",
"transfused.",
"The",
"results",
"also",
"showed",
"that",
"initial",
"RBC",
"transfusion",
"tends",
"to",
"occur",
"early",
"in",
"the",
"ICU",
"stay,",
"with",
"ongoing",
"RBC",
"transfusions",
"throughout",
"the",
"ICU",
"stay.",
"The",
"mean",
"pretransfusion",
"hemoglobin",
"observed",
"(i.e.",
"the",
"‘transfusion",
"trigger’)",
"was",
"8.6",
"±",
"1.7",
"g/dl",
"–",
"a",
"value",
"that",
"is",
"com-",
"parable",
"to",
"that",
"described",
"in",
"earlier",
"reports",
"[4,5].",
"Interestingly,",
"RBC",
"transfusions",
"were",
"not",
"restricted",
"to",
"the",
"ICU;",
"13%",
"of",
"patients",
"received",
"on",
"average",
"almost",
"3",
"units",
"after",
"ICU",
"dis-",
"charge.",
"A",
"similar",
"observational",
"study",
"of",
"transfusion",
"practice",
"in",
"ICUs",
"was",
"performed",
"across",
"Western",
"Europe",
"[6].",
"Data",
"were",
"col-",
"lected",
"for",
"a",
"maximum",
"of",
"28",
"days",
"on",
"3534",
"patients",
"admitted",
"to",
"the",
"ICU",
"during",
"a",
"2-week",
"period",
"in",
"late",
"1999.",
"Of",
"these",
"patients",
"37%",
"received",
"a",
"mean",
"of",
"4.8",
"RBC",
"units",
"while",
"in",
"the",
"ICU",
"and",
"12.7%",
"of",
"patients",
"were",
"transfused",
"during",
"the",
"post-",
"ICU",
"period,",
"for",
"an",
"overall",
"transfusion",
"rate",
"of",
"42%",
"during",
"the",
"28-day",
"study",
"period.",
"The",
"mean",
"pretransfusion",
"hemoglobin",
"level",
"was",
"8.4",
"g/dl.",
"S42",
"EPO",
"=",
"erythropoietin;",
"ICU",
"=",
"intensive",
"care",
"unit;",
"RBC",
"=",
"red",
"blood",
"cell;",
"rHuEPO",
"=",
"recombinant",
"human",
"erythropoietin."
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] | [
"Kruse",
"et",
"al.",
"Head",
"&",
"Neck",
"Oncology",
"2010,",
"2:24",
"http://www.headandneckoncology.org/content/2/1/24",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"Oral",
"squamous",
"cell",
"carcinoma",
"in",
"non-smoking",
"and",
"non-drinking",
"patients",
"Astrid",
"L",
"Kruse*,",
"Marius",
"Bredell,",
"Klaus",
"W",
"Grätz",
"Abstract",
"Introduction:",
"Of",
"the",
"many",
"different",
"factors",
"associated",
"with",
"an",
"increased",
"risk",
"for",
"oral",
"squamous",
"cell",
"carcinoma",
"(SCC),",
"tobacco",
"and",
"alcohol",
"seem",
"to",
"be",
"the",
"most",
"studied.",
"The",
"aim",
"of",
"the",
"current",
"study",
"was",
"to",
"evaluate",
"the",
"clinicopathologic",
"characteristics",
"of",
"patients",
"without",
"the",
"mentioned",
"risk",
"factors.",
"Patients",
"and",
"Methods:",
"Out",
"of",
"278",
"patients",
"(159",
"male",
"and",
"119",
"female",
"patients)",
"with",
"oral",
"SCC,",
"67",
"patients",
"had",
"no",
"history",
"of",
"tobacco",
"or",
"alcohol",
"use.",
"The",
"minimum",
"follow-up",
"time",
"was",
"12",
"months.",
"Results:",
"Of",
"the",
"67",
"patients,",
"45",
"(67.2%)",
"were",
"women,",
"and",
"the",
"mean",
"age",
"was",
"70",
"years.",
"The",
"most",
"common",
"tumor",
"sites",
"were",
"mandibular",
"alveolar",
"ridge",
"(22)",
"and",
"maxilla",
"(18).",
"Fifteen",
"patients",
"experienced",
"a",
"recurrence,",
"and",
"10",
"developed",
"lymph",
"node",
"metastases",
"during",
"the",
"follow-up",
"period.",
"Conclusion:",
"The",
"group",
"of",
"patients",
"with",
"no",
"tobacco",
"and",
"alcohol",
"use",
"tends",
"toward",
"a",
"higher",
"proportion",
"of",
"females,",
"a",
"higher",
"proportion",
"of",
"patients",
"over",
"70",
"years,",
"and",
"a",
"higher",
"number",
"of",
"oral",
"maxillary",
"SCC.",
"Introduction",
"Of",
"the",
"many",
"different",
"factors",
"associated",
"with",
"an",
"increased",
"risk",
"for",
"oral",
"squamous",
"cell",
"carcinoma",
"(SCC),",
"tobacco",
"and",
"alcohol",
"seem",
"to",
"be",
"the",
"most",
"studied.",
"Indi-",
"viduals",
"who",
"smoke",
"more",
"than",
"20",
"cigarettes",
"a",
"day",
"and",
"consume",
"more",
"than",
"100",
"g",
"of",
"alcohol",
"a",
"day",
"are",
"at",
"increased",
"risk",
"for",
"oral",
"epithelial",
"dysplasia,",
"but",
"ex-smo-",
"kers",
"of",
"10",
"or",
"more",
"years",
"seem",
"to",
"have",
"no",
"greater",
"risk",
"than",
"non-smokers",
"[1].",
"In",
"addition,",
"alcohol",
"has",
"been",
"found",
"to",
"be",
"an",
"independent",
"risk",
"factor",
"for",
"oral",
"SCC",
"among",
"non-smokers",
"[2]",
"and",
"tobacco",
"smoke",
"in",
"non-",
"drinkers",
"[3,4].",
"The",
"combination",
"of",
"both",
"factors",
"seems",
"to",
"enhance",
"the",
"carcinogenic",
"effect",
"[5,6].",
"Blot",
"et",
"al.",
"(1988)",
"[6]",
"stated",
"that",
"tobacco",
"smoking",
"and",
"alcohol",
"drinking",
"combine",
"to",
"account",
"for",
"approximately",
"three-fourths",
"of",
"all",
"oral",
"and",
"pharyngeal",
"cancers",
"in",
"the",
"United",
"States.",
"However,",
"the",
"other",
"fourth",
"of",
"patients",
"are",
"then",
"of",
"special",
"interest,",
"because",
"this",
"group",
"has",
"rarely",
"been",
"studied.",
"Regarding",
"lung",
"cancer",
"in",
"patients",
"without",
"tobacco",
"use,",
"some",
"authors",
"have",
"stated",
"that",
"these",
"cancers",
"are",
"their",
"own",
"entity",
"due",
"to",
"their",
"special",
"characteristics.",
"Therefore,",
"the",
"aim",
"of",
"the",
"current",
"study",
"was",
"to",
"evalu-",
"ate",
"the",
"clinicopathologic",
"characteristics",
"of",
"the",
"patient",
"*",
"Correspondence:",
"astridkruse@gmx.ch",
"University",
"Hospital",
"Zurich,",
"Department",
"of",
"Craniomaxillofacial",
"and",
"Oral",
"Surgery,",
"Zurich/Switzerland",
"group",
"without",
"the",
"tobacco",
"and",
"alcohol",
"risk",
"factors,",
"in",
"particular",
"concerning",
"gender,",
"location,",
"TN",
"status,",
"and",
"rates",
"of",
"metastases",
"or",
"recurrence.",
"Patients",
"and",
"Methods",
"The",
"files",
"of",
"278",
"patients",
"(159",
"male",
"and",
"119",
"female",
"patients)",
"with",
"newly",
"diagnosed,",
"previously",
"untreated",
"oral",
"SCC",
"and",
"who",
"were",
"treated",
"between",
"1999",
"and",
"2008,",
"with",
"a",
"minimum",
"follow-up",
"time",
"of",
"12",
"months,",
"were",
"searched",
"for",
"patients",
"without",
"the",
"risk",
"factors",
"of",
"tobacco",
"or",
"alcohol",
"use.",
"Out",
"of",
"these",
"67",
"patients,",
"tumor",
"data–",
"including",
"site,",
"grade,",
"TN",
"status,",
"recurrence,",
"and",
"metas-",
"tases–were",
"obtained",
"from",
"a",
"review",
"of",
"the",
"medical",
"records.",
"Results",
"In",
"sum,",
"22",
"male",
"and",
"45",
"female",
"patients",
"were",
"without",
"the",
"tobacco",
"or",
"alcohol",
"risk",
"factors.",
"Of",
"these",
"67",
"patients,",
"43",
"(64.2%)",
"patients",
"were",
"over",
"70",
"years",
"and",
"only",
"3",
"(6%)",
"below",
"the",
"age",
"of",
"40.",
"The",
"mean",
"age",
"was",
"70",
"years",
"(Fig.",
"1).",
"The",
"most",
"common",
"tumor",
"sites",
"were",
"the",
"mandibular",
"alveolar",
"ridge",
"(22",
"patients)",
"and",
"the",
"maxilla",
"(18",
"patients).",
"The",
"most",
"frequent",
"sites",
"in",
"female",
"patients",
"were",
"oral",
"maxillary",
"SCC",
"(15/67),",
"followed",
"by",
"the",
"mandibular",
"alveolar",
"ridge",
"(16/67)",
"(Fig.",
"2).",
"©",
"2010",
"Kruse",
"et",
"al;",
"licensee",
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] | [
"BMC",
"Neurology",
"Research",
"article",
"Prediction",
"of",
"the",
"survival",
"and",
"functional",
"ability",
"of",
"severe",
"stroke",
"patients",
"after",
"ICU",
"therapeutic",
"intervention",
"Moussa",
"Riachy*1,",
"Frida",
"Sfeir1,",
"Ghassan",
"Sleilaty2,",
"Samer",
"Hage-Chahine†3,",
"Georges",
"Dabar1,",
"Taha",
"Bazerbachi1,",
"Zeina",
"Aoun-Bacha1,",
"Georges",
"Khayat1",
"and",
"Salam",
"Koussa†3",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"1Department",
"of",
"Pulmonary",
"and",
"Critical",
"Care",
"Medicine,",
"Hotel",
"Dieu",
"de",
"France,",
"Beirut,",
"Lebanon,",
"2Department",
"of",
"Cardiothoracic",
"Surgery,",
"Hotel",
"Dieu",
"de",
"France,",
"Beirut,",
"Lebanon",
"and",
"3Department",
"of",
"Neurology,",
"Hotel",
"Dieu",
"de",
"France,",
"Beirut,",
"Lebanon",
"Email:",
"Moussa",
"Riachy*",
"-",
"riachy@dm.net.lb;",
"Frida",
"Sfeir",
"-",
"fridasfeir@hotmail.com;",
"Ghassan",
"Sleilaty",
"-",
"sanasl@inco.com.lb;",
"Samer",
"Hage-",
"Chahine",
"-",
"samerhagechahine@hotmail.com;",
"Georges",
"Dabar",
"-",
"gdabar@cyberia.net.lb;",
"Taha",
"Bazerbachi",
"-",
"tbazarbachi@hotmail.com;",
"Zeina",
"Aoun-Bacha",
"-",
"zeinaabacha@yahoo.com;",
"Georges",
"Khayat",
"-",
"gck@data2.dm.net.lb;",
"Salam",
"Koussa",
"-",
"koussalam@hotmail.com",
"*",
"Corresponding",
"author",
"†Equal",
"contributors",
"Published:",
"26",
"June",
"2008",
"BMC",
"Neurology",
"2008,",
"8:24",
"doi:10.1186/1471-2377-8-24",
"This",
"article",
"is",
"available",
"from:",
"http://www.biomedcentral.com/1471-2377/8/24",
"Received:",
"16",
"December",
"2007",
"Accepted:",
"26",
"June",
"2008",
"©",
"2008",
"Riachy",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Background:",
"This",
"study",
"evaluated",
"the",
"benefits",
"and",
"impact",
"of",
"ICU",
"therapeutic",
"interventions",
"on",
"the",
"survival",
"and",
"functional",
"ability",
"of",
"severe",
"cerebrovascular",
"accident",
"(CVA)",
"patients.",
"Methods:",
"Sixty-two",
"ICU",
"patients",
"suffering",
"from",
"severe",
"ischemic/haemorrhagic",
"stroke",
"were",
"evaluated",
"for",
"CVA",
"severity",
"using",
"APACHE",
"II",
"and",
"the",
"Glasgow",
"coma",
"scale",
"(GCS).",
"Survival",
"was",
"determined",
"using",
"Kaplan-Meier",
"survival",
"tables",
"and",
"survival",
"prediction",
"factors",
"were",
"determined",
"by",
"Cox",
"multivariate",
"analysis.",
"Functional",
"ability",
"was",
"assessed",
"using",
"the",
"stroke",
"impact",
"scale",
"(SIS-16)",
"and",
"Karnofsky",
"score.",
"Risk",
"factors,",
"life",
"support",
"techniques",
"and",
"neurosurgical",
"interventions",
"were",
"recorded.",
"One",
"year",
"post-CVA",
"dependency",
"was",
"investigated",
"using",
"multivariate",
"analysis",
"based",
"on",
"linear",
"regression.",
"Results:",
"The",
"study",
"cohort",
"constituted",
"6%",
"of",
"all",
"CVA",
"(37.8%",
"haemorrhagic/62.2%",
"ischemic)",
"admissions.",
"Patient",
"mean(SD)",
"age",
"was",
"65.8(12.3)",
"years",
"with",
"a",
"1:1",
"male:",
"female",
"ratio.",
"During",
"the",
"study",
"period",
"16",
"patients",
"had",
"died",
"within",
"the",
"ICU",
"and",
"seven",
"in",
"the",
"year",
"following",
"hospital",
"release.",
"The",
"mean(SD)",
"APACHE",
"II",
"score",
"at",
"hospital",
"admission",
"was",
"14.9(6.0)",
"and",
"ICU",
"mean",
"duration",
"of",
"stay",
"was",
"11.2(15.4)",
"days.",
"Mechanical",
"ventilation",
"was",
"required",
"in",
"37.1%",
"of",
"cases.",
"Risk",
"ratios",
"were;",
"GCS",
"at",
"admission",
"0.8(0.14),",
"(p",
"=",
"0.024),",
"APACHE",
"II",
"1.11(0.11),",
"(p",
"=",
"0.05)",
"and",
"duration",
"of",
"mechanical",
"ventilation",
"1.07(0.07),",
"(p",
"=",
"0.046).",
"Linear",
"coefficients",
"were:",
"type",
"of",
"CVA",
"–",
"haemorrhagic",
"versus",
"ischemic:",
"-18.95(4.58)",
"(p",
"=",
"0.007),",
"GCS",
"at",
"hospital",
"admission:",
"-6.83(1.08),",
"(p",
"=",
"0.001),",
"and",
"duration",
"of",
"hospital",
"stay",
"-0.38(0.14),",
"(p",
"=",
"0.40).",
"Conclusion:",
"To",
"ensure",
"a",
"better",
"prognosis",
"CVA",
"patients",
"require",
"ICU",
"therapeutic",
"interventions.",
"However,",
"as",
"we",
"have",
"shown,",
"where",
"tests",
"can",
"determine",
"the",
"worst",
"affected",
"patients",
"with",
"a",
"poor",
"vital",
"and",
"functional",
"outcome",
"should",
"treatment",
"be",
"withheld?",
"Page",
"1",
"of",
"8",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Effect",
"of",
"C-factor",
"and",
"LED",
"Curing",
"Mode",
"on",
"Microleakage",
"of",
"Class",
"V",
"Resin",
"Composite",
"Restorations",
"Qasem",
"Diefallah",
"Alomaria",
"Kefah",
"Barrieshi-Nusairb",
"Mohammad",
"Alic",
"AbstrAct",
"Objectives:",
"To",
"investigate",
"the",
"effects",
"of",
"cavity",
"C-factor",
"and",
"LED",
"curing",
"mode",
"on",
"microleakage",
"of",
"class",
"V",
"resin",
"composite",
"restorations.",
"Methods:",
"Eighty",
"extracted",
"human",
"maxillary",
"premolars",
"were",
"divided",
"into",
"four",
"groups.",
"In",
"groups",
"I",
"and",
"II,",
"V-shaped",
"class",
"V",
"cavities",
"(C-factor",
"≈",
"1.5)",
"were",
"prepared",
"while",
"box-shaped",
"class",
"V",
"cavities",
"(high",
"C-factor",
"≈",
"4)",
"were",
"prepared",
"in",
"groups",
"III",
"and",
"IV.",
"All",
"the",
"cavities",
"were",
"prepared",
"on",
"the",
"vestibular",
"surfaces",
"of",
"the",
"teeth.",
"All",
"the",
"cavities",
"were",
"prepared",
"by",
"one",
"operator",
"with",
"specific",
"dimensions.",
"The",
"same",
"adhesive",
"system",
"(Excite)",
"and",
"the",
"same",
"restorative",
"composite",
"(Tetric",
"Ceram)",
"were",
"used",
"in",
"all",
"the",
"groups.",
"The",
"restorations",
"in",
"groups",
"I",
"and",
"III",
"were",
"cured",
"with",
"the",
"fast",
"curing",
"mode",
"of",
"LED",
"curing",
"light,",
"while",
"the",
"restorations",
"in",
"groups",
"II",
"and",
"IV",
"were",
"cured",
"with",
"the",
"soft-start",
"mode",
"of",
"the",
"same",
"cur-",
"ing",
"light.",
"The",
"samples",
"were",
"thermocycled,",
"immersed",
"in",
"a",
"0.5%",
"basic",
"fuchsin",
"solution",
"for",
"24",
"hours,",
"and",
"sectioned.",
"The",
"degree",
"of",
"dye",
"penetration",
"was",
"measured",
"quantitatively",
"and",
"then",
"qualitatively",
"at",
"both",
"enamel",
"and",
"dentin/cementum",
"margins.",
"Results:",
"Quantitatively,",
"there",
"was",
"no",
"statistical",
"difference",
"in",
"the",
"degree",
"of",
"microleakage",
"between",
"the",
"groups",
"at",
"the",
"enamel",
"margin",
"(P>.05).",
"At",
"the",
"dentin/cementum",
"margin,",
"group",
"III",
"showed",
"signifi-",
"cantly",
"more",
"dye",
"penetration",
"than",
"the",
"other",
"groups",
"(P<.001).",
"Similarly,",
"qualitative",
"measurements",
"of",
"dye",
"penetration",
"showed",
"that",
"group",
"III",
"had",
"higher",
"microleakage",
"at",
"dentin/cementum",
"margin",
"than",
"the",
"remaining",
"groups",
"(I",
"and",
"III",
"P<.001;",
"II",
"and",
"III",
"P<.01;",
"III",
"and",
"IV",
"P<.01).",
"Paired",
"sample",
"statistics",
"showed",
"that",
"microleakage",
"at",
"the",
"dentin/cementum",
"margin",
"was",
"not",
"statistically",
"different",
"from",
"enamel",
"mi-",
"croleakage",
"(P>.05),",
"except",
"for",
"group",
"III",
"(P<.000).",
"Conclusions:",
"Fast",
"curing",
"mode",
"of",
"LED",
"curing",
"light",
"resulted",
"in",
"more",
"microleakage",
"at",
"the",
"gingi-",
"val",
"floor",
"of",
"class",
"V",
"cavities",
"with",
"high",
"C-factor.",
"There",
"was",
"no",
"difference",
"in",
"dye",
"penetration",
"between",
"enamel",
"and",
"dentin",
"margins",
"of",
"the",
"cavities",
"except",
"when",
"the",
"fast",
"curing",
"mode",
"was",
"used",
"with",
"high",
"C-factor",
"cavities.",
"Both",
"quantitative",
"and",
"qualitative",
"measurements",
"of",
"microleakage",
"gave",
"the",
"same",
"results",
"at",
"both",
"enamel",
"and",
"dentin",
"margins.",
"(Eur",
"J",
"Dent",
"2011;5:400-408)",
"Key",
"words:",
"Resin",
"composite;",
"Microleakage;",
"C-factor;",
"LED",
"curing",
"units;",
"Curing",
"modes.",
"a",
"Department",
"of",
"Restorative",
"Sciences,",
"Faculty",
"of",
"Dentistry,",
"Kuwait",
"University,",
"Kuwait.",
"b",
"Deceased.",
"c",
"Department",
"of",
"Diagnostic",
"Sciences,",
"Faculty",
"of",
"Dentistry,",
"Kuwait",
"University,",
"Kuwait.",
"Corresponding",
"author:",
"Qasem",
"Diefallah",
"Alomari",
"Department",
"of",
"Restorative",
"Sciences,",
"Faculty",
"of",
"Dentistry,",
"Kuwait",
"University,",
"P.",
"O.",
"Box",
"24923,",
"Alsafat",
"13110,",
"Kuwait.",
"E-mail:",
"qalomari@hsc.edu.kw",
"qasemalomari70@yahoo.com",
"400",
"European",
"Journal",
"of",
"Dentistry"
] | [
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] | [
"Restless",
"leg",
"syndrome:",
"is",
"it",
"a",
"real",
"problem?",
"Paul",
"E",
"Cotter",
"Shaun",
"T",
"O’Keeffe",
"Department",
"of",
"Geriatric",
"Medicine,",
"Galway",
"University",
"Hospitals,",
"Galway,",
"Ireland",
"Correspondence:",
"S",
"O’Keeffe",
"Unit",
"4,",
"Merlin",
"Park",
"Regional",
"Hospital,",
"Galway,",
"Ireland",
"Tel",
"+",
"353",
"91",
"775",
"561",
"Fax",
"+",
"353",
"91",
"770",
"515",
"Email",
"s.okeeffe@mailn.hse.ie",
"R",
"E",
"V",
"I",
"E",
"W",
"Abstract:",
"Restless",
"legs",
"syndrome",
"(RLS)",
"is",
"a",
"common",
"condition",
"that",
"is",
"frequently",
"unrecognized,",
"misdiagnosed",
"and",
"poorly",
"managed.",
"It",
"is",
"characterized",
"by",
"uncomfortable",
"sensations",
"deep",
"in",
"the",
"legs",
"developing",
"at",
"rest",
"that",
"compel",
"the",
"person",
"to",
"move;",
"symptoms",
"are",
"worst",
"at",
"night",
"and",
"sleep",
"disturbance",
"is",
"common.",
"RLS",
"occurs",
"in",
"7%–11%",
"of",
"the",
"population",
"in",
"Western",
"countries,",
"and",
"many",
"such",
"people",
"experience",
"troublesome",
"symptoms.",
"Primary",
"RLS",
"is",
"familial",
"in",
"up",
"to",
"two",
"thirds",
"of",
"patients.",
"RLS",
"may",
"also",
"be",
"secondary",
"to",
"a",
"number",
"of",
"conditions",
"including",
"iron",
"deficiency,",
"pregnancy",
"and",
"end-stage",
"renal",
"failure",
"and,",
"perhaps,",
"neuropathy.",
"Secondary",
"RLS",
"is",
"most",
"common",
"in",
"those",
"presenting",
"for",
"the",
"first",
"time",
"in",
"later",
"life.",
"The",
"pathogenesis",
"of",
"RLS",
"probably",
"involves",
"the",
"interplay",
"of",
"systemic",
"or",
"brain",
"iron",
"deficiency",
"and",
"impaired",
"dopaminergic",
"neurotransmission",
"in",
"the",
"subcortex",
"of",
"the",
"brain.",
"RLS",
"is",
"very",
"responsive",
"to",
"dopaminergic",
"therapies.",
"Rebound",
"of",
"RLS",
"symptoms",
"during",
"the",
"early",
"morning",
"and",
"development",
"of",
"severe",
"symptoms",
"earlier",
"in",
"the",
"day",
"(augmentation)",
"are",
"problematic",
"in",
"those",
"treated",
"for",
"a",
"prolonged",
"period",
"with",
"levodopa.",
"Consequently,",
"dopamine",
"agonists",
"have",
"become",
"first",
"line",
"treatment.",
"Anti-convulsant",
"medications",
"and",
"opioids",
"are",
"helpful",
"in",
"some",
"patients.",
"Correction",
"of",
"underlying",
"problem",
"wherever",
"possible",
"is",
"important",
"in",
"the",
"management",
"of",
"secondary",
"RLS.",
"Keywords:",
"Restless",
"legs",
"syndrome;",
"sleep;",
"iron",
"deficiency;",
"neuropathy",
"Introduction",
"Restless",
"Legs",
"Syndrome",
"(RLS)",
"was",
"first",
"described",
"in",
"the",
"medical",
"literature",
"by",
"the",
"anatomist",
"and",
"physician",
"Thomas",
"Willis",
"in",
"1685",
"and",
"has",
"been",
"recognized",
"as",
"a",
"well-",
"defined,",
"common",
"and",
"frequently",
"distressing",
"entity",
"since",
"Ekbom’s",
"classic",
"description",
"in",
"1945.",
"Nevertheless,",
"RLS",
"has",
"attracted",
"little",
"attention",
"in",
"medical",
"textbooks",
"until",
"recently,",
"and,",
"even",
"now,",
"it",
"is",
"often",
"unrecognized,",
"misdiagnosed",
"and",
"poorly",
"managed.",
"In",
"this",
"paper,",
"we",
"explore",
"the",
"reasons",
"for",
"the",
"relative",
"neglect",
"of",
"RLS,",
"explain",
"current",
"thinking",
"regarding",
"the",
"pathogenesis",
"and",
"management",
"of",
"the",
"condition",
"and",
"show",
"why",
"patients",
"with",
"RLS",
"will",
"benefit",
"from",
"careful",
"investigation",
"and",
"treatment.",
"What",
"is",
"RLS?",
"RLS",
"is",
"both",
"a",
"sensorimotor",
"and",
"a",
"sleep",
"disorder.",
"It",
"is",
"characterized",
"by",
"unusual,",
"uncomfortable",
"sensations",
"deep",
"in",
"the",
"legs",
"(and",
"sometimes",
"arms)",
"that",
"compel",
"the",
"person",
"to",
"move",
"to",
"relieve",
"the",
"sensation",
"and",
"that",
"are",
"brought",
"on",
"and",
"exacerbated",
"by",
"rest;",
"symptoms",
"are",
"particularly",
"troublesome",
"in",
"the",
"evening",
"and",
"at",
"night,",
"and",
"sleep",
"disturbance",
"is",
"common.",
"The",
"original",
"report",
"by",
"Willis",
"(1685)",
"described",
"the",
"motor",
"features",
"and",
"the",
"sleep",
"disruption",
"but",
"did",
"not",
"mention",
"the",
"sensory",
"features",
"that",
"are",
"often",
"the",
"main",
"complaint",
"of",
"patients.",
"In",
"contrast,",
"Karl-Axel",
"Ekbom",
"(1945)",
"emphasized",
"the",
"importance",
"of",
"the",
"sensory",
"component",
"of",
"the",
"condition.",
"The",
"current",
"diagnostic",
"criteria",
"were",
"developed",
"at",
"an",
"National",
"Institutes",
"of",
"Health",
"(NIH)-supported",
"workgroup",
"on",
"RLS",
"and",
"represent",
"a",
"slight",
"modification",
"of",
"the",
"original",
"diagnostic",
"criteria",
"published",
"by",
"the",
"International",
"RLS",
"Study",
"Group",
"in",
"1995",
"(Walters",
"1995;",
"Allen",
"et",
"al",
"2003).",
"There",
"are",
"four",
"essential",
"criteria",
"and",
"three",
"supportive",
"clinical",
"features",
"(Table",
"1).",
"Therapeutics",
"and",
"Clinical",
"Risk",
"Management",
"2006:2(4)",
"465–475",
"©",
"2006",
"Dove",
"Medical",
"Press",
"Limited.",
"All",
"rights",
"reserved",
"465"
] | [
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] | [
"Qian",
"et",
"al.",
"Journal",
"of",
"Experimental",
"&",
"Clinical",
"Cancer",
"Research",
"2010,",
"29:111",
"http://www.jeccr.com/content/29/1/111",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"GTPase",
"regulator",
"associated",
"with",
"the",
"focal",
"adhesion",
"kinase",
"(GRAF)",
"transcript",
"was",
"down-",
"regulated",
"in",
"patients",
"with",
"myeloid",
"malignancies",
"Zhen",
"Qian1,",
"Jun",
"Qian1*,",
"Jiang",
"Lin1,",
"Dong-ming",
"Yao1,",
"Qin",
"Chen1,",
"Run-bi",
"Ji1,",
"Yun",
"Li1,",
"Gao-fei",
"Xiao1,",
"Jian-yong",
"Li2",
"Abstract",
"Background:",
"GTPase",
"regulator",
"associated",
"with",
"the",
"focal",
"adhesion",
"kinase",
"(GRAF),",
"a",
"putative",
"tumor",
"suppressor",
"gene,",
"is",
"found",
"inactivated",
"in",
"hematopoietic",
"malignancies",
"by",
"either",
"genetic",
"or",
"epigenetic",
"abnormalities.",
"However,",
"the",
"expression",
"level",
"of",
"GRAF",
"gene",
"has",
"not",
"yet",
"been",
"studied",
"in",
"leukemia.",
"The",
"aim",
"of",
"this",
"study",
"was",
"to",
"investigate",
"the",
"expression",
"level",
"of",
"GRAF",
"gene",
"in",
"those",
"patients",
"with",
"myeloid",
"malignancies",
"including",
"acute",
"myeloid",
"leukemia",
"(AML),",
"myelodysplastic",
"syndrome",
"(MDS)",
"and",
"chronic",
"myeloid",
"leukemia",
"(CML).",
"Methods:",
"The",
"expression",
"levels",
"of",
"GRAF",
"transcript",
"were",
"determined",
"in",
"94",
"patients",
"using",
"real-time",
"quantitative",
"PCR",
"(RQ-PCR).",
"Clinical",
"and",
"laboratory",
"data",
"of",
"these",
"patients",
"were",
"collected",
"and",
"analyzed.",
"Results:",
"The",
"significantly",
"decreased",
"level",
"of",
"GRAF",
"transcript",
"was",
"observed",
"in",
"three",
"myeloid",
"malignancies",
"compared",
"to",
"controls.",
"Within",
"AML,",
"there",
"was",
"no",
"difference",
"in",
"the",
"level",
"of",
"GRAF",
"transcript",
"among",
"different",
"FAB",
"subtypes",
"(P",
">",
"0.05).",
"Difference",
"was",
"not",
"observed",
"in",
"the",
"amount",
"of",
"GRAF",
"mRNA",
"between",
"CML",
"at",
"chronic",
"phase",
"and",
"controls.",
"As",
"CML",
"progressed,",
"GRAF",
"transcript",
"significantly",
"decreased.",
"In",
"MDS,",
"three",
"cases",
"with",
"5q",
"deletion",
"had",
"lower",
"GRAF",
"transcript",
"than",
"four",
"without",
"5q",
"deletion",
"(median",
"0.76",
"vs",
"2.99)",
"(P",
">",
"0.05).",
"Conclusion:",
"our",
"results",
"demonstrate",
"that",
"the",
"GRAF",
"transcript",
"is",
"decreased",
"in",
"myeloid",
"malignancies.",
"Background",
"Focal",
"adhesion",
"kinase",
"(FAK),",
"a",
"non-receptor",
"tyrosine",
"kinase",
"that",
"resides",
"at",
"the",
"sites",
"of",
"integrin",
"clustering",
"[1],",
"plays",
"an",
"important",
"role",
"in",
"the",
"modulation",
"of",
"cell",
"growth,",
"proliferation,",
"survival",
"and",
"migration",
"[2].",
"Recently,",
"FAK",
"has",
"been",
"found",
"to",
"be",
"overexpressed",
"and/",
"or",
"constitutively",
"activated",
"and",
"correlated",
"with",
"increased",
"motility,",
"invasiveness,",
"and",
"proliferation",
"of",
"neoplastic",
"cells",
"of",
"various",
"tissue",
"types",
"[2].",
"Two",
"published",
"articles",
"revealed",
"that",
"aberrant",
"expression",
"of",
"FAK",
"was",
"observed",
"in",
"CD34+",
"leukemic",
"cells",
"and",
"associated",
"with",
"enhanced",
"blast",
"migration,",
"increased",
"cellularity",
"and",
"poor",
"prognosis",
"[3,4].",
"Le",
"et",
"al",
"showed",
"that",
"FAK",
"silencing",
"inhibited",
"leu-",
"kemogenesis",
"in",
"BCR/ABL-transformed",
"hematopoietic",
"cells",
"[5].",
"Tyner",
"et",
"al",
"also",
"identified",
"FAK",
"as",
"one",
"of",
"thera-",
"peutic",
"molecular",
"targets",
"in",
"acute",
"myeloid",
"leukemia",
"(AML)",
"[6].",
"*",
"Correspondence:",
"qianjun0007@hotmail.com",
"1Department",
"of",
"Hematology,",
"Affiliated",
"People’s",
"Hospital",
"of",
"Jiangsu",
"University,",
"Zhenjiang,",
"Jiangsu",
"212002,",
"China",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"FAK",
"protein",
"is",
"composed",
"of",
"an",
"N-terminal",
"FERM",
"domain,",
"a",
"central",
"kinase",
"domain,",
"and",
"a",
"C-terminal",
"domain",
"that",
"includes",
"the",
"focal",
"adhesion",
"targeting",
"(FAT)",
"sequence",
"responsible",
"for",
"FAK’s",
"localization",
"to",
"focal",
"adhesions.",
"Both",
"the",
"N-terminal",
"and",
"C-terminal",
"domains",
"have",
"been",
"shown",
"to",
"mediate",
"FAK",
"interaction",
"with",
"a",
"variety",
"of",
"other",
"proteins",
"critical",
"for",
"activation",
"of",
"FAK",
"by",
"integrins",
"or",
"other",
"cell",
"surface",
"receptors",
"as",
"well",
"as",
"FAK",
"regulation",
"of",
"different",
"cellular",
"functions",
"[2].",
"GTPase",
"regulator",
"associated",
"with",
"focal",
"adhesion",
"kinase",
"(GRAF)",
"is",
"a",
"newly",
"identified",
"protein",
"specifically",
"binding",
"to",
"the",
"proline-rich",
"region",
"in",
"the",
"COOH",
"termi-",
"nus",
"of",
"FAK",
"and",
"negatively",
"regulates",
"the",
"small",
"GTP-",
"binding",
"protein",
"RhoA,",
"which",
"is",
"well",
"known",
"for",
"its",
"growth-promoting",
"effect",
"in",
"RAS-mediated",
"malignant",
"transformation",
"[7,8].",
"GRAF",
"gene",
"is",
"located",
"at",
"chromo-",
"some",
"5q31",
"and",
"its",
"protein",
"is",
"ubiquitously",
"expressed",
"in",
"various",
"tissues",
"[9].",
"Mutations",
"and",
"deletions",
"of",
"GRAF",
"gene",
"were",
"found",
"in",
"some",
"cases",
"with",
"AML",
"or",
"myelodys-",
"plastic",
"syndrome",
"(MDS)",
"with",
"a",
"deletion",
"5q",
"[9].",
"Further-",
"more,",
"Bojesen",
"et",
"al",
"[10]",
"found",
"that",
"GRAF",
"gene",
"©",
"2010",
"Qian",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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469,
706,
483
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[
707,
469,
751,
483
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[
753,
469,
764,
483
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[
540,
485,
557,
499
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[
559,
485,
614,
499
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[
615,
485,
626,
499
],
[
628,
485,
745,
499
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[
746,
485,
763,
499
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[
540,
500,
579,
514
],
[
582,
500,
593,
514
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[
597,
500,
614,
514
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[
617,
500,
644,
514
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648,
500,
691,
514
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[
694,
500,
705,
514
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709,
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540,
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571,
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622,
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656,
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689,
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594
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737,
580,
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540,
596,
578,
610
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580,
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617,
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619,
596,
657,
610
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658,
596,
679,
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680,
596,
727,
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728,
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540,
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566,
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622,
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661,
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687,
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703,
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540,
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554,
628,
575,
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556,
644,
612,
658
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614,
644,
679,
658
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682,
644,
704,
658
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[
706,
644,
723,
658
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[
726,
644,
764,
658
],
[
540,
660,
562,
674
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[
567,
660,
588,
674
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[
593,
660,
604,
674
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[
609,
660,
663,
674
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[
668,
660,
747,
674
],
[
752,
660,
763,
674
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[
540,
676,
593,
690
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[
596,
676,
607,
690
],
[
611,
676,
628,
690
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[
631,
676,
696,
690
],
[
700,
676,
732,
690
],
[
734,
676,
764,
690
],
[
540,
692,
557,
706
],
[
561,
692,
569,
706
],
[
572,
692,
582,
706
],
[
585,
692,
604,
706
],
[
608,
692,
640,
706
],
[
643,
692,
688,
706
],
[
691,
692,
731,
706
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[
734,
692,
764,
706
],
[
540,
708,
554,
722
],
[
560,
708,
571,
722
],
[
578,
708,
631,
722
],
[
637,
708,
705,
722
],
[
711,
708,
764,
722
],
[
540,
724,
574,
738
],
[
578,
724,
639,
738
],
[
643,
724,
654,
738
],
[
658,
724,
707,
738
],
[
710,
724,
739,
738
],
[
743,
724,
763,
738
],
[
540,
740,
570,
754
],
[
575,
740,
631,
754
],
[
636,
740,
647,
754
],
[
652,
740,
711,
754
],
[
716,
740,
764,
754
],
[
540,
756,
560,
770
],
[
564,
756,
575,
770
],
[
579,
756,
598,
770
],
[
602,
756,
648,
770
],
[
652,
756,
662,
770
],
[
665,
756,
681,
770
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[
685,
756,
714,
770
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[
718,
756,
764,
770
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[
540,
772,
550,
786
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[
553,
772,
569,
786
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[
572,
772,
606,
786
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[
610,
772,
638,
786
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[
641,
772,
660,
786
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[
663,
772,
700,
786
],
[
704,
772,
745,
786
],
[
749,
772,
764,
786
],
[
540,
788,
569,
802
],
[
575,
788,
647,
802
],
[
654,
788,
725,
802
],
[
732,
788,
764,
802
],
[
540,
804,
563,
818
],
[
569,
804,
612,
818
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[
619,
804,
672,
818
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[
678,
804,
730,
818
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[
736,
804,
764,
818
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[
540,
820,
568,
834
],
[
572,
820,
612,
834
],
[
616,
820,
665,
834
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[
669,
820,
739,
834
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[
743,
820,
763,
834
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[
540,
836,
577,
850
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[
582,
836,
611,
850
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[
616,
836,
661,
850
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[
666,
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676,
850
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[
679,
836,
695,
850
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[
700,
836,
729,
850
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[
734,
836,
764,
850
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[
540,
852,
550,
866
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553,
852,
569,
866
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574,
852,
608,
866
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613,
852,
663,
866
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668,
852,
685,
866
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691,
852,
764,
866
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540,
868,
551,
882
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559,
868,
625,
882
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632,
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685,
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693,
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722,
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540,
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557,
898
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562,
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589,
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593,
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629,
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634,
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688,
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729,
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764,
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540,
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565,
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] | [
"CELLULAR",
"NEUROSCIENCE",
"How",
"do",
"soluble",
"oligomers",
"of",
"amyloid",
"β-protein",
"impair",
"hippocampal",
"synaptic",
"plasticity?",
"Shaomin",
"Li,",
"Ganesh",
"M.",
"Shankar",
"and",
"Dennis",
"J.",
"Selkoe*",
"Center",
"for",
"Neurologic",
"Diseases,",
"Brigham",
"and",
"Women’s",
"Hospital,",
"Harvard",
"Medical",
"School,",
"Boston,",
"MA,",
"USA",
"*Correspondence:",
"dselkoe@rics.bwh.harvard.edu",
"GENERAL",
"COMMENTARY",
"published:",
"19",
"March",
"2010",
"doi:",
"10.3389/fncel.2010.00005",
"A",
"commentary",
"on",
"Soluble",
"oligomers",
"of",
"amyloid",
"β-protein",
"facilitate",
"hippocampal",
"long-term",
"depres-",
"sion",
"by",
"disrupting",
"neuronal",
"glutamate",
"uptake",
"by",
"Li,",
"S.,",
"Hong,",
"S.,",
"Shepardson,",
"N.E.,",
"Walsh,",
"D.M.,",
"Shankar,",
"G.M.,",
"Selkoe,",
"D.",
"Neuron",
"2009;",
"62,",
"788–801.",
"Alzheimer’s",
"disease",
"(AD),",
"the",
"most",
"common",
"neurodegenerative",
"disorder,",
"is",
"character-",
"ized",
"by",
"progressive",
"memory",
"and",
"cognitive",
"impairment",
"and",
"the",
"cerebral",
"accumula-",
"tion",
"of",
"extracellular",
"amyloid",
"plaques",
"and",
"intraneuronal",
"neurofibrillary",
"tangles.",
"A",
"principal",
"neuropathological",
"finding",
"in",
"AD",
"subjects",
"is",
"cortical",
"atrophy",
"associated",
"with",
"degeneration",
"of",
"neurites,",
"decreased",
"den-",
"dritic",
"spine",
"density",
"and",
"frank",
"neuronal",
"loss",
"(Terry",
"et",
"al.,",
"1991;",
"Knobloch",
"and",
"Mansuy,",
"2008).",
"Although",
"the",
"specific",
"molecular",
"initi-",
"ators",
"of",
"the",
"AD",
"process",
"remain",
"unknown",
"in",
"most",
"patients,",
"biochemical",
"studies",
"indicate",
"that",
"the",
"severity",
"of",
"cognitive",
"impairment",
"in",
"AD",
"correlates",
"more",
"strongly",
"with",
"the",
"corti-",
"cal",
"levels",
"of",
"soluble",
"amyloid",
"β-protein",
"(Aβ",
"assemblies",
"than",
"with",
"the",
"burden",
"of",
"insoluble",
"amyloid",
"plaques",
"(Lue",
"et",
"al.,",
"1999;",
"McLean",
"et",
"al.,",
"1999;",
"Shankar",
"et",
"al.,",
"2008).",
"Extensive",
"experimental",
"work",
"on",
"hippocampal",
"plastic-",
"ity",
"has",
"indicated",
"that",
"the",
"induction",
"of",
"long-",
"term",
"synaptic",
"depression",
"(LTD)",
"results",
"in",
"decreased",
"dendritic",
"spine",
"volume",
"or",
"out-",
"right",
"elimination",
"of",
"spines",
"(Matsuzaki",
"et",
"al.,",
"2004;",
"Nägerl",
"et",
"al.,",
"2004;",
"Zhou",
"et",
"al.,",
"2004),",
"changes",
"which",
"may",
"parallel",
"molecular",
"and",
"structural",
"aspects",
"of",
"synaptic",
"failure",
"in",
"AD.",
"Therefore,",
"understanding",
"how",
"Aβ",
"impairs",
"hippocampal",
"synaptic",
"function",
"at",
"the",
"molecular",
"level",
"could",
"enable",
"the",
"develop-",
"ment",
"of",
"specific",
"neuroprotective",
"therapies",
"for",
"AD.",
"Studies",
"from",
"numerous",
"laboratories",
"have",
"now",
"established",
"that",
"soluble",
"Aβ",
"oligomers",
"can",
"inhibit",
"long-term",
"potentiation",
"(LTP),",
"or",
"the",
"strengthening",
"of",
"synapses,",
"in",
"the",
"hippocampus.",
"But",
"heretofore,",
"only",
"a",
"few",
"studies",
"have",
"examined",
"the",
"effects",
"of",
"Aβ",
"on",
"the",
"induction",
"of",
"LTD,",
"and",
"those",
"few",
"have",
"yielded",
"inconsistent",
"results.",
"For",
"example,",
"synthetic",
"Aβ",
"peptides",
"were",
"reported",
"to",
"potently",
"enable",
"the",
"induction",
"of",
"LTD",
"in",
"CA1",
"in",
"an",
"NMDAR-",
"dependent",
"manner",
"in",
"vivo",
"(Kim",
"et",
"al.,",
"2001;",
"Cheng",
"et",
"al.,",
"2009),",
"whereas",
"other",
"studies",
"found",
"no",
"effect",
"on",
"LTD",
"in",
"slices",
"(Wang",
"et",
"al.,",
"2002,",
"2004;",
"Raymond",
"et",
"al.,",
"2003).",
"To",
"address",
"this",
"problem,",
"we",
"recently",
"extracted",
"buffer-",
"soluble",
"Aβ",
"oligomers",
"directly",
"from",
"the",
"brains",
"of",
"typical",
"AD",
"patients",
"and",
"demonstrated",
"that",
"these",
"species",
"can",
"facilitate",
"LTD",
"induc-",
"tion",
"in",
"hippocampal",
"slices",
"of",
"wild-type",
"mice",
"(Shankar",
"et",
"al.,",
"2008).",
"While",
"the",
"induction",
"of",
"both",
"LTP",
"and",
"LTD",
"requires",
"glutamatergic",
"transmission,",
"the",
"direction",
"in",
"which",
"synaptic",
"strength",
"is",
"modulated",
"by",
"the",
"specific",
"class",
"of",
"glutamate",
"receptor",
"that",
"is",
"activated,",
"the",
"kinetics",
"of",
"cytosolic",
"calcium",
"concentration,",
"and",
"the",
"initiation",
"of",
"intracellular",
"signaling",
"cascades.",
"Specifically,",
"we",
"found",
"that",
"LTD",
"induction",
"was",
"facilitated",
"by",
"pathophysiologi-",
"cally",
"relevant",
"low",
"concentrations",
"of",
"soluble",
"Aβ",
"oligomers",
"through",
"activation",
"of",
"either",
"NMDA",
"receptors",
"or",
"metabotropic",
"glutamate",
"receptors",
"(mGluRs),",
"depending",
"on",
"the",
"elec-",
"trical",
"stimulation",
"protocol",
"used",
"to",
"induce",
"the",
"LTD",
"(Li",
"et",
"al.,",
"2009).",
"Given",
"that",
"several",
"prior",
"studies,",
"including",
"our",
"own,",
"have",
"already",
"shown",
"that",
"Aβ",
"has",
"little",
"or",
"no",
"effect",
"on",
"pre-",
"synaptic",
"neurotransmitter",
"release",
"probability",
"(e.g.,",
"Townsend",
"et",
"al.,",
"2006;",
"Shankar",
"et",
"al.,",
"2008;",
"Cheng",
"et",
"al.,",
"2009),",
"we",
"hypothesized",
"that",
"the",
"Aβ",
"oligomers",
"alter",
"synaptic",
"gluta-",
"mate",
"concentration",
"by",
"disrupting",
"glutamate",
"transport",
"mechanisms.",
"In",
"the",
"current",
"study,",
"we",
"report",
"that",
"pharmacologically",
"blocking",
"glutamate",
"uptake",
"closely",
"recapitulates",
"the",
"effects",
"of",
"Aβ",
"on",
"LTD",
"induction,",
"suggest-",
"ing",
"that",
"Aβ",
"oligomers",
"bias",
"towards",
"synapse",
"weakening",
"in",
"part",
"through",
"such",
"a",
"mecha-",
"nism",
"(Li",
"et",
"al.,",
"2009).",
"A",
"growing",
"number",
"of",
"reports",
"indicate",
"that",
"glutamate",
"transporters",
"are",
"disturbed",
"in",
"AD",
"(Masliah",
"et",
"al.,",
"1996).",
"The",
"levels",
"of",
"transporters",
"such",
"as",
"GLAST/EAAT1",
"and",
"GLT-1/EAAT2",
"are",
"reduced",
"in",
"postmor-",
"tem",
"AD",
"brain",
"tissue",
"and",
"in",
"APP",
"transgenic",
"mice",
"(Maragakis",
"et",
"al.,",
"2004;",
"Jacob",
"et",
"al.,",
"2007).",
"Synthetic",
"Aβ",
"(at",
"supraphysiological",
"concentrations)",
"has",
"been",
"shown",
"to",
"inhibit",
"glutamate",
"uptake",
"in",
"cultured",
"neurons",
"and",
"astrocytes",
"(Harris",
"et",
"al.,",
"1996;",
"Harkany",
"et",
"al.,",
"2000;",
"Fernández-Tomé",
"et",
"al.,",
"2004)",
"and",
"in",
"oocytes",
"(Gu",
"et",
"al.,",
"2004).",
"Although",
"most",
"glutamate",
"transporters",
"are",
"located",
"on",
"astrocytes,",
"reduced",
"neuronal",
"expression",
"of",
"EAAT1",
"was",
"also",
"suggested",
"to",
"be",
"an",
"early",
"marker",
"of",
"neuronal",
"dysfunction",
"in",
"AD,",
"pre-",
"ceding",
"or",
"occurring",
"on",
"a",
"similar",
"timeline",
"to",
"the",
"expression",
"of",
"hyper-phosphorylated",
"tau",
"protein",
"in",
"the",
"same",
"neurons",
"of",
"AD",
"brains",
"(Scott",
"et",
"al.,",
"2002).",
"Interestingly,",
"it",
"was",
"dem-",
"onstrated",
"recently",
"that",
"detergent",
"insoluble",
"EAAC1/EAAT3",
"transporters",
"accumulate",
"aberrantly",
"in",
"hippocampus",
"in",
"AD",
"subjects",
"(Duerson",
"et",
"al.,",
"2009).",
"Taken",
"together,",
"these",
"various",
"reports",
"suggest",
"that",
"neuronal",
"and/or",
"glial",
"glutamate",
"uptake",
"may",
"be",
"interrupted",
"in",
"AD.",
"Glutamate",
"transporters",
"play",
"the",
"impor-",
"tant",
"role",
"of",
"regulating",
"concentrations",
"of",
"glutamate",
"in",
"the",
"extracellular",
"space,",
"keep-",
"ing",
"it",
"at",
"low",
"levels.",
"Without",
"normal",
"activ-",
"ity",
"of",
"glutamate",
"transporters,",
"glutamate",
"would",
"accumulate",
"to",
"cytotoxic",
"levels",
"and",
"could",
"contribute",
"to",
"progressive",
"neuronal",
"loss",
"in",
"AD",
"(Pomara",
"et",
"al.,",
"1992;",
"Harkany",
"et",
"al.,",
"2000).",
"Early",
"AD",
"studies",
"focused",
"on",
"frank",
"Aβ-enhanced",
"excitotoxicity",
"medi-",
"ated",
"through",
"glutamate",
"receptors,",
"espe-",
"cially",
"NMDA",
"receptors",
"(Greenamyre",
"and",
"Young,",
"1989;",
"Mattson",
"et",
"al.,",
"1992;",
"Hynd",
"et",
"al.,",
"2004).",
"However,",
"the",
"perturbations",
"in",
"extracellular",
"glutamate",
"levels",
"result-",
"ing",
"from",
"altered",
"transport",
"kinetics",
"could",
"even",
"be",
"responsible",
"for",
"the",
"more",
"subtle",
"ultrastructural",
"alterations",
"noted",
"in",
"AD,",
"such",
"as",
"dendritic",
"spine",
"loss.",
"In",
"vivo",
"microdialysis",
"recently",
"revealed",
"that",
"soluble",
"Aβ",
"oligom-",
"ers",
"secreted",
"by",
"APP-transfected",
"cells,",
"when",
"microinjected",
"into",
"wild-type",
"rat",
"brain,",
"can",
"Frontiers",
"in",
"Cellular",
"Neuroscience",
"www.frontiersin.org",
"March",
"2010",
"|",
"Volume",
"4",
"|",
"Article",
"5",
"|",
"1"
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] | [
"Nucleic",
"Acids",
"Research,",
"2006,",
"Vol.",
"34,",
"Web",
"Server",
"issue",
"W729–W732",
"doi:10.1093/nar/gkl320",
"Taverna:",
"a",
"tool",
"for",
"building",
"and",
"running",
"workflows",
"of",
"services",
"1",
"Duncan",
"Hull*,",
"Katy",
"Wolstencroft,",
"Robert",
"Stevens,",
"Carole",
"Goble,",
"Mathew",
"R.",
"Pocock",
",",
"Peter",
"Li2",
"and",
"Tom",
"Oinn3",
"School",
"of",
"Computer",
"Science,",
"University",
"of",
"Manchester,",
"M13",
"9PL,",
"UK,",
"1School",
"of",
"Computing",
"Science,",
"University",
"of",
"Newcastle,",
"NE1",
"7RU,",
"UK,",
"2School",
"of",
"Chemistry,",
"University",
"of",
"Manchester,",
"M60",
"1QD,",
"UK",
"and",
"3EMBL",
"European",
"Bioinformatics",
"Institute,",
"Hinxton,",
"Cambridge,",
"CB10",
"1SD,",
"UK",
"Received",
"February",
"14,",
"2006;",
"Revised",
"March",
"1,",
"2006;",
"Accepted",
"April",
"13,",
"2006",
"ABSTRACT",
"Taverna",
"is",
"an",
"application",
"that",
"eases",
"the",
"use",
"and",
"inte-",
"gration",
"of",
"the",
"growing",
"number",
"of",
"molecular",
"biology",
"tools",
"and",
"databases",
"available",
"on",
"the",
"web,",
"especially",
"web",
"services.",
"It",
"allows",
"bioinformaticians",
"to",
"construct",
"workflows",
"or",
"pipelines",
"of",
"services",
"to",
"perform",
"a",
"range",
"of",
"different",
"analyses,",
"such",
"as",
"sequence",
"analysis",
"and",
"genome",
"annotation.",
"These",
"high-level",
"workflows",
"can",
"integrate",
"many",
"different",
"resources",
"into",
"a",
"single",
"analysis.",
"Taverna",
"is",
"available",
"freely",
"under",
"the",
"terms",
"of",
"the",
"GNU",
"Lesser",
"General",
"Public",
"License",
"(LGPL)",
"from",
"http://taverna.sourceforge.net/.",
"INTRODUCTION",
"The",
"number",
"of",
"applications",
"and",
"databases",
"providing",
"tools",
"to",
"perform",
"computations",
"on",
"DNA,",
"RNA",
"and",
"proteins",
"are",
"rapidly",
"growing.",
"However,",
"the",
"lack",
"of",
"communication",
"between",
"such",
"tools",
"in",
"molecular",
"biology",
"is",
"commonly",
"a",
"barrier",
"to",
"extracting",
"new",
"knowledge",
"using",
"these",
"resources.",
"Many",
"tools",
"and",
"databases",
"already",
"communicate",
"using",
"the",
"web,",
"as",
"shown",
"by",
"the",
"ever-growing",
"list",
"of",
"servers",
"in",
"this",
"issue",
"of",
"Nucleic",
"Acids",
"Research.",
"Currently,",
"integrating",
"tools",
"and",
"databases",
"available",
"on",
"the",
"web",
"frequently",
"involves",
"either",
"‘screen-scraping’",
"web",
"pages",
"using",
"scripting",
"languages",
"like",
"PERL",
"or",
"manual",
"cut-and-",
"paste",
"of",
"data",
"between",
"applications.",
"Each",
"of",
"these",
"methods",
"has",
"its",
"problems.",
"Screen-scraping",
"is",
"notoriously",
"fragile,",
"because",
"the",
"integrating",
"script",
"is",
"prone",
"to",
"break",
"when",
"the",
"web",
"page",
"or",
"form",
"changes,",
"and",
"for",
"this",
"reason",
"has",
"been",
"likened",
"to",
"‘medieval",
"torture’",
"(1).",
"Cutting",
"and",
"pasting",
"data",
"between",
"applications",
"is",
"another",
"common",
"way",
"to",
"quickly",
"achieve",
"interoperation.",
"However,",
"cut-and-paste",
"procedures",
"are",
"laborious",
"to",
"repeat",
"and",
"verify.",
"Web",
"services",
"technology",
"provides",
"some",
"solutions",
"for",
"improving",
"this",
"situation.",
"In",
"addition",
"to",
"providing",
"form-",
"based",
"interfaces,",
"tool",
"and",
"database",
"providers",
"can",
"describe",
"their",
"application",
"or",
"database",
"using",
"the",
"standard",
"Web",
"Services",
"Description",
"Language",
"(WSDL).",
"These",
"WSDL",
"descriptions",
"can",
"then",
"be",
"indexed",
"to",
"build",
"a",
"searchable",
"and",
"browsable",
"registry",
"of",
"operations",
"for",
"end-users.",
"Applications",
"can",
"then",
"exchange",
"data,",
"typically",
"using",
"SOAP,",
"a",
"protocol",
"for",
"exchang-",
"ing",
"XML-based",
"messages",
"over",
"a",
"network,",
"normally",
"using",
"HTTP.",
"For",
"a",
"full",
"description",
"of",
"web",
"service",
"technology,",
"lan-",
"guages",
"and",
"protocols",
"see",
"(2).",
"Using",
"web",
"services",
"has",
"several",
"advantages:",
"Tools",
"and",
"databases",
"do",
"not",
"need",
"to",
"be",
"installed",
"locally",
"on",
"the",
"users",
"machine",
"or",
"laboratory",
"server,",
"as",
"they",
"are",
"program-",
"matically",
"accessible",
"over",
"the",
"web.",
"Tools",
"created",
"using",
"different",
"programming",
"languages",
"(e.g.",
"Python,",
"PERL,",
"Java,",
"etc.)",
"and",
"platforms",
"(e.g.",
"Unix,",
"Windows,",
"etc.)",
"can",
"be",
"accessed",
"through",
"the",
"same",
"web",
"service",
"interface.",
"This",
"removes",
"the",
"need",
"for",
"the",
"user",
"to",
"know",
"about",
"all",
"the",
"different",
"platforms",
"and",
"programming",
"languages",
"underneath.",
"The",
"need",
"for",
"fragile",
"screen-scraping",
"integration",
"scripts",
"is",
"reduced.",
"It",
"provides",
"an",
"alternative",
"to",
"time-consuming",
"and",
"laborious",
"‘cut-and-paste’",
"integration",
"between",
"web",
"applications.",
"Workflows,",
"or",
"pipelines,",
"of",
"web",
"services",
"can",
"be",
"built",
"to",
"provide",
"high-level",
"descriptions",
"of",
"analyses.",
"These",
"can",
"be",
"created",
"and",
"tested",
"relatively",
"quickly",
"to",
"integrate",
"many",
"dif-",
"ferent",
"tools",
"and",
"applications",
"in",
"a",
"single",
"analysis",
"However,",
"there",
"are",
"also",
"several",
"limitations",
"of",
"using",
"web",
"services:",
"Since",
"services",
"are",
"provided",
"by",
"autonomous",
"third-parties",
"around",
"the",
"world,",
"they",
"frequently",
"have",
"insufficient",
"or",
"non-existent",
"metadata.",
"Where",
"metadata",
"exists",
"it",
"often",
"pro-",
"vides",
"little",
"indication",
"of",
"the",
"purpose",
"of",
"a",
"service.",
"So",
"for",
"example,",
"inputs",
"can",
"have",
"cryptic",
"names",
"like",
"‘in1’",
"with",
"*To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"Tel:",
"+44",
"0",
"161",
"275",
"0677;",
"Fax:",
"+44",
"0",
"161",
"275",
"6204;",
"Email:",
"duncan.hull@cs.man.ac.uk",
"The",
"Author",
"2006.",
"Published",
"by",
"Oxford",
"University",
"Press.",
"All",
"rights",
"reserved.",
"The",
"online",
"version",
"of",
"this",
"article",
"has",
"been",
"published",
"under",
"an",
"open",
"access",
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"I",
"N",
"A",
"L",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Pain",
"and",
"efficacy",
"of",
"local",
"anesthetics",
"for",
"central",
"venous",
"access",
"William",
"C",
"Culp",
"Jr1",
"Mohammed",
"Yousaf2",
"Benjamin",
"Lowr",
"y1",
"Timothy",
"C",
"McCowan3",
"William",
"C",
"Culp2",
"1Division",
"of",
"Cardiothoracic",
"Anesthesiology,",
"Scott",
"and",
"White",
"Hospital,",
"The",
"Texas",
"A&M",
"University",
"College",
"of",
"Medicine,",
"Temple,",
"TX,",
"USA;",
"2Division",
"of",
"Interventional",
"Radiology,",
"University",
"of",
"Arkansas",
"for",
"Medical",
"Sciences,",
"Little",
"Rock,",
"AR,",
"USA;",
"3Department",
"of",
"Radiology,",
"University",
"of",
"Mississippi",
"Medical",
"Center,",
"Jackson,",
"MS,",
"USA",
"Correspondence:William",
"C",
"Culp",
"Division",
"of",
"Interventional",
"Radiology,",
"4301",
"West",
"Markham",
"Street,",
"#556,",
"Little",
"Rock,AR",
"72205-7199,",
"USA",
"Tel",
"+1",
"501",
"686",
"6910",
"Fax",
"+1",
"501",
"686",
"6900",
"Email",
"culpwilliamc@uams.edu",
"Purpose:",
"To",
"compare",
"pain",
"during",
"injection",
"and",
"efficacy",
"of",
"analgesia",
"of",
"local",
"anesthetics",
"during",
"central",
"venous",
"line",
"placement.",
"Methods:",
"Sixty-two",
"patients",
"were",
"studied",
"in",
"a",
"randomized,",
"double-blinded",
"prospective",
"fashion.",
"Patients",
"received",
"1%",
"lidocaine",
"(L),",
"buffered",
"1%",
"lidocaine",
"(LB),",
"or",
"2%",
"chloroprocaine",
"(CP)",
"injected",
"around",
"the",
"internal",
"jugular",
"vein",
"for",
"procedural",
"analgesia",
"for",
"central",
"venous",
"access.",
"Patients",
"reported",
"pain",
"via",
"a",
"standard",
"linear",
"visual",
"analog",
"scale,",
"with",
"0",
"representing",
"no",
"pain",
"and",
"10",
"being",
"the",
"worst",
"pain",
"imaginable.",
"Results:",
"Overall",
"patient",
"perception",
"of",
"pain",
"was",
"better",
"with",
"CP",
"and",
"L",
"than",
"LB",
"with",
"mean",
"scores",
"of",
"CP",
"2.4,",
"L",
"2.6,",
"LB",
"4.2.",
"Pain",
"with",
"injection",
"mean",
"scores",
"were",
"CP",
"2.1,",
"L",
"2.5,",
"LB",
"3.2.",
"Pain",
"with",
"catheter",
"placement",
"scores",
"were",
"CP",
"2.5,",
"L",
"1.7,",
"LB",
"3.4.",
"Operator",
"assessment",
"of",
"overall",
"pain",
"values",
"were",
"CP",
"1.9,",
"L",
"2.2,",
"LB",
"3.4.",
"LB",
"consistently",
"scored",
"the",
"worst,",
"though",
"compared",
"with",
"CP,",
"this",
"only",
"reached",
"statistical",
"significance",
"in",
"overall",
"patient",
"pain",
"and",
"pain",
"at",
"catheter",
"insertion",
"compared",
"with",
"L.",
"Conclusion:",
"Though",
"chloroprocaine",
"scored",
"better",
"than",
"lidocaine",
"in",
"3",
"of",
"4",
"parameters,",
"this",
"trend",
"did",
"not",
"achieve",
"statistical",
"significance.",
"Adding",
"sodium",
"bicarbonate",
"to",
"lidocaine",
"isn’t",
"justified",
"in",
"routine",
"practice,",
"nor",
"is",
"routine",
"replacement",
"of",
"lidocaine",
"with",
"chloroprocaine.",
"Keywords:",
"local",
"anesthesia,",
"analgesia,",
"central",
"venous",
"access,",
"lidocaine,",
"chloroprocaine",
"Introduction",
"Central",
"venous",
"catheter",
"placement",
"as",
"well",
"as",
"many",
"other",
"surgical",
"procedures",
"can",
"be",
"painful,",
"and",
"this",
"pain",
"is",
"often",
"reduced",
"with",
"the",
"use",
"of",
"local",
"anesthetics.",
"The",
"local",
"anes-",
"thetic",
"used",
"to",
"reduce",
"pain,",
"however,",
"often",
"causes",
"pain",
"itself.",
"The",
"best",
"local",
"anesthetic",
"compound",
"to",
"utilize",
"in",
"order",
"to",
"minimize",
"this",
"pain",
"upon",
"injection",
"while",
"still",
"providing",
"adequate",
"and",
"effective",
"anesthesia",
"for",
"various",
"procedures",
"has",
"long",
"been",
"the",
"center",
"of",
"controversy.",
"Several",
"studies",
"have",
"suggested",
"that",
"a",
"buffered",
"lidocaine",
"(LB)",
"solution",
"causes",
"less",
"pain",
"during",
"intra-",
"and",
"subdermal",
"injection",
"in",
"comparison",
"with",
"the",
"most",
"commonly",
"used",
"local",
"anesthetic,",
"lidocaine",
"(L)",
"(Nuttal",
"et",
"al",
"1993;",
"Prien",
"1994;",
"Xia",
"et",
"al",
"2002;",
"Davies",
"2003).",
"Alternatively,",
"other",
"data",
"suggest",
"that",
"chloroprocaine",
"(CP)",
"is",
"associated",
"with",
"the",
"least",
"amount",
"of",
"pain",
"on",
"injection",
"and/or",
"that",
"buffering",
"L",
"does",
"not",
"decrease",
"pain",
"on",
"injection",
"(Marica",
"et",
"al",
"2002;",
"Burns",
"et",
"al",
"2006).",
"This",
"study",
"attempts",
"to",
"assess",
"the",
"analgesic",
"efficacy",
"and",
"associated",
"pain",
"on",
"injection",
"of",
"three",
"local",
"anesthetic",
"solutions",
"used",
"for",
"procedural",
"analgesia",
"for",
"central",
"venous",
"access.",
"Methods",
"After",
"approval",
"of",
"the",
"local",
"Institutional",
"Review",
"Board,",
"62",
"consecutive",
"patients",
"requir-",
"ing",
"central",
"venous",
"access",
"with",
"planned",
"placement",
"in",
"the",
"internal",
"jugular",
"vein",
"were",
"consented",
"and",
"enrolled",
"in",
"the",
"study.",
"Each",
"patient",
"was",
"randomized",
"and",
"assigned",
"into",
"a",
"group",
"via",
"computer",
"randomizer",
"program",
"to",
"receive",
"one",
"of",
"three",
"local",
"anesthetics",
"for",
"procedural",
"analgesia.",
"Each",
"patient",
"was",
"to",
"receive",
"5",
"mL",
"of",
"either",
"L",
"1%",
"(Xylocaine",
"1%,",
"Local",
"and",
"Regional",
"Anesthesia",
"2008:1",
"11–15",
"©",
"2008",
"Culp",
"et",
"al,",
"publisher",
"and",
"licensee",
"Dove",
"Medical",
"Press",
"Ltd.This",
"is",
"an",
"Open",
"Access",
"article",
"which",
"permits",
"unrestricted",
"noncommercial",
"use,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"11"
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] | [
"MEDITERRANEAN",
"JOURNAL",
"OF",
"HEMATOLOGY",
"AND",
"INFECTIOUS",
"DISEASES",
"www.mjhid.org",
"ISSN",
"2035-3006",
"Case",
"Reports",
"Takayasu",
"Arteritis",
"Initially",
"Mimicking",
"Infective",
"Endocarditis",
"Aytekin",
"Alcelik,",
"Sevim",
"Karacay,",
"Ismail",
"Necati",
"Hakyemez,",
"Busra",
"Akin,",
"Serkan",
"Ozturk",
"and",
"Haluk",
"Savli",
"Deparment",
"of",
"Internal",
"Medicine,",
"Abant",
"Izzet",
"Baysal",
"University,",
"Bolu,",
"Turkey",
"Correspondance:",
"Dr.",
"Aytekin",
"Alcelik.",
"E-mail:",
"aytekinalcelik@yahoo.com",
"Competing",
"interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"Published:",
"September",
"8,",
"2011",
"Received:",
"June",
"8,",
"2011",
"Accepted:",
"August",
"3,",
"2011",
"Mediterr",
"J",
"Hematol",
"Infect",
"Dis",
"2011,",
"3:",
"e2011040,",
"DOI",
"10.4084/MJHID.2011.040",
"This",
"article",
"is",
"available",
"from:",
"http://www.mjhid.org/article/view/8801",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Takayasu’s",
"arteritis",
"(TA)",
"is",
"a",
"chronic",
"inflammatory",
"disease",
"that",
"affects",
"large",
"vessels,",
"predominantly",
"the",
"aorta",
"and",
"its",
"main",
"branches,",
"leading",
"to",
"vessel",
"wall",
"thickening,",
"fibrosis",
"and",
"stenosis.",
"Cardiac",
"and",
"vascular",
"symptoms",
"are",
"also",
"commonly",
"present",
"at",
"disease",
"onset.",
"In",
"TA",
"with",
"thoracic",
"or",
"abdominal",
"involvement,",
"although",
"murmur",
"can",
"be",
"present",
"at",
"physical",
"examination,",
"the",
"pulse",
"difference",
"may",
"be",
"absent.",
"Here,",
"we",
"report",
"a",
"case",
"of",
"TA",
"who",
"initially",
"resembled",
"infective",
"endocarditis",
"and",
"had",
"widespread",
"thoracic",
"murmur.",
"Introduction:",
"Takayasu’s",
"arteritis",
"(TA)",
"is",
"a",
"chronic",
"inflammatory",
"disease",
"that",
"affects",
"large",
"vessels,",
"predominantly",
"the",
"aorta",
"and",
"its",
"main",
"branches,",
"leading",
"to",
"vessel",
"wall",
"thickening,",
"fibrosis",
"and",
"stenosis.",
"The",
"etiology",
"and",
"predisposing",
"factors",
"of",
"TA",
"are",
"so",
"far",
"unknown.",
"The",
"main",
"clinical",
"symptoms",
"and",
"signs",
"are",
"weakness,",
"fever,",
"arthralgia,",
"hypertension,",
"intermittent",
"claudication",
"of",
"the",
"upper",
"or",
"lower",
"limbs,",
"cardiac",
"diseases",
"(cardiac",
"failure,",
"valvular",
"or",
"ischemic",
"heart",
"disease)",
"and",
"impaired",
"renal",
"function.",
"Laboratory",
"findings",
"are",
"non-specific.",
"Treatment",
"of",
"the",
"active",
"disease",
"is",
"primarily",
"based",
"on",
"corticosteroids.1-2",
"Cardiac",
"and",
"vascular",
"symptoms",
"are",
"also",
"commonly",
"present",
"at",
"disease",
"onset.",
"In",
"TA",
"with",
"thoracic",
"or",
"abdominal",
"involvement,",
"although",
"murmur",
"can",
"be",
"present",
"at",
"physical",
"examination,",
"the",
"pulse",
"difference",
"may",
"be",
"absent.3-4",
"Therefore,",
"TA",
"can",
"be",
"misdiagnosed",
"as",
"infective",
"endocarditis",
"because",
"of",
"murmur",
"and",
"fever",
"associated",
"with",
"the",
"active",
"phase",
"of",
"the",
"disease.",
"Here,",
"we",
"report",
"a",
"case",
"of",
"TA",
"who",
"initially",
"resembled",
"infective",
"endocarditis",
"and",
"had",
"widespread",
"Mediterr",
"J",
"Hematol",
"Infect",
"Dis",
"2011;",
"3;",
"Open",
"Journal",
"System",
"thoracic",
"murmur.",
"Case:",
"A",
"30-year-old",
"woman",
"was",
"admitted",
"with",
"the",
"complaint",
"of",
"sore",
"throat",
"and",
"polyarthralgia",
"for",
"five",
"days.",
"The",
"patient",
"also",
"reported",
"headache,",
"dizziness",
"and",
"fever.",
"At",
"presentation,",
"her",
"body",
"temperature",
"was",
"37.5°C",
"and",
"blood",
"pressure",
"in",
"right",
"arm",
"was",
"180/90",
"mmHg",
"and",
"in",
"left",
"arm",
"was",
"170/80",
"mmHg.",
"Physical",
"examination",
"showed",
"widespread",
"thoracic",
"murmur",
"and",
"weak",
"pulses",
"in",
"both",
"arms.",
"Ophthalmoscopic",
"examination",
"was",
"normal.",
"Laboratory",
"findings",
"were",
"as",
"follows:",
"hemoglobin",
"was",
"12.2",
"g/dL,",
"hematocrit",
"was",
"36%,",
"white",
"blood",
"cell",
"count",
"was",
"12,500/mm3,",
"platelet",
"count",
"was",
"296,000/mm3",
"and",
"mean",
"corpuscular",
"volume",
"was",
"80",
"femtoliter.",
"Fasting",
"glucose",
"level,",
"calcium,",
"albumin,",
"urea",
"and",
"creatinine",
"levels",
"were",
"within",
"the",
"normal",
"range.",
"Sedimentation",
"rate",
"was",
"31",
"mm,",
"C",
"reactive",
"protein",
"(CRP)",
"was",
"52",
"mg/dL",
"(range",
"from",
"0-",
"3.19",
"mg/dL).",
"Urine",
"examination",
"was",
"normal.",
"Throat",
"culture",
"did",
"not",
"yield",
"beta",
"hemolytic",
"Streptococci.",
"Telecardiography",
"(Figure1)",
"and",
"electrocardiogram"
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] | [
"Liu",
"et",
"al.",
"Molecular",
"Neurodegeneration",
"2011,",
"6:21",
"http://www.molecularneurodegeneration.com/content/6/1/21",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Transcriptional",
"Regulation",
"of",
"TMP21",
"by",
"NFAT",
"Shengchun",
"Liu1,2*†,",
"Si",
"Zhang2†,",
"Kelley",
"Bromley-Brits2,",
"Fang",
"Cai2,",
"Weihui",
"Zhou2,",
"Kun",
"Xia3,",
"Jill",
"Mittelholtz2,",
"Weihong",
"Song2*",
"Abstract",
"Background:",
"TMP21",
"is",
"a",
"member",
"of",
"the",
"p24",
"cargo",
"protein",
"family,",
"which",
"is",
"involved",
"in",
"protein",
"transport",
"between",
"the",
"Golgi",
"apparatus",
"and",
"ER.",
"Alzheimer’s",
"Disease",
"(AD)",
"is",
"the",
"most",
"common",
"neurodegenerative",
"disorder",
"leading",
"to",
"dementia",
"and",
"deposition",
"of",
"amyloid",
"b",
"protein",
"(Ab)",
"is",
"the",
"pathological",
"feature",
"of",
"AD",
"pathogenesis.",
"Knockdown",
"of",
"TMP21",
"expression",
"by",
"siRNA",
"causes",
"a",
"sharp",
"increase",
"in",
"Ab",
"production;",
"however",
"the",
"underlying",
"mechanism",
"by",
"which",
"TMP21",
"regulates",
"Ab",
"generation",
"is",
"unknown,",
"and",
"human",
"TMP21",
"gene",
"expression",
"regulation",
"has",
"not",
"yet",
"been",
"studied.",
"Results:",
"In",
"this",
"report",
"we",
"have",
"cloned",
"a",
"3.3-kb",
"fragment",
"upstream",
"of",
"the",
"human",
"TMP21",
"gene.",
"The",
"transcription",
"start",
"site",
"(TSS)",
"of",
"the",
"human",
"TMP21",
"gene",
"was",
"identified.",
"A",
"series",
"of",
"nested",
"deletions",
"of",
"the",
"5’",
"flanking",
"region",
"of",
"the",
"human",
"TMP21",
"gene",
"were",
"subcloned",
"into",
"the",
"pGL3-basic",
"luciferase",
"reporter",
"plasmid.",
"We",
"identified",
"the",
"-120",
"to",
"+2",
"region",
"as",
"containing",
"the",
"minimal",
"sequence",
"necessary",
"for",
"TMP21",
"gene",
"promoter",
"activity.",
"Gel",
"shift",
"assays",
"revealed",
"that",
"the",
"human",
"TMP21",
"gene",
"promoter",
"contains",
"NFAT",
"response",
"elements.",
"Expression",
"of",
"NFAT",
"increased",
"TMP21",
"gene",
"expression",
"and",
"inhibition",
"of",
"NFAT",
"by",
"siRNA",
"reduced",
"TMP21",
"gene",
"expression.",
"Conclusion:",
"NFAT",
"plays",
"a",
"very",
"important",
"role",
"in",
"the",
"regulation",
"of",
"human",
"TMP21",
"gene",
"expression.",
"This",
"study",
"demonstrates",
"that",
"the",
"human",
"TMP21",
"gene",
"expression",
"is",
"transcriptionally",
"regulated",
"by",
"NFAT",
"signaling.",
"Background",
"Alzheimer’s",
"disease",
"is",
"the",
"most",
"common",
"neurodegen-",
"erative",
"disorder",
"leading",
"to",
"dementia.",
"Deposition",
"of",
"amy-",
"loid",
"b",
"protein",
"(Ab)",
"in",
"the",
"brain",
"is",
"one",
"of",
"the",
"hallmarks",
"of",
"AD",
"pathogenesis.",
"Ab",
"is",
"generated",
"from",
"a",
"larger",
"b-",
"amyloid",
"precursor",
"protein",
"(APP)",
"by",
"sequential",
"cleavages",
"of",
"b-secretase",
"and",
"g-secretase",
"[1-4].",
"Beta-site",
"APP",
"cleav-",
"ing",
"enzyme",
"1",
"(BACE1)",
"is",
"the",
"b-secretase",
"in",
"vivo",
"[5,6],",
"and",
"g-secretase",
"activity",
"is",
"catalyzed",
"by",
"a",
"presenilin",
"(PS)-",
"containing",
"macromolecular",
"complex",
"[7].",
"This",
"high",
"molecular",
"weight",
"complex",
"also",
"requires",
"nicastrin",
"(Nct)",
"[8],",
"anterior",
"pharynx-defective",
"1",
"(Aph-1)",
"[9-11],",
"and",
"presenilin",
"enhancer",
"2",
"(Pen-2)",
"[9,10]",
"for",
"its",
"enzymatic",
"activity",
"[7,11-13].",
"CD147",
"was",
"also",
"found",
"to",
"closely",
"associate",
"with",
"the",
"g-secretase",
"complex",
"[14].",
"Despite",
"robust",
"expression",
"of",
"the",
"APP",
"gene",
"resulting",
"in",
"a",
"high",
"*",
"Correspondence:",
"liushengchun1968@163.com;",
"weihong@exchange.ubc.ca",
"†",
"Contributed",
"equally",
"1Department",
"of",
"Surgery,",
"The",
"First",
"Affiliated",
"Hospital,",
"Chongqing",
"University",
"of",
"Medical",
"Sciences,",
"Chongqing",
"410006,",
"China",
"2Townsend",
"Family",
"Laboratories,",
"Department",
"of",
"Psychiatry,",
"Brain",
"Research",
"Center,",
"Graduate",
"Program",
"in",
"Neuroscience,",
"The",
"University",
"of",
"British",
"Columbia,",
"2255",
"Wesbrook",
"Mall,",
"Vancouver,",
"BC",
"V6T",
"1Z3,",
"Canada",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"level",
"of",
"APP",
"protein",
"in",
"vivo,",
"Ab",
"production",
"through",
"the",
"amyloidogenic",
"pathway",
"of",
"APP",
"processing",
"is",
"a",
"rare",
"occurrence",
"under",
"normal",
"conditions",
"[15,16].",
"Missense",
"mutations",
"in",
"PS1",
"and",
"PS2",
"are",
"a",
"major",
"cause",
"of",
"early-onset",
"familial",
"AD",
"(FAD).",
"PS",
"mutant",
"forms",
"have",
"been",
"shown",
"to",
"increase",
"g-secretase",
"activity,",
"resulting",
"in",
"elevated",
"Ab42",
"production",
"[17-19].",
"In",
"addition",
"to",
"its",
"pathogenic",
"g-secretase",
"activity,",
"the",
"PS",
"complex",
"can",
"cleave",
"Notch",
"[20,21]",
"at",
"a",
"separate",
"ε-cleavage",
"site",
"which",
"may",
"be",
"involved",
"in",
"learning",
"and",
"memory.",
"Intramembra-",
"nous",
"cleavage",
"of",
"Notch",
"to",
"release",
"the",
"Notch",
"intracellu-",
"lar",
"domain",
"(NICD)",
"is",
"inhibited",
"in",
"PS1-deficient",
"cells",
"[8,20,22-24].",
"In",
"addition",
"to",
"APP",
"and",
"Notch,",
"the",
"sub-",
"strates",
"for",
"g-secretase",
"include",
"Jagged,",
"Delta,",
"E-cadherin,",
"ErbB-4,",
"Nectin-1a,",
"CD44",
"and",
"LRP.",
"The",
"ε-",
"and",
"g-secre-",
"tase",
"activities",
"of",
"the",
"presenilin",
"complex",
"seem",
"to",
"be",
"inde-",
"pendently",
"regulated,",
"as",
"certain",
"g-secretase",
"inhibitors",
"can",
"affect",
"APP",
"cleavage",
"without",
"affecting",
"Notch",
"cleavage,",
"and",
"presenilin",
"mutations",
"can",
"increase",
"Ab-42",
"production",
"while",
"decreasing",
"Notch",
"cleavage",
"[25,26].",
"Human",
"TMP21,",
"a",
"member",
"of",
"the",
"p24",
"protein",
"family,",
"is",
"a",
"type",
"I",
"transmembrane",
"protein",
"with",
"a",
"large",
"luminal",
"domain",
"[27].",
"It",
"is",
"ubiquitously",
"transcribed",
"with",
"higher",
"©",
"2011",
"Liu",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"International",
"Journal",
"for",
"Equity",
"in",
"Health",
"Research",
"Area",
"deprivation",
"and",
"its",
"association",
"with",
"health",
"in",
"a",
"cross-sectional",
"study:",
"are",
"the",
"results",
"biased",
"by",
"recent",
"migration?",
"Fredrik",
"Niclas",
"Piro*,",
"Øyvind",
"Næss",
"and",
"Bjørgulf",
"Claussen",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"Institute",
"of",
"General",
"Practice",
"and",
"Community",
"Medicine,",
"University",
"of",
"Oslo,",
"Norway",
"Email:",
"Fredrik",
"Niclas",
"Piro*",
"-",
"fnp@econ.no;",
"Øyvind",
"Næss",
"-",
"oyvind.nass@medisin.uio.no;",
"Bjørgulf",
"Claussen",
"-",
"bjorgulf.claussen@medisin.uio.no",
"*",
"Corresponding",
"author",
"Published:",
"20",
"September",
"2007",
"International",
"Journal",
"for",
"Equity",
"in",
"Health",
"2007,",
"6:10",
"doi:10.1186/1475-9276-6-10",
"This",
"article",
"is",
"available",
"from:",
"http://www.equityhealthj.com/content/6/1/10",
"Received:",
"12",
"October",
"2006",
"Accepted:",
"20",
"September",
"2007",
"©",
"2007",
"Piro",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Background:",
"The",
"association",
"between",
"area",
"deprivation",
"and",
"health",
"has",
"mostly",
"been",
"examined",
"in",
"cross-sectional",
"studies",
"or",
"prospective",
"studies",
"with",
"short",
"follow-up.",
"These",
"studies",
"have",
"rarely",
"taken",
"migration",
"into",
"account.",
"This",
"is",
"a",
"possible",
"source",
"of",
"misclassification",
"of",
"exposure,",
"i.e.",
"an",
"unknown",
"number",
"of",
"study",
"participants",
"are",
"attributed",
"an",
"exposure",
"of",
"area",
"deprivation",
"that",
"they",
"may",
"have",
"experienced",
"too",
"short",
"for",
"it",
"to",
"have",
"any",
"influence.",
"The",
"aim",
"of",
"this",
"article",
"was",
"to",
"examine",
"to",
"what",
"extent",
"associations",
"between",
"area",
"deprivation",
"and",
"health",
"outcomes",
"were",
"biased",
"by",
"recent",
"migration.",
"Methods:",
"Based",
"on",
"data",
"from",
"the",
"Oslo",
"Health",
"Study,",
"a",
"cross-sectional",
"study",
"conducted",
"in",
"2000",
"in",
"Oslo,",
"Norway,",
"we",
"used",
"six",
"health",
"outcomes",
"(self",
"rated",
"health,",
"mental",
"health,",
"coronary",
"heart",
"disease,",
"chronic",
"obstructive",
"pulmonary",
"disease,",
"smoking",
"and",
"exercise)",
"and",
"considered",
"migration",
"nine",
"years",
"prior",
"to",
"the",
"study",
"conduct.",
"Migration",
"into",
"Oslo,",
"between",
"the",
"areas",
"of",
"Oslo,",
"and",
"the",
"changes",
"in",
"area",
"deprivation",
"during",
"the",
"period",
"were",
"taken",
"into",
"account.",
"Associations",
"were",
"investigated",
"by",
"multilevel",
"logistic",
"regression",
"analyses.",
"Results:",
"After",
"adjustment",
"for",
"individual",
"socio-demographic",
"variables",
"we",
"found",
"significant",
"associations",
"between",
"area",
"deprivation",
"and",
"all",
"health",
"outcomes.",
"Accounting",
"for",
"migration",
"into",
"Oslo",
"and",
"between",
"areas",
"of",
"Oslo",
"did",
"not",
"change",
"these",
"associations",
"much.",
"However,",
"the",
"people",
"who",
"migrated",
"into",
"Oslo",
"were",
"younger",
"and",
"had",
"lower",
"prevalences",
"of",
"unfavourable",
"health",
"outcomes",
"than",
"those",
"who",
"were",
"already",
"living",
"in",
"Oslo.",
"But",
"since",
"they",
"were",
"evenly",
"distributed",
"across",
"the",
"area",
"deprivation",
"quintiles,",
"they",
"had",
"little",
"influence",
"on",
"the",
"associations",
"between",
"area",
"deprivation",
"and",
"health.",
"Evidence",
"of",
"selective",
"migration",
"within",
"Oslo",
"was",
"weak,",
"as",
"both",
"moving",
"up",
"and",
"down",
"in",
"the",
"deprivation",
"hierarchy",
"was",
"associated",
"with",
"significantly",
"worse",
"health",
"than",
"not",
"moving.",
"Conclusion:",
"We",
"have",
"documented",
"significant",
"associations",
"between",
"area",
"deprivation",
"and",
"health",
"outcomes",
"in",
"Oslo",
"after",
"adjustment",
"for",
"socio-demographic",
"variables",
"in",
"a",
"cross-sectional",
"study.",
"These",
"associations",
"were",
"weakly",
"biased",
"by",
"recent",
"migration.",
"From",
"our",
"results",
"it",
"still",
"appears",
"that",
"migration",
"prior",
"to",
"study",
"conduct",
"may",
"be",
"relevant",
"to",
"investigate",
"even",
"within",
"a",
"relatively",
"short",
"period",
"of",
"time,",
"whereas",
"changes",
"in",
"area",
"deprivation",
"during",
"such",
"a",
"period",
"is",
"of",
"limited",
"interest.",
"Page",
"1",
"of",
"15",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"The",
"Scientific",
"World",
"Journal",
"Volume",
"2012,",
"Article",
"ID",
"615057,",
"6",
"pages",
"doi:10.1100/2012/615057",
"Clinical",
"Study",
"The",
"cientificWorldJOURNAL",
"Ultrasonographic",
"Prevalence",
"and",
"Factors",
"Predicting",
"Left",
"Ventricular",
"Diastolic",
"Dysfunction",
"in",
"Patients",
"with",
"Liver",
"Cirrhosis:",
"Is",
"There",
"a",
"Correlation",
"between",
"the",
"Grade",
"of",
"Diastolic",
"Dysfunction",
"and",
"the",
"Grade",
"of",
"Liver",
"Disease?",
"Vasilios",
"Papastergiou,1",
"Lamprini",
"Skorda,2",
"Phillipos",
"Lisgos,1",
"Nikolaos",
"Papakonstantinou,3",
"Tsampikos",
"Giakoumakis,3",
"Konstantinos",
"Ntousikos,3",
"and",
"Stylianos",
"Karatapanis1",
"1",
"Liver",
"Clinic,",
"First",
"Department",
"of",
"Internal",
"Medicine,",
"General",
"Hospital",
"of",
"Rhodes,",
"85100",
"Rhodes,",
"Greece",
"2",
"Department",
"of",
"Internal",
"Medicine,",
"“Konstantopoulio”",
"General",
"Hospital,",
"14233",
"Athens,",
"Greece",
"3",
"Cardiology",
"Department,",
"General",
"Hospital",
"of",
"Rhodes,",
"85100",
"Rhodes,",
"Greece",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Stylianos",
"Karatapanis,",
"stylkar@otenet.gr",
"Received",
"12",
"October",
"2011;",
"Accepted",
"20",
"November",
"2011",
"Academic",
"Editors:",
"R.",
"Moreno",
"Gomez",
"and",
"P.",
"Muiesan",
"Copyright",
"©",
"2012",
"Vasilios",
"Papastergiou",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Presence",
"of",
"cardiac",
"dysfunction",
"has",
"been",
"associated",
"with",
"an",
"unfavorable",
"prognosis",
"in",
"patients",
"with",
"liver",
"cirrhosis.",
"In",
"the",
"present",
"study,",
"92",
"consecutive,",
"newly-diagnosed",
"patients",
"with",
"liver",
"cirrhosis",
"were",
"prospectively",
"evaluated.",
"Liver",
"disease",
"was",
"graded",
"according",
"to",
"the",
"modified",
"Child-Turcotte-Pugh",
"(CTP)",
"score",
"whereas",
"left",
"ventricular",
"diastolic",
"function",
"was",
"assessed",
"by",
"Doppler-",
"echocardiography",
"and",
"graded",
"(Stage",
"0",
"to",
"4)",
"according",
"to",
"current",
"guidelines.",
"Overall,",
"DD",
"was",
"diagnosed",
"in",
"55/92",
"(59.8%)",
"patients",
"[DD-stage-1:",
"36/92",
"(39.1%),",
"DD-stage-2:",
"19/92",
"(20.6%)].",
"Prevalence",
"of",
"DD-stage-1",
"among",
"the",
"different",
"stages",
"of",
"liver",
"cirrhosis",
"was:",
"CTP-class",
"A:",
"11/29",
"(37.9%),",
"B:",
"15/39",
"(38.5%),",
"C:",
"10/24",
"(41.6%),",
"(P",
">",
"0.05",
"in",
"all",
"comparisons),",
"whereas",
"for",
"DD-stage-2",
"the",
"corresponding",
"proportions",
"were",
"CTP-class",
"A:",
"3/29",
"(10.3%),",
"B:",
"5/39",
"(12.8%),",
"C:",
"11/24",
"(45.8%),",
"(P",
"=",
"0.0009",
"between",
"CTP-class",
"C",
"versus",
"A",
"and",
"B).",
"Age",
">",
"53",
"years",
"(Odd’s",
"Ratio",
"[OR]:",
"4.2;",
"95%",
"confidence",
"interval",
"[CI]:",
"1.5–12.1)",
"and",
"CTP-class",
"C",
"(OR:",
"4.6;",
"95%",
"CI:",
"1.1–20)",
"could",
"independently",
"predict",
"DD.",
"No",
"relation",
"between",
"presence",
"of",
"DD",
"and",
"the",
"etiology",
"of",
"the",
"liver",
"disease",
"was",
"found.",
"We",
"conclude",
"that",
"DD",
"is",
"a",
"common",
"feature",
"in",
"liver",
"cirrhosis.",
"DD-stage-1",
"is",
"fairly",
"prevalent",
"among",
"all",
"CTP-classes",
"whereas",
"DD-stage-2",
"seems",
"to",
"be",
"characteristic",
"of",
"the",
"advanced",
"liver",
"disease",
"(CTP-class",
"C).",
"A",
"high",
"level",
"of",
"awareness",
"for",
"the",
"presence",
"of",
"the",
"syndrome",
"is",
"required,",
"especially",
"if",
"cirrhotic",
"patients",
"are",
"CTP-class",
"C",
"and/or",
"of",
"older",
"age.",
"1.",
"Introduction",
"Hemodynamic",
"alterations",
"characterized",
"by",
"increased",
"cardiac",
"output",
"and",
"decreased",
"systemic",
"vascular",
"resistances",
"are",
"well",
"known",
"to",
"be",
"extremely",
"common",
"among",
"patients",
"with",
"liver",
"cirrhosis",
"[1,",
"2].",
"During",
"the",
"past",
"2",
"decades,",
"various",
"obser-",
"vations",
"have",
"indicated",
"the",
"presence",
"of",
"a",
"latent",
"cardiac",
"dys-",
"function",
"which",
"includes",
"a",
"combination",
"of",
"blunted",
"myocar-",
"dial",
"contractility,",
"altered",
"diastolic",
"relaxation,",
"and",
"electro-",
"physiological",
"abnormalities,",
"all",
"occurring",
"in",
"the",
"absence",
"of",
"a",
"concomitant",
"heart",
"disease",
"[3–5].",
"This",
"clinical",
"entity,",
"called",
"“cirrhotic",
"cardiomyopathy,”",
"has",
"been",
"repeatedly",
"shown",
"to",
"have",
"a",
"negative",
"prognostic",
"impact,",
"especially",
"on",
"the",
"outcome",
"of",
"invasive",
"procedures",
"such",
"as",
"surgery,",
"transjugular",
"intrahe-",
"patic",
"portosystemic",
"shunt",
"insertion",
"(TIPS),",
"and",
"liver",
"trans-",
"plantation",
"[6–9].",
"Diastolic",
"dysfunction",
"(DD),",
"caused",
"by",
"de-",
"creased",
"left",
"ventricular",
"compliance",
"and",
"relaxation,",
"is",
"believed",
"by",
"some",
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] | [
"Salsolinol",
"Facilitates",
"Glutamatergic",
"Transmission",
"to",
"Dopamine",
"Neurons",
"in",
"the",
"Posterior",
"Ventral",
"Tegmental",
"Area",
"of",
"Rats",
"Guiqin",
"Xie,",
"Jiang-Hong",
"Ye*",
"Department",
"of",
"Anesthesiology,",
"Pharmacology",
"and",
"Physiology,",
"University",
"of",
"Medicine",
"and",
"Dentistry",
"of",
"New",
"Jersey,",
"New",
"Jersey",
"Medical",
"School,",
"Newark,",
"New",
"Jersey,",
"United",
"States",
"of",
"America",
"Abstract",
"Although",
"in",
"vivo",
"evidence",
"indicates",
"that",
"salsolinol,",
"the",
"condensation",
"product",
"of",
"acetaldehyde",
"and",
"dopamine,",
"has",
"properties",
"that",
"may",
"contribute",
"to",
"alcohol",
"abuse,",
"the",
"underlying",
"mechanisms",
"have",
"not",
"been",
"fully",
"elucidated.",
"We",
"have",
"reported",
"previously",
"that",
"salsolinol",
"stimulates",
"dopamine",
"neurons",
"in",
"the",
"posterior",
"ventral",
"tegmental",
"area",
"(p-VTA)",
"partly",
"by",
"reducing",
"inhibitory",
"GABAergic",
"transmission,",
"and",
"that",
"ethanol",
"increases",
"glutamatergic",
"transmission",
"to",
"VTA-dopamine",
"neurons",
"via",
"the",
"activation",
"of",
"dopamine",
"D1",
"receptors",
"(D1Rs).",
"In",
"this",
"study,",
"we",
"tested",
"the",
"hypothesis",
"that",
"salsolinol",
"stimulates",
"dopamine",
"neurons",
"involving",
"activation",
"of",
"D1Rs.",
"By",
"using",
"whole-cell",
"recordings",
"on",
"p-VTA-dopamine",
"neurons",
"in",
"acute",
"brain",
"slices",
"of",
"rats,",
"we",
"found",
"that",
"salsolinol-induced",
"increase",
"in",
"spike",
"frequency",
"of",
"dopamine",
"neurons",
"was",
"substantially",
"attenuated",
"by",
"DL-2-amino-5-",
"phosphono-valeric",
"acid",
"and",
"6,",
"7-dinitroquinoxaline-2,",
"3-dione,",
"the",
"antagonists",
"of",
"glutamatergic",
"N-Methyl-D-aspartic",
"acid",
"and",
"a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic",
"acid",
"receptors.",
"Moreover,",
"salsolinol",
"increased",
"the",
"amplitude",
"of",
"evoked",
"excitatory",
"postsynaptic",
"currents",
"(EPSCs)",
"and",
"the",
"frequency",
"but",
"not",
"the",
"amplitude",
"of",
"spontaneous",
"EPSCs.",
"Additionally,",
"SKF83566,",
"a",
"D1R",
"antagonist",
"attenuated",
"the",
"salsolinol-induced",
"facilitation",
"of",
"EPSCs",
"and",
"of",
"spontaneous",
"firing",
"of",
"dopamine",
"neurons.",
"Our",
"data",
"reveal",
"that",
"salsolinol",
"enhances",
"glutamatergic",
"transmission",
"onto",
"dopamine",
"neurons",
"via",
"activation",
"of",
"D1Rs",
"at",
"the",
"glutamatergic",
"afferents",
"in",
"dopamine",
"neurons,",
"which",
"contributes",
"to",
"salsolinol’s",
"stimulating",
"effect",
"on",
"p-VTA",
"dopamine",
"neurons.",
"This",
"appears",
"to",
"be",
"a",
"novel",
"mechanism",
"which",
"contributes",
"toward",
"rewarding",
"properties",
"of",
"salsolinol.",
"Citation:",
"Xie",
"G,",
"Ye",
"J-H",
"(2012)",
"Salsolinol",
"Facilitates",
"Glutamatergic",
"Transmission",
"to",
"Dopamine",
"Neurons",
"in",
"the",
"Posterior",
"Ventral",
"Tegmental",
"Area",
"of",
"Rats.",
"PLoS",
"ONE",
"7(5):",
"e36716.",
"doi:10.1371/journal.pone.0036716",
"Editor:",
"Kuei-Sen",
"Hsu,",
"National",
"Cheng",
"Kung",
"University,",
"Taiwan",
"Received",
"February",
"8,",
"2012;",
"Accepted",
"April",
"12,",
"2012;",
"Published",
"May",
"10,",
"2012",
"Copyright:",
"2012",
"Xie,",
"Ye.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"is",
"made",
"possible",
"by",
"the",
"support",
"from",
"National",
"Institutes",
"of",
"Health",
"–",
"National",
"Institute",
"on",
"Alcohol",
"Abuse",
"and",
"Alcoholism",
"[grants",
"AA016964",
"and",
"AA016618]",
"to",
"JHY.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"ye@umdnj.edu",
"Introduction",
"The",
"racemic",
"mixture",
"of",
"salsolinol",
"((R)",
"+",
"(s)-salsolinol)",
"is",
"formed",
"by",
"nonenzymatic",
"Pictet-Spengler",
"condensation",
"of",
"dopamine",
"with",
"acetaldehyde,",
"the",
"major",
"metabolite",
"of",
"ethanol",
"in",
"the",
"brains",
"of",
"mammals",
"[1,2].",
"Salsolinol",
"has",
"been",
"proposed",
"to",
"play",
"a",
"role",
"in",
"the",
"etiology",
"of",
"alcoholism",
"[3],",
"and",
"to",
"the",
"rewarding",
"properties",
"of",
"ethanol",
"[4].",
"Early",
"animal",
"studies",
"revealed",
"that",
"salsolinol",
"promotes",
"alcohol",
"drinking",
"[5,6].",
"More",
"recent",
"studies",
"showed",
"that",
"rats",
"self-administer",
"salsolinol",
"into",
"posterior",
"VTA",
"(p-VTA),",
"a",
"key",
"region",
"in",
"the",
"brain",
"reward",
"system",
"[7,8],",
"and",
"that",
"microinjection",
"of",
"salsolinol",
"into",
"the",
"p-VTA",
"of",
"rats",
"induces",
"conditioned",
"place",
"preference",
"[9].",
"Furthermore,",
"such",
"behaviors",
"seem",
"to",
"depend",
"on",
"activation",
"of",
"dopaminergic",
"(DA)",
"neurons",
"[8]",
"and",
"associated",
"with",
"enhanced",
"dopamine",
"levels",
"in",
"the",
"ipsilateral",
"nucleus",
"accumbens",
"shell",
"[9].",
"With",
"patch",
"clamp",
"techniques,",
"we",
"recently",
"showed",
"that",
"salsolinol",
"(0.01–1",
"mM)",
"dose-dependently",
"stimulates",
"DA",
"neurons",
"in",
"the",
"p-VTA",
"in",
"acute",
"midbrain",
"slices",
"of",
"rats.",
"Salsolinol",
"decreased",
"GABAergic",
"synaptic",
"transmission",
"onto",
"p-VTA",
"DA",
"neurons,",
"and",
"gabazine,",
"an",
"antagonist",
"of",
"GABAA",
"receptors",
"substantially",
"attenuated",
"salsolinol-induced",
"increase",
"in",
"firing",
"rate",
"of",
"DA",
"neurons.",
"This",
"phenomenon",
"suggests",
"that",
"salsolinol",
"stimulates",
"DA",
"neurons",
"through",
"a",
"mechanism",
"of",
"disinhibition",
"[10].",
"Interestingly,",
"gabazine",
"(10",
"mM)",
"failed",
"to",
"completely",
"abolish",
"salsolinol-induced",
"increase",
"in",
"DA",
"neuron",
"firing,",
"indicating",
"that",
"other",
"mechanisms",
"may",
"also",
"be",
"involved.",
"In",
"addition",
"to",
"potent",
"inhibitory",
"GABAergic",
"afferents",
"[11],",
"VTA",
"DA",
"neurons",
"receive",
"glutamatergic",
"(Gluergic)",
"inputs",
"from",
"diverse",
"brain",
"nuclei",
"[12,13]",
"and",
"from",
"the",
"Gluergic",
"neurons",
"in",
"the",
"VTA",
"[14].",
"These",
"diverse",
"sources",
"of",
"Gluergic",
"afferents",
"may",
"enable",
"DA",
"neurons",
"to",
"respond",
"to",
"a",
"wide",
"range",
"of",
"environmental",
"stimuli.",
"Such",
"excitatory",
"Gluergic",
"synaptic",
"input",
"is",
"a",
"key",
"component",
"in",
"the",
"regulation",
"of",
"DA",
"cell",
"excitability",
"[15,16]",
"and",
"is",
"known",
"to",
"play",
"an",
"important",
"role",
"in",
"the",
"actions",
"of",
"many",
"drugs",
"of",
"abuse",
"[17,18]",
"including",
"ethanol",
"[19].",
"Previous",
"in",
"vivo",
"evidence",
"indicates",
"that",
"activation",
"of",
"dopamine",
"D1",
"receptors",
"(D1Rs)",
"can",
"increase",
"the",
"release",
"of",
"glutamate",
"in",
"the",
"VTA",
"[20].",
"In",
"recent",
"in",
"vitro",
"studies,",
"we",
"have",
"demonstrated",
"that",
"acute",
"ethanol",
"facilitates",
"Gluergic",
"transmission",
"to",
"VTA",
"DA",
"neurons",
"via",
"the",
"activation",
"of",
"D1Rs",
"at",
"Gluergic",
"afferents",
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] | [
"CLINICS",
"2010;65(10):971-974",
"CLINICAL",
"SCIENCE",
"DOI:10.1590/S1807-59322010001000008",
"Markers",
"of",
"autoimmune",
"liver",
"diseases",
"in",
"postmenopausal",
"women",
"with",
"osteoporosis",
"Umit",
"Secil",
"Demirdal,I",
"Ihsan",
"Hakkı",
"Ciftci,II",
"Vural",
"KavuncuI",
"I",
"Department",
"of",
"Physical",
"Medicine",
"and",
"Rehabilitation,",
"School",
"of",
"Medicine,",
"Afyon",
"Kocatepe",
"University,",
"Afyonkarahisar,",
"Turkey.",
"II",
"Department",
"of",
"Microbiology,",
"School",
"of",
"Medicine,",
"Afyon",
"Kocatepe",
"University,",
"Afyonkarahisar,",
"Turkey.",
"INTRODUCTION:",
"Osteoporosis",
"is",
"a",
"common",
"complication",
"of",
"chronic",
"liver",
"diseases.",
"However,",
"there",
"is",
"limited",
"information",
"about",
"autoimmune",
"liver",
"diseases",
"as",
"a",
"factor",
"of",
"secondary",
"osteoporosis.",
"Therefore,",
"we",
"aimed",
"to",
"investigate",
"the",
"autoantibodies",
"of",
"autoimmune",
"liver",
"diseases",
"in",
"patients",
"with",
"osteoporosis.",
"METHODS:",
"One",
"hundred",
"fifty",
"female",
"patients",
"with",
"postmenopausal",
"osteoporosis",
"were",
"included.",
"Bone",
"mineral",
"density",
"was",
"measured",
"by",
"dual",
"energy",
"X-ray",
"absorptiometry.",
"We",
"analysized",
"autoantibodies",
"including",
"antinuclear",
"antibodies,",
"liver",
"membrane",
"antibodies,",
"anti-liver/kidney",
"microsomal",
"autoantibodies1,",
"liver-specific",
"protein,",
"anti-",
"smooth",
"muscle",
"antibodies,",
"and",
"anti-mitochondrial",
"antibodies",
"by",
"indirect",
"immunofluorescence.",
"Serum",
"was",
"assayed",
"for",
"the",
"levels",
"of",
"aminotransferases.",
"RESULTS:",
"The",
"mean",
"age",
"of",
"the",
"patients",
"was",
"63,13¡8,6",
"years.",
"The",
"mean",
"values",
"of",
"L1-L4",
"T-scores",
"and",
"femur",
"total",
"T-scores",
"were",
"-3,08¡0,58",
"and",
"-1,53¡0,81,",
"respectively.",
"Among",
"the",
"150",
"patients",
"with",
"osteoporosis,",
"14",
"(9.3%)",
"were",
"antinuclear",
"antibodies,",
"four",
"(2.7%)",
"were",
"liver",
"membrane",
"antibodies,",
"three",
"(2.0%)",
"were",
"anti-liver/kidney",
"microsomal",
"autoantibodies1,",
"and",
"two",
"(1.3%)",
"were",
"liver-specific",
"protein",
"positive.",
"None",
"of",
"the",
"patients",
"had",
"anti-mitochondrial",
"antibodies",
"or",
"smooth",
"muscle",
"antibodies",
"positivity.",
"The",
"mean",
"values",
"of",
"levels",
"of",
"aminotransferases",
"were",
"within",
"normal",
"range.",
"CONCLUSIONS:",
"The",
"presence",
"of",
"liver",
"membrane",
"antibodies,",
"liver-specific",
"protein,",
"and",
"anti-liver/kidney",
"microsomal",
"autoantibodies1",
"has",
"permitted",
"us",
"to",
"see",
"that",
"there",
"may",
"be",
"some",
"suspicious",
"clues",
"of",
"autoimmune",
"liver",
"diseases",
"in",
"patients",
"with",
"osteoporosis",
"as",
"a",
"secondary",
"risk",
"factor.",
"On",
"the",
"other",
"hand,",
"there",
"is",
"a",
"need",
"for",
"comprehensive",
"studies",
"with",
"a",
"larger",
"sample",
"size",
"and",
"studies",
"designed",
"to",
"compare",
"the",
"results",
"with",
"a",
"normal",
"population",
"to",
"understand",
"the",
"clinical",
"importance",
"of",
"our",
"findings.",
"KEYWORDS:",
"Osteoporosis;",
"Autoimmune;",
"Liver",
"disease;",
"liver",
"autoantibodies;",
"Aminotransferases.",
"Demirdal",
"US,",
"Ciftci",
"IH,",
"Kavuncu",
"V.",
"Markers",
"of",
"autoimmune",
"liver",
"diseases",
"in",
"postmenopausal",
"women",
"with",
"osteoporosis.",
"Clinics.",
"2010;65(10):971-974.",
"Received",
"for",
"publication",
"on",
"May",
"2,",
"2010;",
"First",
"review",
"completed",
"on",
"May",
"25,",
"2010;",
"Accepted",
"for",
"publication",
"on",
"July",
"13,",
"2010",
"E-mail:",
"secilbabaoglu@yahoo.com",
"Tel.:",
"+90",
"272",
"246",
"33",
"33-3012",
"INTRODUCTION",
"Osteoporosis",
"(OP)",
"is",
"usually",
"defined",
"as",
"a",
"skeletal",
"disease",
"characterized",
"by",
"low",
"bone",
"mass",
"and",
"microarchitectural",
"deterioration",
"of",
"bone",
"tissue,",
"leading",
"to",
"enhanced",
"bone",
"fragility",
"and",
"increase",
"in",
"fracture",
"risk.1",
"It",
"affects",
"up",
"to",
"one",
"in",
"two",
"women",
"and",
"one",
"in",
"five",
"men",
"over",
"the",
"age",
"of",
"50.2",
"It",
"is",
"a",
"worldwide",
"disease",
"seen",
"in",
"all",
"racial",
"groups",
"and",
"in",
"both",
"males",
"and",
"females.3",
"In",
"addition",
"to",
"being",
"a",
"common",
"disease,",
"OP",
"becomes",
"a",
"serious",
"health",
"issue",
"due",
"to",
"the",
"increase",
"in",
"morbidity,",
"mortality,",
"and",
"financial",
"burden",
"related",
"with",
"osteoporotic",
"fractures.4-6",
"Osteoporosis",
"can",
"be",
"classified",
"as",
"primary",
"and",
"secondary",
"OP",
"according",
"to",
"the",
"underlying",
"causes.",
"Secondary",
"OP",
"may",
"be",
"described",
"as",
"the",
"low",
"mineral",
"density",
"in",
"which",
"an",
"Copyright",
"2010",
"CLINICS",
"–",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://",
"creativecommons.org/licenses/by-nc/3.0/)",
"which",
"permits",
"unrestricted",
"non-",
"commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"underlying",
"cause",
"or",
"factor",
"can",
"be",
"defined",
"other",
"than",
"those",
"attributable",
"to",
"the",
"postmenopausal",
"state",
"or",
"aging.7",
"Primary",
"OP",
"refers",
"to",
"OP",
"when",
"a",
"secondary",
"cause",
"cannot",
"be",
"found.8",
"There",
"are",
"a",
"number",
"of",
"secondary",
"causes",
"of",
"osteoporosis",
"such",
"as",
"hypogonadism",
"or",
"hyperparathyroidism,",
"which",
"are",
"treatable,",
"and",
"renal",
"failure,",
"which",
"should",
"be",
"considered",
"more",
"seriously.",
"Chronic",
"liver",
"diseases",
"also",
"play",
"an",
"important",
"role",
"among",
"secondary",
"factors",
"of",
"OP.9,10",
"Bone",
"disease",
"is",
"a",
"major",
"complication",
"of",
"chronic",
"liver",
"disease.",
"OP",
"is",
"more",
"commonly",
"seen",
"in",
"patients",
"with",
"liver",
"diseases",
"as",
"compared",
"to",
"the",
"normal",
"population,",
"showing",
"variable",
"prevalence",
"according",
"to",
"the",
"patient",
"selection",
"and",
"diagnostic",
"criteria.11,12",
"OP",
"is",
"a",
"common",
"complication",
"of",
"chronic",
"liver",
"diseases",
"such",
"as",
"cholestatic",
"disorders,",
"alcoholic",
"liver",
"diseases,",
"posthepatitic",
"cirrhosis,",
"and",
"autoimmune",
"liver",
"diseases",
"(ALD).13",
"Types",
"of",
"ALD",
"are",
"autoimmune",
"hepatitis",
"(AH),",
"primary",
"biliary",
"cirrhosis",
"(PBC),",
"and",
"sclerosing",
"cholangitis.",
"ALD",
"affects",
"women",
"at",
"any",
"age",
"with",
"a",
"wide",
"range",
"of",
"clinical",
"presentations.",
"In",
"some",
"cases,",
"the",
"disease",
"is",
"incidentally",
"diagnosed",
"during",
"routine",
"laboratory",
"tests,",
"while",
"it",
"shows",
"a",
"fulminate",
"course",
"in",
"some",
"others.14",
"971"
] | [
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] | [
"Morrissey",
"et",
"al.",
"BMC",
"Developmental",
"Biology",
"2011,",
"11:3",
"http://www.biomedcentral.com/1471-213X/11/3",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"PRE-1,",
"a",
"cis",
"element",
"sufficient",
"to",
"enhance",
"cone-",
"and",
"rod-",
"specific",
"expression",
"in",
"differentiating",
"zebrafish",
"photoreceptors",
"Maria",
"E",
"Morrissey1,",
"Sara",
"Shelton2,",
"Susan",
"E",
"Brockerhoff2,",
"James",
"B",
"Hurley2,",
"Breandán",
"N",
"Kennedy1*",
"Abstract",
"Background:",
"Appropriate",
"transcriptional",
"regulation",
"is",
"required",
"for",
"cone",
"photoreceptor",
"development",
"and",
"integrity.",
"To",
"date,",
"only",
"a",
"few",
"cis-regulatory",
"elements",
"that",
"control",
"cone",
"photoreceptor-specific",
"expression",
"have",
"been",
"characterised.",
"The",
"alpha-subunit",
"of",
"cone",
"transducin",
"(TaC)",
"is",
"specifically",
"expressed",
"in",
"cone",
"photoreceptors",
"and",
"is",
"required",
"for",
"colour",
"vision.",
"In",
"order",
"to",
"better",
"understand",
"the",
"molecular",
"genetics",
"controlling",
"the",
"initiation",
"of",
"cone",
"photoreceptor-specific",
"expression",
"in",
"vivo,",
"we",
"have",
"utilised",
"zebrafish",
"to",
"identify",
"cis-regulatory",
"elements",
"in",
"the",
"upstream",
"promoter",
"region",
"of",
"the",
"TaC",
"gene.",
"Results:",
"A",
"0.5",
"kb",
"TaC",
"promoter",
"fragment",
"is",
"sufficient",
"to",
"direct",
"cone-specific",
"expression",
"in",
"transgenic",
"larvae.",
"Within",
"this",
"minimal",
"promoter,",
"we",
"identify",
"photoreceptor",
"regulatory",
"element-1",
"(PRE-1),",
"a",
"unique",
"41",
"bp",
"sequence.",
"PRE-1",
"specifically",
"binds",
"nuclear",
"factors",
"expressed",
"in",
"ocular",
"tissue.",
"PRE-1",
"is",
"not",
"required",
"for",
"cone-specific",
"expression",
"directed",
"from",
"a",
"2.5",
"kb",
"TaC",
"promoter.",
"However,",
"PRE-1-like",
"sequences,",
"with",
"potential",
"functional",
"redundancy,",
"are",
"located",
"in",
"this",
"2.5",
"kb",
"promoter.",
"PRE-1-rho",
"which",
"has",
"the",
"highest",
"sequence",
"and",
"structural",
"homology",
"to",
"PRE-1",
"is",
"located",
"in",
"the",
"rhodopsin",
"promoter.",
"Surprisingly,",
"PRE-1",
"and",
"PRE-1-rho",
"are",
"functionally",
"distinct.",
"We",
"demonstrate",
"that",
"PRE-1,",
"but",
"not",
"PRE-1-rho,",
"is",
"sufficient",
"to",
"enhance",
"expression",
"from",
"a",
"heterologous",
"UV",
"cone",
"promoter.",
"PRE-1",
"is",
"also",
"sufficient",
"to",
"enhance",
"expression",
"from",
"a",
"heterologous",
"rhodopsin",
"promoter",
"without",
"altering",
"its",
"rod",
"photoreceptor",
"specificity.",
"Finally,",
"mutations",
"in",
"consensus",
"E-box",
"and",
"Otx",
"sites",
"prevent",
"PRE-1",
"from",
"forming",
"complexes",
"with",
"eye",
"nuclear",
"protein",
"and",
"enhancing",
"photoreceptor",
"expression.",
"Conclusions:",
"PRE-1",
"is",
"a",
"novel",
"cis-regulatory",
"module",
"that",
"is",
"sufficient",
"to",
"enhance",
"the",
"initiation",
"of",
"photoreceptor-",
"specific",
"gene",
"expression",
"in",
"differentiating",
"rod",
"and",
"cone",
"photoreceptors.",
"Background",
"Photoreceptors",
"are",
"specialised",
"sensory",
"neurons",
"that",
"enable",
"images",
"of",
"the",
"external",
"environment",
"to",
"be",
"cap-",
"tured.",
"Structurally,",
"cone",
"and",
"rod",
"photoreceptors",
"appear",
"grossly",
"similar.",
"Both",
"have",
"outer",
"segments",
"rich",
"in",
"photo-",
"sensitive",
"membranes,",
"inner",
"segments",
"rich",
"in",
"transport",
"and",
"metabolic",
"machinery,",
"and",
"synaptic",
"termini",
"that",
"che-",
"mically",
"transmit",
"light",
"signals",
"to",
"downstream",
"neurons",
"[1].",
"However,",
"cone",
"and",
"rod",
"photoreceptors",
"function",
"dis-",
"tinctly.",
"Rods",
"are",
"specialised",
"to",
"function",
"in",
"low-light,",
"whereas",
"cones",
"enable",
"colour",
"vision",
"and",
"visual",
"acuity",
"[2].",
"These",
"functional",
"differences",
"are",
"partly",
"explained",
"by",
"the",
"*",
"Correspondence:",
"brendan.kennedy@ucd.ie",
"1UCD",
"School",
"of",
"Biomolecular",
"and",
"Biomedical",
"Sciences,",
"UCD",
"Conway",
"Institute,",
"University",
"College",
"Dublin,",
"Dublin,",
"Ireland",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"distinct",
"morphological",
"specialisations",
"of",
"outer",
"segments",
"and",
"synaptic",
"termini",
"present",
"in",
"rods",
"or",
"cones",
"[1].",
"In",
"addition,",
"unique",
"transcripts",
"encode",
"rod-",
"or",
"cone-specific",
"components",
"of",
"the",
"G-protein",
"coupled",
"receptor",
"photo-",
"transduction",
"pathway.",
"This",
"includes",
"the",
"a-subunit",
"of",
"the",
"heterotrimeric",
"G-protein",
"transducin",
"(Ta)",
"encoded",
"by",
"gnat1",
"in",
"rods",
"and",
"by",
"gnat2",
"in",
"cones.",
"Underlining",
"these",
"molecular",
"differences,",
"these",
"photoreceptor-specific",
"isoforms",
"associate",
"with",
"distinct",
"forms",
"of",
"blindness.",
"Mutations",
"in",
"the",
"gene",
"encoding",
"rod",
"transducin",
"alpha",
"(TaR)",
"cause",
"inherited",
"night",
"blindness",
"whereas",
"muta-",
"tions",
"in",
"the",
"gene",
"encoding",
"cone",
"transducin",
"alpha",
"(TaC)",
"cause",
"achromatopsia,",
"or",
"total",
"colour",
"blindness",
"[3,4].",
"During",
"retinal",
"neurogenesis,",
"rod",
"and",
"cone",
"photorecep-",
"tors",
"differentiate",
"from",
"a",
"population",
"of",
"retinal",
"progenitor",
"cells",
"[5].",
"In",
"2",
"day",
"post-fertilisation",
"(dpf)",
"zebrafish,",
"©",
"2011",
"Morrissey",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
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] | [
"Original",
"article",
"http://dx.doi.org/10.3345/kjp.2012.55.3.100",
"Korean",
"J",
"Pediatr",
"2012;55(3):100-106",
"Outcome",
"of",
"allogeneic",
"hematopoietic",
"stem",
"cell",
"transplantation",
"for",
"childhood",
"acute",
"lymphoblastic",
"leukemia",
"in",
"second",
"complete",
"remission:",
"a",
"single",
"institution",
"study",
"Copyright",
"©",
"2012",
"by",
"The",
"Korean",
"Pediatric",
"Society",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/by-",
"nc/3.0/)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Key",
"words:",
"Acute",
"lymphoblastic",
"leukemia,",
"Child,",
"Second",
"complete",
"remission,",
"Transplantation",
"Eun-Jung",
"Lee,",
"MD,",
"Ji",
"Yoon",
"Han,",
"MD,",
"Jae",
"Wook",
"Lee,",
"MD,",
"Pil-Sang",
"Jang,",
"MD,",
"PhD,",
"Nack-Gyun",
"Chung,",
"MD,",
"PhD,",
"Dae-Chul",
"Jeong,",
"MD,",
"PhD,",
"Bin",
"Cho,",
"MD,",
"PhD,",
"Hack-Ki",
"Kim,",
"MD,",
"PhD",
"Department",
"of",
"Pediatrics,",
"The",
"Catholic",
"University",
"of",
"Korea,",
"School",
"of",
"Medicine,",
"Seoul,",
"Korea",
"Received:",
"15",
"September",
"2011,",
"Revised:",
"31",
"October",
"2011",
"Accepted:",
"14",
"November",
"2011",
"Corresponding",
"author:",
"Bin",
"Cho,",
"MD,",
"PhD",
"Department",
"of",
"Pediatrics,",
"Seoul",
"St.",
"Mary’s",
"Hospital,",
"The",
"Catholic",
"University",
"of",
"Korea",
"School",
"of",
"Medicine,",
"222",
"Ban-",
"po-daero,",
"Seocho-gu,",
"Seoul",
"137-701,",
"Korea",
"Tel:",
"+82-2-2258-6187,",
"Fax:",
"+82-2-588-3589",
"E-mail:",
"chobinkr@catholic.ac.kr",
"Purpose:",
"The",
"survival",
"rate",
"for",
"childhood",
"acute",
"lymphoblastic",
"leukemia",
"(ALL)",
"has",
"improved",
"significantly.",
"However,",
"overall",
"prognosis",
"for",
"the",
"20",
"to",
"25%",
"of",
"patients",
"who",
"relapse",
"is",
"poor,",
"and",
"allogeneic",
"hematopoietic",
"stem",
"cell",
"transplantation",
"(HSCT)",
"offers",
"the",
"best",
"chance",
"for",
"cure.",
"In",
"this",
"study,",
"we",
"identified",
"significant",
"prognostic",
"variables",
"by",
"analyzing",
"the",
"outcomes",
"of",
"allogeneic",
"HSCT",
"in",
"ALL",
"patients",
"in",
"second",
"complete",
"remission",
"(CR).",
"Methods:",
"Fifty-three",
"ALL",
"patients",
"(42",
"men,",
"79%)",
"who",
"received",
"HSCT",
"in",
"second",
"CR",
"from",
"August",
"1991",
"to",
"February",
"2009",
"were",
"included",
"(26",
"sibling",
"donor",
"HSCTs,",
"49%;",
"42",
"bone",
"marrow",
"transplantations,",
"79%).",
"Study",
"endpoints",
"included",
"cumulative",
"incidence",
"of",
"acute",
"and",
"chronic",
"graft-versus-host",
"disease",
"(GVHD),",
"relapse,",
"1-year",
"transplant-related",
"mortality",
"(TRM),",
"disease-free",
"survival",
"(DFS),",
"and",
"overall",
"survival",
"(OS).",
"Results:",
"Cumulative",
"incidences",
"of",
"acute",
"GVHD",
"(grade",
"2",
"or",
"above)",
"and",
"chronic",
"GVHD",
"were",
"45.3%",
"and",
"28.5%,",
"respectively.",
"The",
"estimated",
"5-year",
"DFS",
"and",
"OS",
"for",
"the",
"cohort",
"was",
"45.2±6.8%",
"and",
"48.3±7%,",
"respectively.",
"Only",
"donor",
"type,",
"i.e.,",
"sibling",
"versus",
"unrelated,",
"showed",
"significant",
"correlation",
"with",
"DFS",
"in",
"multivariate",
"analysis",
"(P",
"=0.010).",
"The",
"rates",
"of",
"relapse",
"and",
"1",
"year",
"TRM",
"were",
"28.9±6.4%",
"and",
"26.4±6.1%,",
"respectively,",
"and",
"unrelated",
"donor",
"HSCT",
"(P",
"=0.002)",
"and",
"HLA",
"mismatch",
"(P",
"=0.022)",
"were",
"significantly",
"correlated",
"with",
"increased",
"TRM",
"in",
"univariate",
"analysis.",
"Conclusion:",
"In",
"this",
"single",
"institution",
"study",
"spanning",
"more",
"than",
"17",
"years,",
"sibling",
"donor",
"HSCT",
"was",
"the",
"only",
"factor",
"predicting",
"a",
"favorable",
"result",
"in",
"multivariate",
"analysis,",
"possibly",
"due",
"to",
"increased",
"TRM",
"resulting",
"from",
"unrelated",
"donor",
"HSCT.",
"100"
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] | [
"Yonsei",
"Med",
"J",
"49(6):1052",
"-",
"1054,",
"2008",
"DOI",
"10.3349/ymj.2008.49.6.1052",
"Gastric",
"Schwannoma",
"Ho",
"Young",
"Yoon,1",
"Choong",
"Bai",
"Kim,1",
"Yoon",
"Hee",
"Lee,2",
"and",
"Ho",
"Guen",
"Kim2",
"Departments",
"of",
"1Surgery",
"and",
"2Pathology,",
"Yonsei",
"University",
"College",
"of",
"Medicine,",
"Seoul,",
"Korea.",
"Schwannomas,",
"also",
"known",
"as",
"neurinomas",
"or",
"neurilem-",
"momas,",
"are",
"generally",
"benign,",
"slow-growing",
"neoplasms",
"origi-",
"nating",
"in",
"any",
"nerve",
"that",
"has",
"a",
"Schwann",
"cell",
"sheath.",
"These",
"neoplasms",
"are",
"rare",
"among",
"the",
"spindle",
"cell",
"mesenchymal",
"tumors",
"of",
"the",
"gastrointestinal",
"tract,",
"but",
"develop",
"most",
"commonly",
"in",
"the",
"stomach",
"representing",
"0.2%",
"of",
"all",
"gastric",
"tumors.",
"We",
"present",
"the",
"case",
"of",
"a",
"57-year-old",
"female",
"patient",
"with",
"a",
"large",
"schwannoma",
"in",
"the",
"stomach",
"that",
"was",
"palpable",
"in",
"the",
"abdomen.",
"She",
"under-",
"went",
"subtotal",
"gastrectomy",
"under",
"suspicion",
"of",
"gastrointestinal",
"stromal",
"tumor",
"(GIST),",
"but",
"post-operative",
"histopathological",
"and",
"immunohistochemical",
"findings",
"showed",
"a",
"fascicular",
"arrange-",
"ment",
"of",
"spindle",
"cell",
"with",
"pallisading",
"nuclei,",
"and",
"positive",
"for",
"S-100",
"protein",
"with",
"negative",
"smooth",
"muscle",
"actin",
"(SMA).",
"These",
"results",
"confirmed",
"schwannoma",
"as",
"the",
"diagnosis.",
"Key",
"Words:",
"Schwannoma,",
"stomach,",
"submucosal",
"tumor,",
"S-100",
"protein",
"INTRODUCTION",
"Schwannomas",
"also",
"known",
"as",
"neurinomas",
"or",
"neurilemmomas,",
"are",
"tumors",
"originating",
"from",
"any",
"nerve",
"that",
"has",
"a",
"Schwann",
"cell",
"sheath.",
"These",
"rarely",
"develop",
"in",
"the",
"gastrointestinal",
"tract,",
"and",
"the",
"most",
"common",
"site",
"along",
"the",
"GI",
"tract",
"is",
"the",
"stomach.",
"Schwannomas",
"make-up",
"0.2%",
"of",
"all",
"gastric",
"neo-",
"plasm.1",
"The",
"tumors",
"are",
"usually",
"benign,",
"slow-gro-",
"wing,",
"and",
"asymptomatic,",
"but",
"in",
"some",
"cases,",
"bleeding",
"or",
"a",
"palpable",
"mass",
"is",
"present.",
"Gastroin-",
"testinal",
"endoscopy",
"is",
"the",
"principal",
"diagnostic",
"tool.",
"However,",
"when",
"the",
"tumor",
"has",
"the",
"characteristics",
"of",
"an",
"exophytic",
"mass",
"from",
"the",
"gastric",
"wall",
"to",
"the",
"abdominal",
"cavity,",
"the",
"differentiation",
"of",
"a",
"schwan-",
"noma",
"from",
"other",
"submucosal",
"tumors",
"is",
"very",
"dif-",
"Received",
"June",
"12,",
"2007",
"Accepted",
"July",
"4,",
"2007",
"Reprint",
"address:",
"requests",
"to",
"Dr.",
"Choong",
"Bai",
"Kim,",
"Department",
"of",
"surgery,",
"Yonsei",
"University",
"College",
"of",
"Medicine,",
"250",
"Seongsanno,",
"Seodaemun-gu,",
"Seoul",
"120-752,",
"Korea.",
"Tel:",
"82-2-2228-2113,",
"Fax:",
"82-2-313-8289,",
"E-mail:",
"cbkimmd@yuhs.ac",
"Yonsei",
"Med",
"J",
"Vol.",
"49,",
"No.",
"6,",
"2008",
"ficult",
"on",
"pre-operative",
"examination.",
"The",
"diagno-",
"stic",
"determination",
"of",
"schwannomas",
"requires",
"his-",
"tological",
"testing",
"to",
"be",
"positive",
"for",
"the",
"S-100",
"pro-",
"tein",
"and",
"vimentin",
"but",
"negative",
"for",
"both",
"smooth",
"muscle",
"actin",
"and",
"c-KIT.",
"Because",
"most",
"schwan-",
"nomas",
"have",
"an",
"excellent",
"prognosis,",
"surgical",
"removal",
"is",
"sufficient",
"for",
"treatment.",
"Here",
"we",
"present",
"a",
"57-year-old",
"woman",
"with",
"a",
"gastric",
"schwannoma",
"manifesting",
"as",
"a",
"palpable",
"mass",
"in",
"the",
"abdomen,",
"which",
"was",
"confirmed",
"pathologi-",
"cally",
"after",
"surgery.",
"CASE",
"REPORT",
"A",
"57-year-old",
"woman",
"with",
"diabetic",
"nephropathy,",
"hypertension,",
"and",
"angina",
"was",
"referred",
"to",
"our",
"institution",
"for",
"an",
"incidentally-detected",
"abdominal",
"mass",
"detected",
"by",
"sonography.",
"She",
"did",
"not",
"have",
"any",
"other",
"clinical",
"complaints.",
"Physical",
"examination",
"revealed",
"a",
"palpated",
"golf",
"ball-sized",
"mass",
"in",
"the",
"epigastric",
"area",
"without",
"tenderness",
"or",
"rebound",
"tenderness.",
"Gastrointestinal",
"endoscopy",
"was",
"not",
"performed",
"due",
"to",
"her",
"medical",
"history",
"of",
"angina.",
"Instead,",
"an",
"upper",
"gastrointestinal",
"barium",
"study",
"showed",
"a",
"large",
"submucosal",
"mass",
"in",
"the",
"gastric",
"angle",
"(Fig.",
"1).",
"Computed",
"tomography",
"of",
"the",
"abdomen",
"revealed",
"an",
"ovoid",
"and",
"homogenous",
"7",
"×",
"5",
"×",
"4",
"cm",
"soft",
"tissue",
"mass",
"at",
"the",
"lesser",
"curvature",
"in",
"the",
"lower",
"body",
"of",
"the",
"stomach",
"(Fig.",
"2).",
"Aside",
"from",
"splenomegaly,",
"there",
"was",
"no",
"evidence",
"of",
"metastasis.",
"To",
"facilitate",
"visualization",
"of",
"the",
"mass,",
"we",
"performed",
"a",
"sono-",
"graphy,",
"which",
"depicted",
"an",
"ill-defined",
"round",
"mass",
"neighboring",
"the",
"antrum.",
"The",
"mass",
"was",
"approxi-",
"mately",
"6",
"×",
"5",
"×",
"4",
"cm",
"in",
"diameter",
"and",
"had",
"a",
"homo-",
"genous",
"internal",
"echo",
"(Fig.",
"3)."
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] | [
"e",
"n",
"i",
"c",
"i",
"d",
"e",
"M",
"l",
"a",
"t",
"n",
"e",
"m",
"i",
"r",
"e",
"p",
"x",
"E",
"f",
"o",
"l",
"a",
"n",
"r",
"u",
"o",
"J",
"e",
"h",
"T",
"CORRESPONDENCE",
"Ross",
"M.",
"Kedl:",
"ross.kedl@uchsc.edu",
"OR",
"Stephen",
"C.",
"Jameson:",
"james024@umn.edu",
"Abbreviations",
"used:",
"BFA,",
"brefeldin",
"A;",
"gB,",
"glycoprotein",
"B;",
"GF,",
"germ",
"free;",
"HP,",
"homeostatic",
"proliferation;",
"SPF,",
"specific",
"pathogen",
"free;",
"VM,",
"virtual",
"memory.",
"The",
"Rockefeller",
"University",
"Press",
"$30.00",
"J.",
"Exp.",
"Med.",
"Vol.",
"206",
"No.",
"2",
"435-448",
"www.jem.org/cgi/doi/10.1084/jem.20081829",
"A",
"RT",
"I",
"C",
"L",
"E",
"The",
"antigen-specific",
"CD8+",
"T",
"cell",
"repertoire",
"in",
"unimmunized",
"mice",
"includes",
"memory",
"phenotype",
"cells",
"bear",
"ing",
"markers",
"of",
"homeostatic",
"expansion",
"Catherine",
"Haluszczak,1",
"Adovi",
"D.",
"Akue,2",
"Sara",
"E.",
"Hamilton,2",
"Lisa",
"D.S.",
"Johnson,2",
"Lindsey",
"Pujanauski,1",
"Lenka",
"Teodorovic,1",
"Stephen",
"C.",
"Jameson,2",
"and",
"Ross",
"M.",
"Kedl1",
"1Integrated",
"Department",
"of",
"Immunology,",
"University",
"of",
"Colorado",
"Health",
"Science",
"Center,",
"Denver,",
"CO",
"80045",
"2Laboratory",
"Medicine",
"and",
"Pathology,",
"Center",
"for",
"Immunology,",
"University",
"of",
"Minnesota,",
"Minneapolis,",
"MN",
"55455",
"Memory",
"T",
"cells",
"exhibit",
"superior",
"responses",
"to",
"pathogens",
"and",
"tumors",
"compared",
"with",
"their",
"naive",
"counterparts.",
"Memory",
"is",
"typically",
"generated",
"via",
"an",
"immune",
"response",
"to",
"a",
"foreign",
"antigen,",
"but",
"functional",
"memory",
"T",
"cells",
"can",
"also",
"be",
"produced",
"from",
"naive",
"cells",
"by",
"homeo-",
"static",
"mechanisms.",
"Using",
"a",
"recently",
"developed",
"method,",
"we",
"studied",
"CD8",
"T",
"cells,",
"which",
"are",
"specific",
"for",
"model",
"(ovalbumin)",
"and",
"viral",
"(HSV,",
"vaccinia)",
"antigens,",
"in",
"unimmunized",
"mice",
"and",
"found",
"a",
"subpopulation",
"bearing",
"markers",
"of",
"memory",
"cells.",
"Based",
"on",
"their",
"phenotypic",
"markers",
"and",
"by",
"their",
"presence",
"in",
"germ-free",
"mice,",
"these",
"preexisting",
"memory-like",
"CD44hi",
"CD8",
"T",
"cells",
"are",
"likely",
"to",
"arise",
"via",
"physiological",
"homeostatic",
"proliferation",
"rather",
"than",
"a",
"response",
"to",
"environmental",
"microbes.",
"These",
"antigen-inexperienced",
"memory",
"phenotype",
"CD8",
"T",
"cells",
"display",
"several",
"functions",
"that",
"distinguish",
"them",
"from",
"their",
"CD44lo",
"counterparts,",
"including",
"a",
"rapid",
"initiation",
"of",
"proliferation",
"after",
"T",
"cell",
"stimulation",
"and",
"rapid",
"IFN-",
"production",
"after",
"exposure",
"to",
"proinflammatory",
"cytokines.",
"Collectively,",
"these",
"data",
"indicate",
"that",
"the",
"unprimed",
"antigen-specific",
"CD8",
"T",
"cell",
"repertoire",
"contains",
"antigen-inexperienced",
"cells",
"that",
"display",
"phenotypic",
"and",
"functional",
"traits",
"of",
"memory",
"cells.",
"During",
"normal",
"primary",
"T",
"cell",
"responses,",
"naive",
"T",
"cells",
"are",
"induced",
"to",
"proliferate",
"and",
"differentiate,",
"giving",
"rise",
"first",
"to",
"an",
"effector",
"pool",
"and",
"then",
"to",
"a",
"long-lived",
"memory",
"population",
"(1,",
"2).",
"The",
"size",
"of",
"the",
"antigen-specific",
"memory",
"T",
"cell",
"pool",
"is",
"typi-",
"cally",
"larger",
"than",
"the",
"naive",
"population",
"from",
"which",
"they",
"are",
"derived,",
"but",
"in",
"addition",
"to",
"their",
"elevated",
"frequency,",
"memory",
"T",
"cells",
"exhibit",
"multiple",
"qua-",
"litative",
"advantages",
"over",
"their",
"naive",
"counterparts",
"with",
"respect",
"to",
"their",
"functional",
"versatility,",
"speed",
"of",
"response,",
"and",
"capacity",
"to",
"migrate",
"to",
"multiple",
"sites",
"besides",
"lymphoid",
"tissues",
"(1,",
"2).",
"Aside",
"from",
"this",
"standard",
"pathway,",
"however,",
"there",
"is",
"accumulating",
"data",
"that",
"memory",
"pheno-",
"type",
"T",
"cells",
"can",
"arise",
"from",
"naive",
"T",
"cells",
"via",
"ho-",
"meostatic",
"mechanisms",
"without",
"activation",
"of",
"the",
"T",
"cell",
"by",
"foreign",
"antigen.",
"This",
"has",
"been",
"well",
"studied",
"in",
"situations",
"of",
"extreme",
"lymphopenia,",
"as",
"induced",
"by",
"irradiation",
"or",
"genetic",
"T",
"cell",
"defi-",
"C.",
"Haluszczak,",
"A.D.",
"Akue,",
"and",
"S.E.",
"Hamilton",
"contributed",
"equally",
"to",
"this",
"paper.",
"ciency,",
"which",
"induces",
"homeostatic",
"proliferation",
"(HP)",
"of",
"naive",
"T",
"cells",
"(3–5).",
"In",
"addition,",
"there",
"is",
"also",
"evidence",
"that",
"HP",
"can",
"occur",
"within",
"unprimed",
"neonatal",
"mice",
"(3–9).",
"T",
"cell",
"HP",
"in",
"the",
"lympho-",
"penic",
"environment",
"is",
"thought",
"to",
"be",
"driven",
"by",
"reduced",
"competition",
"for",
"limiting",
"resources,",
"in-",
"cluding",
"IL-7",
"and",
"low-affinity",
"TCR",
"ligands",
"(3–5,",
"10,",
"11),",
"and",
"can",
"be",
"further",
"influenced",
"by",
"other",
"cytokines",
"(12–15).",
"HP",
"memory",
"cells",
"resemble",
"conventional",
"memory",
"cells",
"in",
"many",
"of",
"their",
"phenotypic",
"and",
"functional",
"traits.",
"After",
"HP,",
"T",
"cells",
"display",
"nu-",
"merous",
"phenotypic",
"markers",
"that",
"are",
"similar",
"to",
"those",
"of",
"true",
"antigen-driven",
"memory",
"cells,",
"such",
"as",
"increased",
"CD44,",
"LFA1,",
"Ly6C,",
"and",
"CD122",
"expression",
"(3–5,",
"16,",
"17).",
"Antigen-driven",
"mem-",
"ory",
"cells",
"display",
"increased",
"sensitivity",
"to",
"antigen",
"©",
"2009",
"Haluszczak",
"et",
"al.",
"This",
"article",
"is",
"distributed",
"under",
"the",
"terms",
"of",
"an",
"Attribu-",
"tion–Noncommercial–Share",
"Alike–No",
"Mirror",
"Sites",
"license",
"for",
"the",
"first",
"six",
"months",
"after",
"the",
"publication",
"date",
"(see",
"http://www.jem.org/misc/terms.shtml).",
"After",
"six",
"months",
"it",
"is",
"available",
"under",
"a",
"Creative",
"Commons",
"License",
"(Attribution–Noncom-",
"mercial–Share",
"Alike",
"3.0",
"Unported",
"license,",
"as",
"described",
"at",
"http://creativecommons",
".org/licenses/by-nc-sa/3.0/).",
"435"
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] | [
"Prolonged",
"Antigen",
"Presentation",
"Is",
"Required",
"for",
"Optimal",
"CD8+",
"T",
"Cell",
"Responses",
"against",
"Malaria",
"Liver",
"Stage",
"Parasites",
"Ian",
"A.",
"Cockburn1,",
"Yun-Chi",
"Chen1,",
"Michael",
"G.",
"Overstreet1¤,",
"Jason",
"R.",
"Lees2,",
"Nico",
"van",
"Rooijen3,",
"Donna",
"L.",
"Farber2,",
"Fidel",
"Zavala1*",
"1",
"Johns",
"Hopkins",
"Malaria",
"Research",
"Institute",
"and",
"Department",
"of",
"Molecular",
"Microbiology",
"and",
"Immunology,",
"Bloomberg",
"School",
"of",
"Public",
"Health,",
"Baltimore,",
"Maryland,",
"United",
"States",
"of",
"America,",
"2",
"Department",
"of",
"Surgery,",
"University",
"of",
"Maryland",
"at",
"Baltimore,",
"Baltimore,",
"Maryland,",
"United",
"States",
"of",
"America,",
"3",
"Vrije",
"Universiteit,",
"VUMC,",
"Department",
"of",
"Molecular",
"Cell",
"Biology,",
"Faculty",
"of",
"Medicine,",
"Amsterdam,",
"The",
"Netherlands",
"Abstract",
"Immunization",
"with",
"irradiated",
"sporozoites",
"is",
"currently",
"the",
"most",
"effective",
"vaccination",
"strategy",
"against",
"liver",
"stages",
"of",
"malaria",
"parasites,",
"yet",
"the",
"mechanisms",
"underpinning",
"the",
"success",
"of",
"this",
"approach",
"are",
"unknown.",
"Here",
"we",
"show",
"that",
"the",
"complete",
"development",
"of",
"protective",
"CD8+",
"T",
"cell",
"responses",
"requires",
"prolonged",
"antigen",
"presentation.",
"Using",
"TCR",
"transgenic",
"cells",
"specific",
"for",
"the",
"malaria",
"circumsporozoite",
"protein,",
"a",
"leading",
"vaccine",
"candidate,",
"we",
"found",
"that",
"sporozoite",
"antigen",
"persists",
"for",
"over",
"8",
"weeks",
"after",
"immunization—a",
"remarkable",
"finding",
"since",
"irradiated",
"sporozoites",
"are",
"incapable",
"of",
"replication",
"and",
"do",
"not",
"differentiate",
"beyond",
"early",
"liver",
"stages.",
"Persisting",
"antigen",
"was",
"detected",
"in",
"lymphoid",
"organs",
"and",
"depends",
"on",
"the",
"presence",
"of",
"CD11c+",
"cells.",
"Prolonged",
"antigen",
"presentation",
"enhanced",
"the",
"magnitude",
"of",
"the",
"CD8+",
"T",
"cell",
"response",
"in",
"a",
"number",
"of",
"ways.",
"Firstly,",
"reducing",
"the",
"time",
"primed",
"CD8+",
"T",
"cells",
"were",
"exposed",
"to",
"antigen",
"in",
"vivo",
"severely",
"reduced",
"the",
"final",
"size",
"of",
"the",
"developing",
"memory",
"population.",
"Secondly,",
"fully",
"developed",
"memory",
"cells",
"expanded",
"in",
"previously",
"immunized",
"mice",
"but",
"not",
"when",
"transferred",
"to",
"na¨ıve",
"animals.",
"Finally,",
"persisting",
"antigen",
"was",
"able",
"to",
"prime",
"na¨ıve",
"cells,",
"including",
"recent",
"thymic",
"emigrants,",
"to",
"become",
"functional",
"effector",
"cells",
"capable",
"of",
"eliminating",
"parasites",
"in",
"the",
"liver.",
"Together",
"these",
"data",
"show",
"that",
"the",
"optimal",
"development",
"of",
"protective",
"CD8+",
"T",
"cell",
"immunity",
"against",
"malaria",
"liver",
"stages",
"is",
"dependent",
"upon",
"the",
"prolonged",
"presentation",
"of",
"sporozoite-derived",
"antigen.",
"Citation:",
"Cockburn",
"IA,",
"Chen",
"Y-C,",
"Overstreet",
"MG,",
"Lees",
"JR,",
"van",
"Rooijen",
"N,",
"et",
"al.",
"(2010)",
"Prolonged",
"Antigen",
"Presentation",
"Is",
"Required",
"for",
"Optimal",
"CD8+",
"T",
"Cell",
"Responses",
"against",
"Malaria",
"Liver",
"Stage",
"Parasites.",
"PLoS",
"Pathog",
"6(5):",
"e1000877.",
"doi:10.1371/journal.ppat.1000877",
"Editor:",
"James",
"W.",
"Kazura,",
"Case",
"Western",
"Reserve",
"University,",
"United",
"States",
"of",
"America",
"Received",
"January",
"14,",
"2010;",
"Accepted",
"March",
"25,",
"2010;",
"Published",
"May",
"6,",
"2010",
"Copyright:",
"2010",
"Cockburn",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"FZ",
"is",
"supported",
"by",
"NIH",
"grant",
"number",
"AI44375",
"(http://www.nih.gov/);",
"IAC",
"is",
"supported",
"by",
"a",
"post-doctoral",
"fellowship",
"from",
"the",
"Johns",
"Hopkins",
"Malaria",
"Research",
"Institute",
"(http://malaria.jhsph.edu/).",
"The",
"authors",
"are",
"grateful",
"for",
"the",
"support",
"of",
"the",
"Bloomberg",
"Family",
"Foundation.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"fzavala@jhsph.edu",
"¤",
"Current",
"address:",
"David",
"H.",
"Smith",
"Center",
"for",
"Vaccine",
"Biology",
"and",
"Immunology,",
"University",
"of",
"Rochester",
"Medical",
"Center,",
"Rochester,",
"New",
"York,",
"United",
"States",
"of",
"America",
"Introduction",
"Immunization",
"with",
"irradiated",
"malaria",
"sporozoites",
"can",
"induce",
"sterile",
"protection",
"against",
"subsequent",
"challenge",
"with",
"live",
"parasites",
"in",
"both",
"mice",
"and",
"men",
"[1,2].",
"In",
"murine",
"models",
"protection",
"is",
"mediated",
"at",
"least",
"in",
"part",
"by",
"CD8+",
"T",
"cells",
"[3,4].",
"Understanding",
"the",
"mechanistic",
"underpinnings",
"of",
"this",
"protective",
"response",
"is",
"consid-",
"ered",
"essential",
"if",
"we",
"are",
"to",
"emulate",
"it",
"with",
"a",
"practical",
"and",
"effective",
"vaccine.",
"It",
"has",
"been",
"proposed",
"previously,",
"based",
"on",
"the",
"detection",
"of",
"parasite",
"remnants",
"in",
"the",
"livers",
"of",
"immunized",
"mice,",
"that",
"antigen",
"persists",
"after",
"sporozoite",
"immunization",
"and",
"that",
"this",
"may",
"help",
"generate",
"protective",
"immune",
"responses",
"[5];",
"however,",
"there",
"is",
"no",
"evidence",
"that",
"this",
"material,",
"assumed",
"to",
"be",
"of",
"parasite",
"origin,",
"is",
"immunogenic",
"or",
"that",
"it",
"is",
"presented",
"to",
"effector",
"cells",
"of",
"the",
"immune",
"system.",
"The",
"requirement",
"for",
"antigen",
"in",
"the",
"full",
"development",
"of",
"effector",
"and",
"memory",
"responses",
"in",
"different",
"microbial",
"systems",
"is",
"an",
"area",
"of",
"controversy.",
"Studies,",
"that",
"are",
"now",
"considered",
"seminal,",
"have",
"proposed",
"that",
"only",
"a",
"short",
"(,24",
"hour)",
"exposure",
"to",
"antigen",
"is",
"required",
"to",
"trigger",
"the",
"complete",
"developmental",
"program",
"of",
"CD8+",
"T",
"cells",
"[6,7,8].",
"Following",
"initial",
"antigen",
"exposure",
"CD8+",
"T",
"cells",
"expand",
"into",
"effector",
"cells",
"before",
"forming",
"a",
"numerically",
"stable",
"memory",
"population,",
"a",
"process",
"that",
"has",
"been",
"characterized",
"as",
"T",
"cells",
"on",
"‘‘autopilot’’",
"[9].",
"In",
"the",
"longer",
"term,",
"persisting",
"antigen",
"during",
"chronic",
"viral",
"infection",
"is",
"often",
"considered",
"detrimental",
"to",
"T",
"cell",
"immunity",
"as",
"over-stimulated",
"T",
"cells",
"may",
"become",
"exhausted",
"and",
"lose",
"effector",
"function",
"[10,11].",
"However,",
"not",
"all",
"data",
"suggests",
"short",
"exposures",
"to",
"antigen",
"are",
"optimal",
"for",
"T",
"cell",
"responses.",
"The",
"largest",
"antigen",
"specific",
"CD8+",
"T",
"cell",
"responses",
"observed",
"in",
"humans",
"are",
"seen",
"during",
"chronic",
"infection",
"with",
"various",
"Herpesviruses",
"[12,13].",
"For",
"Herpesviruses",
"and",
"other",
"chronic",
"infections",
"it",
"maybe",
"that",
"continued",
"recruitment",
"of",
"thymic",
"emigrants",
"by",
"the",
"continued",
"presence",
"of",
"foreign",
"antigen",
"can",
"maximize",
"and",
"maintain",
"the",
"immune",
"response",
"[14,15].",
"Recently",
"a",
"number",
"of",
"authors",
"have",
"reported",
"antigen",
"persistence",
"after",
"acute",
"viral",
"infections",
"[16,17,18].",
"Although",
"the",
"significance",
"of",
"this",
"prolonged",
"antigen",
"presentation",
"is",
"not",
"fully",
"understood,",
"some",
"authors",
"have",
"suggested",
"that",
"it",
"may",
"have",
"an",
"important",
"role",
"in",
"maintaining",
"protective",
"CD8+",
"T",
"cell",
"PLoS",
"Pathogens",
"|",
"www.plospathogens.org",
"1",
"May",
"2010",
"|",
"Volume",
"6",
"|",
"Issue",
"5",
"|",
"e1000877"
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"E",
"A",
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"H",
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"E",
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"in",
"technology",
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"P",
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"Manuela",
"A",
"Joore2,3,",
"Sabine",
"C",
"Linn4,",
"Emiel",
"JT",
"Rutgers5",
"and",
"Wim",
"H",
"van",
"Harten1,6*",
"Abstract",
"Background:",
"Health",
"Technology",
"Assessment",
"(HTA)",
"information,",
"and",
"in",
"particular",
"cost-effectiveness",
"data",
"is",
"needed",
"to",
"guide",
"decisions,",
"preferably",
"already",
"in",
"early",
"stages",
"of",
"technological",
"development.",
"However,",
"at",
"that",
"moment",
"there",
"is",
"usually",
"a",
"high",
"degree",
"of",
"uncertainty,",
"because",
"evidence",
"is",
"limited",
"and",
"different",
"development",
"paths",
"are",
"still",
"possible.",
"We",
"developed",
"a",
"multi-parameter",
"framework",
"to",
"assess",
"dynamic",
"aspects",
"of",
"a",
"technology",
"-still",
"in",
"development-,",
"by",
"means",
"of",
"scenario",
"drafting",
"to",
"determine",
"the",
"effects,",
"costs",
"and",
"cost-effectiveness",
"of",
"possible",
"future",
"diffusion",
"patterns.",
"Secondly,",
"we",
"explored",
"the",
"value",
"of",
"this",
"method",
"on",
"the",
"case",
"of",
"the",
"clinical",
"implementation",
"of",
"the",
"70-gene",
"signature",
"for",
"breast",
"cancer,",
"a",
"gene",
"expression",
"profile",
"for",
"selecting",
"patients",
"who",
"will",
"benefit",
"most",
"from",
"chemotherapy.",
"Methods:",
"To",
"incorporate",
"process-uncertainty,",
"ten",
"possible",
"scenarios",
"regarding",
"the",
"introduction",
"of",
"the",
"70-gene",
"signature",
"were",
"drafted",
"with",
"European",
"experts.",
"Out",
"of",
"5",
"most",
"likely",
"scenarios,",
"3",
"drivers",
"of",
"diffusion",
"(non-compliance,",
"technical",
"failure,",
"and",
"uptake)",
"were",
"quantitatively",
"integrated",
"in",
"a",
"decision-analytical",
"model.",
"For",
"these",
"scenarios,",
"the",
"cost-effectiveness",
"of",
"the",
"70-gene",
"signature",
"expressed",
"in",
"Incremental",
"Cost-Effectiveness",
"Ratios",
"(ICERs)",
"was",
"compared",
"to",
"clinical",
"guidelines,",
"calculated",
"from",
"the",
"past",
"(2005)",
"until",
"the",
"future",
"(2020).",
"Results:",
"In",
"2005",
"the",
"ICER",
"was",
"€1,9",
"million/quality-adjusted-life-year",
"(QALY),",
"meaning",
"that",
"the",
"70-gene",
"signature",
"was",
"not",
"yet",
"cost-effective",
"compared",
"to",
"the",
"current",
"clinical",
"guideline.",
"The",
"ICER",
"for",
"the",
"70-gene",
"signature",
"improved",
"over",
"time",
"with",
"a",
"range",
"of",
"€1,9",
"million",
"to",
"€26,145",
"in",
"2010",
"and",
"€1,9",
"million",
"to",
"€11,123/QALY",
"in",
"2020",
"depending",
"on",
"the",
"separate",
"scenario",
"used.",
"From",
"2010,",
"the",
"70-gene",
"signature",
"should",
"be",
"cost-effective,",
"based",
"on",
"the",
"combined",
"scenario.",
"The",
"uptake-scenario",
"had",
"strongest",
"influence",
"on",
"the",
"cost-effectiveness.",
"Conclusions:",
"When",
"optimal",
"diffusion",
"of",
"a",
"technology",
"is",
"sought,",
"incorporating",
"process-uncertainty",
"by",
"means",
"of",
"scenario",
"drafting",
"into",
"a",
"decision",
"model",
"may",
"reveal",
"unanticipated",
"developments",
"and",
"can",
"demonstrate",
"a",
"range",
"of",
"possible",
"cost-effectiveness",
"outcomes.",
"The",
"effect",
"of",
"scenarios",
"give",
"additional",
"information",
"on",
"the",
"speed",
"with",
"cost",
"effectiveness",
"might",
"be",
"reached",
"and",
"thus",
"provide",
"a",
"more",
"realistic",
"picture",
"for",
"policy",
"makers,",
"opinion",
"leaders",
"and",
"manufacturers.",
"Keywords:",
"Early",
"technology",
"assessment,",
"Scenario",
"drafting,",
"Genomic",
"profiling,",
"70-gene",
"signature,",
"Breast",
"cancer",
"Open",
"Access",
"*",
"Correspondence:",
"w.h.vanharten@utwente.nl",
"1Netherlands",
"Cancer",
"Institute-Antoni",
"van",
"Leeuwenhoek",
"Hospital",
"(NKI-AVL),",
"Department",
"of",
"Psychosocial",
"Research",
"and",
"Epidemiology,",
"Plesmanlaan",
"121,",
"Amsterdam",
"1066",
"CX,",
"The",
"Netherlands",
"6University",
"of",
"Twente,",
"School",
"of",
"Governance",
"and",
"Management,",
"MB-HTSR,",
"PO",
"Box",
"217,",
"Enschede",
"7500",
"AE,",
"The",
"Netherlands",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"©",
"2012",
"Retèl",
"et",
"al.;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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"CNRS",
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"3525,",
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"France",
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"IP32637",
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"be",
"horizontally",
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"a",
"large",
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"here",
"that",
"at",
"low",
"temperature",
"other",
"chromosomal",
"loci,",
"as",
"well",
"as",
"a",
"non-mobilizable",
"plasmid",
"(pUC4K),",
"are",
"also",
"transferable.",
"This",
"transfer,",
"designated",
"GDT4",
"(Generalized",
"DNA",
"Transfer",
"at",
"4uC),",
"required",
"the",
"presence",
"of",
"an",
"IP32637",
"endogenous",
"plasmid",
"(pGDT4)",
"that",
"carries",
"several",
"mobile",
"genetic",
"elements",
"and",
"a",
"conjugation",
"machinery.",
"We",
"established",
"that",
"cure",
"of",
"this",
"plasmid",
"or",
"inactivation",
"of",
"its",
"sex",
"pilus",
"fully",
"abrogates",
"this",
"process.",
"Analysis",
"of",
"the",
"mobilized",
"pUC4K",
"recovered",
"from",
"transconjugants",
"revealed",
"the",
"insertion",
"of",
"one",
"of",
"the",
"pGDT4–borne",
"ISs,",
"designated",
"ISYps1,",
"at",
"different",
"sites",
"on",
"the",
"transferred",
"plasmid",
"molecules.",
"This",
"IS",
"belongs",
"to",
"the",
"IS6",
"family,",
"which",
"moves",
"by",
"replicative",
"transposition,",
"and",
"thus",
"could",
"drive",
"the",
"formation",
"of",
"cointegrates",
"between",
"pGDT4",
"and",
"the",
"host",
"chromosome",
"and",
"could",
"mediate",
"the",
"transfer",
"of",
"chromosomal",
"regions",
"in",
"an",
"Hfr-like",
"manner.",
"In",
"support",
"of",
"this",
"model,",
"we",
"show",
"that",
"a",
"suicide",
"plasmid",
"carrying",
"ISYps1",
"is",
"able",
"to",
"integrate",
"itself,",
"flanked",
"by",
"ISYps1",
"copies,",
"at",
"multiple",
"locations",
"into",
"the",
"Escherichia",
"coli",
"chromosome.",
"Furthermore,",
"we",
"demonstrate",
"the",
"formation",
"of",
"RecA-independent",
"cointegrates",
"between",
"the",
"ISYps1-",
"harboring",
"plasmid",
"and",
"an",
"ISYps1-free",
"replicon,",
"leading",
"to",
"the",
"passive",
"transfer",
"of",
"the",
"non-conjugative",
"plasmid.",
"We",
"thus",
"demonstrate",
"here",
"a",
"natural",
"mechanism",
"of",
"horizontal",
"gene",
"exchange,",
"which",
"is",
"less",
"constrained",
"and",
"more",
"powerful",
"than",
"the",
"classical",
"Hfr",
"mechanism,",
"as",
"it",
"only",
"requires",
"the",
"presence",
"of",
"an",
"IS6-type",
"element",
"on",
"a",
"conjugative",
"replicon",
"to",
"drive",
"the",
"horizontal",
"transfer",
"of",
"any",
"large",
"block",
"of",
"plasmid",
"or",
"chromosomal",
"DNA.",
"This",
"natural",
"mechanism",
"of",
"chromosome",
"transfer,",
"which",
"occurs",
"under",
"conditions",
"mimicking",
"those",
"found",
"in",
"the",
"environment,",
"may",
"thus",
"play",
"a",
"significant",
"role",
"in",
"bacterial",
"evolution,",
"pathogenesis,",
"and",
"adaptation",
"to",
"new",
"ecological",
"niches.",
"Citation:",
"Lesic",
"B,",
"Zouine",
"M,",
"Ducos-Galand",
"M,",
"Huon",
"C,",
"Rosso",
"M-L,",
"et",
"al.",
"(2012)",
"A",
"Natural",
"System",
"of",
"Chromosome",
"Transfer",
"in",
"Yersinia",
"pseudotuberculosis.",
"PLoS",
"Genet",
"8(3):",
"e1002529.",
"doi:10.1371/journal.pgen.1002529",
"Editor:",
"Josep",
"Casadesu´",
"s,",
"Universidad",
"de",
"Sevilla,",
"Spain",
"Received",
"September",
"15,",
"2011;",
"Accepted",
"December",
"23,",
"2011;",
"Published",
"March",
"8,",
"2012",
"Copyright:",
"2012",
"Lesic",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"funded",
"by",
"a",
"grant",
"from",
"the",
"French",
"‘‘Ministe`re",
"de",
"la",
"Recherche",
"et",
"de",
"la",
"Technologie’’",
"to",
"BL",
"and",
"by",
"the",
"Centre",
"National",
"de",
"la",
"Recherche",
"Scientifique",
"(CNRS-URA",
"2171),",
"the",
"Fondation",
"pour",
"la",
"Recherche",
"Me´dicale,",
"and",
"the",
"EU",
"(STREP",
"CRAB,",
"LSHM-CT-2005-019023,",
"and",
"NoE",
"EuroPathoGenomics,",
"LSHB-",
"CT-2005-512061)",
"to",
"DM.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"didier.mazel@pasteur.fr",
"(DM);",
"elisabeth.carniel@pasteur.fr",
"(EC)",
"Introduction",
"Horizontal",
"gene",
"transfer",
"(HGT)",
"is",
"a",
"driving",
"force",
"for",
"bacterial",
"evolution,",
"as",
"it",
"allows",
"the",
"dispersion",
"of",
"adaptive",
"loci",
"between",
"closely",
"related",
"and",
"also",
"phylogenetically",
"distant",
"bacterial",
"species.",
"Well-characterized",
"mobile",
"genetic",
"elements",
"such",
"as",
"conjugative",
"plasmids,",
"transposons,",
"Integrative",
"conjugative",
"elements",
"(ICE),",
"pathogenicity",
"islands",
"(PAI),",
"or",
"phages",
"are",
"associated",
"with",
"HGT",
"of",
"specific",
"adaptive",
"functions",
"(antibiotic",
"resistance,",
"virulence,",
"meta-",
"bolic",
"pathways)",
"and",
"participate",
"to",
"genome",
"plasticity.",
"However,",
"exchanges",
"of",
"chromosomal",
"regions",
"that",
"form",
"the",
"core",
"genome",
"and",
"are",
"not",
"part",
"of",
"the",
"mobile",
"genetic",
"pool",
"are",
"also",
"observed.",
"While",
"their",
"importance",
"in",
"bacterial",
"evolution",
"and",
"speciation",
"is",
"now",
"well",
"established,",
"the",
"underlying",
"mechanisms",
"are",
"often",
"loosely",
"described",
"and",
"remain",
"hypothetical",
"in",
"many",
"cases.",
"The",
"Gram-negative",
"enteropathogen",
"Yersinia",
"pseudotuberculosis",
"carries",
"a",
"PAI",
"termed",
"High",
"Pathogenicity",
"Island",
"(HPI)",
"[1],",
"which",
"encodes",
"the",
"siderophore",
"yersiniabactin",
"[2].",
"The",
"fact",
"that",
"this",
"island",
"is",
"mobile",
"within",
"the",
"genome",
"of",
"its",
"host",
"strain",
"[3],",
"and",
"is",
"present",
"and",
"often",
"conserved",
"both",
"in",
"terms",
"of",
"genetic",
"organization",
"and",
"nucleotide",
"sequence",
"in",
"various",
"bacterial",
"genera",
"such",
"as",
"Escherichia",
"coli",
"(various",
"pathotypes),",
"Klebsiella",
"or",
"Citrobacter",
"[4],",
"suggested",
"that",
"it",
"may",
"have",
"retained",
"its",
"ability",
"to",
"be",
"horizontally",
"transmitted",
"to",
"new",
"bacterial",
"hosts.",
"Indeed,",
"we",
"evidenced",
"the",
"transfer",
"of",
"the",
"HPI",
"between",
"natural",
"Y.",
"pseudotuberculosis",
"isolates",
"[3].",
"This",
"phenomenon",
"was",
"observed",
"only",
"when",
"the",
"bacteria",
"were",
"incubated",
"at",
"low",
"temperature",
"(optimal",
"at",
"4uC)",
"and",
"in",
"broth,",
"and",
"was",
"more",
"efficient",
"in",
"an",
"iron-poor",
"medium",
"[5].",
"However,",
"this",
"transfer",
"did",
"not",
"require",
"the",
"integration/excision",
"machinery",
"encoded",
"by",
"the",
"HPI,",
"was",
"RecA-dependent",
"in",
"the",
"recipient",
"strain,",
"and",
"involved",
"not",
"only",
"the",
"HPI",
"but",
"also",
"adjacent",
"sequences",
"encompassing",
"at",
"least",
"46",
"kb",
"of",
"chromosomal",
"DNA",
"[3].",
"Similar",
"results",
"were",
"recently",
"obtained",
"for",
"the",
"HPI",
"of",
"natural",
"Escherichia",
"coli",
"isolates,",
"using",
"a",
"multi",
"locus",
"sequence",
"typing",
"approach.",
"The",
"E.",
"coli",
"HPI",
"was",
"found",
"to",
"have",
"been",
"acquired",
"simultaneously",
"with",
"the",
"chromosomal",
"flanking",
"regions",
"of",
"the",
"donor",
"strains",
"[6],",
"indicating",
"again",
"that",
"the",
"island",
"was",
"transmitted",
"as",
"part",
"of",
"a",
"larger",
"chromosomal",
"region.",
"This",
"phenomenon",
"is",
"not",
"restricted",
"to",
"the",
"HPI",
"and",
"to",
"enterobacteria",
"since",
"it",
"has",
"been",
"recently",
"reported",
"that",
"movement",
"of",
"the",
"Enterococcus",
"faecalis",
"PAI",
"was",
"invariably",
"accompanied",
"by",
"transfer",
"of",
"flanking",
"donor",
"chromosome",
"sequences",
"[7].",
"PLoS",
"Genetics",
"|",
"www.plosgenetics.org",
"1",
"March",
"2012",
"|",
"Volume",
"8",
"|",
"Issue",
"3",
"|",
"e1002529"
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] | [
"Nucleic",
"Acids",
"Research,",
"2005,",
"Vol.",
"33,",
"No.",
"22",
"e189",
"doi:10.1093/nar/gni192",
"Iterative",
"in",
"vivo",
"assembly",
"of",
"large",
"and",
"complex",
"transgenes",
"by",
"combining",
"the",
"activities",
"of",
"fC31",
"integrase",
"and",
"Cre",
"recombinase",
"Felix",
"Dafhnis-Calas,",
"Zhengyao",
"Xu,",
"Steve",
"Haines,",
"Sunir",
"K.",
"Malla,",
"Margaret",
"C.",
"M.",
"Smith",
"and",
"William",
"R.",
"A.",
"Brown*",
"Institute",
"of",
"Genetics,",
"Queen’s",
"Medical",
"Centre,",
"University",
"of",
"Nottingham,",
"Nottingham",
"NG7",
"2UH,",
"UK",
"Received",
"September",
"21,",
"2005;",
"Revised",
"October",
"17,",
"2005;",
"Accepted",
"November",
"25,",
"2005",
"ABSTRACT",
"We",
"have",
"used",
"the",
"fC31",
"integrase",
"to",
"introduce",
"large",
"DNA",
"sequences",
"into",
"a",
"vertebrate",
"genome",
"and",
"meas-",
"ure",
"the",
"efficiency",
"of",
"integration",
"of",
"intact",
"DNA",
"as",
"a",
"function",
"of",
"insert",
"size.",
"Inserts",
"of",
"110",
"kb",
"and",
"140",
"kb",
"in",
"length",
"may",
"be",
"integrated",
"with",
"about",
"25%",
"and",
"10%",
"efficiency",
"respectively.",
"In",
"order",
"to",
"overcome",
"the",
"prob-",
"lems",
"of",
"constructing",
"transgenes",
"longer",
"than",
"150",
"kb",
"we",
"have",
"established",
"a",
"method",
"that",
"we",
"call;",
"‘Iterative",
"Site",
"Specific",
"Integration’",
"(ISSI).",
"ISSI",
"combines",
"the",
"activities",
"of",
"fC31",
"integrase",
"and",
"Cre",
"recombinase",
"to",
"enable",
"the",
"iterative",
"and",
"serial",
"integration",
"of",
"trans-",
"genic",
"DNA",
"sequences.",
"In",
"principle",
"the",
"procedure",
"may",
"be",
"repeated",
"an",
"arbitrary",
"number",
"of",
"times",
"and",
"thereby",
"allow",
"the",
"integration",
"of",
"tracts",
"of",
"DNA",
"many",
"hundreds",
"of",
"kilobase",
"pairs",
"long.",
"In",
"practice",
"it",
"may",
"be",
"limited",
"by",
"the",
"time",
"needed",
"to",
"check",
"the",
"accuracy",
"of",
"integration",
"at",
"each",
"step",
"of",
"the",
"procedure.",
"We",
"describe",
"two",
"ISSI",
"experiments,",
"in",
"one",
"of",
"which",
"we",
"have",
"constructed",
"a",
"complex",
"array",
"of",
"vertebrate",
"centromeric",
"sequences",
"of",
"150",
"kb",
"in",
"size.",
"The",
"principle",
"that",
"underlies",
"ISSI",
"is",
"applicable",
"to",
"transgenesis",
"in",
"all",
"organisms.",
"ISSI",
"may",
"thus",
"facilitate",
"the",
"reconstitution",
"of",
"biosynthetic",
"pathways",
"encoded",
"by",
"many",
"different",
"genes",
"in",
"trans-",
"genic",
"plants,",
"the",
"assembly",
"of",
"large",
"vertebrate",
"loci",
"as",
"transgenes",
"and",
"the",
"synthesis",
"of",
"complete",
"genomes",
"in",
"bacteria.",
"INTRODUCTION",
"Site-specific",
"recombinases",
"are",
"used",
"to",
"manipulate",
"chromo-",
"somal",
"DNA",
"sequence",
"organization",
"in",
"vivo,",
"in",
"vitro",
"(1)",
"and",
"in",
"a",
"range",
"of",
"different",
"experimental",
"systems.",
"The",
"enzymes",
"Cre",
"and",
"Flp",
"(2)",
"are",
"the",
"most",
"widely",
"employed,",
"both",
"are",
"members",
"of",
"the",
"tyrosine",
"recombinase",
"family",
"and",
"catalyse",
"reversible",
"reactions",
"between",
"identical",
"sites",
"of",
"35",
"bp",
"in",
"the",
"absence",
"of",
"any",
"accessory",
"proteins.",
"The",
"reversibility",
"of",
"the",
"reactions",
"catalysed",
"by",
"these",
"enzymes",
"has",
"limited",
"their",
"applicability.",
"They",
"are",
"generally",
"used",
"to",
"promote",
"deletion",
"reactions",
"since",
"integration",
"reactions",
"are",
"kinetically",
"unfavourable.",
"However",
"Cre",
"and",
"Flp",
"have",
"also",
"been",
"used",
"to",
"engineer",
"integrations",
"and",
"translocations",
"in",
"cells",
"in",
"culture",
"where",
"it",
"has",
"been",
"possible",
"to",
"provide",
"the",
"enzyme",
"transiently",
"and",
"trap",
"the",
"potentially",
"unstable",
"product,",
"often",
"but",
"not",
"always,",
"by",
"selection",
"(3,4).",
"A",
"technology",
"that",
"would",
"allow",
"the",
"construction",
"of",
"large",
"segments",
"of",
"transgenic",
"DNA",
"would",
"be",
"of",
"widespread",
"utility.",
"Thus",
"it",
"would",
"be",
"valuable",
"to",
"be",
"able",
"to",
"assemble",
"large",
"tracts",
"of",
"transgenic",
"DNA",
"at",
"defined",
"chromosomal",
"loci",
"in",
"order",
"to",
"con-",
"struct",
"animal",
"models",
"of",
"human",
"genetic",
"disease",
"and",
"to",
"study",
"the",
"factors",
"controlling",
"expression",
"of",
"large",
"genes.",
"This",
"goal",
"has",
"become",
"more",
"attractive",
"with",
"the",
"ability",
"to",
"precisely",
"and",
"effi-",
"ciently",
"manipulate",
"DNA",
"cloned",
"in",
"Escherichia",
"coli",
"by",
"homo-",
"logous",
"recombination",
"(5,6)",
"and",
"with",
"the",
"availability",
"of",
"a",
"complete",
"genome",
"sequence",
"and",
"well-characterized",
"libraries",
"of",
"bacterial",
"artificial",
"chromosome",
"(BAC)",
"clones.",
"Similarly",
"it",
"would",
"be",
"useful",
"to",
"be",
"able",
"to",
"build",
"plants",
"with",
"multiple",
"transgenes",
"at",
"a",
"single",
"locus.",
"Finally",
"it",
"would",
"be",
"interesting",
"to",
"be",
"able",
"to",
"construct",
"synthetic",
"bacterial",
"genomes",
"in",
"order",
"to",
"identify",
"the",
"minimal",
"set",
"of",
"genes",
"consistent",
"with",
"independent",
"life",
"(7).",
"Strategies",
"describing",
"how",
"Cre",
"or",
"Flp",
"might",
"be",
"used",
"to",
"promote",
"irreversible",
"integrations",
"have",
"been",
"presented",
"(8–10)",
"However",
"all",
"of",
"these",
"approaches",
"suffer",
"from",
"the",
"limitation",
"that",
"they",
"only",
"allow",
"one",
"cycle",
"of",
"site-specific",
"recombination",
"and",
"thus",
"cannot",
"be",
"used",
"iteratively.",
"It",
"is",
"difficult",
"therefore",
"to",
"see",
"how",
"they",
"could",
"be",
"used",
"to",
"construct",
"large",
"tracts",
"of",
"trans-",
"genic",
"DNA.",
"*To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"Tel:",
"+44",
"115",
"849",
"3244;",
"Fax:",
"+44",
"115",
"970",
"9906;",
"Email:",
"William.brown@nottingham.ac.uk",
"Present",
"address:",
"Margaret",
"C.",
"M.",
"Smith,",
"Institute",
"of",
"Medical",
"Sciences,",
"University",
"of",
"Aberdeen,",
"Aberdeen",
"AB25",
"2ZD,",
"UK",
"The",
"Author",
"2005.",
"Published",
"by",
"Oxford",
"University",
"Press.",
"All",
"rights",
"reserved.",
"The",
"online",
"version",
"of",
"this",
"article",
"has",
"been",
"published",
"under",
"an",
"open",
"access",
"model.",
"Users",
"are",
"entitled",
"to",
"use,",
"reproduce,",
"disseminate,",
"or",
"display",
"the",
"open",
"access",
"version",
"of",
"this",
"article",
"for",
"non-commercial",
"purposes",
"provided",
"that:",
"the",
"original",
"authorship",
"is",
"properly",
"and",
"fully",
"attributed;",
"the",
"Journal",
"and",
"Oxford",
"University",
"Press",
"are",
"attributed",
"as",
"the",
"original",
"place",
"of",
"publication",
"with",
"the",
"correct",
"citation",
"details",
"given;",
"if",
"an",
"article",
"is",
"subsequently",
"reproduced",
"or",
"disseminated",
"not",
"in",
"its",
"entirety",
"but",
"only",
"in",
"part",
"or",
"as",
"a",
"derivative",
"work",
"this",
"must",
"be",
"clearly",
"indicated.",
"For",
"commercial",
"re-use,",
"please",
"contact",
"journals.permissions@oxfordjournals.org"
] | [
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] | [
"Research",
"Farmworkers",
"Pneumoconiosis",
"from",
"Agricultural",
"Dust",
"Exposure",
"among",
"Young",
"California",
"Marc",
"B.",
"Schenker,1",
"Kent",
"E.",
"Pinkerton,2",
"Diane",
"Mitchell,1",
"Val",
"Vallyathan,3",
"Brenda",
"Elvine-Kreis,1",
"and",
"Francis",
"H.Y.",
"Green",
"4",
"1Department",
"of",
"Public",
"Health",
"Sciences,",
"and",
"2Center",
"for",
"Health",
"and",
"the",
"Environment",
"University",
"of",
"California",
"at",
"Davis,",
"Davis,",
"California,",
"USA;",
"3Pathology",
"and",
"Physiology",
"Research",
"Branch,",
"National",
"Institute",
"for",
"Occupational",
"Safety",
"and",
"Health,",
"Morgantown,",
"West",
"Virginia,",
"USA;",
"4Department",
"of",
"Pathology",
"and",
"Laboratory",
"Medicine,",
"University",
"of",
"Calgary,",
"Calgary,",
"Alberta,",
"Canada",
"Background",
"inorganic",
"(mineral)",
"dusts.",
":",
"Agricultural",
"workers",
"are",
"exposed",
"to",
"airborne",
"pollutants,",
"including",
"organic",
"and",
"o",
"Bjectivs",
":",
"Lung",
"autopsy",
"specimens",
"from",
"consecutive",
"coroner’s",
"cases",
"of",
"Hispanic",
"males",
"in",
"Fresno",
"County,",
"California,",
"(n",
"=",
"112)",
"were",
"obtained",
"to",
"determine",
"whether",
"mineral",
"dust",
"exposure",
"in",
"agricul-",
"tural",
"work",
"leads",
"to",
"pneumoconiosis.",
"Methods",
":",
"The",
"left",
"lung",
"was",
"fixed",
"by",
"inflation.",
"We",
"evaluated",
"airway",
"and",
"parenchymal",
"pathology",
"using",
"standardized",
"diagnostic",
"criteria",
"and",
"semiquantitative",
"grading",
"schemata,",
"including",
"the",
"grading",
"of",
"small",
"airways",
"for",
"fibrosis",
"and",
"birefringent",
"mineral",
"dust",
"particles.",
"We",
"analyzed",
"lung",
"dust",
"burden",
"on",
"a",
"subset",
"of",
"37",
"lungs",
"following",
"bleach",
"digestion,",
"using",
"scanning",
"electron",
"microscopy",
"(SEM),",
"X-ray",
"spectrometry",
"(XRS)",
"and",
"image",
"analysis,",
"and",
"by",
"X-ray",
"diffraction",
"for",
"crystalline",
"silica",
"(CSi).",
"Farmworkers",
"comprised",
"51.5%",
"and",
"nonfarmworkers",
"48.5%",
"of",
"the",
"samples.",
"words",
"r",
"esult",
":",
"Proximal",
"airways",
"demonstrated",
"little",
"mineral",
"dust",
"accumulation,",
"but",
"membranous",
"and",
"respiratory",
"bronchioles",
"had",
"wall",
"thickening,",
"remodeling,",
"and",
"inflammation",
"associated",
"with",
"carbo-",
"naceous",
"and",
"mineral",
"dust",
"deposition.",
"These",
"changes",
"were",
"independently",
"associated",
"with",
"agricultural",
"work,",
"cigarette",
"smoking,",
"and",
"increased",
"age.",
"Mineral",
"dust",
"small",
"airways",
"disease,",
"pneumoconiosis",
"(macules",
"and",
"nodules),",
"and",
"pathologic",
"changes",
"consistent",
"with",
"chronic",
"bronchitis,",
"emphysema,",
"and",
"interstitial",
"fibrosis",
"predominated",
"in",
"farmworkers",
"compared",
"with",
"nonfarmworkers.",
"CSi,",
"determined",
"gravimetrically,",
"and",
"aluminum",
"silicate",
"particles,",
"determined",
"by",
"SEM/XRS,",
"were",
"increased",
"in",
"the",
"lungs",
"of",
"farmworkers",
"compared",
"with",
"nonfarmworkers",
"and",
"were",
"significantly",
"(p",
"<",
"0.05)",
"associated",
"with",
"small",
"airway",
"disease",
"and",
"pneumoconiosis.",
"c",
"onclusi",
":",
"Mineral",
"dust",
"exposure",
"is",
"associated",
"with",
"increased",
"small",
"airway",
"disease",
"and",
"pneu-",
"moconiosis",
"among",
"California",
"farmworkers;",
"however,",
"the",
"clinical",
"significance",
"and",
"natural",
"history",
"of",
"these",
"changes",
"remains",
"to",
"be",
"determined.",
"k",
"ey",
":",
"agriculture,",
"dust,",
"farmworker,",
"interstitial",
"fibrosis,",
"pneumoconiosis,",
"respiratory,",
"small",
"airways",
"disease.",
"Environ",
"Health",
"Perspect",
"117:988–994",
"(2009).",
"doi:10.1289/ehp.0800144",
"available",
"via",
"http://dx.doi.org/",
"[Online",
"25",
"February",
"2009]",
"Approximately",
"5",
"million",
"workers",
"in",
"the",
"United",
"States",
"work",
"in",
"the",
"agricultural",
"industry",
"with",
"potential",
"exposure",
"to",
"a",
"wide",
"variety",
"of",
"respiratory",
"toxicants.",
"Among",
"the",
"various",
"respiratory",
"hazards",
"not",
"well",
"studied",
"is",
"obstructive",
"and",
"restrictive",
"lung",
"disease",
"caused",
"by",
"inorganic",
"minerals",
"(American",
"Thoracic",
"Society",
"1998).",
"California",
"agricultural",
"work-",
"ers",
"have",
"increased",
"respiratory",
"symptoms,",
"decreased",
"respiratory",
"function,",
"and",
"increased",
"mortality",
"rates",
"from",
"chronic",
"pulmonary",
"disease",
"compared",
"with",
"the",
"general",
"popula-",
"tion",
"(Schenker",
"et",
"al.",
"2005;",
"Singleton",
"and",
"Beaumont",
"1989;",
"Stubbs",
"et",
"al.",
"1984).",
"The",
"agricultural",
"environment",
"of",
"the",
"Central",
"Valley",
"of",
"California",
"places",
"individuals",
"at",
"increased",
"risk",
"of",
"exposure",
"to",
"inorganic",
"par-",
"ticles.",
"This",
"region",
"encompasses",
"a",
"rich",
"farming",
"area",
"as",
"well",
"as",
"extensive",
"urban",
"development.",
"The",
"predominantly",
"dry",
"farming",
"techniques",
"of",
"the",
"Central",
"Valley",
"result",
"in",
"high",
"levels",
"of",
"air-",
"borne",
"dust",
"from",
"operations",
"such",
"as",
"field",
"prep-",
"aration",
"and",
"harvesting",
"of",
"row",
"crops",
"and",
"tree",
"fruits",
"(Nieuwenhuijsen",
"and",
"Schenker",
"1998;",
"Nieuwenhuijsen",
"et",
"al.",
"1998).",
"Although",
"soil",
"consists",
"of",
"a",
"mixture",
"of",
"organic",
"and",
"inorganic",
"988",
"materials,",
"potential",
"health",
"effects",
"from",
"the",
"ever-present",
"mineral",
"dusts",
"have",
"been",
"largely",
"overlooked.",
"In",
"theory,",
"soil",
"should",
"contain",
"representative",
"portions",
"of",
"all",
"major",
"mineral",
"classes",
"in",
"the",
"earth’s",
"crust;",
"in",
"reality,",
"most",
"agricultural",
"soils",
"are",
"composed",
"largely",
"of",
"sili-",
"cate",
"materials",
"(e.g.,",
"feldspars,",
"mica,",
"clay",
"min-",
"erals)",
"and",
"crystalline",
"silica",
"(CSi)",
"(quartz)",
"with",
"varying",
"amounts",
"of",
"other",
"mineral",
"classes,",
"depending",
"on",
"the",
"local",
"geologic",
"history.",
"The",
"evidence",
"that",
"mineral",
"dust",
"exposure",
"poses",
"a",
"significant",
"hazard",
"to",
"agricultural",
"workers",
"for",
"interstitial",
"lung",
"disease",
"is",
"based",
"on",
"a",
"handful",
"of",
"case",
"reports,",
"inferences",
"from",
"exposures",
"to",
"mineral",
"dusts",
"in",
"other",
"industries,",
"studies",
"of",
"wild",
"and",
"farm",
"animals",
"exposed",
"to",
"environ-",
"mental",
"dusts,",
"and",
"toxicologic",
"studies",
"(Gylseth",
"et",
"al.",
"1984;",
"Schenker",
"2000;",
"Schoning",
"1996;",
"Vallyathan",
"et",
"al.",
"2007).",
"The",
"deposition",
"and",
"clearance",
"of",
"particles",
"within",
"the",
"respiratory",
"system",
"occurs",
"in",
"an",
"inhomogeneous",
"manner.",
"The",
"fate",
"of",
"parti-",
"cles",
"is",
"not",
"well",
"established,",
"and",
"there",
"is",
"little",
"information",
"on",
"the",
"distribution",
"and",
"reten-",
"tion",
"of",
"particles",
"under",
"conditions",
"of",
"ambi-",
"ent",
"exposure.",
"One",
"purpose",
"of",
"this",
"study",
"was",
"to",
"design",
"and",
"implement",
"an",
"approach",
"that",
"would",
"allow",
"the",
"assessment",
"of",
"particle",
"reten-",
"tion",
"as",
"well",
"as",
"histologic",
"analysis",
"of",
"response",
"in",
"different",
"lung",
"compartments.",
"Our",
"findings",
"in",
"this",
"regard",
"have",
"been",
"previously",
"published",
"and",
"show",
"that",
"the",
"deposition",
"of",
"particles",
"is",
"primarily",
"in",
"the",
"centriacinar",
"portion",
"of",
"the",
"lung",
"lobule",
"(Pinkerton",
"et",
"al.",
"2000).",
"Unfortunately,",
"no",
"reported",
"epidemiologic",
"studies",
"have",
"directly",
"assessed",
"environmental",
"exposure",
"to",
"mineral",
"dusts",
"and",
"interstitial",
"lung",
"and",
"airway",
"disease",
"in",
"farmers",
"or",
"farmworkers,",
"although",
"respiratory",
"symptoms",
"have",
"been",
"associated",
"with",
"exposure",
"to",
"agricultural",
"dusts",
"with",
"high",
"mineral",
"content",
"(Schenker",
"et",
"al.",
"2005).",
"A",
"few",
"studies,",
"however,",
"have",
"suggested",
"that",
"pneumoconiosis",
"(Gylseth",
"et",
"al.",
"1984;",
"Sherwin",
"et",
"al.",
"1979)",
"and",
"restrictive",
"lung",
"disease",
"(Sasagawa",
"et",
"al.",
"1989)",
"are",
"increased",
"in",
"some",
"agricultural",
"populations",
"exposed",
"to",
"mineral",
"dusts.",
"A",
"fundamental",
"question",
"remains",
"whether",
"occupational",
"exposure",
"to",
"agricultural",
"dusts",
"can",
"cause",
"pulmonary",
"fibro-",
"sis,",
"persistent",
"inflammation,",
"and",
"cell/tissue",
"remodeling",
"in",
"specific",
"regions",
"of",
"the",
"lungs",
"where",
"these",
"mineral",
"dusts",
"are",
"present.",
"The",
"objective",
"of",
"this",
"study",
"was",
"to",
"docu-",
"ment",
"and",
"quantify",
"pathologic",
"lesions",
"in",
"lung",
"tissues",
"from",
"consecutive",
"Hispanic",
"males",
"autopsied",
"by",
"the",
"coroner’s",
"office",
"in",
"Fresno,",
"California,",
"and",
"to",
"determine",
"their",
"relation-",
"ship",
"to",
"agricultural",
"work",
"and",
"to",
"mineral",
"dust",
"retained",
"in",
"the",
"lungs.",
"We",
"focused",
"on",
"pneu-",
"moconiosis",
"and",
"lesions",
"of",
"the",
"small",
"airways.",
"The",
"latter",
"are",
"the",
"primary",
"target",
"of",
"mineral",
"dusts",
"(Churg",
"et",
"al.",
"1999;",
"Craighead",
"et",
"al.",
"1982)",
"and",
"are",
"most",
"likely",
"to",
"reflect",
"early",
"dis-",
"ease",
"in",
"a",
"young",
"population",
"(Pinkerton",
"et",
"al.",
"Address",
"correspondence",
"to",
"M.",
"Schenker,",
"Department",
"of",
"Public",
"Health",
"Sciences,",
"University",
"of",
"California,",
"One",
"Shields",
"Ave.,",
"Davis,",
"California",
"95616",
"USA.",
"Telephone:",
"(530)",
"752-5676.",
"Fax:",
"(530)",
"752-3239.",
"E-mail:",
"mbschenker@ucdavis.edu",
"Supplemental",
"Material",
"is",
"available",
"online",
"at",
"http://",
"www.ehponline.org/members/2009/0800144/suppl.pdf",
"We",
"thank",
"S.",
"Smiley-Jewell",
"for",
"assisting",
"with",
"manu-",
"script",
"preparation.",
"This",
"research",
"has",
"been",
"funded",
"in",
"part",
"by",
"National",
"Institute",
"for",
"Occupational",
"Safety",
"and",
"Health",
"U07/",
"CCU906162,",
"U.S.",
"Environmental",
"Protection",
"Agency",
"grants",
"R826246",
"and",
"RD832414,",
"and",
"the",
"Alberta",
"Lung",
"Association.",
"The",
"authors",
"declare",
"they",
"have",
"no",
"competing",
"Received",
"2",
"September",
"2008;",
"accepted",
"25",
"February",
"financial",
"interests.",
"2009.",
"ovlume",
"117",
"|",
"number",
"6",
"|",
"June",
"2009",
"•",
"Environmental",
"Health",
"Perspectives"
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] | [
"96",
"Acta",
"Orthopaedica",
"2011;",
"82",
"(1):",
"96–101",
"Surgery",
"for",
"skeletal",
"metastases",
"in",
"lung",
"cancer",
"Complications",
"and",
"survival",
"in",
"98",
"patients",
"Rudiger",
"J",
"Weiss",
"and",
"Rikard",
"Wedin",
"Department",
"of",
"Molecular",
"Medicine",
"and",
"Surgery,",
"Section",
"of",
"Orthopaedics",
"and",
"Sports",
"Medicine,",
"Karolinska",
"University",
"Hospital,",
"Karolinska",
"Institutet,",
"Stockholm,",
"Sweden",
"Correspondence:",
"rudiger.weiss@karolinska.se",
"Submitted",
"10-04-30",
"Accepted",
"10-09-17",
"Background",
"and",
"purpose",
"Most",
"lung",
"cancer",
"patients",
"with",
"skeletal",
"metastases",
"have",
"a",
"short",
"survival",
"and",
"it",
"is",
"difficult",
"to",
"identify",
"those",
"patients",
"who",
"will",
"benefit",
"from",
"palliative",
"surgery.",
"We",
"report",
"com-",
"plication",
"and",
"survival",
"rates",
"in",
"a",
"consecutive",
"series",
"of",
"lung",
"cancer",
"patients",
"who",
"were",
"operated",
"for",
"symptomatic",
"skeletal",
"metastases.",
"Methods",
"This",
"study",
"was",
"based",
"on",
"data",
"recorded",
"in",
"the",
"Karolinska",
"Skeletal",
"Metastasis",
"Register.",
"The",
"study",
"period",
"was",
"1987–2006.",
"We",
"identified",
"98",
"lung",
"cancer",
"patients",
"(52",
"females).",
"The",
"median",
"age",
"at",
"surgery",
"was",
"62",
"(34–88)",
"years.",
"78",
"lesions",
"were",
"located",
"in",
"the",
"femur",
"or",
"spine.",
"Results",
"The",
"median",
"survival",
"time",
"after",
"surgery",
"was",
"3",
"(0–127)",
"months.",
"The",
"cumulative",
"12-month",
"survival",
"after",
"surgery",
"was",
"13%",
"(95%",
"CI:",
"6–20).",
"There",
"was",
"a",
"difference",
"between",
"the",
"survival",
"after",
"spinal",
"surgery",
"(2",
"months)",
"and",
"after",
"extremity",
"surgery",
"(4",
"months)",
"(p",
"=",
"0.03).",
"Complete",
"pathological",
"fracture",
"in",
"non-spinal",
"metastases",
"(50",
"patients)",
"was",
"an",
"independent",
"negative",
"predictor",
"of",
"survival",
"(hazard",
"ratio",
"(HR)",
"=",
"1.8,",
"95%",
"CI:",
"1–3).",
"16",
"of",
"31",
"patients",
"with",
"spinal",
"metastases",
"experienced",
"a",
"considerable",
"improvement",
"in",
"their",
"neurological",
"function",
"after",
"surgery.",
"The",
"overall",
"complica-",
"tion",
"rate",
"was",
"20%,",
"including",
"a",
"reoperation",
"rate",
"of",
"15%.",
"Interpretation",
"Bone",
"metastases",
"and",
"their",
"subsequent",
"surgical",
"treatment",
"in",
"lung",
"cancer",
"patients",
"are",
"associated",
"with",
"high",
"mor-",
"bidity",
"and",
"mortality.",
"Our",
"findings",
"will",
"help",
"to",
"set",
"appropriate",
"expectations",
"for",
"these",
"patients,",
"their",
"families,",
"and",
"surgeons.",
"",
"Lung",
"cancer",
"has",
"become",
"one",
"of",
"the",
"most",
"common",
"cancers",
"worldwide",
"and",
"is",
"the",
"predominant",
"cause",
"of",
"death",
"among",
"cancer",
"patients.",
"The",
"American",
"Cancer",
"Society",
"estimated",
"that",
"almost",
"160,000",
"patients",
"would",
"die",
"from",
"lung",
"and",
"bronchus",
"cancer",
"in",
"the",
"USA",
"in",
"2009",
"(Jemal",
"et",
"al.",
"2009).",
"Some",
"authors",
"have",
"stated",
"that",
"lung",
"cancer",
"is",
"one",
"of",
"the",
"most",
"important",
"chal-",
"lenges",
"in",
"oncology",
"at",
"the",
"present",
"time",
"(Boyle",
"and",
"Dresler",
"2005).",
"Historically,",
"about",
"one",
"third",
"of",
"all",
"lung",
"cancer",
"patients",
"are",
"found",
"to",
"have",
"bone",
"metastases",
"during",
"the",
"course",
"of",
"the",
"dis-",
"ease.",
"Symptoms",
"and",
"events",
"of",
"skeletal",
"origin",
"such",
"as",
"pain,",
"pathological",
"fractures,",
"spinal",
"cord",
"compression",
"with",
"para-",
"paresis,",
"and",
"hypercalcemia",
"are",
"common",
"complications.",
"The",
"decline",
"in",
"quality",
"of",
"life",
"and",
"eventual",
"death",
"of",
"these",
"patients",
"can",
"be",
"explained",
"to",
"some",
"extent",
"by",
"skeletal",
"complications",
"and",
"their",
"treatment",
"(Coleman",
"1997).",
"Lung",
"cancer",
"patients",
"with",
"skeletal",
"events",
"have",
"a",
"short",
"expected",
"survival;",
"however,",
"some",
"case",
"reports",
"have",
"involved",
"patients",
"who",
"survived",
"several",
"years",
"after",
"pathological",
"frac-",
"tures",
"(Agarwala",
"and",
"Hanna",
"2005,",
"Hirano",
"et",
"al.",
"2005).",
"A",
"major",
"problem",
"in",
"selecting",
"patients",
"for",
"surgery",
"is",
"to",
"avoid",
"operat-",
"ing",
"on",
"those",
"who",
"are",
"likely",
"to",
"die",
"very",
"soon",
"after",
"surgery.",
"Although",
"several",
"features",
"help",
"to",
"identify",
"patients",
"with",
"long",
"survival",
"(Bauer",
"and",
"Wedin",
"1995,",
"Tomita",
"et",
"al.",
"2001),",
"it",
"is",
"still",
"difficult",
"to",
"identify",
"those",
"who",
"will",
"die",
"early.",
"We",
"analyzed",
"a",
"consecutive",
"series",
"of",
"lung",
"cancer",
"patients",
"who",
"were",
"operated",
"on",
"for",
"skeletal",
"metastases",
"at",
"our",
"depart-",
"ment,",
"to",
"determine",
"the",
"complications",
"and",
"reoperation",
"rates",
"after",
"surgery",
"and",
"to",
"identify",
"risk",
"factors",
"for",
"early",
"death.",
"Patients",
"and",
"methods",
"This",
"study",
"was",
"based",
"on",
"data",
"recorded",
"in",
"the",
"Karolinska",
"Skel-",
"etal",
"Metastasis",
"Register",
"(Wedin",
"and",
"Bauer",
"2005).",
"The",
"reg-",
"ister",
"is",
"a",
"quality-control",
"database",
"that",
"prospectively",
"collects",
"individual-based",
"information",
"for",
"cancer",
"patients",
"admitted",
"to",
"Karolinska",
"University",
"Hospital",
"in",
"Stockholm.",
"All",
"data",
"are",
"col-",
"lected",
"based",
"on",
"the",
"national",
"registration",
"number",
"(a",
"10-digit",
"number),",
"which",
"is",
"unique",
"for",
"each",
"Swedish",
"resident.",
"The",
"cri-",
"terion",
"for",
"inclusion",
"in",
"the",
"database",
"is",
"surgical",
"treatment",
"for",
"complete",
"or",
"impending",
"fractures",
"due",
"to",
"skeletal",
"metastasis.",
"The",
"register",
"gathers",
"data",
"on",
"patient",
"identity,",
"age,",
"sex,",
"pri-",
"mary",
"tumor,",
"location",
"of",
"metastases,",
"type",
"of",
"pathological",
"fracture,",
"and",
"surgical",
"treatment",
"such",
"as",
"method",
"of",
"fixation,",
"type",
"of",
"implant,",
"and",
"postoperative",
"complications.",
"It",
"includes",
"staging",
"information",
"for",
"patients",
"diagnosed",
"with",
"lung",
"cancer",
"Open",
"Access",
"-",
"This",
"article",
"is",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Noncommercial",
"License",
"which",
"permits",
"any",
"noncommercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"source",
"is",
"credited.",
"DOI",
"10.3109/17453674.2011.552779"
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] | [
"Cheng",
"et",
"al.",
"BMC",
"Infectious",
"Diseases",
"2010,",
"10:126",
"http://www.biomedcentral.com/1471-2334/10/126",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"RResiesakrchoarfticple",
"neumocystosis",
"after",
"early",
"discontinuation",
"of",
"prophylaxis",
"among",
"HIV-infected",
"patients",
"receiving",
"highly",
"active",
"antiretroviral",
"therapy",
"Chien-Yu",
"Cheng†1,",
"Mao-Yuan",
"Chen1,",
"Szu-Min",
"Hsieh1,",
"Wang-Huei",
"Sheng1,",
"Hsin-Yun",
"Sun1,",
"Yi-Chun",
"Lo2,",
"Wen-",
"Chun",
"Liu1",
"and",
"Chien-Ching",
"Hung*1",
"Abstract",
"Background:",
"Risk",
"of",
"pneumocystosis",
"after",
"discontinuation",
"of",
"primary",
"or",
"secondary",
"prophylaxis",
"among",
"HIV-infected",
"patients",
"before",
"CD4",
"counts",
"increase",
"to",
"^200",
"cells/μL",
"(early",
"discontinuation)",
"after",
"receiving",
"highly",
"active",
"antiretroviral",
"therapy",
"(HAART)",
"is",
"rarely",
"investigated.",
"Methods:",
"Medical",
"records",
"of",
"660",
"HIV-infected",
"patients",
"with",
"baseline",
"CD4",
"counts",
"<200",
"cells/μL",
"who",
"sought",
"HIV",
"care",
"and",
"received",
"HAART",
"at",
"a",
"university",
"hospital",
"in",
"Taiwan",
"between",
"1",
"April,",
"1997",
"and",
"30",
"September,",
"2007",
"were",
"reviewed",
"to",
"assess",
"the",
"incidence",
"rate",
"of",
"pneumocystosis",
"after",
"discontinuation",
"of",
"prophylaxis",
"for",
"pneumocystosis.",
"Results:",
"The",
"incidence",
"rate",
"of",
"pneumocystosis",
"after",
"HAART",
"was",
"2.81",
"per",
"100",
"person-years",
"among",
"521",
"patients",
"who",
"did",
"not",
"initiate",
"prophylaxis",
"or",
"had",
"early",
"discontinuation",
"of",
"prophylaxis,",
"which",
"was",
"significantly",
"higher",
"than",
"the",
"incidence",
"rate",
"of",
"0.45",
"per",
"100",
"person-years",
"among",
"139",
"patients",
"who",
"continued",
"prophylaxis",
"until",
"CD4",
"counts",
"increased",
"to",
"^200",
"cells/μL",
"(adjusted",
"risk",
"ratio,",
"5.32;",
"95%",
"confidence",
"interval,",
"1.18,",
"23.94).",
"Among",
"the",
"215",
"patients",
"who",
"had",
"early",
"discontinuation",
"of",
"prophylaxis",
"after",
"achievement",
"of",
"undetectable",
"plasma",
"HIV",
"RNA",
"load,",
"the",
"incidence",
"rate",
"of",
"pneumocystosis",
"was",
"reduced",
"to",
"0.31",
"per",
"100",
"person-years,",
"which",
"was",
"similar",
"to",
"that",
"of",
"the",
"patients",
"who",
"continued",
"prophylaxis",
"until",
"CD4",
"counts",
"increased",
"to",
"^200",
"cells/μL",
"(adjusted",
"risk",
"ratio,",
"0.63;",
"95%",
"confidence",
"interval,",
"0.03,",
"14.89).",
"Conclusions:",
"Compared",
"with",
"the",
"risk",
"of",
"pneumocystosis",
"among",
"patients",
"who",
"continued",
"prophylaxis",
"until",
"CD4",
"counts",
"increased",
"to",
"^200",
"cells/μL",
"after",
"HAART,",
"the",
"risk",
"was",
"significantly",
"higher",
"among",
"patients",
"who",
"discontinued",
"prophylaxis",
"when",
"CD4",
"counts",
"remained",
"<200",
"cells/μL,",
"while",
"the",
"risk",
"could",
"be",
"reduced",
"among",
"patients",
"who",
"achieved",
"undetectable",
"plasma",
"HIV",
"RNA",
"load",
"after",
"HAART.",
"Background",
"With",
"the",
"widespread",
"use",
"of",
"highly",
"active",
"antiretroviral",
"therapy",
"(HAART)",
"after",
"1996,",
"HIV-related",
"mortality",
"and",
"the",
"risks",
"of",
"several",
"major",
"opportunistic",
"infections,",
"such",
"as",
"Pneumocystis",
"jirovecii",
"pneumonia",
"(formerly",
"P.",
"carinii",
"pneumonia),",
"disseminated",
"Mycobacterium",
"avium",
"com-",
"plex",
"infection,",
"and",
"cytomegalovirus",
"diseases,",
"have",
"signif-",
"icantly",
"declined",
"in",
"patients",
"receiving",
"HAART",
"[1-3].",
"For",
"example,",
"an",
"incidence",
"rate",
"of",
"20",
"cases",
"of",
"pneumocystosis",
"per",
"100",
"person-months",
"was",
"reported",
"in",
"the",
"pre-HAART",
"*",
"Correspondence:",
"hcc0401@ntu.edu.tw",
"1",
"Department",
"of",
"Internal",
"Medicine,",
"National",
"Taiwan",
"University",
"Hospital",
"and",
"National",
"Taiwan",
"University",
"College",
"of",
"Medicine,",
"7",
"Chung-Shan",
"South",
"Road,",
"Taipei,",
"Taiwan",
"100",
"†",
"Contributed",
"equally",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"era",
"[4],",
"which",
"decreased",
"to",
"1.2",
"cases",
"per",
"100",
"person-years",
"(100",
"PY)",
"of",
"follow-up",
"in",
"the",
"era",
"of",
"antimicrobial",
"prophy-",
"laxis",
"for",
"pneumocystosis",
"and",
"HAART",
"[5].",
"In",
"the",
"HAART",
"era,",
"the",
"majority",
"of",
"cases",
"of",
"pneumocystosis",
"occur",
"in",
"patients",
"who",
"are",
"unaware",
"of",
"their",
"HIV",
"infection",
"or",
"have",
"delay",
"in",
"seeking",
"HIV",
"care,",
"or",
"in",
"those",
"with",
"advanced",
"immunosuppression",
"(CD4+",
"count",
"<",
"100",
"cells/μL)",
"who",
"have",
"limited",
"access",
"to",
"HAART",
"and",
"related",
"HIV",
"care",
"[6,7].",
"In",
"the",
"guidelines",
"recommended",
"by",
"the",
"National",
"Insti-",
"tutes",
"of",
"Health,",
"the",
"Centers",
"for",
"Disease",
"Control",
"and",
"Pre-",
"vention,",
"and",
"the",
"HIV",
"Medicine",
"Association",
"of",
"the",
"Infectious",
"Diseases",
"Society",
"of",
"America",
"[8],",
"HIV-infected",
"patients",
"should",
"receive",
"trimethoprim-sulfamethoxazole",
"(TMP-SMX)",
"as",
"primary",
"prophylaxis",
"for",
"pneumocystosis",
"if",
"they",
"have",
"CD4",
"counts",
"of",
"<200",
"cells/μL.",
"Primary",
"pro-",
"©",
"2010",
"Cheng",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"BioMed",
"Central",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
] | [
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] | [
"Comprehensive",
"Gene",
"Expression",
"Analysis",
"of",
"Human",
"Embryonic",
"Stem",
"Cells",
"during",
"Differentiation",
"into",
"Neural",
"Cells",
"Ali",
"Fathi1,",
"Maryam",
"Hatami2,",
"Vahid",
"Hajihosseini1,3,",
"Faranak",
"Fattahi1,3,",
"Sahar",
"Kiani2,",
"Hossein",
"Baharvand1,4*,",
"Ghasem",
"Hosseini",
"Salekdeh1,5*",
"1",
"Department",
"of",
"Molecular",
"Systems",
"Biology,",
"Cell",
"Science",
"Research",
"Centre,",
"Royan",
"Institute",
"for",
"Stem",
"Cell",
"Biology",
"and",
"Technology,",
"Avicenna",
"Research",
"Institute",
"(ACECR),",
"Tehran,",
"Iran,",
"2",
"Department",
"of",
"Stem",
"Cells",
"and",
"Developmental",
"Biology,",
"Cell",
"Science",
"Research",
"Centre,",
"Royan",
"Institute",
"for",
"Stem",
"Cell",
"Biology",
"and",
"Technology,",
"Avicenna",
"Research",
"Institute",
"(ACECR),",
"Tehran,",
"Iran,",
"3",
"Department",
"of",
"Biotechnology,",
"College",
"of",
"Science,",
"University",
"of",
"Tehran,",
"Tehran,",
"Iran,",
"4",
"Department",
"of",
"Developmental",
"Biology,",
"University",
"of",
"Science",
"and",
"Culture,",
"Avicenna",
"Research",
"Institute",
"(ACECR),",
"Tehran,",
"Iran,",
"5",
"Department",
"of",
"Systems",
"Biology,",
"Agricultural",
"Biotechnology",
"Research",
"Institute",
"of",
"Iran,",
"Karaj,",
"Iran",
"Abstract",
"Global",
"gene",
"expression",
"analysis",
"of",
"human",
"embryonic",
"stem",
"cells",
"(hESCs)",
"that",
"differentiate",
"into",
"neural",
"cells",
"would",
"help",
"to",
"further",
"define",
"the",
"molecular",
"mechanisms",
"involved",
"in",
"neurogenesis",
"in",
"humans.",
"We",
"performed",
"a",
"comprehensive",
"transcripteome",
"analysis",
"of",
"hESC",
"differentiation",
"at",
"three",
"different",
"stages:",
"early",
"neural",
"differentiation,",
"neural",
"ectoderm,",
"and",
"differentiated",
"neurons.",
"We",
"identified",
"and",
"validated",
"time-dependent",
"gene",
"expression",
"patterns",
"and",
"showed",
"that",
"the",
"gene",
"expression",
"patterns",
"reflect",
"early",
"ESC",
"differentiation.",
"Sets",
"of",
"genes",
"are",
"induced",
"in",
"primary",
"ectodermal",
"lineages",
"and",
"then",
"in",
"differentiated",
"neurons,",
"constituting",
"consecutive",
"waves",
"of",
"known",
"and",
"novel",
"genes.",
"Pathway",
"analysis",
"revealed",
"dynamic",
"expression",
"patterns",
"of",
"members",
"of",
"several",
"signaling",
"pathways,",
"including",
"NOTCH,",
"mTOR",
"and",
"Toll",
"like",
"receptors",
"(TLR),",
"during",
"neural",
"differentiation.",
"An",
"interaction",
"network",
"analysis",
"revealed",
"that",
"the",
"TGFb",
"family",
"of",
"genes,",
"including",
"LEFTY1,",
"ID1",
"and",
"ID2,",
"are",
"possible",
"key",
"players",
"in",
"the",
"proliferation",
"and",
"maintenance",
"of",
"neural",
"ectoderm.",
"Collectively,",
"these",
"results",
"enhance",
"our",
"understanding",
"of",
"the",
"molecular",
"dynamics",
"underlying",
"neural",
"commitment",
"and",
"differentiation.",
"Citation:",
"Fathi",
"A,",
"Hatami",
"M,",
"Hajihosseini",
"V,",
"Fattahi",
"F,",
"Kiani",
"S,",
"et",
"al.",
"(2011)",
"Comprehensive",
"Gene",
"Expression",
"Analysis",
"of",
"Human",
"Embryonic",
"Stem",
"Cells",
"during",
"Differentiation",
"into",
"Neural",
"Cells.",
"PLoS",
"ONE",
"6(7):",
"e22856.",
"doi:10.1371/journal.pone.0022856",
"Editor:",
"Joseph",
"Charles",
"Glorioso,",
"University",
"of",
"Pittsburgh",
"School",
"of",
"Medicine,",
"United",
"States",
"of",
"America",
"Received",
"April",
"16,",
"2011;",
"Accepted",
"June",
"29,",
"2011;",
"Published",
"July",
"28,",
"2011",
"Copyright:",
"2011",
"Fathi",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"study",
"was",
"funded",
"by",
"a",
"grant",
"provided",
"from",
"the",
"Royan",
"Institute.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"Salekdeh@Royaninstitute.org",
"(GHS);",
"Baharvand@RoyanInstitute.org",
"(HB)",
"Introduction",
"Embryonic",
"stem",
"cells",
"(ESCs)",
"are",
"a",
"promising",
"tool",
"for",
"the",
"study",
"of",
"neural",
"development",
"and",
"cell",
"lineage",
"specification.",
"The",
"current",
"lack",
"of",
"knowledge",
"about",
"cues",
"for",
"mammalian",
"neuronal",
"commit-",
"ment",
"and",
"differentiation",
"is",
"at",
"least",
"partly",
"due",
"to",
"a",
"paucity",
"of",
"available",
"model",
"systems",
"that",
"permit",
"direct",
"observation",
"of",
"developmental",
"processes.",
"Studies",
"of",
"the",
"molecular",
"mechanisms",
"underlying",
"the",
"neural",
"differentiation",
"of",
"human",
"ESCs",
"(hESCs)",
"can",
"help",
"to",
"unravel",
"the",
"complex",
"gene",
"pathways",
"that",
"are",
"involved",
"in",
"neural",
"cell",
"commitment",
"and",
"differentiation",
"processes.",
"High",
"throughput",
"studies",
"of",
"gene",
"expression",
"have",
"been",
"applied",
"to",
"neural",
"stem",
"cells",
"(NSCs)",
"derived",
"from",
"the",
"subventricular",
"zone",
"(SVZ)",
"[1],",
"NSCs",
"derived",
"from",
"mouse",
"ESCs",
"and",
"the",
"fetal",
"brain",
"[2],",
"dopaminergic",
"neurons",
"from",
"mouse",
"ESCs",
"[3],",
"heterogeneous",
"neural",
"cells",
"from",
"mouse",
"ESCs",
"[4]",
"and",
"neural",
"progenitors",
"(NPs)",
"differentiated",
"from",
"mouse",
"ESCs",
"[5]",
"and",
"forebrain",
"periventricular",
"zone",
"NPs",
"compared",
"to",
"neuroectoderm",
"from",
"mESCs",
"[6].",
"Cytoskeletal",
"genes,",
"cell",
"membrane",
"receptor",
"genes,",
"and",
"transcrip-",
"tion",
"factor",
"genes",
"are",
"differentially",
"expressed",
"in",
"most",
"cell",
"types.",
"Recently,",
"Wu",
"et",
"al.",
"(2010)",
"analyzed",
"the",
"transcriptome",
"of",
"hESCs",
"during",
"differentiation",
"into",
"the",
"neural",
"lineage",
"at",
"the",
"early",
"initiation,",
"neural",
"progenitor,",
"and",
"early",
"glial-like",
"stages",
"[7]",
"and",
"found",
"an",
"extraordinary",
"degree",
"of",
"stage-specific",
"transcription",
"and",
"splicing.",
"The",
"diversity",
"was",
"highest",
"in",
"undifferentiated",
"hESCs",
"and",
"decreased",
"upon",
"differentiation",
"[7].",
"Previously,",
"we",
"described",
"the",
"differentiation",
"of",
"hESCs",
"into",
"NPs",
"and",
"neural",
"cells",
"with",
"typical",
"cellular,",
"molecular",
"and",
"ultrastructural",
"markers",
"using",
"a",
"defined",
"adherent",
"culture",
"protocol",
"[8,9].",
"Here",
"we",
"analyzed",
"the",
"transcriptome",
"of",
"hESCs",
"during",
"differentiation",
"into",
"neural",
"cells",
"[8]",
"using",
"a",
"whole",
"genome",
"microarray",
"chip.",
"We",
"identified",
"differentially",
"expressed",
"genes",
"that",
"may",
"be",
"linked",
"to",
"neural",
"fate",
"specification,",
"proliferation,",
"and",
"differentiation.",
"Our",
"data",
"extend",
"the",
"gene",
"expression",
"network",
"for",
"neural",
"differentiation",
"and",
"reveal",
"novel",
"aspects",
"of",
"transcriptional",
"control",
"pathways",
"underlying",
"the",
"multistep",
"process",
"of",
"commitment",
"and",
"differentia-",
"tion",
"of",
"hESCs",
"into",
"neural",
"cells.",
"Materials",
"and",
"Methods",
"Human",
"ESC",
"culture",
"and",
"sample",
"preparation",
"The",
"hESC",
"line",
"Royan",
"H6",
"[10]",
"was",
"passaged",
"and",
"cultured",
"under",
"feeder-free",
"culture",
"conditions",
"on",
"Matrigel",
"in",
"hESC",
"medium",
"containing",
"DMEM/F12",
"medium",
"supplemented",
"with",
"20%",
"knock-",
"out",
"serum",
"replacement,",
"2",
"mM",
"L-glutamine,",
"1%",
"nonessential",
"amino",
"acids,",
"100",
"units/ml",
"penicillin",
"and",
"100",
"mg/ml",
"streptomycin,",
"insulin-transferrin-selenite,",
"(All",
"from",
"Invitrogen),",
"0.1",
"mM",
"b-",
"mercaptoethanol",
"and",
"100",
"ng/ml",
"basic-fibroblast",
"growth",
"factor",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"July",
"2011",
"|",
"Volume",
"6",
"|",
"Issue",
"7",
"|",
"e22856"
] | [
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] | [
"Ramsay",
"et",
"al.",
"Implementation",
"Science",
"2010,",
"5:71",
"http://www.implementationscience.com/content/5/1/71",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Implementation",
"Science",
"Open",
"Access",
"Using",
"the",
"theory",
"of",
"planned",
"behaviour",
"as",
"a",
"process",
"evaluation",
"tool",
"in",
"randomised",
"trials",
"of",
"knowledge",
"translation",
"strategies:",
"A",
"case",
"study",
"from",
"UK",
"primary",
"care",
"Craig",
"R",
"Ramsay1*,",
"Ruth",
"E",
"Thomas1,",
"Bernard",
"L",
"Croal2,",
"Jeremy",
"M",
"Grimshaw3,",
"Martin",
"P",
"Eccles4",
"Abstract",
"Background:",
"Randomised",
"trials",
"of",
"knowledge",
"translation",
"strategies",
"for",
"professional",
"behaviour",
"change",
"can",
"provide",
"robust",
"estimates",
"of",
"effectiveness,",
"but",
"offer",
"little",
"insight",
"into",
"the",
"causal",
"mechanisms",
"by",
"which",
"any",
"change",
"is",
"produced.",
"To",
"illustrate",
"the",
"applicability",
"of",
"causal",
"methods",
"within",
"randomised",
"trials,",
"we",
"undertook",
"a",
"theory-based",
"process",
"evaluation",
"study",
"within",
"an",
"implementation",
"trial",
"to",
"explore",
"whether",
"the",
"cognitions",
"of",
"primary",
"care",
"doctors’",
"predicted",
"their",
"test",
"requesting",
"behaviours",
"and,",
"secondly,",
"whether",
"the",
"trial",
"results",
"were",
"mediated",
"by",
"the",
"theoretical",
"constructs.",
"Methods:",
"The",
"process",
"evaluation",
"comprised",
"a",
"cross-sectional",
"questionnaire",
"survey",
"of",
"a",
"random",
"50%",
"sample",
"of",
"the",
"randomised",
"groups",
"of",
"primary",
"care",
"practices",
"in",
"Grampian",
"(NHS",
"Grampian),",
"UK,",
"who",
"took",
"part",
"in",
"a",
"trial",
"of",
"the",
"effect",
"of",
"enhanced",
"feedback",
"and",
"brief",
"educational",
"reminders",
"on",
"test",
"requesting",
"behaviour.",
"The",
"process",
"evaluation",
"was",
"based",
"upon",
"the",
"Theory",
"of",
"Planned",
"Behaviour",
"and",
"focussed",
"on",
"three",
"of",
"the",
"test",
"requesting",
"behaviours",
"that",
"were",
"targeted",
"in",
"the",
"trial",
"–",
"ferritin,",
"follicle",
"stimulating",
"hormone",
"(FSH),",
"and",
"Helicobacter",
"Pylori",
"serology",
"(HPS).",
"Results:",
"The",
"questionnaire",
"was",
"completed",
"by",
"131",
"primary",
"care",
"doctors",
"(56%)",
"from",
"42",
"(98%)",
"of",
"the",
"sampled",
"practices.",
"Behavioural",
"intention,",
"attitude,",
"and",
"subjective",
"norm",
"were",
"highly",
"correlated",
"for",
"all",
"the",
"tests.",
"There",
"was",
"no",
"evidence",
"that",
"perceived",
"behavioural",
"control",
"was",
"correlated",
"with",
"any",
"of",
"the",
"other",
"measures.",
"Simple",
"linear",
"regression",
"analysis",
"of",
"the",
"rate",
"of",
"test",
"requests",
"on",
"minimum",
"behavioural",
"intentions",
"had",
"R2",
"of",
"11.1%,",
"12.5%,",
"and",
"0.1%",
"for",
"ferritin,",
"FSH,",
"and",
"HPS",
"requesting,",
"respectively.",
"Mediational",
"analysis",
"showed",
"that",
"the",
"trial",
"results",
"for",
"ferritin",
"and",
"FSH",
"were",
"partially",
"mediated",
"(between",
"23%",
"and",
"78%",
"mediation)",
"through",
"intentions.",
"The",
"HPS",
"trial",
"result",
"was",
"not",
"mediated",
"through",
"intention.",
"Conclusions:",
"This",
"study",
"demonstrated",
"that",
"a",
"theory-based",
"process",
"evaluation",
"can",
"provide",
"useful",
"information",
"on",
"causal",
"mechanisms",
"that",
"aid",
"not",
"only",
"interpretation",
"of",
"the",
"trial",
"but",
"also",
"inform",
"future",
"evaluations",
"and",
"intervention",
"development.",
"Introduction",
"Randomised",
"trials",
"of",
"knowledge",
"translation",
"(KT)",
"strate-",
"gies",
"for",
"professional",
"behaviour",
"change",
"can",
"provide",
"robust",
"estimates",
"of",
"effectiveness,",
"but",
"offer",
"little",
"insight",
"into",
"the",
"causal",
"mechanisms",
"by",
"which",
"any",
"change",
"is",
"pro-",
"duced.",
"This",
"would",
"not",
"be",
"an",
"issue",
"if",
"interventions",
"had",
"a",
"*",
"Correspondence:",
"c.r.ramsay@abdn.ac.uk",
"1Health",
"Services",
"Research",
"Unit,",
"University",
"of",
"Aberdeen,",
"Foresterhill,",
"Aberdeen,",
"AB25",
"2ZD,",
"UK",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"uniform",
"effect",
"across",
"different",
"conditions",
"that",
"could",
"be",
"generalised",
"to",
"all",
"practitioners",
"outside",
"of",
"the",
"trials.",
"However,",
"the",
"effects",
"of",
"interventions",
"do",
"appear",
"to",
"vary",
"by",
"condition,",
"professional",
"group,",
"and",
"context,",
"presum-",
"ably",
"because",
"the",
"causal",
"mechanisms",
"of",
"the",
"interventions",
"are",
"modified",
"in",
"the",
"presence",
"of",
"different",
"barriers",
"and",
"enablers",
"[1].",
"Therefore",
"the",
"interpretation",
"of",
"a",
"trial",
"and",
"assessment",
"of",
"its",
"likely",
"generalisability",
"would",
"be",
"enhanced",
"if",
"additional",
"information",
"was",
"obtained",
"about",
"the",
"causal",
"mechanisms",
"through",
"which",
"the",
"intervention",
"©",
"2010",
"Ramsay",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Int.",
"J.",
"Environ.",
"Res.",
"Public",
"Health",
"2012,",
"9,",
"985-994;",
"doi:10.3390/ijerph9030985",
"OPEN",
"ACCESS",
"International",
"Journal",
"of",
"Environmental",
"Research",
"and",
"Public",
"Health",
"ISSN",
"1660-4601",
"www.mdpi.com/journal/ijerph",
"Review",
"Social",
"Aspects",
"of",
"Suicidal",
"Behavior",
"and",
"Prevention",
"in",
"Early",
"Life:",
"A",
"Review",
"Maya",
"Amitai",
"1,2",
"and",
"Alan",
"Apter",
"2,3,*",
"1",
"Child",
"and",
"Adolescent",
"Division,",
"Geha",
"Mental",
"Health",
"Center,",
"Petach",
"Tikva,",
"Israel;",
"E-Mail:",
"maya47@zahav.net.il",
"2",
"Sackler",
"Faculty",
"of",
"Medicine,",
"Tel",
"Aviv",
"University,",
"Tel",
"Aviv,",
"Israel",
"3",
"Department",
"of",
"Psychiatry,",
"The",
"Feinberg",
"Child",
"Study",
"Center,",
"Schneider",
"Children’s",
"Medical",
"Center",
"of",
"Israel,",
"Petach",
"Tikva,",
"Israel",
"*",
"Author",
"to",
"whom",
"correspondence",
"should",
"be",
"addressed;",
"E-Mail:",
"eapter@clalit.org.il;",
"Tel.:",
"+972-3-925-3617;",
"Fax:",
"+972-3-925-3864.",
"Received:",
"2",
"February",
"2012;",
"in",
"revised",
"form:",
"5",
"March",
"2012",
"/",
"Accepted:",
"12",
"March",
"2012",
"/",
"Published:",
"19",
"March",
"2012",
"Abstract:",
"Purpose:",
"The",
"present",
"review",
"summarizes",
"the",
"updated",
"literature",
"on",
"the",
"social",
"aspects",
"of",
"suicidal",
"behavior",
"and",
"prevention",
"in",
"adolescents.",
"Recent",
"findings:",
"The",
"predictive",
"role",
"of",
"psychiatric",
"disorders",
"and",
"past",
"history",
"are",
"well",
"recognized",
"in",
"adolescent",
"suicide,",
"but",
"the",
"role",
"of",
"social",
"and",
"cultural",
"factors",
"is",
"less",
"clear.",
"Studies",
"have",
"focused",
"on",
"the",
"importance",
"of",
"ethnicity,",
"gender,",
"family",
"characteristics,",
"and",
"socioeconomic",
"status.",
"More",
"recently,",
"attention",
"has",
"been",
"addressed",
"to",
"broader",
"social",
"risk",
"factors,",
"such",
"as",
"bullying",
"in",
"adolescents,",
"suicide",
"contagion,",
"sexual",
"orientation,",
"and",
"the",
"popular",
"media.",
"Further",
"empirical",
"evidence",
"is",
"needed",
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"our",
"understanding",
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"suicidal",
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"develop",
"better",
"assessment",
"tools,",
"and",
"formulate",
"effective",
"prevention",
"and",
"treatment",
"programs.",
"Summary:",
"Suicidal",
"behavior",
"remains",
"an",
"important",
"clinical",
"problem",
"and",
"major",
"cause",
"of",
"death",
"in",
"youth.",
"Social",
"factors",
"may",
"be",
"at",
"least",
"as",
"important",
"as",
"genetics.",
"Advancing",
"our",
"understanding",
"of",
"underlying",
"cultural",
"and",
"sociological",
"issues",
"in",
"youth",
"suicide",
"will",
"help",
"clinicians",
"achieve",
"more",
"efficient",
"prediction,",
"prevention",
"and",
"treatment.",
"Keywords:",
"adolescents;",
"social;",
"cultural;",
"risk",
"factors;",
"suicide;",
"bullying"
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] | [
"J",
"Appl",
"Genetics",
"(2012)",
"53:237–247",
"DOI",
"10.1007/s13353-012-0087-z",
"MICROBIAL",
"GENETICS",
"·",
"ORIGINAL",
"PAPER",
"Genetic",
"variation",
"of",
"Fusarium",
"oxysporum",
"isolates",
"forming",
"fumonisin",
"B1",
"and",
"moniliformin",
"Lidia",
"Irzykowska",
"&",
"Jan",
"Bocianowski",
"&",
"Agnieszka",
"Waśkiewicz",
"&",
"Zbigniew",
"Weber",
"&",
"Zbigniew",
"Karolewski",
"&",
"Piotr",
"Goliński",
"&",
"Marian",
"Kostecki",
"&",
"Witold",
"Irzykowski",
"Received:",
"2",
"December",
"2011",
"/",
"Revised:",
"21",
"January",
"2012",
"/",
"Accepted:",
"27",
"January",
"2012",
"/",
"Published",
"online:",
"25",
"February",
"2012",
"#",
"The",
"Author(s)",
"2012.",
"This",
"article",
"is",
"published",
"with",
"open",
"access",
"at",
"Springerlink.com",
"Abstract",
"Thirty",
"single-spore",
"isolates",
"of",
"a",
"toxigenic",
"fungus,",
"Fusarium",
"oxysporum,",
"were",
"isolated",
"from",
"asparagus",
"spears",
"and",
"identified",
"by",
"species-specific",
"polymerase",
"chain",
"reaction",
"(PCR)",
"and",
"translation",
"elongation",
"factor",
"1-α",
"(TEF)",
"sequence",
"analysis.",
"In",
"the",
"examined",
"sets",
"of",
"F.",
"oxysporum",
"isolates,",
"the",
"DNA",
"sequences",
"of",
"mating",
"type",
"genes",
"(MAT)",
"were",
"identified.",
"The",
"distribution",
"of",
"MAT",
"idiomorph",
"may",
"suggest",
"that",
"MAT1-2",
"is",
"a",
"predominant",
"mating",
"type",
"in",
"the",
"F.",
"oxysporum",
"population.",
"F.",
"oxysporum",
"is",
"mainly",
"recognised",
"as",
"a",
"producer",
"of",
"monili-",
"formin—the",
"highly",
"toxic",
"secondary",
"metabolite.",
"Moniliformin",
"content",
"was",
"determined",
"by",
"high-performance",
"liquid",
"chroma-",
"tography",
"(HPLC)",
"analysis",
"in",
"the",
"range",
"0.05–1,007.47",
"μg",
"g−1",
"(mean",
"115.93",
"μg",
"g−1)",
"but,",
"also,",
"fumonisin",
"B1",
"was",
"detected,",
"in",
"the",
"concentration",
"range",
"0.01–0.91",
"μg",
"g−1",
"(mean",
"0.19",
"μg",
"g−1).",
"L.",
"Irzykowska",
"(*)",
":",
"Z.",
"Weber",
":",
"Z.",
"Karolewski",
"Department",
"of",
"Phytopathology,",
"Poznan",
"University",
"of",
"Life",
"Sciences,",
"Dąbrowskiego",
"159,",
"60-594",
"Poznań,",
"Poland",
"e-mail:",
"irzyk@up.poznan.pl",
"J.",
"Bocianowski",
"Department",
"of",
"Mathematical",
"and",
"Statistical",
"Methods,",
"Poznan",
"University",
"of",
"Life",
"Sciences,",
"Wojska",
"Polskiego",
"28,",
"60-637",
"Poznan,",
"Poland",
"A.",
"Waśkiewicz",
":",
"P.",
"Goliński",
":",
"M.",
"Kostecki",
"Department",
"of",
"Chemistry,",
"Poznan",
"University",
"of",
"Life",
"Sciences,",
"Wojska",
"Polskiego",
"75,",
"60-625",
"Poznań,",
"Poland",
"W.",
"Irzykowski",
"Institute",
"of",
"Plant",
"Genetics",
"Polish",
"Academy",
"of",
"Science,",
"Strzeszyńska",
"34,",
"60-479",
"Poznań,",
"Poland",
"There",
"was",
"no",
"association",
"between",
"mating",
"types",
"and",
"the",
"mycotoxins",
"biosynthesis",
"level.",
"Additionally,",
"a",
"significant",
"intra-species",
"genetic",
"diversity",
"was",
"revealed",
"and",
"molecular",
"markers",
"associated",
"with",
"toxins",
"biosynthesis",
"were",
"identified.",
"Keywords",
"Fusarium",
"oxysporum",
".",
"Fumonisin",
"B1",
".",
"Moniliformin",
".",
"Mating",
"type",
"idiomorphs",
".",
"Genetic",
"fingerprinting",
".",
"HPLC",
"analysis",
"Introduction",
"Asparagus",
"(Asparagus",
"officinalis",
"L.)",
"is",
"a",
"worldwide",
"well-",
"known",
"vegetable",
"not",
"only",
"due",
"to",
"its",
"high",
"nutritional",
"value,",
"but",
"also",
"because",
"of",
"the",
"biologically",
"active",
"compounds",
"present,",
"including",
"protodioscin",
"and",
"rutin,",
"with",
"a",
"strong",
"cytotoxic",
"ac-",
"tivity",
"against",
"many",
"cancer",
"cell",
"lines",
"(Kinghorn",
"et",
"al.",
"2003;",
"Chin",
"and",
"Garrison",
"2008).",
"However,",
"the",
"asparagus",
"is",
"often",
"infected",
"by",
"fungi",
"of",
"the",
"Fusarium",
"genus,",
"a",
"causal",
"agent",
"of",
"crown",
"and",
"root",
"rot",
"which",
"decreases",
"the",
"quantity",
"and",
"quality",
"of",
"the",
"yield.",
"A",
"visible",
"chlorosis",
"and",
"wilting",
"of",
"the",
"individual",
"stalks,",
"progressive",
"discolouration",
"of",
"plants",
"and",
"destruction",
"of",
"roots",
"and",
"crown",
"are",
"the",
"main",
"symptoms",
"of",
"this",
"serious",
"disease",
"(Logrieco",
"et",
"al.",
"2003).",
"F.",
"oxysporum",
"Schlechtend.",
"emend.",
"Snyder",
"&",
"Hansen",
"and",
"F.",
"proliferatum",
"(Matsus.)",
"Nirenberg",
"are",
"the",
"most",
"severe",
"asparagus",
"pathogens",
"(Blok",
"and",
"Bollen",
"1995;",
"von",
"Bargen",
"et",
"al.",
"2009).",
"Both",
"species",
"are",
"well-known",
"mycotoxins",
"producers,",
"so",
"their",
"precise",
"identification",
"is",
"of",
"prime",
"concern.",
"New",
"molecular",
"methods",
"have",
"been",
"applied",
"to",
"complement,",
"support",
"and",
"confirm",
"identification",
"based",
"on",
"morphological",
"characters",
"(Geiser",
"et",
"al.",
"2004).",
"F.",
"oxysporum",
"is",
"identified",
"worldwide",
"and",
"is",
"known",
"to",
"be",
"phylogenetically",
"diverse",
"and",
"recognised",
"as",
"a",
"moniliformin"
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"Standards",
"in",
"Genomic",
"Sciences",
"(2011)",
"5:211-223",
"DOI:10.4056/sigs.2025347",
"Minimal",
"Information",
"for",
"Neural",
"Electromagnetic",
"Ontologies",
"(MINEMO):",
"A",
"standards-compliant",
"method",
"for",
"analysis",
"and",
"integration",
"of",
"event-related",
"potentials",
"(ERP)",
"data",
"Gwen",
"Frishkoff1,",
"2,",
"3",
"Jason",
"Sydes4,",
"Kurt",
"Mueller4,",
"Robert",
"Frank2,",
"Tim",
"Curran3,5,",
"John",
"Connolly3,",
"6,",
"Kerry",
"Kilborn3,7,",
"Dennis",
"Molfese3,8,",
"Charles",
"Perfetti3,9,",
"&",
"Allen",
"Malony2,",
"4",
"1Department",
"of",
"Psychology",
"&",
"Neuroscience",
"Institute,",
"Georgia",
"State",
"University,",
"Atlanta,",
"GA",
"2NeuroInformatics",
"Center,",
"University",
"of",
"Oregon,",
"Eugene,",
"OR",
"3Neural",
"ElectroMagnetic",
"Ontologies",
"(NEMO)",
"ERP",
"Consortium",
"4Department",
"of",
"Computer",
"&",
"Information",
"Science,",
"University",
"of",
"Oregon,",
"Eugene,",
"OR",
"5Department",
"of",
"Psychology",
"&",
"Neuroscience,",
"University",
"of",
"Colorado,",
"Boulder,",
"CO",
"6Department",
"of",
"Psychology",
"and",
"Linguistics,",
"McMaster",
"University,",
"Ontario,",
"CA",
"7Department",
"of",
"Psychology,",
"Glasgow",
"University,",
"Scotland,",
"UK",
"8Department",
"of",
"Psychology,",
"University",
"of",
"Nebraska-Lincoln,",
"Lincoln,",
"NE",
"9Department",
"of",
"Psychology",
"and",
"Linguistics,",
"University",
"of",
"Pittsburgh,",
"Pittsburgh,",
"PA",
"We",
"present",
"MINEMO",
"(Minimal",
"Information",
"for",
"Neural",
"ElectroMagnetic",
"Ontologies),",
"a",
"checklist",
"for",
"the",
"description",
"of",
"event-related",
"potentials",
"(ERP)",
"studies.",
"MINEMO",
"extends",
"MINI",
"(Minimal",
"Information",
"for",
"Neuroscience",
"Investigations)to",
"the",
"ERP",
"domain.",
"Checklist",
"terms",
"are",
"explicated",
"in",
"NEMO,",
"a",
"formal",
"ontology",
"that",
"is",
"designed",
"to",
"support",
"ERP",
"data",
"sharing",
"and",
"integration.",
"MINEMO",
"is",
"also",
"linked",
"to",
"an",
"ERP",
"database",
"and",
"web",
"application",
"(the",
"NEMO",
"portal).",
"Users",
"upload",
"their",
"data",
"and",
"enter",
"MINEMO",
"information",
"through",
"the",
"portal.",
"The",
"database",
"then",
"stores",
"these",
"entries",
"in",
"RDF",
"(Resource",
"Description",
"Framework),",
"along",
"with",
"summary",
"metrics,",
"i.e.,",
"spatial",
"and",
"temporal",
"metadata.",
"Together",
"these",
"spatial,",
"temporal,",
"and",
"functional",
"metadata",
"provide",
"a",
"complete",
"description",
"of",
"ERP",
"data",
"and",
"the",
"context",
"in",
"which",
"these",
"data",
"were",
"acquired.",
"The",
"RDF",
"files",
"then",
"serve",
"as",
"inputs",
"to",
"ontology-based",
"labeling",
"and",
"meta-analysis.",
"Our",
"ultimate",
"goal",
"is",
"to",
"represent",
"ERPs",
"using",
"a",
"rich",
"semantic",
"structure,",
"so",
"results",
"can",
"be",
"queried",
"at",
"multiple",
"levels,",
"to",
"stimulate",
"novel",
"hypotheses",
"and",
"to",
"promote",
"a",
"high-level,",
"integrative",
"account",
"of",
"ERP",
"results",
"across",
"diverse",
"study",
"methods",
"and",
"paradigms.",
"Keywords:",
"Ontology,",
"database,",
"data",
"sharing,",
"standardization,",
"experiment",
"metadata,",
"neuroscience,",
"electrophysiology,",
"event-related",
"potentials",
"Introduction",
"Over",
"the",
"last",
"few",
"decades,",
"neuroscience",
"has",
"witnessed",
"an",
"explosion",
"of",
"methods",
"for",
"the",
"measurement",
"of",
"human",
"brain",
"function,",
"including",
"high-density",
"(multi-sensor)",
"event-related",
"potentials",
"(ERPs).",
"In",
"comparison",
"with",
"other",
"techniques,",
"the",
"ERP",
"method",
"has",
"several",
"advantages:",
"it",
"is",
"completely",
"safe",
"and",
"noninvasive,",
"it",
"is",
"inexpensive",
"and",
"portable,",
"and",
"—",
"unlike",
"methods",
"such",
"as",
"functional",
"magnetic",
"resonance",
"imaging",
"(fMRI)",
"—",
"it",
"is",
"a",
"direct",
"measure",
"of",
"neuronal",
"activity.",
"The",
"ERP",
"method",
"also",
"has",
"excellent",
"(millisecond)",
"temporal",
"resolution,",
"which",
"is",
"critical",
"for",
"representation",
"of",
"neural",
"dynamics.",
"Remarkably,",
"despite",
"these",
"many",
"virtues,",
"there",
"are",
"few",
"quantitative",
"comparisons",
"(“meta-analyses”)",
"of",
"ERP",
"results,",
"reflecting",
"the",
"complexity",
"of",
"ERP",
"data",
"and",
"the",
"wide",
"variety",
"of",
"methods",
"that",
"are",
"used",
"to",
"extract",
"and",
"analyze",
"ERP",
"metadata",
"[1-3].",
"To",
"address",
"this",
"gap,",
"we",
"have",
"gathered",
"an",
"interdisciplinary",
"team",
"of",
"researchers",
"in",
"informatics",
"and",
"human",
"neuroscience",
"to",
"form",
"project",
"NEMO",
"(Neural",
"ElectroMagnetic",
"Ontologies).",
"Our",
"neuroscience",
"experts",
"are",
"internationally",
"known",
"for",
"their",
"ERP",
"studies",
"of",
"language",
"and",
"cognition",
"and",
"have",
"partnered",
"to",
"form",
"a",
"consortium.",
"Consortium",
"members",
"provide",
"ERP",
"datasets",
"and",
"contribute",
"to",
"the",
"design",
"and",
"testing",
"of",
"ERP",
"ontologies",
"and",
"ontology-based",
"methods",
"for",
"meta-analysis",
"[3].",
"The",
"Genomic",
"Standards",
"Consortium"
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"Hindawi",
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"1–5",
"DOI",
"10.1155/IDOG/2006/79512",
"Clinical",
"Study",
"Postpartum",
"Morbidity",
"Associated",
"With",
"Advanced",
"HIV",
"Disease",
"Judette",
"Louis,1",
"Mudathiru",
"A.",
"Buhari,2",
"Dianne",
"Allen,1",
"Bernard",
"Gonik,1",
"and",
"Theodore",
"B.",
"Jones1",
"1",
"Department",
"of",
"Obstetrics",
"and",
"Gynecology,",
"Division",
"of",
"Maternal",
"Fetal",
"Medicine,",
"Wayne",
"State",
"University,",
"Detroit,",
"MI",
"48201,",
"USA",
"2",
"Department",
"of",
"Internal",
"Medicine,",
"Division",
"of",
"Infectious",
"Diseases,",
"Wayne",
"State",
"University,",
"Detroit,",
"MI",
"48201,",
"USA",
"Received",
"28",
"May",
"2006;",
"Revised",
"25",
"September",
"2006;",
"Accepted",
"10",
"October",
"2006",
"Objective.",
"To",
"investigate",
"the",
"postpartum",
"morbidity",
"and",
"postpartum",
"management",
"of",
"febrile",
"morbidity",
"associated",
"with",
"advanced",
"HIV",
"infection.",
"Methods.",
"A",
"case",
"control",
"study",
"of",
"HIV",
"infected",
"women",
"at",
"a",
"tertiary",
"care",
"center",
"during",
"January",
"2000–June",
"2005",
"was",
"performed.",
"Postpartum",
"morbidity",
"was",
"defined",
"as",
"endometritis,",
"blood",
"transfusion,",
"wound",
"complication,",
"readmission,",
"infectious",
"morbidity,",
"or",
"unexpected",
"surgery.",
"Results.",
"Women",
"in",
"Group",
"1",
"had",
"AIDS",
"(N",
"=",
"33),",
"Group",
"2",
"were",
"relatively",
"immunocompetent",
"HIV",
"infected",
"women",
"(N",
"=",
"115),",
"and",
"Group",
"3",
"were",
"uninfected",
"women",
"(N",
"=",
"152).",
"Group",
"1",
"was",
"more",
"likely",
"to",
"have",
"a",
"postpartum",
"morbidity",
"(32.3",
"versus",
"19.3",
"and",
"13.2%,",
"P",
"=",
".03)",
"and",
"to",
"have",
"postpartum",
"imaging",
"18.8",
"versus",
"7.9",
"and",
"2.6%,",
"P",
"=",
".002.",
"After",
"controlling",
"for",
"potential",
"confounders,",
"cesarean",
"delivery",
"(OR",
"6.2,",
"95%",
"CI",
"2.1–505.5)",
"but",
"not",
"advanced",
"HIV",
"disease",
"was",
"associated",
"with",
"an",
"increased",
"risk",
"of",
"postpartum",
"morbidity.",
"Conclusion.",
"Cesarean",
"delivery",
"and",
"not",
"advanced",
"HIV",
"disease",
"increases",
"the",
"risk",
"of",
"postpartum",
"morbidity",
"in",
"women",
"with",
"AIDS.",
"Copyright",
"©",
"2006",
"Judette",
"Louis",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"INTRODUCTION",
"Women",
"are",
"making",
"up",
"an",
"increasing",
"part",
"of",
"the",
"acquired",
"im-",
"mune",
"deficiency",
"syndrome",
"(AIDS)",
"epidemic",
"in",
"the",
"United",
"States",
"[1].",
"In",
"2001",
"HIV",
"infection",
"was",
"the",
"6th",
"leading",
"cause",
"of",
"death",
"among",
"all",
"women",
"aged",
"25–34",
"years",
"and",
"the",
"4th",
"lead-",
"ing",
"cause",
"of",
"death",
"among",
"all",
"women",
"aged",
"35–44",
"years.",
"By",
"the",
"end",
"of",
"2003,",
"women",
"and",
"adolescents",
"represented",
"22%",
"of",
"the",
"people",
"living",
"with",
"AIDS",
"[1].",
"With",
"the",
"considerable",
"num-",
"ber",
"of",
"women",
"of",
"childbearing",
"age",
"with",
"AIDS,",
"issues",
"related",
"to",
"pregnancy",
"remain",
"a",
"concern.",
"Initial",
"studies",
"in",
"the",
"field",
"of",
"perinatal",
"HIV",
"focused",
"on",
"vertical",
"transmission.",
"As",
"we",
"have",
"made",
"great",
"strides",
"to",
"reduce",
"vertical",
"transmission",
"to",
"less",
"than",
"2%",
"in",
"the",
"US,",
"there",
"has",
"been",
"an",
"increased",
"focus",
"on",
"maternal",
"health.",
"While",
"childbirth",
"in",
"developed",
"countries",
"is",
"relatively",
"safe,",
"there",
"exists",
"a",
"risk",
"of",
"morbidity.",
"Of",
"significance,",
"cesarean",
"sec-",
"tion",
"is",
"associated",
"with",
"an",
"increased",
"risk",
"and,",
"in",
"particu-",
"lar,",
"infectious",
"morbidity",
"[2].",
"Risk",
"factors",
"for",
"morbidity",
"in-",
"clude",
"prolonged",
"rupture",
"of",
"membranes,",
"obesity,",
"immune",
"suppression,",
"and",
"type",
"of",
"anesthesia,",
"nonelective",
"cesarean",
"de-",
"livery,",
"and",
"a",
"number",
"of",
"vaginal",
"examinations",
"among",
"oth-",
"ers",
"[3].",
"Women",
"with",
"AIDS",
"are",
"severely",
"immunocompro-",
"mised",
"and",
"may",
"be",
"at",
"increased",
"risk",
"for",
"postpartum",
"morbid-",
"ity.",
"While",
"studies",
"have",
"indicated",
"that",
"the",
"risk",
"may",
"be",
"greater",
"for",
"HIV-infected",
"patients,",
"few",
"studies",
"have",
"estimated",
"the",
"risk",
"among",
"the",
"most",
"immunocompromised",
"of",
"these",
"patients",
"[4].",
"Further",
"more,",
"no",
"studies",
"have",
"examined",
"the",
"difference",
"in",
"postpartum",
"management.",
"This",
"study",
"sought",
"to",
"estimate",
"the",
"risk",
"of",
"postpartum",
"morbidity",
"among",
"patients",
"with",
"AIDS",
"compared",
"to",
"more",
"immunocompetent",
"HIV-infected",
"patients",
"and",
"HIV-uninfected",
"women.",
"An",
"additional",
"objective",
"was",
"to",
"determine",
"the",
"impact",
"of",
"their",
"diagnosis",
"on",
"the",
"management",
"of",
"puerperal",
"infections.",
"SUBJECTS",
"AND",
"METHODS",
"This",
"retrospective",
"chart",
"review",
"was",
"approved",
"by",
"the",
"In-",
"stitutional",
"Review",
"Board",
"at",
"Wayne",
"State",
"University.",
"All",
"of",
"the",
"patients",
"delivered",
"at",
"a",
"single",
"urban",
"tertiary",
"care",
"center.",
"Cases",
"consisted",
"of",
"patients",
"with",
"a",
"diagnosis",
"of",
"HIV",
"infec-",
"tion",
"who",
"delivered",
"from",
"January",
"1,",
"2000–June",
"1,",
"2005.",
"Un-",
"infected",
"controls",
"were",
"selected",
"utilizing",
"a",
"computerized",
"peri-",
"natal",
"database",
"and",
"random",
"number",
"allocation.",
"Charts",
"with",
"incomplete",
"medical",
"records",
"or",
"undocumented",
"HIV",
"testing",
"during",
"the",
"current",
"pregnancy",
"were",
"excluded.",
"Medical",
"charts",
"were",
"reviewed",
"for",
"demographic",
"data,",
"clinical",
"characteris-",
"tics,",
"antenatal",
"course,",
"delivery",
"data,",
"and",
"postpartum",
"man-",
"agement.",
"Among",
"HIV-infected",
"patients,",
"treatment",
"data",
"were",
"recorded",
"including",
"CD4",
"cell",
"count,",
"HIV-1",
"RNA",
"viral",
"load",
"measurements,",
"and",
"use",
"of",
"highly",
"active",
"antiretroviral",
"ther-",
"apy",
"(HAART).",
"Group",
"1",
"consisted",
"of",
"patients",
"diagnosed",
"with",
"AIDS",
"as",
"defined",
"by",
"a",
"current",
"or",
"prior",
"history",
"of",
"a",
"CD4",
"cell",
"count",
"<",
"200",
"cells/µL",
"or",
"an",
"opportunistic",
"infection",
"[5].",
"Group"
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] | [
"www.jkns.or.kr",
"http://dx.doi.org/10.3340/jkns.2012.52.3.193",
"J",
"Korean",
"Neurosurg",
"Soc",
"52",
":",
"193-199,",
"2012",
"Print",
"ISSN",
"2005-3711",
"On-line",
"ISSN",
"1598-7876",
"Copyright",
"©",
"2012",
"The",
"Korean",
"Neurosurgical",
"Society",
"Clinical",
"Article",
"Incidence",
"and",
"Risk",
"Factors",
"for",
"Leptomeningeal",
"Carcinomatosis",
"in",
"Breast",
"Cancer",
"Patients",
"with",
"Parenchymal",
"Brain",
"Metastases",
"Jong-myung",
"Jung,",
"M.D.,1",
"Sohee",
"Kim,",
"M.S.,2",
"Jungnam",
"Joo,",
"Ph.D.,2",
"Kyung",
"Hwan",
"Shin,",
"M.D.,",
"Ph.D.,3",
"Ho-Shin",
"Gwak,",
"M.D.,",
"Ph.D.,4",
"Seung",
"Hoon",
"Lee,",
"M.D.,",
"Ph.D.4",
"Department",
"of",
"Neurosurgery,1",
"Seoul",
"National",
"University",
"College",
"of",
"Medicine,",
"Cancer",
"Biostatistics",
"Branch,2",
"Seoul,",
"Korea",
"Department",
"of",
"Radiation",
"Oncology,3",
"Neuro-Oncology",
"Clinic,4",
"National",
"Cancer",
"Center,",
"Goyang,",
"Korea",
"Objective",
":",
"The",
"objective",
"of",
"study",
"is",
"to",
"evaluate",
"the",
"incidence",
"of",
"leptomeningeal",
"carcinomatosis",
"(LMC)",
"in",
"breast",
"cancer",
"patients",
"with",
"parenchymal",
"brain",
"metastases",
"(PBM)",
"and",
"clinical",
"risk",
"factors",
"for",
"the",
"development",
"of",
"LMC.",
"Methods",
":",
"We",
"retrospectively",
"analyzed",
"27",
"patients",
"who",
"had",
"undergone",
"surgical",
"resection",
"(SR)",
"and",
"156",
"patients",
"with",
"whole",
"brain",
"radiation",
"therapy",
"(WBRT)",
"as",
"an",
"initial",
"treatment",
"for",
"their",
"PBM",
"from",
"breast",
"cancer",
"in",
"our",
"institution",
"and",
"compared",
"the",
"difference",
"of",
"incidence",
"of",
"LMC",
"according",
"to",
"clinical",
"factors.",
"The",
"diagnosis",
"of",
"LMC",
"was",
"made",
"by",
"cerebrospinal",
"fluid",
"cytology",
"and/or",
"magnetic",
"resonance",
"imaging.",
"Results",
":",
"A",
"total",
"of",
"27",
"patients",
"(14%)",
"in",
"the",
"study",
"population",
"developed",
"LMC",
"at",
"a",
"median",
"of",
"6.0",
"months",
"(range,",
"1.0-50).",
"Ten",
"of",
"27",
"patients",
"(37%)",
"developed",
"LMC",
"after",
"SR,",
"whereas",
"17",
"of",
"156",
"(11%)",
"patients",
"who",
"received",
"WBRT",
"were",
"diagnosed",
"with",
"LMC",
"after",
"the",
"index",
"procedure.",
"The",
"inci-",
"dence",
"of",
"LMC",
"was",
"significantly",
"higher",
"in",
"the",
"SR",
"group",
"compared",
"with",
"the",
"WBRT",
"group",
"and",
"the",
"hazard",
"ratio",
"was",
"2.95",
"(95%",
"confidence",
"interval;",
"1.33-6.54,",
"p<0.01).",
"Three",
"additional",
"factors",
"were",
"identified",
"in",
"the",
"multivariable",
"analysis",
":",
"the",
"younger",
"age",
"group",
"(<40",
"years",
"old),",
"the",
"progressing",
"systemic",
"disease",
"showed",
"significantly",
"increased",
"incidence",
"of",
"LMC,",
"whereas",
"the",
"adjuvant",
"chemotherapy",
"reduce",
"the",
"incidence.",
"Conclusion",
":",
"There",
"is",
"an",
"increased",
"risk",
"of",
"LMC",
"after",
"SR",
"for",
"PBM",
"from",
"breast",
"cancer",
"compared",
"with",
"WBRT.",
"The",
"young",
"age",
"(<40)",
"and",
"systemic",
"bur-",
"den",
"of",
"cancer",
"in",
"terms",
"of",
"progressing",
"systemic",
"disease",
"without",
"adjuvant",
"chemotherapy",
"could",
"be",
"additional",
"risk",
"factors",
"for",
"the",
"development",
"of",
"LMC.",
"Key",
"Words",
":",
"Brain",
"metastasis",
"·",
"Breast",
"cancer",
"·",
"Leptomeningeal",
"carcinomatosis",
"·",
"Surgery",
"·",
"Whole",
"brain",
"radiation",
"therapy.",
"INTRODUCTION",
"The",
"incidence",
"of",
"parenchymal",
"brain",
"metastasis",
"(PBM)",
"from",
"primary",
"systemic",
"cancer",
"has",
"been",
"increasing",
"along",
"with",
"pro-",
"longed",
"survival",
"of",
"the",
"patients",
"with",
"cancer.",
"Recent",
"report",
"showed",
"that",
"up",
"to",
"30%",
"of",
"cancer",
"patients",
"can",
"be",
"expected",
"to",
"develop",
"PBM",
"according",
"to",
"the",
"types",
"of",
"primary",
"cancer6,12).",
"A",
"popula-",
"tion-based",
"estimate",
"of",
"the",
"incidence",
"proportion",
"of",
"PBM",
"was",
"highest",
"for",
"lung",
"cancer",
"followed",
"by",
"melanoma,",
"renal-,",
"and",
"breast",
"cancer3).",
"However,",
"leptomeningeal",
"carcinomatosis",
"(LMC),",
"which",
"is",
"one",
"of",
"terminal",
"manifestations",
"of",
"central",
"nervous",
"system",
"(CNS)",
"me-",
"tastasis",
"from",
"systemic",
"malignancy,",
"remains",
"incurable",
"without",
"a",
"discernible",
"advance",
"in",
"treatment",
"over",
"the",
"past",
"decades.",
"LMC",
"also",
"has",
"been",
"diagnosed",
"more",
"frequently",
"with",
"the",
"advancement",
"of",
"neuroimaging",
"and",
"prolonged",
"survival",
"of",
"cancer",
"patients8,13,29).",
"Among",
"the",
"pathogenesis",
"of",
"LMC,",
"spread",
"of",
"cancer",
"cells",
"fol-",
"lowed",
"by",
"surgical",
"resection",
"(SR)",
"has",
"been",
"suggested",
"from",
"sev-",
"eral",
"clinical",
"observations",
"of",
"solid",
"tumors",
"including",
"malignant",
"brain",
"tumors2,11,16,22,23,34).",
"Although",
"the",
"overall",
"incidence",
"of",
"LMC",
"is",
"difficult",
"to",
"estimate",
"according",
"to",
"PBM",
"status,",
"it",
"is",
"apparent",
"that",
"the",
"primary",
"cancer",
"showing",
"a",
"high",
"incidence",
"of",
"PBM,",
"such",
"as",
"lung",
"cancer,",
"breast",
"cancer",
"or",
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"Several",
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"location",
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"tu-",
"•",
"Received",
":",
"January",
"10,",
"2012",
"•",
"Revised",
":",
"June",
"14,",
"2012",
"•",
"Accepted",
":",
"September",
"17,",
"2012",
"•",
"Address",
"for",
"reprints",
":",
"Ho-Shin",
"Gwak,",
"M.D.,",
"Ph.D.",
"Neuro-Oncology",
"Clinic,",
"National",
"Cancer",
"Center,",
"323",
"Ilsan-ro,",
"Ilsandong-gu,",
"Goyang",
"410-769,",
"Korea",
"Tel",
":",
"+82-31-920-1666,",
"Fax",
":",
"+82-31-920-2798,",
"E-mail",
":",
"nsghs@ncc.re.kr",
"•",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/by-nc/3.0)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"193"
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] | [
"Pleiotrophin",
"(PTN)",
"Expression",
"and",
"Function",
"and",
"in",
"the",
"Mouse",
"Mammary",
"Gland",
"and",
"Mammary",
"Epithelial",
"Cells",
"Sonia",
"M.",
"Rosenfield1,",
"Emma",
"T.",
"Bowden2,",
"Shani",
"Cohen-Missner1,",
"Krissa",
"A.",
"Gibby1,",
"Virginie",
"Ory1,",
"Ralf",
"T.",
"Henke1,",
"Anna",
"T.",
"Riegel1,",
"Anton",
"Wellstein1*",
"1",
"Lombardi",
"Cancer",
"Center,",
"Georgetown",
"University,",
"Washington,",
"District",
"of",
"Columbia,",
"United",
"States",
"of",
"America,",
"2",
"MedImmune,",
"Gaithersburg,",
"Maryland,",
"United",
"States",
"of",
"America",
"Abstract",
"Expression",
"of",
"the",
"heparin-binding",
"growth",
"factor,",
"pleiotrophin",
"(PTN)",
"in",
"the",
"mammary",
"gland",
"has",
"been",
"reported",
"but",
"its",
"function",
"during",
"mammary",
"gland",
"development",
"is",
"not",
"known.",
"We",
"examined",
"the",
"expression",
"of",
"PTN",
"and",
"its",
"receptor",
"ALK",
"(Anaplastic",
"Lymphoma",
"Kinase)",
"at",
"various",
"stages",
"of",
"mouse",
"mammary",
"gland",
"development",
"and",
"found",
"that",
"their",
"expression",
"in",
"epithelial",
"cells",
"is",
"regulated",
"in",
"parallel",
"during",
"pregnancy.",
"A",
"30-fold",
"downregulation",
"of",
"PTN",
"mRNA",
"expression",
"was",
"observed",
"during",
"mid-pregnancy",
"when",
"the",
"mammary",
"gland",
"undergoes",
"lobular-alveolar",
"differentiation.",
"After",
"weaning",
"of",
"pups,",
"PTN",
"expression",
"was",
"restored",
"although",
"baseline",
"expression",
"of",
"PTN",
"was",
"reduced",
"significantly",
"in",
"mammary",
"glands",
"of",
"mice",
"that",
"had",
"undergone",
"multiple",
"pregnancies.",
"We",
"found",
"PTN",
"expressed",
"in",
"epithelial",
"cells",
"of",
"the",
"mammary",
"gland",
"and",
"thus",
"used",
"a",
"monoclonal",
"anti-PTN",
"blocking",
"antibody",
"to",
"elucidate",
"its",
"function",
"in",
"cultured",
"mammary",
"epithelial",
"cells",
"(MECs)",
"as",
"well",
"as",
"during",
"gland",
"development.",
"Real-time",
"impedance",
"monitoring",
"of",
"MECs",
"growth,",
"migration",
"and",
"invasion",
"during",
"anti-PTN",
"blocking",
"antibody",
"treatment",
"showed",
"that",
"MECs",
"motility",
"and",
"invasion",
"but",
"not",
"proliferation",
"depend",
"on",
"the",
"activity",
"of",
"endogenous",
"PTN.",
"Increased",
"number",
"of",
"mammospheres",
"with",
"laminin",
"deposition",
"after",
"anti-PTN",
"blocking",
"antibody",
"treatment",
"of",
"MECs",
"in",
"3D",
"culture",
"and",
"expression",
"of",
"progenitor",
"markers",
"suggest",
"that",
"the",
"endogenously",
"expressed",
"PTN",
"inhibits",
"the",
"expansion",
"and",
"differentiation",
"of",
"epithelial",
"progenitor",
"cells",
"by",
"disrupting",
"cell-matrix",
"adhesion.",
"In",
"vivo,",
"PTN",
"activity",
"was",
"found",
"to",
"inhibit",
"ductal",
"outgrowth",
"and",
"branching",
"via",
"the",
"inhibition",
"of",
"phospho",
"ERK1/2",
"signaling",
"in",
"the",
"mammary",
"epithelial",
"cells.",
"We",
"conclude",
"that",
"PTN",
"delays",
"the",
"maturation",
"of",
"the",
"mammary",
"gland",
"by",
"maintaining",
"mammary",
"epithelial",
"cells",
"in",
"a",
"progenitor",
"phenotype",
"and",
"by",
"inhibiting",
"their",
"differentiation",
"during",
"mammary",
"gland",
"development.",
"Citation:",
"Rosenfield",
"SM,",
"Bowden",
"ET,",
"Cohen-Missner",
"S,",
"Gibby",
"KA,",
"Ory",
"V,",
"et",
"al.",
"(2012)",
"Pleiotrophin",
"(PTN)",
"Expression",
"and",
"Function",
"and",
"in",
"the",
"Mouse",
"Mammary",
"Gland",
"and",
"Mammary",
"Epithelial",
"Cells.",
"PLoS",
"ONE",
"7(10):",
"e47876.",
"doi:10.1371/journal.pone.0047876",
"Editor:",
"John",
"P.",
"Lydon,",
"Baylor",
"College",
"of",
"Medicine,",
"United",
"States",
"of",
"America",
"Received",
"February",
"7,",
"2012;",
"Accepted",
"September",
"24,",
"2012;",
"Published",
"October",
"15,",
"2012",
"Copyright:",
"2012",
"Rosenfield",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"research",
"was",
"supported",
"by",
"grants",
"awarded",
"to",
"AW",
"from",
"the",
"NCI/NIH",
"(RO1",
"CA101811);",
"to",
"Shani",
"Cohen-Missner",
"from",
"the",
"Pharmaceutical",
"Manufacturers",
"Association",
"(Fellowship);",
"to",
"Sonia",
"M.",
"Rosenfield",
"from",
"the",
"Department",
"of",
"Defense",
"Breast",
"Cancer",
"Research",
"Program",
"(Predoctoral",
"Grant:",
"BC083308).",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"Dr.",
"Wellstein",
"is",
"named",
"as",
"an",
"inventor",
"on",
"Georgetown",
"University",
"owned",
"patents",
"related",
"to",
"pleiotrophin",
"and",
"ALK.",
"Dr.",
"Bowden",
"is",
"an",
"employee",
"at",
"Medimmune",
"Gaithersburg.",
"This",
"does",
"not",
"alter",
"the",
"authors9",
"adherence",
"to",
"all",
"the",
"PLOS",
"ONE",
"policies",
"on",
"sharing",
"data",
"and",
"materials.",
"*",
"E-mail:",
"wellstea@georgetown.edu",
"Introduction",
"The",
"heparin-binding",
"growth",
"factor",
"pleiotrophin",
"(PTN;",
"also",
"known",
"as",
"HB-GAM",
"or",
"HARP;",
"reviewed",
"in",
"[1])",
"is",
"a",
"15",
"kDa",
"secreted",
"protein",
"named",
"for",
"its",
"pleiotrophic",
"effects",
"on",
"different",
"cell",
"types.",
"In",
"mice,",
"PTN",
"and",
"its",
"tyrosine",
"kinase",
"receptor",
"ALK",
"are",
"prominently",
"expressed",
"during",
"embryonic",
"and",
"early",
"postnatal",
"development",
"of",
"the",
"central",
"and",
"peripheral",
"nervous",
"system",
"[2,3,4,5,6].",
"In",
"addition",
"to",
"neuronal",
"functions,",
"PTN",
"contributes",
"to",
"the",
"epithelial-mesenchymal",
"interactions",
"in",
"organs",
"undergoing",
"branching",
"morphogenesis",
"and",
"in",
"bone",
"formation",
"[7,8,9,10,11,12].",
"In",
"the",
"adult,",
"PTN",
"and",
"ALK",
"expressions",
"are",
"downregulated",
"in",
"most",
"tissues,",
"with",
"residual",
"expression",
"in",
"the",
"nervous",
"system",
"[4,13].",
"An",
"increase",
"in",
"PTN",
"expression",
"has",
"been",
"observed",
"in",
"the",
"uterus",
"during",
"gestation,",
"in",
"the",
"human",
"placenta",
"and",
"during",
"bone",
"repair,",
"inflammatory",
"diseases",
"and",
"in",
"human",
"cancers",
"[2,13,14,15,16,17,18,19].",
"The",
"biological",
"effects",
"of",
"PTN-mediated",
"signaling",
"include",
"neurite",
"outgrowth",
"and",
"repair,",
"angiogenesis",
"and",
"mitogenesis",
"of",
"fibroblasts,",
"endothelial",
"and",
"some",
"tumor",
"cell",
"lines",
"[19,20,21,22,23].",
"PTN",
"signaling",
"can",
"induce",
"the",
"activation",
"of",
"both",
"the",
"MAPK",
"and",
"PI3",
"kinase",
"pathways",
"in",
"epithelial",
"cells",
"[24]",
"and",
"a",
"direct",
"role",
"for",
"PTN",
"in",
"mitogenesis",
"and",
"anti-apoptotic",
"signaling",
"was",
"previously",
"reported",
"[19,25,26,27,28].",
"PTN",
"activity",
"has",
"recently",
"been",
"shown",
"to",
"stimulate",
"the",
"differentiation",
"and",
"expansion",
"of",
"neuronal",
"stem",
"cells,",
"osteoprogenitors",
"and",
"bone",
"marrow",
"stem",
"cells",
"[29,30,31].",
"The",
"PTN",
"protein",
"was",
"first",
"purified",
"from",
"the",
"supernatants",
"of",
"human",
"breast",
"cancer",
"cells",
"[32].",
"PTN",
"mRNA",
"expression",
"has",
"been",
"shown",
"in",
"different",
"estrogen",
"receptor",
"negative",
"breast",
"cancer",
"cell",
"lines",
"and",
"in",
"primary",
"breast",
"cancers",
"derived",
"from",
"different",
"patients",
"[19].",
"In",
"NIH3T3",
"fibroblasts,",
"PTN",
"leads",
"to",
"transformation,",
"whereas",
"overexpression",
"of",
"a",
"dominant",
"negative,",
"mutant",
"PTN",
"protein",
"reverses",
"the",
"transformed",
"phenotype",
"of",
"breast",
"and",
"other",
"cancer",
"cell",
"lines",
"[26,33].",
"PTN",
"has",
"also",
"been",
"shown",
"to",
"be",
"an",
"angiogenic",
"factor",
"during",
"tumor",
"growth",
"and",
"a",
"promoter",
"of",
"invasion",
"and",
"metastasis",
"in",
"different",
"tumor",
"types",
"including",
"breast",
"cancers",
"[19,22,34,35].",
"A",
"role",
"for",
"PTN-mediated",
"signaling",
"through",
"the",
"receptor",
"tyrosine",
"kinase",
"ALK",
"as",
"well",
"as",
"the",
"receptor",
"phosphatase",
"PTPRz",
"has",
"been",
"suggested",
"in",
"breast",
"cancers",
"[36,37,38].",
"In",
"normal",
"human",
"breast",
"tissues,",
"PTN",
"is",
"expressed",
"in",
"the",
"epithelial,",
"myoepithelial",
"and",
"endothelial",
"cells",
"[39].",
"In",
"the",
"mouse",
"mammary",
"gland,",
"PTN",
"expression",
"has",
"been",
"described",
"in",
"both",
"PLOS",
"ONE",
"|",
"www.plosone.org",
"1",
"October",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"10",
"|",
"e47876"
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] | [
"metal-organic",
"compounds",
"Acta",
"Crystallographica",
"Section",
"E",
"Structure",
"Reports",
"Online",
"ISSN",
"1600-5368",
"Poly[tetra-l-cyanido-dipyridine-",
"cadmium(II)zinc(II)]",
"Sheng",
"Li,*",
"Kun",
"Tang",
"and",
"Fu-Li",
"Zhang",
"College",
"of",
"Medicine,",
"Henan",
"University,",
"Kaifeng",
"475003,",
"People’s",
"Republic",
"of",
"China",
"Correspondence",
"e-mail:",
"lisheng0821@sina.com",
"Received",
"26",
"October",
"2009;",
"accepted",
"18",
"December",
"2009",
"Key",
"indicators:",
"single-crystal",
"X-ray",
"study;",
"T",
"=",
"296",
"K;",
"mean",
"(C–C)",
"=",
"0.010",
"A˚;",
"R",
"factor",
"=",
"0.050;",
"wR",
"factor",
"=",
"0.136;",
"data-to-parameter",
"ratio",
"=",
"14.5.",
"In",
"the",
"title",
"coordination",
"polymer,",
"[CdZn(CN)4(C5H5N)2]n,",
"the",
"ZnII",
"atom",
"(site",
"symmetry",
"222)",
"adopts",
"a",
"distorted",
"ZnC4",
"tetrahedral",
"geometry,",
"being",
"coordinated",
"by",
"four",
"crystal-",
"lographically",
"equivalent",
"cyanide",
"ions.",
"The",
"cyanide",
"ion",
"bridges",
"to",
"a",
"CdII",
"centre",
"via",
"its",
"N",
"atom.",
"The",
"Cd",
"atom",
"(site",
"symmetry",
"2/m)",
"coordination",
"is",
"a",
"distorted",
"CdN6",
"octahedron,",
"arising",
"from",
"four",
"cyanide",
"N",
"atoms",
"and",
"two",
"pyridine",
"N",
"atoms.",
"The",
"complete",
"pyridine",
"molecule",
"is",
"generated",
"by",
"m",
"symmetry,",
"with",
"the",
"N",
"atom",
"and",
"one",
"C",
"atom",
"lying",
"on",
"the",
"reflecting",
"plane.",
"In",
"the",
"crystal,",
"the",
"bridging",
"cyanide",
"ions",
"result",
"in",
"a",
"three-",
"dimensional",
"network.",
"Related",
"literature",
"For",
"background",
"to",
"cyanide-containing",
"coordination",
"networks,",
"see:",
"Vasylyev",
"&",
"Neumann",
"(2006).",
"Experimental",
"Crystal",
"data",
"[CdZn(CN)4(C5H5N)2]",
"Mr",
"=",
"440.05",
"Orthorhombic,",
"Cccm",
"a",
"=",
"9.514",
"(4)",
"A˚",
"b",
"=",
"13.935",
"(6)",
"A˚",
"c",
"=",
"13.965",
"(6)",
"A˚",
"Data",
"collection",
"Bruker",
"APEXII",
"CCD",
"diffractometer",
"Absorption",
"correction:",
"multi-scan",
"(SADABS;",
"Bruker,",
"2001)",
"Tmin",
"=",
"0.412,",
"Tmax",
"=",
"0.615",
"Refinement",
"R[F",
"2",
">",
"2",
"(F",
"2)]",
"=",
"0.050",
"wR(F",
"2)",
"=",
"0.136",
"S",
"=",
"1.00",
"827",
"reflections",
"Table",
"1",
"Selected",
"bond",
"lengths",
"(A˚",
").",
"Cd—N3",
"Cd—N1",
"2.345",
"(4)",
"2.354",
"(5)",
"V",
"=",
"1851.5",
"(14)",
"A˚",
"3",
"Z",
"=",
"4",
"Mo",
"K",
"radiation",
"=",
"2.45",
"mm",
"1",
"T",
"=",
"296",
"K",
"0.44",
"0.28",
"0.22",
"mm",
"4068",
"measured",
"reflections",
"827",
"independent",
"reflections",
"711",
"reflections",
"with",
"I",
">",
"2",
"(I)",
"Rint",
"=",
"0.051",
"57",
"parameters",
"H-atom",
"parameters",
"not",
"refined",
"max",
"=",
"2.77",
"e",
"A˚",
"3",
"min",
"=",
"1.34",
"e",
"A˚",
"3",
"Zn1—C4",
"2.037",
"(4)",
"Data",
"collection:",
"APEX2",
"(Bruker,",
"2004);",
"cell",
"refinement:",
"SAINT-",
"Plus",
"(Bruker,",
"2001);",
"data",
"reduction:",
"SAINT-Plus;",
"program(s)",
"used",
"to",
"solve",
"structure:",
"SHELXS97",
"(Sheldrick,",
"2008);",
"program(s)",
"used",
"to",
"refine",
"structure:",
"SHELXL97",
"(Sheldrick,",
"2008);",
"molecular",
"graphics:",
"SHELXTL",
"(Sheldrick,",
"2008);",
"software",
"used",
"to",
"prepare",
"material",
"for",
"publication:",
"SHELXTL.",
"The",
"authors",
"are",
"grateful",
"for",
"financial",
"support",
"from",
"Henan",
"University.",
"Supplementary",
"data",
"and",
"figures",
"for",
"this",
"paper",
"are",
"available",
"from",
"the",
"IUCr",
"electronic",
"archives",
"(Reference:",
"HB5184).",
"References",
"Bruker",
"(2001).",
"SAINT-Plus",
"and",
"SADABS.",
"Bruker",
"AXS",
"Inc.,",
"Madison,Wis-",
"consin,",
"USA.",
"Bruker",
"(2004).",
"APEX2.",
"Bruker",
"AXS",
"Inc.,",
"Madison,",
"Wisconsin,",
"USA.",
"Sheldrick,",
"G.",
"M.",
"(2008).",
"Acta",
"Cryst.",
"A64,",
"112–122.",
"Vasylyev,",
"M.",
"&",
"Neumann,",
"R.",
"(2006).",
"Chem.",
"Mater.",
"18,",
"2781–2783.",
"m108",
"Li",
"et",
"al.",
"doi:10.1107/S1600536809054579",
"Acta",
"Cryst.",
"(2010).",
"E66,",
"m108"
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] | [
"D16–D20",
"Nucleic",
"Acids",
"Research,",
"2007,",
"Vol.",
"35,",
"Database",
"issue",
"doi:10.1093/nar/gkl913",
"Published",
"online",
"5",
"December",
"2006",
"EMBL",
"Nucleotide",
"Sequence",
"Database",
"in",
"2006",
"Tamara",
"Kulikova*,",
"Ruth",
"Akhtar,",
"Philippe",
"Aldebert,",
"Nicola",
"Althorpe,",
"Mikael",
"Andersson,",
"Alastair",
"Baldwin,",
"Kirsty",
"Bates,",
"Sumit",
"Bhattacharyya,",
"Lawrence",
"Bower,",
"Paul",
"Browne,",
"Matias",
"Castro,",
"Guy",
"Cochrane,",
"Karyn",
"Duggan,",
"Ruth",
"Eberhardt,",
"Nadeem",
"Faruque,",
"Gemma",
"Hoad,",
"Carola",
"Kanz,",
"Charles",
"Lee,",
"Rasko",
"Leinonen,",
"Quan",
"Lin,",
"Vincent",
"Lombard,",
"Rodrigo",
"Lopez,",
"Dariusz",
"Lorenc,",
"Hamish",
"McWilliam,",
"Gaurab",
"Mukherjee,",
"Francesco",
"Nardone,",
"Maria",
"Pilar",
"Garcia",
"Pastor,",
"Sheila",
"Plaister,",
"Siamak",
"Sobhany,",
"Peter",
"Stoehr,",
"Robert",
"Vaughan,",
"Dan",
"Wu,",
"Weimin",
"Zhu",
"and",
"Rolf",
"Apweiler",
"EMBL",
"Outstation—European",
"Bioinformatics",
"Institute,",
"Wellcome",
"Trust",
"Genome",
"Campus,",
"Hinxton,",
"Cambridge,",
"CB10",
"1SD,",
"UK",
"Received",
"September",
"15,",
"2006;",
"Revised",
"and",
"Accepted",
"October",
"16,",
"2006",
"ABSTRACT",
"The",
"EMBL",
"Nucleotide",
"Sequence",
"Database",
"(http://",
"www.ebi.ac.uk/embl)",
"at",
"the",
"EMBL",
"European",
"Bioinformatics",
"Institute,",
"UK,",
"offers",
"a",
"large",
"and",
"freely",
"accessible",
"collection",
"of",
"nucleotide",
"sequences",
"and",
"accompanying",
"annotation.",
"The",
"database",
"is",
"main-",
"tained",
"in",
"collaboration",
"with",
"DDBJ",
"and",
"GenBank.",
"Data",
"are",
"exchanged",
"between",
"the",
"collaborating",
"databases",
"on",
"a",
"daily",
"basis",
"to",
"achieve",
"optimal",
"synchrony.",
"Webin",
"is",
"the",
"preferred",
"tool",
"for",
"individual",
"submissions",
"of",
"nucleotide",
"sequences,",
"including",
"Third",
"Party",
"Annotation,",
"alignments",
"and",
"bulk",
"data.",
"Automated",
"procedures",
"are",
"provided",
"for",
"submissions",
"from",
"large-scale",
"sequencing",
"projects",
"and",
"data",
"from",
"the",
"European",
"Patent",
"Office.",
"In",
"2006,",
"the",
"volume",
"of",
"data",
"has",
"continued",
"to",
"grow",
"exponentially.",
"Access",
"to",
"the",
"data",
"is",
"provided",
"via",
"SRS,",
"ftp",
"and",
"variety",
"of",
"other",
"methods.",
"Extensive",
"external",
"and",
"internal",
"cross-references",
"enable",
"users",
"to",
"search",
"for",
"related",
"information",
"across",
"other",
"databases",
"and",
"within",
"the",
"database.",
"All",
"available",
"resources",
"can",
"be",
"accessed",
"via",
"the",
"EBI",
"home",
"page",
"at",
"http://www.ebi.ac.uk/.",
"Changes",
"over",
"the",
"past",
"year",
"include",
"changes",
"to",
"the",
"file",
"format,",
"further",
"development",
"of",
"the",
"EMBLCDS",
"dataset",
"and",
"developments",
"to",
"the",
"XML",
"format.",
"INTRODUCTION",
"The",
"EMBL",
"Nucleotide",
"Sequence",
"Database",
"is",
"the",
"European",
"node",
"of",
"the",
"International",
"Nucleotide",
"Sequence",
"Database",
"Col-",
"laboration",
"(INSDC,",
"http://www.insdc.org/)",
"between",
"DDBJ",
"(1),",
"EMBL",
"and",
"GenBank",
"(2).",
"The",
"collaborative",
"aim",
"is",
"to",
"collect",
"and",
"present",
"nucleotide",
"sequence",
"and",
"annotation",
"as",
"comprehensively",
"as",
"possible.",
"The",
"EMBL",
"Nucleotide",
"Sequence",
"Database",
"(EMBL)",
"is",
"maintained",
"at",
"the",
"European",
"Bioinformatics",
"Institute,",
"which",
"hosts",
"several",
"other",
"core",
"biological",
"databases",
"(3).",
"The",
"main",
"goal",
"of",
"the",
"EMBL",
"Nucleotide",
"Sequence",
"Database",
"is",
"to",
"accept,",
"process",
"and",
"make",
"freely",
"available",
"sequence",
"data",
"from",
"individual",
"researchers,",
"research",
"groups",
"and",
"the",
"European",
"Patent",
"Office",
"(EPO).",
"Collected",
"nucleotide",
"sequences",
"and",
"accompanying",
"annotation",
"are",
"made",
"available",
"via",
"the",
"EBI",
"Sequence",
"Retrieval",
"System",
"(SRS),",
"ftp,",
"web",
"services",
"and",
"simi-",
"larity",
"search",
"tools.",
"EMBL",
"database",
"releases,",
"with",
"accompanying",
"release",
"notes,",
"are",
"produced",
"quarterly.",
"The",
"database",
"is",
"presented",
"as",
"individual",
"entries,",
"each",
"carry-",
"ing",
"sequence",
"or",
"information",
"on",
"sequence",
"construction,",
"sub-",
"mission",
"information",
"(submission",
"and",
"update",
"dates,",
"version",
"numbers",
"and",
"submitter",
"details),",
"literature",
"citations",
"and",
"anno-",
"tation",
"in",
"the",
"form",
"of",
"a",
"feature",
"table.",
"Full",
"details",
"of",
"database",
"flatfile",
"format",
"are",
"available",
"in",
"the",
"user",
"manual.",
"Details",
"of",
"fea-",
"ture",
"table",
"format",
"are",
"available",
"in",
"the",
"INSDC",
"Feature",
"Table",
"Definition.",
"Data",
"are",
"also",
"presented",
"in",
"XML",
"formats",
"via",
"the",
"web",
"tools,",
"dbfetch",
"and",
"ftp.",
"Each",
"entry",
"in",
"the",
"database",
"belongs",
"to",
"one",
"of",
"the",
"several",
"entry",
"types,",
"which",
"differ",
"in",
"either",
"data",
"format",
"or",
"handling",
"of",
"data",
"by",
"the",
"database.",
"Entry",
"types",
"include",
"standard",
"(STD),",
"con-",
"structed",
"(CON),",
"third",
"party",
"annotation",
"(TPA),",
"whole",
"genome",
"shotgun",
"(WGS),",
"annotated",
"constructed",
"(ANN)",
"and",
"mass",
"gen-",
"ome",
"annotation",
"library",
"(MGA).",
"New",
"entry",
"types",
"are",
"created",
"as",
"new",
"types",
"of",
"data",
"arrive",
"at",
"the",
"database.",
"Over",
"the",
"past",
"year,",
"the",
"size",
"of",
"the",
"EMBL",
"Nucleotide",
"Sequence",
"Database",
"has",
"increased",
"from",
"58.7",
"million",
"entries",
"in",
"Release",
"84,",
"September",
"2005",
"to",
"80.5",
"million",
"entries",
"in",
"Release",
"88,",
"September",
"2006,",
"of",
"which",
"18",
"million",
"entries",
"are",
"WGS",
"data.",
"The",
"WGS",
"entries",
"now",
"account",
"for",
">50%",
"of",
"the",
"nucleotide",
"content",
"of",
"the",
"database—80.3",
"Gbp",
"out",
"of",
"146.5",
"Gbp",
"in",
"September",
"2006.",
"There",
"are",
"now",
"over",
"260",
"000",
"organisms",
"represented",
"in",
"the",
"database.",
"*To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"Tel:",
"+44",
"01223",
"494463;",
"Fax:",
"+44",
"1223",
"494468;",
"Email:",
"kulikova@ebi.ac.uk",
"2006",
"The",
"Author(s).",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/",
"by-nc/2.0/uk/)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Li",
"et",
"al.",
"BMC",
"Bioinformatics",
"2010,",
"11(Suppl",
"2):S7",
"http://www.biomedcentral.com/1471-2105/11/S2/S7",
"P",
"R",
"O",
"C",
"E",
"E",
"D",
"I",
"N",
"G",
"S",
"Open",
"Access",
"Learning",
"an",
"enriched",
"representation",
"from",
"unlabeled",
"data",
"for",
"protein-protein",
"interaction",
"extraction",
"Yanpeng",
"Li1,2*,",
"Xiaohua",
"Hu2,",
"Hongfei",
"Lin1,",
"Zhihao",
"Yang1",
"From",
"Third",
"International",
"Workshop",
"on",
"Data",
"and",
"Text",
"Mining",
"in",
"Bioinformatics",
"(DTMBio)",
"2009",
"Hong",
"Kong.",
"6",
"November",
"2009",
"Abstract",
"Background:",
"Extracting",
"protein-protein",
"interactions",
"from",
"biomedical",
"literature",
"is",
"an",
"important",
"task",
"in",
"biomedical",
"text",
"mining.",
"Supervised",
"machine",
"learning",
"methods",
"have",
"been",
"used",
"with",
"great",
"success",
"in",
"this",
"task",
"but",
"they",
"tend",
"to",
"suffer",
"from",
"data",
"sparseness",
"because",
"of",
"their",
"restriction",
"to",
"obtain",
"knowledge",
"from",
"limited",
"amount",
"of",
"labelled",
"data.",
"In",
"this",
"work,",
"we",
"study",
"the",
"use",
"of",
"unlabeled",
"biomedical",
"texts",
"to",
"enhance",
"the",
"performance",
"of",
"supervised",
"learning",
"for",
"this",
"task.",
"We",
"use",
"feature",
"coupling",
"generalization",
"(FCG)",
"–",
"a",
"recently",
"proposed",
"semi-supervised",
"learning",
"strategy",
"–",
"to",
"learn",
"an",
"enriched",
"representation",
"of",
"local",
"contexts",
"in",
"sentences",
"from",
"47",
"million",
"unlabeled",
"examples",
"and",
"investigate",
"the",
"performance",
"of",
"the",
"new",
"features",
"on",
"AIMED",
"corpus.",
"Results:",
"The",
"new",
"features",
"generated",
"by",
"FCG",
"achieve",
"a",
"60.1",
"F-score",
"and",
"produce",
"significant",
"improvement",
"over",
"supervised",
"baselines.",
"The",
"experimental",
"analysis",
"shows",
"that",
"FCG",
"can",
"utilize",
"well",
"the",
"sparse",
"features",
"which",
"have",
"little",
"effect",
"in",
"supervised",
"learning.",
"The",
"new",
"features",
"perform",
"better",
"in",
"non-linear",
"classifiers",
"than",
"linear",
"ones.",
"We",
"combine",
"the",
"new",
"features",
"with",
"local",
"lexical",
"features,",
"obtaining",
"an",
"F-score",
"of",
"63.5",
"on",
"AIMED",
"corpus,",
"which",
"is",
"comparable",
"with",
"the",
"current",
"state-of-the-art",
"results.",
"We",
"also",
"find",
"that",
"simple",
"Boolean",
"lexical",
"features",
"derived",
"only",
"from",
"local",
"contexts",
"are",
"able",
"to",
"achieve",
"competitive",
"results",
"against",
"most",
"syntactic",
"feature/kernel",
"based",
"methods.",
"Conclusions:",
"FCG",
"creates",
"a",
"lot",
"of",
"opportunities",
"for",
"designing",
"new",
"features,",
"since",
"a",
"lot",
"of",
"sparse",
"features",
"ignored",
"by",
"supervised",
"learning",
"can",
"be",
"utilized",
"well.",
"Interestingly,",
"our",
"results",
"also",
"demonstrate",
"that",
"the",
"state-of-the",
"art",
"performance",
"can",
"be",
"achieved",
"without",
"using",
"any",
"syntactic",
"information",
"in",
"this",
"task.",
"Background",
"With",
"the",
"exponential",
"explosion",
"of",
"biomedical",
"literature",
"such",
"as",
"MEDLINE,",
"developing",
"automatic",
"information",
"extraction",
"(IE)",
"tools",
"is",
"essential",
"for",
"people",
"to",
"seek",
"information",
"more",
"accurately",
"and",
"efficiently",
"[1].",
"The",
"task",
"of",
"protein-protein",
"interaction",
"extraction",
"(PPIE)",
"aims",
"to",
"extract",
"interacting",
"protein",
"pairs",
"from",
"biomedi-",
"cal",
"literature,",
"which",
"contributes",
"to",
"PPI",
"network",
"analy-",
"sis",
"and",
"discovery",
"of",
"new",
"functions",
"of",
"proteins.",
"In",
"recent",
"years,",
"it",
"has",
"attracted",
"a",
"lot",
"of",
"research",
"interests",
"[2-16]",
"from",
"different",
"domains",
"such",
"as",
"bioinformatics,",
"natural",
"language",
"processing",
"(NLP),",
"and",
"machine",
"*",
"Correspondence:",
"liyanpeng.lyp@gmail.com",
"1Department",
"of",
"Computer",
"Science",
"and",
"Engineering,",
"Dalian",
"University",
"of",
"Technology,",
"Dalian,",
"Liaoning,",
"116024,",
"China",
"learning",
"(ML).",
"Bioinformatics",
"researchers",
"focus",
"on",
"constructing",
"corpus",
"[2,3],",
"designing",
"domain-specific",
"rules",
"for",
"PPIE",
"[4,5]",
"and",
"integrating",
"the",
"extraction",
"results",
"into",
"PPI",
"network",
"analysis",
"[6].",
"In",
"NLP",
"commu-",
"nity,",
"a",
"lot",
"of",
"works",
"focus",
"on",
"how",
"to",
"apply",
"linguistic",
"parsing",
"to",
"enhance",
"the",
"extraction",
"performance",
"[7-12,15,16].",
"People",
"find",
"that",
"methods",
"that",
"incorporate",
"syntactic",
"parsing",
"information",
"can",
"improve",
"the",
"extrac-",
"tion",
"performance",
"significantly",
"and",
"outperform",
"methods",
"that",
"use",
"only",
"lexical",
"information.",
"In",
"addition,",
"most",
"of",
"these",
"methods",
"are",
"in",
"the",
"framework",
"of",
"machine",
"learn-",
"ing.",
"Recent",
"studies",
"[10-12,16]",
"show",
"that",
"integrating",
"all",
"the",
"lexical",
"and",
"parsing",
"features",
"in",
"a",
"kernel-based",
"supervised",
"learning",
"model",
"achieves",
"state-of-the-art",
"performance",
"on",
"benchmark",
"datasets.",
"Since",
"in",
"©",
"2010",
"Li",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
] | [
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0,
0,
0,
0,
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0,
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] | [
"Phosphoinositide",
"3-Kinase",
"C2b",
"Regulates",
"RhoA",
"and",
"the",
"Actin",
"Cytoskeleton",
"through",
"an",
"Interaction",
"with",
"Dbl",
"Karolina",
"Błajecka1.,",
"Marin",
"Marinov2.,",
"Laura",
"Leitner3,",
"Kristin",
"Uth1,",
"Guido",
"Posern3,",
"Alexandre",
"Arcaro1*",
"1",
"Department",
"of",
"Clinical",
"Research,",
"University",
"of",
"Bern,",
"Bern,",
"Switzerland,",
"2",
"Department",
"of",
"Oncology,",
"University",
"Children’s",
"Hospital",
"Zurich,",
"Zurich,",
"Switzerland,",
"3",
"Department",
"of",
"Molecular",
"Biology,",
"AG",
"Regulation",
"of",
"Gene",
"Expression,",
"Max-Planck-Institute",
"of",
"Biochemistry,",
"Martinsried,",
"Germany",
"Abstract",
"The",
"regulation",
"of",
"cell",
"morphology",
"is",
"a",
"dynamic",
"process",
"under",
"the",
"control",
"of",
"multiple",
"protein",
"complexes",
"acting",
"in",
"a",
"coordinated",
"manner.",
"Phosphoinositide",
"3-kinases",
"(PI3K)",
"and",
"their",
"lipid",
"products",
"are",
"widely",
"involved",
"in",
"cytoskeletal",
"regulation",
"by",
"interacting",
"with",
"proteins",
"regulating",
"RhoGTPases.",
"Class",
"II",
"PI3K",
"isoforms",
"have",
"been",
"implicated",
"in",
"the",
"regulation",
"of",
"the",
"actin",
"cytoskeleton,",
"although",
"their",
"exact",
"role",
"and",
"mechanism",
"of",
"action",
"remain",
"to",
"be",
"established.",
"In",
"this",
"report,",
"we",
"have",
"identified",
"Dbl,",
"a",
"Rho",
"family",
"guanine",
"nucleotide",
"exchange",
"factor",
"(RhoGEF)",
"as",
"an",
"interaction",
"partner",
"of",
"PI3KC2b.",
"Dbl",
"was",
"co-immunoprecipitated",
"with",
"PI3KC2b",
"in",
"NIH3T3",
"cells",
"and",
"cancer",
"cell",
"lines.",
"Over-expression",
"of",
"Class",
"II",
"phosphoinositide",
"3-kinase",
"PI3KC2b",
"in",
"NIH3T3",
"fibroblasts",
"led",
"to",
"increased",
"stress",
"fibres",
"formation",
"and",
"cell",
"spreading.",
"Accordingly,",
"we",
"found",
"high",
"basal",
"RhoA",
"activity",
"and",
"increased",
"serum",
"response",
"factor",
"(SRF)",
"activation",
"downstream",
"of",
"RhoA",
"upon",
"serum",
"stimulation.",
"In",
"contrast,",
"the",
"dominant-negative",
"form",
"of",
"PI3KC2b",
"strongly",
"reduced",
"cell",
"spreading",
"and",
"stress",
"fibres",
"formation,",
"as",
"well",
"as",
"SRF",
"response.",
"Platelet-derived",
"growth",
"factor",
"(PDGF)",
"stimulation",
"of",
"wild-type",
"PI3KC2b",
"over-expressing",
"NIH3T3",
"cells",
"strongly",
"increased",
"Rac",
"and",
"c-Jun",
"N-terminal",
"kinase",
"(JNK)",
"activation,",
"but",
"failed",
"to",
"show",
"similar",
"effect",
"in",
"the",
"cells",
"with",
"the",
"dominant-",
"negative",
"enzyme.",
"Interestingly,",
"epidermal",
"growth",
"factor",
"(EGF)",
"and",
"PDGF",
"stimulation",
"led",
"to",
"increased",
"extracellular",
"signal-",
"regulated",
"kinase",
"(Erk)",
"and",
"Akt",
"pathway",
"activation",
"in",
"cells",
"with",
"elevated",
"wild-type",
"PI3KC2b",
"expression.",
"Furthermore,",
"increased",
"expression",
"of",
"PI3KC2b",
"protected",
"NIH3T3",
"from",
"detachment-dependent",
"death",
"(anoikis)",
"in",
"a",
"RhoA-dependent",
"manner.",
"Taken",
"together,",
"these",
"findings",
"suggest",
"that",
"PI3KC2b",
"modulates",
"the",
"cell",
"morphology",
"and",
"survival",
"through",
"a",
"specific",
"interaction",
"with",
"Dbl",
"and",
"the",
"activation",
"of",
"RhoA.",
"Citation:",
"Błajecka",
"K,",
"Marinov",
"M,",
"Leitner",
"L,",
"Uth",
"K,",
"Posern",
"G,",
"et",
"al.",
"(2012)",
"Phosphoinositide",
"3-Kinase",
"C2b",
"Regulates",
"RhoA",
"and",
"the",
"Actin",
"Cytoskeleton",
"through",
"an",
"Interaction",
"with",
"Dbl.",
"PLoS",
"ONE",
"7(9):",
"e44945.",
"doi:10.1371/journal.pone.0044945",
"Editor:",
"Pontus",
"Aspenstrom,",
"Karolinska",
"Institutet,",
"Sweden",
"Received",
"December",
"20,",
"2011;",
"Accepted",
"August",
"14,",
"2012;",
"Published",
"September",
"12,",
"2012",
"Copyright:",
"2012",
"Błajecka",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"study",
"was",
"funded",
"by",
"the",
"Swiss",
"National",
"Science",
"Foundation",
"(grants",
"3100A0-105321",
"and",
"31003A-120294).",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"alexandre.arcaro@dkf.unibe.ch",
".",
"These",
"authors",
"contributed",
"equally",
"to",
"this",
"work.",
"Introduction",
"The",
"phosphoinositide-3",
"kinase",
"(PI3K)",
"family",
"comprises",
"evolu-",
"tionary",
"conserved",
"lipid",
"kinases",
"characterised",
"by",
"their",
"ability",
"to",
"phosphorylate",
"phosphoinositides",
"at",
"the",
"D-3",
"position",
"of",
"the",
"inositol",
"ring.",
"This",
"reaction",
"leads",
"to",
"the",
"production",
"of",
"essential",
"for",
"the",
"cell",
"second",
"messengers",
"as",
"PI(3)P,",
"PI(3,4)P2",
"and",
"PI(3,4,5)P3",
"[1].",
"The",
"subsequent",
"membrane",
"recruitment",
"of",
"enzymes",
"recognizing",
"and",
"binding",
"D-3",
"phosphorylated",
"phosphoinositides",
"leads",
"to",
"their",
"activation,",
"which",
"results",
"in",
"the",
"initiation",
"of",
"multiple",
"signalling",
"cascades",
"providing",
"growth,",
"survival",
"and",
"motility",
"signals",
"to",
"the",
"cell.",
"The",
"biological",
"functions",
"of",
"PI3K",
"have",
"been",
"widely",
"investigated",
"by",
"the",
"use",
"of",
"transgenic",
"mouse",
"models",
"and",
"in",
"vitro",
"cell",
"systems.",
"It",
"became",
"clear",
"that",
"PI3K",
"are",
"extremely",
"important",
"for",
"cell",
"proliferation,",
"differentiation,",
"chemotaxis",
"and",
"motility.",
"Further-",
"more,",
"they",
"are",
"implicated",
"in",
"the",
"embryonic",
"development,",
"immunity",
"and",
"the",
"development",
"of",
"diseases",
"such",
"as",
"cancer,",
"inflammation",
"and",
"diabetes",
"[1–3].",
"The",
"family",
"of",
"PI3K",
"comprises",
"three",
"classes,",
"based",
"on",
"structural",
"similarity",
"and",
"in",
"vitro",
"substrate",
"specificity.",
"Class",
"I",
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"[4].",
"To",
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"[16–",
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"However,",
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"II",
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"[20].",
"It",
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"in",
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"PLOS",
"ONE",
"|",
"www.plosone.org",
"1",
"September",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"9",
"|",
"e44945"
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] | [
"Orthopedic",
"Reviews",
"2012;",
"volume",
"4:e11",
"The",
"correlation",
"between",
"the",
"sagittal",
"lumbopelvic",
"alignments",
"in",
"standing",
"position",
"and",
"the",
"risk",
"factors",
"influencing",
"low",
"back",
"pain",
"Pongsthorn",
"Chanplakorn,",
"Paphon",
"Sa-ngasoongsong,",
"Siwadol",
"Wongsak,",
"Patarawan",
"Woratanarat,",
"Wiwat",
"Wajanavisit,",
"Wichien",
"Laohacharoensombat",
"Department",
"of",
"Orthopedics,",
"Faculty",
"of",
"Medicine",
"Ramathibodi",
"Hospital,",
"Mahidol",
"University,",
"Bangkok,",
"Thailand",
"Abstract",
"Low",
"back",
"pain",
"(LBP)",
"is",
"the",
"most",
"common",
"health",
"problem.",
"Many",
"factors",
"have",
"been",
"demonstrated",
"to",
"be",
"fundamental",
"risk",
"factors",
"of",
"LBP",
"such",
"as",
"body",
"mass",
"index",
"(BMI),",
"age",
"and",
"sex.",
"However,",
"so",
"far",
"there",
"have",
"been",
"few",
"stud-",
"ies",
"demonstrating",
"the",
"association",
"between",
"lumbo-pelvic",
"alignment",
"(LPA)",
"and",
"these",
"fac-",
"tors.",
"This",
"present",
"study",
"was",
"aimed",
"to",
"clarify",
"the",
"correlation",
"between",
"the",
"LPA",
"and",
"the",
"risk",
"factors",
"contributing",
"to",
"LBP.",
"Standing",
"lateral",
"X-",
"rays",
"were",
"taken",
"from",
"100",
"healthy",
"volunteers",
"(70",
"males",
"and",
"30",
"females)",
"with",
"no",
"history",
"of",
"low",
"back",
"pain",
"before",
"their",
"participation.",
"Average",
"age",
"of",
"subjects",
"was",
"33.3±6.8",
"years",
"(rang",
"21-50).",
"Mean",
"body",
"weight",
"was",
"59.1±7.9kg",
"(range",
"40-82),",
"mean",
"body",
"height",
"was",
"163.6±7.2",
"cm",
"(range",
"145-178)",
"and",
"mean",
"BMI",
"was",
"22.1±2.4",
"kg/m2",
"(range",
"18.0-29.3).",
"The",
"LPA",
"was",
"classified",
"into",
"3",
"types",
"according",
"to",
"the",
"recently",
"proposed",
"pelvic",
"orientation",
"guide-",
"lines.",
"No",
"direct",
"correlation",
"was",
"found",
"between",
"the",
"pelvic",
"orientation",
"and",
"age",
"or",
"BMI.",
"Each",
"LPA",
"type",
"was",
"associated",
"with",
"sex",
"but",
"not",
"BMI",
"and",
"age",
"(P=0.00,",
"0.71,",
"and",
"0.36,",
"respectively).",
"The",
"results",
"from",
"this",
"study",
"demonstrated",
"the",
"differences",
"in",
"LPA",
"between",
"male",
"and",
"female,",
"and",
"also",
"confirmed",
"that",
"the",
"sagittal",
"orienta-",
"tion",
"of",
"the",
"pelvis",
"remained",
"constant",
"in",
"adults.",
"The",
"high",
"prevalence",
"of",
"LPA",
"type",
"1",
"in",
"males",
"may",
"reduce",
"the",
"occurrence",
"of",
"LBP",
"in",
"obese",
"male",
"individuals.",
"Introduction",
"Low",
"back",
"pain",
"(LBP)",
"is",
"one",
"of",
"the",
"most",
"com-",
"mon",
"health",
"problems",
"and",
"affects",
"more",
"than",
"80%",
"of",
"people",
"over",
"their",
"lifetime.1",
"It",
"is",
"an",
"enor-",
"mous",
"clinical",
"and",
"public",
"health",
"problem",
"that",
"is",
"associated",
"with",
"high",
"health",
"care",
"burden",
"and",
"[page",
"50]",
"social",
"costs.1,2",
"Moreover,",
"despite",
"its",
"benign",
"nature,",
"in",
"many",
"countries,",
"LBP",
"is",
"the",
"leading",
"activity-limiting",
"complaint,",
"cause",
"of",
"disability",
"and",
"sick",
"leave,",
"and",
"with",
"the",
"highest",
"cost",
"of",
"workers’",
"compensation.1,3",
"In",
"addition,",
"regard-",
"ing",
"therapeutic",
"interventions,",
"a",
"large",
"number",
"of",
"systematic",
"reviews",
"have",
"been",
"published",
"concerning",
"the",
"effectiveness",
"of",
"a",
"large",
"variety",
"of",
"treatment",
"available",
"for",
"the",
"LBP;",
"unfortu-",
"nately",
"the",
"results",
"have",
"not",
"been",
"convincingly",
"demonstrated.4",
"Therefore,",
"preventive",
"strate-",
"gies",
"might",
"be",
"beneficial",
"in",
"the",
"management",
"of",
"LBP,",
"with",
"regard",
"to",
"treatment",
"costs,",
"outcomes",
"and",
"disease",
"burden.",
"Given",
"this,",
"it",
"is",
"essential",
"to",
"know",
"the",
"potential",
"risk",
"factors.",
"Numerous",
"potential",
"risk",
"factors",
"of",
"the",
"LBP",
"have",
"been",
"suggested,",
"such",
"as",
"age",
"and",
"gen-",
"der,3,5",
"body",
"mass",
"index",
"(BMI),6,7",
"or",
"physical",
"activity.5",
"Unfortunately,",
"despite",
"many",
"clinical",
"studies,",
"the",
"associations",
"between",
"these",
"fac-",
"tors",
"and",
"LBP",
"have",
"remained",
"inconclusive.",
"The",
"alteration",
"in",
"sagittal",
"spinal",
"alignment",
"is",
"thought",
"to",
"be",
"one",
"of",
"the",
"potential",
"risk",
"factor",
"of",
"LBP.8,9",
"However,",
"there",
"is",
"great",
"variability",
"in",
"spinal",
"alignment",
"in",
"the",
"normal",
"population",
"and",
"this",
"makes",
"it",
"difficult",
"to",
"clarify",
"whether",
"the",
"alteration",
"in",
"spinal",
"posture",
"has",
"any",
"influence",
"and",
"there",
"is",
"still",
"some",
"conflicting",
"evidence",
"linking",
"different",
"spinal",
"postures",
"to",
"LBP",
"in",
"adults.10",
"Recently,",
"Pongsthorn",
"et",
"al.",
"have",
"suggested",
"classifying",
"lumbo-pelvic",
"alignments",
"(LPA)",
"in",
"the",
"normal",
"population.11",
"In",
"brief,",
"LPA",
"has",
"been",
"classified",
"into",
"3",
"types",
"according",
"to",
"the",
"sagittal",
"orientation",
"of",
"the",
"pelvis:",
"in",
"type",
"1,",
"the",
"sacro-",
"pelvis",
"is",
"relatively",
"horizontal",
"with",
"low",
"lumbar",
"lordosis,",
"whereas",
"in",
"type",
"3,",
"the",
"sacro-pelvis",
"is",
"more",
"vertical",
"with",
"higher",
"lumbar",
"lordosis,",
"and",
"type",
"2",
"has",
"the",
"average",
"sacro-pelvis",
"and",
"lumbar",
"lordosis",
"pattern.",
"However,",
"the",
"association",
"between",
"the",
"new",
"LPA",
"classification",
"and",
"the",
"internal",
"risk",
"factors",
"such",
"as",
"age,",
"gender",
"and",
"BMI",
"has",
"not",
"yet",
"been",
"studied.",
"Therefore,",
"the",
"aim",
"of",
"this",
"present",
"study",
"was",
"to",
"determine",
"the",
"correlation",
"between",
"LPA",
"and",
"the",
"LPA",
"classifi-",
"cation",
"and",
"the",
"contribution",
"of",
"internal",
"risk",
"fac-",
"tors",
"to",
"low",
"back",
"pain.",
"Materials",
"and",
"Methods",
"Demographic",
"data",
"and",
"X-ray",
"parameters",
"from",
"100",
"asymptomatic",
"Thai",
"volunteers",
"who",
"had",
"previously",
"participated",
"in",
"studies",
"on",
"lumbo-pelvic",
"alignment",
"analysis",
"were",
"used",
"in",
"this",
"present",
"study.",
"Inclusion",
"study",
"criteria",
"were:",
"i)",
"age",
"20-60",
"years;",
"ii)",
"no",
"prior",
"spine",
"sur-",
"gery;",
"and",
"iii)",
"no",
"history",
"of",
"low",
"back",
"pain,",
"except",
"for",
"occasional",
"episodes",
"after",
"work",
"or",
"exertion,",
"for",
"at",
"least",
"six",
"months",
"before",
"their",
"participation",
"in",
"the",
"study.",
"Exclusion",
"criteria",
"were:",
"i)",
"definite",
"diagnosis",
"of",
"lumbar",
"spinal",
"pathology,",
"such",
"as",
"spinal",
"stenosis,",
"spondylolis-",
"[Orthopedic",
"Reviews",
"2012;",
"4:e11]",
"Correspondence:",
"Pongsthorn",
"Chanplakorn",
"Department",
"of",
"Orthopedics,",
"Faculty",
"of",
"Medicine",
"Ramathibodi",
"Hospital,",
"Mahidol",
"University,",
"270",
"Rama",
"VI",
"road,",
"Payathai,",
"Ratchathewi,",
"Bangkok,",
"10400,",
"Thailand.",
"Tel.",
"+66.2.2011589",
"-",
"Fax:",
"+66.2.2011599.",
"E-mail:",
"rapcl@mahidol.ac.th",
"Key",
"words:",
"pelvic",
"morphology,",
"lumbar",
"lordosis,",
"sagittal",
"spinal",
"alignments,",
"low",
"back",
"pain,",
"risk",
"factors.",
"Received",
"for",
"publication:",
"6",
"December",
"2011.",
"Accepted",
"for",
"publication:",
"28",
"December",
"2011.",
"This",
"work",
"is",
"licensed",
"under",
"a",
"Creative",
"Commons",
"Attribution",
"NonCommercial",
"3.0",
"License",
"(CC",
"BY-",
"NC",
"3.0).",
"©Copyright",
"P.",
"Chanplakorn",
"et",
"al.,",
"2012",
"Licensee",
"PAGEPress",
"srl,",
"Italy",
"Orthopedic",
"Reviews",
"2012;",
"4:e11",
"doi:10.4081/or.2012.e11",
"thesis,",
"degenerative",
"disc",
"disease",
"or",
"inflamma-",
"tory",
"spinal",
"diseases,",
"or",
"definite",
"clinical",
"spine",
"deformities",
"from",
"physical",
"examination",
"or",
"X-",
"ray;",
"ii)",
"definite",
"diagnosis",
"of",
"diabetic",
"mellitus,",
"hypertension,",
"rickets,",
"osteoporosis;",
"iii)",
"history",
"of",
"smoking;",
"and",
"iv)",
"incomplete",
"demographic",
"data",
"records.",
"Age,",
"gender,",
"body",
"weight",
"and",
"height",
"were",
"recorded",
"and",
"then",
"the",
"body",
"mass",
"index",
"(BMI)",
"for",
"each",
"subject",
"was",
"calculated.",
"In",
"order",
"to",
"better",
"understand",
"the",
"correlation",
"between",
"the",
"types",
"of",
"the",
"lumbo-pelvic",
"align-",
"ment",
"and",
"the",
"demographic",
"parameters,",
"we",
"divided",
"subjects",
"into",
"3",
"subcategories",
"according",
"to",
"age:",
"group",
"1,",
"under",
"30",
"years",
"of",
"age",
"(n=30);",
"group",
"2,",
"aged",
"between",
"30",
"and",
"39",
"years",
"(n=46);",
"and",
"group",
"3,",
"over",
"40",
"years",
"of",
"age",
"(n=20),",
"according",
"to",
"the",
"risk",
"of",
"low",
"back",
"pain",
"in",
"the",
"Thai",
"worker",
"population.3",
"The",
"BMI",
"was",
"also",
"sub-",
"categorized",
"into",
"3",
"groups:",
"group",
"1,",
"BMI",
"less",
"than",
"19",
"kg/m2;",
"group",
"2,",
"BMI",
"between",
"19",
"and",
"24.5",
"kg/m2;",
"and",
"group",
"3,",
"BMI",
"over",
"24.5",
"kg/m2",
"according",
"to",
"the",
"World",
"Health",
"Organization",
"(WHO)",
"criteria",
"for",
"the",
"Asian",
"population.12",
"The",
"previous",
"standing",
"lateral",
"standing",
"X-",
"rays",
"of",
"the",
"lumbar",
"spine",
"and",
"pelvis",
"in",
"a",
"stan-",
"dardized",
"position",
"that",
"were",
"used",
"in",
"a",
"previous",
"study",
"were",
"reviewed",
"by",
"2",
"of",
"the",
"authors",
"(PC",
"and",
"SW)",
"and",
"then",
"used",
"for",
"this",
"correlation",
"study.",
"Details",
"of",
"the",
"X-ray",
"techniques",
"were:",
"i)",
"all",
"subjects",
"had",
"standing",
"lateral",
"X-ray",
"of",
"the",
"spine",
"and",
"pelvis",
"performed",
"by",
"the",
"same",
"radio-",
"technologist",
"using",
"the",
"same",
"radiographic",
"equipments;",
"ii)",
"X-ray",
"cassettes",
"were",
"set",
"into",
"a",
"standard",
"upright",
"cassette",
"adjustment",
"device",
"then",
"adjusted",
"for",
"a",
"72-inch",
"long",
"focal",
"film",
"dis-",
"tance",
"from",
"the",
"radiation",
"source;",
"iii)",
"the",
"volun-",
"teers",
"were",
"carefully",
"positioned",
"with",
"their",
"right",
"side",
"against",
"the",
"cassette.",
"They",
"were",
"asked",
"to",
"stand",
"up",
"straight,",
"but",
"to",
"remain",
"in",
"a",
"relaxed",
"position",
"with",
"the",
"knees",
"extended.",
"The",
"arms"
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] | [
"IEFS",
"PROCEEDINGS",
"A",
"systematic",
"approach",
"to",
"the",
"failed",
"plastic",
"surgical",
"reconstruction",
"of",
"the",
"diabetic",
"foot",
"Ioannis",
"I.",
"Ignatiadis,",
"MD,",
"PhD1*,",
"Vassiliki",
"A.",
"Tsiampa,",
"MD2",
"and",
"Apostolos",
"E.",
"Papalois,",
"PhD3",
"1Hand",
"Surgery",
"and",
"Microsurgery",
"Department,",
"KAT",
"General",
"Hospital,",
"Athens,",
"Greece;",
"22nd",
"Orthopaedic",
"Department,",
"University",
"of",
"Athens",
"Medical",
"School,",
"Athens,",
"Greece;",
"3Head",
"of",
"Experimental-Research",
"Center,",
"ELPEN",
"SA",
"Pharma-Co,",
"Pikermi-Attika,",
"Greece",
"Plastic",
"reconstruction",
"for",
"diabetic",
"foot",
"wounds",
"must",
"be",
"approached",
"carefully",
"and",
"follow",
"sound",
"micro-surgical",
"principles",
"as",
"it",
"relates",
"to",
"the",
"anatomy",
"of",
"the",
"designated",
"flap",
"chosen",
"for",
"coverage.",
"First,",
"the",
"surgeon",
"always",
"needs",
"to",
"evaluate",
"the",
"local",
"and",
"general",
"conditions",
"of",
"the",
"presenting",
"pathology",
"and",
"patient,",
"respectively",
"when",
"considering",
"a",
"flap",
"for",
"reconstruction.",
"The",
"flap",
"that",
"is",
"chosen",
"is",
"based",
"on",
"the",
"vascularity,",
"location,",
"and",
"size",
"of",
"the",
"defect.",
"Salvage",
"of",
"the",
"failed",
"flap",
"and",
"revisional",
"reconstructive",
"procedures",
"are",
"very",
"challenging.",
"Often,",
"adjunctive",
"therapies",
"such",
"as",
"hyperbaric",
"oxygen,",
"negative",
"pressure",
"wound",
"therapy,",
"vasodilators,",
"and/or",
"vascular",
"surgery",
"is",
"required.",
"In",
"certain",
"case",
"scenarios,",
"such",
"as",
"patients",
"with",
"poor",
"general",
"health",
"and",
"compromised",
"local",
"vascularity",
"in",
"which",
"revisional",
"flap",
"coverage",
"cannot",
"be",
"performed,",
"the",
"above",
"mentioned",
"adjunctive",
"therapies",
"could",
"be",
"used",
"as",
"a",
"primary",
"treatment",
"to",
"potentially",
"salvage",
"a",
"failing",
"flap.",
"Keywords:",
"pedicle",
"flaps;",
"muscle",
"flaps;",
"diabetic",
"foot;",
"osteomyelitis;",
"plastic",
"surgery",
"Srepresents",
"oft",
"tissue",
"coverage",
"a",
"challenge",
"for",
"most",
"to",
"the",
"diabetic",
"reconstructive",
"foot",
"wounds",
"sur-",
"geon.",
"In",
"our",
"experience,",
"patients",
"suffering",
"with",
"diabetic",
"foot",
"and",
"ankle",
"soft",
"tissue",
"defects",
"that",
"require",
"plastic",
"reconstruction",
"could",
"be",
"divided",
"into",
"two",
"broad",
"categories",
"concerning",
"their",
"etiological",
"mechanism:",
"(1)",
"traumatic",
"wounds",
"with",
"a",
"‘pathological",
"evolution’",
"such",
"as",
"degloving",
"injuries,",
"burns,",
"and/or",
"open",
"fractures",
"to",
"diabetic",
"patients",
"and",
"(2)",
"chronic",
"wounds",
"that",
"could",
"be",
"related",
"to",
"decubitus",
"ulcerations",
"in",
"a",
"diabetic",
"background",
"such",
"as",
"heel",
"‘pressure’",
"wounds,",
"wounds",
"associated",
"with",
"peripheral",
"neuropathy",
"including",
"Charcot",
"foot",
"deformity",
"or",
"an",
"osseous",
"prominence",
"with",
"ulceration,",
"with",
"or",
"without",
"diabetic",
"foot",
"infections.",
"Wounds",
"could",
"be",
"associated",
"with",
"peripheral",
"arterial",
"disease",
"or",
"vascular",
"insufficiency",
"in",
"diabetic",
"patients.",
"Concerning",
"the",
"nature",
"and",
"the",
"morphological",
"aspect",
"of",
"the",
"wound",
"we",
"recom-",
"mend",
"the",
"University",
"of",
"Texas",
"Health",
"Science",
"Center",
"San",
"Antonio",
"diabetic",
"wound",
"classification",
"system",
"(1)",
"that",
"presents",
"the",
"depth,",
"quality,",
"level",
"of",
"maturity",
"and",
"healing,",
"This",
"study",
"was",
"presented",
"at",
"the",
"6th",
"Annual",
"International",
"External",
"Fixation",
"Symposium",
"(IEFS),",
"December",
"2010,",
"San",
"Antonio,",
"Texas,",
"USA.",
"and",
"the",
"involvement",
"or",
"not",
"of",
"any",
"local",
"infectious",
"factors",
"(Table",
"1).",
"The",
"most",
"important",
"initial",
"step",
"in",
"treating",
"soft",
"tissue",
"defects",
"related",
"to",
"the",
"diabetic",
"foot",
"is",
"to",
"perform",
"a",
"timely",
"and",
"complete",
"surgical",
"debridement.",
"This",
"entails",
"the",
"surgical",
"excision",
"of",
"all",
"non-viable",
"and/or",
"infected",
"soft",
"tissue",
"and",
"bone",
"so",
"that",
"the",
"wound",
"margins",
"and",
"base",
"of",
"the",
"soft",
"tissue",
"defect",
"are",
"healthy",
"and",
"viable.",
"This",
"does",
"not",
"imply",
"that",
"de´bridement",
"should",
"be",
"limited",
"because",
"of",
"the",
"size",
"or",
"location",
"of",
"the",
"index",
"wound",
"since",
"proper",
"soft",
"tissue",
"reconstruction",
"can",
"only",
"be",
"performed",
"after",
"suc-",
"cessful",
"de´bridement",
"and",
"wound",
"preparation",
"regardless",
"of",
"size,",
"depth,",
"or",
"location.",
"If",
"there",
"is",
"exposed",
"bone",
"or",
"suspicion",
"for",
"underlying",
"osteomyelitis,",
"then",
"bone",
"cultures",
"and",
"biopsies",
"are",
"obtained",
"and",
"empiric",
"systemic",
"antibiotic",
"therapy",
"is",
"started",
"and",
"eventually",
"tailored",
"to",
"the",
"identified",
"pathogen.",
"It",
"is",
"common",
"for",
"a",
"patient",
"to",
"be",
"brought",
"back",
"to",
"the",
"operating",
"room",
"several",
"times",
"for",
"de´bridement",
"before",
"the",
"wound",
"is",
"optimized",
"for",
"flap",
"coverage.",
"Failure",
"to",
"have",
"an",
"adequately",
"de´brided",
"wound",
"will",
"most",
"likely",
"lead",
"to",
"failure",
"of",
"any",
"attempt",
"at",
"flap",
"coverage",
"(2",
"9).",
"In",
"addition",
"to",
"adequate",
"soft",
"tissue",
"and",
"bone",
"debride-",
"ment,",
"the",
"utilization",
"of",
"an",
"external",
"fixator",
"is",
"applied",
"to",
"stabilize",
"significant",
"osseous",
"defects",
"and/or",
"unstable",
"Diabetic",
"Foot",
"&",
"Ankle",
"2011.",
"#",
"2011",
"Ioannis",
"I.",
"Ignatiadis",
"et",
"al.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"1",
"Attribution-Noncommercial",
"3.0",
"Unported",
"License",
"(http://creativecommons.org/licenses/by-nc/3.0/),",
"permitting",
"all",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Citation:",
"Diabetic",
"Foot",
"&",
"Ankle",
"2011,",
"2:",
"6435",
"-",
"DOI:",
"10.3402/dfa.v2i0.6435",
"(page",
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] | [
"Sensors",
"2010,",
"10,",
"5962-5974;",
"doi:10.3390/s100605962",
"OPEN",
"ACCESS",
"sensors",
"ISSN",
"1424-8220",
"www.mdpi.com/journal/sensors",
"Article",
"Exploring",
"Infrared",
"Sensoring",
"for",
"Real",
"Time",
"Welding",
"Defects",
"Monitoring",
"in",
"GTAW",
"Sadek",
"C.",
"A.",
"Alfaro*",
"and",
"Fernand",
"Díaz",
"Franco",
"Automation",
"and",
"Control",
"Group,",
"Departamento",
"de",
"Engenharia",
"Mecânica/Mecatrônica,",
"Faculdade",
"de",
"Tecnologia,",
"The",
"Brasilia",
"University,",
"Brasília–DF,",
"CEP:",
"70910-900,",
"Brazil",
"*",
"Author",
"to",
"whom",
"correspondence",
"should",
"be",
"addressed;",
"E-Mail:",
"sadek@unb.br;",
"Tel.:",
"+55-61-31075697;",
"Fax:",
"+55-61-31075707.",
"Received:",
"25",
"April",
"2010;",
"in",
"revised",
"form:",
"15",
"May",
"2010",
"/",
"Accepted:",
"30",
"May",
"2010",
"/",
"Published:",
"14",
"June",
"2010",
"Abstract:",
"This",
"paper",
"presents",
"an",
"evaluation",
"of",
"an",
"infrared",
"sensor",
"for",
"monitoring",
"the",
"welding",
"pool",
"temperature",
"in",
"a",
"Gas",
"Tungsten",
"Arc",
"Welding",
"(GTAW)",
"process.",
"The",
"purpose",
"of",
"the",
"study",
"is",
"to",
"develop",
"a",
"real",
"time",
"system",
"control.",
"It",
"is",
"known",
"that",
"the",
"arc",
"welding",
"pool",
"temperature",
"is",
"related",
"to",
"the",
"weld",
"penetration",
"depth;",
"therefore,",
"by",
"monitoring",
"the",
"temperature,",
"the",
"arc",
"pool",
"temperature",
"and",
"penetration",
"depth",
"are",
"also",
"monitored.",
"Various",
"experiments",
"were",
"performed;",
"in",
"some",
"of",
"them",
"the",
"current",
"was",
"varied",
"and",
"the",
"temperature",
"changes",
"were",
"registered,",
"in",
"others,",
"defects",
"were",
"induced",
"throughout",
"the",
"path",
"of",
"the",
"weld",
"bead",
"for",
"a",
"fixed",
"current.",
"These",
"simulated",
"defects",
"resulted",
"in",
"abrupt",
"changes",
"in",
"the",
"average",
"temperature",
"values,",
"thus",
"providing",
"an",
"indication",
"of",
"the",
"presence",
"of",
"a",
"defect.",
"The",
"data",
"has",
"been",
"registered",
"with",
"an",
"acquisition",
"card.",
"To",
"identify",
"defects",
"in",
"the",
"samples",
"under",
"infrared",
"emissions,",
"the",
"timing",
"series",
"were",
"analyzed",
"through",
"graphics",
"and",
"statistic",
"methods.",
"The",
"selection",
"of",
"this",
"technique",
"demonstrates",
"the",
"potential",
"for",
"infrared",
"emission",
"as",
"a",
"welding",
"monitoring",
"parameter",
"sensor.",
"Keywords:",
"Gas",
"Tungsten",
"Arc",
"Welding;",
"welding",
"monitoring;",
"infrared;",
"statistic",
"methods",
"1.",
"Introduction",
"Technology",
"advancements",
"seek",
"to",
"meet",
"the",
"demands",
"for",
"quality",
"and",
"performance",
"through",
"product",
"improvements",
"and",
"cost",
"reductions.",
"An",
"important",
"area",
"of",
"research",
"is",
"the",
"optimization",
"of",
"applications"
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] | [
"Avila",
"et",
"al.",
"Parasites",
"&",
"Vectors",
"2011,",
"4:39",
"http://www.parasitesandvectors.com/content/4/1/39",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"Gene",
"discovery",
"in",
"Triatoma",
"infestans",
"María",
"L",
"Avila1,",
"Valeria",
"Tekiel1,",
"Georgina",
"Moretti1,",
"Soledad",
"Nicosia1,",
"Jacqueline",
"Bua2,",
"Estela",
"M",
"Lammel",
"3",
",",
"María",
"M",
"Stroppa4,",
"Nelia",
"M",
"Gerez",
"de",
"Burgos4,",
"Daniel",
"O",
"Sánchez1*",
"Abstract",
"Background:",
"Triatoma",
"infestans",
"is",
"the",
"most",
"relevant",
"vector",
"of",
"Chagas",
"disease",
"in",
"the",
"southern",
"cone",
"of",
"South",
"America.",
"Since",
"its",
"genome",
"has",
"not",
"yet",
"been",
"studied,",
"sequencing",
"of",
"Expressed",
"Sequence",
"Tags",
"(ESTs)",
"is",
"one",
"of",
"the",
"most",
"powerful",
"tools",
"for",
"efficiently",
"identifying",
"large",
"numbers",
"of",
"expressed",
"genes",
"in",
"this",
"insect",
"vector.",
"Results:",
"In",
"this",
"work,",
"we",
"generated",
"826",
"ESTs,",
"resulting",
"in",
"an",
"increase",
"of",
"47%",
"in",
"the",
"number",
"of",
"ESTs",
"available",
"for",
"T.",
"infestans.",
"These",
"ESTs",
"were",
"assembled",
"in",
"471",
"unique",
"sequences,",
"151",
"of",
"which",
"represent",
"136",
"new",
"genes",
"for",
"the",
"Reduviidae",
"family.",
"Conclusions:",
"Among",
"the",
"putative",
"new",
"genes",
"for",
"the",
"Reduviidae",
"family,",
"we",
"identified",
"and",
"described",
"an",
"interesting",
"subset",
"of",
"genes",
"involved",
"in",
"development",
"and",
"reproduction,",
"which",
"constitute",
"potential",
"targets",
"for",
"insecticide",
"development.",
"Background",
"Chagas",
"disease",
"affects",
"8",
"million",
"people,",
"and",
"~28",
"million,",
"in",
"21",
"endemic",
"countries",
"of",
"Latin",
"America,",
"are",
"at",
"risk",
"of",
"infection",
"[1].",
"The",
"etiologic",
"agent",
"of",
"Chagas",
"disease",
"is",
"the",
"parasite",
"Trypanosoma",
"cruzi,",
"which",
"is",
"mainly",
"trans-",
"mitted",
"through",
"blood-sucking",
"insect",
"vectors",
"of",
"the",
"Tria-",
"tominae",
"subfamily,",
"being",
"Triatoma",
"infestans,",
"Rhodnius",
"prolixus,",
"and",
"Triatoma",
"dimidiata",
"the",
"most",
"epidemiolo-",
"gically",
"important",
"vectors.",
"T.",
"infestans",
"is",
"currently",
"the",
"main",
"vector",
"in",
"the",
"southern",
"part",
"of",
"South",
"America",
"including",
"regions",
"of",
"northern",
"Argentina,",
"Bolivia,",
"Para-",
"guay,",
"and",
"southern",
"Peru.",
"R.",
"prolixus,",
"on",
"the",
"other",
"hand,",
"is",
"distributed",
"in",
"northern",
"South",
"America",
"(mainly",
"in",
"Colombia",
"and",
"Venezuela)",
"and",
"has",
"few",
"foci",
"in",
"Central",
"America.",
"T.",
"dimidiata,",
"is",
"present",
"in",
"Central",
"America",
"and",
"Mexico,",
"and",
"also",
"has",
"limited",
"foci",
"in",
"northern",
"South",
"America",
"[2-4].",
"Due",
"to",
"population",
"migration",
"from",
"Latin",
"America,",
"Chagas",
"disease",
"is",
"becoming",
"an",
"important",
"health",
"issue",
"in",
"North",
"America,",
"Europe",
"and",
"in",
"the",
"western",
"Pacific",
"region",
"[5].",
"Currently,",
"there",
"are",
">390,000",
"individuals",
"infected",
"with",
"T.",
"cruzi",
"in",
"non-endemic",
"regions",
"and,",
"accordingly,",
"serological",
"monitoring",
"of",
"blood",
"banks",
"and",
"*",
"Correspondence:",
"dsanchez@unsam.edu.ar",
"1Instituto",
"de",
"Investigaciones",
"Biotecnológicas,",
"Universidad",
"Nacional",
"de",
"San",
"Martín",
"-",
"CONICET.",
"Av.",
"Gral",
"Paz",
"5445,",
"Edificio",
"24,",
"B1650KNA,",
"San",
"Martín,",
"Provincia",
"de",
"Buenos",
"Aires,",
"Argentina",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"organ",
"donors",
"as",
"well",
"as",
"additional",
"controls",
"to",
"detect",
"vertical",
"transmission",
"in",
"newborns",
"must",
"be",
"implemented",
"to",
"prevent",
"the",
"spread",
"of",
"the",
"disease.",
"As",
"there",
"are",
"currently",
"no",
"vaccines",
"available",
"against",
"T.",
"cruzi",
"and",
"effective",
"treatments",
"are",
"limited",
"to",
"che-",
"motherapies",
"that",
"exhibit",
"high",
"toxicity,",
"large",
"efforts",
"are",
"being",
"made",
"to",
"implement",
"prevention",
"strategies,",
"such",
"as",
"domestic",
"vector",
"control",
"and",
"improvement",
"of",
"blood",
"bank",
"surveillance",
"[6].",
"Currently,",
"the",
"main",
"method",
"of",
"vector",
"control",
"is",
"spraying",
"houses",
"with",
"residual",
"insecti-",
"cides.",
"However,",
"the",
"occurrence",
"of",
"T.",
"infestans",
"popula-",
"tions",
"resistant",
"to",
"pyrethroid",
"compounds",
"in",
"the",
"north",
"of",
"Argentina",
"and",
"Bolivia",
"[7,8]",
"poses",
"the",
"alternative",
"of",
"orga-",
"nophosphate",
"insecticides.",
"Unfortunately,",
"these",
"insecti-",
"cides,",
"although",
"effective,",
"are",
"very",
"toxic",
"and",
"less",
"accepted",
"by",
"the",
"community",
"due",
"to",
"their",
"unpleasant",
"odor",
"[9].",
"Novel",
"methods",
"of",
"control",
"will",
"undoubtedly",
"require",
"detailed",
"understanding",
"of",
"the",
"molecular",
"biology",
"of",
"Chagas",
"disease",
"vectors.",
"This",
"will",
"provide",
"unique",
"oppor-",
"tunities",
"to",
"develop",
"new",
"vector",
"control",
"tools",
"such",
"as",
"the",
"use",
"of",
"transgenic",
"vectors",
"refractory",
"to",
"pathogens.",
"The",
"identification",
"of",
"trait",
"genes",
"linked",
"to",
"transposable",
"ele-",
"ments",
"could",
"drive",
"those",
"alleles",
"into",
"wild",
"populations",
"and",
"interrupt",
"disease",
"transmission",
"in",
"the",
"long-term",
"[10,11].",
"Although",
"in",
"the",
"short",
"run,",
"this",
"strategy",
"is",
"not",
"feasible",
"for",
"Chagas",
"disease",
"control",
"due",
"to",
"the",
"need",
"of",
"an",
"intense",
"laboratory",
"and",
"field",
"research,",
"it",
"is,",
"nevertheless,",
"an",
"approach",
"that",
"deserves",
"to",
"be",
"explored.",
"©",
"2011",
"Avila",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
] | [
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] | [
"Souza",
"et",
"al.",
"BMC",
"Infectious",
"Diseases",
"2010,",
"10:209",
"http://www.biomedcentral.com/1471-2334/10/209",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Resistance",
"of",
"Leishmania",
"(Viannia)",
"braziliensis",
"to",
"nitric",
"oxide:",
"correlation",
"with",
"antimony",
"therapy",
"and",
"TNF-a",
"production",
"Anselmo",
"S",
"Souza1†,",
"Angela",
"Giudice1†,",
"Júlia",
"MB",
"Pereira1,",
"Luís",
"H",
"Guimarães1,",
"Amelia",
"R",
"de",
"Jesus2,",
"Tatiana",
"R",
"de",
"Moura2,",
"Mary",
"E",
"Wilson3†,",
"Edgar",
"M",
"Carvalho1,",
"Roque",
"P",
"Almeida2*†",
"Abstract",
"Background:",
"Nitric",
"oxide",
"(NO)",
"produced",
"in",
"macrophages",
"plays",
"a",
"pivotal",
"role",
"as",
"a",
"leishmanicidal",
"agent.",
"A",
"previous",
"study",
"has",
"demonstrated",
"that",
"20%",
"of",
"the",
"L.",
"(V.)",
"braziliensis",
"isolated",
"from",
"initial",
"cutaneous",
"lesions",
"of",
"patients",
"from",
"the",
"endemic",
"area",
"of",
"Corte",
"de",
"Pedra,",
"Bahia,",
"Brazil,",
"were",
"NO",
"resistant.",
"Additionally,",
"5",
"to",
"11%",
"of",
"the",
"patients",
"did",
"not",
"respond",
"to",
"three",
"or",
"more",
"antimony",
"treatments”",
"(refractory",
"patients).",
"The",
"aim",
"of",
"this",
"study",
"is",
"to",
"investigate",
"if",
"there",
"is",
"an",
"association",
"between",
"the",
"resistance",
"of",
"L.",
"(V.)",
"braziliensis",
"to",
"NO",
"and",
"nonresponsiveness",
"to",
"antimony",
"therapy",
"and",
"cytokine",
"production.",
"Methods:",
"We",
"evaluated",
"the",
"in",
"vitro",
"toxicity",
"of",
"NO",
"against",
"the",
"promastigotes",
"stages",
"of",
"L.",
"(V.)",
"braziliensis",
"isolated",
"from",
"responsive",
"and",
"refractory",
"patients,",
"and",
"the",
"infectivity",
"of",
"the",
"amastigote",
"forms",
"of",
"these",
"isolates",
"against",
"human",
"macrophages.",
"The",
"supernatants",
"from",
"Leishmania",
"infected",
"macrophage",
"were",
"used",
"to",
"measure",
"TNF-a",
"and",
"IL-10",
"levels.",
"Results:",
"Using",
"NaNO2",
"(pH",
"5.0)",
"as",
"the",
"NO",
"source,",
"L.",
"(V.)",
"braziliensis",
"isolated",
"from",
"refractory",
"patients",
"were",
"more",
"NO",
"resistant",
"(IC50",
"=",
"5.8",
"±",
"4.8)",
"than",
"L.",
"(V.)",
"braziliensis",
"isolated",
"from",
"responsive",
"patients",
"(IC50",
"=",
"2.0",
"±",
"1.4).",
"Four",
"isolates",
"were",
"selected",
"to",
"infect",
"human",
"macrophages:",
"NO-susceptible",
"and",
"NO-resistant",
"L.",
"(V.)",
"braziliensis",
"isolated",
"from",
"responsive",
"and",
"refractory",
"patients.",
"NO-resistant",
"L.",
"(V.)",
"braziliensis",
"isolated",
"from",
"refractory",
"patients",
"infected",
"more",
"macrophages",
"stimulated",
"with",
"LPS",
"and",
"IFN-g",
"at",
"120",
"hours",
"than",
"NO-susceptible",
"L.",
"(V.)",
"braziliensis",
"isolated",
"from",
"refractory",
"patients.",
"Also,",
"lower",
"levels",
"of",
"TNF-a",
"were",
"detected",
"in",
"supernatants",
"of",
"macrophages",
"infected",
"with",
"NO-resistant",
"L.",
"(V.)",
"braziliensis",
"as",
"compared",
"to",
"macrophages",
"infected",
"with",
"NO-susceptible",
"L.",
"(V.)",
"braziliensis",
"(p",
"<",
"0.05",
"at",
"2,",
"24",
"and",
"120",
"hours),",
"while",
"no",
"differences",
"were",
"detected",
"in",
"IL-10",
"levels.",
"Conclusion:",
"These",
"data",
"suggest",
"that",
"NO",
"resistance",
"could",
"be",
"related",
"to",
"the",
"nonresponsiveness",
"to",
"antimony",
"therapy",
"seen",
"in",
"American",
"Tegumentary",
"Leishmaniasis.",
"Background",
"Leishmaniasis",
"is",
"a",
"parasitic",
"disease",
"considered",
"a",
"major",
"public",
"health",
"problem",
"affecting",
"88",
"countries",
"throughout",
"Europe,",
"Asia,",
"Africa",
"and",
"America,",
"with",
"an",
"annual",
"incidence",
"of",
"1",
"to",
"1.5",
"million",
"of",
"cases,",
"and",
"350",
"million",
"exposures",
"according",
"to",
"the",
"World",
"Health",
"Organization.",
"Specifically",
"in",
"Brazil,",
"the",
"Ministry",
"of",
"Health",
"reports",
"an",
"annual",
"incidence",
"of",
"around",
"28.000",
"cases.",
"American",
"Tegu-",
"mentary",
"Leishmaniasis",
"(ATL)",
"presents",
"with",
"a",
"spectrum",
"of",
"*",
"Correspondence:",
"roquepacheco@uol.com.br",
"†",
"Contributed",
"equally",
"2Universidade",
"Federal",
"de",
"Sergipe,",
"Aracaju,",
"Sergipe,",
"Brazil",
"clinical",
"manifestations,",
"including",
"cutaneous",
"(CL),",
"mucosal",
"(ML),",
"disseminated",
"(DL)",
"and",
"diffuse",
"cutaneous",
"leishmania-",
"sis",
"(DCL).",
"The",
"major",
"species",
"that",
"cause",
"ATL",
"in",
"the",
"New",
"World",
"are",
"L.",
"(Viannia)",
"braziliensis,",
"L.",
"(V.)",
"guyanensis,",
"L.",
"(Leishmania)",
"amazonensis",
"and",
"L.",
"(L.)",
"mexicana",
"[1].",
"In",
"the",
"Northeast",
"region",
"of",
"Brazil,",
"CL,",
"ML",
"and",
"DL",
"are",
"caused",
"most",
"often",
"by",
"L.",
"(V.)",
"braziliensis;",
"and",
"DCL",
"is",
"most",
"often",
"caused",
"by",
"L.",
"amazonensis",
"in",
"the",
"New",
"World",
"[2].",
"The",
"typical",
"clinical",
"manifestation",
"of",
"cutaneous",
"leishmaniasis",
"(CL)",
"is",
"a",
"single",
"ulcerated",
"lesion",
"with",
"elevated",
"borders,",
"frequently",
"located",
"on",
"the",
"inferior",
"limbs",
"[3].",
"ML",
"is",
"a",
"destructive",
"disease",
"that",
"predominantly",
"affects",
"the",
"©",
"2010",
"Souza",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"NAD(P)H:Quinone",
"Oxidoreductase",
"1",
"(NQO1)",
"Localizes",
"to",
"the",
"Mitotic",
"Spindle",
"in",
"Human",
"Cells",
"David",
"Siegel*,",
"Jadwiga",
"K.",
"Kepa,",
"David",
"Ross",
"Department",
"of",
"Pharmaceutical",
"Sciences,",
"Skaggs",
"School",
"of",
"Pharmacy",
"and",
"Pharmaceutical",
"Sciences,",
"University",
"of",
"Colorado",
"Anschutz",
"Medical",
"Campus,",
"Aurora,",
"Colorado,",
"United",
"States",
"of",
"America",
"Abstract",
"NAD(P)H:quinone",
"oxidoreductase",
"1",
"(NQO1)",
"is",
"an",
"FAD",
"containing",
"quinone",
"reductase",
"that",
"catalyzes",
"the",
"2-electron",
"reduction",
"of",
"a",
"broad",
"range",
"of",
"quinones.",
"The",
"2-electron",
"reduction",
"of",
"quinones",
"to",
"hydroquinones",
"by",
"NQO1",
"is",
"believed",
"to",
"be",
"a",
"detoxification",
"process",
"since",
"this",
"reaction",
"bypasses",
"the",
"formation",
"of",
"the",
"highly",
"reactive",
"semiquinone.",
"NQO1",
"is",
"expressed",
"at",
"high",
"levels",
"in",
"normal",
"epithelium,",
"endothelium",
"and",
"adipocytes",
"as",
"well",
"as",
"in",
"many",
"human",
"solid",
"tumors.",
"In",
"addition",
"to",
"its",
"function",
"as",
"a",
"quinone",
"reductase",
"NQO1",
"has",
"been",
"shown",
"to",
"reduce",
"superoxide",
"and",
"regulate",
"the",
"20",
"S",
"proteasomal",
"degradation",
"of",
"proteins",
"including",
"p53.",
"Biochemical",
"studies",
"have",
"indicated",
"that",
"NQO1",
"is",
"primarily",
"located",
"in",
"the",
"cytosol,",
"however,",
"lower",
"levels",
"of",
"NQO1",
"have",
"also",
"been",
"found",
"in",
"the",
"nucleus.",
"In",
"these",
"studies",
"we",
"demonstrate",
"using",
"immunocytochemistry",
"and",
"confocal",
"imaging",
"that",
"NQO1",
"was",
"found",
"associated",
"with",
"mitotic",
"spindles",
"in",
"cells",
"undergoing",
"division.",
"The",
"association",
"of",
"NQO1",
"with",
"the",
"mitotic",
"spindles",
"was",
"observed",
"in",
"many",
"different",
"human",
"cell",
"lines",
"including",
"nontransformed",
"cells",
"(astrocytes,",
"HUVEC)",
"immortalized",
"cell",
"lines",
"(HBMEC,",
"16HBE)",
"and",
"cancer",
"(pancreatic",
"adenocarcinoma,",
"BXPC3).",
"Confocal",
"analysis",
"of",
"double-labeling",
"experiments",
"demonstrated",
"co-localization",
"of",
"NQO1with",
"alpha-tubulin",
"in",
"mitotic",
"spindles.",
"In",
"studies",
"with",
"BxPc-3",
"human",
"pancreatic",
"cancer",
"cells",
"the",
"association",
"of",
"NQO1",
"with",
"mitotic",
"spindles",
"appeared",
"to",
"be",
"unchanged",
"in",
"the",
"presence",
"of",
"NQO1",
"inhibitors",
"ES936",
"or",
"dicoumarol",
"suggesting",
"that",
"NQO1",
"can",
"associate",
"with",
"the",
"mitotic",
"spindle",
"and",
"still",
"retain",
"catalytic",
"activity.",
"Analysis",
"of",
"archival",
"human",
"squamous",
"lung",
"carcinoma",
"tissue",
"immunostained",
"for",
"NQO1",
"demonstrated",
"positive",
"staining",
"for",
"NQO1",
"in",
"the",
"spindles",
"of",
"mitotic",
"cells.",
"The",
"purpose",
"of",
"this",
"study",
"is",
"to",
"demonstrate",
"for",
"the",
"first",
"time",
"the",
"association",
"of",
"the",
"quinone",
"reductase",
"NQO1",
"with",
"the",
"mitotic",
"spindle",
"in",
"human",
"cells.",
"Citation:",
"Siegel",
"D,",
"Kepa",
"JK,",
"Ross",
"D",
"(2012)",
"NAD(P)H:Quinone",
"Oxidoreductase",
"1",
"(NQO1)",
"Localizes",
"to",
"the",
"Mitotic",
"Spindle",
"in",
"Human",
"Cells.",
"PLoS",
"ONE",
"7(9):",
"e44861.",
"doi:10.1371/journal.pone.0044861",
"Editor:",
"Stefan",
"Strack,",
"University",
"of",
"Iowa,",
"United",
"States",
"of",
"America",
"Received",
"April",
"12,",
"2012;",
"Accepted",
"August",
"8,",
"2012;",
"Published",
"September",
"11,",
"2012",
"Copyright:",
"2012",
"Siegel",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"supported",
"by",
"National",
"Institutes",
"of",
"Health",
"grant",
"R01ES108943.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"DS,",
"DR",
"and",
"the",
"University",
"of",
"Colorado",
"are",
"the",
"licensor",
"for",
"the",
"anti-NQO1",
"monoclonal",
"antibody",
"(clone",
"A180).",
"This",
"does",
"not",
"alter",
"the",
"authors’",
"adherence",
"to",
"all",
"the",
"PLOS",
"ONE",
"policies",
"on",
"sharing",
"data",
"and",
"materials.",
"*",
"E-mail:",
"david.siegel@ucdenver.edu",
"Introduction",
"NAD(P)H:quinone",
"oxidoreductase",
"1",
"(NQO1,",
"DT-diaphorase,",
"EC",
"1.6.99.2)",
"is",
"a",
"homodimeric",
"flavoprotein",
"that",
"utilizes",
"either",
"NADH",
"or",
"NADPH",
"and",
"catalyzes",
"the",
"2-electron",
"reduction",
"of",
"a",
"broad",
"range",
"of",
"substrates",
"most",
"notably",
"quinones",
"[1].",
"The",
"two-",
"electron",
"reduction",
"of",
"quinones",
"to",
"hydroquinones",
"by",
"NQO1",
"is",
"believed",
"to",
"be",
"primarily",
"a",
"detoxification",
"reaction",
"since",
"it",
"bypasses",
"the",
"formation",
"of",
"the",
"highly",
"reactive",
"semiquinone",
"[1].",
"In",
"many",
"cases,",
"however,",
"the",
"reduction",
"of",
"quinones",
"by",
"NQO1",
"results",
"in",
"the",
"formation",
"cytotoxic",
"hydroquinones",
"and",
"the",
"bioactivation",
"of",
"quinone",
"prodrugs",
"by",
"NQO1",
"has",
"been",
"utilized",
"as",
"a",
"strategy",
"to",
"target",
"NQO1-rich",
"cancer",
"cells",
"[2].",
"In",
"normal",
"tissues,",
"NQO1",
"is",
"expressed",
"at",
"relatively",
"high",
"levels",
"in",
"epithelial",
"tissues,",
"vascular",
"endothelium",
"and",
"adipocytes",
"while",
"in",
"cancer,",
"NQO1",
"is",
"expressed",
"at",
"high",
"levels",
"in",
"many",
"solid",
"tumors",
"including",
"lung",
"(NSCLC),",
"breast",
"and",
"pancreatic",
"[3,4].",
"In",
"humans,",
"the",
"NQO1*2",
"polymorphism",
"plays",
"a",
"major",
"role",
"in",
"governing",
"basal",
"protein",
"levels",
"of",
"NQO1",
"[5].",
"The",
"NQO1*2",
"polymorphism",
"results",
"in",
"a",
"proline",
"to",
"serine",
"amino",
"acid",
"substitution",
"at",
"position",
"187",
"in",
"NQO1",
"and",
"this",
"mutant",
"protein",
"undergoes",
"rapid",
"polyubiquitina-",
"tion",
"by",
"the",
"E3",
"ubiquitin",
"ligase",
"STUB1/CHIP",
"with",
"subsequent",
"proteasomal",
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"PLOS",
"ONE",
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"www.plosone.org",
"1",
"September",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"9",
"|",
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] | [
"Irreversible",
"EGFR",
"Inhibitor",
"EKB-569",
"Targets",
"Low-LET",
"c-",
"Radiation-Triggered",
"Rel",
"Orchestration",
"and",
"Potentiates",
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"Death",
"in",
"Squamous",
"Cell",
"Carcinoma",
"4",
"1",
"Natarajan",
"Aravindan2,4,5,",
"Charles",
"R.",
"Thomas",
"Jr3.",
",",
"Sheeja",
"Aravindan",
",",
"Aswathi",
"S.",
"Mohan",
",",
"Jamunarani",
"Veeraraghavan2,5,",
"Mohan",
"Natarajan",
"1",
"*",
"1",
"Department",
"of",
"Otolaryngology,",
"Head",
"and",
"Neck",
"Surgery,",
"University",
"of",
"Texas",
"Health",
"Science",
"Center",
"at",
"San",
"Antonio,",
"San",
"Antonio,",
"Texas,",
"United",
"States",
"of",
"America,",
"2",
"Department",
"of",
"Radiation",
"Oncology,",
"The",
"University",
"of",
"Oklahoma",
"Health",
"Sciences",
"Center,",
"Oklahoma",
"City,",
"Oklahoma,",
"United",
"States",
"of",
"America,",
"3",
"Department",
"of",
"Radiation",
"Medicine,",
"Oregon",
"Health",
"and",
"Science",
"University",
"Knight",
"Cancer",
"Institute,",
"Portland,",
"Oregon,",
"United",
"States",
"of",
"America,",
"4",
"Department",
"of",
"Pathology,",
"The",
"University",
"of",
"Oklahoma",
"Health",
"Sciences",
"Center,",
"Oklahoma",
"City,",
"Oklahoma,",
"United",
"States",
"of",
"America,",
"5",
"Department",
"of",
"Pediatrics,",
"The",
"University",
"of",
"Oklahoma",
"Health",
"Sciences",
"Center,",
"Oklahoma",
"City,",
"Oklahoma,",
"United",
"States",
"of",
"America",
"Abstract",
"EKB-569",
"(Pelitinib),",
"an",
"irreversible",
"EGFR",
"tyrosine",
"kinase",
"inhibitor",
"has",
"shown",
"potential",
"therapeutic",
"efficiency",
"in",
"solid",
"tumors.",
"However,",
"cell-killing",
"potential",
"in",
"combination",
"with",
"radiotherapy",
"and",
"its",
"underlying",
"molecular",
"orchestration",
"remain",
"to",
"be",
"explored.",
"The",
"objective",
"of",
"this",
"study",
"was",
"to",
"determine",
"the",
"effect",
"of",
"EKB-569",
"on",
"ionizing",
"radiation",
"(IR)-",
"associated",
"NFkB-dependent",
"cell",
"death.",
"SCC-4",
"and",
"SCC-9",
"cells",
"exposed",
"to",
"IR",
"(2Gy)",
"with",
"and",
"without",
"EKB-569",
"treatment",
"were",
"analyzed",
"for",
"transactivation",
"of",
"88",
"NFkB",
"pathway",
"molecules,",
"NFkB",
"DNA-binding",
"activity,",
"translation",
"of",
"the",
"NFkB",
"downstream",
"mediators,",
"Birc1,",
"2",
"and",
"5,",
"cell",
"viability,",
"metabolic",
"activity",
"and",
"apoptosis.",
"Selective",
"targeting",
"of",
"IR-induced",
"NFkB",
"by",
"EKB-569",
"and",
"its",
"influence",
"on",
"cell-fate",
"were",
"assessed",
"by",
"overexpressing",
"(p50/p65)",
"and",
"silencing",
"(DIkBa)",
"NFkB.",
"QPCR",
"profiling",
"after",
"IR",
"exposure",
"revealed",
"a",
"significant",
"induction",
"of",
"74",
"NFkB",
"signal",
"transduction",
"molecules.",
"Of",
"those,",
"72",
"were",
"suppressed",
"with",
"EKB-569.",
"EMSA",
"revealed",
"a",
"dose",
"dependent",
"inhibition",
"of",
"NFkB",
"by",
"EKB-569.",
"More",
"importantly,",
"EKB-",
"569",
"inhibited",
"IR-induced",
"NFkB",
"in",
"a",
"dose-dependent",
"manner,",
"and",
"this",
"inhibition",
"was",
"sustained",
"up",
"to",
"at",
"least",
"72",
"h.",
"Immunoblotting",
"revealed",
"a",
"significant",
"suppression",
"of",
"IR-induced",
"Birc1,",
"2",
"and",
"5",
"by",
"EKB-569.",
"We",
"observed",
"a",
"dose-",
"dependent",
"inhibition",
"of",
"cell",
"viability,",
"metabolic",
"activity",
"and",
"apoptosis",
"with",
"EKB-569.",
"EKB-569",
"significantly",
"enhanced",
"IR-",
"induced",
"cell",
"death",
"and",
"apoptosis.",
"Blocking",
"NFkB",
"improved",
"IR-induced",
"cell",
"death.",
"Conversely,",
"NFkB",
"overexpression",
"negates",
"EKB-569",
"-induced",
"cell-killing.",
"Together,",
"these",
"pre-clinical",
"data",
"suggest",
"that",
"EKB-569",
"is",
"a",
"radiosensitizer",
"of",
"squamous",
"cell",
"carcinoma",
"and",
"may",
"mechanistically",
"involve",
"selective",
"targeting",
"of",
"IR-induced",
"NFkB-dependent",
"survival",
"signaling.",
"Further",
"pre-clinical",
"in-vivo",
"studies",
"are",
"warranted.",
"Citation:",
"Aravindan",
"N,",
"Thomas",
"CR",
"Jr,",
"Aravindan",
"S,",
"Mohan",
"AS,",
"Veeraraghavan",
"J,",
"et",
"al.",
"(2011)",
"Irreversible",
"EGFR",
"Inhibitor",
"EKB-569",
"Targets",
"Low-LET",
"c-Radiation-",
"Triggered",
"Rel",
"Orchestration",
"and",
"Potentiates",
"Cell",
"Death",
"in",
"Squamous",
"Cell",
"Carcinoma.",
"PLoS",
"ONE",
"6(12):",
"e29705.",
"doi:10.1371/journal.pone.0029705",
"Editor:",
"Christina",
"Lynn",
"Addison,",
"Ottawa",
"Hospital",
"Research",
"Institute,",
"Canada",
"Received",
"August",
"8,",
"2011;",
"Accepted",
"December",
"1,",
"2011;",
"Published",
"December",
"29,",
"2011",
"Copyright:",
"2011",
"Aravindan",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"supported,",
"in",
"whole",
"or",
"in",
"part,",
"by",
"National",
"Institutes",
"of",
"Health",
"Grant",
"R01",
"CA112175",
"(to",
"M.N.)",
"and",
"funds",
"from",
"the",
"Office",
"of",
"Science",
"(Biological",
"and",
"Environmental",
"Research),",
"United",
"States",
"Department",
"of",
"Energy",
"Grant",
"No.",
"DE-FG03-02ER63449",
"(to",
"M.N.).",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"natarajan@uthscsa.edu",
"Introduction",
"Head",
"and",
"neck",
"squamous",
"cell",
"carcinoma",
"(HNSCC)",
"is",
"the",
"sixth",
"most",
"common",
"cancer",
"in",
"the",
"world",
"and",
"accounts",
"for",
"90%",
"of",
"malignant",
"neoplasias",
"of",
"the",
"upper",
"respiratory",
"system",
"[1].",
"Despite",
"recent",
"advances",
"in",
"the",
"management",
"of",
"locally",
"advanced",
"HNSCC,",
"the",
"overall",
"survival",
"of",
"patients",
"has",
"improved",
"only",
"marginally",
"over",
"the",
"past",
"three",
"decades",
"[2]",
"mainly",
"due",
"to",
"development",
"of",
"therapy-",
"induced",
"chemo",
"and",
"radioresistance.",
"To",
"that",
"note,",
"in",
"recent",
"years",
"there",
"has",
"been",
"substantial",
"interest",
"in",
"developing",
"novel",
"therapeutic",
"agents",
"that",
"specifically",
"target",
"growth",
"factor",
"pathways",
"that,",
"are",
"dysregulated",
"in",
"tumor",
"cells.",
"Such",
"targeted",
"‘‘biological’’",
"agents",
"might",
"offer",
"alternative",
"treatment",
"options",
"for",
"patients",
"refractive",
"to",
"chemoradiotherapy.",
"Also,",
"with",
"unique",
"mechanisms",
"of",
"action",
"and",
"toxic",
"profiles",
"that",
"generally",
"do",
"not",
"overlap,",
"targeted",
"agents",
"and",
"standard",
"therapies",
"can",
"be",
"used",
"in",
"combinations",
"to",
"enhance",
"overall",
"treatment",
"efficacies",
"and",
"prevent",
"dose",
"reduction.",
"Because",
"many",
"solid",
"tumors,",
"including",
"HNSCC",
"have",
"hyper",
"activated",
"epidermal",
"growth",
"factor",
"receptor",
"(EGFR)",
"[3,4],",
"there",
"has",
"been",
"great",
"interest",
"in",
"the",
"use",
"of",
"EGFR",
"inhibitors",
"to",
"control",
"cancer",
"growth.",
"EGFR",
"is",
"a",
"170",
"kDa",
"glycoprotein",
"containing",
"an",
"extracellular",
"ligand",
"binding",
"domain,",
"and",
"an",
"intracellular",
"tyrosine",
"kinase",
"(TK)",
"domain",
"[5].",
"Upon",
"binding",
"to",
"ligands",
"such",
"as",
"EGF",
"or",
"TGFa,",
"EGFR",
"dimerizes",
"with",
"itself",
"(homodimers)",
"or",
"other",
"members",
"of",
"the",
"family",
"such",
"as",
"c-ErbB-2",
"(heterodimers).",
"Upon",
"dimerization,",
"TK",
"activation",
"increases",
"and",
"receptor",
"gets",
"autopho-",
"sphorylated",
"at",
"tyrosine",
"residues.",
"Phosphorylated",
"EGFR",
"(p-EGFR),",
"like",
"other",
"activated",
"receptor",
"TKs,",
"involved",
"in",
"phosphorylation",
"and",
"activation",
"of",
"several",
"signal",
"transduction",
"pathways",
"including",
"phosphoinositide",
"3-kinase-AKT,",
"extra",
"cellular",
"signal-regulated",
"kinase",
"1and",
"2",
"(ERK1/2),",
"and",
"the",
"signal",
"transducer",
"and",
"activator",
"of",
"transcription",
"3",
"(STAT3).",
"Activation",
"of",
"these",
"signal",
"transduction",
"pathways",
"subsequently",
"activate",
"key",
"transcriptional",
"machineries",
"such",
"as",
"NFkB",
"that",
"promote",
"tumor",
"growth",
"and",
"progression",
"by",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"December",
"2011",
"|",
"Volume",
"6",
"|",
"Issue",
"12",
"|",
"e29705"
] | [
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] | [
"Published",
"online",
"8",
"May",
"2008",
"Nucleic",
"Acids",
"Research,",
"2008,",
"Vol.",
"36,",
"Web",
"Server",
"issue",
"W327–W331",
"doi:10.1093/nar/gkn213",
"Microarray",
"retriever:",
"a",
"web-based",
"tool",
"for",
"searching",
"and",
"large",
"scale",
"retrieval",
"of",
"public",
"microarray",
"data",
"Alexander",
"E.",
"Ivliev1,2,",
"Peter",
"A.",
"C.",
"’t",
"Hoen1,*,",
"Michel",
"P.",
"Villerius",
"1",
",",
"Johan",
"T.",
"den",
"Dunnen1",
"and",
"Bernd",
"W.",
"Brandt3,4",
"1Center",
"for",
"Human",
"and",
"Clinical",
"Genetics,",
"Leiden",
"University",
"Medical",
"Center,",
"Leiden,",
"The",
"Netherlands,",
"2Department",
"of",
"Bioengineering",
"and",
"Bioinformatics,",
"Lomonosov",
"Moscow",
"State",
"University,",
"Moscow,",
"Russia,",
"3Centre",
"for",
"Integrative",
"Bioinformatics",
"(IBIVU),",
"VU",
"University",
"Amsterdam,",
"Amsterdam",
"and",
"4Department",
"of",
"Medical",
"Microbiology,",
"Leiden",
"University",
"Medical",
"Center,",
"Leiden,",
"The",
"Netherlands",
"Received",
"January",
"28,",
"2008;",
"Revised",
"April",
"2,",
"2008;",
"Accepted",
"April",
"9,",
"2008",
"ABSTRACT",
"The",
"major",
"public",
"microarray",
"repositories",
"Gene",
"Expression",
"Omnibus",
"and",
"ArrayExpress",
"are",
"growing",
"rapidly.",
"This",
"enables",
"meta-analysis",
"studies,",
"in",
"which",
"expression",
"data",
"from",
"multiple",
"individual",
"studies",
"are",
"combined.",
"To",
"facilitate",
"these",
"types",
"of",
"studies,",
"we",
"developed",
"Microarray",
"Retriever",
"for",
"searching",
"and",
"retrieval",
"of",
"data",
"from",
"GEO",
"and",
"ArrayExpress.",
"The",
"tool",
"allows",
"access",
"to",
"the",
"two",
"repositories",
"simulta-",
"neously,",
"to",
"search",
"in",
"the",
"repositories",
"using",
"complex",
"queries,",
"to",
"retrieve",
"microarray",
"data",
"for",
"published",
"articles",
"and",
"to",
"download",
"data",
"in",
"one",
"structured",
"archive.",
"The",
"tool",
"is",
"available",
"on",
"the",
"web",
"at:",
"http://",
"www.lgtc.nl/MaRe/",
"INTRODUCTION",
"Microarray",
"technology",
"is",
"now",
"routinely",
"used",
"for",
"genome-",
"wide",
"mRNA",
"expression",
"and",
"epigenetic",
"profiling.",
"As",
"a",
"consequence,",
"there",
"is",
"a",
"quickly",
"growing",
"amount",
"of",
"microarray",
"data",
"made",
"available",
"in",
"public",
"databases.",
"This",
"may",
"improve",
"the",
"interpretation",
"of",
"new",
"experimental",
"studies",
"through",
"comparison",
"with",
"data",
"already",
"publicly",
"available,",
"and",
"allow",
"for",
"large-scale",
"meta-analysis.",
"Use",
"of",
"data",
"in",
"the",
"repositories",
"gives",
"increased",
"statistical",
"power,",
"and",
"facilitates",
"confirmation",
"of",
"hypotheses",
"coming",
"from",
"one",
"study",
"with",
"data",
"from",
"another",
"study,",
"identification",
"of",
"artifacts",
"and",
"separation",
"of",
"primary",
"effects",
"from",
"secondary",
"(1).",
"For",
"example,",
"meta-analysis",
"of",
"microarray",
"data",
"was",
"useful",
"for",
"identification",
"of",
"common",
"transcriptional",
"profiles",
"of",
"neoplastic",
"transformation",
"and",
"progression",
"(2),",
"discovery",
"of",
"genes",
"disproportionately",
"overexpressed",
"in",
"specific",
"cancer",
"types",
"(3),",
"construction",
"of",
"robust",
"high-",
"resolution",
"gene",
"coexpression",
"networks",
"(4),",
"and",
"identifica-",
"tion",
"of",
"rhythmically",
"expressed",
"genes",
"in",
"Drosophila",
"(5).",
"There",
"are",
"many",
"hurdles",
"to",
"be",
"taken",
"when",
"integrating",
"data",
"from",
"different",
"studies,",
"such",
"as",
"the",
"necessity",
"to",
"map",
"the",
"probes",
"on",
"different",
"arrays",
"to",
"transcripts,",
"the",
"necessity",
"to",
"account",
"for",
"different",
"experimental",
"designs",
"and",
"analysis",
"algorithms,",
"and",
"to",
"retrieve",
"the",
"relevant",
"datasets",
"from",
"microarray",
"data",
"repositories.",
"The",
"latter",
"is",
"addressed",
"by",
"MaRe,",
"the",
"tool",
"that",
"we",
"developed.",
"Currently,",
"there",
"are",
"no",
"public",
"software",
"tools,",
"which",
"provide",
"combined",
"and",
"interactive",
"access",
"to",
"the",
"main",
"microarray",
"data",
"repositories.",
"Microarray",
"Retriever",
"(MaRe)",
"facilitates",
"meta-analysis",
"by",
"enabling",
"searching",
"and",
"batch",
"data",
"retrieval",
"from",
"the",
"two",
"major",
"public",
"microarray",
"repositories:",
"Gene",
"Expression",
"Omnibus",
"(GEO,",
"National",
"Center",
"for",
"Biotechnology",
"Information;",
"6,7)",
"and",
"ArrayExpress",
"(AE,",
"European",
"Bioinformatics",
"Institute;",
"8,9).",
"MaRe",
"allows",
"the",
"user",
"to",
"search",
"these",
"repositories",
"for",
"experiments",
"with",
"accession",
"numbers,",
"authors,",
"species,",
"date",
"of",
"submission,",
"array",
"platform",
"and",
"keyword",
"search",
"terms.",
"In",
"addition,",
"users",
"can",
"first",
"search",
"PubMed",
"on",
"authors",
"and",
"keywords",
"for",
"relevant",
"literature",
"and",
"then",
"search",
"GEO",
"and",
"ArrayExpress",
"for",
"experimental",
"data",
"associated",
"with",
"this",
"literature.",
"Alternatively,",
"a",
"custom",
"list",
"of",
"PubMed",
"IDs",
"can",
"be",
"uploaded",
"to",
"obtain",
"data",
"for",
"specific",
"articles",
"known",
"in",
"advance.",
"After",
"the",
"search",
"is",
"complete,",
"MaRe",
"enables",
"downloading",
"of",
"selected",
"results",
"in",
"one",
"step.",
"This",
"avoids",
"the",
"time-consuming",
"procedure",
"of",
"manual",
"and",
"sequential",
"downloading",
"from",
"the",
"web",
"or",
"ftp",
"sites",
"of",
"the",
"repositories.",
"All",
"retrieved",
"results",
"are",
"stored",
"using",
"a",
"clear",
"directory",
"structure.",
"METHODS",
"Implementation",
"MaRe",
"is",
"written",
"in",
"Perl.",
"Searches",
"in",
"GEO",
"are",
"performed",
"remotely",
"by",
"sending",
"queries",
"to",
"NCBI",
"E-Utilities",
"(10).",
"A",
"3-s",
"delay",
"between",
"E-Utilities",
"calls",
"is",
"implemented",
"according",
"to",
"the",
"NCBI",
"guidelines.",
"Search",
"in",
"ArrayExpress",
"is",
"done",
"locally",
"by",
"parsing",
"the",
"ArrayExpress",
"annotation",
"XML",
"file.",
"The",
"file",
"is",
"downloaded",
"from",
"the",
"EBI",
"during",
"*To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"Tel:",
"+31",
"71",
"5269421;",
"Fax:",
"+31",
"71",
"5268285;",
"Email:",
"p.a.c.hoen@lumc.nl",
"2008",
"The",
"Author(s)",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/",
"by-nc/2.0/uk/)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Degradation",
"of",
"PsbO",
"by",
"the",
"Deg",
"Protease",
"HhoA",
"Is",
"Thioredoxin",
"Dependent",
"Irma",
"N.",
"Roberts¤,",
"Xuan",
"Tam",
"Lam,",
"Helder",
"Miranda,",
"Thomas",
"Kieselbach,",
"Christiane",
"Funk*",
"Department",
"of",
"Chemistry",
"and",
"Umea˚",
"Plant",
"Science",
"Centre,",
"Umea˚",
"University,",
"Umea˚,",
"Sweden",
"Abstract",
"The",
"widely",
"distributed",
"members",
"of",
"the",
"Deg/HtrA",
"protease",
"family",
"play",
"an",
"important",
"role",
"in",
"the",
"proteolysis",
"of",
"misfolded",
"and",
"damaged",
"proteins.",
"Here",
"we",
"show",
"that",
"the",
"Deg",
"protease",
"rHhoA",
"is",
"able",
"to",
"degrade",
"PsbO,",
"the",
"extrinsic",
"protein",
"of",
"the",
"Photosystem",
"II",
"(PSII)",
"oxygen-evolving",
"complex",
"in",
"Synechocystis",
"sp.",
"PCC",
"6803",
"and",
"in",
"spinach.",
"PsbO",
"is",
"known",
"to",
"be",
"stable",
"in",
"its",
"oxidized",
"form,",
"but",
"after",
"reduction",
"by",
"thioredoxin",
"it",
"became",
"a",
"substrate",
"for",
"recombinant",
"HhoA",
"(rHhoA).",
"rHhoA",
"cleaved",
"reduced",
"eukaryotic",
"(specifically,",
"spinach)",
"PsbO",
"at",
"defined",
"sites",
"and",
"created",
"distinct",
"PsbO",
"fragments",
"that",
"were",
"not",
"further",
"degraded.",
"As",
"for",
"the",
"corresponding",
"prokaryotic",
"substrate",
"(reduced",
"PsbO",
"of",
"Synechocystis",
"sp.",
"PCC",
"6803),",
"no",
"PsbO",
"fragments",
"were",
"observed.",
"Assembly",
"to",
"PSII",
"protected",
"PsbO",
"from",
"degradation.",
"For",
"Synechocystis",
"sp.",
"PCC",
"6803,",
"our",
"results",
"show",
"that",
"HhoA,",
"HhoB,",
"and",
"HtrA",
"are",
"localized",
"in",
"the",
"periplasma",
"and/or",
"at",
"the",
"thylakoid",
"membrane.",
"In",
"agreement",
"with",
"the",
"idea",
"that",
"PsbO",
"could",
"be",
"a",
"physiological",
"substrate",
"for",
"Deg",
"proteases,",
"part",
"of",
"the",
"cellular",
"fraction",
"of",
"the",
"three",
"Deg",
"proteases",
"of",
"Synechocystis",
"sp.",
"PCC",
"6803",
"(HhoA,",
"HhoB,",
"and",
"HtrA)",
"was",
"detected",
"in",
"the",
"PSII-enriched",
"membrane",
"fraction.",
"Citation:",
"Roberts",
"IN,",
"Lam",
"XT,",
"Miranda",
"H,",
"Kieselbach",
"T,",
"Funk",
"C",
"(2012)",
"Degradation",
"of",
"PsbO",
"by",
"the",
"Deg",
"Protease",
"HhoA",
"Is",
"Thioredoxin",
"Dependent.",
"PLoS",
"ONE",
"7(9):",
"e45713.",
"doi:10.1371/journal.pone.0045713",
"Editor:",
"Frederik",
"Bo¨",
"rnke,",
"Friedrich-Alexander-University",
"Erlangen-Nurenberg,",
"Germany",
"Received",
"May",
"14,",
"2012;",
"Accepted",
"August",
"24,",
"2012;",
"Published",
"September",
"19,",
"2012",
"Copyright:",
"2012",
"Roberts",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"supported",
"by",
"grants",
"of",
"the",
"Swedish",
"Energy",
"Agency",
"(2009-000928",
"to",
"CF),",
"the",
"Royal",
"Swedish",
"Academy",
"of",
"Sciences",
"(312-3820-06",
"to",
"CF),",
"the",
"Lawsky",
"Foundation",
"(to",
"XTL)",
"and",
"Umea˚",
"University",
"(to",
"CF).",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"Christiane.Funk@chem.umu.se",
"€",
"Current",
"address:",
"Instituto",
"de",
"Investigaciones",
"en",
"Biociencias",
"Agr´ıcolas",
"y",
"Ambientales,",
"Universidad",
"de",
"Buenos",
"Aires,",
"Buenos",
"Aires,",
"Argentina",
"Introduction",
"Cells",
"have",
"evolved",
"an",
"extensive",
"system",
"of",
"molecular",
"chaperones,",
"folding",
"catalysts,",
"and",
"proteases;",
"that",
"control",
"protein",
"quality",
"and",
"prevent",
"protein",
"damage.",
"Biochemical",
"and",
"molecular",
"biological",
"studies",
"have",
"successfully",
"identified",
"many",
"plastidic",
"protease",
"families,",
"most",
"of",
"which",
"are",
"homologs",
"of",
"defined",
"bacterial",
"proteases.",
"Deg/HtrA",
"proteases",
"were",
"initially",
"identified",
"because",
"of",
"their",
"essential",
"role",
"in",
"the",
"degradation",
"of",
"abnormal",
"periplasmic",
"proteins",
"and",
"because",
"they",
"are",
"crucial",
"for",
"the",
"survival",
"of",
"E.",
"coli",
"at",
"high",
"temperatures",
"[1,2].",
"They",
"have",
"since",
"been",
"found",
"in",
"nearly",
"all",
"organisms;",
"including",
"Archae,",
"bacteria",
"and",
"eukaryotes.",
"Deg",
"proteases",
"are",
"ATP-independent",
"serine",
"endopeptidases,",
"containing",
"a",
"trypsin/chymotrypsin-like",
"protease",
"domain,",
"followed",
"by",
"zero",
"to",
"three",
"PDZ",
"or",
"PDZ-like",
"domains",
"[3,4]–PDZ",
"domains",
"being",
"those",
"that",
"mediate",
"complex",
"assembly,",
"substrate",
"binding,",
"and/or",
"regulation",
"of",
"proteolytic",
"activity",
"[5–7].",
"In",
"Arabidopsis",
"thaliana,",
"16",
"genes",
"coding",
"for",
"Deg-like",
"proteases",
"have",
"been",
"identified",
"and",
"at",
"least",
"seven",
"gene",
"products",
"have",
"been",
"predicted",
"to",
"be",
"located",
"in",
"chloroplasts",
"[8–10].",
"Based",
"on",
"biochemical",
"data,",
"five",
"Deg",
"proteases",
"have",
"been",
"shown",
"to",
"be",
"localized",
"in",
"the",
"chloroplast:",
"Deg1,",
"Deg5,",
"and",
"Deg8",
"are",
"located",
"in",
"the",
"thylakoid",
"lumen",
"[11,12],",
"and",
"Deg2",
"[13]",
"and",
"Deg7",
"[14]",
"are",
"peripherally",
"associated",
"with",
"the",
"stromal",
"side",
"of",
"the",
"thylakoid",
"membrane.",
"Degradation",
"of",
"the",
"Photosystem",
"II",
"(PSII)",
"reaction-center",
"protein",
"D1",
"under",
"photoinhibition",
"has",
"been",
"linked",
"to",
"the",
"lumen-located",
"Deg1",
"[15],",
"and",
"to",
"Deg5",
"and",
"Deg8",
"[16].",
"Additionally,",
"Deg1",
"seems",
"to",
"assist",
"the",
"assembly",
"of",
"PSII",
"via",
"interaction",
"with",
"the",
"PSII",
"reaction-center",
"D2",
"protein",
"[17].",
"It",
"has",
"been",
"shown",
"in",
"vitro",
"that",
"recombinant",
"Deg1",
"of",
"Arabidopsis",
"is",
"able",
"to",
"degrade",
"in",
"vitro–translated",
"plastocyanin",
"and",
"PsbO",
"[18].",
"So",
"far,",
"no",
"details",
"of",
"the",
"molecular",
"mechanism",
"of",
"Deg",
"function",
"are",
"known,",
"but",
"recently",
"it",
"has",
"been",
"suggested",
"that",
"some",
"Deg",
"proteases",
"might",
"be",
"redox",
"regulated.",
"In",
"one",
"study",
"it",
"was",
"found",
"that",
"the",
"proteolysis",
"of",
"casein",
"by",
"recombinant",
"Deg1",
"and",
"Deg2",
"of",
"Arabidopsis",
"was",
"dependent",
"on",
"the",
"redox",
"potential",
"of",
"the",
"surrounding",
"medium;",
"and",
"while",
"the",
"activity",
"of",
"Deg1",
"was",
"maximal",
"under",
"reducing",
"conditions,",
"the",
"opposite",
"was",
"true",
"for",
"Deg2",
"[19].",
"Deg1",
"and",
"Deg5",
"have",
"been",
"identified",
"as",
"potential",
"thioredoxin",
"targets",
"from",
"their",
"ability",
"to",
"form",
"mixed",
"disulfides",
"with",
"Trx",
"A",
"(thioredoxin",
"A)",
"of",
"the",
"unicellular",
"cyanobacterium",
"Synechocystis",
"sp.",
"PCC",
"6803",
"(hereafter:",
"Synechocystis",
"6803)",
"[20].",
"In",
"Synechocystis",
"6803,",
"three",
"Deg/HtrA",
"proteases",
"have",
"been",
"identified.",
"Owing",
"to",
"their",
"relationship",
"to",
"E.",
"coli",
"they",
"have",
"been",
"named",
"DegP/HtrA",
"(slr1204),",
"DegQ/HhoA",
"(sll1679),",
"and",
"DegS/",
"HhoB",
"(sll1427)",
"[21].",
"However,",
"they",
"are",
"more",
"closely",
"related",
"to",
"each",
"other",
"than",
"to",
"the",
"E.",
"coli",
"Deg",
"proteases",
"with",
"the",
"same",
"name",
"[8,9];",
"so",
"they",
"are",
"probably",
"not",
"orthologs",
"of",
"the",
"E.",
"coli",
"Deg",
"proteases.",
"HhoA,",
"HtrA,",
"and",
"HhoB",
"have",
"very",
"high",
"homology",
"with",
"the",
"lumen-located",
"plant",
"Deg",
"proteases",
"Deg1,",
"Deg5,",
"and",
"Deg8",
"[8].",
"Single-deletion",
"mutants",
"of",
"HtrA",
"[22]",
"and",
"HhoA",
"[23]",
"have",
"been",
"found",
"to",
"be",
"more",
"sensitive",
"than",
"wild",
"type,",
"towards",
"light",
"and",
"heat",
"stress,",
"respectively.",
"However,",
"these",
"results",
"were",
"controversial",
"[24,25].",
"While",
"a",
"triple",
"Deg-deletion",
"mutant",
"displayed",
"a",
"significant",
"phenotype",
"towards",
"light-",
"and",
"heat-stress",
"and",
"phototaxis,",
"none",
"of",
"the",
"double",
"mutants",
"did.",
"Therefore",
"it",
"was",
"concluded",
"that",
"the",
"Deg",
"PLOS",
"ONE",
"|",
"www.plosone.org",
"1",
"September",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"9",
"|",
"e45713"
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] | [
"Bigliardi",
"et",
"al.",
"Reproductive",
"Biology",
"and",
"Endocrinology",
"2011,",
"9:12",
"http://www.rbej.com/content/9/1/12",
"M",
"E",
"T",
"H",
"O",
"D",
"O",
"L",
"O",
"G",
"Y",
"Open",
"Access",
"Clinical,",
"genetic,",
"and",
"pathological",
"features",
"of",
"male",
"pseudohermaphroditism",
"in",
"dog",
"Enrico",
"Bigliardi1*,",
"Pietro",
"Parma3,",
"Paolo",
"Peressotti2,",
"Lisa",
"De",
"Lorenzi3,",
"Peter",
"Wohlsein4,",
"Benedetta",
"Passeri1,",
"Stefano",
"Jottini1,",
"Anna",
"Maria",
"Cantoni1",
"Abstract",
"Male",
"pseudohermaphroditism",
"is",
"a",
"sex",
"differentiation",
"disorder",
"in",
"which",
"the",
"gonads",
"are",
"testes",
"and",
"the",
"genital",
"ducts",
"are",
"incompletely",
"masculinized.",
"An",
"8",
"years",
"old",
"dog",
"with",
"normal",
"male",
"karyotype",
"was",
"referred",
"for",
"examination",
"of",
"external",
"genitalia",
"abnormalities.",
"Adjacent",
"to",
"the",
"vulva",
"subcutaneous",
"undescended",
"testes",
"were",
"observed.",
"The",
"histology",
"of",
"the",
"gonads",
"revealed",
"a",
"Leydig",
"and",
"Sertoli",
"cell",
"neoplasia.",
"The",
"contemporaneous",
"presence",
"of",
"testicular",
"tissue,",
"vulva,",
"male",
"karyotype",
"were",
"compatible",
"with",
"a",
"male",
"pseudohermaphrodite",
"(MPH)",
"condition.",
"Background",
"Mammalian",
"sexual",
"development",
"depends",
"on",
"the",
"suc-",
"cessful",
"completion",
"of",
"a",
"series",
"of",
"steps",
"under",
"genetic",
"and",
"hormonal",
"control.",
"This",
"process",
"requires",
"the",
"accomplish-",
"ment",
"of",
"three",
"steps:",
"chromosomal",
"sex,",
"gonadal",
"sex",
"and",
"phenotypic",
"sex.",
"At",
"fertilization",
"the",
"chromosomal",
"sex",
"is",
"determined",
"and",
"successively",
"XY",
"embryos",
"will",
"develop",
"testes",
"whereas",
"XX",
"ones",
"will",
"develop",
"ovaries",
"(gonadal",
"sex).",
"The",
"process",
"regulating",
"gonadal",
"development",
"is",
"under",
"genetic",
"control",
"and",
"is",
"referred",
"as",
"sex",
"determina-",
"tion.",
"Once",
"gonads",
"are",
"well",
"developed",
"and",
"fully",
"func-",
"tional,",
"hormones",
"play",
"a",
"key",
"role",
"in",
"phenotypic",
"sex",
"establishment.",
"In",
"male,",
"embryonic",
"testes",
"produce",
"two",
"key",
"hormones:",
"anti-Muellerian",
"hormone",
"(AMH;",
"also",
"called",
"mullerian-inhibiting",
"substance",
"[MIS]",
"or",
"factor",
"[MIF])",
"and",
"testosterone.",
"These",
"hormones,",
"together",
"with",
"testosterone",
"derivative",
"dehydrotestosterone,",
"are",
"respon-",
"sible",
"for",
"the",
"development",
"of",
"internal",
"and",
"external",
"male",
"phenotype.",
"In",
"the",
"XX",
"embryos",
"the",
"absence",
"of",
"these",
"hor-",
"mones",
"lead",
"to",
"female",
"phenotypic",
"sex",
"development",
"[1].",
"In",
"mammals,",
"the",
"SRY",
"gene",
"represents",
"the",
"key",
"gene",
"for",
"testis",
"differentiation",
"in",
"the",
"embryos.",
"There",
"is",
"substantial",
"evidence",
"that",
"this",
"gene",
"product",
"is",
"necessary",
"and",
"suffi-",
"cient",
"to",
"induce",
"the",
"undifferentiated",
"gonads",
"to",
"develop",
"as",
"testes",
"[2].",
"Moreover,",
"since",
"its",
"discovery",
"the",
"analyses",
"of",
"sex-reversal",
"subjects",
"leads",
"to",
"the",
"identification",
"of",
"sev-",
"eral",
"other",
"genes",
"involved",
"in",
"sex",
"determination",
"process,",
"*",
"Correspondence:",
"enrico.bigliardi@unipr.it",
"1Faculty",
"of",
"Veterinary",
"Medicine,",
"Department",
"of",
"Animal",
"Health,",
"Parma,",
"Italy",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"and",
"among",
"them",
"Sox9,",
"Wnt4",
"and",
"Rspo1",
"seems",
"to",
"play",
"a",
"major",
"role",
"[1].",
"Abnormal",
"sex",
"development",
"could",
"derive",
"from",
"sex",
"determination",
"errors",
"(i.e.",
"discordance",
"between",
"chromo-",
"somal",
"and",
"gonadic",
"sex)",
"or",
"from",
"discordance",
"from",
"gona-",
"dal",
"and",
"phenotypic",
"sex",
"(i.e.",
"errors",
"in",
"sex",
"differentiation",
"process).",
"In",
"the",
"first",
"case",
"the",
"affected",
"animals",
"are",
"referred",
"as",
"sex",
"reversal,",
"whereas",
"in",
"the",
"second",
"one",
"they",
"are",
"called",
"pseudohermaphrodites.",
"In",
"small",
"animals",
"there",
"are",
"four",
"principal",
"categories",
"of",
"intersex",
"individuals:",
"1)",
"True",
"hermaphroditism:",
"in",
"these",
"animals",
"there",
"are",
"both",
"gonadal",
"tissues,",
"but",
"the",
"secondary",
"sex",
"characteristics",
"and",
"external",
"genitalia",
"of",
"the",
"opposite",
"sex.",
"Testes",
"and",
"ovaries",
"are",
"present",
"in",
"various",
"combination.",
"A",
"testis",
"may",
"be",
"found",
"on",
"one",
"side",
"and",
"an",
"ovary",
"on",
"the",
"other",
"side,",
"an",
"ovotestis",
"or",
"bilateral",
"ovotestes",
"may",
"be",
"present",
"[3].",
"2)",
"Female",
"pseudohermaphroditism:",
"these",
"animals",
"have",
"XX",
"chromosomes",
"(without",
"sign",
"of",
"SRY",
"gene",
"presence)",
"and",
"ovaries",
"but",
"external",
"genitals",
"appear",
"masculine.",
"The",
"bitch",
"has",
"an",
"enlarged",
"clitoris",
"and",
"even",
"a",
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"The",
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"the",
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"during",
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"even",
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"the",
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"con-",
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"Normally",
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"and",
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"is",
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"[4].",
"3)",
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"pseudohermaphroditism:",
"the",
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"is",
"XY",
"with",
"an",
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"SRY",
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"The",
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"are",
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"but",
"the",
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"the",
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"the",
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"or",
"lateral",
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"A",
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"can",
"be",
"©",
"2011",
"Bigliardi",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Rotavirus",
"NSP1",
"Inhibits",
"NFkB",
"Activation",
"by",
"Inducing",
"Proteasome-Dependent",
"Degradation",
"of",
"b-TrCP:",
"A",
"Novel",
"Mechanism",
"of",
"IFN",
"Antagonism",
"Joel",
"W.",
"Graff.,",
"Khalil",
"Ettayebi.,",
"Michele",
"E.",
"Hardy*",
"Veterinary",
"Molecular",
"Biology,",
"Montana",
"State",
"University,",
"Bozeman,",
"Montana,",
"United",
"States",
"of",
"America",
"Abstract",
"Mechanisms",
"by",
"which",
"viruses",
"counter",
"innate",
"host",
"defense",
"responses",
"generally",
"involve",
"inhibition",
"of",
"one",
"or",
"more",
"components",
"of",
"the",
"interferon",
"(IFN)",
"system.",
"Multiple",
"steps",
"in",
"the",
"induction",
"and",
"amplification",
"of",
"IFN",
"signaling",
"are",
"targeted",
"for",
"inhibition",
"by",
"viral",
"proteins,",
"and",
"many",
"of",
"the",
"IFN",
"antagonists",
"have",
"direct",
"or",
"indirect",
"effects",
"on",
"activation",
"of",
"latent",
"cytoplasmic",
"transcription",
"factors.",
"Rotavirus",
"nonstructural",
"protein",
"NSP1",
"blocks",
"transcription",
"of",
"type",
"I",
"IFNa/b",
"by",
"inducing",
"proteasome-dependent",
"degradation",
"of",
"IFN-regulatory",
"factors",
"3",
"(IRF3),",
"IRF5,",
"and",
"IRF7.",
"In",
"this",
"study,",
"we",
"show",
"that",
"rotavirus",
"NSP1",
"also",
"inhibits",
"activation",
"of",
"NFkB",
"and",
"does",
"so",
"by",
"a",
"novel",
"mechanism.",
"Proteasome-mediated",
"degradation",
"of",
"inhibitor",
"of",
"kB",
"(IkBa)",
"is",
"required",
"for",
"NFkB",
"activation.",
"Phosphorylated",
"IkBa",
"is",
"a",
"substrate",
"for",
"polyubiquitination",
"by",
"a",
"multisubunit",
"E3",
"ubiquitin",
"ligase",
"complex,",
"Skp1/Cul1/F-box,",
"in",
"which",
"the",
"F-box",
"substrate",
"recognition",
"protein",
"is",
"b-transducin",
"repeat",
"containing",
"protein",
"(b-TrCP).",
"The",
"data",
"presented",
"show",
"that",
"phosphorylated",
"IkBa",
"is",
"stable",
"in",
"rotavirus-infected",
"cells",
"because",
"infection",
"induces",
"proteasome-dependent",
"degradation",
"of",
"b-TrCP.",
"NSP1",
"expressed",
"in",
"isolation",
"in",
"transiently",
"transfected",
"cells",
"is",
"sufficient",
"to",
"induce",
"this",
"effect.",
"Targeted",
"degradation",
"of",
"an",
"F-box",
"protein",
"of",
"an",
"E3",
"ligase",
"complex",
"with",
"a",
"prominent",
"role",
"in",
"modulation",
"of",
"innate",
"immune",
"signaling",
"and",
"cell",
"proliferation",
"pathways",
"is",
"a",
"unique",
"mechanism",
"of",
"IFN",
"antagonism",
"and",
"defines",
"a",
"second",
"strategy",
"of",
"immune",
"evasion",
"used",
"by",
"rotaviruses.",
"Citation:",
"Graff",
"JW,",
"Ettayebi",
"K,",
"Hardy",
"ME",
"(2009)",
"Rotavirus",
"NSP1",
"Inhibits",
"NFkB",
"Activation",
"by",
"Inducing",
"Proteasome-Dependent",
"Degradation",
"of",
"b-TrCP:",
"A",
"Novel",
"Mechanism",
"of",
"IFN",
"Antagonism.",
"PLoS",
"Pathog",
"5(1):",
"e1000280.",
"doi:10.1371/journal.ppat.1000280",
"Editor:",
"Barbara",
"Sherry,",
"North",
"Carolina",
"State",
"University,",
"United",
"States",
"of",
"America",
"Received",
"July",
"10,",
"2008;",
"Accepted",
"December",
"26,",
"2008;",
"Published",
"January",
"30,",
"2009",
"Copyright:",
"2009",
"Graff",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"study",
"has",
"been",
"funded",
"by",
"USDA/NRICGP",
"02657,",
"DoD",
"contract",
"W9113M-04-1-0010,",
"PHS",
"grant",
"P20",
"RR020185,",
"and",
"the",
"Montana",
"Agriculture",
"Experiment",
"Station.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"mhardy@montana.edu",
".",
"These",
"authors",
"contributed",
"equally",
"to",
"this",
"work.",
"Introduction",
"Research",
"into",
"mechanisms",
"by",
"which",
"viruses",
"evade",
"host",
"defense",
"has",
"received",
"increased",
"attention",
"in",
"the",
"past",
"several",
"years",
"because",
"of",
"the",
"potential",
"to",
"develop",
"attenuated",
"vaccines",
"based",
"on",
"viruses",
"with",
"weakened",
"evasion",
"strategies,",
"or",
"antiviral",
"therapies",
"that",
"target",
"specific",
"immune",
"system",
"antagonists.",
"Most,",
"if",
"not",
"all,",
"viruses",
"encode",
"proteins",
"that",
"interfere",
"with",
"signal",
"transduction",
"pathways",
"involved",
"in",
"induction",
"or",
"amplification",
"of",
"the",
"immune",
"response,",
"particularly",
"the",
"innate",
"response",
"driven",
"by",
"type",
"I",
"interferon",
"(IFNa/b)",
"[1].",
"IFNa/b",
"are",
"cytokines",
"that",
"stimulate",
"expression",
"of",
"genes",
"that",
"interfere",
"directly",
"with",
"steps",
"in",
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"A",
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"target",
"more",
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"C,",
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"[1,9].",
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"of",
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"C",
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"in",
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"[8].",
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"and",
"the",
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"the",
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"IRF3,",
"or",
"the",
"steps",
"preceding",
"its",
"PLoS",
"Pathogens",
"|",
"www.plospathogens.org",
"1",
"January",
"2009",
"|",
"Volume",
"5",
"|",
"Issue",
"1",
"|",
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] | [
"1",
"2",
"9",
"2",
"Research",
"Article",
"Received",
"6",
"July",
"2010,",
"Accepted",
"21",
"December",
"2010",
"Published",
"online",
"21",
"February",
"2011",
"in",
"Wiley",
"Online",
"Library",
"(wileyonlinelibrary.com)",
"DOI:",
"10.1002/sim.4200",
"Comparing",
"paired",
"vs",
"non-paired",
"statistical",
"methods",
"of",
"analyses",
"when",
"making",
"inferences",
"about",
"absolute",
"risk",
"reductions",
"in",
"propensity-score",
"matched",
"samples",
"Peter",
"C.",
"Austina,b,c∗",
"†",
"Propensity-score",
"matching",
"allows",
"one",
"to",
"reduce",
"the",
"effects",
"of",
"treatment-selection",
"bias",
"or",
"confounding",
"when",
"estimating",
"the",
"effects",
"of",
"treatments",
"when",
"using",
"observational",
"data.",
"Some",
"authors",
"have",
"suggested",
"that",
"methods",
"of",
"inference",
"appropriate",
"for",
"independent",
"samples",
"can",
"be",
"used",
"for",
"assessing",
"the",
"statistical",
"significance",
"of",
"treatment",
"effects",
"when",
"using",
"propensity-score",
"matching.",
"Indeed,",
"many",
"authors",
"in",
"the",
"applied",
"medical",
"literature",
"use",
"methods",
"for",
"independent",
"samples",
"when",
"making",
"inferences",
"about",
"treatment",
"effects",
"using",
"propensity-score",
"matched",
"samples.",
"Dichotomous",
"outcomes",
"are",
"common",
"in",
"healthcare",
"research.",
"In",
"this",
"study,",
"we",
"used",
"Monte",
"Carlo",
"simulations",
"to",
"examine",
"the",
"effect",
"on",
"inferences",
"about",
"risk",
"differences",
"(or",
"absolute",
"risk",
"reductions)",
"when",
"statistical",
"methods",
"for",
"independent",
"samples",
"are",
"used",
"compared",
"with",
"when",
"statistical",
"methods",
"for",
"paired",
"samples",
"are",
"used",
"in",
"propensity-score",
"matched",
"samples.",
"We",
"found",
"that",
"compared",
"with",
"using",
"methods",
"for",
"independent",
"samples,",
"the",
"use",
"of",
"methods",
"for",
"paired",
"samples",
"resulted",
"in:",
"(i)",
"empirical",
"type",
"I",
"error",
"rates",
"that",
"were",
"closer",
"to",
"the",
"advertised",
"rate;",
"(ii)",
"empirical",
"coverage",
"rates",
"of",
"95",
"per",
"cent",
"confidence",
"intervals",
"that",
"were",
"closer",
"to",
"the",
"advertised",
"rate;",
"(iii)",
"narrower",
"95",
"per",
"cent",
"confidence",
"intervals;",
"and",
"(iv)",
"estimated",
"standard",
"errors",
"that",
"more",
"closely",
"reflected",
"the",
"sampling",
"variability",
"of",
"the",
"estimated",
"risk",
"difference.",
"Differences",
"between",
"the",
"empirical",
"and",
"advertised",
"performance",
"of",
"methods",
"for",
"independent",
"samples",
"were",
"greater",
"when",
"the",
"treatment-selection",
"process",
"was",
"stronger",
"compared",
"with",
"when",
"treatment-selection",
"process",
"was",
"weaker.",
"We",
"recommend",
"using",
"statistical",
"methods",
"for",
"paired",
"samples",
"when",
"using",
"propensity-score",
"matched",
"samples",
"for",
"making",
"inferences",
"on",
"the",
"effect",
"of",
"treatment",
"on",
"the",
"reduction",
"in",
"the",
"probability",
"of",
"an",
"event",
"occurring.",
"Copyright",
"©",
"2011",
"John",
"Wiley",
"&",
"Sons,",
"Ltd.",
"Keywords:",
"propensity",
"score;",
"propensity-score",
"matching;",
"risk",
"difference;",
"absolute",
"risk",
"reduction;",
"Monte",
"Carlo",
"simulations;",
"statistical",
"inference;",
"hypothesis",
"testing;",
"type",
"I",
"error",
"rate;",
"categorical",
"data",
"analysis",
"1.",
"Introduction",
"Propensity-score",
"matching",
"is",
"increasingly",
"being",
"used",
"to",
"estimate",
"the",
"effects",
"of",
"treatments,",
"exposures",
"and",
"interventions",
"on",
"outcomes",
"in",
"observational",
"studies.",
"The",
"propensity",
"score",
"is",
"the",
"probability",
"of",
"treatment",
"assignment",
"conditional",
"on",
"the",
"observed",
"baseline",
"covariates",
"[1].",
"If",
"treatment",
"assignment",
"is",
"strongly",
"ignorable,",
"then",
"conditioning",
"on",
"the",
"propensity",
"score",
"allows",
"one",
"to",
"obtain",
"an",
"unbiased",
"estimate",
"of",
"average",
"treatment",
"effects",
"[1].",
"Matching",
"on",
"the",
"propensity",
"score",
"allows",
"one",
"to",
"construct",
"a",
"matched",
"sample",
"in",
"which",
"systematic",
"differences",
"in",
"observed",
"baseline",
"covariates",
"are",
"reduced",
"or",
"eliminated",
"between",
"treatment",
"groups",
"[2].",
"Outcomes",
"often",
"can",
"be",
"directly",
"compared",
"between",
"treatment",
"groups",
"in",
"the",
"propensity-score",
"matched",
"a",
"Institute",
"for",
"Clinical",
"Evaluative",
"Sciences,",
"Toronto,",
"Ont.,",
"Canada",
"bDepartment",
"of",
"Health",
"Management,",
"Policy",
"and",
"Evaluation,",
"University",
"of",
"Toronto,",
"Toronto,",
"Ont.,",
"Canada",
"cDalla",
"Lana",
"School",
"of",
"Public",
"Health,",
"University",
"of",
"Toronto,",
"Toronto,",
"Ont.,",
"Canada",
"∗Correspondence",
"to:",
"Peter",
"C.",
"Austin,",
"Institute",
"for",
"Clinical",
"Evaluative",
"Sciences,",
"G1",
"06,",
"2075",
"Bayview",
"Avenue,",
"Toronto,",
"Ont.,",
"Canada",
"M4N",
"3M5.",
"†E-mail:",
"peter.austin@ices.on.ca",
"Copyright",
"©",
"2011",
"John",
"Wiley",
"&",
"Sons,",
"Ltd.",
"Statist.",
"Med.",
"2011,",
"30",
"1292--1301"
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] | [
"Hindawi",
"Publishing",
"Corporation",
"International",
"Journal",
"of",
"Peptides",
"Volume",
"2011,",
"Article",
"ID",
"708710,",
"3",
"pages",
"doi:10.1155/2011/708710",
"Research",
"Article",
"Activity",
"of",
"Cathelicidin",
"Peptides",
"against",
"Simkania",
"negevensis",
"Manuela",
"Donati,1",
"Antonietta",
"Di",
"Francesco,2",
"Maria",
"Di",
"Paolo,1",
"Natascia",
"Fiani,1",
"Monica",
"Benincasa,3",
"Renato",
"Gennaro,3",
"Paola",
"Nardini,1",
"Claudio",
"Foschi,1",
"and",
"Roberto",
"Cevenini1",
"1",
"Section",
"of",
"Microbiology",
"DESOS,",
"Policlinico",
"S.",
"Orsola,",
"University",
"of",
"Bologna,",
"40138",
"Bologna,",
"Italy",
"2",
"Department",
"of",
"Veterinary",
"Medical",
"Sciences,",
"University",
"of",
"Bologna,",
"40064",
"Ozzano",
"dell’Emilia,",
"Italy",
"3",
"Department",
"of",
"Life",
"Sciences,",
"University",
"of",
"Trieste,",
"34127,",
"Trieste,",
"Italy",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Antonietta",
"Di",
"Francesco,",
"antoniet.difrancesco@unibo.it",
"Received",
"10",
"December",
"2010;",
"Accepted",
"30",
"January",
"2011",
"Academic",
"Editor:",
"Peter",
"Bergman",
"Copyright",
"©",
"2011",
"Manuela",
"Donati",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"The",
"in",
"vitro",
"activity",
"of",
"six",
"cathelicidin",
"peptides",
"against",
"the",
"reference",
"strain",
"Z",
"of",
"Simkania",
"negevensis",
"was",
"investigated.",
"Five",
"peptides—PG-1,",
"Bac7,",
"SMAP-29,",
"BMAP-27,",
"and",
"BMAP-28—proved",
"to",
"be",
"active",
"at",
"very",
"low",
"concentrations",
"(1",
"to",
"0.1",
"µg/mL),",
"while",
"LL-37",
"cathelicidin",
"was",
"ineffective",
"even",
"at",
"a",
"concentration",
"of",
"100",
"µg/mL.",
"In",
"comparison",
"to",
"chlamydiae,",
"S.",
"negevensis",
"proved",
"to",
"be",
"more",
"susceptible",
"to",
"the",
"antimicrobial",
"peptides",
"tested.",
"1.",
"Introduction",
"Simkania",
"negevensis",
"is",
"an",
"obligate",
"intracellular",
"Gram-nega-",
"tive",
"bacterium",
"belonging",
"to",
"the",
"family",
"of",
"Simkaniaceae",
"in",
"the",
"order",
"Chlamydiales",
"[1],",
"discovered",
"as",
"a",
"contaminant",
"in",
"a",
"variety",
"of",
"cell",
"cultures",
"[2],",
"and",
"is",
"able",
"to",
"grow",
"also",
"in",
"various",
"environmental",
"free-living",
"amoebae",
"such",
"as",
"Acanthamoeba",
"poliphaga",
"[3].",
"Epidemiologic",
"studies",
"have",
"reported",
"a",
"human",
"widesp-",
"read",
"exposure",
"to",
"this",
"bacterium",
"[4,",
"5],",
"both",
"in",
"healthy",
"sub-",
"jects",
"and",
"in",
"association",
"with",
"respiratory",
"diseases",
"in",
"infants",
"and",
"adults",
"[6–10].",
"Coinfections",
"with",
"other",
"pathogens",
"have",
"been",
"described,",
"such",
"as",
"respiratory",
"syncytial",
"virus",
"in",
"children",
"and",
"influenza",
"virus",
"and",
"other",
"bacterial",
"species",
"in",
"adults",
"[7,",
"8,",
"11].",
"A",
"possible",
"association",
"between",
"S.",
"negevensis",
"and",
"acute",
"rejection",
"in",
"lung",
"transplant",
"recipients",
"has",
"been",
"suggested",
"[12].",
"S.",
"negevensis",
"DNA",
"has",
"also",
"been",
"amplified",
"from",
"an",
"aortic",
"aneurysm",
"[13,",
"14].",
"Previous",
"investigations",
"reported",
"S.",
"negevensis",
"in",
"vitro",
"sus-",
"ceptibility",
"to",
"azithromycin,",
"minocycline,",
"erithromycin,",
"dox-",
"ycycline,",
"and",
"ofloxacin",
"like",
"chlamydiae",
"[15]",
"and",
"the",
"lack",
"of",
"susceptibility",
"to",
"ampicillin,",
"penicillin",
"G,",
"bacitracin,",
"cycl-",
"osporine,",
"and",
"fluoroquinolones",
"[2,",
"15,",
"16].",
"Several",
"studies",
"[17–20]",
"demonstrated",
"the",
"in",
"vitro",
"antich-",
"lamydial",
"activity",
"of",
"peptides,",
"such",
"as",
"cathelicidins,",
"stored",
"by",
"mammalian",
"leucocytes",
"and",
"show",
"an",
"antimicrobial",
"activity",
"against",
"bacteria,",
"fungi,",
"protozoa,",
"and",
"enveloped",
"viruses.",
"With",
"regard",
"to",
"the",
"mode",
"of",
"action",
"of",
"these",
"peptides",
"against",
"chlamydiae,",
"previous",
"investigations",
"on",
"the",
"activity",
"of",
"prote-",
"grins",
"[21]",
"suggested",
"an",
"initial",
"binding",
"to",
"lipopolysaccharide",
"followed",
"by",
"insertion",
"into",
"the",
"membrane",
"that",
"results",
"in",
"permeabilization.",
"Yasin",
"et",
"al.",
"[22]",
"demonstrated",
"that",
"the",
"antichlamydial",
"activity",
"of",
"protegrins",
"resided",
"especially",
"in",
"residues",
"5",
"to",
"15",
"of",
"native",
"protegrin-1",
"and",
"required",
"both",
"intramolecular",
"disulfide",
"bonds.",
"In",
"the",
"present",
"study,",
"we",
"investigate",
"the",
"in",
"vitro",
"activity",
"of",
"six",
"antimicrobial",
"peptides",
"against",
"the",
"reference",
"strain",
"Z",
"of",
"S.",
"negevensis.",
"2.",
"Materials",
"and",
"Methods",
"The",
"cathelicidin",
"peptides—PG-1",
"from",
"pig,",
"Bac7",
"(1–35)",
"from",
"cattle,",
"SMAP-29",
"from",
"sheep,",
"LL-37",
"from",
"human,",
"BMAP-",
"27,",
"and",
"BMAP-28",
"from",
"cattle—were",
"chemically",
"synthesized,",
"purified,",
"characterized,",
"and",
"provided",
"as",
"lyophilized",
"peptide,",
"as",
"previously",
"reported",
"[19].",
"The",
"reference",
"strain",
"Z",
"of",
"S.",
"negevensis",
"(American",
"Type",
"Culture",
"Collection",
"VR-1471)",
"was",
"grown",
"in",
"LLC-MK2",
"cells",
"[23]",
"in",
"6-large",
"well",
"plates",
"and",
"elementary",
"bodies",
"(EBs)",
"were",
"purified",
"by",
"use",
"of",
"sucrose",
"gradients",
"[24],",
"resuspended",
"in",
"sucrose-phosphate-glutamic"
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] | [
"Dubé",
"et",
"al.",
"BMC",
"Public",
"Health",
"2011,",
"11:128",
"http://www.biomedcentral.com/1471-2458/11/128",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"A(H1N1)",
"pandemic",
"influenza",
"and",
"its",
"prevention",
"by",
"vaccination:",
"Paediatricians’",
"opinions",
"before",
"and",
"after",
"the",
"beginning",
"of",
"the",
"vaccination",
"campaign",
"Eve",
"Dubé1,2*,",
"Defay",
"Fannie2,",
"Gilca",
"Vladimir1,2,",
"Bettinger",
"A",
"Julie3,",
"Sauvageau",
"Chantal1,2,",
"Lavoie",
"France2,",
"Boucher",
"D",
"François2,",
"McNeil",
"Shelly4,",
"Gemmill",
"Ian5,",
"Boulianne",
"Nicole1,2",
"Abstract",
"Background:",
"In",
"June",
"2009,",
"the",
"World",
"Health",
"Organization",
"declared",
"an",
"A(H1N1)",
"influenza",
"pandemic.",
"In",
"October",
"2009,",
"the",
"largest",
"vaccination",
"campaign",
"in",
"Canadian",
"history",
"began.",
"The",
"aim",
"of",
"this",
"study",
"was",
"to",
"document",
"paediatricians’",
"knowledge,",
"attitudes",
"and",
"practices",
"(KAP)",
"regarding",
"A(H1N1)",
"pandemic",
"influenza",
"and",
"its",
"prevention",
"by",
"vaccination",
"just",
"after",
"the",
"beginning",
"of",
"the",
"A(H1N1)",
"vaccination",
"campaign",
"and",
"to",
"compare",
"the",
"results",
"with",
"those",
"obtained",
"before",
"campaign",
"initiation.",
"Methods:",
"A",
"self-administered",
"mail-based",
"questionnaire",
"was",
"sent",
"to",
"all",
"Canadian",
"paediatricians.",
"Questionnaires",
"were",
"analyzed",
"in",
"two",
"subsets:",
"those",
"received",
"before",
"and",
"after",
"the",
"beginning",
"of",
"the",
"vaccination",
"campaign.",
"Results:",
"Overall",
"the",
"response",
"rate",
"was",
"50%.",
"Respondents’",
"characteristics",
"were",
"comparable",
"between",
"the",
"two",
"subsets.",
"Before",
"the",
"beginning",
"of",
"the",
"campaign,",
"63%",
"of",
"paediatricians",
"perceived",
"A(H1N1)",
"pandemic",
"infection",
"as",
"a",
"serious",
"disease,",
"that",
"would",
"occur",
"frequently",
"without",
"vaccination",
"compared",
"to",
"more",
"than",
"75%",
"after.",
"Before",
"the",
"vaccination",
"campaign,",
"half",
"of",
"respondents",
"or",
"less",
"thought",
"that",
"the",
"A(H1N1)",
"vaccine",
"was",
"safe",
"(50%)",
"and",
"effective",
"(35%)",
"compared",
"to",
"77%",
"and",
"72%",
"after.",
"The",
"proportion",
"of",
"paediatricians",
"who",
"reported",
"they",
"had",
"received",
"sufficient",
"information",
"on",
"A",
"(H1N1)",
"vaccine",
"increased",
"from",
"31%",
"before",
"to",
"73%",
"after",
"the",
"beginning",
"of",
"the",
"vaccination",
"campaign.",
"The",
"majority",
"of",
"respondents",
"intended",
"to",
"get",
"vaccinated",
"against",
"A(H1N1)",
"influenza",
"themselves",
"(84%",
"before",
"and",
"92%",
"after).",
"Respondents’",
"intention",
"to",
"recommend",
"the",
"A(H1N1)",
"vaccine",
"to",
"their",
"patients",
"increased",
"from",
"80%",
"before",
"the",
"beginning",
"of",
"the",
"campaign",
"to",
"92%",
"after.",
"In",
"multivariate",
"analysis,",
"the",
"main",
"determinants",
"of",
"paediatricians’",
"intention",
"to",
"recommend",
"the",
"A(H1N1)",
"vaccine",
"were",
"their",
"intention",
"to",
"get",
"vaccinated",
"against",
"A(H1N1)",
"influenza",
"themselves",
"and",
"a",
"belief",
"that",
"A",
"(H1N1)",
"vaccine",
"would",
"be",
"well",
"accepted",
"by",
"health",
"professionals",
"who",
"administer",
"vaccines",
"to",
"the",
"public.",
"Conclusion:",
"Results",
"of",
"this",
"study",
"show",
"important",
"increases",
"in",
"physicians’",
"level",
"of",
"confidence",
"about",
"A(H1N1)",
"vaccine’s",
"safety",
"and",
"immunogenicity",
"and",
"their",
"willingness",
"to",
"recommend",
"this",
"vaccine",
"to",
"their",
"patients.",
"These",
"changes",
"could",
"be",
"explained,",
"at",
"least",
"partially,",
"by",
"the",
"important",
"effort",
"done",
"by",
"public",
"health",
"authorities",
"to",
"disseminate",
"information",
"regarding",
"A(H1N1)",
"vaccination.",
"Background",
"In",
"June",
"2009,",
"the",
"World",
"Health",
"Organization",
"(WHO)",
"declared",
"an",
"A(H1N1)",
"influenza",
"pandemic",
"[1].",
"In",
"Octo-",
"ber",
"2009,",
"the",
"largest",
"vaccination",
"campaign",
"in",
"Canadian",
"history",
"began.",
"Before",
"the",
"start",
"of",
"the",
"A(H1N1)",
"pan-",
"demic",
"influenza",
"vaccination",
"campaign,",
"limited",
"*",
"Correspondence:",
"eve.dube@ssss.gouv.qc.ca",
"1Institut",
"National",
"de",
"Santé",
"publique",
"du",
"Québec,",
"2400",
"d’Estimauville,",
"Québec,",
"Canada",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"information",
"on",
"the",
"safety",
"and",
"immunogenicity",
"of",
"A",
"(H1N1)",
"influenza",
"vaccines",
"was",
"available.",
"However,",
"the",
"spread",
"of",
"A(H1N1)",
"influenza",
"generated",
"intense",
"media",
"interest",
"in",
"pandemic",
"preparedness",
"and",
"contradictory",
"information",
"around",
"the",
"vaccine",
"and",
"the",
"vaccination",
"campaign",
"was",
"reported",
"[2-6].",
"During",
"the",
"first",
"wave",
"of",
"A",
"(H1N1)",
"influenza",
"in",
"Canada,",
"77",
"deaths",
"were",
"reported,",
"mostly",
"in",
"the",
"provinces",
"of",
"Quebec",
"and",
"Ontario.",
"During",
"the",
"second",
"wave,",
"in",
"early",
"fall",
"2009,",
"351",
"deaths",
"were",
"reported",
"across",
"the",
"country",
"[7].",
"In",
"Canada,",
"almost",
"©",
"2011",
"Dubé",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Insights",
"Imaging",
"(2012)",
"3:247–250",
"DOI",
"10.1007/s13244-012-0168-x",
"PICTORIAL",
"REVIEW",
"Hypertrophic",
"pyloric",
"stenosis:",
"tips",
"and",
"tricks",
"for",
"ultrasound",
"diagnosis",
"Sílvia",
"Costa",
"Dias",
"&",
"Sophie",
"Swinson",
"&",
"Helena",
"Torrão",
"&",
"Lígia",
"Gonçalves",
"&",
"Svitlana",
"Kurochka",
"&",
"Carlos",
"Pina",
"Vaz",
"&",
"Vasco",
"Mendes",
"Received:",
"5",
"October",
"2011",
"/",
"Revised:",
"11",
"February",
"2012",
"/",
"Accepted:",
"19",
"March",
"2012",
"/",
"Published",
"online:",
"1",
"May",
"2012",
"#",
"European",
"Society",
"of",
"Radiology",
"2012",
"Abstract",
"We",
"describe",
"a",
"systematic",
"approach",
"to",
"the",
"ultra-",
"sound",
"(US)",
"examination",
"of",
"the",
"antropyloric",
"region",
"in",
"chil-",
"dren.",
"US",
"is",
"the",
"modality",
"of",
"choice",
"for",
"the",
"diagnosis",
"of",
"hypertrophic",
"pyloric",
"stenosis",
"(HPS).",
"The",
"imaging",
"features",
"of",
"the",
"normal",
"pylorus",
"and",
"the",
"diagnostic",
"findings",
"in",
"HPS",
"are",
"reviewed",
"and",
"illustrated",
"in",
"this",
"pictorial",
"essay.",
"Common",
"difficulties",
"in",
"performing",
"the",
"examination",
"and",
"tips",
"to",
"help",
"overcome",
"them",
"will",
"also",
"be",
"discussed.",
"Main",
"Messages",
"Hypertrophic",
"Pyloric",
"Stenosis",
"is",
"defined",
"by",
"thickening",
"of",
"the",
"muscular",
"layer",
"and",
"failure",
"in",
"relaxation",
"of",
"the",
"pyloric",
"canal.",
"The",
"main",
"diagnostic",
"criterion",
"is",
"a",
"measurement",
"of",
"more",
"than",
"3mm",
"in",
"thickness",
"of",
"the",
"muscular",
"layer.",
"Abnormal",
"elongation",
"of",
"the",
"canal",
"is",
"characterised",
"as",
"greater",
"than",
"12",
"mm",
"in",
"length.",
"Keywords",
"Hypertrophic",
"pyloric",
"stenosis",
".",
"Ultrasound",
"S.",
"Costa",
"Dias",
":",
"H.",
"Torrão",
":",
"L.",
"Gonçalves",
":",
"S.",
"Kurochka",
":",
"C.",
"P.",
"Vaz",
":",
"V.",
"Mendes",
"Radiology",
"Department,",
"Hospital",
"de",
"Braga,",
"Braga,",
"Portugal",
"S.",
"Costa",
"Dias",
"(*)",
"Rua",
"Pedro",
"Hispano,",
"n",
"190,",
"2",
"Dto,",
"4100-393",
"Porto,",
"Portugal",
"e-mail:",
"silviacostadias@hotmail.com",
"S.",
"Swinson",
"Radiology",
"Department,",
"Great",
"Ormond",
"Street",
"Hospital",
"for",
"Children",
"NHS",
"Trust,",
"Great",
"Ormond",
"Street,",
"London",
"WC1N",
"3JH,",
"UK",
"Introduction",
"Hypertrophic",
"pyloric",
"stenosis",
"(HPS)",
"is",
"the",
"most",
"frequent",
"sur-",
"gical",
"condition",
"in",
"infants",
"in",
"the",
"first",
"few",
"months",
"of",
"life",
"[1].",
"The",
"condition",
"is",
"characterised",
"by",
"thickening",
"of",
"the",
"muscular",
"layer",
"and",
"failure",
"of",
"the",
"pyloric",
"canal",
"to",
"relax",
"resulting",
"in",
"gastric",
"outlet",
"obstruction.",
"Elongation",
"of",
"the",
"canal",
"and",
"thickened",
"mucosa",
"are",
"also",
"seen.",
"Ultrasound",
"(US)",
"is",
"the",
"preferred",
"diagnostic",
"modality",
"[2]",
"as",
"it",
"is",
"a",
"non-invasive",
"technique,",
"allowing",
"direct",
"observation",
"of",
"the",
"pyloric",
"canal",
"morphology",
"and",
"behaviour.",
"It",
"is",
"important",
"to",
"carry",
"out",
"a",
"systematic",
"and",
"dynamic",
"study",
"and",
"to",
"be",
"aware",
"of",
"the",
"common",
"technical",
"difficulties",
"and",
"how",
"to",
"overcome",
"them.",
"Clinical",
"features",
"HPS",
"is",
"the",
"most",
"common",
"surgical",
"cause",
"of",
"vomiting",
"in",
"infants.",
"It",
"has",
"an",
"incidence",
"of",
"3",
"per",
"1,000",
"live",
"births",
"per",
"year,",
"although",
"wide",
"variations",
"have",
"been",
"documented",
"with",
"geographic",
"location,",
"season",
"and",
"ethnic",
"origin",
"[3].",
"This",
"dis-",
"ease",
"usually",
"presents",
"between",
"the",
"second",
"and",
"sixth",
"weeks",
"of",
"life,",
"more",
"commonly",
"in",
"the",
"white",
"population,",
"in",
"males",
"(male:female",
"ratio",
"4:1)",
"and",
"typically",
"in",
"first-born",
"children",
"[4].",
"A",
"history",
"of",
"an",
"affected",
"first-degree",
"relative",
"increases",
"the",
"risk",
"more",
"than",
"five-fold",
"[5].",
"The",
"US",
"examination",
"allows",
"the",
"radiologist",
"to",
"perform",
"a",
"brief",
"clinical",
"history,",
"which",
"can",
"reveal",
"essential",
"clues",
"to",
"the",
"diagnosis.",
"A",
"recent",
"history",
"of",
"projectile",
"and",
"nonbilious",
"vomiting,",
"which",
"may",
"be",
"intermittent",
"or",
"with",
"every",
"feeding",
"is",
"the",
"classical",
"com-",
"plaint.",
"Typically",
"the",
"infant",
"has",
"a",
"voracious",
"appetite.",
"When",
"the",
"vomiting",
"persists,",
"other",
"clinical",
"and",
"biochemical",
"findings",
"may",
"occur",
"such",
"as",
"dehydration,",
"hypochloraemic"
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] | [
"J",
"Neurodevelop",
"Disord",
"(2011)",
"3:144–151",
"DOI",
"10.1007/s11689-011-9080-9",
"Salivary",
"biomarkers",
"of",
"HPA",
"axis",
"and",
"autonomic",
"activity",
"in",
"adults",
"with",
"intellectual",
"disability",
"with",
"and",
"without",
"stereotyped",
"and",
"self-injurious",
"behavior",
"disorders",
"Frank",
"J.",
"Symons",
"&",
"Jason",
"J.",
"Wolff",
"&",
"Laura",
"S.",
"Stone",
"&",
"Tony",
"K.",
"Y.",
"Lim",
"&",
"James",
"W.",
"Bodfish",
"Received:",
"9",
"September",
"2010",
"/",
"Accepted:",
"25",
"March",
"2011",
"/",
"Published",
"online:",
"12",
"April",
"2011",
"#",
"Springer",
"Science+Business",
"Media,",
"LLC",
"2011",
"Abstract",
"Salivary",
"levels",
"of",
"biomarkers",
"for",
"the",
"hypothalamic–",
"pituitary–adrenal",
"axis",
"(HPA;",
"cortisol)",
"and",
"sympatho-adreno-",
"medullary",
"system",
"(SAM;",
"α-amylase)",
"were",
"measured",
"in",
"51",
"adults",
"(57%",
"male)",
"with",
"neurodevelopmental",
"disorders",
"associ-",
"ated",
"with",
"intellectual",
"disability",
"(i.e.,",
"mental",
"retardation)",
"and",
"chronic",
"self-injurious",
"behavior",
"(SIB)",
"and",
"compared",
"with",
"matched",
"controls",
"without",
"SIB.",
"Cortisol",
"levels",
"differed",
"signif-",
"icantly",
"(p<0.01)",
"between",
"the",
"SIB",
"and",
"control",
"group",
"(SIB>",
"control).",
"Within-group",
"analyses",
"showed",
"significant",
"differences",
"(p<0.05)",
"in",
"levels",
"of",
"salivary",
"α-amylase",
"between",
"individuals",
"with",
"SIB",
"and",
"those",
"with",
"SIB",
"meeting",
"criteria",
"for",
"stereotyped",
"movement",
"disorder",
"(SMD;",
"SIB+SMD>SIB).",
"Salivary",
"α-",
"amylase",
"was",
"significantly",
"correlated",
"with",
"frequency",
"of",
"stereotypy",
"among",
"the",
"SIB",
"group",
"(r=0.36,",
"p<0.05).",
"These",
"preliminary",
"findings",
"warrant",
"further",
"exploration",
"into",
"the",
"role",
"of",
"the",
"SAM",
"system",
"in",
"the",
"pathophysiology",
"of",
"SIB",
"and",
"related",
"The",
"preparation",
"of",
"this",
"report",
"was",
"supported,",
"in",
"part,",
"by",
"NICHD",
"Grant",
"No.",
"44763",
"and",
"47201",
"to",
"the",
"University",
"of",
"Minnesota.",
"We",
"are",
"grateful",
"to",
"Jamie",
"Clary",
"for",
"assistance",
"with",
"saliva",
"collection.",
"Our",
"sincere",
"thanks",
"go",
"to",
"a",
"committed",
"group",
"of",
"parents",
"and",
"staff",
"for",
"their",
"support.",
"F.",
"J.",
"Symons",
"(*)",
"Department",
"of",
"Educational",
"Psychology,",
"Center",
"for",
"Neurobehavioral",
"Development,",
"University",
"of",
"Minnesota,",
"Education",
"Science",
"Building,",
"56",
"River",
"Road,",
"Minneapolis,",
"MN",
"55455,",
"USA",
"e-mail:",
"symon007@umn.edu",
"J.",
"J.",
"Wolff",
":",
"J.",
"W.",
"Bodfish",
"Carolina",
"Institute",
"for",
"Developmental",
"Disabilities,",
"University",
"of",
"North",
"Carolina",
"at",
"Chapel",
"Hill,",
"200",
"East",
"Cameron",
"Avenue,",
"Chapell",
"Hill,",
"NC,",
"USA",
"L.",
"S.",
"Stone",
":",
"T.",
"K.",
"Y.",
"Lim",
"Alan",
"Edwards",
"Center",
"for",
"Research",
"on",
"Pain,",
"McGill",
"University,",
"Montreal,",
"QC,",
"Canada",
"repetitive",
"behaviors",
"among",
"individuals",
"with",
"neurodevelop-",
"mental",
"disorders",
"associated",
"with",
"intellectual",
"disability.",
"Keywords",
"Salivary",
".",
"Self-injury",
".",
"Stereotypy",
".",
"HPA",
"axis",
".",
"Hypothalamic–pituitary–adrenal",
"axis",
"(HPA)",
".",
"Sympatho-",
"adreno-medullary",
"system",
"(SAM)",
"Self-injurious",
"behavior",
"(SIB)",
"is",
"a",
"relatively",
"prevalent",
"behavior",
"disorder",
"among",
"populations",
"of",
"people",
"with",
"neurodevelop-",
"mental",
"disorders",
"associated",
"with",
"intellectual",
"and",
"develop-",
"mental",
"disabilities",
"(IDD),",
"with",
"estimated",
"prevalence",
"rates",
"between",
"5–20%",
"of",
"persons",
"with",
"IDD",
"engaging",
"in",
"SIB",
"(Schroeder",
"et",
"al.",
"2001).",
"The",
"presentation",
"of",
"SIB",
"can",
"be",
"severe,",
"characterized",
"by",
"non-accidental",
"and",
"self-inflicted",
"head-banging,",
"body-hitting,",
"eye-gouging,",
"self-biting,",
"hair-",
"pulling,",
"and",
"other",
"activities",
"causing",
"injury.",
"The",
"pathophys-",
"iology",
"of",
"SIB",
"is",
"poorly",
"understood,",
"and",
"consequentially,",
"the",
"disorder",
"can",
"be",
"difficult",
"to",
"treat",
"effectively.",
"There",
"are",
"no",
"standard",
"first",
"choice",
"pharmacological",
"treatments",
"for",
"SIB,",
"making",
"the",
"clinician’s",
"judgement",
"the",
"primary",
"determinant",
"of",
"treatment",
"(Osman",
"and",
"Loschen",
"1992).",
"Limited",
"research",
"on",
"biological",
"mechanisms",
"and",
"their",
"markers",
"has",
"impeded",
"the",
"identification",
"of",
"specific",
"and",
"effective",
"forms",
"of",
"psychophar-",
"macological",
"treatment",
"(but",
"see",
"Sandman",
"et",
"al.",
"1999).",
"The",
"study",
"of",
"biological",
"markers,",
"therefore,",
"may",
"be",
"especially",
"useful",
"in",
"aiding",
"diagnosis,",
"treatment",
"course",
"decisions,",
"and",
"in",
"gaining",
"a",
"greater",
"understanding",
"of",
"SIB",
"pathophysiology.",
"Studies",
"of",
"biological",
"markers",
"among",
"individuals",
"with",
"SIB",
"and",
"IDD",
"have",
"demonstrated",
"a",
"relationship",
"between",
"SIB",
"and",
"stress,",
"which",
"has",
"mostly",
"been",
"focused",
"around",
"the",
"hypothalamic–pituitary–adrenal",
"(HPA)",
"axis.",
"After",
"a",
"SIB",
"episode,",
"plasma",
"β-endorphin",
"levels",
"increase",
"and",
"uncouple",
"from",
"adrenocorticotropic",
"hormone",
"(ACTH;",
"Sandman",
"et",
"al.",
"1997;",
"Sandman",
"et",
"al.",
"2003).",
"Under",
"normal",
"circumstances,",
"ACTH",
"and",
"β-endorphin",
"levels",
"are",
"highly",
"correlated,",
"as",
"they"
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551,
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567,
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574,
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599,
873
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606,
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664,
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672,
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730,
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738,
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437,
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508,
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] | [
"Versican",
"G3",
"Domain",
"Modulates",
"Breast",
"Cancer",
"Cell",
"Apoptosis:",
"A",
"Mechanism",
"for",
"Breast",
"Cancer",
"Cell",
"Response",
"to",
"Chemotherapy",
"and",
"EGFR",
"Therapy",
"William",
"Weidong",
"Du1,2,",
"Burton",
"B.",
"Yang2,3,",
"Bing",
"L.",
"Yang1,2,",
"Zhaoqun",
"Deng2,3,",
"Ling",
"Fang2,3,",
"Sze",
"Wan",
"Shan2,3,",
"Zina",
"Jeyapalan2,3,",
"Yaou",
"Zhang",
"4",
",",
"Arun",
"Seth2,3,",
"Albert",
"J.",
"Yee1*",
"1",
"Department",
"of",
"Surgery,",
"Sunnybrook",
"Health",
"Sciences",
"Centre",
"and",
"Centre",
"for",
"the",
"Study",
"of",
"Bone",
"Metastasis,",
"Odette",
"Cancer",
"Centre,",
"University",
"of",
"Toronto,",
"Toronto,",
"Canada,",
"2",
"Sunnybrook",
"Research",
"Institute,",
"Toronto,",
"Canada,",
"3",
"Department",
"of",
"Laboratory",
"Medicine",
"and",
"Pathobiology,",
"University",
"of",
"Toronto,",
"Canada,",
"4",
"Division",
"of",
"Life",
"Science,",
"Graduate",
"School",
"at",
"Shenzhen,",
"Tsinghua",
"University,",
"Shenzhen,",
"China",
"Abstract",
"Overexpression",
"of",
"EGFR",
"and",
"versican",
"has",
"been",
"reported",
"in",
"association",
"with",
"breast",
"cancers.",
"Considered",
"oncogenic,",
"these",
"molecules",
"may",
"be",
"attractive",
"therapeutic",
"targets.",
"Possessing",
"anti-apoptotic",
"and",
"drug",
"resistant",
"properties,",
"overexpression",
"of",
"these",
"molecules",
"is",
"accompanied",
"by",
"selective",
"sensitization",
"to",
"the",
"process",
"of",
"apoptosis.",
"In",
"this",
"study,",
"we",
"exogenously",
"expressed",
"a",
"versican",
"G3",
"construct",
"in",
"breast",
"cancer",
"cell",
"lines",
"and",
"analyzed",
"the",
"effects",
"of",
"G3",
"on",
"cell",
"viability",
"in",
"fetal",
"bovine",
"serum",
"free",
"conditioned",
"media",
"and",
"evaluated",
"the",
"effects",
"of",
"apoptotic",
"agent",
"C2-ceramide,",
"and",
"chemotherapeutic",
"agents",
"including",
"Docetaxel,",
"Doxorubicin,",
"and",
"Epirubicin.",
"Versican",
"G3",
"domain",
"enhanced",
"tumor",
"cell",
"resistance",
"to",
"apoptosis",
"when",
"cultured",
"in",
"serum",
"free",
"medium,",
"Doxorubicin,",
"or",
"Epirubicin",
"by",
"up-regulating",
"pERK",
"and",
"GSK-3b",
"(S9P).",
"However,",
"it",
"could",
"be",
"prevented",
"by",
"selective",
"EGFR",
"inhibitor",
"AG",
"1478",
"and",
"selective",
"MEK",
"inhibitor",
"PD",
"98059.",
"Both",
"AG",
"1478",
"and",
"PD",
"98059",
"enhanced",
"expression",
"of",
"pSAPK/JNK,",
"while",
"selective",
"JNK",
"inhibitor",
"SP",
"600125",
"enhanced",
"expression",
"of",
"GSK-3b",
"(S9P).",
"Versican",
"G3",
"promoted",
"cell",
"apoptosis",
"induced",
"by",
"C2-ceramide",
"or",
"Docetaxel",
"by",
"enhancing",
"expression",
"of",
"pSAPK/JNK",
"and",
"decreasing",
"expression",
"of",
"GSK-3b",
"(S9P),",
"an",
"observation",
"blocked",
"by",
"AG",
"1478",
"or",
"SP",
"6000125.",
"Inhibition",
"of",
"endogenous",
"versican",
"expression",
"by",
"siRNA",
"or",
"reduction",
"of",
"versican",
"G3’s",
"expression",
"by",
"linking",
"G3",
"with",
"39UTR",
"prevented",
"G3",
"modulated",
"cell",
"apoptosis.",
"The",
"dual",
"roles",
"of",
"G3",
"in",
"modulating",
"breast",
"cancer",
"cell",
"resistance",
"to",
"chemotherapeutic",
"agents",
"may",
"in",
"part",
"explain",
"a",
"potential",
"mechanism",
"for",
"breast",
"cancer",
"cell",
"resistance",
"to",
"chemotherapy",
"and",
"EGFR",
"therapy.",
"The",
"apoptotic",
"effects",
"of",
"chemotherapeutics",
"depend",
"upon",
"the",
"activation",
"and",
"balance",
"of",
"down",
"stream",
"signals",
"in",
"the",
"EGFR",
"pathway.",
"GSK-3b",
"(S9P)",
"appears",
"to",
"function",
"as",
"a",
"key",
"checkpoint",
"in",
"this",
"balance",
"of",
"apoptosis",
"and",
"anti-apoptosis.",
"Investigation",
"and",
"potential",
"consideration",
"of",
"targeting",
"GSK-3b",
"(S9P)",
"merits",
"further",
"study.",
"Citation:",
"Du",
"WW,",
"Yang",
"BB,",
"Yang",
"BL,",
"Deng",
"Z,",
"Fang",
"L,",
"et",
"al.",
"(2011)",
"Versican",
"G3",
"Domain",
"Modulates",
"Breast",
"Cancer",
"Cell",
"Apoptosis:",
"A",
"Mechanism",
"for",
"Breast",
"Cancer",
"Cell",
"Response",
"to",
"Chemotherapy",
"and",
"EGFR",
"Therapy.",
"PLoS",
"ONE",
"6(11):",
"e26396.",
"doi:10.1371/journal.pone.0026396",
"Editor:",
"Ilya",
"Ulasov,",
"University",
"of",
"Chicago,",
"United",
"States",
"of",
"America",
"Received",
"March",
"7,",
"2011;",
"Accepted",
"September",
"26,",
"2011;",
"Published",
"November",
"9,",
"2011",
"Copyright:",
"2011",
"Du",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"This",
"work",
"was",
"supported",
"by",
"a",
"grant",
"from",
"National",
"Sciences",
"and",
"Engineering",
"Research",
"Council",
"of",
"Canada",
"(227937-01)",
"to",
"Dr.",
"Yang",
"who",
"is",
"the",
"recipient",
"of",
"a",
"Career",
"Investigator",
"Award",
"(CI5958)",
"from",
"the",
"Heart",
"and",
"Stroke",
"Foundation",
"of",
"Ontario.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"albert.yee@sunnybrook.ca",
"Introduction",
"Chemotherapeutic",
"drugs",
"exhibit",
"varied",
"selectivity",
"for",
"tumour",
"cells",
"dependent",
"on",
"cell",
"origins",
"and",
"are",
"capable",
"of",
"inducing",
"tumour",
"cell",
"death",
"[1,2].",
"Additionally",
"many",
"of",
"the",
"commonly",
"used",
"chemotherapeutic",
"drugs",
"also",
"appear",
"to",
"influence",
"cellular",
"signaling",
"pathways",
"that",
"induce",
"apoptosis",
"in",
"susceptible",
"cancer",
"cells",
"[1,3].",
"Apoptosis",
"seems",
"to",
"be",
"one",
"of",
"the",
"major",
"physiologic",
"safeguards",
"against",
"uncontrolled",
"proliferation",
"[4].",
"Growth",
"and",
"apoptosis",
"are",
"two",
"diametrically",
"opposed",
"biological",
"processes",
"that",
"ensure",
"that",
"multi-cellular",
"organisms",
"can",
"cope",
"with",
"the",
"normal",
"physiologic",
"yet",
"mutagenic",
"environment",
"that",
"generates",
"millions",
"of",
"potential",
"cancer",
"cells",
"every",
"day",
"[5].",
"With",
"its",
"effects",
"on",
"tumor",
"cell",
"proliferation",
"and",
"migration,",
"versican",
"has",
"been",
"shown",
"to",
"increase",
"the",
"resistance",
"of",
"cancer",
"cells",
"to",
"apoptosis",
"[6].",
"Our",
"previous",
"research",
"demonstrated",
"that",
"versican",
"appeared",
"to",
"confer",
"cell",
"resistance",
"to",
"apoptosis",
"following",
"treatment",
"with",
"low",
"serum",
"medium",
"or",
"hydrogen",
"peroxide",
"[7,8].",
"The",
"combination",
"of",
"selective",
"apoptotic",
"resistance",
"and",
"sensitivity",
"has",
"been",
"reported",
"in",
"overexpression",
"of",
"the",
"V1",
"versican",
"isoform",
"[7];",
"the",
"intimate",
"relationship",
"between",
"proliferation",
"and",
"apoptosis",
"cannot",
"be",
"separated",
"and",
"cancer",
"cells",
"often",
"express",
"either",
"hypersensitivity",
"or",
"resistance",
"to",
"apoptosis",
"that",
"is",
"dependent",
"upon",
"tissue",
"conditions.",
"As",
"a",
"member",
"of",
"the",
"large",
"aggregating",
"chondroitin",
"sulfate",
"proteoglycan",
"family,",
"versican",
"is",
"structurally",
"composed",
"of",
"a",
"N-",
"terminal",
"G1",
"domain,",
"a",
"glycosaminoglycan",
"(GAG)",
"attachment",
"region,",
"and",
"a",
"C",
"terminus",
"(or",
"G3)",
"selectin-like",
"domain",
"[9,10].",
"The",
"G3",
"domain",
"interacts",
"with",
"different",
"ECM",
"proteins",
"[11]",
"and",
"binds",
"to",
"certain",
"cell",
"surface",
"proteins",
"including",
"epidermal",
"growth",
"factor",
"receptor",
"(EGFR)",
"[12,13].",
"Extracellular",
"versican",
"has",
"been",
"observed",
"to",
"be",
"elevated",
"in",
"a",
"variety",
"of",
"human",
"tumors",
"including",
"breast",
"carcinoma",
"[14,15,16].",
"High",
"expression",
"has",
"been",
"observed",
"in",
"the",
"interstitial",
"tissues",
"at",
"the",
"invasive",
"margins",
"of",
"breast",
"carcinoma",
"and",
"appears",
"prognositic",
"being",
"predictive",
"of",
"cancer",
"relapse",
"in",
"patients",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"November",
"2011",
"|",
"Volume",
"6",
"|",
"Issue",
"11",
"|",
"e26396"
] | [
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] | [
"2596–2606",
"Nucleic",
"Acids",
"Research,",
"2009,",
"Vol.",
"37,",
"No.",
"8",
"doi:10.1093/nar/gkp115",
"Published",
"online",
"6",
"March",
"2009",
"Plasmodium",
"falciparum",
"heterochromatin",
"protein",
"1",
"binds",
"to",
"tri-methylated",
"histone",
"3",
"lysine",
"9",
"and",
"is",
"linked",
"to",
"mutually",
"exclusive",
"expression",
"of",
"var",
"genes",
"Karla",
"Pe´",
"rez-Toledo",
"1",
",",
"Ana",
"Paola",
"Rojas-Meza1,2,",
"Liliana",
"Mancio-Silva2,",
"Nora",
"Adriana",
"Herna´",
"ndez-Cuevas1,",
"Dulce",
"Maria",
"Delgadillo1,",
"Miguel",
"Vargas1,",
"Santiago",
"Martı´nez-Calvillo3,",
"Artur",
"Scherf2",
"and",
"Rosaura",
"Hernandez-Rivas1,*",
"1Departamento",
"de",
"Biomedicina",
"Molecular,",
"Centro",
"de",
"Investigacio´",
"n",
"y",
"de",
"Estudios",
"Avanzados",
"del",
"Instituto",
"Polite´",
"cnico",
"Nacional",
"(IPN),",
"Apartado",
"Postal",
"14-740,",
"07360,",
"Me´",
"xico",
"D.",
"F.,",
"Me´",
"xico,",
"2Institut",
"Pasteur,",
"Unite´",
"de",
"Biologie",
"des",
"Interactions",
"H",
"oˆte-Parasite",
"–",
"CNRS",
"URA2581.",
"25,",
"Rue",
"du",
"Dr.",
"Roux,",
"75724",
"Paris,",
"France",
"and",
"3Unidad",
"de",
"Biomedicina,",
"Facultad",
"de",
"Estudios",
"Superiores",
"Iztacala,",
"Universidad",
"Nacional",
"Auto´",
"noma",
"de",
"Me´",
"xico.",
"Av.",
"de",
"los",
"Barrios",
"1,",
"Col.",
"Los",
"Reyes",
"Iztacala,",
"Tlalnepantla,",
"Edo.",
"de",
"Me´",
"xico,",
"CP",
"54090,",
"Me´",
"xico",
"Received",
"December",
"1,",
"2008;",
"Revised",
"February",
"6,",
"2009;",
"Accepted",
"February",
"10,",
"2009",
"ABSTRACT",
"Increasing",
"experimental",
"evidence",
"shows",
"a",
"promi-",
"nent",
"role",
"of",
"histone",
"modifications",
"in",
"the",
"coordinated",
"control",
"of",
"gene",
"expression",
"in",
"the",
"human",
"malaria",
"parasite",
"Plasmodium",
"falciparum.",
"The",
"search",
"for",
"the",
"histone-mark-reading",
"machinery",
"that",
"translates",
"histone",
"modifications",
"into",
"biological",
"processes,",
"such",
"as",
"formation",
"of",
"heterochromatin",
"and",
"antigenic",
"variation",
"is",
"of",
"foremost",
"importance.",
"In",
"this",
"work,",
"we",
"identified",
"the",
"first",
"member",
"of",
"a",
"histone",
"modification",
"specific",
"recognition",
"protein,",
"an",
"orthologue",
"of",
"heterochromatin",
"protein",
"1",
"(PfHP1).",
"Analysis",
"of",
"the",
"PfHP1",
"amino-acid",
"sequence",
"revealed",
"the",
"presence",
"of",
"the",
"two",
"characteristic",
"HP1",
"domains:",
"a",
"chromo-",
"domain",
"(CD)",
"and",
"a",
"chromo",
"shadow",
"domain",
"(CSD).",
"Recombinant",
"CD",
"binds",
"to",
"di-",
"and",
"tri-methylated",
"lysine",
"9",
"from",
"histone",
"H3,",
"but",
"not",
"to",
"unmodified",
"or",
"methylated",
"histone",
"H3",
"in",
"lysine",
"4.",
"PfHP1",
"is",
"able",
"to",
"interact",
"with",
"itself",
"to",
"form",
"dimers,",
"underlying",
"its",
"potential",
"role",
"in",
"aggregating",
"nucleosomes",
"to",
"form",
"heterochromatin.",
"Antibodies",
"raised",
"against",
"PfHP1",
"detect",
"this",
"molecule",
"in",
"foci",
"at",
"the",
"perinuclear",
"region.",
"ChIP",
"analysis",
"using",
"anti-PfHP1",
"shows",
"that",
"this",
"protein",
"is",
"linked",
"to",
"heterochromatin",
"of",
"subtelo-",
"meric",
"non-coding",
"repeat",
"regions",
"and",
"monoallelic",
"expression",
"of",
"the",
"major",
"virulence",
"var",
"gene",
"family.",
"This",
"is",
"the",
"first",
"report",
"implicating",
"an",
"HP1",
"protein",
"in",
"the",
"control",
"of",
"antigenic",
"variation",
"of",
"a",
"protozoan",
"parasite.",
"INTRODUCTION",
"Plasmodium",
"falciparum,",
"the",
"causal",
"protozoan",
"agent",
"of",
"the",
"most",
"severe",
"form",
"of",
"human",
"malaria,",
"has",
"a",
"complex",
"life",
"cycle",
"with",
"two",
"different",
"hosts,",
"the",
"Anopheles",
"mosquito",
"and",
"humans.",
"In",
"order",
"to",
"complete",
"its",
"life",
"cycle,",
"P.",
"falciparum",
"invades",
"different",
"types",
"of",
"cells",
"and",
"self-propagates",
"in",
"very",
"distinct",
"environments",
"in",
"the",
"mosquito",
"(gut,",
"hemolymph",
"and",
"salivary",
"glands)",
"as",
"well",
"as",
"in",
"the",
"human",
"host",
"(skin,",
"liver",
"and",
"erythrocytes).",
"Each",
"of",
"these",
"distinct",
"environ-",
"ments",
"exerts",
"selective",
"pressure",
"related",
"to",
"morphological",
"changes",
"that",
"force",
"P.",
"falciparum",
"to",
"exhibit",
"differential",
"gene",
"expression",
"during",
"its",
"life",
"cycle",
"(1,2).",
"A",
"surprising",
"finding",
"was",
"the",
"identification",
"of",
"a",
"relatively",
"low",
"number",
"of",
"genes",
"encoding",
"transcription",
"factors",
"in",
"the",
"parasite,",
"although",
"the",
"basal",
"core",
"transcriptional",
"machinery",
"and",
"the",
"protein-coding",
"genes",
"involved",
"in",
"nucleosome",
"assembly",
"and",
"regulation",
"of",
"chromatin",
"structure",
"were",
"found",
"to",
"be",
"conserved",
"(3–5).",
"To",
"date,",
"no",
"specific",
"DNA-binding",
"proteins",
"have",
"been",
"identified",
"other",
"than",
"PfMyb1",
"(6)",
"and",
"the",
"ApiAp2",
"gene",
"family",
"(7).",
"This",
"suggested",
"that",
"epigenetic",
"mechanisms",
"play",
"a",
"significant",
"role",
"in",
"controlling",
"gene",
"expression",
"in",
"Plasmodium",
"(3,8–10).",
"The",
"importance",
"of",
"reversible",
"chromatin",
"modifications",
"involving",
"histone",
"modifications",
"and",
"the",
"chromatin-associated",
"protein",
"PfSir2",
"was",
"first",
"demonstrated",
"for",
"a",
"subtelomeric",
"gene",
"family",
"(var",
"gene",
"family)",
"involved",
"in",
"the",
"control",
"of",
"anti-",
"genic",
"variation",
"in",
"P.",
"falciparum",
"(10).",
"Knock",
"out",
"of",
"PfSir2",
"resulted",
"in",
"the",
"de-repression",
"of",
"a",
"fraction",
"of",
"the",
"members",
"of",
"the",
"var",
"gene",
"family",
"(11).",
"A",
"screen",
"for",
"histone",
"modifica-",
"tions",
"revealed",
"that",
"H3K9me3",
"plays",
"a",
"particular",
"role",
"in",
"var",
"gene",
"repression",
"(12,13)",
"and",
"H3K4me2/3",
"in",
"transcriptional",
"*To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"Tel:",
"+(52)",
"55",
"5747",
"3325;",
"Fax:",
"+(52)",
"55",
"5747",
"3938;",
"Email:",
"rohernan@cinvestav.mx",
"The",
"authors",
"wish",
"it",
"to",
"be",
"known",
"that,",
"in",
"their",
"opinion,",
"the",
"first",
"two",
"authors",
"should",
"be",
"regarded",
"as",
"joint",
"First",
"Authors.",
"2009",
"The",
"Author(s)",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/",
"by-nc/2.0/uk/)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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817,
571,
830
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[
576,
817,
596,
830
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[
602,
817,
642,
830
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[
646,
817,
656,
830
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662,
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679,
830
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[
684,
817,
717,
830
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[
722,
817,
743,
830
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[
437,
831,
479,
844
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[
483,
831,
491,
844
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[
495,
831,
535,
844
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[
538,
831,
548,
844
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[
552,
831,
604,
844
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609,
831,
629,
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[
633,
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[
437,
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475,
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480,
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499,
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505,
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550,
859
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555,
846,
579,
859
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846,
623,
859
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[
628,
846,
653,
859
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[
658,
846,
689,
859
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[
694,
846,
748,
859
],
[
754,
846,
770,
859
],
[
437,
860,
510,
873
],
[
520,
860,
563,
873
],
[
574,
860,
584,
873
],
[
594,
860,
646,
873
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[
656,
860,
671,
873
],
[
681,
860,
702,
873
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[
712,
860,
746,
873
],
[
756,
860,
769,
873
],
[
437,
875,
492,
888
],
[
500,
875,
511,
888
],
[
519,
875,
561,
888
],
[
568,
875,
576,
888
],
[
584,
875,
598,
888
],
[
606,
875,
636,
888
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[
643,
875,
663,
888
],
[
671,
875,
713,
888
],
[
721,
875,
769,
888
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[
437,
889,
484,
902
],
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489,
889,
505,
902
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509,
889,
535,
902
],
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539,
889,
561,
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566,
889,
655,
902
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660,
889,
717,
902
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721,
889,
749,
902
],
[
754,
889,
770,
902
],
[
437,
904,
478,
917
],
[
481,
904,
524,
917
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528,
904,
551,
917
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554,
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917
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[
572,
904,
593,
917
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[
597,
904,
628,
917
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[
631,
904,
644,
917
],
[
648,
904,
703,
917
],
[
706,
904,
724,
917
],
[
728,
904,
770,
917
],
[
437,
919,
499,
932
],
[
503,
919,
531,
932
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[
535,
919,
600,
932
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604,
919,
666,
932
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[
670,
919,
689,
932
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[
693,
919,
709,
932
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[
713,
919,
770,
932
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933,
451,
946
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946
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] | [
"Cellular",
"Cytoskeleton",
"Dynamics",
"Modulates",
"Non-Viral",
"Gene",
"Delivery",
"through",
"RhoGTPases",
"Anandika",
"Dhaliwal1,",
"Maricela",
"Maldonado",
"2",
",",
"Clayton",
"Lin2,",
"Tatiana",
"Segura1,2*",
"1",
"Biomedical",
"Engineering",
"Interdepartmental",
"Program,",
"University",
"of",
"California",
"Los",
"Angeles,",
"Los",
"Angeles,",
"California,",
"United",
"States",
"of",
"America,",
"2",
"Chemical",
"and",
"Biomolecular",
"Engineering",
"Department,",
"University",
"of",
"California",
"Los",
"Angeles,",
"Los",
"Angeles,",
"California,",
"United",
"States",
"of",
"America",
"Abstract",
"Although",
"it",
"is",
"well",
"accepted",
"that",
"the",
"constituents",
"of",
"the",
"cellular",
"microenvironment",
"modulate",
"a",
"myriad",
"of",
"cellular",
"processes,",
"including",
"cell",
"morphology,",
"cytoskeletal",
"dynamics",
"and",
"uptake",
"pathways,",
"the",
"underlying",
"mechanism",
"of",
"how",
"these",
"pathways",
"influence",
"non-viral",
"gene",
"transfer",
"have",
"not",
"been",
"studied.",
"Transgene",
"expression",
"is",
"increased",
"on",
"fibronectin",
"(Fn)",
"coated",
"surfaces",
"as",
"a",
"consequence",
"of",
"increased",
"proliferation,",
"cell",
"spreading",
"and",
"active",
"engagement",
"of",
"clathrin",
"endocytosis",
"pathway.",
"RhoGTPases",
"mediate",
"the",
"crosstalk",
"between",
"the",
"cell",
"and",
"Fn,",
"and",
"regulate",
"cellular",
"processes",
"involving",
"filamentous",
"actin,",
"in-response",
"to",
"cellular",
"interaction",
"with",
"Fn.",
"Here",
"the",
"role",
"of",
"RhoGTPases",
"specifically",
"Rho,",
"Rac",
"and",
"Cdc42",
"in",
"modulation",
"of",
"non-viral",
"gene",
"transfer",
"in",
"mouse",
"mesenchymal",
"stem",
"(mMSCs)",
"plated",
"in",
"a",
"fibronectin",
"microenvironment",
"was",
"studied.",
"More",
"than",
"90%",
"decrease",
"in",
"transgene",
"expression",
"was",
"observed",
"after",
"inactivation",
"of",
"RhoGTPases",
"using",
"difficile",
"toxin",
"B",
"(TcdB)",
"and",
"C3",
"transferase.",
"Expression",
"of",
"dominant",
"negative",
"RhoA",
"(RhoAT19N),",
"Rac1(Rac1T17N)",
"and",
"Cdc42",
"(Cdc42T17N)",
"also",
"significantly",
"reduced",
"polyplex",
"uptake",
"and",
"transgene",
"expression.",
"Interactions",
"of",
"cells",
"with",
"Fn",
"lead",
"to",
"activation",
"of",
"RhoGTPases.",
"However,",
"further",
"activation",
"of",
"RhoA,",
"Rac1",
"and",
"Cdc42",
"by",
"expression",
"of",
"constitutively",
"active",
"genes",
"(RhoAQ63L,",
"Rac1Q61L",
"and",
"Cdc42Q61L)",
"did",
"not",
"further",
"enhance",
"transgene",
"expression",
"in",
"mMSCs,",
"when",
"plated",
"on",
"Fn.",
"In",
"contrast,",
"activation",
"of",
"RhoA,",
"Rac1",
"and",
"Cdc42",
"by",
"expression",
"of",
"constitutively",
"active",
"genes",
"for",
"cells",
"plated",
"on",
"collagen",
"I,",
"which",
"by",
"itself",
"did",
"not",
"increase",
"RhoGTPase",
"activation,",
"resulted",
"in",
"enhanced",
"transgene",
"expression.",
"Our",
"study",
"shows",
"that",
"RhoGTPases",
"regulate",
"internalization",
"and",
"effective",
"intracellular",
"processing",
"of",
"polyplexes",
"that",
"results",
"in",
"efficient",
"gene",
"transfer.",
"Citation:",
"Dhaliwal",
"A,",
"Maldonado",
"M,",
"Lin",
"C,",
"Segura",
"T",
"(2012)",
"Cellular",
"Cytoskeleton",
"Dynamics",
"Modulates",
"Non-Viral",
"Gene",
"Delivery",
"through",
"RhoGTPases.",
"PLoS",
"ONE",
"7(4):",
"e35046.",
"doi:10.1371/journal.pone.0035046",
"Editor:",
"Neil",
"A.",
"Hotchin,",
"University",
"of",
"Birmingham,",
"United",
"Kingdom",
"Received",
"November",
"30,",
"2011;",
"Accepted",
"March",
"12,",
"2012;",
"Published",
"April",
"11,",
"2012",
"Copyright:",
"2012",
"Dhaliwal",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"Funding",
"was",
"provided",
"by",
"National",
"Institutes",
"of",
"Health",
"R21EB009516,",
"Understanding",
"the",
"Role",
"of",
"the",
"Extracellular",
"Matrix",
"on",
"Non-Viral",
"Gene",
"Transfer",
"(www.nih.gov).",
"The",
"funder",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"tsegura@ucla.edu",
"Introduction",
"Although",
"gene",
"delivery",
"can",
"be",
"a",
"robust",
"approach",
"to",
"treat",
"disease",
"and",
"augment",
"tissue",
"formation,",
"limitations",
"with",
"effective",
"and",
"save",
"delivery",
"have",
"limited",
"its",
"success",
"as",
"a",
"therapy.",
"Gene",
"delivery",
"to",
"mammalian",
"cells",
"can",
"be",
"achieved",
"using",
"viral",
"as",
"well",
"as",
"non-viral",
"delivery",
"systems",
"[1].",
"Non-viral",
"gene",
"delivery",
"systems",
"have",
"the",
"advantage",
"of",
"being",
"less",
"immunogenic",
"compared",
"to",
"viral",
"gene",
"delivery",
"systems",
"as",
"well",
"as",
"allow",
"for",
"large-scale",
"production",
"and",
"modularity.",
"However,",
"they",
"are",
"limited",
"by",
"their",
"efficacy.",
"Previous",
"studies",
"have",
"focused",
"on",
"engineering",
"more",
"efficient",
"delivery",
"vehicles",
"that",
"can",
"overcome",
"one",
"or",
"more",
"of",
"the",
"barriers",
"to",
"efficient",
"gene",
"transfer",
"[2,3].",
"Although",
"less",
"common,",
"recent",
"studies",
"have",
"looked",
"at",
"the",
"cellular",
"microenvironment",
"and",
"the",
"cell",
"itself",
"to",
"elucidate",
"other",
"approaches",
"to",
"enhance",
"non-viral",
"gene",
"transfer",
"[4–",
"8].",
"For",
"example,",
"the",
"stiffness",
"of",
"the",
"matrix",
"where",
"the",
"cells",
"are",
"plated",
"modulates",
"non-viral",
"gene",
"delivery",
"with",
"cells",
"plated",
"on",
"stiff",
"surfaces",
"(110",
"KPa)",
"resulting",
"in",
"enhanced",
"gene",
"transfer",
"due",
"to",
"increased",
"cell",
"proliferation",
"and",
"survival",
"[8].",
"Collagen",
"I",
"and",
"IV",
"have",
"been",
"shown",
"to",
"enhance",
"gene",
"transfer",
"in",
"PC12",
"cells,",
"which",
"was",
"correlated",
"with",
"the",
"relative",
"projected",
"nuclear",
"area",
"of",
"the",
"plated",
"cells",
"[9],",
"while",
"fibronectin",
"and",
"collagen",
"I",
"have",
"been",
"shown",
"to",
"enhance",
"gene",
"expression",
"in",
"NIH/3T3",
"cells",
"which",
"has",
"been",
"correlated",
"to",
"the",
"relative",
"increased",
"internalization",
"on",
"these",
"surfaces",
"and",
"the",
"pathway",
"of",
"internalization",
"[11].",
"Cationic",
"lipid-",
"mediated",
"gene",
"transfer",
"to",
"rat",
"smooth",
"muscle",
"cells",
"is",
"enhanced",
"when",
"the",
"cells",
"are",
"plated",
"on",
"surfaces",
"that",
"promote",
"avß3",
"binding,",
"with",
"antibodies",
"against",
"avß3",
"and",
"ß3",
"decreasing",
"the",
"amount",
"of",
"gene",
"transfer",
"[9].",
"Further,",
"our",
"laboratory",
"has",
"shown",
"that",
"cellular",
"microenvironment",
"modulates",
"non-viral",
"gene",
"delivery",
"to",
"mouse",
"mesenchymal",
"stem",
"cells",
"(mMSCs),",
"specifically",
"we",
"screened",
"6",
"different",
"ECM",
"proteins",
"and",
"their",
"combinations",
"for",
"their",
"ability",
"to",
"enhance",
"gene",
"transfer",
"to",
"mouse",
"mesenchymal",
"stem",
"cells",
"(mMSCs)",
"using",
"poly(ethylene",
"imine)",
"polyplexes.",
"We",
"found",
"that",
"proteins",
"that",
"promoted",
"well",
"spread",
"cells",
"(e.g.",
"fibronectin",
"and",
"collagen",
"IV)",
"resulted",
"in",
"polyplexes",
"being",
"trafficked",
"to",
"the",
"nucleus",
"and",
"enhanced",
"gene",
"transfer,",
"while",
"those",
"that",
"resulted",
"in",
"less",
"spread",
"cells",
"(e.g.",
"collagen",
"I)",
"resulted",
"in",
"polyplexes",
"that",
"did",
"not",
"colocalize",
"with",
"the",
"nucleus",
"and",
"inhibited",
"gene",
"transfer",
"[10].",
"When",
"comparing",
"the",
"internalization",
"pathway",
"of",
"polyplexes",
"for",
"cells",
"seeded",
"on",
"fibronectin",
"or",
"collagen",
"I,",
"we",
"found",
"that",
"different",
"endocytic",
"pathways",
"are",
"used,",
"with",
"clathrin-mediated",
"endocytosis",
"being",
"the",
"primary",
"pathway",
"used",
"for",
"cells",
"plated",
"on",
"fibronectin",
"[6].",
"Further,",
"polymerized",
"actin,",
"actin-myosin",
"interactions,",
"and",
"the",
"microtubu-",
"lar",
"network",
"were",
"found",
"to",
"influence",
"non-viral",
"gene",
"transfer",
"to",
"different",
"extends",
"for",
"cells",
"seeded",
"on",
"fibronectin",
"versus",
"collagen",
"I",
"[6].",
"Structural",
"components",
"of",
"the",
"ECM",
"such",
"as",
"Fn",
"are",
"able",
"to",
"actively",
"mediate",
"crosstalk",
"between",
"the",
"ECM",
"and",
"RhoGTPases",
"by",
"associating",
"with",
"cell",
"surface",
"receptors,",
"namely",
"integrins",
"[11]",
"and",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"April",
"2012",
"|",
"Volume",
"7",
"|",
"Issue",
"4",
"|",
"e35046"
] | [
8,
8,
8,
8,
8,
8,
8,
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] | [
"Purinergic",
"Signalling",
"(2008)",
"4:125–137",
"DOI",
"10.1007/s11302-007-9053-3",
"ORIGINAL",
"PAPER",
"Endogenous",
"ATP",
"release",
"inhibits",
"electrogenic",
"Na+",
"absorption",
"and",
"stimulates",
"Cl−",
"secretion",
"in",
"MDCK",
"cells",
"Yi",
"Xie",
"&",
"James",
"A.",
"Schafer",
"Received:",
"7",
"December",
"2006",
"/",
"Accepted:",
"2",
"February",
"2007",
"/",
"Published",
"online:",
"8",
"March",
"2007",
"#",
"Springer",
"Science",
"+",
"Business",
"Media",
"B.V.",
"2007",
"Abstract",
"Our",
"previous",
"studies",
"with",
"a",
"line",
"of",
"Madin-Darby",
"canine",
"kidney",
"(MDCK)",
"cells",
"(FL-MDCK)",
"transfected",
"with",
"FLAG-labeled",
"a,",
"b,",
"and",
"g",
"subunits",
"of",
"epithelial",
"Na+",
"channel",
"(ENaC)",
"showed",
"that,",
"although",
"most",
"of",
"the",
"short-",
"circuit",
"current",
"(Isc)",
"was",
"amiloride",
"sensitive",
"(AS-Isc),",
"there",
"was",
"also",
"an",
"amiloride-insensitive",
"component",
"(NS-Isc)",
"due",
"to",
"Cl−",
"secretion",
"(Morris",
"and",
"Schafer,",
"J",
"Gen",
"Physiol",
"120:71–",
"85,",
"2002).",
"In",
"the",
"present",
"studies,",
"we",
"observed",
"a",
"progressive",
"increase",
"in",
"NS-Isc",
"and",
"a",
"corresponding",
"decrease",
"in",
"AS-Isc",
"during",
"experiments.",
"There",
"was",
"a",
"significant",
"negative",
"correlation",
"between",
"AS-Isc",
"and",
"NS-Isc",
"both",
"in",
"the",
"presence",
"and",
"absence",
"of",
"treatment",
"with",
"cyclic",
"adenosine",
"mono-",
"phosphate",
"(cAMP).",
"NS-Isc",
"could",
"be",
"attributed",
"to",
"both",
"cystic",
"fibrosis",
"transmembrane",
"conductance",
"regulator",
"(CFTR)",
"and",
"a",
"4,",
"4'-diisothiocyano-2,",
"2'-disulfonic",
"acid",
"stilbene",
"(DIDS)-",
"sensitive",
"Ca2+-activated",
"Cl−",
"channel",
"(CaCC).",
"Continuous",
"perfusion",
"of",
"both",
"sides",
"of",
"the",
"Ussing",
"chamber",
"with",
"fresh",
"rather",
"than",
"recirculated",
"bathing",
"solutions,",
"or",
"addition",
"of",
"hexokinase",
"(6",
"U/ml),",
"prevented",
"the",
"time-dependent",
"changes",
"and",
"increased",
"AS-Isc",
"by",
"40–60%,",
"with",
"a",
"proportional",
"decrease",
"in",
"NS-Isc.",
"Addition",
"of",
"100",
"μM",
"adenosine",
"Y.",
"Xie",
":",
"J.",
"A.",
"Schafer",
"Department",
"of",
"Physiology",
"and",
"Biophysics,",
"and",
"Medicine,",
"University",
"of",
"Alabama",
"at",
"Birmingham,",
"Birmingham,",
"AL",
"35294,",
"USA",
"J.",
"A.",
"Schafer",
"(*)",
"Departments",
"of",
"Physiology",
"and",
"Biophysics,",
"University",
"of",
"Alabama",
"at",
"Birmingham,",
"1918",
"University",
"Blvd.,",
"Rm.",
"834",
"MCLM,",
"Birmingham,",
"AL",
"35294-0005,",
"USA",
"e-mail:",
"jschafer@uab.edu",
"Present",
"address:",
"Y.",
"Xie",
"Department",
"of",
"Physiology,",
"UCLA",
"School",
"of",
"Medicine,",
"650",
"Charles",
"Young",
"Dr.",
"S.",
"3-609",
"MRL,",
"Los",
"Angeles,",
"CA",
"90095-1751,",
"USA",
"triphosphate",
"(ATP)",
"in",
"the",
"presence",
"of",
"luminal",
"amiloride",
"produced",
"a",
"transient",
"four-fold",
"increase",
"in",
"NS-Isc",
"that",
"was",
"followed",
"by",
"a",
"sustained",
"increase",
"of",
"50–60%",
"above",
"the",
"basal",
"level.",
"ATP",
"release",
"from",
"the",
"monolayers,",
"measured",
"by",
"bioluminescence,",
"was",
"found",
"to",
"occur",
"across",
"the",
"apical",
"but",
"not",
"the",
"basolateral",
"membrane,",
"and",
"the",
"apical",
"release",
"was",
"tripled",
"by",
"cAMP",
"treatment.",
"These",
"data",
"show",
"that",
"constitu-",
"tive",
"apical",
"ATP",
"release,",
"which",
"occurs",
"under",
"both",
"basal",
"and",
"cAMP-stimulated",
"conditions,",
"underlies",
"the",
"time-dependent",
"rise",
"in",
"Cl−",
"secretion",
"and",
"the",
"proportional",
"fall",
"in",
"ENaC-",
"mediated",
"Na+",
"absorption",
"in",
"FL-MDCK",
"cells.",
"Thus,",
"endog-",
"enous",
"ATP",
"release",
"can",
"introduce",
"a",
"significant",
"confounding",
"variable",
"in",
"experiments",
"with",
"this",
"and",
"similar",
"epithelial",
"cells,",
"and",
"it",
"may",
"underlie",
"at",
"least",
"some",
"of",
"the",
"observed",
"interaction",
"between",
"Cl−",
"secretion",
"and",
"Na+",
"absorption.",
"Keywords",
"ATP.",
"CFTR",
".",
"CLC",
".",
"Calcium-activated",
"Cl−",
"channel",
".",
"ENaC",
".",
"Purinergic",
"effects",
"Introduction",
"Madin-Darby",
"canine",
"kidney",
"(MDCK,",
"type",
"I)",
"cells",
"grown",
"as",
"epithelial",
"monolayers",
"have",
"been",
"used",
"extensively",
"as",
"a",
"model",
"of",
"the",
"mammalian",
"collecting",
"duct",
"(CD).",
"These",
"monolayers",
"exhibit",
"many",
"characteristics",
"of",
"the",
"CD,",
"including",
"a",
"high",
"transepithelial",
"resistance",
"and",
"amiloride-",
"sensitive",
"Na+",
"reabsorption",
"that",
"is",
"mediated",
"by",
"the",
"epithelial",
"Na+",
"channel",
"(ENaC)",
"and",
"stimulated",
"by",
"agonists",
"that",
"increase",
"intracellular",
"cyclic",
"adenosine",
"monophosphate",
"(cAMP)",
"[1,",
"2].",
"Similar",
"cell",
"lines",
"that",
"are",
"derived",
"from",
"the",
"CD,",
"including",
"mouse",
"cortical",
"CD",
"(M-1)",
"and",
"inner",
"medullary",
"CD",
"(mIMCD-K2)",
"cells",
"[3–5]",
"and",
"A6",
"cells",
"from",
"the",
"Xenopus",
"distal",
"nephron",
"[6,",
"7]",
"share",
"these",
"character-",
"istics.",
"However,",
"in",
"contrast",
"to",
"the",
"CD,",
"all",
"of",
"these",
"cell",
"lines",
"also",
"have",
"Cl−",
"channels",
"in",
"their",
"apical",
"membranes,",
"and,"
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] | [
"SAGE-Hindawi",
"Access",
"to",
"Research",
"Journal",
"of",
"Osteoporosis",
"Volume",
"2011,",
"Article",
"ID",
"924595,",
"6",
"pages",
"doi:10.4061/2011/924595",
"Clinical",
"Study",
"Predictors",
"of",
"Fracture",
"Risk",
"and",
"Bone",
"Mineral",
"Density",
"in",
"Men",
"with",
"Prostate",
"Cancer",
"on",
"Androgen",
"Deprivation",
"Therapy",
"Katherine",
"Neubecker,1",
"Beverley",
"Adams-Huet,2",
"Irfan",
"M.",
"Farukhi,3",
"Rosinda",
"C.",
"Delapena,3",
"and",
"Ugis",
"Gruntmanis4",
"1",
"Department",
"of",
"Medicine,",
"University",
"of",
"Texas,",
"Southwestern",
"Medical",
"Center,",
"Dallas,",
"TX",
"75390,",
"USA",
"2",
"Departments",
"of",
"Clinical",
"Sciences",
"and",
"Medicine,",
"University",
"of",
"Texas,",
"Southwestern",
"Medical",
"Center,",
"Dallas,",
"TX",
"75390,",
"USA",
"3",
"Department",
"of",
"Nuclear",
"Medicine,",
"Dallas",
"Veterans",
"Affairs",
"Medical",
"Center,",
"Dallas,",
"TX",
"75216,",
"USA",
"4",
"Department",
"of",
"Medicine,",
"Dallas",
"Veterans",
"Affairs",
"Medical",
"Center",
"and",
"University",
"of",
"Texas,",
"Southwestern",
"Medical",
"Center,",
"Dallas,",
"TX",
"75216,",
"USA",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Ugis",
"Gruntmanis,",
"ugis.gruntmanis@utsouthwestern.edu",
"Received",
"8",
"March",
"2011;",
"Revised",
"26",
"April",
"2011;",
"Accepted",
"9",
"May",
"2011",
"Academic",
"Editor:",
"Pawel",
"Szulc",
"Copyright",
"©",
"2011",
"Katherine",
"Neubecker",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Decrease",
"of",
"bone",
"mineral",
"density",
"(BMD)",
"and",
"fracture",
"risk",
"is",
"increased",
"in",
"men",
"with",
"prostate",
"cancer",
"receiving",
"androgen",
"deprivation",
"therapy",
"(ADT).",
"We",
"looked",
"at",
"possible",
"predictors",
"of",
"decreased",
"BMD",
"and",
"increased",
"fracture",
"risk",
"in",
"men",
"with",
"prostate",
"cancer;",
"most",
"of",
"whom",
"were",
"on",
"ADT.",
"In",
"a",
"retrospective",
"study,",
"we",
"analyzed",
"serum,",
"BMD,",
"and",
"clinical",
"risk",
"factors",
"used",
"in",
"the",
"Fracture",
"Risk",
"Assessment",
"(FRAX)",
"tool",
"and",
"others",
"in",
"78",
"men",
"with",
"prostate",
"cancer",
"with",
"reported",
"height",
"loss.",
"The",
"subjects",
"were",
"divided",
"in",
"two",
"groups:",
"22",
"men",
"with",
"and",
"56",
"without",
"vertebral",
"fractures.",
"17",
"of",
"the",
"22",
"men",
"with",
"vertebral",
"fractures",
"on",
"spine",
"X-rays",
"did",
"not",
"know",
"they",
"had",
"a",
"vertebral",
"fracture.",
"Of",
"those",
"17",
"men,",
"9",
"had",
"not",
"previously",
"qualified",
"for",
"treatment",
"based",
"on",
"preradiograph",
"FRAX",
"score",
"calculated",
"with",
"BMD,",
"and",
"6",
"based",
"on",
"FRAX",
"calculated",
"without",
"BMD.",
"Performing",
"spine",
"films",
"increased",
"the",
"predictive",
"ability",
"of",
"FRAX",
"for",
"vertebral",
"fracture.",
"Vertebral",
"fracture",
"was",
"better",
"predicted",
"by",
"FRAX",
"for",
"other",
"osteoporotic",
"fractures",
"than",
"FRAX",
"for",
"hip",
"fractures.",
"The",
"inclusion",
"of",
"BMD",
"in",
"FRAX",
"calculations",
"did",
"not",
"affect",
"the",
"predictive",
"ability",
"of",
"FRAX.",
"The",
"PSA",
"level",
"showed",
"a",
"positive",
"correlation",
"with",
"lumbar",
"spine",
"BMD",
"and",
"accounted",
"for",
"about",
"9%",
"of",
"spine",
"BMD.",
"1.",
"Introduction",
"220,000",
"men",
"are",
"diagnosed",
"with",
"prostate",
"cancer",
"each",
"year,",
"and",
"more",
"than",
"40",
"percent",
"receive",
"androgen",
"deprivation",
"therapy",
"(ADT)",
"as",
"initial",
"treatment",
"[1,",
"2].",
"ADT",
"has",
"been",
"shown",
"to",
"decrease",
"bone",
"mineral",
"density",
"(BMD)",
"as",
"measured",
"by",
"dual-energy",
"X-ray",
"absorptiometry",
"(DXA)",
"as",
"well",
"as",
"increase",
"risk",
"of",
"fracture.",
"After",
"initiating",
"ADT,",
"BMD",
"decline",
"starts",
"shortly",
"after",
"[3,",
"4].",
"A",
"meta-analysis",
"of",
"almost",
"117,000",
"men",
"demonstrated",
"that",
"patients",
"on",
"ADT",
"had",
"lower",
"total",
"BMD,",
"30%",
"increased",
"risk",
"of",
"osteoporosis,",
"and",
"70%",
"increased",
"risk",
"of",
"fractures",
"[5].",
"In",
"a",
"study",
"of",
"over",
"47,000",
"men",
"with",
"prostate",
"cancer",
"by",
"the",
"National",
"Cancer",
"Institute",
"(NCI)",
"and",
"Medicare,",
"those",
"treated",
"with",
"ADT",
"or",
"bilateral",
"orchiectomy",
"within",
"six",
"months",
"of",
"diagnosis",
"had",
"a",
"5-year",
"fracture",
"risk",
"of",
"19.4%",
"versus",
"12.6%",
"in",
"controls",
"matched",
"for",
"patient",
"and",
"tumor",
"characteristics",
"[6].",
"A",
"systematic",
"review",
"of",
"five",
"studies",
"on",
"prostate",
"cancer",
"patients",
"in",
"the",
"US",
"and",
"abroad,",
"which",
"included",
"the",
"NCI-Medicare",
"study,",
"found",
"a",
"23%",
"increase",
"in",
"fracture",
"risk",
"for",
"men",
"treated",
"with",
"ADT",
"[7].",
"Fracture",
"Risk",
"Assessment",
"(FRAX)",
"is",
"an",
"algorithm",
"devel-",
"oped",
"by",
"the",
"World",
"Health",
"Organization",
"to",
"determine",
"fracture",
"risk",
"of",
"men",
"and",
"women",
"[8].",
"The",
"risk",
"factors",
"in",
"the",
"algorithm",
"include",
"age,",
"current",
"height,",
"prior",
"fracture,",
"parental",
"history",
"of",
"fracture,",
"BMD",
"of",
"the",
"femoral",
"neck,",
"and",
"secondary",
"osteoporosis",
"risk",
"factors",
"such",
"as",
"hypogonadism.",
"Yet,",
"inclusion",
"of",
"secondary",
"causes",
"such",
"as",
"hypogonadism",
"does",
"not",
"change",
"FRAX-calculated",
"risk",
"of",
"fracture",
"when",
"femoral",
"neck",
"BMD",
"is",
"included.",
"The",
"National",
"Osteoporosis",
"Foundation’s",
"recommended",
"treatment",
"thresholds",
"based",
"on",
"FRAX",
"score",
"are",
"3%",
"for",
"hip",
"(“Hip",
"FRAX”)",
"and",
"20%",
"for",
"major",
"osteoporotic",
"fractures",
"(“Osteoporotic",
"FRAX”)",
"[9]."
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] | [
"Journal",
"of",
"Experimental",
"Botany,",
"Vol.",
"62,",
"No.",
"3,",
"pp.",
"1169–1177,",
"2011",
"doi:10.1093/jxb/erq347",
"Advance",
"Access",
"publication",
"1",
"November,",
"2010",
"This",
"paper",
"is",
"available",
"online",
"free",
"of",
"all",
"access",
"charges",
"(see",
"http://jxb.oxfordjournals.org/open_access.html",
"for",
"further",
"details)",
"RESEARCH",
"PAPER",
"Evidence",
"for",
"phenotypic",
"plasticity",
"in",
"the",
"Antarctic",
"extremophile",
"Chlamydomonas",
"raudensis",
"Ettl.",
"UWO",
"241",
"Tessa",
"Pocock*,",
"Adrien",
"Vetterli",
"and",
"Stefan",
"Falk†",
"Department",
"of",
"Natural",
"Sciences,",
"Engineering",
"and",
"Mathematics,",
"Mid",
"Sweden",
"University,",
"Sundsvall",
"85170,",
"Sweden",
"*",
"Present",
"address:",
"Department",
"of",
"Biological",
"Research,",
"Heliospectra",
"AB,",
"Bora˚",
"s",
"50630,",
"Sweden.",
"y",
"To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"E-mail:",
"stefan.falk@miun.se",
"Received",
"20",
"August",
"2010;",
"Revised",
"11",
"October",
"2010;",
"Accepted",
"11",
"October",
"2010",
"Abstract",
"Life",
"in",
"extreme",
"environments",
"poses",
"unique",
"challenges",
"to",
"photosynthetic",
"organisms.",
"The",
"ability",
"for",
"an",
"extremophilic",
"green",
"alga",
"and",
"its",
"genetic",
"and",
"mesophilic",
"equivalent",
"to",
"acclimate",
"to",
"changes",
"in",
"their",
"environment",
"was",
"examined",
"to",
"determine",
"the",
"extent",
"of",
"their",
"phenotypic",
"plasticities.",
"The",
"Antarctic",
"extremophile",
"Chlamydomonas",
"raudensis",
"Ettl.",
"UWO",
"241",
"(UWO)",
"was",
"isolated",
"from",
"an",
"ice-covered",
"lake",
"in",
"Antarctica,",
"whereas",
"its",
"mesophilic",
"counterpart",
"C.",
"raudensis",
"Ettl.",
"SAG",
"49.72",
"(SAG)",
"was",
"isolated",
"from",
"a",
"meadow",
"pool",
"in",
"the",
"Czech",
"Republic.",
"The",
"effects",
"of",
"changes",
"in",
"temperature",
"and",
"salinity",
"on",
"growth,",
"morphology,",
"and",
"photochemistry",
"were",
"examined",
"in",
"the",
"two",
"strains.",
"Differential",
"acclimative",
"responses",
"were",
"observed",
"in",
"UWO",
"which",
"include",
"a",
"wider",
"salinity",
"range",
"for",
"growth,",
"and",
"broader",
"temperature-",
"and",
"salt-induced",
"fluctuations",
"in",
"Fv/Fm,",
"relative",
"to",
"SAG.",
"Furthermore,",
"the",
"redox",
"state",
"of",
"the",
"photosynthetic",
"electron",
"transport",
"chain,",
"measured",
"as",
"1–qP,",
"was",
"modulated",
"in",
"the",
"extremophile",
"whereas",
"this",
"was",
"not",
"observed",
"in",
"the",
"mesophile.",
"Interestingly,",
"it",
"is",
"shown",
"for",
"the",
"first",
"time",
"that",
"SAG",
"is",
"similar",
"to",
"UWO",
"in",
"that",
"it",
"is",
"unable",
"to",
"undergo",
"state",
"transitions.",
"The",
"different",
"natural",
"histories",
"of",
"these",
"two",
"strains",
"exert",
"different",
"evolutionary",
"pressures",
"and,",
"consequently,",
"different",
"abilities",
"for",
"acclimation,",
"an",
"important",
"component",
"of",
"phenotypic",
"plasticity.",
"In",
"contrast",
"to",
"SAG,",
"UWO",
"relied",
"on",
"a",
"redox",
"sensing",
"and",
"signalling",
"system",
"under",
"the",
"growth",
"conditions",
"used",
"in",
"this",
"study.",
"It",
"is",
"proposed",
"that",
"growth",
"and",
"adaptation",
"of",
"UWO",
"under",
"a",
"stressful",
"and",
"extreme",
"environment",
"poises",
"this",
"extremophile",
"for",
"better",
"success",
"under",
"changing",
"environmental",
"conditions.",
"Key",
"words:",
"Acclimation,",
"Antarctica,",
"Chlamydomonas",
"raudensis,",
"climate",
"change,",
"phenotypic",
"plasticity,",
"photostasis,",
"PSII",
"excitation",
"pressure.",
"Introduction",
"Over",
"80%",
"of",
"the",
"earth’s",
"biosphere",
"is",
"permanently",
"cold",
"(Russel,",
"1990),",
"and",
"many",
"photoautotrophic",
"organisms",
"such",
"as",
"green",
"algae",
"are",
"able",
"to",
"withstand,",
"and",
"even",
"flourish",
"under,",
"conditions",
"that",
"are",
"considered",
"non-optimal",
"for",
"life.",
"Algae",
"living",
"in",
"the",
"Arctic",
"and",
"Antarctic",
"have",
"been",
"studied",
"for",
"the",
"last",
"170",
"years,",
"but",
"it",
"is",
"only",
"in",
"the",
"last",
"20",
"years",
"that",
"great",
"effort",
"and",
"success",
"has",
"been",
"achieved",
"in",
"isolating",
"these",
"unique",
"organisms",
"and",
"cultivating",
"them",
"in",
"the",
"laboratory",
"for",
"physiological",
"studies",
"(reviewed",
"in",
"Mock",
"and",
"Thomas,",
"2008).",
"The",
"extremophilic",
"green",
"alga,",
"Chlamydomonas",
"raudensis",
"Ettl.",
"UWO",
"241",
"(hereafter",
"referred",
"to",
"as",
"UWO),",
"was",
"isolated",
"from",
"the",
"deepest",
"photobiotic",
"zone",
"17",
"m",
"below",
"the",
"perma-",
"nent",
"ice",
"cover",
"of",
"Lake",
"Bonney,",
"Antarctica",
"(Lizotte",
"and",
"Priscu,",
"1994).",
"Photosynthetic",
"organisms",
"play",
"a",
"critical",
"role",
"in",
"the",
"permanently",
"ice-covered",
"lakes",
"in",
"West",
"Antarctica",
"as",
"the",
"primary",
"productivity",
"of",
"the",
"continent",
"is",
"largely",
"provided",
"by",
"green",
"algae",
"and",
"as",
"algal",
"symbionts",
"with",
"fungi.",
"Temper-",
"ature",
"gradients",
"are",
"responsible",
"for",
"vertical",
"stratification",
"in",
"aquatic",
"systems;",
"however,",
"in",
"Lake",
"Bonney,",
"stratification",
"is",
"Abbreviations:",
"1–qP,",
"PSII",
"excitation",
"pressure;",
"Chl,",
"chlorophyll;",
"Fm,",
"maximal",
"fluorescence",
"level",
"in",
"dark-adapted",
"cultures;",
"Fm’,",
"maximal",
"fluorescence",
"level",
"in",
"light-",
"adapted",
"cultures;",
"Fo,",
"minimal",
"fluorescence",
"level",
"in",
"dark-adapted",
"cultures;",
"F",
",",
"maximal",
"variable",
"fluorescence",
"in",
"dark-adapted",
"cultures;",
"Fv/Fm,",
"maximum",
"PSII",
"v",
"photochemical",
"efficiciency;",
"LHCII,",
"light",
"harvesting",
"complexes",
"associated",
"with",
"PSII;",
"PSI,",
"photosystem",
"I;",
"PSII,",
"photosystem",
"II;",
"QA,",
"first",
"stable",
"quinone",
"electron",
"acceptor",
"in",
"PSII;",
"SAG,",
"Chlamydomonas",
"raudensis",
"Ettl.",
"49.72;",
"UWO,",
"Chlamydomonas",
"raudensis",
"Ettl.",
"UWO",
"241.",
"ª",
"2010",
"The",
"Author(s).",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/by-",
"nc/2.5),",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Huda",
"et",
"al.",
"Mobile",
"DNA",
"2010,",
"1:2",
"http://www.mobilednajournal.com/content/1/1/2",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"Open",
"Access",
"Epigenetic",
"histone",
"modifications",
"of",
"human",
"transposable",
"elements:",
"genome",
"defense",
"versus",
"exaptation",
"Ahsan",
"Huda1,",
"Leonardo",
"Mariño-Ramírez2,3,",
"I",
"King",
"Jordan1*",
"Abstract",
"Background:",
"Transposition",
"is",
"disruptive",
"in",
"nature",
"and,",
"thus,",
"it",
"is",
"imperative",
"for",
"host",
"genomes",
"to",
"evolve",
"mechanisms",
"that",
"suppress",
"the",
"activity",
"of",
"transposable",
"elements",
"(TEs).",
"At",
"the",
"same",
"time,",
"transposition",
"also",
"provides",
"diverse",
"sequences",
"that",
"can",
"be",
"exapted",
"by",
"host",
"genomes",
"as",
"functional",
"elements.",
"These",
"notions",
"form",
"the",
"basis",
"of",
"two",
"competing",
"hypotheses",
"pertaining",
"to",
"the",
"role",
"of",
"epigenetic",
"modifications",
"of",
"TEs",
"in",
"eukaryotic",
"genomes:",
"the",
"genome",
"defense",
"hypothesis",
"and",
"the",
"exaptation",
"hypothesis.",
"To",
"date,",
"all",
"available",
"evidence",
"points",
"to",
"the",
"genome",
"defense",
"hypothesis",
"as",
"the",
"best",
"explanation",
"for",
"the",
"biological",
"role",
"of",
"TE",
"epigenetic",
"modifications.",
"Results:",
"We",
"evaluated",
"several",
"predictions",
"generated",
"by",
"the",
"genome",
"defense",
"hypothesis",
"versus",
"the",
"exaptation",
"hypothesis",
"using",
"recently",
"characterized",
"epigenetic",
"histone",
"modification",
"data",
"for",
"the",
"human",
"genome.",
"To",
"this",
"end,",
"we",
"mapped",
"chromatin",
"immunoprecipitation",
"sequence",
"tags",
"from",
"38",
"histone",
"modifications,",
"characterized",
"in",
"CD4+",
"T",
"cells,",
"to",
"the",
"human",
"genome",
"and",
"calculated",
"their",
"enrichment",
"and",
"depletion",
"in",
"all",
"families",
"of",
"human",
"TEs.",
"We",
"found",
"that",
"several",
"of",
"these",
"families",
"are",
"significantly",
"enriched",
"or",
"depleted",
"for",
"various",
"histone",
"modifications,",
"both",
"active",
"and",
"repressive.",
"The",
"enrichment",
"of",
"human",
"TE",
"families",
"with",
"active",
"histone",
"modifications",
"is",
"consistent",
"with",
"the",
"exaptation",
"hypothesis",
"and",
"stands",
"in",
"contrast",
"to",
"previous",
"analyses",
"that",
"have",
"found",
"mammalian",
"TEs",
"to",
"be",
"exclusively",
"repressively",
"modified.",
"Comparisons",
"between",
"TE",
"families",
"revealed",
"that",
"older",
"families",
"carry",
"more",
"histone",
"modifications",
"than",
"younger",
"ones,",
"another",
"observation",
"consistent",
"with",
"the",
"exaptation",
"hypothesis.",
"However,",
"data",
"from",
"within",
"family",
"analyses",
"on",
"the",
"relative",
"ages",
"of",
"epigenetically",
"modified",
"elements",
"are",
"consistent",
"with",
"both",
"the",
"genome",
"defense",
"and",
"exaptation",
"hypotheses.",
"Finally,",
"TEs",
"located",
"proximal",
"to",
"genes",
"carry",
"more",
"histone",
"modifications",
"than",
"the",
"ones",
"that",
"are",
"distal",
"to",
"genes,",
"as",
"may",
"be",
"expected",
"if",
"epigenetically",
"modified",
"TEs",
"help",
"to",
"regulate",
"the",
"expression",
"of",
"nearby",
"host",
"genes.",
"Conclusions:",
"With",
"a",
"few",
"exceptions,",
"most",
"of",
"our",
"findings",
"support",
"the",
"exaptation",
"hypothesis",
"for",
"the",
"role",
"of",
"TE",
"epigenetic",
"modifications",
"when",
"vetted",
"against",
"the",
"genome",
"defense",
"hypothesis.",
"The",
"recruitment",
"of",
"epigenetic",
"modifications",
"may",
"represent",
"an",
"additional",
"mechanism",
"by",
"which",
"TEs",
"can",
"contribute",
"to",
"the",
"regulatory",
"functions",
"of",
"their",
"host",
"genomes.",
"Background",
"Transposable",
"elements",
"(TEs)",
"are",
"mobile",
"DNA",
"sequences",
"that",
"can",
"replicate",
"to",
"extremely",
"high",
"genomic",
"copy",
"num-",
"bers.",
"TEs",
"are",
"also",
"widely",
"distributed;",
"they",
"have",
"been",
"found",
"within",
"genomes",
"representing",
"all",
"major",
"eukaryotic",
"lineages.",
"Accordingly,",
"TEs",
"have",
"had",
"a",
"profound",
"impact",
"on",
"the",
"structure,",
"function",
"and",
"evolution",
"of",
"their",
"host",
"genomes.",
"In",
"this",
"study,",
"we",
"explore",
"the",
"relationship",
"*",
"Correspondence:",
"king.jordan@biology.gatech.edu",
"1School",
"of",
"Biology,",
"Georgia",
"Institute",
"of",
"Technology,",
"310",
"Ferst",
"Drive,",
"Atlanta,",
"GA",
"30332,",
"USA",
"between",
"TEs",
"and",
"the",
"epigenetic",
"regulatory",
"mechanisms",
"that",
"are",
"thought",
"to",
"have",
"evolved",
"in",
"response",
"to",
"their",
"proliferation",
"in",
"eukaryotic",
"genomes",
"[1].",
"Transposition",
"is",
"inherently",
"disruptive",
"in",
"nature.",
"Therefore,",
"in",
"order",
"to",
"ensure",
"their",
"own",
"survival,",
"host",
"genomes",
"must",
"have",
"evolved",
"various",
"repressive",
"mechan-",
"isms",
"to",
"guard",
"against",
"deleterious",
"TE",
"insertions.",
"Epige-",
"netic",
"regulatory",
"modifications",
"represent",
"a",
"broad",
"class",
"of",
"silencing",
"mechanisms",
"that",
"may",
"have",
"come",
"into",
"exis-",
"tence",
"in",
"response",
"to",
"the",
"need",
"to",
"repress",
"TEs",
"[1-4].",
"The",
"notion",
"that",
"epigenetic",
"regulatory",
"systems",
"evolved",
"to",
"©",
"2010",
"Huda",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
] | [
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869
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] | [
"Tan",
"et",
"al.",
"BMC",
"Pregnancy",
"and",
"Childbirth",
"2010,",
"10:3",
"http://www.biomedcentral.com/1471-2393/10/3",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Cost-effectiveness",
"of",
"external",
"cephalic",
"version",
"for",
"term",
"breech",
"presentation",
"Jonathan",
"M",
"Tan1*,",
"Alex",
"Macario2,3,",
"Brendan",
"Carvalho2,",
"Maurice",
"L",
"Druzin4,",
"Yasser",
"Y",
"El-Sayed4",
"Abstract",
"Background:",
"External",
"cephalic",
"version",
"(ECV)",
"is",
"recommended",
"by",
"the",
"American",
"College",
"of",
"Obstetricians",
"and",
"Gynecologists",
"to",
"convert",
"a",
"breech",
"fetus",
"to",
"vertex",
"position",
"and",
"reduce",
"the",
"need",
"for",
"cesarean",
"delivery.",
"The",
"goal",
"of",
"this",
"study",
"was",
"to",
"determine",
"the",
"incremental",
"cost-effectiveness",
"ratio,",
"from",
"society’s",
"perspective,",
"of",
"ECV",
"compared",
"to",
"scheduled",
"cesarean",
"for",
"term",
"breech",
"presentation.",
"Methods:",
"A",
"computer-based",
"decision",
"model",
"(TreeAge",
"Pro",
"2008,",
"Tree",
"Age",
"Software,",
"Inc.)",
"was",
"developed",
"for",
"a",
"hypothetical",
"base",
"case",
"parturient",
"presenting",
"with",
"a",
"term",
"singleton",
"breech",
"fetus",
"with",
"no",
"contraindications",
"for",
"vaginal",
"delivery.",
"The",
"model",
"incorporated",
"actual",
"hospital",
"costs",
"(e.g.,",
"$8,023",
"for",
"cesarean",
"and",
"$5,581",
"for",
"vaginal",
"delivery),",
"utilities",
"to",
"quantify",
"health-related",
"quality",
"of",
"life,",
"and",
"probabilities",
"based",
"on",
"analysis",
"of",
"published",
"literature",
"of",
"successful",
"ECV",
"trial,",
"spontaneous",
"reversion,",
"mode",
"of",
"delivery,",
"and",
"need",
"for",
"unanticipated",
"emergency",
"cesarean",
"delivery.",
"The",
"primary",
"endpoint",
"was",
"the",
"incremental",
"cost-effectiveness",
"ratio",
"in",
"dollars",
"per",
"quality-adjusted",
"year",
"of",
"life",
"gained.",
"A",
"threshold",
"of",
"$50,000",
"per",
"quality-adjusted",
"life-years",
"(QALY)",
"was",
"used",
"to",
"determine",
"cost-effectiveness.",
"Results:",
"The",
"incremental",
"cost-effectiveness",
"of",
"ECV,",
"assuming",
"a",
"baseline",
"58%",
"success",
"rate,",
"equaled",
"$7,900/QALY.",
"If",
"the",
"estimated",
"probability",
"of",
"successful",
"ECV",
"is",
"less",
"than",
"32%,",
"then",
"ECV",
"costs",
"more",
"to",
"society",
"and",
"has",
"poorer",
"QALYs",
"for",
"the",
"patient.",
"However,",
"as",
"the",
"probability",
"of",
"successful",
"ECV",
"was",
"between",
"32%",
"and",
"63%,",
"ECV",
"cost",
"more",
"than",
"cesarean",
"delivery",
"but",
"with",
"greater",
"associated",
"QALY",
"such",
"that",
"the",
"cost-effectiveness",
"ratio",
"was",
"less",
"than",
"$50,000/",
"QALY.",
"If",
"the",
"probability",
"of",
"successful",
"ECV",
"was",
"greater",
"than",
"63%,",
"the",
"computer",
"modeling",
"indicated",
"that",
"a",
"trial",
"of",
"ECV",
"is",
"less",
"costly",
"and",
"with",
"better",
"QALYs",
"than",
"a",
"scheduled",
"cesarean.",
"The",
"cost-effectiveness",
"of",
"a",
"trial",
"of",
"ECV",
"is",
"most",
"sensitive",
"to",
"its",
"probability",
"of",
"success,",
"and",
"not",
"to",
"the",
"probabilities",
"of",
"a",
"cesarean",
"after",
"ECV,",
"spontaneous",
"reversion",
"to",
"breech,",
"successful",
"second",
"ECV",
"trial,",
"or",
"adverse",
"outcome",
"from",
"emergency",
"cesarean.",
"Conclusions:",
"From",
"society’s",
"perspective,",
"ECV",
"trial",
"is",
"cost-effective",
"when",
"compared",
"to",
"a",
"scheduled",
"cesarean",
"for",
"breech",
"presentation",
"provided",
"the",
"probability",
"of",
"successful",
"ECV",
"is",
">",
"32%.",
"Improved",
"algorithms",
"are",
"needed",
"to",
"more",
"precisely",
"estimate",
"the",
"likelihood",
"that",
"a",
"patient",
"will",
"have",
"a",
"successful",
"ECV.",
"Background",
"Breech",
"presentation",
"at",
"term",
"occurs",
"in",
"3-4%",
"of",
"pregnan-",
"cies",
"and",
"is",
"managed",
"with",
"elective",
"cesarean,",
"assisted",
"vagi-",
"nal",
"delivery,",
"or",
"external",
"cephalic",
"version",
"(ECV)",
"[1,2].",
"Approximately",
"87%",
"of",
"breech",
"presentations",
"in",
"the",
"Uni-",
"ted",
"States",
"resulted",
"in",
"cesarean",
"delivery",
"[3],",
"a",
"significant",
"increase",
"from",
"previous",
"years",
"[4,5].",
"Breech",
"presentation",
"is",
"the",
"third",
"most",
"common",
"indication",
"for",
"cesarean",
"and",
"in",
"some",
"hospitals",
"breech",
"presentations",
"are",
"managed",
"exclusively",
"by",
"cesarean",
"delivery",
"[6,7].",
"This",
"may",
"in",
"part",
"be",
"due",
"to",
"the",
"Term",
"Breech",
"Trial",
"in",
"2000",
"that",
"confirmed",
"*",
"Correspondence:",
"jonathan.tan@stonybrook.edu",
"1Department",
"of",
"Anesthesiology,",
"Stony",
"Brook",
"University",
"Medical",
"Center,",
"Stony",
"Brook,",
"New",
"York,",
"11794-8480,",
"USA",
"that",
"breech",
"presentations",
"delivered",
"by",
"cesareans",
"resulted",
"in",
"less",
"neonatal",
"mortality",
"and",
"short-term",
"morbidity",
"compared",
"to",
"vaginal",
"breech",
"delivery",
"[8].",
"Maternal",
"com-",
"plications",
"were",
"also",
"found",
"to",
"be",
"similar",
"for",
"cesarean",
"and",
"vaginal",
"delivery",
"in",
"the",
"short",
"[9]",
"and",
"long",
"term",
"[10,11].",
"Practice",
"guidelines",
"from",
"the",
"American",
"College",
"of",
"Obstetrics",
"and",
"Gynecologists",
"(ACOG)",
"in",
"2006",
"recom-",
"mend",
"that",
"decisions",
"regarding",
"the",
"mode",
"of",
"delivery",
"for",
"breech",
"presentation",
"are",
"dependent",
"on",
"the",
"health",
"care",
"provider’s",
"experience.",
"ACOG",
"also",
"suggests",
"that",
"cesarean",
"deliveries",
"are",
"preferred",
"over",
"vaginal",
"breech",
"deliveries",
"[12].",
"The",
"desire",
"to",
"decrease",
"the",
"number",
"of",
"cesareans",
"has",
"renewed",
"interest",
"in",
"ECV",
"[13,14].",
"In",
"fact,",
"ACOG",
"recommends",
"ECV",
"to",
"lower",
"the",
"number",
"of",
"breech",
"©",
"2010",
"Tan",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"CELLULAR",
"NEUROSCIENCE",
"At",
"immature",
"mossy",
"fibers-CA3",
"connections,",
"activation",
"of",
"presynaptic",
"GABA",
"receptors",
"by",
"endogenously",
"released",
"B",
"GABA",
"contributes",
"to",
"synapses",
"silencing",
"Victoria",
"F.",
"Safiulina",
"and",
"Enrico",
"Cherubini*",
"Neuroscience",
"Programme,",
"International",
"School",
"for",
"Advanced",
"Studies,Trieste,",
"Italy",
"ORIGINAL",
"RESEARCH",
"ARTICLE",
"published:",
"26",
"February",
"2009",
"doi:",
"10.3389/neuro.03.001.2009",
"Edited",
"by:",
"Daniel",
"Johnston,",
"University",
"ofTexas,",
"USA",
"Reviewed",
"by:",
"Daniel",
"Johnston,",
"University",
"ofTexas,",
"USA",
"German",
"Barrionuevo,",
"University",
"of",
"Pittsburgh,",
"USA",
"*Correspondence:",
"Enrico",
"Cherubini,",
"International",
"School",
"of",
"Advanced",
"Studies",
"(SISSA),",
"Department",
"of",
"Neurobiology,",
"Ed.",
"Q1",
"Area",
"Science",
"Park,",
"S.S.14",
"Km",
"163.5,",
"34012",
"Basovizza,",
"Trieste,",
"Italy.",
"e-mail:",
"cher@sissa.it",
"Early",
"in",
"postnatal",
"life",
"correlated",
"GABAergic",
"activity",
"in",
"the",
"hippocampus",
"is",
"thought",
"to",
"play",
"a",
"crucial",
"role",
"in",
"synaptogenesis",
"and",
"in",
"the",
"development",
"of",
"adult",
"neuronal",
"networks.",
"Unlike",
"adulthood,",
"at",
"this",
"developmental",
"stage,",
"mossy",
"fibers",
"(MF)",
"which",
"are",
"the",
"axons",
"of",
"granule",
"cells,",
"release",
"GABA",
"into",
"CA3",
"principal",
"cells",
"and",
"interneurons.",
"Here,",
"we",
"tested",
"the",
"hypothesis",
"that",
"at",
"MF-CA3",
"connections,",
"tonic",
"activation",
"of",
"GABAB",
"autoreceptors",
"by",
"GABA",
"is",
"responsible",
"for",
"the",
"low",
"probability",
"of",
"release",
"and",
"synapse",
"silencing.",
"Blocking",
"GABAB",
"receptors",
"with",
"CGP55845",
"enhanced",
"the",
"probability",
"of",
"GABA",
"release",
"and",
"switched",
"on",
"silent",
"synapses",
"while",
"the",
"opposite",
"was",
"observed",
"with",
"baclofen.",
"Both",
"these",
"effects",
"were",
"presynaptic",
"and",
"were",
"associated",
"with",
"changes",
"in",
"paired-pulse",
"ratio",
"and",
"coefficient",
"of",
"variation.",
"In",
"addition,",
"enhancing",
"the",
"extracellular",
"GABA",
"concentration",
"by",
"repetitive",
"stimulation",
"of",
"MF",
"or",
"by",
"blocking",
"the",
"GABA",
"transporter",
"GAT-1,",
"switched",
"off",
"active",
"synapses,",
"an",
"effect",
"that",
"was",
"prevented",
"by",
"CGP55845.",
"In",
"the",
"presence",
"of",
"CGP55845,",
"stimulation",
"of",
"MF-induced",
"synaptic",
"potentiation.",
"The",
"shift",
"of",
"EGABA",
"from",
"the",
"depolarizing",
"to",
"the",
"hyperpolarizing",
"direction",
"with",
"bumetanide,",
"a",
"blocker",
"of",
"the",
"cation-chloride",
"co-transporter",
"NKCC1,",
"prevented",
"synaptic",
"potentiation",
"and",
"caused",
"synaptic",
"depression,",
"suggesting",
"that",
"the",
"depolarizing",
"action",
"of",
"GABA",
"observed",
"in",
"the",
"presence",
"of",
"CGP55845",
"is",
"responsible",
"for",
"the",
"potentiating",
"effect.",
"It",
"is",
"proposed",
"that,",
"activation",
"of",
"GABAB",
"receptors",
"by",
"spillover",
"of",
"GABA",
"from",
"MF",
"terminals",
"reduces",
"the",
"probability",
"of",
"release",
"and",
"contributes",
"to",
"synapses",
"silencing.",
"This",
"would",
"act",
"as",
"a",
"filter",
"to",
"prevent",
"excessive",
"activation",
"of",
"the",
"auto-associative",
"CA3",
"network",
"and",
"the",
"emergence",
"of",
"seizures.",
"Keywords:",
"mossy",
"fiber-CA3",
"synapses,",
"immature",
"hippocampus,",
"probability",
"of",
"GABA",
"release,",
"GABAA-mediated",
"synaptic",
"currents,",
"GABAB",
"autoreceptors,",
"GABA",
"transporters,",
"frequency-dependent",
"synaptic",
"depression",
"INTRODUCTION",
"1998;",
"Vogt",
"and",
"Nicoll,",
"1999),",
"adenosine",
"receptors",
"(Thompson",
"In",
"the",
"developing",
"hippocampus,",
"GABAergic",
"signaling",
"plays",
"a",
"et",
"al.,",
"1992),",
"kainate",
"receptors",
"(Castillo",
"et",
"al.,",
"1997;",
"Vignes",
"and",
"crucial",
"role",
"in",
"generating",
"primitive",
"patterns",
"of",
"network",
"activity",
"Collingridge,",
"1997)",
"and",
"peptides",
"(Weisskopf",
"et",
"al.,",
"1993).",
"GABAB",
"known",
"as",
"giant",
"depolarizing",
"potentials",
"or",
"GDPs",
"(Ben-Ari",
"et",
"al.,",
"receptors",
"which",
"are",
"coupled",
"to",
"Gi",
"and",
"Go",
"proteins",
"are",
"localized",
"on",
"2007).",
"The",
"higher",
"intracellular",
"chloride",
"concentration",
"present",
"in",
"both",
"pre",
"and",
"postsynaptic",
"membranes",
"(Bettler",
"et",
"al.,",
"2004;",
"Misgeld",
"immature",
"neurons",
"(Rivera",
"et",
"al.,",
"1999)",
"leads",
"to",
"an",
"efflux",
"of",
"chlo-",
"et",
"al.,",
"1995).",
"Activation",
"of",
"postsynaptic",
"GABAB",
"receptors",
"causes",
"the",
"ride",
"and",
"to",
"a",
"membrane",
"depolarization",
"which",
"triggers",
"sodium",
"opening",
"of",
"inwardly",
"rectifying",
"potassium",
"channels",
"(Lüscher",
"et",
"al.,",
"spikes",
"and",
"excites",
"postsynaptic",
"cells",
"(Ben-Ari",
"et",
"al.,",
"1989).",
"1997)",
"whereas",
"activation",
"of",
"presynaptic",
"GABAB",
"receptors",
"causes",
"GABA-induced",
"membrane",
"depolarization",
"activates",
"N-methyl-",
"a",
"reduction",
"in",
"transmitter",
"release",
"mainly",
"via",
"inhibition",
"of",
"P/Q",
"d-aspartate",
"receptors",
"and",
"voltage-dependent",
"calcium",
"channels",
"and",
"N",
"types",
"of",
"voltage-dependent",
"calcium",
"channels",
"(Poncer",
"et",
"al.,",
"with",
"consequent",
"calcium",
"rise",
"inside",
"the",
"cells",
"and",
"activation",
"of",
"1997).",
"While",
"postsynaptic",
"GABAB",
"receptors",
"are",
"developmentally",
"intracellular",
"signaling",
"cascades.",
"Such",
"mechanisms",
"are",
"central",
"to",
"regulated",
"(Cherubini",
"et",
"al.,",
"1998;",
"Gaiarsa",
"et",
"al.,",
"1995),",
"presynap-",
"the",
"well-known",
"trophic",
"action",
"of",
"GABA",
"which",
"regulates",
"several",
"tic",
"GABAB",
"receptors",
"are",
"present",
"and",
"functional",
"already",
"at",
"birth.",
"key",
"developmental",
"steps",
"including",
"DNA",
"synthesis,",
"cell",
"migration,",
"It",
"has",
"been",
"shown",
"that",
"they",
"control",
"network",
"activity",
"(McLean",
"cell",
"growth",
"and",
"synapse",
"formation",
"(Owens",
"and",
"Kriegstein,",
"2002).",
"et",
"al.,",
"1996)",
"and",
"modulate",
"the",
"amplitude",
"of",
"glutamate-",
"or",
"GABA-",
"In",
"addition,",
"evidence",
"has",
"been",
"recently",
"provided",
"that",
"the",
"prin-",
"mediated",
"postsynaptic",
"currents",
"in",
"CA3",
"principal",
"cells",
"(Gaiarsa",
"cipal",
"neurotransmitter",
"released",
"from",
"mossy",
"fibers",
"(MF)",
"during",
"et",
"al.,",
"1995).",
"However,",
"these",
"studies",
"failed",
"in",
"identifying",
"where",
"the",
"first",
"week",
"of",
"postnatal",
"life",
"is",
"GABA",
"(Safiulina",
"et",
"al.,",
"2006).",
"In",
"GABAA-mediated",
"synaptic",
"currents",
"originated",
"from.",
"adulthood,",
"these",
"fibers",
"are",
"glutamatergic",
"and",
"are",
"endowed",
"with",
"a",
"Here,",
"we",
"addressed",
"whether,",
"immediately",
"after",
"birth,",
"number",
"of",
"receptor",
"types",
"which",
"up",
"or",
"down-regulate",
"the",
"trans-",
"MF-induced",
"GABAergic",
"responses",
"in",
"CA3",
"principal",
"cells",
"could",
"mitter",
"release.",
"These",
"include",
"metabotropic",
"glutamate",
"receptors",
"be",
"modulated",
"by",
"GABAB",
"autoreceptors.",
"We",
"report",
"that",
"block-",
"(Kamiya",
"et",
"al.,",
"1996),",
"GABAA",
"and",
"GABAB",
"receptors",
"(Min",
"et",
"al.,",
"ing",
"GABAB",
"receptors",
"with",
"CGP55845",
"enhanced",
"synaptic",
"efficacy",
"Frontiers",
"in",
"Cellular",
"Neuroscience",
"www.frontiersin.org",
"February",
"2009",
"|",
"Volume",
"3",
"|",
"Article",
"1",
"|",
"1"
] | [
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] | [
"Tremblay",
"et",
"al.",
"Diabetology",
"&",
"Metabolic",
"Syndrome",
"2012,",
"4:4",
"http://www.dmsjournal.com/content/4/1/4",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"DIABETOLOGY",
"&",
"METABOLIC",
"SYNDROME",
"Open",
"Access",
"Salivary",
"pH",
"as",
"a",
"Marker",
"of",
"Plasma",
"Adiponectin",
"Concentrations",
"in",
"Women",
"Monique",
"Tremblay,",
"Yacine",
"Loucif,",
"Julie",
"Methot,",
"Diane",
"Brisson",
"and",
"Daniel",
"Gaudet*",
"Abstract",
"Background:",
"Plasma",
"adiponectin",
"is",
"a",
"significant",
"correlate",
"of",
"the",
"pro-inflammatory",
"cardiometabolic",
"risk",
"profile",
"associated",
"with",
"obesity",
"and",
"type",
"2",
"diabetes.",
"Salivary",
"pH",
"is",
"influenced",
"by",
"several",
"cardiometabolic",
"risk",
"components",
"such",
"as",
"inflammation,",
"oxidation",
"and",
"numerous",
"oral",
"and",
"systemic",
"health",
"modulators,",
"including",
"the",
"menopausal",
"status.",
"This",
"study",
"aimed",
"to",
"assess",
"the",
"association",
"between",
"plasma",
"adiponectin",
"concentrations",
"and",
"salivary",
"pH",
"in",
"women",
"according",
"to",
"the",
"menopausal",
"status.",
"Method:",
"Unstimulated",
"saliva",
"collection",
"was",
"performed",
"in",
"151",
"Caucasian",
"women",
"of",
"French-Canadian",
"origin",
"(53",
"premenopausal",
"women",
"(PMW)",
"and",
"98",
"menopausal",
"women",
"(MW)).",
"Student’s",
"t",
"test,",
"ANOVA",
"and",
"linear",
"regression",
"models",
"were",
"used",
"to",
"assess",
"the",
"association",
"between",
"plasma",
"adiponectin",
"concentrations",
"and",
"salivary",
"pH.",
"Results:",
"Plasma",
"adiponectin",
"levels",
"increased",
"as",
"a",
"function",
"of",
"salivary",
"pH",
"in",
"the",
"whole",
"sample",
"and",
"among",
"MW",
"(r",
"=",
"0.29",
"and",
"r",
"=",
"0.36,",
"p",
"<",
"0.001).",
"The",
"proportion",
"of",
"the",
"variance",
"of",
"plasma",
"adiponectin",
"levels",
"explained",
"by",
"the",
"salivary",
"pH",
"(R2)",
"was",
"10.8%",
"(p",
"<",
"0.001).",
"Plasma",
"adiponectin",
"levels",
"progressively",
"increased",
"across",
"salivary",
"pH",
"quartiles",
"(p",
"=",
"0.005).",
"Conclusions:",
"These",
"results",
"suggest",
"that",
"salivary",
"pH",
"is",
"a",
"significant",
"correlate",
"of",
"plasma",
"adiponectin",
"levels",
"in",
"women.",
"With",
"the",
"increasing",
"prevalence",
"of",
"type",
"2",
"diabetes",
"and",
"obesity,",
"new",
"technologies",
"should",
"be",
"developed",
"to",
"more",
"easily",
"monitor",
"health",
"status,",
"disease",
"onset",
"and",
"progression.",
"Salivary",
"pH,",
"a",
"simple,",
"inexpensive",
"and",
"non-",
"invasive",
"measure,",
"could",
"be",
"a",
"very",
"promising",
"avenue.",
"Keywords:",
"Salivary",
"pH,",
"Adiponectin,",
"Cardiometabolic",
"risk,",
"Diabetes",
"Introduction",
"According",
"to",
"the",
"World",
"Health",
"Organization,",
"by",
"2015",
"approximately",
"2.3",
"billion",
"adults",
"worldwide",
"will",
"be",
"over-",
"weight",
"and",
"more",
"than",
"700",
"million",
"obese",
"[1].",
"The",
"bur-",
"den",
"of",
"the",
"associated",
"cardiometabolic",
"risk",
"components,",
"such",
"as",
"type",
"2",
"diabetes",
"mellitus",
"(T2DM),",
"dyslipidemia",
"and",
"cardiovascular",
"disease",
"(CVD),",
"is",
"also",
"set",
"to",
"grow",
"rapidly.",
"Not",
"only",
"is",
"this",
"epidemic",
"progression",
"observed",
"in",
"developed",
"countries,",
"but",
"it",
"increasingly",
"affects",
"devel-",
"oping",
"countries",
"too.",
"Moreover,",
"it",
"has",
"been",
"estimated",
"that",
"by",
"2025,",
"three",
"out",
"of",
"four",
"people",
"with",
"T2DM",
"or",
"other",
"cardiometabolic",
"risk",
"components",
"will",
"be",
"living",
"in",
"third",
"world",
"countries",
"[2].",
"It",
"is",
"therefore",
"mandatory",
"to",
"develop",
"improved",
"and",
"more",
"accessible",
"screening",
"tools",
"in",
"order",
"to",
"devise",
"finer",
"preventive",
"and",
"therapeutic",
"strategies.",
"*",
"Correspondence:",
"daniel.gaudet@umontreal.ca",
"Department",
"of",
"Medicine,",
"Université",
"de",
"Montréal,",
"ECOGENE-21",
"and",
"Lipid",
"Clinic,",
"Chicoutimi",
"Hospital,",
"Saguenay,",
"QC,",
"Canada",
"Adiponectin",
"has",
"been",
"identified",
"as",
"a",
"new",
"biochemical",
"marker",
"of",
"visceral",
"fat",
"accumulation",
"and",
"could",
"represent",
"a",
"critical",
"link",
"between",
"obesity",
"and",
"the",
"cardiometabolic",
"risk",
"profile",
"[3].",
"Adiponectin",
"is",
"an",
"adipocyte-derived",
"protein,",
"highly",
"abundant",
"in",
"plasma,",
"with",
"concentrations",
"ranging",
"from",
"5",
"to",
"30",
"μg/ml",
"(0.01%",
"of",
"total",
"plasma)",
"[4].",
"Its",
"levels",
"correlate",
"with",
"the",
"development",
"of",
"T2DM",
"[5,6],",
"dyslipide-",
"mia,",
"hypertension",
"[7]",
"and",
"CVD",
"[8].",
"Adiponectin",
"may",
"also",
"have",
"different",
"immune",
"functions",
"in",
"several",
"biological",
"systems.",
"It",
"exerts",
"anti-inflammatory,",
"insulin-sensitizing",
"and",
"anti-atherosclerotic",
"effects",
"when",
"secreted",
"into",
"the",
"circula-",
"tion",
"[9].",
"Therefore,",
"in",
"the",
"search",
"for",
"indexes",
"of",
"metabolic",
"perturbations",
"and",
"proinflammatory",
"status",
"predisposing",
"to",
"a",
"deteriorated",
"cardiometabolic",
"risk",
"profile,",
"the",
"measure-",
"ment",
"of",
"plasma",
"adiponectin",
"concentrations",
"is",
"increasingly",
"studied.",
"However,",
"in",
"the",
"context",
"of",
"this",
"epidemic",
"progres-",
"sion",
"of",
"T2DM",
"and",
"obesity",
"and",
"in",
"order",
"to",
"develop",
"accessi-",
"ble",
"tools",
"without",
"increasing",
"the",
"burden",
"of",
"healthcare",
"costs,",
"it",
"is",
"imperative",
"to",
"develop",
"alternatives",
"to",
"the",
"traditional",
"©",
"2012",
"Tremblay",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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"The",
"expression",
"of",
"a",
"large",
"set",
"of",
"neuronal",
"mRNAs",
"is",
"altered",
"when",
"FMRP",
"is",
"lost,",
"thus",
"causing",
"defects",
"in",
"neuronal",
"morphology",
"and",
"physiology.",
"FMRP",
"regulates",
"mRNA",
"stability,",
"dendritic",
"targeting,",
"and",
"protein",
"synthesis.",
"At",
"synapses,",
"FMRP",
"represses",
"protein",
"synthesis",
"by",
"forming",
"a",
"complex",
"with",
"the",
"Cytoplasmic",
"FMRP",
"Interacting",
"Protein",
"1",
"(CYFIP1)",
"and",
"the",
"cap-binding",
"protein",
"eIF4E.",
"Here,",
"we",
"review",
"the",
"clinical,",
"genetic,",
"and",
"molecular",
"aspects",
"of",
"FXS",
"with",
"a",
"special",
"focus",
"on",
"the",
"receptor",
"signaling",
"that",
"regulates",
"FMRP-dependent",
"protein",
"synthesis.",
"We",
"further",
"discuss",
"the",
"FMRP–CYFIP1",
"complex",
"and",
"its",
"potential",
"relevance",
"for",
"ID",
"and",
"autism.",
"Keywords",
"Fragile",
"X",
"syndrome",
".",
"Autism",
".",
"FMRP.",
"Protein",
"synthesis",
".",
"mRNPs",
".",
"mRNA",
"metabolism",
".",
"Synaptic",
"plasticity",
"S.",
"De",
"Rubeis",
":",
"C.",
"Bagni",
"Center",
"for",
"Human",
"Genetics,",
"Katholieke",
"Universiteit",
"Leuven,",
"3000",
"Leuven,",
"Belgium",
"S.",
"De",
"Rubeis",
":",
"C.",
"Bagni",
"Department",
"of",
"Molecular",
"and",
"Developmental",
"Genetics,",
"Flanders",
"Institute",
"for",
"Biotechnology",
"(VIB),",
"3000",
"Leuven,",
"Belgium",
"C.",
"Bagni",
"(*)",
"Department",
"of",
"Experimental",
"Medicine",
"and",
"Biochemical",
"Sciences,",
"University",
"“Tor",
"Vergata”,",
"00133",
"Rome,",
"Italy",
"e-mail:",
"claudia.bagni@uniroma2.it",
"e-mail:",
"claudia.bagni@med.kuleuven.be",
"Fragile",
"X",
"and",
"fragile",
"X",
"tremor",
"ataxia",
"syndromes:",
"clinical",
"phenotypes",
"The",
"Fragile",
"X",
"syndrome",
"(FXS)",
"is",
"the",
"most",
"frequent",
"form",
"of",
"inherited",
"intellectual",
"disability",
"(Jacquemont",
"et",
"al.",
"2007).",
"Patients",
"with",
"FXS",
"have",
"physical",
"features,",
"such",
"as",
"large",
"ears,",
"an",
"elongated",
"face,",
"and",
"a",
"high",
"arched",
"palate,",
"which",
"have",
"been",
"reported",
"in",
"60%",
"of",
"prepubertal",
"FXS",
"boys.",
"Other",
"symptoms",
"include",
"connective",
"tissue",
"anomalies,",
"which",
"can",
"lead",
"to",
"a",
"prolapsed",
"mitral",
"valve,",
"scoliosis,",
"flat",
"feet,",
"and",
"joint",
"laxity",
"and",
"macro-orchidism",
"in",
"boys.",
"Macro-orchidism",
"affects",
"about",
"90%",
"of",
"boys",
"with",
"FXS",
"(Jacquemont",
"et",
"al.",
"2007)",
"but",
"the",
"causes",
"are",
"still",
"largely",
"unknown.",
"In",
"addition,",
"subtle",
"dysfunctions",
"of",
"the",
"hypothalamic-pituitary-thyroid",
"axis",
"have",
"been",
"reported",
"in",
"FXS",
"patients",
"(Bregman",
"et",
"al.",
"1990).",
"Studies",
"performed",
"in",
"Fmr1",
"KO",
"animals",
"did",
"not",
"reveal",
"altered",
"levels",
"of",
"the",
"follicle-stimulating",
"hormone,",
"but",
"an",
"increase",
"of",
"Sertoli",
"cell",
"proliferation",
"during",
"testis",
"development",
"(Slegtenhorst-Eegdeman",
"et",
"al.",
"1998).",
"Patients",
"display",
"a",
"broad",
"spectrum",
"of",
"cognitive",
"and",
"behavioral",
"deficits.",
"The",
"developmental",
"delay",
"is",
"the",
"most",
"consistent",
"feature,",
"with",
"a",
"mean",
"IQ",
"of",
"42",
"in",
"boys",
"and",
"severe",
"mental",
"retardation",
"in",
"about",
"25%",
"of",
"cases.",
"Since",
"the",
"disorder",
"is",
"X-linked",
"and",
"the",
"penetrance",
"is",
"variable,",
"females",
"are",
"usually",
"in",
"a",
"low-normal",
"range,",
"with",
"an",
"IQ",
"ranging",
"from",
"70",
"to",
"90",
"(Jacquemont",
"et",
"al.",
"2007).",
"Moreover,",
"epilepsy",
"has",
"been",
"described",
"in",
"13–18%",
"of",
"boys",
"and",
"4%",
"in",
"girls,",
"but",
"the",
"seizures",
"tend",
"to",
"resolve",
"during",
"childhood",
"(Berry-Kravis",
"2002).",
"Despite",
"the",
"severe",
"neurobehavioral",
"symptoms,",
"the",
"anatomical",
"studies",
"only",
"revealed",
"minor",
"abnormalities",
"in",
"post",
"mortem",
"brains",
"from",
"FXS",
"patients",
"(Hallahan",
"et",
"al.",
"2011;",
"Reiss",
"et",
"al.",
"1995).",
"The",
"most",
"prominent",
"neuroanatomical",
"feature",
"is",
"the",
"dysgenesis",
"of",
"dendritic",
"spines",
"that",
"appear",
"longer",
"and",
"thinner",
"than",
"normal,",
"likely",
"due",
"to",
"a",
"developmen-",
"tal",
"delay",
"in",
"spine",
"dynamics",
"and",
"in",
"transition",
"from",
"immature"
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] | [
"Cherrier",
"et",
"al.",
"BMC",
"Cancer",
"2010,",
"10:1",
"http://www.biomedcentral.com/1471-2407/10/1",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Changes",
"in",
"neuronal",
"activation",
"patterns",
"in",
"response",
"to",
"androgen",
"deprivation",
"therapy:",
"a",
"pilot",
"study",
"Monique",
"M",
"Cherrier1,3*,",
"Paul",
"R",
"Borghesani1,",
"Amy",
"L",
"Shelton4,",
"Celestia",
"S",
"Higano2",
"Abstract",
"Background:",
"A",
"common",
"treatment",
"option",
"for",
"men",
"with",
"prostate",
"cancer",
"is",
"androgen",
"deprivation",
"therapy",
"(ADT).",
"However,",
"men",
"undergoing",
"ADT",
"may",
"experience",
"physical",
"side",
"effects,",
"changes",
"in",
"quality",
"of",
"life",
"and",
"sometimes",
"psychiatric",
"and",
"cognitive",
"side",
"effects.",
"Methods:",
"In",
"this",
"study,",
"hormone",
"naïve",
"patients",
"without",
"evidence",
"of",
"metastases",
"with",
"a",
"rising",
"PSA",
"were",
"treated",
"with",
"nine",
"months",
"of",
"ADT.",
"Functional",
"magnetic",
"resonance",
"imaging",
"(fMRI)",
"of",
"the",
"brain",
"during",
"three",
"visuospatial",
"tasks",
"was",
"performed",
"at",
"baseline",
"prior",
"to",
"treatment",
"and",
"after",
"nine",
"months",
"of",
"ADT",
"in",
"five",
"subjects.",
"Seven",
"healthy",
"control",
"patients,",
"underwent",
"neuroimaging",
"at",
"the",
"same",
"time",
"intervals.",
"Results:",
"ADT",
"patients",
"showed",
"reduced,",
"task-related",
"BOLD-fMRI",
"activation",
"during",
"treatment",
"that",
"was",
"not",
"observed",
"in",
"control",
"subjects.",
"Reduction",
"in",
"activation",
"in",
"right",
"parietal-occipital",
"regions",
"from",
"baseline",
"was",
"observed",
"during",
"recall",
"of",
"the",
"spatial",
"location",
"of",
"objects",
"and",
"mental",
"rotation.",
"Conclusions:",
"Findings,",
"while",
"preliminary,",
"suggest",
"that",
"ADT",
"reduces",
"task-related",
"neural",
"activation",
"in",
"brain",
"regions",
"that",
"are",
"involved",
"in",
"mental",
"rotation",
"and",
"accurate",
"recall",
"of",
"spatial",
"information.",
"Background",
"Prostate",
"cancer",
"is",
"the",
"most",
"common",
"form",
"of",
"non-skin",
"cancer",
"diagnosed",
"in",
"U.S.",
"men",
"with",
"over",
"218,000",
"newly",
"diagnosed",
"cases",
"each",
"year",
"estimated",
"per",
"year",
"[1].",
"While",
"androgen",
"deprivation",
"therapy",
"(ADT)",
"used",
"to",
"be",
"reserved",
"for",
"those",
"with",
"metastatic",
"disease",
"and",
"resulted",
"in",
"a",
"med-",
"ian",
"survival",
"of",
"2-5",
"years",
"[2,3],",
"ADT",
"is",
"now",
"commonly",
"prescribed",
"in",
"the",
"setting",
"of",
"localized",
"disease",
"(e.g.",
"in",
"combination",
"with",
"radiation",
"therapy)",
"or",
"for",
"the",
"22%",
"of",
"patients",
"who",
"fail",
"primary",
"therapy",
"and",
"have",
"a",
"rising",
"PSA",
"without",
"evidence",
"of",
"metastases",
"[4].",
"In",
"contrast",
"to",
"those",
"with",
"metastatic",
"disease",
"the",
"latter",
"patients",
"often",
"have",
"no",
"disease",
"related",
"symptoms",
"and",
"may",
"live",
"for",
"many",
"years.",
"Physiological",
"consequences",
"of",
"androgen",
"deprivation",
"include",
"obesity,",
"anemia,",
"loss",
"of",
"bone",
"mineral",
"density,",
"muscle",
"atrophy,",
"gynecomastia",
"and",
"mood",
"changes",
"[2,5,6].",
"A",
"recent",
"population",
"based",
"study",
"showed",
"that",
"ADT",
"was",
"associated",
"with",
"an",
"increased",
"risk",
"of",
"diabetes,",
"*",
"Correspondence:",
"cherrier@u.washington.edu",
"1Department",
"of",
"Psychiatry",
"and",
"Behavioral",
"Sciences,",
"University",
"of",
"Washington",
"School",
"of",
"Medicine,",
"Seattle,",
"WA;",
"98195;",
"USA",
"myocardial",
"infarction,",
"and",
"hypertension",
"[7].",
"Psychiatric",
"changes",
"can",
"include",
"depression",
"and",
"anxiety",
"[8]",
"and",
"cog-",
"nitive",
"problems",
"can",
"include",
"impairments",
"in",
"verbal",
"memory",
"[9,10],",
"spatial",
"reasoning",
"[11]",
"and",
"attention",
"[12].",
"Given",
"these",
"cognitive",
"and",
"medical",
"side",
"effects",
"of",
"ADT",
"understanding",
"the",
"immediate",
"and",
"long-term",
"conse-",
"quence",
"of",
"treatment",
"is",
"essential.",
"Based",
"on",
"findings",
"from",
"our",
"previous",
"study",
"demon-",
"strating",
"a",
"decline",
"in",
"spatial",
"reasoning",
"abilities",
"in",
"healthy",
"men",
"undergoing",
"ADT",
"[11],",
"the",
"aim",
"of",
"this",
"study",
"was",
"to",
"examine",
"if",
"neural",
"activation",
"changes",
"were",
"evident",
"in",
"response",
"to",
"androgen",
"deprivation",
"while",
"performing",
"spa-",
"tial",
"reasoning",
"and",
"spatial",
"memory",
"tasks",
"using",
"functional",
"magnetic",
"resonance",
"imaging",
"(fMRI).",
"Spatial",
"reasoning",
"and",
"spatial",
"memory",
"were",
"specifically",
"chosen",
"to",
"examine",
"the",
"effects",
"of",
"ADT",
"on",
"brain",
"function",
"because",
"task-",
"related",
"brain",
"activation",
"has",
"been",
"clearly",
"identified,",
"parti-",
"cularly",
"in",
"regions",
"of",
"the",
"parietal",
"cortex",
"[13-16]",
"along",
"with",
"evidence",
"of",
"hormone",
"influences",
"on",
"these",
"brain",
"regions",
"[17-19].",
"The",
"aim",
"of",
"the",
"present",
"study",
"was",
"to",
"assess",
"changes",
"in",
"neural",
"activation",
"in",
"response",
"to",
"andro-",
"gen",
"deprivation",
"using",
"functional",
"magnetic",
"resonance",
"©",
"2010",
"Cherrier",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Journal",
"of",
"Medical",
"Case",
"Reports",
"Case",
"report",
"Combined",
"adenocarcinoid",
"and",
"mucinous",
"cystadenoma",
"of",
"the",
"appendix:",
"a",
"case",
"report",
"A",
"Velusamy*1,",
"S",
"Saw2,",
"J",
"Gossage1,",
"STR",
"Bailey1",
"and",
"J",
"Schofield2",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"1Department",
"of",
"Surgery,",
"Maidstone",
"Hospital,",
"Maidstone",
"ME16",
"9QQ,",
"UK",
"and",
"2Department",
"of",
"Pathology,",
"Preston",
"Hall",
"Hospital,",
"Aylesford,",
"Kent",
"ME20",
"7NJ,",
"UK",
"Email:",
"A",
"Velusamy*",
"-",
"avsamy@gmail.com;",
"S",
"Saw",
"-",
"soniasaw@nhs.net;",
"J",
"Gossage",
"-",
"jgossage@doctors.org.uk;",
"STR",
"Bailey",
"-",
"simonbailey@nhs.net;",
"J",
"Schofield",
"-",
"john.schofield@nhs.net",
"*",
"Corresponding",
"author",
"Published:",
"26",
"January",
"2009",
"Journal",
"of",
"Medical",
"Case",
"Reports",
"2009,",
"3:28",
"doi:10.1186/1752-1947-3-28",
"This",
"article",
"is",
"available",
"from:",
"http://www.jmedicalcasereports.com/content/3/1/28",
"Received:",
"21",
"February",
"2008",
"Accepted:",
"26",
"January",
"2009",
"©",
"2009",
"Velusamy",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Introduction:",
"Adenocarcinoid",
"of",
"the",
"appendix",
"is",
"a",
"rare",
"malignant",
"tumour",
"with",
"features",
"of",
"both",
"adenocarcinoma",
"and",
"carcinoid,",
"showing",
"both",
"epithelial",
"and",
"endocrine",
"differentiation.",
"Mucinous",
"cystadenoma",
"is",
"the",
"commonest",
"of",
"the",
"benign",
"neoplasms",
"of",
"the",
"appendix,",
"with",
"an",
"incidence",
"of",
"0.6%",
"in",
"appendicectomy",
"specimens.",
"We",
"report",
"a",
"rare",
"combination",
"of",
"these",
"tumours",
"and",
"discuss",
"the",
"latest",
"treatment",
"options.",
"To",
"the",
"best",
"of",
"our",
"knowledge,",
"only",
"six",
"cases",
"have",
"been",
"reported",
"in",
"the",
"literature",
"to",
"date.",
"Case",
"presentation:",
"A",
"71-year-old",
"Caucasian",
"man",
"presented",
"to",
"our",
"department",
"with",
"a",
"right",
"iliac",
"fossa",
"mass",
"associated",
"with",
"pain.",
"Laparoscopy",
"revealed",
"an",
"adenocarcinoid",
"of",
"the",
"appendix",
"in",
"combination",
"with",
"mucinous",
"cystadenoma.",
"He",
"underwent",
"a",
"radical",
"right",
"hemicolectomy",
"with",
"clear",
"margins",
"and",
"lymph",
"nodes.",
"Conclusion:",
"Adenocarcinoids",
"account",
"for",
"2%",
"of",
"primary",
"appendiceal",
"malignancies.",
"Most",
"tumours",
"are",
"less",
"than",
"2",
"cm",
"in",
"diameter",
"and",
"20%",
"of",
"them",
"metastasize",
"to",
"the",
"ovaries.",
"The",
"mean",
"age",
"for",
"presentation",
"is",
"59",
"years",
"and",
"the",
"5-year",
"survival",
"rate",
"ranges",
"from",
"60%",
"to",
"84%.",
"Right",
"hemicolectomy",
"is",
"generally",
"advised",
"if",
"any",
"of",
"the",
"following",
"features",
"are",
"present:",
"tumours",
"greater",
"than",
"2",
"cm,",
"involvement",
"of",
"resection",
"margins,",
"greater",
"than",
"2",
"mitoses/10",
"high-power",
"fields",
"on",
"histology,",
"extension",
"of",
"tumour",
"beyond",
"serosa.",
"Chemotherapy",
"mostly",
"with",
"5-Fluorouracil",
"and",
"Leucovorin",
"is",
"advised",
"for",
"remnant",
"disease",
"after",
"surgery.",
"Cytoreductive",
"surgery",
"with",
"intraperitoneal",
"chemotherapy",
"can",
"offer",
"improved",
"survival",
"for",
"advanced",
"peritoneal",
"dissemination.",
"Introduction",
"Mucinous",
"cystadenoma",
"is",
"the",
"commonest",
"of",
"the",
"benign",
"neoplasms",
"of",
"the",
"appendix,",
"with",
"an",
"incidence",
"of",
"0.6%",
"in",
"appendicectomy",
"specimens",
"[1].",
"Adenocarcinoid",
"is",
"a",
"rare",
"but",
"well",
"recognised",
"tumour",
"of",
"the",
"appendix",
"which",
"exhib-",
"its",
"features",
"of",
"both",
"carcinoid",
"and",
"adenocarcinoma.",
"We",
"report",
"a",
"patient",
"with",
"combined",
"adenocarcinoid",
"and",
"muci-",
"nous",
"cystadenoma",
"of",
"the",
"appendix.",
"To",
"the",
"best",
"of",
"our",
"knowledge,",
"only",
"six",
"cases",
"have",
"been",
"reported",
"in",
"the",
"liter-",
"ature",
"to",
"date",
"[2,3].",
"Case",
"presentation",
"Case",
"report",
"A",
"71-year-old",
"man",
"presented",
"to",
"the",
"surgical",
"department",
"with",
"a",
"2-week",
"history",
"of",
"colicky",
"right",
"iliac",
"fossa",
"pain",
"and",
"a",
"1-week",
"history",
"of",
"diarrhoea.",
"He",
"did",
"not",
"have",
"rectal",
"Page",
"1",
"of",
"3",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
] | [
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] | [
"Aging",
"Cell",
"(2008)",
"7,",
"pp451–458",
"Doi:",
"10.1111/j.1474-9726.2008.00397.x",
"BLlackwel",
"ePublishinguLtdkocyte",
"telomeres",
"are",
"longer",
"in",
"African",
"Americans",
"than",
"in",
"whites:",
"the",
"National",
"Heart,",
"Lung,",
"and",
"Blood",
"Institute",
"Family",
"Heart",
"Study",
"and",
"the",
"Bogalusa",
"Heart",
"Study",
"Steven",
"C.",
"Hunt,1",
"Wei",
"Chen,2",
"Jeffrey",
"P.",
"Gardner,3",
"Masayuki",
"Kimura,3",
"Sathanur",
"R.",
"Srinivasan,2",
"John",
"H.",
"Eckfeldt,4",
"Gerald",
"S.",
"Berenson2",
"and",
"Abraham",
"Aviv3",
"1Cardiovascular",
"Genetics",
"Division,",
"University",
"of",
"Utah",
"School",
"of",
"Medicine,",
"Salt",
"Lake",
"City,",
"UT,",
"USA",
"(NHLBI",
"Family",
"Heart",
"Study)",
"2Tulane",
"Center",
"for",
"Cardiovascular",
"Health,",
"Tulane",
"University",
"Health",
"Sciences",
"Center,",
"New",
"Orleans,",
"LA,",
"USA",
"(The",
"Bogalusa",
"Heart",
"Study)",
"3Center",
"of",
"Human",
"Development",
"and",
"Aging,",
"University",
"of",
"Medicine",
"and",
"Dentistry",
"of",
"New",
"Jersey,",
"New",
"Jersey",
"Medical",
"School,",
"Newark,",
"NJ,",
"USA",
"4Department",
"of",
"Laboratory",
"Medicine",
"and",
"Pathology,",
"University",
"of",
"Minnesota,",
"Minneapolis,",
"MN,",
"USA",
"(NHLBI",
"Family",
"Heart",
"Study)",
"Summary",
"Leukocyte",
"telomere",
"length",
"(LTL)",
"is",
"ostensibly",
"a",
"bio-",
"indicator",
"of",
"human",
"aging.",
"Here",
"we",
"report",
"that",
"African",
"Americans",
"have",
"longer",
"LTL",
"than",
"whites.",
"We",
"studied",
"cross-",
"sectionally",
"2453",
"individuals",
"from",
"the",
"National",
"Heart,",
"Lung,",
"and",
"Blood",
"Institute",
"(NHLBI)",
"Family",
"Heart",
"Study",
"(age",
"=",
"30–93",
"years)",
"and",
"the",
"Bogalusa",
"Heart",
"Study",
"(age",
"=",
"19–37",
"years),",
"comprising",
"1742",
"whites",
"and",
"711",
"Afri-",
"can",
"Americans.",
"We",
"measured",
"LTL",
"by",
"Southern",
"blots",
"of",
"the",
"terminal",
"restriction",
"fragments",
"length.",
"In",
"234",
"participants,",
"telomere",
"repeats",
"were",
"also",
"measured",
"by",
"quantitative",
"polymerase",
"chain",
"reaction",
"(qPCR).",
"Adjusted",
"for",
"age",
"and",
"body",
"mass",
"index",
"(BMI),",
"the",
"respective",
"leukocyte",
"telomere",
"lengths",
"(mean",
"±",
"SEM)",
"were",
"considerably",
"longer",
"in",
"African",
"Americans",
"than",
"in",
"whites",
"both",
"in",
"the",
"Family",
"Heart",
"Study",
"(7.004",
"±",
"0.033",
"kb",
"vs.",
"6.735",
"±",
"0.024",
"kb,",
"p",
"<",
"0.0001)",
"and",
"the",
"Bogalusa",
"Heart",
"Study",
"(7.923",
"±",
"0.063",
"kb",
"vs.",
"7.296",
"±",
"0.039",
"kb,",
"p",
"<",
"0.0001).",
"We",
"confirmed",
"the",
"racial",
"effect",
"on",
"LTL",
"by",
"qPCR",
"(3.038",
"±",
"0.565",
"T/S",
"units",
"for",
"African",
"Americans",
"vs.",
"2.714",
"±",
"0.487",
"T/S",
"units",
"for",
"whites,",
"p",
"<",
"0.001).",
"Cross-sectionally,",
"sex-",
"and",
"BMI-adjusted",
"LTL",
"became",
"shorter",
"with",
"age",
"(range",
"Correspondence",
"Abraham",
"Aviv,",
"Center",
"of",
"Human",
"Development",
"and",
"Aging,",
"Room",
"F-464,",
"University",
"of",
"Medicine",
"and",
"Dentistry",
"of",
"New",
"Jersey,",
"New",
"Jersey",
"Medical",
"School,",
"185",
"South",
"Orange",
"Ave.,",
"Newark,",
"NJ",
"07103,",
"USA,",
"Tel.:",
"973",
"972",
"5280;",
"fax:",
"973",
"972",
"5576;",
"e-mail:",
"avivab@umdnj.edu",
"Accepted",
"for",
"publication",
"01",
"March",
"2008",
"Re-use",
"of",
"this",
"article",
"is",
"permitted",
"in",
"accordance",
"with",
"the",
"Creative",
"Commons",
"Deed,",
"Attribution",
"2·5,",
"which",
"does",
"not",
"permit",
"commercial",
"exploitation.",
"19–93",
"years)",
"at",
"a",
"steeper",
"slope",
"in",
"African",
"Americans",
"than",
"in",
"whites",
"(0.029",
"kb",
"year–1",
"vs.",
"0.020",
"kb",
"year–1,",
"respectively,",
"p",
"=",
"0.0001).",
"We",
"suggest",
"that",
"racial",
"difference",
"in",
"LTL",
"arises",
"from",
"a",
"host",
"of",
"interacting",
"biological",
"factors,",
"including",
"replication",
"rates",
"of",
"hematopoietic",
"stem",
"cells.",
"Key",
"words:",
"age;",
"demography;",
"gender;",
"leukocyte;",
"race;",
"telomere.",
"Introduction",
"Mounting",
"evidence",
"suggests",
"that",
"leukocyte",
"telomere",
"length",
"(LTL)",
"is",
"a",
"bio-indicator",
"of",
"human",
"aging,",
"cardiovascular",
"aging",
"in",
"particular.",
"LTL",
"is",
"heritable",
"(Slagboom",
"et",
"al.,",
"1994;",
"Jeanclos",
"et",
"al.,",
"2000;",
"Vasa-Nicotera",
"et",
"al.,",
"2005;",
"Andrew",
"et",
"al.,",
"2006),",
"although",
"it",
"is",
"unknown",
"how",
"much",
"of",
"this",
"heritability",
"relates",
"to",
"birth",
"LTL",
"and",
"the",
"rate",
"of",
"its",
"shortening",
"from",
"birth",
"onward.",
"Age-dependent",
"LTL",
"shortening",
"is",
"due",
"to",
"successive",
"divisions",
"of",
"hematopoietic",
"stem",
"cells",
"(HSCs)",
"and",
"progenitor",
"cells",
"(PCs)",
"that",
"form",
"peripheral",
"leukocytes.",
"Inflammation",
"and",
"oxidative",
"stress",
"–",
"two",
"central",
"elements",
"in",
"the",
"biology",
"of",
"aging",
"and",
"aging-related",
"diseases",
"(Finch",
"&",
"Crimmins,",
"2004;",
"Balaban",
"et",
"al.,",
"2005)",
"–",
"were",
"reported",
"to",
"be",
"associated",
"with",
"LTL",
"(Aviv",
"et",
"al.,",
"2006a;",
"Demissie",
"et",
"al.,",
"2006;",
"Bekaert",
"et",
"al.,",
"2007;",
"Fitzpatrick",
"et",
"al.,",
"2007).",
"Inflammation",
"entails",
"an",
"increase",
"in",
"number",
"and",
"diminished",
"biological",
"life",
"of",
"leukocyte",
"subsets",
"in",
"the",
"circulation,",
"which",
"would",
"heighten",
"the",
"demand",
"on",
"HSCs/PCs",
"to",
"replicate,",
"a",
"phenomenon",
"expressed",
"in",
"an",
"accelerated",
"telomere",
"attrition",
"and",
"ultimately",
"shortened",
"LTL.",
"Oxidative",
"stress",
"heightens",
"the",
"loss",
"of",
"telomere",
"repeats",
"per",
"cell",
"division",
"(Sitte",
"et",
"al.,",
"1998;",
"Saretzki",
"et",
"al.,",
"1999;",
"Tchirkov",
"&",
"Lansdorp,",
"2003).",
"The",
"compounded",
"effect",
"of",
"inflam-",
"mation/oxidative",
"stress",
"on",
"the",
"paces",
"of",
"both",
"aging",
"and",
"LTL",
"attrition",
"conceivably",
"explains",
"the",
"shortened",
"LTL",
"observed",
"in",
"individuals",
"with",
"aging-related",
"diseases,",
"particularly",
"atherosclerotic",
"cardiovascular",
"(CV)",
"disease",
"(Brouilette",
"et",
"al.,",
"2003;",
"Cawthon",
"et",
"al.,",
"2003;",
"Benetos",
"et",
"al.,",
"2004;",
"Martin-Ruiz",
"et",
"al.,",
"2005;",
"Matsubara",
"et",
"al.,",
"2006;",
"Brouilette",
"et",
"al.,",
"2007;",
"Fitzpatrick",
"et",
"al.,",
"2007;",
"van",
"der",
"Harst",
"et",
"al.,",
"2007),",
"which",
"is",
"strongly",
"linked",
"to",
"inflammation",
"(Hansson",
"&",
"Libby,",
"2006).",
"The",
"paradigm",
"that",
"links",
"LTL",
"to",
"CV",
"disease",
"draws",
"on",
"data",
"derived",
"mainly",
"from",
"non-African",
"American",
"populations.",
"But",
"the",
"developmental",
"pattern",
"of",
"CV",
"disease",
"differs",
"between",
"African",
"Americans",
"and",
"whites.",
"For",
"instance,",
"African",
"Americans",
"are",
"more",
"prone",
"to",
"heart",
"failure",
"due",
"to",
"hypertension",
"(Yancy,",
"2005;",
"Whittle",
"et",
"al.,",
"2006),",
"but",
"they",
"have",
"considerably",
"less",
"coronary",
"©",
"2008",
"The",
"Authors",
"Journal",
"compilation",
"©",
"Blackwell",
"Publishing",
"Ltd/Anatomical",
"Society",
"of",
"Great",
"Britain",
"and",
"Ireland",
"2008",
"451"
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] | [
"J",
"Headache",
"Pain",
"(2008)",
"9:29–32",
"DOI",
"10.1007/s10194-008-0004-3",
"O",
"R",
"I",
"G",
"I",
"N",
"A",
"L",
"Performances",
"in",
"cerebellar",
"and",
"neuromuscular",
"transmission",
"tests",
"are",
"correlated",
"in",
"migraine",
"with",
"aura",
"Anna",
"Ambrosini",
"Æ",
"Peter",
"S.",
"Sa´",
"ndor",
"Æ",
"Victor",
"De",
"Pasqua",
"Æ",
"Francesco",
"Pierelli",
"Æ",
"Jean",
"Schoenen",
"Received:",
"2",
"October",
"2007",
"/",
"Accepted:",
"24",
"November",
"2007",
"/",
"Published",
"online:",
"5",
"February",
"2008",
"Springer-Verlag",
"2008",
"Abstract",
"In",
"previous",
"studies,",
"we",
"described",
"subclinical",
"abnormalities",
"of",
"neuromuscular",
"transmission",
"and",
"cerebel-",
"lar",
"functions",
"in",
"migraineurs.",
"The",
"aim",
"of",
"this",
"study",
"was",
"to",
"search",
"if",
"these",
"two",
"functions",
"are",
"correlated",
"in",
"the",
"same",
"patient.",
"Thirteen",
"migraineurs",
"[five",
"without",
"aura",
"(MO)",
"and",
"eight",
"with",
"aura",
"(MA)]",
"underwent",
"both",
"stimulation-SFEMG",
"and",
"3D-movement",
"analysis.",
"Single",
"fiber",
"EMG",
"(SFEMG)",
"results",
"were",
"expressed",
"as",
"the",
"‘‘mean",
"value",
"of",
"consecutive",
"differences’’",
"(mean",
"MCD).",
"Precision",
"of",
"arm-reaching",
"movements",
"(measured",
"with",
"an",
"infrared",
"optoelectronic",
"tracking",
"system)",
"was",
"expressed",
"as",
"the",
"average",
"deviation",
"in",
"the",
"horizontal",
"plane.",
"Median",
"values",
"of",
"mean",
"MCD",
"and",
"mean",
"horizontal",
"deviation",
"were",
"not",
"different",
"between",
"MO",
"and",
"MA.",
"However,",
"in",
"MA,",
"but",
"not",
"in",
"MO,",
"both",
"variables",
"were",
"positively",
"correlated.",
"Thus,",
"we",
"conclude",
"that",
"neuro-",
"muscular",
"transmission",
"and",
"cerebellar",
"functions",
"are",
"correlated",
"in",
"the",
"same",
"patient",
"when",
"affected",
"by",
"migraine",
"A.",
"Ambrosini",
"(&)",
"Headache",
"Clinic,",
"IRCCS",
"INM",
"Neuromed,",
"via",
"Atinense",
"18,",
"86077",
"Pozzilli,",
"Isernia,",
"Italy",
"e-mail:",
"anna.ambrosini@neuromed.it",
"P.",
"S.",
"Sa´ndor",
"Headache",
"and",
"Pain",
"Unit,",
"Department",
"of",
"Neurology,",
"University",
"of",
"Zurich,",
"Zurich,",
"Switzerland",
"V.",
"De",
"Pasqua",
"Headache",
"Research",
"Unit,",
"Department",
"of",
"Neurology,",
"University",
"of",
"Lie`ge,",
"Lie`ge,",
"Belgium",
"F.",
"Pierelli",
"Department",
"of",
"Neurorehabilitation,",
"University",
"‘‘La",
"Sapienza’’",
"of",
"Rome,",
"Polo",
"Pontino,",
"ICOT,",
"Latina,",
"Italy",
"J.",
"Schoenen",
"Headache",
"Research",
"Unit,",
"Departments",
"of",
"Neurology",
"and",
"Neuroanatomy,",
"University",
"of",
"Lie`ge,",
"Lie`ge,",
"Belgium",
"with",
"aura.",
"We",
"suggest",
"that",
"this",
"correlation",
"might",
"be",
"due",
"to",
"a",
"common",
"molecular",
"abnormality.",
"Keywords",
"junction",
"Migraine",
"Genetics",
"Introduction",
"Cerebellum",
"Neuromuscular",
"Migraine",
"is",
"a",
"paroxysmal",
"neurological",
"disorder",
"with",
"a",
"high",
"prevalence",
"in",
"the",
"general",
"population.",
"There",
"is",
"strong",
"epi-",
"demiological",
"and",
"genetic",
"evidence",
"that",
"genetic",
"factors",
"play",
"a",
"major,",
"though",
"variable",
"role,",
"in",
"its",
"pathogenesis.",
"Migraine",
"patients",
"are",
"characterized",
"between",
"attacks",
"on",
"various",
"CNS-",
"evoked",
"responses",
"by",
"a",
"deficit",
"of",
"habituation",
"[1,",
"2],",
"which",
"may",
"have",
"a",
"familial",
"character",
"[3–5].",
"The",
"lack",
"of",
"habitua-",
"tion",
"may",
"play",
"a",
"role",
"in",
"migraine",
"pathogenesis",
"[6].",
"By",
"contrast,",
"other",
"mild",
"abnormalities",
"have",
"been",
"identified",
"that",
"are",
"unlikely",
"to",
"play",
"a",
"pathogenic",
"role:",
"a",
"decreased",
"safety",
"factor",
"at",
"the",
"neuromuscular",
"junction",
"on",
"single",
"fiber",
"EMG",
"(SFEMG)",
"[7–9]",
"and",
"subclinical",
"cerebellar",
"hypermetria",
"in",
"the",
"horizontal",
"plane",
"on",
"opto-electronic",
"analysis",
"of",
"upper",
"arm-reaching",
"movements",
"[10].",
"It",
"was",
"suggested",
"that",
"these",
"two",
"abnormalities",
"might",
"reflect",
"the",
"same",
"underlying",
"genetic",
"abnormality.",
"If",
"this",
"is",
"correct,",
"one",
"may",
"expect",
"that",
"in",
"the",
"same",
"individual",
"they",
"be",
"of",
"a",
"similar",
"degree.",
"We",
"have",
"therefore",
"compared",
"in",
"the",
"same",
"migraine",
"patient",
"the",
"SFEMG",
"and",
"3D-movement",
"analysis.",
"Materials",
"and",
"methods",
"Patients",
"Thirteen",
"migraine",
"patients",
"(ICHD-II)",
"[11]",
"were",
"recruited",
"from",
"the",
"Headache",
"Clinic",
"of",
"the",
"Headache",
"Research",
"Unit",
"123"
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] | [
"organic",
"compounds",
"Acta",
"Crystallographica",
"Section",
"E",
"Structure",
"Reports",
"Online",
"ISSN",
"1600-5368",
"6-Allyl-8-methoxy-3-phenyl-3,4-dihydro-",
"2H-benzo[e][1,3]oxazine",
"Jing",
"Zhu,*",
"Zhi-Dong",
"Ren,",
"Yang",
"Liu,",
"Lei",
"Zhao",
"and",
"Yong",
"Wu",
"School",
"of",
"Chemistry",
"and",
"Chemical",
"Engineering,",
"Henan",
"University",
"of",
"Technology,",
"Zhengzhou",
"450001,",
"People’s",
"Republic",
"of",
"China",
"Correspondence",
"e-mail:",
"jingzhuhaut@126.com",
"Received",
"27",
"June",
"2011;",
"accepted",
"8",
"July",
"2011",
"Key",
"indicators:",
"single-crystal",
"X-ray",
"study;",
"T",
"=",
"291",
"K;",
"mean",
"(C–C)",
"=",
"0.003",
"A˚;",
"disorder",
"in",
"main",
"residue;",
"R",
"factor",
"=",
"0.047;",
"wR",
"factor",
"=",
"0.137;",
"data-to-parameter",
"ratio",
"=",
"13.9.",
"In",
"the",
"title",
"compound,",
"C18H19NO2,",
"the",
"allyl",
"group",
"is",
"disordered",
"over",
"two",
"sets",
"of",
"sites",
"[occupancy",
"ratio",
"0.662",
"(4):0.338",
"(4)].",
"The",
"dihedral",
"angle",
"between",
"the",
"phenyl",
"and",
"benzene",
"rings",
"is",
"87.44",
"(10)",
".",
"The",
"oxazinane",
"ring",
"adopts",
"a",
"sofa",
"conformation.",
"Related",
"literature",
"For",
"similar",
"heterocyclic",
"compounds,",
"see:",
"Chen",
"et",
"al.",
"(2007);",
"Kiskan",
"et",
"al.",
"(2007);",
"Liu",
"et",
"al.",
"(2007);",
"Ran",
"&",
"Gu",
"(2011);",
"Sawaryn",
"et",
"al.",
"(2010);",
"Su",
"et",
"al.",
"(2005).",
"For",
"puckering",
"para-",
"meters,",
"see:",
"Cremer",
"&",
"Pople",
"(1975).",
"Experimental",
"Crystal",
"data",
"C18H19NO2",
"Mr",
"=",
"281.34",
"Triclinic,",
"P1",
"a",
"=",
"8.4087",
"(5)",
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"References",
"Chen,",
"X.-L.,",
"Diao,",
"X.-J.",
"&",
"Wu,",
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"Cryst.",
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] | [
"ORIGINAL",
"RESEARCH",
"ARTICLE",
"published:",
"09",
"April",
"2012",
"doi:",
"10.3389/fonc.2012.00032",
"Cytotoxic",
"capacity",
"of",
"IL-15-stimulated",
"cytokine-induced",
"killer",
"cells",
"against",
"human",
"acute",
"myeloid",
"leukemia",
"and",
"rhabdomyosarcoma",
"in",
"humanized",
"preclinical",
"mouse",
"models",
"Eva",
"Rettinger",
"1*,",
"Vida",
"Meyer",
"1,",
"Hermann",
"Kreyenberg",
"1,",
"Andreas",
"Volk",
"2,",
"Selim",
"Kuçi",
"1,",
"Andre",
"Willasch1,",
"Ewa",
"Koscielniak",
"3,",
"Simone",
"Fulda4,",
"Winfried",
"S.",
"Wels",
"2,",
"Halvard",
"Boenig",
"5,",
"Thomas",
"Klingebiel",
"1",
"and",
"Peter",
"Bader",
"1*",
"1",
"Department",
"of",
"Pediatric",
"Hematology,",
"Oncology",
"and",
"Hemostaseology,",
"University",
"Children’s",
"Hospital",
"of",
"Frankfurt/Main,",
"Goethe-University",
"Frankfurt/Main,",
"Frankfurt/Main,",
"Germany",
"2",
"Chemotherapeutisches",
"Forschungsinstitut,",
"Georg-Speyer-Haus,",
"Frankfurt/Main,",
"Germany",
"3",
"Department",
"of",
"Pediatric",
"Oncology",
"and",
"Hematology,",
"Olgahospital",
"Stuttgart,",
"Stuttgart,",
"Germany",
"4",
"Institute",
"for",
"Experimental",
"Cancer",
"Research",
"in",
"Pediatrics,",
"Goethe-University",
"Frankfurt/Main,",
"Frankfurt/Main,",
"Germany",
"5",
"Institute",
"for",
"Transfusion",
"Medicine",
"and",
"Immunohematology,",
"Goethe-University",
"Frankfurt/Main,",
"Division",
"for",
"Cell",
"Processing,",
"German",
"Red",
"Cross",
"Blood",
"Donor",
"Service",
"Baden-Württemberg-Hessen,",
"Frankfurt/Main,",
"Germany",
"Edited",
"by:",
"Charles",
"G.",
"Mullighan,",
"St.",
"Jude",
"Children’s",
"Research",
"Hospital,",
"USA",
"Reviewed",
"by:",
"David",
"Shook,",
"St.",
"Jude",
"Children’s",
"Research",
"Hospital,",
"USA",
"Michael",
"R.",
"Verneris,",
"University",
"of",
"Minnesota,",
"USA",
"*Correspondence:",
"Eva",
"Rettinger",
"and",
"Peter",
"Bader",
",",
"Department",
"of",
"Pediatric",
"Hematology,",
"Oncology",
"and",
"Hemostaseology,",
"University",
"Children’s",
"Hospital",
"of",
"Frankfurt/Main,",
"Goethe-University",
"Frankfurt/Main,",
"Theodor-Stern-Kai",
"7,",
"60590",
"Frankfurt/Main,",
"Germany.",
"e-mail:",
"eva.rettinger@kgu.de;",
"peter.bader@kgu.de",
"Allogeneic",
"stem",
"cell",
"transplantation",
"(allo-SCT)",
"has",
"become",
"an",
"important",
"treatment",
"modal-",
"ity",
"for",
"patients",
"with",
"high-risk",
"acute",
"myeloid",
"leukemia",
"(AML)",
"and",
"is",
"also",
"under",
"investigation",
"for",
"soft",
"tissue",
"sarcomas.",
"The",
"therapeutic",
"success",
"is",
"still",
"limited",
"by",
"minimal",
"residual",
"disease",
"(MRD)",
"status",
"ultimately",
"leading",
"to",
"patients’",
"relapse.",
"Adoptive",
"donor",
"lymphocyte",
"infusions",
"based",
"on",
"MRD",
"status",
"using",
"IL-15-expanded",
"cytokine-induced",
"killer",
"(CIK)",
"cells",
"may",
"pre-",
"vent",
"relapse",
"without",
"causing",
"graft-versus-host-disease",
"(GvHD).",
"To",
"generate",
"preclinical",
"data",
"we",
"developed",
"mouse",
"models",
"to",
"study",
"anti-leukemic-",
"and",
"anti-tumor-potential",
"of",
"CIK",
"cells",
"in",
"vivo.",
"Immunodeficient",
"mice",
"(NOD/SCID/IL-2Rγc−,",
"NSG)",
"were",
"injected",
"intravenously",
"with",
"human",
"leukemic",
"cell",
"linesTHP-1,",
"SH-2",
"and",
"with",
"human",
"rhabdomyosarcoma",
"(RMS)",
"cell",
"lines",
"RH41",
"and",
"RH30",
"at",
"minimal",
"doses",
"required",
"for",
"leukemia",
"or",
"tumor",
"engraftment.",
"Mice",
"trans-",
"planted",
"withTHP-1",
"or",
"RH41",
"cells",
"were",
"randomly",
"assigned",
"for",
"analysis",
"of",
"CIK",
"cell",
"treatment.",
"Organs",
"of",
"mice",
"were",
"analyzed",
"by",
"flow",
"cytometry",
"as",
"well",
"as",
"quantitative",
"polymerase",
"chain",
"reaction",
"for",
"engraftment",
"of",
"malignant",
"cells",
"and",
"CIK",
"cells.",
"Potential",
"of",
"CIK",
"cells",
"to",
"induce",
"GvHD",
"was",
"determined",
"by",
"histological",
"analysis.",
"Tissues",
"of",
"the",
"highest",
"degree",
"of",
"THP-1",
"cell",
"expansion",
"included",
"bone",
"marrow",
"followed",
"by",
"liver,",
"lung,",
"spleen,",
"peripheral",
"blood",
"(PB),",
"and",
"brain.",
"RH30",
"and",
"RH41",
"engraftment",
"mainly",
"took",
"place",
"in",
"liver",
"and",
"lung,",
"but",
"was",
"also",
"detectable",
"in",
"spleen",
"and",
"PB.",
"In",
"spite",
"of",
"delayed",
"CIK",
"cell",
"expansion",
"compared",
"with",
"malig-",
"nant",
"cells,",
"CIK",
"cells",
"injected",
"at",
"equal",
"amounts",
"were",
"sufficient",
"for",
"significant",
"reduction",
"of",
"RH41",
"cells,",
"whereas",
"against",
"fast-expanding",
"THP-1",
"cells",
"250",
"times",
"more",
"CIK",
"than",
"THP-1",
"cells",
"were",
"needed",
"to",
"achieve",
"comparable",
"results.",
"Our",
"preclinical",
"in",
"vivo",
"mouse",
"models",
"showed",
"a",
"reliable",
"100%",
"engraftment",
"of",
"malignant",
"cells",
"which",
"is",
"essential",
"for",
"analysis",
"of",
"anti-cancer",
"therapy.",
"Furthermore",
"our",
"data",
"demonstrated",
"that",
"IL-15-activated",
"CIK",
"cells",
"have",
"potent",
"cytotoxic",
"capacity",
"against",
"AML",
"and",
"RMS",
"cells",
"without",
"causing",
"GvHD.",
"Keywords:",
"preclinical,",
"NSG",
"mice,",
"CIK",
"cells,",
"rhabdomyosarcoma,",
"leukemia,",
"immunotherapy",
"INTRODUCTION",
"Allogeneic",
"stem",
"cell",
"transplantation",
"(allo-SCT)",
"is",
"an",
"established",
"method",
"in",
"the",
"treatment",
"of",
"high-risk",
"acute",
"leukemia",
"in",
"children",
"(Bader",
"et",
"al.,",
"2004;",
"Rettinger",
"et",
"al.,",
"2011),",
"and",
"may",
"also",
"play",
"a",
"role",
"in",
"the",
"treatment",
"of",
"high-risk",
"soft",
"tissue",
"sarcoma",
"in",
"children.",
"Espe-",
"cially",
"patients",
"with",
"primary",
"alveolar",
"rhabdomyosarcoma",
"(RMS)",
"above",
"the",
"age",
"of",
"10",
"years",
"with",
"bone",
"or",
"bone",
"marrow",
"(BM)",
"metas-",
"tases",
"have",
"no",
"realistic",
"chance",
"to",
"survive",
"their",
"disease",
"with",
"conven-",
"tional",
"treatment",
"(Koscielniak",
"et",
"al.,",
"1997;",
"Klingebiel",
"et",
"al.,",
"2008;",
"Perez",
"et",
"al.,",
"2011).",
"By",
"evaluating",
"the",
"impact",
"of",
"allo-SCT",
"in",
"both,",
"leukemia",
"and",
"soft",
"tissue",
"sarcoma",
"patients,",
"minimal",
"residual",
"disease",
"(MRD)",
"after",
"transplantation",
"is",
"the",
"reason",
"for",
"disease",
"recurrence,",
"and",
"therefore",
"is",
"the",
"strongest",
"negative",
"effector",
"of",
"the",
"therapeutic",
"success",
"of",
"allo-SCT.",
"Once",
"a",
"stem",
"cell",
"recipient",
"relapses,",
"further",
"therapeutic",
"options",
"are",
"limited.",
"For",
"instance,",
"donor",
"lymphocyte",
"infusion",
"(DLI)",
"is",
"only",
"efficacious",
"for",
"a",
"limited",
"number",
"of",
"diseases,",
"and",
"the",
"high",
"T",
"cell",
"doses",
"required",
"for",
"DLI",
"raise",
"the",
"risk",
"for",
"severe",
"graft-versus-host-disease",
"(GvHD;",
"Rettinger",
"et",
"al.,",
"2011).",
"Cytokine-induced",
"killer",
"(CIK)",
"cells",
"are",
"known",
"in",
"principle",
"to",
"be",
"capable",
"of",
"eradicating",
"a",
"variety",
"of",
"both",
"hematological",
"and",
"solid",
"malignancies",
"in",
"a",
"non-MHC-restricted",
"manner,",
"without",
"possess-",
"ing",
"significant",
"alloreactive",
"potential",
"(Takayama",
"et",
"al.,",
"2000;",
"Baker",
"www.frontiersin.org",
"April",
"2012",
"|",
"Volume",
"2",
"|",
"Article",
"32",
"|",
"1"
] | [
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] | [
"Planta",
"(2009)",
"229:235–247",
"DOI",
"10.1007/s00425-008-0823-0",
"O",
"R",
"I",
"G",
"I",
"N",
"A",
"L",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"The",
"promoter",
"of",
"ZmMRP-1,",
"a",
"maize",
"transfer",
"cell-speciWc",
"transcriptional",
"activator,",
"is",
"induced",
"at",
"solute",
"exchange",
"surfaces",
"and",
"responds",
"to",
"transport",
"demands",
"Cristina",
"Barrero",
"·",
"Joaquín",
"Royo",
"·",
"Carmen",
"Grijota-Martinez",
"·",
"Christian",
"Faye",
"·",
"Wyatt",
"Paul",
"·",
"Soledad",
"Sanz",
"·",
"H.-H.",
"Steinbiss",
"·",
"Gregorio",
"Hueros",
"Received:",
"24",
"June",
"2008",
"/",
"Revised:",
"15",
"August",
"2008",
"/",
"Accepted:",
"11",
"September",
"2008",
"/",
"Published",
"online:",
"2",
"October",
"2008",
"©",
"Springer-Verlag",
"2008",
"Abstract",
"Transfer",
"cells",
"have",
"specializations",
"that",
"facili-",
"tate",
"the",
"transport",
"of",
"solutes",
"across",
"plant",
"exchange",
"surfaces.",
"ZmMRP-1",
"is",
"a",
"maize",
"(Zea",
"mays)",
"endosperm",
"transfer",
"cell-",
"speciWc",
"transcriptional",
"activator",
"that",
"plays",
"a",
"central",
"role",
"in",
"the",
"regulatory",
"pathways",
"controlling",
"transfer",
"cell",
"diVerentia-",
"tion",
"and",
"function.",
"The",
"present",
"work",
"investigates",
"the",
"signals",
"controlling",
"the",
"expression",
"of",
"ZmMRP-1",
"through",
"the",
"pro-",
"duction",
"of",
"transgenic",
"lines",
"of",
"maize,",
"Arabidopsis,",
"tobacco",
"and",
"barley",
"containing",
"ZmMRP-1promoter:GUS",
"reporter",
"constructs.",
"The",
"GUS",
"signal",
"predominantly",
"appeared",
"in",
"regions",
"of",
"active",
"transport",
"between",
"source",
"and",
"sink",
"tissues,",
"including",
"nematode-induced",
"feeding",
"structures",
"and",
"at",
"sites",
"of",
"vascular",
"connection",
"between",
"developing",
"organs",
"and",
"the",
"main",
"plant",
"vasculature.",
"In",
"those",
"cases,",
"promoter",
"induction",
"was",
"associated",
"with",
"the",
"initial",
"developmental",
"stages",
"of",
"transport",
"structures.",
"SigniWcantly,",
"transfer",
"cells",
"also",
"diVer-",
"entiated",
"in",
"these",
"regions",
"suggesting",
"that,",
"independent",
"of",
"C.",
"Barrero",
"·",
"J.",
"Royo",
"·",
"C.",
"Grijota-Martinez",
"·",
"G.",
"Hueros",
"(&)",
"Departamento",
"de",
"Biología",
"Celular",
"y",
"Genética,",
"Universidad",
"de",
"Alcalá,",
"Campus",
"Universitario,",
"Carretera",
"Madrid-Barcelona",
"Km",
"33.600,",
"28871",
"Alcalá",
"de",
"Henares,",
"Madrid,",
"Spain",
"e-mail:",
"gregorio.hueros@uah.es",
"C.",
"Faye",
"·",
"W.",
"Paul",
"Cereal",
"Functional",
"Analysis",
"Group,",
"Biogemma",
"SAS,",
"8",
"Rue",
"des",
"Frères",
"Lumière,",
"63028",
"Clermont-Ferrand",
"Cedex",
"2,",
"France",
"S.",
"Sanz",
"Departamento",
"de",
"Biología,",
"Facultad",
"de",
"Ciencias,",
"Universidad",
"Autónoma",
"de",
"Madrid,",
"Madrid,",
"Spain",
"H.-H.",
"Steinbiss",
"Max",
"Planck",
"Institut",
"für",
"Züchturnsforschung,",
"Carl",
"von",
"Linne",
"Weg",
"10,",
"Cologne,",
"Germany",
"species,",
"location",
"or",
"morphological",
"features,",
"transfer",
"cells",
"might",
"diVerentiate",
"in",
"a",
"similar",
"way",
"under",
"the",
"inXuence",
"of",
"conserved",
"induction",
"signals.",
"In",
"planta",
"and",
"yeast",
"experi-",
"ments",
"showed",
"that",
"the",
"promoter",
"activity",
"is",
"modulated",
"by",
"carbohydrates,",
"glucose",
"being",
"the",
"most",
"eVective",
"inducer.",
"Keywords",
"Endosperm",
"·",
"Maize",
"·",
"Source–sink",
"relationship",
"·",
"Transfer",
"cells",
"·",
"Transport",
"Abbreviations",
"BETL",
"Basal",
"endosperm",
"transfer",
"cell",
"layer",
"ESR",
"Embryo",
"surrounding",
"region",
"MU",
"4-Methylumbelliferone",
"MUG",
"4-Methylumbelliferyl",
"-D-glucuronide",
"MUG-a",
"4-Methylumbelliferyl",
"-D-galactoside",
"pmol",
"MU",
"min¡1",
"Picomoles",
"of",
"MU",
"produced",
"per",
"minute",
"mg",
"protein¡1",
"and",
"milligram",
"of",
"total",
"protein",
"X-glucuronide",
"5-Bromo-4-chloro-3-indolyl-beta-D-glu-",
"curonic",
"acid",
"cyclohexylammonium",
"salt",
"ZmMRP-1",
"Zea",
"mays",
"Myb",
"related",
"protein",
"1",
"Introduction",
"In",
"higher",
"land",
"plants,",
"nutrients",
"Xow",
"between",
"the",
"photosyn-",
"thetically",
"active",
"tissues",
"(known",
"as",
"sources)",
"and",
"the",
"storage",
"organs",
"or",
"the",
"young",
"parts",
"of",
"the",
"plant",
"(known",
"as",
"sinks);",
"the",
"growth",
"of",
"the",
"latter",
"depends",
"on",
"this",
"supply",
"(Williams",
"et",
"al.",
"2000).",
"This",
"Xux",
"takes",
"place",
"through",
"phloem",
"sieve",
"elements,",
"cells",
"that",
"are",
"intimately",
"connected",
"to",
"modiWed",
"companion",
"cells",
"by",
"numerous,",
"branched",
"plasmodesmata.",
"The",
"companion",
"cells,",
"which",
"nurse",
"and",
"feed",
"the",
"sieve",
"elements,",
"are",
"located",
"in",
"the",
"loading",
"and",
"unloading",
"areas",
"of",
"the",
"vascu-",
"lar",
"tissues,",
"and",
"often",
"show",
"typical",
"transfer",
"cell",
"morphology",
"characterized",
"by",
"a",
"large",
"number",
"of",
"cell",
"wall",
"ingrowths",
"123"
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] | [
"R",
"E",
"V",
"I",
"E",
"W",
"Role",
"of",
"5",
"alpha-reductase",
"inhibitors",
"in",
"the",
"management",
"of",
"prostate",
"cancer",
"Steven",
"J",
"Hudak1",
"Javier",
"Hernandez1",
"Ian",
"M",
"Thompson2",
"1Urology",
"Service,",
"Department",
"of",
"Surgery,",
"Brooke",
"Army",
"Medical",
"Center,",
"Fort",
"Sam",
"Houston,",
"TX,",
"USA;",
"2Department",
"of",
"Urology,",
"University",
"of",
"Texas",
"Health",
"Science",
"Center",
"at",
"San",
"Antonio,",
"San",
"Antonio,",
"TX,",
"USA",
"Correspondence:",
"Javier",
"Hernandez",
"Urology",
"Service,",
"Department",
"of",
"Surgery,",
"Brooke",
"Army",
"Medical",
"Center,",
"3851",
"Roger",
"Brooke",
"Drive,",
"Fort",
"Sam",
"Houston,",
"TX",
"78234-6200,",
"Tel",
"+1",
"210",
"916",
"1163",
"Fax",
"+1",
"210",
"916",
"5076",
"Email",
"javier.hernandez@us.army.mil",
"Note:",
"The",
"views",
"expressed",
"in",
"this",
"article",
"are",
"those",
"of",
"the",
"authors",
"and",
"do",
"not",
"reflect",
"the",
"official",
"policy",
"of",
"the",
"Department",
"of",
"Defense",
"or",
"other",
"Departments",
"of",
"the",
"US",
"Government.",
"Abstract:",
"Prostate",
"cancer",
"is",
"one",
"of",
"the",
"most",
"complex",
"and",
"enigmatic",
"oncologic",
"problems",
"in",
"medicine.",
"It",
"is",
"highly",
"prevalent,",
"particularly",
"in",
"elderly",
"males.",
"Unfortunately,",
"its",
"generally",
"protracted",
"and",
"variable",
"clinical",
"course",
"and",
"high",
"association",
"with",
"treatment-related",
"morbidity",
"raise",
"serious",
"questions",
"about",
"the",
"ideal",
"treatment",
"strategy",
"for",
"the",
"individual",
"patient.",
"5",
"alpha-",
"reductase",
"(5AR)",
"inhibitors",
"have",
"a",
"dramatic",
"effect",
"on",
"benign",
"prostatic",
"disease",
"with",
"low",
"toxicity.",
"Thus,",
"there",
"is",
"much",
"interest",
"in",
"the",
"potential",
"role",
"of",
"5AR",
"inhibitors",
"in",
"the",
"prevention",
"and",
"treatment",
"of",
"prostate",
"cancer.",
"Finasteride",
"is",
"the",
"only",
"agent",
"that",
"has",
"been",
"shown",
"in",
"a",
"randomized",
"clinical",
"trial",
"to",
"decrease",
"the",
"risk",
"of",
"prostate",
"cancer",
"with",
"a",
"reduction",
"of",
"almost",
"25%.",
"Additionally,",
"a",
"recent",
"analysis",
"of",
"the",
"Prostate",
"Cancer",
"Prevention",
"Trial",
"(PCPT)",
"has",
"found",
"that",
"finasteride",
"improves",
"the",
"performance",
"characteristics",
"of",
"prostate-specific",
"antigen",
"(PSA)",
"blood",
"test",
"as",
"a",
"screening",
"tool",
"for",
"prostate",
"cancer,",
"for",
"both",
"cancer",
"detection",
"as",
"well",
"as",
"for",
"detection",
"of",
"high",
"risk",
"disease.",
"Finally,",
"5AR",
"inhibitors",
"have",
"been",
"studied",
"as",
"a",
"component",
"of",
"multimodal",
"therapy",
"for",
"all",
"stages",
"of",
"prostate",
"cancer,",
"with",
"the",
"goal",
"of",
"improving",
"oncologic",
"outcomes",
"while",
"avoiding",
"the",
"toxicity",
"of",
"medical",
"and",
"surgical",
"castration.",
"Keywords:",
"prostate",
"cancer,",
"5-α-reductase",
"inhibitors,",
"finasteride,",
"dutasteride,",
"chemoprevention",
"Introduction",
"Prostate",
"cancer",
"is",
"the",
"most",
"common",
"noncutaneous",
"malignancy",
"in",
"males.",
"The",
"American",
"Cancer",
"Society",
"estimates",
"that",
"in",
"the",
"year",
"2006,",
"a",
"total",
"of",
"234",
"460",
"men",
"will",
"be",
"diagnosed",
"with",
"prostate",
"cancer",
"and",
"27",
"350",
"will",
"die",
"of",
"this",
"disease",
"(Jemal",
"et",
"al",
"2006).",
"At",
"the",
"start",
"of",
"the",
"year",
"2003,",
"nearly",
"2",
"million",
"American",
"men",
"were",
"living",
"with",
"prostate",
"cancer.",
"Most",
"commonly",
"a",
"disease",
"of",
"elderly",
"men,",
"the",
"average",
"age",
"at",
"diagnosis",
"is",
"68",
"and",
"27.3%",
"of",
"all",
"new",
"diagnoses",
"are",
"in",
"men",
"75",
"years",
"of",
"age",
"or",
"older",
"(Ries",
"et",
"al",
"2006).",
"The",
"characteristics",
"of",
"prostate",
"cancer",
"have",
"changed",
"dramatically",
"since",
"the",
"introduction",
"of",
"prostate-specific",
"antigen",
"(PSA)-based",
"screening",
"in",
"1986.",
"PSA",
"screening",
"has",
"led",
"to",
"a",
"drastic",
"increase",
"in",
"the",
"detection",
"rate",
"of",
"prostate",
"cancer",
"along",
"with",
"an",
"associated",
"downward",
"stage",
"migration.",
"While",
"there",
"are",
"no",
"prospective,",
"randomized",
"studies",
"that",
"prove",
"earlier",
"detection",
"of",
"prostate",
"cancer",
"leads",
"to",
"decreased",
"mortality,",
"the",
"reality",
"is",
"that",
"widespread",
"PSA-based",
"screening",
"for",
"prostate",
"cancer",
"has",
"continued.",
"Taking",
"into",
"consideration",
"that",
"many",
"tumors",
"currently",
"detected",
"may",
"be",
"of",
"an",
"indolent",
"nature,",
"a",
"current",
"challenge",
"is",
"identifying",
"the",
"patient",
"who",
"may",
"benefit",
"from",
"treatment",
"for",
"whom",
"side",
"effects",
"of",
"treatment",
"may",
"be",
"acceptable.",
"The",
"high",
"prevalence",
"and",
"considerably",
"lower",
"mortality",
"of",
"prostate",
"cancer,",
"coupled",
"with",
"the",
"significant",
"potential",
"morbidity",
"of",
"therapy",
"for",
"prostate",
"cancer,",
"have",
"sparked",
"much",
"interest",
"in",
"alternative",
"approaches",
"against",
"prostate",
"cancer",
"such",
"as",
"prevention",
"(Thompson",
"et",
"al",
"2003),",
"minimally",
"invasive",
"surgical",
"therapies",
"(Ahmed",
"et",
"al",
"2005;",
"Tooher",
"et",
"al",
"2006)",
"and",
"active",
"surveillance",
"strategies",
"(Carter",
"et",
"al",
"2002).",
"Well",
"designed",
"randomized",
"clinical",
"trials",
"addressing",
"questions",
"in",
"these",
"areas",
"will",
"hopefully",
"lead",
"to",
"more",
"efficacious",
"and",
"appropriate",
"treatment",
"of",
"prostate",
"cancer",
"with",
"lower",
"disease",
"specific",
"mortality,",
"while",
"minimizing",
"treatment",
"related",
"morbidity.",
"Medical",
"therapy",
"Clinical",
"Interventions",
"in",
"Aging",
"2006:1(4)",
"425–431",
"©",
"2006",
"Dove",
"Medical",
"Press",
"Limited.",
"All",
"rights",
"reserved",
"425"
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] | [
"Rudwaleit",
"et",
"al.",
"Arthritis",
"Research",
"&",
"Therapy",
"2010,",
"12:R117",
"http://arthritis-research.com/content/12/3/R117",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"REefsefaercch",
"taritvicleeness",
"and",
"safety",
"of",
"adalimumab",
"in",
"patients",
"with",
"ankylosing",
"spondylitis",
"or",
"psoriatic",
"arthritis",
"and",
"history",
"of",
"anti-tumor",
"necrosis",
"factor",
"therapy",
"Martin",
"Rudwaleit*1,",
"Filip",
"Van",
"den",
"Bosch2,",
"Martina",
"Kron3,",
"Sonja",
"Kary3",
"and",
"Hartmut",
"Kupper3",
"Abstract",
"Introduction:",
"Tumor",
"necrosis",
"factor",
"(TNF)",
"antagonists",
"reduce",
"the",
"signs",
"and",
"symptoms",
"of",
"spondyloarthritides,",
"including",
"ankylosing",
"spondylitis",
"(AS)",
"and",
"psoriatic",
"arthritis",
"(PsA).",
"Our",
"objective",
"was",
"to",
"evaluate",
"the",
"effectiveness",
"and",
"safety",
"of",
"adalimumab,",
"40",
"mg",
"every",
"other",
"week,",
"for",
"patients",
"with",
"AS",
"or",
"PsA",
"and",
"prior",
"treatment",
"with",
"infliximab",
"(IFX)",
"and/or",
"etanercept",
"(ETN).",
"Methods:",
"Both",
"trials",
"were",
"12-week,",
"open-label",
"studies",
"with",
"an",
"optional",
"extension",
"period",
"up",
"to",
"week",
"20.",
"Patients",
"were",
"stratified",
"by",
"history",
"of",
"anti-TNF",
"treatment,",
"prior",
"anti-TNF",
"therapy",
"received",
"(IFX,",
"ETN,",
"or",
"both),",
"and",
"reason",
"for",
"discontinuation",
"of",
"prior",
"TNF",
"antagonist.",
"ETN",
"was",
"discontinued",
"≥",
"3",
"weeks,",
"and",
"IFX",
"was",
"discontinued",
"≥",
"2",
"months",
"before",
"the",
"first",
"adalimumab",
"administration.",
"Effectiveness",
"at",
"week",
"12",
"was",
"evaluated",
"by",
"using",
"observed",
"standard-outcome",
"measurements",
"for",
"AS",
"and",
"PsA.",
"Results:",
"At",
"week",
"12",
"of",
"adalimumab",
"treatment,",
"Bath",
"Ankylosing",
"Spondylitis",
"Disease",
"Activity",
"Index",
"50",
"responses",
"were",
"achieved",
"by",
"40.8%",
"of",
"326",
"patients",
"with",
"AS",
"who",
"had",
"received",
"prior",
"anti-TNF",
"therapy",
"and",
"by",
"63.0%",
"of",
"924",
"patients",
"with",
"AS",
"who",
"were",
"naive",
"to",
"TNF",
"antagonist.",
"Observed",
"response",
"rates",
"were",
"generally",
"greater",
"for",
"patients",
"who",
"discontinued",
"the",
"prior",
"anti-TNF",
"therapy",
"because",
"of",
"loss",
"of",
"response",
"or",
"intolerance",
"than",
"for",
"patients",
"who",
"discontinued",
"because",
"of",
"lack",
"of",
"response.",
"Median",
"changes",
"in",
"swollen-joint",
"count",
"and",
"in",
"enthesitis",
"score",
"were",
"similar",
"in",
"patients",
"with",
"and",
"without",
"prior",
"TNF-antagonist",
"treatment.",
"Modified",
"PsA",
"response",
"criteria",
"were",
"fulfilled",
"by",
"71.2%",
"of",
"66",
"patients",
"with",
"PsA,",
"with",
"prior",
"exposure",
"to",
"TNF",
"antagonists,",
"and",
"by",
"78.8%",
"of",
"376",
"patients",
"with",
"no",
"history",
"of",
"anti-TNF",
"therapy.",
"The",
"percentages",
"of",
"patients",
"with",
"PsA",
"attaining",
"a",
"Physician's",
"Global",
"Assessment",
"of",
"psoriasis",
"of",
"\"Clear/Almost",
"clear\"",
"increased",
"from",
"33.3%",
"to",
"61.0%",
"for",
"patients",
"with",
"prior",
"IFX",
"and/or",
"ETN",
"treatment",
"and",
"from",
"34.6%",
"to",
"69.7%",
"for",
"patients",
"without",
"anti-TNF",
"therapy.",
"The",
"median",
"change",
"in",
"the",
"Nail",
"Psoriasis",
"Severity",
"Index",
"was",
"-6",
"for",
"both",
"groups.",
"In",
"both",
"studies,",
"patterns",
"of",
"adverse",
"events",
"were",
"similar",
"for",
"patients",
"with",
"and",
"without",
"prior",
"anti-TNF",
"therapy",
"and",
"were",
"consistent",
"with",
"the",
"known",
"safety",
"profile",
"of",
"adalimumab.",
"Conclusions:",
"Patients",
"with",
"AS",
"or",
"PsA",
"previously",
"treated",
"with",
"IFX",
"and/or",
"ETN",
"experienced",
"clinically",
"relevant",
"improvements",
"of",
"their",
"diseases",
"after",
"12",
"weeks",
"of",
"adalimumab.",
"Trial",
"registrations:",
"ClinicalTrials.gov",
"NCT00478660",
"and",
"NCT00235885.",
"Introduction",
"Agents",
"that",
"target",
"tumor",
"necrosis",
"factor",
"(TNF)",
"are",
"highly",
"effective",
"in",
"treating",
"patients",
"with",
"active",
"rheumatic",
"disor-",
"ders,",
"such",
"as",
"rheumatoid",
"arthritis",
"(RA),",
"ankylosing",
"spon-",
"dylitis",
"(AS),",
"or",
"psoriatic",
"arthritis",
"(PsA)",
"[1].",
"Nevertheless,",
"*",
"Correspondence:",
"publications@jkmed.com",
"1",
"Medical",
"Department",
"I,",
"Rheumatology,",
"Charité,",
"Campus",
"Benjamin",
"Franklin",
"Hospital,",
"Hindenburgdamm",
"30,",
"12200",
"Berlin,",
"Germany",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"patients",
"may",
"not",
"respond",
"optimally",
"to",
"or",
"may",
"be",
"intoler-",
"ant",
"of",
"treatment",
"with",
"a",
"given",
"TNF",
"antagonist.",
"A",
"practical",
"question",
"faced",
"by",
"clinicians",
"and",
"patients",
"is",
"whether",
"switching",
"to",
"another",
"TNF",
"antagonist",
"is",
"likely",
"to",
"result",
"in",
"an",
"improved",
"therapeutic",
"response.",
"Treatment",
"with",
"a",
"second",
"or",
"third",
"TNF",
"antagonist",
"has",
"been",
"shown",
"to",
"be",
"successful",
"and",
"well",
"tolerated",
"in",
"a",
"sub-",
"stantial",
"percentage",
"of",
"patients",
"with",
"RA,",
"regardless",
"of",
"the",
"order",
"of",
"subsequent",
"therapies",
"(etanercept",
"(ETN),",
"inflix-",
"©",
"2010",
"Rudwaleit",
"et",
"al.;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
] | [
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] | [
"Chen",
"et",
"al.",
"BMC",
"Microbiology",
"2010,",
"10:198",
"http://www.biomedcentral.com/1471-2180/10/198",
"R",
"E",
"S",
"E",
"A",
"R",
"C",
"H",
"A",
"R",
"T",
"I",
"C",
"L",
"E",
"Open",
"Access",
"Chromosomal",
"instability",
"in",
"Streptomyces",
"avermitilis:",
"major",
"deletion",
"in",
"the",
"central",
"region",
"and",
"stable",
"circularized",
"chromosome",
"Wei",
"Chen,",
"Fei",
"He,",
"Xiaojuan",
"Zhang,",
"Zhi",
"Chen,",
"Ying",
"Wen*,",
"Jilun",
"Li",
"Abstract",
"Background:",
"The",
"chromosome",
"of",
"Streptomyces",
"has",
"been",
"shown",
"to",
"be",
"unstable,",
"frequently",
"undergoing",
"gross",
"chromosomal",
"rearrangements.",
"However,",
"the",
"mechanisms",
"underlying",
"this",
"phenomenon",
"remain",
"unclear,",
"with",
"previous",
"studies",
"focused",
"on",
"two",
"chromosomal",
"ends",
"as",
"targets",
"for",
"rearrangements.",
"Here",
"we",
"investigated",
"chromosomal",
"instability",
"of",
"Streptomyces",
"avermitilis,",
"an",
"important",
"producer",
"of",
"avermectins,",
"and",
"characterized",
"four",
"gross",
"chromosomal",
"rearrangement",
"events,",
"including",
"a",
"major",
"deletion",
"in",
"the",
"central",
"region.",
"The",
"present",
"findings",
"provide",
"a",
"valuable",
"contribution",
"to",
"the",
"mechanistic",
"study",
"of",
"genetic",
"instability",
"in",
"Streptomyces.",
"Results:",
"Thirty",
"randomly-selected",
"“bald”",
"mutants",
"derived",
"from",
"the",
"wild-type",
"strain",
"all",
"contained",
"gross",
"chromosomal",
"rearrangements",
"of",
"various",
"types.",
"One",
"of",
"the",
"bald",
"mutants,",
"SA1-8,",
"had",
"the",
"same",
"linear",
"chromosomal",
"structure",
"as",
"the",
"high",
"avermectin-producing",
"mutant",
"76-9.",
"Chromosomes",
"of",
"both",
"strains",
"displayed",
"at",
"least",
"three",
"independent",
"chromosomal",
"rearrangements,",
"including",
"chromosomal",
"arm",
"replacement",
"to",
"form",
"new",
"88-kb",
"terminal",
"inverted",
"repeats",
"(TIRs),",
"and",
"two",
"major",
"deletions.",
"One",
"of",
"the",
"deletions",
"eliminated",
"the",
"36-kb",
"central",
"region",
"of",
"the",
"chromosome,",
"but",
"surprisingly",
"did",
"not",
"affect",
"viability",
"of",
"the",
"cells.",
"The",
"other",
"deletion",
"(74-kb)",
"was",
"internal",
"to",
"the",
"right",
"chromosomal",
"arm.",
"The",
"chromosome",
"of",
"another",
"bald",
"mutant,",
"SA1-6,",
"was",
"circularized",
"with",
"deletions",
"at",
"both",
"ends.",
"No",
"obvious",
"homology",
"was",
"found",
"in",
"all",
"fusion",
"sequences.",
"Generational",
"stability",
"analysis",
"showed",
"that",
"the",
"chromosomal",
"structure",
"of",
"SA1-8",
"and",
"SA1-6",
"was",
"stable.",
"Conclusions:",
"Various",
"chromosomal",
"rearrangements,",
"including",
"chromosomal",
"arm",
"replacement,",
"interstitial",
"deletions",
"and",
"chromosomal",
"circularization,",
"occurred",
"in",
"S.",
"avermitilis",
"by",
"non-homologous",
"recombination.",
"The",
"finding",
"of",
"an",
"inner",
"deletion",
"involving",
"in",
"the",
"central",
"region",
"of",
"S.",
"avermitilis",
"chromosome",
"suggests",
"that",
"the",
"entire",
"Streptomyces",
"chromosome",
"may",
"be",
"the",
"target",
"for",
"rearrangements,",
"which",
"are",
"not",
"limited,",
"as",
"previously",
"reported,",
"to",
"the",
"two",
"chromosomal",
"ends.",
"Background",
"Streptomyces",
"are",
"a",
"genus",
"of",
"Gram-positive,",
"filamentous",
"soil",
"bacteria,",
"which",
"display",
"complex",
"morphological",
"differ-",
"entiation",
"and",
"produce",
"a",
"broad",
"range",
"of",
"bioactive",
"second-",
"ary",
"metabolites",
"such",
"as",
"antibiotics,",
"immunosuppressants",
"and",
"cholesterol-lowering",
"agents.",
"These",
"bacteria",
"thus",
"pro-",
"vide",
"an",
"important",
"natural",
"source",
"of",
"commercial",
"products",
"for",
"the",
"pharmaceutical",
"and",
"agricultural",
"industries",
"[1].",
"The",
"Streptomyces",
"genome",
"consists",
"of",
"an",
"8-",
"to",
"9-Mb",
"linear",
"chromosome,",
"characterized",
"by",
"terminal",
"inverted",
"repeats",
"(TIRs)",
"and",
"a",
"protein",
"covalently",
"attached",
"to",
"5’",
"end",
"[2-4].",
"*",
"Correspondence:",
"wen@cau.edu.cn",
"State",
"Key",
"Laboratories",
"for",
"Agro-biotechnology,",
"College",
"of",
"Biological",
"Sciences,",
"China",
"Agricultural",
"University,",
"Beijing",
"100193,",
"PR",
"China",
"This",
"chromosome",
"is",
"inherently",
"unstable,",
"and",
"frequently",
"undergoes",
"gross",
"chromosomal",
"rearrangements",
"sponta-",
"neously",
"as",
"well",
"as",
"under",
"various",
"mutagenic",
"treatments",
"[5,6],",
"particularly",
"in",
"terminal",
"regions",
"where",
"almost",
"no",
"essential",
"genes",
"reside.",
"Gross",
"chromosomal",
"rearrangements",
"include",
"deletion,",
"amplification,",
"arm",
"replacement,",
"and",
"cir-",
"cularization",
"[7-16].",
"This",
"chromosomal",
"instability",
"leads",
"to",
"genetic",
"instability,",
"which",
"is",
"ubiquitous",
"among",
"Strepto-",
"myces,",
"and",
"affects",
"nearly",
"all",
"life",
"functions,",
"e.g.,",
"differentia-",
"tion,",
"secondary",
"metabolism,",
"and",
"response",
"to",
"environmental",
"changes",
"[5].",
"The",
"chromosomal",
"instability",
"is",
"not",
"attributable",
"to",
"the",
"linear",
"chromosomal",
"structure,",
"since",
"some",
"mutants",
"with",
"circular",
"chromosomes",
"display",
"even",
"higher",
"frequency",
"of",
"genetic",
"instability",
"[7,17,18].",
"©",
"2010",
"Chen",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Bioinformation",
"www.bioinformation.net",
"by",
"Biomedical",
"Informatics",
"Publishing",
"Group",
"open",
"access",
"Hypothesis",
"Specific",
"gene",
"hypomethylation",
"and",
"cancer:",
"New",
"insights",
"into",
"coding",
"region",
"feature",
"trends",
"Elias",
"Daura-Oller,",
"Maria",
"Cabre,",
"Miguel",
"A.",
"Montero,",
"Jose",
"L.",
"Paternain,",
"Antoni",
"Romeu*",
"Biochemistry",
"and",
"Biotechnology",
"Department,",
"Faculty",
"of",
"Chemistry,",
"Rovira",
"i",
"Virgili,",
"University",
"(URV),",
"c/",
"Marcel·li",
"Domingo,",
"s/n.",
"Campus",
"Sescelades,",
"43007",
"Tarragona,",
"Spain,",
"Antoni",
"Romeu",
"-",
"E-mail:",
"antoni.romeu@urv.cat;",
"Phone:",
"34977558188;",
"Fax:",
"34977558232;",
"*Corresponding",
"author",
"received",
"December",
"02,",
"2008;",
"accepted",
"January",
"12,",
"2009;",
"published",
"April",
"21,",
"2009",
"Abstract:",
"Giving",
"coding",
"region",
"structural",
"features",
"a",
"role",
"in",
"the",
"hypomethylation",
"of",
"specific",
"genes,",
"the",
"occurrence",
"of",
"G+C",
"content,",
"CpG",
"islands,",
"repeat",
"and",
"retrotransposable",
"elements",
"in",
"demethylated",
"genes",
"related",
"to",
"cancer",
"has",
"been",
"evaluated.",
"A",
"comparative",
"analysis",
"among",
"different",
"cancer",
"types",
"has",
"also",
"been",
"performed.",
"In",
"this",
"work,",
"the",
"inter-cancer",
"coding",
"region",
"features",
"comparative",
"analysis",
"carried",
"out,",
"show",
"insights",
"into",
"what",
"structural",
"trends/patterns",
"are",
"present",
"in",
"the",
"studied",
"cancers.",
"Keywords:",
"epigenetics;",
"cancer;",
"CpG",
"islands;",
"hypomethylation",
"Background:",
"Alterations",
"of",
"DNA",
"methylation",
"have",
"been",
"recognized",
"as",
"an",
"important",
"component",
"of",
"cancer",
"development",
"[1].",
"Hypomethylation",
"generally",
"arises",
"earlier",
"and",
"is",
"linked",
"to",
"chromosomal",
"instability",
"and",
"loss",
"of",
"imprinting",
"[2-6],",
"whereas",
"hypermethylation",
"is",
"associated",
"with",
"promoters",
"and",
"can",
"arise",
"secondary",
"to",
"gene",
"silencing",
"[7-9],",
"but",
"might",
"be",
"a",
"target",
"for",
"epigenetic",
"therapy",
"[10].",
"It",
"is",
"not",
"currently",
"known",
"why",
"certain",
"CpG",
"islands",
"are",
"hypermethylated",
"or",
"hyphometylated",
"in",
"specific",
"cancers",
"but",
"not",
"in",
"others",
"[1].",
"Some",
"of",
"these",
"events",
"have",
"been",
"observed",
"in",
"vitro",
"and",
"using",
"in",
"vivo",
"animal",
"models",
"[2-4,",
"11,",
"12]",
"but",
"their",
"relative",
"importance",
"in",
"human",
"disease",
"is",
"not",
"understood.",
"Recent",
"studies",
"suggest",
"that",
"some",
"methylation",
"patterns",
"are",
"discernible",
"in",
"risk",
"groups",
"and",
"certain",
"diseases.",
"Indications",
"are",
"that",
"the",
"hypomethylation",
"of",
"specific",
"DNA",
"repeat",
"elements",
"or",
"genes",
"can",
"be",
"disease-specific",
"[13].",
"These",
"repeat",
"sequences",
"may",
"be",
"transposable",
"elements",
"found",
"interspersed",
"throughout",
"the",
"genome,",
"or",
"large",
"repeat",
"sequences",
"and",
"simple",
"repeat",
"ones,",
"such",
"as",
"DNA",
"satellites,",
"that",
"are",
"found",
"commonly",
"in",
"heterochromatin.",
"Hypomethylation",
"of",
"satellites",
"and",
"retroelements",
"together",
"should",
"account",
"for",
"the",
"greater",
"part",
"of",
"the",
"decrease",
"in",
"methyl-cytosine",
"content",
"in",
"cancer",
"cells.",
"Decreased",
"methylation",
"of",
"single-copy",
"genes",
"does",
"not",
"contribute",
"significantly",
"to",
"the",
"decrease",
"in",
"quantity,",
"but",
"whether",
"hypomethylation",
"may",
"lead",
"to",
"the",
"reactivation",
"of",
"genes",
"silenced",
"in",
"normal",
"cells",
"is",
"an",
"important",
"issue.",
"The",
"site",
"reported",
"to",
"be",
"hypomethylated",
"in",
"several",
"human",
"cancers",
"is",
"located",
"within",
"the",
"coding",
"region.",
"It",
"may",
"become",
"demethylated",
"in",
"cancers",
"as",
"a",
"consequence",
"of",
"global",
"hypomethylation",
"or",
"may",
"reflect",
"increased",
"transcriptional",
"activity",
"[14,",
"15,",
"16].",
"The",
"relationship",
"between",
"hypomethylation",
"of",
"specific",
"genes",
"and",
"repeat",
"elements",
"within",
"the",
"genome",
"may",
"serve",
"as",
"useful",
"diagnostic",
"indicators",
"for",
"disease",
"[13].",
"Nowadays,",
"more",
"information",
"is",
"required",
"with",
"regard",
"to",
"what",
"repeat",
"elements",
"are",
"specific",
"to",
"what",
"diseases",
"and",
"whether",
"this",
"information",
"can",
"be",
"used",
"to",
"predict",
"disease",
"onset",
"or",
"progression.",
"Thus,",
"the",
"occurrence",
"of",
"G+C",
"content,",
"CpG",
"islands,",
"repeat",
"and",
"retrotransposable",
"elements",
"in",
"demethylated",
"genes",
"related",
"to",
"cancer",
"has",
"been",
"evaluated",
"in",
"this",
"work.",
"Moreover,",
"a",
"comparative",
"analysis",
"among",
"different",
"cancer",
"types",
"has",
"also",
"been",
"performed",
"in",
"ISSN",
"0973-2063",
"(online)",
"0973-8894",
"(print)",
"Bioinformation",
"3(8):",
"340-343",
"(2009)",
"340",
"order",
"to",
"elucidate",
"what",
"structural",
"trends/patterns",
"are",
"present",
"in",
"the",
"studied",
"cancers.",
"Methodology:",
"All",
"selected",
"genes",
"were",
"compiled",
"from",
"the",
"recent",
"literature",
"(see",
"Table",
"1",
"in",
"supplementary",
"material)",
"and",
"were",
"collected",
"from",
"the",
"NCBI",
"nucleotide",
"database",
"[21].",
"The",
"sequence",
"characteristics",
"of",
"the",
"coding",
"regions",
"of",
"each",
"gene",
"were",
"examined",
"in",
"the",
"analysis.",
"For",
"CpG",
"dinucleotide",
"analysis,",
"we",
"used",
"the",
"NEWCPGREPORT",
"program",
"[17],",
"and",
"the",
"total",
"number",
"of",
"CpG",
"islands",
"was",
"counted.",
"For",
"the",
"repeat",
"element",
"analysis,",
"the",
"Repeat",
"Masker",
"program",
"[18]",
"was",
"used",
"and",
"for",
"tandem",
"repeat",
"analysis,",
"the",
"ETANDEM",
"program",
"[19]",
"was",
"used.",
"All",
"classes",
"of",
"repeat",
"elements",
"output",
"from",
"Repeat-Masker",
"were",
"collected.",
"We",
"used",
"ETANDEM",
"to",
"obtain",
"numbers",
"of",
"tandem",
"repeat",
"elements",
"ranging",
"from",
"5",
"bp",
"to",
"100",
"bp.",
"All",
"the",
"statistical",
"calculations",
"were",
"performed",
"using",
"the",
"Minitab",
"software",
"[20].",
"Discussion:",
"Firstly,",
"a",
"list",
"of",
"genes",
"that",
"are",
"demethylated",
"in",
"cancer",
"according",
"to",
"the",
"recent",
"existing",
"literature",
"was",
"compiled",
"(Table",
"1",
"in",
"supplementary",
"material).",
"We",
"observed",
"that",
"these",
"genes",
"are",
"related",
"with",
"7",
"different",
"cancer",
"types:",
"breast,",
"colon,",
"lung,",
"ovarian,",
"pancreatic,",
"prostate",
"and",
"testicular.",
"As",
"it",
"can",
"be",
"seen",
"in",
"Table",
"1,",
"the",
"ranges",
"of",
"genes",
"affected",
"by",
"hypomethylation",
"includes",
"growth",
"regulatory",
"genes,",
"enzymes,",
"developmentally",
"critical",
"genes",
"and",
"tissue",
"specific",
"genes",
"such",
"as",
"germ",
"cell-specific",
"tumour",
"antigen",
"genes,",
"etc.",
"Then,",
"we",
"selected",
"6",
"representative",
"structural",
"descriptors",
"(variables)",
"for",
"the",
"structural",
"study:",
"GC",
"content,",
"CpG",
"islands,",
"Simple",
"Repeats",
"(SR),",
"Low",
"Complexity",
"(LC),",
"Large",
"Tandem",
"Repeats",
"(LTR)",
"and",
"SINE",
"Alu.",
"The",
"[bp]%",
"sequence",
"characteristics",
"of",
"these",
"descriptors",
"were",
"calculated",
"for",
"all",
"gene",
"coding",
"regions.",
"As",
"it",
"has",
"stated",
"before,",
"the",
"site",
"reported",
"to",
"be",
"hypomethylated",
"in",
"several",
"human",
"cancers",
"is",
"located",
"within",
"the",
"coding",
"region",
"[13,",
"15].",
"For",
"this",
"reason,",
"the",
"structural",
"information",
"related",
"with",
"this",
"region",
"could",
"be",
"very",
"useful",
"in",
"order",
"to",
"develop",
"a",
"first",
"stage",
"approximation.",
"Once",
"the",
"values",
"for",
"all",
"the",
"structural",
"descriptors",
"were",
"calculated,",
"we",
"performed",
"a",
"distribution",
"analysis",
"of",
"the",
"[bp]%",
"differences",
"across",
"all",
"7",
"cancer",
"types.",
"In",
"order",
"to",
"evaluate",
"tendencies,",
"we",
"also",
"calculated",
"the",
"Bioinformation,",
"an",
"open",
"access",
"forum",
"©",
"2009",
"Biomedical",
"Informatics",
"Publishing",
"Group"
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559,
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600,
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616,
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698,
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421,
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497,
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517,
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579,
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594,
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614,
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618,
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678,
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708,
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712,
917,
723,
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726,
917,
764,
931
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421,
933,
427,
947
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430,
933,
479,
947
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[
481,
933,
533,
947
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[
536,
933,
569,
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571,
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581,
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584,
933,
600,
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602,
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710,
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625,
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628,
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655,
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720,
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511,
965,
565,
979
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570,
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687,
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693,
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736,
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] | [
"REVIEW",
"ARTICLE",
"published:",
"02",
"November",
"2012",
"doi:",
"10.3389/fneur.2012.00144",
"Biomarkers",
"of",
"hypoxic-ischemic",
"encephalopathy",
"in",
"newborns",
"Martha",
"Douglas-Escobar",
"1,2*",
"and",
"Michael",
"D.",
"Weiss",
"1,2",
"1",
"Department",
"of",
"Pediatrics,",
"University",
"of",
"Florida,",
"Gainesville,",
"FL,",
"USA",
"2",
"McKnight",
"Brain",
"Institute,",
"University",
"of",
"Florida,",
"Gainesville,",
"FL,",
"USA",
"Edited",
"by:",
"Stefania",
"Mondello,",
"University",
"of",
"Florida,",
"USA",
"Reviewed",
"by:",
"V.",
"Wee",
"Yong,",
"University",
"of",
"Calgary,",
"Canada",
"Wolfgang",
"J.",
"Streit,",
"University",
"of",
"Florida,",
"USA",
"*Correspondence:",
"Martha",
"Douglas-Escobar",
",",
"Department",
"of",
"Pediatrics,",
"University",
"of",
"Florida,",
"PO",
"Box",
"100296,",
"Gainesville,",
"FL",
"32610-0296,",
"USA.",
"e-mail:",
"marthave@ufl.edu",
"As",
"neonatal",
"intensive",
"care",
"has",
"evolved,",
"the",
"focus",
"has",
"shifted",
"from",
"improving",
"mortality",
"alone",
"to",
"an",
"effort",
"to",
"improve",
"both",
"mortality",
"and",
"morbidity.",
"The",
"most",
"frequent",
"source",
"of",
"neonatal",
"brain",
"injury",
"occurs",
"as",
"a",
"result",
"of",
"hypoxic-ischemic",
"injury.",
"Hypoxic-ischemic",
"injury",
"occurs",
"in",
"about",
"2",
"of",
"1,000",
"full-term",
"infants",
"and",
"severe",
"injured",
"infants",
"will",
"have",
"lifetime",
"disabilities",
"and",
"neurodevelopmental",
"delays.",
"Most",
"recently,",
"remarkable",
"efforts",
"toward",
"neu-",
"roprotection",
"have",
"been",
"started",
"with",
"the",
"advent",
"of",
"therapeutic",
"hypothermia",
"and",
"a",
"key",
"step",
"in",
"the",
"evolution",
"of",
"neonatal",
"neuroprotection",
"is",
"the",
"discovery",
"of",
"biomarkers",
"that",
"enable",
"the",
"clinician-scientist",
"to",
"screen",
"infants",
"for",
"brain",
"injury,",
"monitor",
"progression",
"of",
"disease,",
"identify",
"injured",
"brain",
"regions,",
"and",
"assess",
"efficacy",
"of",
"neuroprotective",
"clinical",
"trials.",
"Lastly,",
"biomark-",
"ers",
"offer",
"great",
"hope",
"identifying",
"when",
"an",
"injury",
"occurred",
"shedding",
"light",
"on",
"the",
"potential",
"pathophysiology",
"and",
"the",
"most",
"effective",
"therapy.",
"In",
"this",
"article,",
"we",
"will",
"review",
"biomarkers",
"of",
"HIE",
"including",
"S100B,",
"neuron",
"specific",
"enolase,",
"umbilical",
"cord",
"IL-6,",
"CK-BB,",
"GFAP,",
"myelin",
"basic",
"protein,",
"UCHL-1,",
"and",
"pNF-H.",
"We",
"hope",
"to",
"contribute",
"to",
"the",
"awareness,",
"validation,",
"and",
"clinical",
"use",
"of",
"established",
"as",
"well",
"as",
"novel",
"neonatal",
"brain",
"injury",
"biomarkers.",
"Keywords:",
"biomarkers,",
"hypoxic-ischemic",
"encephalopathy,",
"brain",
"injury",
"INTRODUCTION",
"Biomarkers",
"are",
"molecules",
"released",
"by",
"or",
"specific",
"to",
"a",
"particular",
"organ,",
"can",
"give",
"a",
"glimpse",
"into",
"the",
"physiologic",
"or",
"pathologic",
"status",
"of",
"that",
"specific",
"organ",
"(Ling",
"and",
"Sylvester,",
"2011).",
"Biomarkers",
"can",
"be",
"obtained",
"from",
"the",
"blood,",
"urine,",
"cerebrospinal",
"fluid",
"(CSF),",
"or",
"any",
"other",
"bodily",
"fluid.",
"In",
"neonates",
"with",
"brain",
"injury,",
"biomarkers",
"may",
"be",
"able",
"to",
"predict",
"the",
"degree",
"and",
"location",
"of",
"injury",
"shortly",
"after",
"the",
"injury",
"occurs.",
"The",
"discovery",
"of",
"neonatal",
"brain",
"injury",
"biomarkers",
"is",
"a",
"key",
"step",
"in",
"neonatal",
"neuroprotection.",
"Biomarkers",
"may",
"enable",
"the",
"clinician-scientist",
"to",
"screen",
"infants",
"for",
"brain",
"injury,",
"monitor",
"the",
"progression",
"of",
"disease,",
"identify",
"injured",
"brain",
"regions,",
"and",
"assess",
"the",
"efficacy",
"of",
"neuroprotective",
"strategies",
"procedures",
"in",
"clinical",
"trials.",
"In",
"addition,",
"large-scale",
"validation",
"of",
"the",
"poten-",
"tial",
"biomarkers",
"is",
"required,",
"because",
"the",
"potential",
"confounders",
"(especially",
"for",
"biomarkers",
"that",
"are",
"non-organ",
"specific",
"such",
"as",
"inflammatory",
"mediators).",
"Currently,",
"clinicians",
"do",
"not",
"routinely",
"use",
"biomarkers",
"to",
"care",
"for",
"neonates",
"with",
"brain",
"injuries.",
"This",
"review",
"will",
"examine",
"potential",
"biomarkers",
"the",
"bedside",
"clinician-scientist",
"may",
"use",
"to",
"hone",
"the",
"treatment",
"of",
"neonates",
"with",
"hypoxic-ischemic",
"encephalopathy.",
"HYPOXIC-ISCHEMIC",
"ENCEPHALOPATHY",
"Systemic",
"asphyxia",
"manifests",
"in",
"the",
"brain",
"as",
"hypoxic-ischemic",
"encephalopathy",
"(HIE;",
"Vannucci,",
"1997).",
"Systemic",
"asphyxia",
"occurs",
"Abbreviations:",
"aEEG,",
"amplitude",
"integrated",
"electroencephalogram;",
"BDNF,",
"brain",
"derived",
"neurotrophic",
"factor;",
"CPK-BB,",
"brain",
"type",
"creatine",
"phosphokinase;",
"CSF,",
"cerebrospinal",
"fluid;",
"GFAP,",
"glial",
"fibrillary",
"acidic",
"protein;",
"HIE,",
"hypoxic-ischemic",
"encephalopathy;",
"IL-6,",
"interleukin-6;",
"NSE,",
"neuron",
"specific",
"enolase;",
"UCHL-1,",
"ubiquitin",
"carboxyl-terminal",
"hydrolase",
"L1.",
"in",
"about",
"2%",
"of",
"full-term",
"infants",
"and",
"in",
"nearly",
"60%",
"of",
"very",
"low",
"birth",
"weight",
"(premature)",
"newborns",
"(Mulligan",
"et",
"al.,",
"1980;",
"Gif-",
"fard",
"et",
"al.,",
"1990;",
"Low",
"et",
"al.,",
"1997).",
"Twenty",
"to",
"fifty",
"percent",
"of",
"asphyxiated",
"babies",
"who",
"exhibit",
"severe",
"HIE",
"die",
"during",
"the",
"new-",
"born",
"period",
"(MacDonald",
"et",
"al.,",
"1980).",
"Of",
"the",
"survivors",
"of",
"severe",
"HIE,",
"up",
"to",
"25%",
"have",
"permanent",
"neuropsychological",
"handicaps",
"in",
"the",
"form",
"of",
"learning",
"disabilities,",
"epilepsy,",
"cerebral",
"palsy,",
"with",
"or",
"without",
"associated",
"mental",
"retardation,",
"learning",
"disabilities,",
"or",
"epilepsy",
"(Finer",
"et",
"al.,",
"1981;",
"Robertson",
"et",
"al.,",
"1989).",
"Systemic",
"asphyxia",
"that",
"causes",
"HIE",
"may",
"occur",
"prior",
"to",
"delivery",
"(e.g.,",
"placen-",
"tal",
"abruption,",
"toxemia,",
"maternal",
"collagen",
"vascular",
"disease),",
"during",
"delivery",
"(e.g.,",
"prolonged",
"labor,",
"difficult",
"delivery,",
"abnormal",
"presen-",
"tation),",
"or",
"after",
"delivery",
"(e.g.,",
"sepsis,",
"shock,",
"respiratory",
"distress).",
"Currently,",
"hypoxic-ischemic",
"injury",
"is",
"diagnosed",
"based",
"on",
"clinical",
"criteria.",
"This",
"review",
"will",
"use",
"the",
"term",
"HIE",
"although",
"recently",
"med-",
"ical",
"experts",
"have",
"proposed",
"use",
"the",
"term",
"neonatal",
"encephalopathy",
"instead",
"of",
"HIE.",
"A",
"clinician’s",
"ability",
"to",
"predict",
"the",
"outcome",
"of",
"neonates",
"with",
"HIE",
"is",
"not",
"straightforward.",
"The",
"Sarnat",
"grading",
"system",
"(Sarnat",
"and",
"Sarnat,",
"1976)",
"stages",
"HIE",
"based",
"on",
"clinical",
"criteria.",
"This",
"scoring",
"system",
"divides",
"neonates",
"into",
"mild,",
"moderate,",
"or",
"severe",
"categories,",
"and",
"measures",
"the",
"progression",
"of",
"the",
"neurologic",
"insult",
"to",
"predict",
"a",
"neonate’s",
"prognosis",
"(Finer",
"et",
"al.,",
"1981).",
"Nevertheless,",
"the",
"Sarnat",
"score",
"system",
"is",
"subjective",
"and",
"changes",
"over",
"time.",
"A",
"new",
"bedside",
"tool,",
"amplitude",
"integrated",
"electroencephalogram",
"(aEEG),",
"may",
"help",
"stage",
"the",
"severity",
"of",
"injury",
"and",
"predict",
"prognosis",
"(Hellstrom-",
"Westas",
"et",
"al.,",
"1995).",
"Unfortunately,",
"the",
"Sarnat",
"score",
"and",
"aEEG",
"are",
"not",
"as",
"effective",
"in",
"predicting",
"outcomes",
"in",
"neonates",
"during",
"hypothermia",
"(Thoresen",
"et",
"al.,",
"2010)",
"and",
"do",
"not",
"provide",
"informa-",
"tion",
"about",
"the",
"timing",
"of",
"the",
"injury.",
"Brain",
"MRI",
"can",
"help",
"determine",
"www.frontiersin.org",
"November",
"2012",
"|",
"Volume",
"3",
"|",
"Article",
"144",
"|",
"1"
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] | [
"SAGE-Hindawi",
"Access",
"to",
"Research",
"Journal",
"of",
"Aging",
"Research",
"Volume",
"2011,",
"Article",
"ID",
"138015,",
"10",
"pages",
"doi:10.4061/2011/138015",
"Research",
"Article",
"Body",
"Mass",
"Index",
"Is",
"Associated",
"with",
"Dietary",
"Patterns",
"and",
"Health",
"Conditions",
"in",
"Georgia",
"Centenarians",
"Dorothy",
"B.",
"Hausman,1",
"Mary",
"Ann",
"Johnson,1",
"Adam",
"Davey,2",
"and",
"Leonard",
"W.",
"Poon3",
"1",
"Department",
"of",
"Foods",
"and",
"Nutrition,",
"University",
"of",
"Georgia,",
"280",
"Dawson",
"Hall,",
"Athens,",
"GA",
"30602,",
"USA",
"2",
"Department",
"of",
"Public",
"Health,",
"Temple",
"University,",
"Philadelphia,",
"PA",
"19122,",
"USA",
"3",
"Institute",
"of",
"Gerontology,",
"University",
"of",
"Georgia,",
"Athens,",
"GA",
"30602,",
"USA",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Dorothy",
"B.",
"Hausman,",
"dhausman@uga.edu",
"Received",
"2",
"March",
"2011;",
"Accepted",
"4",
"April",
"2011",
"Academic",
"Editor:",
"Bo",
"A.",
"Hagberg",
"Copyright",
"©",
"2011",
"Dorothy",
"B.",
"Hausman",
"et",
"al.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Associations",
"between",
"body",
"mass",
"index",
"(BMI)",
"and",
"dietary",
"patterns",
"and",
"health",
"conditions",
"were",
"explored",
"in",
"a",
"population-based",
"multiethnic",
"sample",
"of",
"centenarians",
"from",
"northern",
"Georgia.",
"BMI",
"≤20",
"and",
"≥25",
"was",
"prevalent",
"in",
"30.9%",
"and",
"25.3%",
"of",
"study",
"participants,",
"respectively.",
"In",
"a",
"series",
"of",
"logistic",
"regression",
"analyses",
"controlled",
"for",
"gender",
"and",
"place",
"of",
"residence,",
"the",
"probability",
"of",
"having",
"BMI",
"≥25",
"was",
"increased",
"by",
"being",
"black",
"versus",
"white",
"and",
"having",
"a",
"low",
"citrus",
"fruit,",
"noncitrus",
"fruit,",
"orange/yellow",
"vegetable",
"or",
"total",
"fruit",
"and",
"vegetable",
"intake.",
"The",
"probability",
"of",
"having",
"BMI",
"≤20",
"was",
"not",
"associated",
"with",
"dietary",
"intake.",
"When",
"controlled",
"for",
"race,",
"gender,",
"residence,",
"and",
"total",
"fruit",
"and",
"vegetable",
"intake,",
"BMI",
"≥25",
"was",
"an",
"independent",
"risk",
"factor",
"for",
"diabetes",
"or",
"having",
"a",
"systolic",
"blood",
"pressure",
"≥140",
"mmHg",
"or",
"diastolic",
"blood",
"pressure",
"≥90",
"mmHg,",
"whereas",
"BMI",
"≤20",
"was",
"a",
"risk",
"factor",
"for",
"anemia.",
"Given",
"the",
"many",
"potential",
"adverse",
"consequences",
"of",
"under-",
"and",
"overweight,",
"efforts",
"are",
"needed",
"to",
"maintain",
"a",
"healthy",
"weight,",
"even",
"in",
"the",
"oldest",
"old.",
"1.",
"Introduction",
"Body",
"mass",
"index",
"is",
"a",
"simple",
"index",
"of",
"weight",
"for",
"height",
"that",
"is",
"frequently",
"used",
"in",
"the",
"assessment",
"of",
"nutritional",
"status.",
"A",
"low",
"BMI,",
"or",
"underweight",
"status,",
"is",
"often",
"associated",
"with",
"an",
"increased",
"risk",
"of",
"mortality",
"in",
"seriously",
"ill",
"or",
"hospitalized",
"older",
"adults",
"[1,",
"2].",
"Conversely,",
"a",
"high",
"BMI,",
"indicative",
"of",
"overweight",
"or",
"obesity,",
"is",
"associated",
"with",
"an",
"exacerbation",
"in",
"age-related",
"physical",
"and",
"cognitive",
"decline",
"[3,",
"4]",
"and",
"with",
"an",
"increased",
"prevalence",
"or",
"risk",
"of",
"many",
"chronic",
"health",
"conditions",
"common",
"in",
"older",
"adults",
"such",
"as",
"diabetes,",
"hypertension,",
"and",
"cardiovascular",
"disease",
"[3–5].",
"Such",
"asso-",
"ciations",
"are",
"typically",
"determined",
"across",
"the",
"entire",
"spectrum",
"of",
"older",
"adults",
"(aged",
"60+),",
"with",
"no",
"further",
"demarcation",
"within",
"this",
"age",
"classification.",
"Our",
"finding",
"of",
"a",
"much",
"higher",
"prevalence",
"of",
"several",
"nutritional",
"deficiencies",
"in",
"centenarians",
"as",
"compared",
"with",
"octogenarians",
"[6,",
"7],",
"suggests",
"that",
"there",
"is",
"considerable",
"heterogeneity",
"in",
"nutrient",
"status",
"in",
"the",
"“older",
"adult”",
"age",
"group.",
"Likewise,",
"there",
"may",
"also",
"be",
"considerable",
"heterogeneity",
"within",
"the",
"older",
"adult",
"age",
"group",
"with",
"regard",
"to",
"chronic",
"health",
"conditions.",
"Thus,",
"it",
"is",
"not",
"known",
"whether",
"the",
"associations",
"between",
"underweight",
"or",
"overweight/obesity",
"and",
"chronic",
"health",
"conditions",
"as",
"observed",
"in",
"previous",
"studies",
"of",
"older",
"adults",
"extend",
"to",
"the",
"very",
"old.",
"Dietary",
"intake",
"patterns",
"featuring",
"a",
"high",
"intake",
"of",
"nutrient-dense",
"foods",
"such",
"as",
"cereals,",
"fruits,",
"vegetables,",
"and",
"low-fat",
"meat",
"and",
"dairy",
"products",
"have",
"been",
"associated",
"with",
"a",
"number",
"of",
"favorable",
"health",
"outcomes",
"in",
"adults",
"including",
"a",
"decreased",
"prevalence",
"of",
"obesity",
"[8,",
"9],",
"lower",
"rates",
"of",
"weight",
"gain",
"over",
"time",
"[10],",
"and",
"better",
"quality",
"of",
"life",
"and",
"improved",
"survival",
"[11].",
"In",
"contrast,",
"low-nutrient",
"dense",
"dietary",
"patterns",
"with",
"high",
"intakes",
"of",
"sweets,",
"desserts,",
"and",
"high-fat",
"dairy",
"products",
"have",
"been",
"associated",
"with",
"higher",
"rates",
"of",
"obesity",
"and",
"poor",
"nutritional",
"status",
"in",
"older",
"adults",
"[9].",
"Whether",
"these",
"observations",
"extend",
"to",
"the",
"very",
"old",
"is",
"unknown.",
"Studies",
"comparing",
"energy",
"intakes",
"and",
"dietary",
"intake",
"patterns",
"of",
"centenarians",
"to",
"younger",
"older",
"adult",
"cohorts",
"have",
"generally",
"observed",
"lower",
"energy",
"and/or",
"fat",
"intake",
"in",
"the",
"centenarians,",
"while",
"dietary",
"preferences",
"of",
"centenarians",
"are",
"considerably",
"more",
"varied",
"and",
"dependent",
"of",
"the",
"region",
"of",
"study",
"likely",
"reflecting",
"cultural",
"patterns",
"and",
"cohort",
"differences",
"rather",
"than",
"longevity-related",
"differences"
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] | [
"Zheng",
"et",
"al.",
"Journal",
"of",
"Hematology",
"&",
"Oncology",
"2011,",
"4:21",
"http://www.jhoonline.org/content/4/1/21",
"S",
"H",
"O",
"R",
"T",
"R",
"E",
"P",
"O",
"R",
"T",
"JOURNAL",
"OF",
"HEMATOLOGY",
"&",
"ONCOLOGY",
"Open",
"Access",
"Expression",
"and",
"distribution",
"of",
"PPP2R5C",
"gene",
"in",
"leukemia",
"Haitao",
"Zheng1†,",
"Yu",
"Chen1,2†,",
"Shaohua",
"Chen1,",
"Yuzhe",
"Niu1,2,",
"Lijian",
"Yang1,",
"Bo",
"Li1,",
"Yuhong",
"Lu1,",
"Suxia",
"Geng3,",
"Xin",
"Du3",
"and",
"Yangqiu",
"Li1,2*",
"Abstract",
"Background:",
"Recently,",
"we",
"clarified",
"at",
"the",
"molecular",
"level",
"novel",
"chromosomal",
"translocation",
"t(14;14)(q11;q32)",
"in",
"a",
"case",
"of",
"Sézary",
"syndrome,",
"which",
"caused",
"a",
"rearrangement",
"from",
"TRAJ7",
"to",
"the",
"PPP2R5C",
"gene.",
"PPP2R5C",
"is",
"one",
"of",
"the",
"regulatory",
"B",
"subunits",
"of",
"protein",
"phosphatase",
"2A",
"(PP2A).",
"It",
"plays",
"a",
"crucial",
"role",
"in",
"cell",
"proliferation,",
"differentiation,",
"and",
"transformation.",
"To",
"characterize",
"the",
"expression",
"and",
"distribution",
"of",
"five",
"different",
"transcript",
"variants",
"of",
"the",
"PPP2R5C",
"gene",
"in",
"leukemia,",
"we",
"analyzed",
"the",
"expression",
"level",
"of",
"PPP2R5C",
"in",
"peripheral",
"blood",
"mononuclear",
"cells",
"from",
"77",
"patients",
"with",
"de",
"novo",
"leukemia,",
"26",
"patients",
"with",
"leukemia",
"in",
"complete",
"remission",
"(CR),",
"and",
"20",
"healthy",
"individuals",
"by",
"real-time",
"PCR",
"and",
"identified",
"the",
"different",
"variants",
"of",
"PPP2R5C",
"by",
"RT-PCR.",
"Findings:",
"Significantly",
"higher",
"expression",
"of",
"PPP2R5C",
"was",
"found",
"in",
"AML,",
"CML,",
"T-ALL,",
"and",
"B-CLL",
"groups",
"in",
"comparison",
"with",
"healthy",
"controls.",
"High",
"expression",
"of",
"PPP2R5C",
"was",
"detected",
"in",
"the",
"B-ALL",
"group;",
"however,",
"no",
"significant",
"difference",
"was",
"found",
"compared",
"with",
"the",
"healthy",
"group.",
"The",
"expression",
"level",
"of",
"PPP2R5C",
"in",
"the",
"CML-CR",
"group",
"decreased",
"significantly",
"compared",
"with",
"that",
"in",
"the",
"de",
"novo",
"CML",
"group",
"and",
"was",
"not",
"significantly",
"different",
"from",
"the",
"level",
"in",
"the",
"healthy",
"group.",
"By",
"using",
"different",
"primer",
"pairs",
"that",
"covered",
"different",
"exons,",
"five",
"transcript",
"variants",
"of",
"PPP2R5C",
"could",
"be",
"identified.",
"All",
"variants",
"could",
"be",
"detected",
"in",
"healthy",
"samples",
"as",
"well",
"as",
"in",
"all",
"the",
"leukemia",
"samples,",
"and",
"similar",
"frequencies",
"and",
"distributions",
"of",
"PPP2R5C",
"were",
"indicated.",
"Conclusions:",
"Overexpression",
"of",
"PPP2R5C",
"in",
"T-cell",
"malignancy",
"as",
"well",
"as",
"in",
"myeloid",
"leukemia",
"cells",
"might",
"relate",
"to",
"its",
"proliferation",
"and",
"differentiation.",
"Investigation",
"of",
"the",
"effect",
"of",
"target",
"inhibition",
"of",
"this",
"gene",
"might",
"be",
"beneficial",
"to",
"further",
"characterization",
"of",
"molecular",
"mechanisms",
"and",
"targeted",
"therapy",
"in",
"leukemia.",
"Keywords:",
"PPP2R5C",
"leukemia,",
"gene",
"expression,",
"transcript",
"variant",
"Background",
"Molecular",
"genetic",
"aberrations",
"could",
"provide",
"the",
"basis",
"for",
"assays",
"that",
"can",
"predict",
"prognosis",
"of",
"individual",
"patients",
"as",
"well",
"as",
"potential",
"molecular",
"targets",
"for",
"novel",
"therapies",
"[1-3].",
"The",
"process",
"of",
"malignant",
"transformation",
"in",
"leukemia",
"is",
"complex,",
"and",
"many",
"factors",
"such",
"as",
"abnormal",
"gene",
"expression",
"and",
"mutation,",
"chromosomal",
"aberrations,",
"deregulation",
"of",
"various",
"cellular",
"signaling",
"pathways,",
"and",
"deregulation",
"of",
"epigenetic",
"regulation",
"are",
"involved",
"in",
"the",
"development",
"of",
"leukemia",
"[1].",
"Therefore,",
"new",
"data",
"regarding",
"molecular",
"genetic",
"aberrations",
"in",
"*",
"Correspondence:",
"yangqiuli@hotmail.com",
"†",
"Contributed",
"equally",
"1Institute",
"of",
"Hematology,",
"Medical",
"College,",
"Jinan",
"University,",
"Guangzhou,",
"P.R.",
"China",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"different",
"types",
"of",
"leukemia",
"are",
"needed",
"for",
"further",
"characterization.",
"PPP2R5C",
"is",
"one",
"of",
"the",
"regulatory",
"B",
"subunits",
"of",
"protein",
"phosphatase",
"2A",
"(PP2A),",
"which",
"is",
"a",
"major",
"cellu-",
"lar",
"serine/threonine",
"phosphatase",
"that",
"affects",
"the",
"phos-",
"phorylation",
"status",
"of",
"many",
"proteins",
"[4].",
"The",
"PPP2R5C",
"gene",
"encodes",
"five",
"differentially",
"spliced",
"variants:",
"B56g1,",
"B56g2,",
"B56g3,",
"B56g5,",
"and",
"B56g6",
"(Figure",
"1),",
"whereas",
"B56g4",
"is",
"identified",
"only",
"in",
"mice.",
"The",
"functional",
"PPP2R5C",
"gene",
"locus",
"resides",
"at",
"14q32.2,",
"whereas",
"a",
"non-",
"functional",
"B56g1",
"pseudogene",
"PPP2R5C",
"is",
"present",
"at",
"3p21.3",
"[4,5].",
"PPP2R5C",
"plays",
"a",
"crucial",
"role",
"in",
"cell",
"prolif-",
"eration,",
"differentiation,",
"and",
"transformation,",
"based",
"on",
"its",
"induction",
"of",
"dephosphorylation",
"of",
"P53",
"at",
"various",
"resi-",
"dues",
"[6].",
"It",
"has",
"been",
"reported",
"that",
"the",
"dynamic",
"nuclear",
"distribution",
"of",
"the",
"B56g3",
"regulatory",
"subunit",
"controls",
"©",
"2011",
"Zheng",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
] | [
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] | [
"SAGE-Hindawi",
"Access",
"to",
"Research",
"International",
"Journal",
"of",
"Nephrology",
"Volume",
"2011,",
"Article",
"ID",
"364890,",
"5",
"pages",
"doi:10.4061/2011/364890",
"Review",
"Article",
"Clinical",
"Significance",
"of",
"FGF-23",
"in",
"Patients",
"with",
"CKD",
"Domenico",
"Russo",
"and",
"Yuri",
"Battaglia",
"Department",
"of",
"Nephrology,",
"School",
"of",
"Medicine,",
"University",
"Federico",
"II,",
"Via",
"Pansini",
"5,",
"80131",
"Napoli,",
"Italy",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Domenico",
"Russo,",
"domenicorusso51@hotmail.com",
"Received",
"22",
"December",
"2010;",
"Accepted",
"24",
"February",
"2011",
"Academic",
"Editor:",
"Angela",
"Wang",
"Copyright",
"©",
"2011",
"D.",
"Russo",
"and",
"Y.",
"Battaglia.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"FGF23",
"is",
"a",
"bone-derived",
"hormone",
"that",
"plays",
"an",
"important",
"role",
"in",
"the",
"regulation",
"of",
"phosphate",
"and",
"1,25-dihydroxy",
"vitamin",
"D",
"metabolism.",
"FGF23",
"principally",
"acts",
"in",
"the",
"kidney",
"to",
"induce",
"urinary",
"phosphate",
"excretion",
"and",
"suppress",
"1,25-dihydroxyvitamin",
"D",
"synthesis",
"in",
"the",
"presence",
"of",
"FGF",
"receptor",
"1",
"(FGFR1)",
"and",
"its",
"coreceptor",
"Klotho.",
"In",
"patients",
"with",
"chronic",
"kidney",
"disease",
"(CKD),",
"circulating",
"FGF23",
"levels",
"are",
"progressively",
"increased",
"to",
"compensate",
"for",
"persistent",
"phosphate",
"retention,",
"but",
"this",
"results",
"in",
"reduced",
"renal",
"production",
"of",
"1,25-dihydroxyvitamin",
"D",
"and",
"leads",
"to",
"hypersecretion",
"of",
"parathyroid",
"hormone.",
"Furthermore,",
"FGF23",
"is",
"associated",
"with",
"vascular",
"dysfunction,",
"atherosclerosis,",
"and",
"left",
"ventricular",
"hypertrophy.",
"This",
"paper",
"summarizes",
"the",
"role",
"of",
"FGF23",
"in",
"the",
"pathogenesis",
"of",
"mineral,",
"bone,",
"and",
"cadiovascular",
"disorders",
"in",
"CKD.",
"1.",
"Introduction",
"Patients",
"with",
"chronic",
"kidney",
"disease",
"(CKD)",
"are",
"at",
"increased",
"risk",
"for",
"cardiovascular",
"events",
"compared",
"with",
"individuals",
"with",
"normal",
"kidney",
"function",
"[1].",
"In",
"addition",
"to",
"tradi-",
"tional",
"cardiovascular",
"risk",
"factors,",
"disturbances",
"in",
"calcium-",
"phosphate",
"metabolism",
"are",
"regarded",
"as",
"strong",
"contributing",
"factors",
"of",
"higher",
"cardiovascular",
"mortality",
"in",
"CKD",
"patients",
"[2,",
"3].",
"Indeed,",
"elevated",
"serum",
"phosphate,",
"low",
"calcitriol,",
"and",
"high",
"PTH",
"levels",
"represent",
"the",
"classical",
"triad",
"that",
"leads",
"to",
"secondary",
"hyperparathyroidism,",
"each",
"factor",
"being",
"independently",
"associated",
"with",
"cardiovascular",
"events",
"and",
"mortality",
"in",
"patients",
"with",
"CKD",
"[4,",
"5].",
"Recently,",
"the",
"phosphaturic",
"hormone,",
"fibroblast",
"growth",
"factor",
"(FGF-23),",
"is",
"overpoweringly",
"entered",
"into",
"the",
"tradi-",
"tional",
"pathophysiological",
"scheme",
"of",
"secondary",
"hyperpara-",
"thyroidism.",
"2.",
"Structure",
"of",
"FGF-23",
"Seven",
"known",
"subfamilies",
"of",
"human",
"FGFs",
"have",
"been",
"defined",
"[6,",
"7].",
"The",
"FGF-19",
"subfamily",
"is",
"composed",
"of",
"three",
"pro-",
"teins—FGF-19,",
"FGF-21,",
"and",
"FGF-23—which",
"exert",
"diverse",
"physiological",
"functions.",
"FGF-23",
"is",
"a",
"central",
"regulator",
"of",
"phosphate",
"homeostasis",
"and",
"calcitriol",
"blood",
"levels;",
"FGF-19",
"inhibits",
"the",
"expression",
"of",
"enzyme",
"cholesterol",
"7-a-",
"hydroxylase",
"(CYP7A1),",
"which",
"is",
"the",
"first",
"and",
"rate-limiting",
"step",
"in",
"bile",
"acid",
"synthesis",
"[8];",
"FGF-21",
"stimulates",
"insulin-",
"independent",
"glucose",
"uptake",
"in",
"adipocytes",
"and",
"lowers",
"triglyc-",
"erides",
"[9].",
"Interestingly,",
"FGF-19,",
"FGF-21,",
"and",
"FGF-23",
"con-",
"tain",
"a",
"disulfide",
"bond",
"that",
"is",
"absent",
"in",
"most",
"other",
"subfamilies.",
"This",
"may",
"explain",
"why",
"FGF-23",
"can",
"be",
"distributed",
"in",
"the",
"bloodstream",
"to",
"mediate",
"its",
"functions.",
"FGF-23",
"is",
"a",
"251-amino",
"acid",
"protein",
"(MW",
"26",
"kDa)",
"syn-",
"thesized",
"and",
"secreted",
"by",
"bone",
"cells,",
"mainly",
"osteoblast",
"[10].",
"It",
"is",
"composed",
"of",
"an",
"amino-terminal",
"signal",
"peptide",
"(residues",
"1–24),",
"followed",
"by",
"an",
"“FGF-like",
"sequence”",
"(residues",
"25–180)",
"and",
"a",
"carboxyl-terminal",
"extended",
"sequence",
"(residues",
"181–",
"251)",
"that",
"is",
"unique",
"compared",
"with",
"other",
"members",
"of",
"the",
"FGF",
"family",
"[7].",
"The",
"half-life",
"of",
"intact",
"FGF-23",
"in",
"the",
"circulation",
"of",
"healthy",
"individuals",
"has",
"been",
"estimated",
"to",
"be",
"58",
"min",
"[11].",
"FGF-23",
"exerts",
"its",
"biological",
"effects",
"through",
"activation",
"of",
"FGF",
"receptors",
"(FGF-Rs);",
"this",
"activation",
"is",
"Klotho",
"dependent",
"as",
"a",
"Klotho/FGF-R",
"complex",
"binds",
"to",
"FGF-23",
"with",
"higher",
"affinity",
"than",
"does",
"FGF-R",
"or",
"Klotho",
"alone",
"[12].",
"Klotho",
"is",
"a",
"130-",
"kDa",
"transmembrane",
"b-glucuronidase",
"capable",
"of",
"hydrolyzing"
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] | [
"Int.",
"J.",
"Mol.",
"Sci.",
"2009,",
"10,",
"2348-2366;",
"doi:10.3390/ijms10052348",
"OPEN",
"ACCESS",
"International",
"Journal",
"of",
"Molecular",
"Sciences",
"ISSN",
"1422-0067",
"www.mdpi.com/journal/ijms",
"Article",
"Microscopic",
"Investigation",
"of",
"Reversible",
"Nanoscale",
"Surface",
"Size",
"Dependent",
"Protein",
"Conjugation",
"Kazushige",
"Yokoyama",
"1,*,",
"Hyunah",
"Cho",
"1,",
"Sean",
"P.",
"Cullen",
"1,",
"Matthew",
"Kowalik",
"1,",
"Nicole",
"M.",
"Briglio",
"1,",
"Harold",
"J.",
"Hoops",
"2,",
"Zhouying",
"Zhao",
"3",
"and",
"Michael",
"A.",
"Carpenter",
"3",
"1",
"Department",
"of",
"Chemistry,",
"The",
"State",
"University",
"of",
"New",
"York",
"at",
"Geneseo,",
"1",
"College",
"Circle,",
"Geneseo,",
"NY",
"14454,",
"USA;",
"E-Mails:",
"hc7@geneseo.edu",
"(H.C.);",
"spc8@geneseo.edu",
"(S.P.C.);",
"mk16@geneseo.edu",
"(M.K.);",
"nmb11@geneseo.edu",
"(N.M.B.)",
"2",
"Department",
"of",
"Biology,",
"The",
"State",
"University",
"of",
"New",
"York",
"at",
"Geneseo,",
"1",
"College",
"Circle,",
"Geneseo,",
"NY",
"14454,",
"USA;",
"E-Mail:",
"hoops@geneseo.edu",
"(H.J.H.)",
"3",
"College",
"of",
"Nanoscale",
"Science",
"and",
"Engineering,",
"University",
"of",
"Albany-SUNY,",
"255",
"Fuller",
"Road,",
"Albany,",
"NY",
"12203,",
"USA;",
"E-Mails:",
"zzhao@uamail.albany.edu",
"(Z.-Y.Z.);",
"mcarpenter@uamail.albany.edu",
"(M.A.C.)",
"*",
"Author",
"to",
"whom",
"correspondence",
"should",
"be",
"addressed;",
"E-Mail:",
"yokoyama@geneseo.edu;",
"Tel.",
"+1-585-245-5320;",
"Fax:",
"+1-585-245-5288",
"Received:",
"3",
"April",
"2009;",
"in",
"revised",
"form:",
"14",
"May",
"2009",
"/",
"Accepted:",
"18",
"May",
"2009",
"/",
"Published:",
"20",
"May",
"2009",
"Abstract:",
"A1-40",
"coated",
"20",
"nm",
"gold",
"colloidal",
"nanoparticles",
"exhibit",
"a",
"reversible",
"color",
"change",
"as",
"pH",
"is",
"externally",
"altered",
"between",
"pH",
"4",
"and",
"10.",
"This",
"reversible",
"process",
"may",
"contain",
"important",
"information",
"on",
"the",
"initial",
"reversible",
"step",
"reported",
"for",
"the",
"fibrillogenesis",
"of",
"Aa",
"hallmark",
"of",
"Alzheimer’s",
"disease).",
"We",
"examined",
"this",
"reversible",
"color",
"change",
"by",
"microscopic",
"investigations.",
"AFM",
"images",
"on",
"graphite",
"surfaces",
"revealed",
"the",
"morphology",
"of",
"A",
"aggregates",
"with",
"gold",
"colloids.",
"TEM",
"images",
"clearly",
"demonstrate",
"the",
"correspondence",
"between",
"spectroscopic",
"features",
"and",
"conformational",
"changes",
"of",
"the",
"gold",
"colloid.",
"Keywords:",
"amyloid",
"beta;",
"fibrillogenesis;",
"Alzheimer’s",
"disease;",
"ovalbumin;",
"gold",
"nanoparticles;",
"AFM;",
"TEM"
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] | [
"Nucleic",
"Acids",
"Research,",
"2006,",
"Vol.",
"34,",
"No.",
"4",
"e33",
"doi:10.1093/nar/gkl003",
"The",
"use",
"of",
"biotin",
"tagging",
"in",
"Saccharomyces",
"cerevisiae",
"improves",
"the",
"sensitivity",
"of",
"chromatin",
"immunoprecipitation",
"Folkert",
"J.",
"van",
"Werven",
"and",
"H.",
"Th.",
"Marc",
"Timmers*",
"Department",
"of",
"Physiological",
"Chemistry,",
"Division",
"of",
"Biomedical",
"Genetics,",
"University",
"Medical",
"Centre",
"Utrecht,",
"Universiteitsweg",
"100,",
"3584",
"CG",
"Utrecht,",
"The",
"Netherlands",
"Received",
"January",
"20,",
"2006;",
"Accepted",
"February",
"9,",
"2006",
"ABSTRACT",
"Affinity",
"tagging",
"has",
"been",
"used",
"in",
"many",
"global",
"stu-",
"dies",
"towards",
"protein",
"function.",
"We",
"describe",
"a",
"highly",
"efficient",
"system",
"for",
"in",
"vivo",
"biotinylation",
"of",
"transcrip-",
"tion",
"factors",
"in",
"the",
"yeast",
"Saccharomyces",
"cerevisiae,",
"which",
"is",
"based",
"on",
"the",
"bacterial",
"BirA",
"biotin",
"ligase.",
"The",
"strength",
"of",
"the",
"biotin–streptavidin",
"interaction",
"was",
"exploited",
"to",
"improve",
"detection",
"of",
"in",
"vivo",
"protein–DNA",
"complexes",
"in",
"chromatin",
"immunopre-",
"cipitation",
"(ChIP)",
"experiments.",
"In",
"a",
"test",
"system",
"using",
"the",
"biotin-tagged",
"LexA",
"DNA-binding",
"protein,",
"we",
"found",
"that",
"stringent",
"washing",
"conditions",
"resulted",
"in",
"a",
"strong",
"improvement",
"of",
"the",
"signal-to-noise",
"ratios.",
"Yeast",
"strains",
"with",
"chromosomally",
"integrated",
"ver-",
"sions",
"of",
"tagged",
"transcription",
"factor",
"genes",
"were",
"generated",
"using",
"N-",
"or",
"C-terminal",
"biotin-tagging",
"cas-",
"settes.",
"ChIP",
"experiments",
"with",
"biotinylated",
"Rbp3p,",
"a",
"RNA",
"polymerase",
"II",
"subunit,",
"showed",
"that",
"Rbp3p-",
"binding",
"could",
"even",
"be",
"detected",
"at",
"weakly",
"expressed",
"genes.",
"Other",
"methods",
"failed",
"to",
"detect",
"RNA",
"poly-",
"merase",
"II",
"binding",
"at",
"such",
"genes.",
"Our",
"results",
"show",
"that",
"biotinylation",
"of",
"yeast",
"transcription",
"factors",
"impr-",
"oves",
"the",
"detection",
"of",
"in",
"vivo",
"protein–DNA",
"complexes.",
"INTRODUCTION",
"Transcription",
"regulation",
"in",
"eukaryotic",
"cells",
"requires",
"the",
"coordinated",
"and",
"sequential",
"action",
"of",
"a",
"plethora",
"of",
"gene-",
"regulatory",
"proteins,",
"cofactor",
"complexes",
"and",
"basal",
"transcrip-",
"tion",
"factors",
"(1–3).",
"These",
"proteins",
"interact",
"directly",
"with",
"the",
"regulatory",
"DNA",
"sequences",
"encompassing",
"enhancers",
"and",
"pro-",
"moter",
"elements",
"or",
"indirectly",
"via",
"recruitment",
"through",
"DNA-",
"specific",
"gene",
"regulators.",
"Approaches",
"depending",
"on",
"in",
"vitro",
"DNA-binding",
"and",
"transcription",
"assays",
"or",
"on",
"yeast",
"genetic",
"screens",
"were",
"instrumental",
"in",
"identification",
"of",
"transcription",
"regulatory",
"proteins.",
"In",
"many",
"cases",
"it",
"remained",
"uncertain,",
"how-",
"ever,",
"whether",
"the",
"interaction",
"between",
"transcription",
"regulators",
"and",
"promoter",
"DNA",
"occurred",
"in",
"living",
"cells",
"or",
"whether",
"the",
"observed",
"effects",
"were",
"indirect",
"(4,5).",
"This",
"has",
"motivated",
"development",
"of",
"in",
"vivo",
"protein-DNA",
"crosslinking",
"methods",
"(6,7).",
"The",
"so-called",
"chromatin",
"immuno-",
"precipitation",
"(ChIP)",
"assay",
"has",
"found",
"widespread",
"use",
"to",
"study",
"transcription",
"and",
"chromatin",
"regulation.",
"ChIP",
"relies",
"on",
"fixation",
"of",
"protein–DNA",
"interactions",
"by",
"crosslinking",
"agents",
"such",
"as",
"formaldehyde,",
"immunopurification",
"of",
"the",
"covalently",
"cross-",
"linked",
"complexes",
"and",
"detection",
"of",
"the",
"purified",
"DNA",
"(6,7).",
"As",
"formaldehyde",
"instantly",
"penetrates",
"living",
"cells,",
"in",
"vivo",
"bind-",
"ing",
"of",
"transcription",
"factors",
"to",
"DNA",
"can",
"be",
"determined",
"in",
"a",
"time-resolved",
"manner.",
"This",
"has",
"been",
"illustrated",
"by",
"several",
"studies",
"in",
"yeast",
"and",
"human",
"cells",
"(8–11).",
"In",
"addition,",
"sequential",
"ChIP",
"assays",
"allow",
"determination",
"of",
"simultaneous",
"binding",
"of",
"transcription",
"factors",
"to",
"the",
"same",
"DNA",
"fragment",
"(12).",
"Com-",
"bining",
"ChIP",
"experiments",
"with",
"DNA",
"microarray",
"detection",
"allows",
"determination",
"of",
"the",
"genome-wide",
"localization",
"of",
"transcription",
"factors.",
"Recent",
"studies",
"using",
"tiling",
"microarrays",
"to",
"determine",
"histone",
"modifications",
"on",
"yeast",
"chromosomes",
"showed",
"that",
"nearly",
"all",
"fragments",
"can",
"be",
"mapped",
"provided",
"that",
"the",
"signal-to-noise",
"ratios",
"of",
"the",
"ChIP",
"are",
"acceptable",
"(13).",
"The",
"immunoprecipitation",
"step",
"requires",
"highly",
"specific",
"anti-",
"bodies",
"with",
"high",
"affinity",
"for",
"the",
"antigen.",
"In",
"yeast,",
"this",
"can",
"be",
"often",
"circumvented",
"by",
"fusing",
"the",
"gene",
"of",
"interest",
"with",
"one",
"or",
"more",
"copies",
"of",
"generic",
"epitopes",
"like",
"hemagglutinin",
"(HA),",
"Myc",
"and",
"Flag",
"for",
"which",
"high",
"quality",
"antibodies",
"are",
"available.",
"Alternative",
"strategies",
"involve",
"modification",
"with",
"the",
"tandem",
"affinity",
"purification",
"(TAP)",
"tag.",
"However,",
"all",
"approaches",
"suffer",
"from",
"low",
"signal-to-noise",
"ratios",
"compromising",
"the",
"analysis",
"of",
"low-abundant",
"and",
"transient",
"protein–DNA",
"interactions.",
"To",
"increase",
"signal-to-noise",
"ratios",
"we",
"explored",
"the",
"use",
"of",
"in",
"vivo",
"biotinylation",
"in",
"the",
"yeast",
"Saccharomyces",
"cerevisiae.",
"The",
"binding",
"between",
"biotin",
"and",
"streptavidin",
"represents",
"one",
"of",
"the",
"strongest",
"non-covalent",
"interactions",
"known",
"(Kd",
"¼",
"10",
"15",
"M).",
"Several",
"in",
"vivo",
"protein",
"biotinylation",
"systems",
"for",
"bacterial",
"and",
"mammalian",
"cells",
"relying",
"on",
"the",
"BirA",
"biotin",
"*To",
"whom",
"correspondence",
"should",
"be",
"addressed.",
"Tel:",
"+31",
"30",
"2538981;",
"Fax:",
"+31",
"30",
"253",
"9035;",
"Email:",
"h.t.m.timmers@med.uu.nl",
"The",
"Author",
"2006.",
"Published",
"by",
"Oxford",
"University",
"Press.",
"All",
"rights",
"reserved.",
"The",
"online",
"version",
"of",
"this",
"article",
"has",
"been",
"published",
"under",
"an",
"open",
"access",
"model.",
"Users",
"are",
"entitled",
"to",
"use,",
"reproduce,",
"disseminate,",
"or",
"display",
"the",
"open",
"access",
"version",
"of",
"this",
"article",
"for",
"non-commercial",
"purposes",
"provided",
"that:",
"the",
"original",
"authorship",
"is",
"properly",
"and",
"fully",
"attributed;",
"the",
"Journal",
"and",
"Oxford",
"University",
"Press",
"are",
"attributed",
"as",
"the",
"original",
"place",
"of",
"publication",
"with",
"the",
"correct",
"citation",
"details",
"given;",
"if",
"an",
"article",
"is",
"subsequently",
"reproduced",
"or",
"disseminated",
"not",
"in",
"its",
"entirety",
"but",
"only",
"in",
"part",
"or",
"as",
"a",
"derivative",
"work",
"this",
"must",
"be",
"clearly",
"indicated.",
"For",
"commercial",
"re-use,",
"please",
"contact",
"journals.permissions@oxfordjournals.org"
] | [
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] | [
"Martin",
"et",
"al.",
"BMC",
"Bioinformatics",
"2010,",
"11(Suppl",
"3):S10",
"http://www.biomedcentral.com/1471-2105/11/S3/S10",
"P",
"R",
"O",
"C",
"E",
"E",
"D",
"I",
"N",
"G",
"S",
"Open",
"Access",
"Bacillus",
"anthracis",
"genome",
"organization",
"in",
"light",
"of",
"whole",
"transcriptome",
"sequencing",
"Jeffrey",
"Martin1,",
"Wenhan",
"Zhu2,",
"Karla",
"D",
"Passalacqua2,",
"Nicholas",
"Bergman2,3,",
"Mark",
"Borodovsky4,5*",
"From",
"IEEE",
"International",
"Conference",
"on",
"Bioinformatics",
"and",
"Biomedicine",
"2009",
"Washington,",
"DC,",
"USA.",
"1-4",
"November",
"2009",
"Abstract",
"Emerging",
"knowledge",
"of",
"whole",
"prokaryotic",
"transcriptomes",
"could",
"validate",
"a",
"number",
"of",
"theoretical",
"concepts",
"intro-",
"duced",
"in",
"the",
"early",
"days",
"of",
"genomics.",
"What",
"are",
"the",
"rules",
"connecting",
"gene",
"expression",
"levels",
"with",
"sequence",
"deter-",
"minants",
"such",
"as",
"quantitative",
"scores",
"of",
"promoters",
"and",
"terminators?",
"Are",
"translation",
"efficiency",
"measures,",
"e.g.",
"codon",
"adaptation",
"index",
"and",
"RBS",
"score",
"related",
"to",
"gene",
"expression?",
"We",
"used",
"the",
"whole",
"transcriptome",
"shotgun",
"sequen-",
"cing",
"of",
"a",
"bacterial",
"pathogen",
"Bacillus",
"anthracis",
"to",
"assess",
"correlation",
"of",
"gene",
"expression",
"level",
"with",
"promoter,",
"termi-",
"nator",
"and",
"RBS",
"scores,",
"codon",
"adaptation",
"index,",
"as",
"well",
"as",
"with",
"a",
"new",
"measure",
"of",
"gene",
"translational",
"efficiency,",
"average",
"translation",
"speed.",
"We",
"compared",
"computational",
"predictions",
"of",
"operon",
"topologies",
"with",
"the",
"transcript",
"bor-",
"ders",
"inferred",
"from",
"RNA-Seq",
"reads.",
"Transcriptome",
"mapping",
"may",
"also",
"improve",
"existing",
"gene",
"annotation.",
"Upon",
"assessment",
"of",
"accuracy",
"of",
"current",
"annotation",
"of",
"protein-coding",
"genes",
"in",
"the",
"B.",
"anthracis",
"genome",
"we",
"have",
"shown",
"that",
"the",
"transcriptome",
"data",
"indicate",
"existence",
"of",
"more",
"than",
"a",
"hundred",
"genes",
"missing",
"in",
"the",
"annotation",
"though",
"predicted",
"by",
"an",
"ab",
"initio",
"gene",
"finder.",
"Interestingly,",
"we",
"observed",
"that",
"many",
"pseudogenes",
"possess",
"not",
"only",
"a",
"sequence",
"with",
"detectable",
"coding",
"potential",
"but",
"also",
"promoters",
"that",
"maintain",
"transcriptional",
"activity.",
"Background",
"Significant",
"efforts",
"in",
"the",
"last",
"two",
"decades",
"were",
"directed",
"to",
"developing",
"methods",
"for",
"genomic",
"sequence",
"functional",
"interpretation,",
"particularly,",
"the",
"means",
"for",
"predicting",
"exact",
"locations",
"of",
"transcribed",
"and",
"translated",
"regions",
"and",
"levels",
"of",
"RNA",
"and",
"protein",
"expression.",
"At",
"this",
"time",
"we",
"were",
"armed",
"with",
"technology",
"able",
"to",
"sequence",
"a",
"whole",
"prokaryotic",
"transcriptome",
"of",
"a",
"bacterial",
"pathogen",
"Bacil-",
"lus",
"anthracis",
"and",
"map",
"RNA-Seq",
"reads",
"to",
"genome.",
"We",
"have",
"used",
"RNA-Seq",
"reads",
"mapped",
"to",
"genomic",
"sequence",
"as",
"an",
"input",
"of",
"an",
"HMM",
"based",
"algorithm",
"for",
"parsing",
"B.",
"anthracis",
"genomic",
"sequence",
"into",
"a",
"sequence",
"of",
"transcribed",
"regions.",
"Thus",
"determined",
"regions",
"pro-",
"vided",
"evidence",
"for",
"RNA",
"transcription",
"for",
"majority",
"of",
"annotated",
"genes.",
"In",
"addition",
"we",
"have",
"seen",
"RNA",
"tran-",
"scription",
"from",
"loci",
"harboring",
"mutated",
"and",
"presumably",
"dysfunctional",
"genes,",
"the",
"pseudogenes,",
"as",
"well",
"as",
"from",
"a",
"few",
"regions",
"containing",
"genes",
"predicted",
"by",
"an",
"ab",
"initio",
"*",
"Correspondence:",
"borodovsky@gatech.edu",
"4Wallace",
"H.",
"Coulter",
"Department",
"of",
"Biomedical",
"Engineering",
"and",
"School",
"of",
"Computational",
"Science",
"and",
"Engineering,",
"Georgia",
"Tech,",
"Atlanta,",
"GA,",
"30332,",
"USA",
"gene",
"finder,",
"GeneMarkS",
"[1],",
"but",
"not",
"annotated",
"yet.",
"We",
"have",
"detected",
"that",
"expression",
"levels",
"of",
"adjacent",
"genes",
"located",
"within",
"borders",
"of",
"predicted",
"transcripts",
"correlate",
"well,",
"while",
"adjacent",
"genes",
"residing",
"in",
"different",
"tran-",
"scripts",
"do",
"not",
"exhibit",
"any",
"correlation.",
"We",
"have",
"analyzed",
"whether",
"the",
"evidence",
"derived",
"from",
"RNA-Seq",
"mapped",
"reads",
"would",
"support",
"operon",
"predictions",
"made",
"by",
"OperonDB",
"[2].",
"Other",
"questions",
"we",
"have",
"addressed",
"here",
"were",
"to",
"find",
"out",
"if",
"a",
"score",
"of",
"a",
"promoter",
"site",
"identified",
"upstream",
"to",
"predicted",
"transcription",
"start",
"site",
"(TSS)",
"correlates",
"with",
"gene",
"expression",
"level",
"of",
"the",
"downstream",
"gene.",
"Also,",
"is",
"there",
"a",
"correlation",
"of",
"the",
"gene",
"expression",
"level",
"with",
"the",
"scores",
"of",
"the",
"hairpin",
"and",
"tail",
"of",
"the",
"downstream",
"tran-",
"scription",
"terminator?",
"Do",
"locations",
"of",
"transcription",
"end",
"sites",
"(TES)",
"predicted",
"by",
"TransTermHP",
"[3]",
"appear",
"in",
"genomic",
"sequence",
"close",
"to",
"locations",
"of",
"the",
"TES",
"sites",
"predicted",
"from",
"the",
"mapped",
"RNA-Seq",
"reads?",
"Codon",
"adaptation",
"index",
"(CAI)",
"introduced",
"by",
"Sharp",
"and",
"Li",
"[4]",
"as",
"a",
"predictor",
"of",
"gene",
"expression",
"level",
"has",
"been",
"broadly",
"used,",
"evaluated",
"and",
"modified",
"[5-13].",
"There",
"is",
"an",
"increasing",
"evidence",
"that",
"evolution",
"of",
"genome",
"GC",
"©",
"2010",
"Martin",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Perspective",
"Prognostic",
"Significance",
"of",
"Subtype",
"Classification",
"for",
"Short-",
"and",
"Long-Term",
"Survival",
"in",
"Breast",
"Cancer:",
"Survival",
"Time",
"Holds",
"the",
"Key",
"Stefan",
"Ambs*",
"Laboratory",
"of",
"Human",
"Carcinogenesis",
"(LHC),",
"Center",
"for",
"Cancer",
"Research",
"(CCR),",
"National",
"Cancer",
"Institute",
"(NCI),",
"Bethesda,",
"Maryland,",
"United",
"States",
"of",
"America",
"‘‘We",
"still",
"lack",
"the",
"ability",
"to",
"accurately",
"predict",
"survival",
"among",
"breast",
"cancer",
"patients",
"with",
"early-stage",
"disease’’",
"Advances",
"in",
"hormone",
"therapy",
"and",
"com-",
"bination",
"chemotherapy",
"have",
"led",
"to",
"signifi-",
"cant",
"declines",
"in",
"disease",
"recurrence",
"and",
"mortality",
"due",
"to",
"breast",
"cancer",
"[1,2].",
"How-",
"ever,",
"the",
"burden",
"of",
"developing",
"a",
"deadly",
"disease",
"remains",
"unequal.",
"A",
"disease",
"diagnosis",
"at",
"age",
"50",
"or",
"younger",
"is",
"still",
"more",
"likely",
"to",
"have",
"a",
"fatal",
"outcome",
"than",
"the",
"same",
"diagnosis",
"at",
"an",
"older",
"age.",
"Moreover,",
"African-American",
"women",
"and",
"women",
"di-",
"agnosed",
"with",
"estrogen,",
"progesterone,",
"and",
"HER2",
"receptor–negative",
"disease",
"(termed",
"triple-negative",
"breast",
"cancer)",
"continue",
"to",
"experience",
"an",
"excessive",
"mortality",
"and",
"have",
"not",
"benefited",
"from",
"the",
"advances",
"in",
"breast",
"cancer",
"therapy",
"as",
"much",
"as",
"other",
"patient",
"groups",
"[3,4].",
"Currently,",
"about",
"10%",
"of",
"breast",
"cancer",
"patients",
"will",
"succumb",
"to",
"the",
"disease",
"within",
"the",
"first",
"5",
"years",
"following",
"the",
"initial",
"diagnosis",
"[5],",
"despite",
"many",
"being",
"diagnosed",
"with",
"an",
"early-stage",
"disease.",
"The",
"relative",
"risk",
"of",
"dying",
"from",
"breast",
"cancer",
"has",
"a",
"peak",
"between",
"2",
"and",
"4",
"years",
"post-diagnosis",
"[2],",
"and",
"we",
"can",
"only",
"speculate",
"why",
"so",
"many",
"women",
"die",
"in",
"that",
"period.",
"It",
"remains",
"a",
"great",
"challenge",
"to",
"prospectively",
"identify",
"those",
"breast",
"cancer",
"patients",
"who",
"have",
"been",
"diagnosed",
"with",
"a",
"primary",
"disease",
"but",
"have",
"a",
"low",
"chance",
"of",
"surviving",
"when",
"treated",
"with",
"current",
"standard",
"therapy.",
"A",
"study",
"by",
"Paul",
"Pharoah",
"and",
"colleagues",
"[6]",
"published",
"in",
"this",
"week’s",
"PLoS",
"Medicine",
"evaluated",
"immunohistochemistry-based",
"subtype",
"classification",
"of",
"breast",
"tumors",
"for",
"prediction",
"of",
"disease",
"outcome.",
"The",
"au-",
"thors",
"recommend",
"that",
"this",
"method",
"is",
"being",
"used",
"in",
"clinical",
"practice.",
"Yet,",
"questions",
"remain",
"of",
"how",
"useful",
"subtype",
"classification",
"will",
"be",
"in",
"the",
"management",
"of",
"breast",
"cancer.",
"The",
"Perspective",
"section",
"is",
"for",
"experts",
"to",
"discuss",
"the",
"clinical",
"practice",
"or",
"public",
"health",
"implications",
"of",
"a",
"published",
"study",
"that",
"is",
"freely",
"available",
"online.",
"Linked",
"Research",
"Article",
"This",
"Perspective",
"discusses",
"the",
"fol-",
"lowing",
"new",
"study",
"published",
"in",
"PLoS",
"Medicine:",
"Blows",
"FM,",
"Driver",
"KE,",
"Schmidt",
"MK,",
"Broeks",
"A,",
"van",
"Leeuwen",
"FE,",
"et",
"al.",
"(2010)",
"Subtyping",
"of",
"Breast",
"Cancer",
"by",
"Immunohistochemistry",
"to",
"Inves-",
"tigate",
"a",
"Relationship",
"between",
"Sub-",
"type",
"and",
"Short-",
"and",
"Long-Term",
"Survival:",
"A",
"Collaborative",
"Analysis",
"of",
"Data",
"for",
"10,159",
"Cases",
"from",
"12",
"Studies.",
"PLoS",
"Med",
"7(5):",
"e1000279.",
"doi:10.1371/journal.pmed.1000279",
"Paul",
"Pharoah",
"and",
"colleagues",
"evalu-",
"ate",
"the",
"prognostic",
"significance",
"of",
"immunohistochemical",
"subtype",
"clas-",
"sification",
"in",
"more",
"than",
"10,000",
"breast",
"cancer",
"cases",
"with",
"early",
"dis-",
"ease,",
"and",
"examine",
"the",
"influence",
"of",
"a",
"patient’s",
"survival",
"time",
"on",
"the",
"prediction",
"of",
"future",
"survival.",
"Breast",
"Cancer",
"Molecular",
"Subtypes",
"Are",
"Biologically",
"Distinct",
"and",
"Have",
"Different",
"Outcomes",
"Landmark",
"studies",
"by",
"Perou",
"et",
"al.",
"and",
"by",
"Sorlie",
"et",
"al.",
"identified",
"five",
"distinct",
"sub-",
"types,",
"which",
"are",
"different",
"from",
"one",
"another",
"in",
"their",
"gene",
"expression",
"charac-",
"teristics",
"[7,8].",
"They",
"include",
"two",
"estrogen",
"receptor",
"(ER)-positive",
"subtypes,",
"termed",
"luminal",
"A",
"and",
"B,",
"and",
"three",
"ER-negative",
"subtypes,",
"termed",
"basal-like,",
"HER2-posi-",
"tive,",
"and",
"normal",
"breast-like",
"tumors.",
"Lu-",
"minal",
"tumors",
"develop",
"more",
"frequently",
"than",
"the",
"other",
"subtypes",
"and",
"share",
"many",
"features",
"with",
"luminal",
"epithelial",
"cells",
"lining",
"the",
"mammary",
"ducts,",
"but",
"tumors",
"in",
"the",
"luminal",
"B",
"subgroup",
"also",
"aberrantly",
"over-",
"express",
"the",
"HER2",
"receptor",
"or",
"prolifera-",
"tion",
"marker",
"genes",
"that",
"distinguish",
"them",
"from",
"the",
"HER2-negative",
"luminal",
"A",
"tu-",
"mors.",
"Basal-like",
"breast",
"cancer",
"has",
"similar-",
"ities",
"with",
"normal",
"breast",
"basal",
"epithelial",
"cells",
"and",
"is",
"commonly",
"identified",
"by",
"a",
"lack",
"of",
"ER",
"and",
"HER2",
"receptor",
"expression",
"and",
"by",
"the",
"expression",
"of",
"either",
"cytokeratin",
"5/6",
"or",
"epidermal",
"growth",
"factor",
"receptor",
"(EGFR).",
"This",
"group",
"of",
"tumors",
"is",
"charac-",
"terized",
"by",
"a",
"high",
"proliferation",
"rate,",
"pushing",
"border",
"of",
"invasion,",
"and",
"the",
"frequent",
"expression",
"of",
"cancer",
"stem",
"cell",
"markers",
"[9].",
"Basal-like",
"breast",
"tumors",
"share",
"many",
"features",
"with",
"triple-negative",
"tumors",
"although",
"the",
"overlap",
"is",
"not",
"complete,",
"raising",
"the",
"question",
"of",
"whether",
"they",
"should",
"be",
"treated",
"as",
"two",
"different",
"entities",
"in",
"clinical",
"practice.",
"A",
"diagnosis",
"of",
"either",
"the",
"basal-like",
"or",
"triple",
"negative",
"disease",
"signals",
"a",
"diminished",
"chance",
"of",
"survival",
"because",
"of",
"high",
"relapse",
"rates",
"within",
"the",
"first",
"three",
"years",
"after",
"diagnosis,",
"mainly",
"affecting",
"patients",
"with",
"residual",
"disease",
"despite",
"the",
"use",
"of",
"adjuvant",
"chemotherapy.",
"Citation:",
"Ambs",
"S",
"(2010)",
"Prognostic",
"Significance",
"of",
"Subtype",
"Classification",
"for",
"Short-",
"and",
"Long-Term",
"Survival",
"in",
"Breast",
"Cancer:",
"Survival",
"Time",
"Holds",
"the",
"Key.",
"PLoS",
"Med",
"7(5):",
"e1000281.",
"doi:10.1371/journal.pmed.1000281",
"Published",
"May",
"25,",
"2010",
"Copyright:",
"2010",
"Stefan",
"Ambs.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"No",
"specific",
"funding",
"was",
"received",
"for",
"this",
"piece.",
"Competing",
"Interests:",
"The",
"author",
"has",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"Abbreviations:",
"ER,",
"estrogen",
"receptor;",
"EGFR,",
"epidermal",
"growth",
"factor",
"receptor",
"*",
"E-mail:",
"ambss@mail.nih.gov",
"Stefan",
"Ambs",
"is",
"a",
"Principal",
"Investigator",
"at",
"LHC.",
"He",
"is",
"supported",
"by",
"the",
"Intramural",
"Research",
"Program",
"of",
"the",
"National",
"Institute",
"of",
"Health,",
"NCI,",
"CCR.",
"Provenance:",
"Commissioned;",
"not",
"externally",
"peer",
"reviewed.",
"PLoS",
"Medicine",
"|",
"www.plosmedicine.org",
"1",
"May",
"2010",
"|",
"Volume",
"7",
"|",
"Issue",
"5",
"|",
"e1000281"
] | [
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] | [
"J",
"Gastrointest",
"Surg",
"(2011)",
"15:304–310",
"DOI",
"10.1007/s11605-010-1376-7",
"ORIGINAL",
"ARTICLE",
"The",
"Use",
"of",
"a",
"Compression",
"Device",
"as",
"an",
"Alternative",
"to",
"Hand-Sewn",
"and",
"Stapled",
"Colorectal",
"Anastomoses:",
"Is",
"Three",
"a",
"Crowd?",
"Brian",
"S.",
"Buchberg",
"&",
"Hossein",
"Masoomi",
"&",
"Herlinda",
"Bergman",
"&",
"Steven",
"D.",
"Mills",
"&",
"Michael",
"J.",
"Stamos",
"Received:",
"10",
"September",
"2010",
"/",
"Accepted:",
"19",
"October",
"2010",
"/",
"Published",
"online:",
"10",
"November",
"2010",
"#",
"2010",
"The",
"Author(s).",
"This",
"article",
"is",
"published",
"with",
"open",
"access",
"at",
"Springerlink.com",
"Abstract",
"Background",
"The",
"NiTi",
"CAR™",
"27",
"is",
"a",
"newer",
"device",
"that",
"uses",
"compression",
"to",
"create",
"an",
"anastomosis.",
"An",
"analysis",
"of",
"this",
"device",
"in",
"the",
"creation",
"of",
"colorectal",
"anastomoses",
"in",
"humans",
"has",
"yet",
"to",
"be",
"reported",
"in",
"the",
"USA.",
"Methods",
"A",
"non-randomized,",
"prospective",
"pilot",
"study",
"of",
"the",
"NiTi",
"CAR™",
"27",
"device",
"in",
"patients",
"undergoing",
"a",
"left-sided",
"colectomy",
"between",
"March",
"2008",
"and",
"August",
"2009",
"was",
"performed.",
"Results",
"Twenty-three",
"patients",
"(9",
"men",
"and",
"14",
"women)",
"underwent",
"a",
"left-sided",
"colectomy",
"and",
"compression",
"anastomosis",
"with",
"the",
"CAR™",
"27",
"device.",
"Minor",
"morbidities,",
"3",
"of",
"23",
"(13%)",
"patients,",
"included",
"one",
"small",
"postoperative",
"abscess",
"requiring",
"antibiotics",
"alone",
"and",
"two",
"postoperative",
"anastomotic",
"strictures",
"requiring",
"balloon",
"dilation.",
"Major",
"morbidities,",
"1",
"of",
"23",
"(4%)",
"patients,",
"included",
"a",
"partial",
"anastomotic",
"dehiscence/leak",
"requiring",
"surgical",
"dismantling",
"of",
"the",
"anastomosis",
"and",
"diversion.",
"Conclusion",
"The",
"CAR™",
"27",
"device",
"shows",
"promise",
"as",
"a",
"safe",
"and",
"effective",
"alternative",
"for",
"the",
"creation",
"of",
"colorectal",
"anastomoses.",
"However,",
"studies",
"in",
"a",
"larger",
"patient",
"population",
"are",
"warranted",
"to",
"demonstrate",
"equivalence",
"of",
"this",
"device.",
"Keywords",
"Anastomosis",
".",
"Anastomotic",
"leak",
".",
"Compression",
".",
"Colorectal",
".",
"Stricture",
".",
"Nitinol",
"Introduction",
"Currently,",
"the",
"two",
"available",
"methods",
"used",
"for",
"the",
"creation",
"of",
"colorectal",
"anastomoses",
"include",
"hand",
"suturing",
"and",
"stapling",
"devices.",
"Although",
"both",
"are",
"well",
"established,",
"they",
"are",
"not",
"without",
"their",
"faults.",
"Neither",
"provides",
"an",
"immediately",
"“sealed”",
"anastomosis",
"and",
"both",
"are",
"prone",
"to",
"uncommon",
"but",
"serious",
"complications",
"such",
"as",
"anastomotic",
"bleeding,",
"strictures,",
"or",
"leaks.",
"After",
"colorectal",
"resection,",
"the",
"incidence",
"Presented",
"as",
"part",
"of",
"an",
"oral",
"presentation",
"session",
"at",
"the",
"62nd",
"Annual",
"Meeting",
"of",
"The",
"Southwestern",
"Surgical",
"Congress",
"held",
"March",
"21-24,",
"2010,",
"at",
"the",
"Loews",
"Ventana",
"Canyon",
"Resort",
"in",
"Tucson,",
"AZ.",
"B.",
"S.",
"Buchberg",
":",
"H.",
"Masoomi",
":",
"H.",
"Bergman",
":",
"S.",
"D.",
"Mills",
":",
"M.",
"J.",
"Stamos",
"(*)",
"Department",
"of",
"Surgery,",
"University",
"of",
"California-Irvine",
"Medical",
"Center,",
"333",
"City",
"Blvd.",
"West,",
"Suite",
"700,",
"Orange,",
"CA",
"92868,",
"USA",
"e-mail:",
"mstamos@uci.edu",
"of",
"anastomotic",
"leak",
"ranges",
"from",
"2.9%",
"to",
"15.3%,1",
"while",
"the",
"incidence",
"of",
"subsequent",
"stenosis",
"or",
"stricture",
"ranges",
"from",
"1.2%",
"to",
"4.2%.2",
"These",
"complications",
"may",
"require",
"further",
"surgical",
"intervention",
"and",
"can",
"lead",
"to",
"significant",
"morbidity",
"and",
"mortality.",
"As",
"a",
"result,",
"the",
"concept",
"of",
"tissue",
"compression",
"during",
"colorectal",
"anastomoses",
"has",
"been",
"revisited.",
"This",
"idea",
"is",
"not",
"new",
"and",
"previous",
"attempts",
"have",
"included",
"the",
"Murphy",
"button,",
"the",
"biofragmentable",
"anastomotic",
"ring,",
"and",
"AKA-2",
"devices.3–11",
"Drawbacks",
"of",
"these",
"devices",
"included",
"retained",
"foreign",
"material",
"within",
"the",
"tissue,",
"narrowing",
"of",
"the",
"lumen,",
"necrosis",
"at",
"the",
"anastomotic",
"site,",
"and",
"problems",
"with",
"passage",
"of",
"the",
"deployment",
"device.3",
"As",
"a",
"result,",
"the",
"use",
"of",
"these",
"devices",
"became",
"extremely",
"limited",
"and",
"was",
"eventually",
"replaced",
"with",
"the",
"more",
"reliable",
"stapling",
"devices.",
"Recently,",
"the",
"FDA-approved",
"NiTi",
"CAR™",
"27",
"(endolu-",
"minal",
"compression",
"anastomosis",
"ring)",
"device",
"has",
"been",
"introduced",
"and",
"may",
"overcome",
"many",
"limitations",
"of",
"the",
"previous",
"compression",
"devices.",
"The",
"device",
"is",
"intended",
"for",
"use",
"in",
"the",
"colon",
"and",
"rectum",
"for",
"the",
"creation",
"of",
"end-to-end,",
"end-to-side,",
"and",
"side-to-side",
"anastomoses",
"in",
"both",
"open",
"and",
"laparoscopic",
"surgeries.",
"This",
"novel",
"device",
"consists",
"of",
"two",
"disposable",
"rings",
"that",
"trap",
"the",
"ends",
"of",
"transected",
"bowel,"
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] | [
"CASE",
"REPORT",
"http://dx.doi.org/10.4306/pi.2011.8.3.269",
"Print",
"ISSN",
"1738-3684",
"/",
"On-line",
"ISSN",
"1976-3026",
"OPEN",
"ACCESS",
"Duloxetine-Induced",
"Liver",
"Injury",
"in",
"Patients",
"with",
"Major",
"Depressive",
"Disorder",
"Seung-Gul",
"Kang1,",
"Young-Min",
"Park2",
",",
"Heon-Jeong",
"Lee3",
"and",
"Byungmun",
"Yoon4",
"1Department",
"of",
"Psychiatry,",
"Catholic",
"University",
"of",
"Daegu",
"School",
"of",
"Medicine,",
"Daegu,",
"Korea",
"2Department",
"of",
"Neuropsychiatry,",
"Ilsan",
"Paik",
"Hospital,",
"Inje",
"University",
"College",
"of",
"Medicine,",
"Goyang,",
"Korea",
"3Department",
"of",
"Psychiatry,",
"Korea",
"University",
"College",
"of",
"Medicine,",
"Seoul,",
"Korea",
"4Department",
"of",
"Psychiatry,",
"Maumtomaum",
"Clinic,",
"Yongin,",
"Korea",
"Duloxetine",
"is",
"a",
"balanced",
"serotonin-norepinephrine",
"reuptake",
"inhibitor.",
"Duloxetine-induced",
"liver",
"injury",
"in",
"patients",
"with",
"preexisting",
"liver",
"disease",
"or",
"chronic",
"alcohol",
"use",
"is",
"known.",
"However,",
"we",
"have",
"found",
"that",
"duloxetine",
"can",
"also",
"induce",
"liver",
"injury",
"in",
"cases",
"without",
"those",
"risk",
"factors.",
"We",
"recommend",
"that",
"clinicians",
"should",
"monitor",
"liver",
"function",
"carefully",
"following",
"duloxetine",
"treatment.",
"Psychiatry",
"Investig",
"2011;8:269-271",
"Key",
"WordsaaDuloxetine,",
"Liver",
"injury,",
"Major",
"depressive",
"disorder.",
"INTRODUCTION",
"Drug-induced",
"liver",
"injury",
"(DILI)",
"is",
"a",
"term",
"that",
"describes",
"ab-",
"normalities",
"in",
"liver",
"function",
"tests",
"(LFTs)",
"that",
"are",
"attributable",
"to",
"medication",
"intake.1",
"DILI",
"accounts",
"for",
"more",
"than",
"50%",
"of",
"acu-",
"te",
"liver",
"failures",
"and",
"is",
"the",
"most",
"common",
"cause",
"of",
"the",
"withdra-",
"wal",
"of",
"drugs",
"from",
"the",
"pharmaceutical",
"market.2,3",
"Eli",
"Lilly",
"and",
"Company",
"informed",
"healthcare",
"professionals",
"that",
"there",
"had",
"been",
"some",
"postmarketing",
"reports",
"of",
"cholestatic",
"jaundice",
"and",
"hepatitis",
"in",
"patients",
"with",
"chronic",
"liver",
"disease",
"or",
"cirrhosis",
"receiving",
"duloxetine",
"in",
"late",
"2005.",
"In",
"addition,",
"the",
"pro-",
"duct",
"labeling",
"was",
"modified",
"by",
"stating",
"that",
"duloxetine",
"should",
"not",
"ordinarily",
"be",
"prescribed",
"to",
"patients",
"with",
"chronic",
"alcohol",
"use",
"or",
"evidence",
"of",
"chronic",
"liver",
"disease.",
"Duloxetine",
"was",
"approved",
"in",
"Korea",
"for",
"major",
"depressive",
"dis-",
"order",
"(MDD),",
"generalized",
"anxiety",
"disorder,",
"and",
"diabetic",
"pe-",
"ripheral",
"neuropathic",
"pain",
"(DPNP)",
"in",
"2009.",
"It",
"is",
"a",
"balanced",
"and",
"potent",
"serotonin-norepinephrine",
"reuptake",
"inhibitor,",
"and",
"has",
"been",
"prescribed",
"increasingly",
"in",
"Korea.",
"However,",
"data",
"regard-",
"Received:",
"January",
"19,",
"2011",
"Revised:",
"May",
"8,",
"2011",
"Accepted:",
"May",
"8,",
"2011",
"Available",
"online:",
"August",
"10,",
"2011",
"",
"Correspondence:",
"Young-Min",
"Park,",
"MD,",
"PhD",
"Department",
"of",
"Neuropsychiatry,",
"Ilsan",
"Paik",
"Hospital,",
"Inje",
"University",
"College",
"of",
"Medicine,",
"2240",
"Daehwa-dong,",
"Ilsansu-ku,",
"Goyang",
"411-706,",
"Korea",
"Tel:",
"+82-31-910-7260,",
"Fax:",
"+82-31-910-7268,",
"E-mail:",
"medipark@hanmail.net",
"cc",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"Non-Commercial",
"License",
"(http://creativecommons.org/licenses/by-",
"nc/3.0)",
"which",
"permits",
"unrestricted",
"non-commercial",
"use,",
"distribution,",
"and",
"reproduc-",
"tion",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"ing",
"its",
"effects",
"on",
"the",
"liver",
"are",
"not",
"well",
"known",
"in",
"this",
"country.",
"We",
"have",
"previously",
"reported",
"a",
"case",
"of",
"duloxetine-induced",
"liver",
"injury",
"in",
"a",
"patient",
"with",
"MDD.4",
"We",
"have",
"now",
"experienced",
"another",
"three",
"cases",
"involving",
"duloxetine-induced",
"liver",
"injury.",
"Thus,",
"we",
"describe",
"herein",
"a",
"case",
"series",
"of",
"liver",
"injury",
"in",
"patients",
"with",
"MDD.",
"A",
"MEDLINE",
"se-",
"arch",
"revealed",
"no",
"other",
"report",
"related",
"to",
"duloxetine-induced",
"liver",
"injury",
"in",
"Asian",
"patients;",
"this",
"therefore",
"appears",
"to",
"be",
"the",
"first",
"reported",
"case",
"thereof",
"in",
"Asia.",
"CASES",
"Case",
"1",
"A",
"22-year-old",
"Korean",
"male",
"visited",
"our",
"clinic",
"due",
"to",
"depres-",
"sion.",
"The",
"patient",
"had",
"no",
"relevant",
"medical",
"history",
"and",
"no",
"his-",
"tory",
"of",
"substance",
"abuse;",
"his",
"laboratory",
"tests",
"were",
"also",
"normal.",
"He",
"was",
"diagnosed",
"with",
"MDD,",
"and",
"initially",
"treated",
"with",
"duloxe-",
"tine",
"at",
"30",
"mg/day.",
"After",
"3",
"weeks,",
"the",
"dosage",
"was",
"increased",
"to",
"60",
"mg/day.",
"However,",
"the",
"patient",
"had",
"only",
"a",
"partial",
"response",
"and",
"complained",
"of",
"fatigue.",
"Laboratory",
"tests",
"were",
"performed,",
"and",
"his",
"total",
"bilirubin",
"was",
"1.8",
"mg/dL",
"and",
"alanine",
"transaminase",
"(ALT)",
"was",
"60",
"U/L",
"(See",
"Table",
"1",
"for",
"normal",
"range",
"in",
"our",
"hospi-",
"tal).",
"Thus,",
"duloxetine",
"was",
"immediately",
"discontinued",
"and",
"re-",
"placed",
"by",
"escitalopram.",
"Liver",
"function",
"had",
"normalized",
"by",
"4",
"months",
"after",
"the",
"discontinuation",
"of",
"duloxetine,",
"at",
"which",
"time",
"the",
"patient’s",
"total",
"bilirubin",
"and",
"ALT",
"levels",
"were",
"1.2",
"mg/dL",
"and",
"7",
"U/L,",
"respectively.",
"Copyright",
"©",
"2011",
"Korean",
"Neuropsychiatric",
"Association",
"269"
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] | [
"Vet.",
"Res.",
"(2009)",
"40:29",
"DOI:",
"10.1051/vetres/2009011",
"INRA,",
"EDP",
"Sciences,",
"2009",
"www.vetres.org",
"Review",
"article",
"Ecological",
"fitness",
"and",
"strategies",
"of",
"adaptation",
"of",
"Bartonella",
"I",
"species",
"to",
"their",
"hosts",
"and",
"vectors",
"Bruno",
"B.",
"CHOMEL1*,",
"Henri-Jean",
"BOULOUIS",
"2",
",",
"Edward",
"B.",
"BREITSCHWERDT",
"3",
",",
"1",
"2",
"4",
"Rickie",
"W.",
"KASTEN",
",",
"Muriel",
"VAYSSIER-TAUSSAT",
",",
"Richard",
"J.",
"BIRTLES",
",",
"Jane",
"E.",
"KOEHLER5,",
"Christoph",
"DEHIO6",
"1",
"Department",
"of",
"Population",
"Health",
"and",
"Reproduction,",
"School",
"of",
"Veterinary",
"Medicine,",
"University",
"of",
"California,",
"Davis,",
"CA",
"95616,",
"USA",
"2",
"UMR",
"BIPAR",
"ENVA/AFSSA/INRA/UPVM,",
"E´",
"cole",
"Nationale",
"Ve´te´rinaire",
"d’Alfort,",
"7",
"avenue",
"du",
"Ge´ne´ral",
"de",
"Gaulle,",
"94704",
"Maisons-Alfort,",
"France",
"3",
"Center",
"for",
"Comparative",
"Medicine",
"and",
"Transitional",
"Research,",
"College",
"of",
"Veterinary",
"Medicine,",
"North",
"Carolina",
"State",
"University,",
"4700",
"Hillsborough",
"St.,",
"Raleigh,",
"NC",
"27606,",
"USA",
"4",
"Department",
"of",
"Veterinary",
"Pathology,",
"Faculty",
"of",
"Veterinary",
"Science,",
"University",
"of",
"Liverpool,",
"Leahurst,",
"CH64",
"7TE,",
"United",
"Kingdom",
"5",
"Division",
"of",
"Infectious",
"Diseases,",
"University",
"of",
"California,",
"San",
"Francisco,",
"513",
"Parnassus",
"Avenue,",
"Room",
"S-380,",
"San",
"Francisco,",
"CA,",
"94143-0654,",
"USA",
"6",
"Focal",
"Area",
"of",
"Infection",
"Biology",
"Biozentrum,",
"University",
"of",
"Basel,",
"Klingelbergstrasse",
"50/70,",
"CH-4056",
"Basel,",
"Switzerland",
"(Received",
"12",
"November",
"2008;",
"accepted",
"12",
"March",
"2009)",
"Abstract",
"–",
"Bartonella",
"spp.",
"are",
"facultative",
"intracellular",
"bacteria",
"that",
"cause",
"characteristic",
"host-",
"restricted",
"hemotropic",
"infections",
"in",
"mammals",
"and",
"are",
"typically",
"transmitted",
"by",
"blood-sucking",
"arthropods.",
"In",
"the",
"mammalian",
"reservoir,",
"these",
"bacteria",
"initially",
"infect",
"a",
"yet",
"unrecognized",
"primary",
"niche,",
"which",
"seeds",
"organisms",
"into",
"the",
"blood",
"stream",
"leading",
"to",
"the",
"establishment",
"of",
"a",
"long-lasting",
"intra-erythrocytic",
"bacteremia",
"as",
"the",
"hall-mark",
"of",
"infection.",
"Bacterial",
"type",
"IV",
"secretion",
"systems,",
"which",
"are",
"supra-molecular",
"transporters",
"ancestrally",
"related",
"to",
"bacterial",
"conjugation",
"systems,",
"represent",
"crucial",
"pathogenicity",
"factors",
"that",
"have",
"contributed",
"to",
"a",
"radial",
"expansion",
"of",
"the",
"Bartonella",
"lineage",
"in",
"nature",
"by",
"facilitating",
"adaptation",
"to",
"unique",
"mammalian",
"hosts.",
"On",
"the",
"molecular",
"level,",
"the",
"type",
"IV",
"secretion",
"system",
"VirB/VirD4",
"is",
"known",
"to",
"translocate",
"a",
"cocktail",
"of",
"different",
"effector",
"proteins",
"into",
"host",
"cells,",
"which",
"subvert",
"multiple",
"cellular",
"functions",
"to",
"the",
"benefit",
"of",
"the",
"infecting",
"pathogen.",
"Furthermore,",
"bacterial",
"adhesins",
"mediate",
"a",
"critical,",
"early",
"step",
"in",
"the",
"pathogenesis",
"of",
"the",
"bartonellae",
"by",
"binding",
"to",
"extracellular",
"matrix",
"components",
"of",
"host",
"cells,",
"which",
"leads",
"to",
"firm",
"bacterial",
"adhesion",
"to",
"the",
"cell",
"surface",
"as",
"a",
"prerequisite",
"for",
"the",
"efficient",
"translocation",
"of",
"type",
"IV",
"secretion",
"effector",
"proteins.",
"The",
"best-",
"studied",
"adhesins",
"in",
"bartonellae",
"are",
"the",
"orthologous",
"trimeric",
"autotransporter",
"adhesins,",
"BadA",
"in",
"Bartonella",
"henselae",
"and",
"the",
"Vomp",
"family",
"in",
"Bartonella",
"quintana.",
"Genetic",
"diversity",
"and",
"strain",
"variability",
"also",
"appear",
"to",
"enhance",
"the",
"ability",
"of",
"bartonellae",
"to",
"invade",
"not",
"only",
"specific",
"reservoir",
"hosts,",
"but",
"also",
"accidental",
"hosts,",
"as",
"shown",
"for",
"B.",
"henselae.",
"Bartonellae",
"have",
"been",
"identified",
"in",
"many",
"different",
"blood-sucking",
"arthropods,",
"in",
"which",
"they",
"are",
"typically",
"found",
"to",
"cause",
"extracellular",
"infections",
"of",
"the",
"mid-gut",
"epithelium.",
"Adaptation",
"to",
"specific",
"vectors",
"and",
"reservoirs",
"seems",
"to",
"be",
"a",
"common",
"strategy",
"of",
"bartonellae",
"for",
"transmission",
"and",
"host",
"diversity.",
"However,",
"knowledge",
"regarding",
"arthropod",
"specificity/",
"I",
"This",
"manuscript",
"is",
"dedicated",
"to",
"the",
"memory",
"of",
"Professor",
"Yves",
"Piemont",
"(1951–2009)",
"from",
"Strasbourg",
"University",
"(France)",
"whose",
"significant",
"contribution",
"to",
"the",
"field",
"of",
"Bartonella",
"knowlegde",
"expended",
"the",
"number",
"of",
"known",
"species",
"and",
"its",
"epidemiology.",
"*",
"Corresponding",
"author:",
"bbchomel@ucdavis.edu",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution-Noncommercial",
"License",
"(http://creativecommons.org/licenses/by-nc/3.0/),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"noncommercial",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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] | [
"Acta",
"Crystallographica",
"Section",
"E",
"Structure",
"Reports",
"Online",
"ISSN",
"1600-5368",
"Quinoxalin-2-yl",
"p-tolyl",
"ether",
"Nor",
"Duha",
"Hassan,",
"Hairul",
"Anuar",
"Tajuddin,",
"Zanariah",
"Abdullah",
"and",
"Seik",
"Weng",
"Ng*",
"Department",
"of",
"Chemistry,",
"University",
"of",
"Malaya,",
"50603",
"Kuala",
"Lumpur,",
"Malaysia",
"Correspondence",
"e-mail:",
"seikweng@um.edu.my",
"Received",
"12",
"August",
"2008;",
"accepted",
"19",
"August",
"2008",
"Key",
"indicators:",
"single-crystal",
"X-ray",
"study;",
"T",
"=",
"100",
"K;",
"mean",
"(C–C)",
"=",
"0.002",
"A˚;",
"R",
"factor",
"=",
"0.036;",
"wR",
"factor",
"=",
"0.100;",
"data-to-parameter",
"ratio",
"=",
"12.4.",
"The",
"dihedral",
"angle",
"between",
"the",
"two",
"aromatic",
"ring",
"systems",
"in",
"the",
"title",
"compound,",
"C15H12N2O,",
"is",
"42.6",
"(1)",
".",
"The",
"angle",
"at",
"the",
"O",
"atom",
"is",
"widened",
"to",
"117.7",
"(1)",
".",
"Related",
"literature",
"The",
"title",
"compound",
"exhibits",
"fluorescence;",
"see:",
"Abdullah",
"(2005);",
"Kawai",
"et",
"al.",
"(2001);",
"Mohd",
"Salleh",
"et",
"al.",
"(2007).",
"Experimental",
"Crystal",
"data",
"C15H12N2O",
"Mr",
"=",
"236.27",
"Triclinic,",
"P1",
"a",
"=",
"5.2655",
"(1)",
"A˚",
"b",
"=",
"9.1713",
"(2)",
"A˚",
"c",
"=",
"12.8112",
"(2)",
"A˚",
"=",
"74.660",
"(1)",
"=",
"81.163",
"(1)",
"=",
"89.095",
"(1)",
"V",
"=",
"589.35",
"(2)",
"A˚",
"3",
"Data",
"collection",
"Bruker",
"SMART",
"APEX",
"diffractometer",
"Absorption",
"correction:",
"none",
"2828",
"measured",
"reflections",
"Refinement",
"R[F",
"2",
">",
"2",
"(F",
"2)]",
"=",
"0.035",
"wR(F",
"2)",
"=",
"0.099",
"S",
"=",
"0.99",
"2030",
"reflections",
"organic",
"compounds",
"Z",
"=",
"2",
"Mo",
"K",
"radiation",
"=",
"0.09",
"mm",
"1",
"T",
"=",
"100",
"(2)",
"K",
"0.25",
"0.25",
"0.25",
"mm",
"2030",
"independent",
"reflections",
"1764",
"reflections",
"with",
"I",
">",
"2",
"(I)",
"Rint",
"=",
"0.012",
"164",
"parameters",
"H-atom",
"parameters",
"constrained",
"max",
"=",
"0.15",
"e",
"A˚",
"3",
"min",
"=",
"0.23",
"e",
"A˚",
"3",
"Data",
"collection:",
"APEX2",
"(Bruker,",
"2007);",
"cell",
"refinement:",
"SAINT",
"(Bruker,",
"2007);",
"data",
"reduction:",
"SAINT;",
"program(s)",
"used",
"to",
"solve",
"structure:",
"SHELXS97",
"(Sheldrick,",
"2008);",
"program(s)",
"used",
"to",
"refine",
"structure:",
"SHELXL97",
"(Sheldrick,",
"2008);",
"molecular",
"graphics:",
"X-",
"SEED",
"(Barbour,",
"2001);",
"software",
"used",
"to",
"prepare",
"material",
"for",
"publication:",
"publCIF",
"(Westrip,",
"2008).",
"We",
"thank",
"the",
"University",
"of",
"Malaya",
"for",
"supporting",
"this",
"study",
"(grant",
"No.",
"358/2008",
"A).",
"Supplementary",
"data",
"and",
"figures",
"for",
"this",
"paper",
"are",
"available",
"from",
"the",
"IUCr",
"electronic",
"archives",
"(Reference:",
"BT2771).",
"References",
"Abdullah,",
"Z.",
"(2005).",
"Int.",
"J.",
"Chem.",
"Sci.",
"3,",
"9–15.",
"Barbour,",
"L.",
"J.",
"(2001).",
"J.",
"Supramol.",
"Chem.",
"1,",
"189–191.",
"Bruker",
"(2007).",
"APEX2",
"and",
"SAINT.",
"Bruker",
"AXS",
"Inc.,",
"Madison,",
"Wisconsin,",
"USA.",
"Kawai,",
"M.,",
"Lee,",
"M.",
"J.,",
"Evans,",
"K.",
"O.",
"&",
"Norlund,",
"T.",
"(2001).",
"J.",
"Fluoresc.",
"11,",
"23–32.",
"Mohd",
"Salleh,",
"N.,",
"Ling,",
"L.",
"P.,",
"Abdullah,",
"Z.",
"M.",
"A.",
"A.",
"&",
"Aiyub,",
"Z.",
"(2007).",
"Malays.",
"J.",
"Anal.",
"Sci.",
"11,",
"229–236.",
"Sheldrick,",
"G.",
"M.",
"(2008).",
"Acta",
"Cryst.",
"A64,",
"112–122.",
"Westrip,",
"S.",
"P.",
"(2008).",
"publCIF.",
"In",
"preparation.",
"Acta",
"Cryst.",
"(2008).",
"E64,",
"o1823",
"doi:10.1107/S1600536808026834",
"Hassan",
"et",
"al.",
"o1823"
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] | [
"SAGE-Hindawi",
"Access",
"to",
"Research",
"International",
"Journal",
"of",
"Inflammation",
"Volume",
"2010,",
"Article",
"ID",
"954051,",
"9",
"pages",
"doi:10.4061/2010/954051",
"Review",
"Article",
"The",
"Bowel",
"Microbiota",
"and",
"Inflammatory",
"Bowel",
"Diseases",
"Gerald",
"W.",
"Tannock",
"Department",
"of",
"Microbiology",
"and",
"Immunology,",
"University",
"of",
"Otago,",
"P.O.",
"Box",
"56,",
"Dunedin",
"9054,",
"New",
"Zealand",
"Correspondence",
"should",
"be",
"addressed",
"to",
"Gerald",
"W.",
"Tannock,",
"gerald.tannock@stonebow.otago.ac.nz",
"Received",
"29",
"April",
"2010;",
"Accepted",
"4",
"July",
"2010",
"Academic",
"Editor:",
"Gerhard",
"Rogler",
"Copyright",
"©",
"2010",
"Gerald",
"W.",
"Tannock.",
"This",
"is",
"an",
"open",
"access",
"article",
"distributed",
"under",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"The",
"human",
"bowel",
"contains",
"a",
"large",
"and",
"biodiverse",
"bacterial",
"community",
"known",
"as",
"the",
"microbiota",
"or",
"microbiome.",
"It",
"seems",
"likely",
"that",
"the",
"microbiota,",
"fractions",
"of",
"the",
"microbiota,",
"or",
"specific",
"species",
"comprising",
"the",
"microbiota",
"provide",
"the",
"antigenic",
"fuel",
"that",
"drives",
"the",
"chronic",
"immune",
"inflammation",
"of",
"the",
"bowel",
"mucosa",
"that",
"is",
"characteristic",
"of",
"Crohn’s",
"disease",
"and",
"ulcerative",
"colitis.",
"At",
"least",
"twenty",
"years",
"of",
"microbiological",
"research",
"have",
"been",
"expended",
"on",
"analysis",
"of",
"the",
"composition",
"of",
"the",
"bowel",
"microbiota",
"of",
"inflammatory",
"bowel",
"disease",
"patients",
"in",
"comparison",
"to",
"that",
"of",
"control",
"subjects.",
"Despite",
"extensive",
"speculations",
"about",
"the",
"aetiological",
"role",
"of",
"dysbiosis",
"in",
"inflammatory",
"bowel",
"diseases,",
"knowledge",
"that",
"can",
"be",
"easily",
"translated",
"into",
"effective",
"remedies",
"for",
"patients",
"has",
"not",
"eventuated.",
"The",
"causes",
"of",
"this",
"failure",
"may",
"be",
"due",
"to",
"poorly",
"defined",
"and",
"executed",
"bacteriological",
"studies,",
"as",
"well",
"as",
"the",
"overwhelming",
"complexity",
"of",
"a",
"biome",
"that",
"contains",
"hundreds",
"of",
"bacterial",
"species",
"and",
"trillions",
"of",
"bacterial",
"cells.",
"1.",
"Introduction",
"The",
"large",
"bowels",
"of",
"mammals",
"comprise",
"a",
"biome",
"(ecosystem)",
"that",
"includes",
"a",
"bacterial",
"community",
"that",
"is",
"biodiverse",
"and",
"numerous.",
"It",
"can",
"be",
"estimated",
"that",
"there",
"are",
"a",
"total",
"of",
"twenty",
"trillion",
"bacterial",
"cells",
"per",
"human",
"colon",
"if",
"it",
"is",
"assumed",
"that",
"the",
"colonic",
"contents",
"weigh",
"on",
"average",
"about",
"200",
"grams.",
"The",
"majority",
"of",
"these",
"bacteria",
"are",
"obligate",
"anaerobes.",
"They",
"are",
"commonly",
"referred",
"to",
"as",
"commensals",
"or",
"symbionts",
"because",
"they",
"form",
"long-lasting,",
"interactive",
"associations",
"with",
"their",
"animal",
"hosts",
"[1,",
"2].",
"These",
"associations",
"are",
"generally",
"regarded",
"to",
"involve",
"mutually",
"beneficial",
"interactions,",
"although",
"some",
"commensals",
"are",
"opportunistic",
"pathogens",
"when",
"appropriate",
"predisposing",
"events",
"occur",
"[3].",
"The",
"bacterial",
"communities",
"(microbiota,",
"microbiome)",
"of",
"human",
"bowels",
"contain",
"pre-",
"dominantly",
"representatives",
"of",
"four",
"phyla:",
"Actinobacteria,",
"Proteobacteria,",
"Bacteroidetes,",
"and",
"Firmicutes",
"(Table",
"1).",
"The",
"Firmicutes",
"and",
"Bacteroidetes",
"are",
"numerically",
"dominant",
"in",
"the",
"community.",
"Numerous",
"genera",
"and",
"species",
"of",
"bacteria",
"are",
"represented",
"in",
"each",
"of",
"these",
"broad",
"phylogenetic",
"groups",
"and,",
"at",
"least",
"in",
"the",
"case",
"of",
"humans,",
"there",
"is",
"person-to-person",
"variation",
"in",
"the",
"composition",
"of",
"the",
"bowel",
"microbiota",
"[4–",
"6].",
"Descriptions",
"of",
"a",
"“normal",
"range”",
"of",
"bowel",
"inhabitants",
"of",
"humans",
"in",
"terms",
"of",
"genera",
"and",
"species",
"has",
"recently",
"begun",
"to",
"emerge,",
"sometimes",
"referred",
"to",
"as",
"the",
"“core”",
"microbiota",
"(5,",
"6;",
"Table",
"2).",
"The",
"bowel",
"microbiota",
"is,",
"like",
"bacterial",
"communities",
"in",
"general,",
"self-regulating",
"and",
"this",
"provides",
"temporal",
"stability",
"in",
"composition.",
"At",
"least",
"in",
"health,",
"the",
"proportions",
"of",
"broad",
"phylogenetic",
"groups",
"of",
"bacteria",
"within",
"the",
"community",
"remain",
"much",
"the",
"same",
"over",
"time",
"[4].",
"Inducible",
"biochemical",
"pathways",
"that",
"mediate",
"hydrolysis",
"of",
"exogenous",
"(dietary",
"plant",
"cell",
"wall",
"polysaccharides)",
"and",
"endogenous",
"(mucins)",
"substrates",
"enable",
"the",
"bacteria",
"to",
"obtain",
"an",
"uninterrupted",
"supply",
"of",
"carbon",
"and",
"energy",
"despite",
"daily",
"changes",
"in",
"the",
"composition",
"of",
"the",
"human",
"diet",
"[7,",
"8].",
"The",
"fermentation",
"of",
"hydrolytic",
"products",
"by",
"the",
"bacteria",
"produces",
"short",
"chain",
"fatty",
"acids,",
"amines,",
"phenols,",
"indoles,",
"and",
"gases",
"[9].",
"Knowledge",
"of",
"the",
"nutritional",
"niches",
"of",
"specific",
"bacterial",
"groups",
"is",
"sparse",
"but",
"a",
"detailed",
"description",
"and",
"importance",
"of",
"the",
"butyrate-producing",
"species",
"in",
"the",
"ecology",
"of",
"the",
"bowel",
"is",
"emerging",
"due",
"to",
"work",
"at",
"the",
"Rowett",
"Institute,",
"Scotland",
"[10,",
"11].",
"Partitioning",
"of",
"bacteria",
"within",
"the",
"contents",
"of",
"the",
"bowel",
"occurs.",
"Some",
"bacterial",
"types",
"are",
"more",
"likely",
"to",
"be",
"associated",
"with",
"particulate",
"(plant",
"residues)",
"material",
"in",
"the",
"digesta",
"than",
"in",
"the",
"liquid",
"fraction",
"[12].",
"The",
"mucus",
"associated",
"with",
"the",
"mucosal",
"surface",
"has",
"a",
"layered",
"conformation",
"and",
"minimizes",
"bacterial",
"contact",
"with",
"the",
"surface",
"of",
"enterocytes.",
"The",
"outer",
"mucus",
"layer",
"is",
"loosely",
"structured",
"and",
"contains",
"bacterial",
"cells",
"that",
"are",
"perhaps",
"living",
"there",
"or",
"are",
"trapped",
"cells",
"that",
"will",
"eventually",
"be",
"swept",
"away",
"by",
"the",
"mucus",
"flow.",
"The"
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] | [
"Published:",
"11",
"February",
"2010",
"©",
"2010",
"Medicine",
"Reports",
"Ltd",
"Recent",
"advances",
"in",
"management",
"of",
"bladder",
"overactivity",
"Ariana",
"L",
"Smith*",
"and",
"Alan",
"J",
"Wein",
"Address:",
"Division",
"of",
"Urology,",
"University",
"of",
"Pennsylvania,",
"School",
"of",
"Medicine,",
"3400",
"Spruce",
"Street,",
"9",
"Penn",
"Tower,",
"Philadelphia,",
"PA",
"19104,",
"USA",
"*",
"Corresponding",
"author:",
"Ariana",
"L",
"Smith",
"(ariana.smith@uphs.upenn.edu)",
"F1000",
"Medicine",
"Reports",
"2010,",
"2:9",
"(doi:10.3410/M2-9)",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution-NonCommercial",
"License",
"(http://creativecommons.org/licenses/by-nc/3.0/legalcode),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"for",
"non-commercial",
"purposes",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"You",
"may",
"not",
"use",
"this",
"work",
"for",
"commercial",
"purposes.",
"The",
"electronic",
"version",
"of",
"this",
"article",
"is",
"the",
"complete",
"one",
"and",
"can",
"be",
"found",
"at:",
"http://f1000.com/reports/medicine/content/2/9",
"Abstract",
"Pharmacologic",
"therapies,",
"primarily",
"antimuscarinic",
"agents,",
"have",
"been",
"the",
"mainstay",
"of",
"treatment",
"for",
"overactive",
"bladder.",
"These",
"drugs",
"produce",
"variable",
"efficacy,",
"a",
"moderate",
"rate",
"of",
"side",
"effects,",
"and",
"rare",
"occurrences",
"of",
"cure.",
"The",
"search",
"for",
"newer",
"and",
"better",
"formulations",
"and",
"derivatives",
"of",
"this",
"class",
"of",
"medication",
"as",
"well",
"as",
"novel",
"therapies",
"is",
"ongoing",
"and",
"primarily",
"fueled",
"by",
"the",
"high",
"prevalence",
"of",
"overactive",
"bladder",
"and",
"the",
"tremendous",
"number",
"of",
"health",
"care",
"dollars",
"spent",
"on",
"current",
"therapy.",
"Surgical",
"options",
"for",
"overactive",
"bladder",
"have",
"evolved",
"slowly",
"and",
"are",
"currently",
"reserved",
"for",
"medical",
"treatment",
"failures",
"and",
"drug",
"intolerance.",
"This",
"article",
"will",
"highlight",
"the",
"new",
"drugs",
"and",
"therapies",
"brought",
"into",
"clinical",
"use",
"for",
"the",
"treatment",
"of",
"overactive",
"bladder",
"over",
"the",
"last",
"few",
"years",
"as",
"well",
"as",
"a",
"promising",
"new",
"agent",
"in",
"the",
"advanced",
"stages",
"of",
"development.",
"Introduction",
"and",
"context",
"Overactive",
"bladder",
"(OAB)",
"affects",
"between",
"8.0-13.9%",
"of",
"the",
"population",
"in",
"Western",
"nations",
"[1].",
"This",
"variation",
"in",
"prevalence",
"is",
"thought",
"to",
"be",
"due",
"primarily",
"to",
"differences",
"in",
"the",
"definition",
"of",
"OAB",
"used",
"across",
"different",
"study",
"populations.",
"The",
"International",
"Continence",
"Society",
"has",
"defined",
"OAB",
"as",
"‘urgency,",
"with",
"or",
"without",
"urge",
"incon-",
"tinence,",
"usually",
"with",
"frequency",
"and",
"nocturia’",
"[2]",
"in",
"attempts",
"to",
"standardize",
"reporting",
"of",
"this",
"highly",
"prevalent",
"and",
"bothersome",
"condition.",
"The",
"drugs",
"most",
"commonly",
"prescribed",
"for",
"the",
"treatment",
"of",
"OAB",
"are",
"the",
"antimuscari-",
"nics;",
"these",
"drugs",
"are",
"proven",
"efficacious",
"and",
"safe",
"and",
"are",
"the",
"mainstay",
"of",
"treatment",
"for",
"OAB",
"[3].",
"These",
"agents",
"produce",
"symptomatic",
"improvement",
"by",
"reducing",
"urgency",
"and",
"therefore",
"urge",
"urinary",
"incontinence",
"(UI)",
"and",
"frequency,",
"decreasing",
"detrusor",
"overactivity",
"and",
"increas-",
"ing",
"bladder",
"capacity",
"[4].",
"There",
"are",
"several",
"drugs",
"available",
"for",
"use",
"today,",
"with",
"some",
"variability",
"based",
"on",
"country",
"of",
"residence.",
"As",
"newer",
"antimuscarinic",
"agents",
"have",
"become",
"available,",
"some",
"progress",
"has",
"been",
"made",
"in",
"maximizing",
"therapeutic",
"efficacy",
"while",
"minimizing",
"bothersome",
"side",
"effects;",
"however,",
"a",
"large",
"number",
"of",
"patients",
"remain",
"dissatisfied",
"with",
"the",
"mix",
"of",
"efficacy",
"and",
"tolerability",
"and",
"discontinue",
"therapy.",
"Nevertheless,",
"most",
"physicians",
"prescribe",
"a",
"trial",
"of",
"antimuscarinic",
"therapy",
"and",
"behavioral",
"modification",
"in",
"patients",
"with",
"bothersome",
"OAB,",
"and",
"if",
"it",
"is",
"not",
"effective,",
"a",
"second",
"trial",
"using",
"a",
"different",
"drug",
"or",
"formulation",
"is",
"often",
"instituted.",
"When",
"these",
"drugs",
"fail,",
"the",
"side",
"effects",
"become",
"intolerable,",
"or",
"the",
"category",
"of",
"drug",
"is",
"contraindicated,",
"physicians",
"have",
"limited",
"ther-",
"apeutic",
"options,",
"including",
"off-label",
"use",
"of",
"other",
"cate-",
"gories",
"of",
"drug",
"or",
"more",
"invasive",
"treatment",
"options",
"such",
"as",
"neuromodulatory",
"agents",
"or",
"devices.",
"With",
"recent",
"advances",
"in",
"the",
"science",
"of",
"OAB,",
"it",
"has",
"become",
"clear",
"that",
"the",
"functioning",
"and",
"malfunctioning",
"of",
"the",
"urinary",
"bladder",
"are",
"much",
"more",
"complex",
"than",
"previously",
"appreciated",
"and",
"that",
"other",
"targets",
"besides",
"the",
"muscarinic",
"receptors",
"should",
"be",
"addressed.",
"The",
"contin-",
"uous",
"evolution",
"and",
"development",
"of",
"innovative",
"agents",
"for",
"the",
"treatment",
"of",
"OAB",
"stem",
"from",
"the",
"fact",
"that",
"the",
"ideal",
"agent",
"–",
"one",
"that",
"is",
"lower",
"urinary",
"tract",
"(LUT)-selective,",
"easily",
"administered,",
"and",
"relatively",
"inexpensive",
"–",
"has",
"yet",
"to",
"be",
"found.",
"This",
"search",
"continues",
"and",
"therapies",
"with",
"different",
"mechanisms",
"of",
"action",
"are",
"currently",
"being",
"studied",
"with",
"some",
"promise.",
"Recent",
"advances",
"Several",
"new",
"therapies",
"have",
"been",
"added",
"to",
"the",
"armamen-",
"tarium",
"of",
"treatment",
"options",
"for",
"OAB",
"over",
"the",
"last",
"couple",
"Page",
"1",
"of",
"7",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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348,
890,
370,
907
],
[
373,
890,
410,
907
],
[
414,
890,
450,
907
],
[
453,
890,
478,
907
],
[
482,
890,
529,
907
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[
532,
890,
586,
907
],
[
590,
890,
612,
907
],
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615,
890,
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907
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890,
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907
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675,
890,
713,
907
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737,
890,
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98,
908,
123,
925
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174,
925
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180,
908,
219,
925
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908,
294,
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535,
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599,
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633,
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653,
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98,
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217,
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] | [
"ORIGINAL",
"RESEARCH",
"Prognostic",
"Significance",
"of",
"in",
"situ",
"Phenotypic",
"Marker",
"Expression",
"in",
"Diffuse",
"Large",
"B-cell",
"Lymphomas",
"Alexandar",
"Tzankov,",
"Philip",
"Went",
"and",
"Stephan",
"Dirnhofer",
"Department",
"of",
"Pathology,",
"University",
"Hospital",
"Basel,",
"Switzerland.",
"Abstract:",
"Diffuse",
"large",
"B-cell",
"lymphomas",
"(DLBCL)",
"are",
"the",
"most",
"common",
"lymphoid",
"malignancies,",
"and",
"encompass",
"all",
"malignant",
"lymphomas",
"characterized",
"by",
"large",
"neoplastic",
"cells",
"and",
"B-cell",
"derivation.",
"In",
"the",
"last",
"decade,",
"DLBCL",
"has",
"been",
"subjected",
"to",
"intense",
"clinical,",
"phenotypic",
"and",
"molecular",
"studies,",
"and",
"were",
"found",
"to",
"represent",
"a",
"heterogeneous",
"group",
"of",
"tumors.",
"These",
"studies",
"suggested",
"new",
"disease",
"subtypes",
"and",
"variants",
"with",
"distinct",
"clinical",
"characteristics,",
"morphologies,",
"immunophe-",
"notypes,",
"genotypes",
"or",
"gene",
"expression",
"profiles,",
"associated",
"with",
"distinct",
"prognoses",
"or",
"unique",
"sensitivities",
"to",
"particular",
"therapy",
"regimens.",
"Unfortunately,",
"the",
"reliability",
"and",
"reproducibility",
"of",
"the",
"molecular",
"results",
"remains",
"unclear",
"due",
"to",
"contra-",
"dictory",
"reports",
"in",
"the",
"literature",
"resulting",
"from",
"small",
"sample",
"sizes,",
"referral",
"and",
"selection",
"biases,",
"and",
"variable",
"methodologies",
"and",
"cut-off",
"levels",
"used",
"to",
"determine",
"positivity.",
"Here,",
"we",
"review",
"phenotypic",
"studies",
"on",
"the",
"prognostic",
"significance",
"of",
"protein",
"expression",
"profiles",
"in",
"DLBCL",
"and",
"reconsider",
"our",
"own",
"retrospective",
"data",
"on",
"301",
"primary",
"DLBCL",
"cases",
"obtained",
"on",
"a",
"pre-",
"viously",
"validated",
"tissue",
"microarray",
"in",
"light",
"of",
"powerful",
"statistical",
"methods",
"of",
"determining",
"optimal",
"cut-off",
"values",
"of",
"pheno-",
"typic",
"factors",
"for",
"prediction",
"of",
"outcome.",
"Keywords:",
"Diffuse",
"large",
"B-cell",
"lymphoma,",
"Phenotype,",
"Prognosis,",
"Tissue",
"microarray,",
"Receiver",
"operating",
"characteristic",
"(ROC)",
"curves",
"Introduction",
"Diffuse",
"large",
"B-cell",
"lymphomas",
"(DLBCL)",
"are",
"the",
"most",
"common",
"lymphoid",
"malignancies,",
"comprising",
"35%",
"to",
"40%",
"of",
"all",
"adult",
"non-Hodgkin",
"lymphomas.",
"This",
"category",
"encompasses",
"all",
"malignant",
"lymphomas",
"characterized",
"by",
"large",
"neoplastic",
"cells",
"and",
"B-cell",
"derivation",
"(Gatter",
"and",
"Warnke,",
"2001;",
"Lossos,",
"2005;",
"Mitterlechner",
"et",
"al.",
"2006).",
"DLBCL",
"may",
"develop",
"de",
"novo",
"(primary",
"DLBCL)",
"or",
"arise",
"from",
"a",
"previously",
"indolent",
"lymphoma",
"(secondary,",
"transformed",
"DLBCL)",
"at",
"virtually",
"every",
"nodal",
"or",
"extranodal",
"location.",
"It",
"is",
"most",
"commonly",
"observed",
"in",
"cervical,",
"axillar",
"and",
"mediastinal",
"nodes,",
"the",
"stomach",
"and",
"the",
"ileo-coecal",
"region",
"(Gatter",
"and",
"Warnke,",
"2001).",
"DLBCL",
"are",
"accompanied",
"by",
"an",
"aggressive",
"clinical",
"presentation",
"with",
"the",
"need",
"for",
"highly",
"effective",
"chemotherapy",
"regimens",
"(e.g.",
"Coiffier,",
"2005).",
"Only",
"about",
"60%",
"of",
"patients",
"can",
"be",
"cured",
"by",
"rituximab,",
"cyclophosphamide,",
"doxorubicin,",
"vincristine,",
"prednisone",
"(R-CHOP)",
"and",
"equivalent",
"treatment",
"regimens",
"(Coiffier,",
"2005;",
"Mitterlchner",
"et",
"al.",
"2006).",
"The",
"gold",
"standard",
"of",
"predicting",
"survival",
"and",
"stratifying",
"patients",
"for",
"risk-adjusted",
"therapy",
"is",
"the",
"international",
"prognostic",
"index",
"(IPI)",
"(Shipp",
"et",
"al.",
"1993),",
"which",
"consists",
"of",
"easily",
"assessable",
"clinical",
"and",
"laboratory",
"parameters:",
"age,",
"serum",
"lactate",
"dehydrogenase",
"(LDH),",
"stage,",
"performance",
"status",
"and",
">1",
"extranodal",
"sites",
"involved.",
"No",
"such",
"histopathologically-defined",
"parameters",
"exist",
"and",
"although",
"the",
"current",
"World",
"Health",
"Organization",
"(WHO)",
"classification",
"(Gatter",
"and",
"Warnke,",
"2001)",
"accepts",
"different",
"morphologic",
"variants",
"and",
"subtypes",
"of",
"DLBCL,",
"their",
"prognostic",
"utility",
"is",
"hampered",
"by",
"a",
"high",
"rate",
"of",
"interobserver",
"variation,",
"which",
"generally",
"minimizes",
"their",
"influence",
"in",
"therapy.",
"In",
"the",
"last",
"decade,",
"extensive",
"studies",
"of",
"the",
"clinical,",
"phenotypic",
"and",
"molecular",
"aspects",
"of",
"DLBCL",
"have",
"identified",
"them",
"as",
"a",
"heterogeneous",
"group",
"of",
"tumors.",
"These",
"studies",
"suggested",
"new",
"disease",
"subtypes",
"and",
"variants",
"with",
"distinct",
"clinical",
"characteristics,",
"morphology,",
"immunophenotypes,",
"genotypes",
"or",
"gene",
"expression",
"profiles",
"associated",
"with",
"distinct",
"prognoses",
"or",
"unique",
"sensitivities",
"to",
"specific",
"therapy",
"regimens",
"(Pileri",
"et",
"al.",
"2002;",
"de",
"Leval",
"and",
"Harris,",
"2003;",
"Wright",
"et",
"al.",
"2003;",
"Rosenwald",
"and",
"Staudt,",
"2003;",
"Lossos,",
"2005;",
"Morgensztern",
"and",
"Lossos,",
"2005;",
"de",
"Paepe",
"and",
"de",
"Wolf-Peeters,",
"2006;",
"Muris",
"et",
"al.",
"2006a).",
"Unfortunately,",
"the",
"reliability",
"and",
"reproducibility",
"of",
"the",
"molecular",
"results",
"remains",
"unclear,",
"and",
"consequently",
"translation",
"into",
"generally",
"accepted",
"standards",
"to",
"predict",
"survival",
"and",
"stratify",
"patients",
"for",
"risk-adjusted",
"therapy",
"has",
"not",
"taken",
"place",
"(for",
"critical",
"remarks",
"see",
"e.g.",
"Hsi,",
"2001;",
"de",
"Leval",
"and",
"Harris,",
"2003;",
"Gascoyne,",
"2004).",
"Technical",
"issues",
"(antibody",
"affinity),",
"lack",
"of",
"standardization",
"of",
"Correspondence:",
"Stephan",
"Dirnhofer,",
"MD,",
"Department",
"of",
"Pathology,",
"University",
"Hospital",
"Basel,",
"Schoenbeinstr.",
"40,",
"CH-4031",
"Basel,",
"Switzerland;",
"Tel:",
"0041",
"61",
"265",
"2789;",
"Fax:",
"0041",
"61",
"265",
"3194;",
"Email:",
"sdirnhofer@uhbs.ch",
"Please",
"note",
"that",
"this",
"article",
"may",
"not",
"be",
"used",
"for",
"commercial",
"purposes.",
"For",
"further",
"information",
"please",
"refer",
"to",
"the",
"copyright",
"statement",
"at",
"http://www.la-press.com/copyright.htm",
"Biomarker",
"Insights",
"2007:",
"2",
"403–417",
"403"
] | [
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] | [
"World",
"Journal",
"of",
"Surgical",
"Oncology",
"Review",
"Guidelines,",
"guidelines",
"and",
"more",
"guidelines:",
"And",
"we",
"still",
"do",
"not",
"know",
"how",
"to",
"follow-up",
"patients",
"with",
"breast",
"cancer",
"Steven",
"D",
"Heys*,",
"Shailesh",
"Chaturvedi,",
"Andrew",
"W",
"Hutcheon",
"and",
"Tarun",
"K",
"Sarkar",
"BioMed",
"Central",
"Open",
"Access",
"Address:",
"Section",
"of",
"Surgical",
"Oncology,",
"Department",
"of",
"Surgery,",
"University",
"of",
"Aberdeen,",
"Medical",
"School,",
"Foresterhill,",
"Aberdeen,",
"Scotland,",
"AB25",
"2ZD,",
"UK",
"Email:",
"Steven",
"D",
"Heys*",
"-",
"s.d.heys@abdn.ac.uk;",
"Shailesh",
"Chaturvedi",
"-",
"shailesh.chaturvedi@arh.grampian.scot.nhs.uk;",
"Andrew",
"W",
"Hutcheon",
"-",
"Andrew.Hutcheon@arh.grampian.scot.nhs.uk;",
"Tarun",
"K",
"Sarkar",
"-",
"Dr.Tarun.Sarkar@arh.grampian.scot.nhs.uk",
"*",
"Corresponding",
"author",
"Published:",
"23",
"August",
"2005",
"World",
"Journal",
"of",
"Surgical",
"Oncology",
"2005,",
"3:54",
"doi:10.1186/1477-7819-3-54",
"This",
"article",
"is",
"available",
"from:",
"http://www.wjso.com/content/3/1/54",
"Received:",
"02",
"May",
"2005",
"Accepted:",
"23",
"August",
"2005",
"©",
"2005",
"Heys",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited.",
"Abstract",
"Background:",
"A",
"major",
"challenge",
"facing",
"us",
"is",
"the",
"provision",
"of",
"health",
"care",
"and",
"appropriate",
"allocation",
"of",
"available",
"resources",
"for",
"the",
"treatment",
"of",
"patients",
"with",
"breast",
"cancer.",
"This",
"is",
"of",
"particular",
"concern",
"in",
"the",
"provision",
"of",
"follow-up",
"care.",
"With",
"the",
"increasing",
"incidence",
"of",
"breast",
"cancer",
"and",
"the",
"improvements",
"in",
"survival",
"which",
"have",
"resulted",
"in",
"up",
"to",
"75%",
"of",
"patients",
"surviving",
"for",
"more",
"than",
"five",
"years,",
"an",
"increasing",
"resource",
"is",
"required.",
"However,",
"there",
"is",
"controversy",
"as",
"to",
"the",
"most",
"appropriate",
"schedule",
"for",
"follow-up",
"of",
"these",
"patients.",
"This",
"brief",
"review",
"has",
"focused",
"on",
"the",
"evidence-base",
"and",
"guidelines",
"that",
"currently",
"exist",
"in",
"the",
"United",
"Kingdom",
"for",
"the",
"follow-up",
"of",
"patients",
"who",
"have",
"been",
"treated",
"for",
"breast",
"cancer.",
"Methods:",
"A",
"review",
"of",
"the",
"current",
"guidelines",
"published",
"in",
"the",
"United",
"Kingdom",
"for",
"the",
"follow-up",
"of",
"patients",
"with",
"breast",
"cancer",
"(National",
"Institute",
"for",
"Clinical",
"Excellence,",
"Scottish",
"Intercollegiate",
"Guidelines",
"Network,",
"British",
"Association",
"of",
"Surgical",
"Oncology)",
"and",
"the",
"randomised",
"controlled",
"trials",
"evaluating",
"the",
"follow-up",
"of",
"patients",
"with",
"breast",
"cancer",
"was",
"undertaken.",
"Results:",
"The",
"results",
"have",
"demonstrated",
"the",
"different",
"follow-up",
"protocols",
"currently",
"indicated",
"in",
"these",
"guidelines",
"within",
"the",
"same",
"country.",
"Furthermore,",
"the",
"lack",
"of",
"well",
"designed,",
"randomised",
"controlled",
"trials",
"on",
"which",
"to",
"base",
"a",
"follow-up",
"protocol",
"for",
"patients",
"with",
"breast",
"cancer",
"is",
"apparent.",
"Conclusion:",
"The",
"evidence-base",
"on",
"which",
"these",
"guidelines",
"have",
"been",
"developed",
"is",
"lacking.",
"It",
"is",
"apparent",
"that",
"well",
"designed",
"randomised",
"controlled",
"trials",
"are",
"needed",
"urgently",
"if",
"we",
"are",
"to",
"understand",
"the",
"most",
"appropriate",
"and",
"effective",
"ways",
"of",
"following",
"up",
"patients",
"with",
"breast",
"cancer.",
"Background",
"A",
"major",
"challenge",
"in",
"the",
"provision",
"of",
"healthcare",
"through-",
"out",
"the",
"world",
"in",
"the",
"21st",
"century",
"is",
"trying",
"to",
"ensure",
"that",
"the",
"resources",
"that",
"are",
"available",
"meet",
"the",
"demand.",
"Nowhere",
"is",
"the",
"situation",
"more",
"acute",
"than",
"in",
"the",
"provision",
"of",
"care",
"for",
"patients",
"with",
"cancer.",
"Whilst",
"current",
"statistics",
"show",
"that",
"one",
"in",
"three",
"people",
"in",
"the",
"world",
"will",
"develop",
"a",
"malignant",
"disease,",
"this",
"figure",
"is",
"the",
"projected",
"to",
"increase",
"dramatically",
"during",
"the",
"next",
"10",
"years.",
"Of",
"particular",
"concern",
"has",
"been",
"the",
"continual",
"rise",
"in",
"the",
"incidence",
"of",
"breast",
"cancer.",
"Each",
"year",
"the",
"incidence",
"Page",
"1",
"of",
"6",
"(page",
"number",
"not",
"for",
"citation",
"purposes)"
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] | [
"Iriarte1*.",
"Abstract",
"Brucella",
"abortus",
"Ornithine",
"Lipids",
"Are",
"Dispensable",
"Outer",
"Membrane",
"Components",
"Devoid",
"of",
"a",
"Marked",
"Pathogen-",
"Associated",
"Molecular",
"Pattern",
"Leyre",
"Palacios-Chaves1,",
"Raquel",
"Conde-A´",
"lvarez1,2,",
"Yolanda",
"Gil-Ramı´rez1,",
"Amaia",
"Zu´",
"n˜",
"iga-Ripa1,",
"Elı´as",
"Barquero-Calvo",
"4",
",",
"Carlos",
"Chaco´",
"n-Dı´az3,4,",
"Esteban",
"Chaves-Olarte3,4,",
"Vilma",
"Arce-Gorvel5,",
"Jean-Pierre",
"Gorvel5,",
"Edgardo",
"Moreno3,6,",
"Marı´a-Jesu´",
"s",
"de",
"Miguel7,",
"Marı´a-Jesu´",
"s",
"Grillo´",
"8,",
"Ignacio",
"Moriyo´",
"n1.,",
"Maite",
"1",
"Departamento",
"de",
"Microbiolog´ıa",
"y",
"Parasitolog´ıa,",
"Universidad",
"de",
"Navarra,",
"Pamplona,",
"Spain,",
"2",
"Focal",
"Area",
"Infection",
"Biology,",
"Biozentrum",
"of",
"the",
"University",
"of",
"Basel,",
"Basel,",
"Switzerland,",
"3",
"Centro",
"de",
"Investigacio´",
"n",
"en",
"Enfermedades",
"Tropicales,",
"Facultad",
"de",
"Microbiolog´ıa,",
"Universidad",
"de",
"Costa",
"Rica,",
"San",
"Jose´,",
"Costa",
"Rica,",
"4",
"Programa",
"de",
"Investigacio´",
"n",
"en",
"Enfermedades",
"Tropicales,",
"Escuela",
"de",
"Medicina",
"Veterinaria,",
"Universidad",
"Nacional,",
"Heredia,",
"Costa",
"Rica,",
"5",
"Centre",
"d’Immunologie",
"de",
"Marseille-Luminy,",
"Aix",
"Marseille",
"Universite´,",
"Faculte´",
"de",
"Sciences",
"de",
"Luminy,",
"Marseille,",
"INSERM",
"U631,",
"CNRS",
"UMR6102,",
"Marseille,",
"France,",
"6",
"Instituto",
"Clodomiro",
"Picado,",
"Facultad",
"de",
"Microbiolog´ıa,",
"Universidad",
"de",
"Costa",
"Rica,",
"San",
"Pedro,",
"Costa",
"Rica,",
"7",
"Centro",
"de",
"Investigacio´",
"n",
"y",
"Tecnolog´ıa",
"Agroalimentaria",
"(CITA),",
"Unidad",
"de",
"Sanidad",
"Animal,",
"Gobierno",
"de",
"Arago´",
"n,",
"Zaragoza,",
"Spain,",
"8",
"Instituto",
"de",
"Agrobiotecnolog´ıa,",
"CSIC-UPNA-Gobierno",
"de",
"Navarra,",
"Pamplona,",
"Spain",
"The",
"brucellae",
"are",
"a-Proteobacteria",
"facultative",
"intracellular",
"parasites",
"that",
"cause",
"an",
"important",
"zoonosis.",
"These",
"bacteria",
"escape",
"early",
"detection",
"by",
"innate",
"immunity,",
"an",
"ability",
"associated",
"to",
"the",
"absence",
"of",
"marked",
"pathogen-associated",
"molecular",
"patterns",
"in",
"the",
"cell",
"envelope",
"lipopolysaccharide,",
"lipoproteins",
"and",
"flagellin.",
"We",
"show",
"here",
"that,",
"in",
"contrast",
"to",
"the",
"outer",
"membrane",
"ornithine",
"lipids",
"(OL)",
"of",
"other",
"Gram",
"negative",
"bacteria,",
"Brucella",
"abortus",
"OL",
"lack",
"a",
"marked",
"pathogen-associated",
"molecular",
"pattern",
"activity.",
"We",
"identified",
"two",
"OL",
"genes",
"(olsB",
"and",
"olsA)",
"and",
"by",
"generating",
"the",
"corresponding",
"mutants",
"found",
"that",
"olsB",
"deficient",
"B.",
"abortus",
"did",
"not",
"synthesize",
"OL",
"or",
"their",
"lyso-OL",
"precursors.",
"Liposomes",
"constructed",
"with",
"B.",
"abortus",
"OL",
"did",
"not",
"trigger",
"IL-6",
"or",
"TNF-a",
"release",
"by",
"macrophages",
"whereas",
"those",
"constructed",
"with",
"Bordetella",
"pertussis",
"OL",
"and",
"the",
"olsB",
"mutant",
"lipids",
"as",
"carriers",
"were",
"highly",
"active.",
"The",
"OL",
"deficiency",
"in",
"the",
"olsB",
"mutant",
"did",
"not",
"promote",
"proinflammatory",
"responses",
"or",
"generated",
"attenuation",
"in",
"mice.",
"In",
"addition,",
"OL",
"deficiency",
"did",
"not",
"increase",
"sensitivity",
"to",
"polymyxins,",
"normal",
"serum",
"or",
"complement",
"consumption,",
"or",
"alter",
"the",
"permeability",
"to",
"antibiotics",
"and",
"dyes.",
"Taken",
"together,",
"these",
"observations",
"indicate",
"that",
"OL",
"have",
"become",
"dispensable",
"in",
"the",
"extant",
"brucellae",
"and",
"are",
"consistent",
"within",
"the",
"trend",
"observed",
"in",
"a-Proteobacteria",
"animal",
"pathogens",
"to",
"reduce",
"and",
"eventually",
"eliminate",
"the",
"envelope",
"components",
"susceptible",
"of",
"recognition",
"by",
"innate",
"immunity.",
"Citation:",
"Palacios-Chaves",
"L,",
"Conde-A´",
"lvarez",
"R,",
"Gil-Ram´ırez",
"Y,",
"Zu´",
"n˜",
"iga-Ripa",
"A,",
"Barquero-Calvo",
"E,",
"et",
"al.",
"(2011)",
"Brucella",
"abortus",
"Ornithine",
"Lipids",
"Are",
"Dispensable",
"Outer",
"Membrane",
"Components",
"Devoid",
"of",
"a",
"Marked",
"Pathogen-Associated",
"Molecular",
"Pattern.",
"PLoS",
"ONE",
"6(1):",
"e16030.",
"doi:10.1371/journal.pone.0016030",
"Editor:",
"David",
"M.",
"Ojcius,",
"University",
"of",
"California",
"Merced,",
"United",
"States",
"of",
"America",
"Received",
"October",
"28,",
"2010;",
"Accepted",
"December",
"3,",
"2010;",
"Published",
"January",
"7,",
"2011",
"Copyright:",
"2011",
"Palacios-Chaves",
"et",
"al.",
"This",
"is",
"an",
"open-access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License,",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"author",
"and",
"source",
"are",
"credited.",
"Funding:",
"Research",
"at",
"the",
"laboratories",
"of",
"the",
"authors",
"is",
"supported",
"by",
"the",
"Ministerio",
"de",
"Ciencia",
"y",
"Tecnolog´ıa",
"of",
"Spain",
"(AGL2008-04514-C03);",
"FIDA,",
"Universidad",
"Nacional",
"de",
"Costa",
"Rica;",
"FS-Conare",
"UNA/UCR",
"IFEG29",
"Costa",
"Rica;",
"NeTropica",
"P00059",
"and",
"F00013-02;",
"MICIT/CONICIT",
"IFDG12;",
"Fundacio´",
"n",
"CRUSA-CSIC",
"(CR2008-0006);",
"Centre",
"National",
"de",
"la",
"Recherche",
"Scientifique,",
"Institut",
"National",
"de",
"la",
"Sante´",
"et",
"de",
"la",
"Recherche",
"Me´dicale",
"and",
"the",
"Ministry",
"of",
"Education",
"in",
"France.",
"Fellowship",
"support",
"for",
"L.P.-C.,",
"Y.G.-R.",
"and",
"A.Z.-R",
"from",
"the",
"Ministerio",
"de",
"Ciencia",
"y",
"Tecnolog´ıa",
"of",
"Spain,",
"Gobierno",
"de",
"Navarra",
"and",
"Friends",
"of",
"the",
"University",
"of",
"Navarra",
"is",
"also",
"acknowledged.",
"The",
"funders",
"had",
"no",
"role",
"in",
"study",
"design,",
"data",
"collection",
"and",
"analysis,",
"decision",
"to",
"publish,",
"or",
"preparation",
"of",
"the",
"manuscript.",
"Competing",
"Interests:",
"The",
"authors",
"have",
"declared",
"that",
"no",
"competing",
"interests",
"exist.",
"*",
"E-mail:",
"miriart@unav.es",
".",
"These",
"authors",
"contributed",
"equally",
"to",
"this",
"work.",
"Introduction",
"The",
"members",
"of",
"the",
"genus",
"Brucella",
"are",
"a-2",
"Proteobacteria",
"that",
"cause",
"brucellosis,",
"an",
"important",
"disease",
"affecting",
"livestock",
"and",
"wild",
"life",
"as",
"well",
"as",
"human",
"beings.",
"These",
"bacteria",
"trigger",
"only",
"low",
"proinflammatory",
"responses",
"in",
"the",
"initial",
"stages",
"of",
"infection",
"and,",
"accordingly,",
"they",
"follow",
"a",
"stealthy",
"behavior",
"that",
"allows",
"them",
"to",
"reach",
"sheltered",
"intracellular",
"niches",
"before",
"effective",
"immunity",
"activation.",
"The",
"outer",
"membranes",
"(OM)",
"of",
"brucellae",
"are",
"of",
"critical",
"importance",
"in",
"this",
"strategy.",
"Whereas",
"most",
"gram-negative",
"have",
"OM",
"molecules",
"bearing",
"the",
"pathogen-associated",
"molecular",
"pat-",
"terns",
"(PAMP)",
"recognized",
"by",
"innate",
"immunity,",
"at",
"least",
"the",
"Brucella",
"OM",
"lipopolysaccharide",
"(LPS),",
"lipoproteins",
"and",
"flagellin",
"display",
"a",
"reduced",
"PAMP",
"[1,2].",
"Moreover,",
"smooth",
"(S)",
"brucellae",
"such",
"as",
"B.",
"abortus",
"and",
"B.",
"melitensis",
"have",
"OMs",
"that",
"are",
"unusually",
"resistant",
"to",
"the",
"disrupting",
"action",
"of",
"bactericidal",
"peptides",
"and",
"complement.",
"Thus,",
"periplasmic",
"and",
"internal",
"PAMP-bearing",
"molecules",
"like",
"peptido-",
"glycan",
"or",
"DNA",
"are",
"not",
"readily",
"accessible",
"to",
"pathogen",
"recognition",
"receptors",
"[1,3–8].",
"The",
"Brucella",
"LPS",
"is",
"clearly",
"implicated",
"in",
"these",
"properties",
"and",
"there",
"is",
"evidence",
"that",
"other",
"lipid",
"molecules",
"also",
"contribute.",
"Brucella",
"OMs",
"contain",
"large",
"amounts",
"of",
"phosphatidyl-",
"choline",
"(PC)",
"and",
"blockage",
"of",
"the",
"synthesis",
"of",
"PC",
"with",
"the",
"subsequent",
"replacement",
"by",
"phosphatidylethanolamine",
"(PE)",
"gen-",
"erates",
"attenuation",
"[9,10].",
"Ornithine",
"lipids",
"(OLs)",
"are",
"present",
"in",
"relatively",
"large",
"amounts",
"in",
"Brucella",
"[11]",
"and,",
"although",
"they",
"have",
"interesting",
"properties",
"in",
"other",
"bacteria,",
"have",
"not",
"been",
"investigated.",
"PLoS",
"ONE",
"|",
"www.plosone.org",
"1",
"January",
"2011",
"|",
"Volume",
"6",
"|",
"Issue",
"1",
"|",
"e16030"
] | [
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] | [
"Acta",
"Crystallographica",
"Section",
"E",
"Structure",
"Reports",
"Online",
"ISSN",
"1600-5368",
"tert-Butyl",
"(2S)-2-{3-[(R)-bis(tert-butoxy-",
"carbonyl)amino]-2-oxopiperidin-1-yl}-",
"1",
"3-methylbutanoate",
"Michael",
"J.",
"Kangas,",
"Frank",
"R.",
"Fronczek*",
"and",
"Steven",
"F.",
"Watkins",
"Department",
"of",
"Chemistry,",
"Louisiana",
"State",
"University,",
"Baton",
"Rouge,",
"LA",
"70803-1804,",
"USA",
"Correspondence",
"e-mail:",
"ffroncz@lsu.edu",
"Received",
"13",
"October",
"2011;",
"accepted",
"18",
"October",
"2011",
"Key",
"indicators:",
"single-crystal",
"X-ray",
"study;",
"T",
"=",
"86",
"K,",
"P",
"=",
"0.0",
"kPa;",
"mean",
"(C–C)",
"=",
"0.002",
"A˚;",
"R",
"factor",
"=",
"0.026;",
"wR",
"factor",
"=",
"0.071;",
"data-to-parameter",
"ratio",
"=",
"15.6.",
"The",
"title",
"compound,",
"C24H42N2O7,",
"is",
"a",
"chiral",
"lactam-",
"constrained",
"amino",
"acid",
"with",
"a",
"six-membered",
"ring",
"backbone",
"and",
"isopropyl",
"and",
"tert-butyl",
"ester",
"side",
"chains.",
"The",
"conforma-",
"tion",
"of",
"the",
"six-membered",
"ring",
"can",
"be",
"described",
"as",
"a",
"half",
"chair,",
"with",
"two",
"CH2",
"C",
"atoms",
"lying",
"0.443",
"(1)",
"and",
"0.310",
"(1)",
"A˚",
"out",
"of",
"the",
"best",
"plane",
"of",
"the",
"other",
"four",
"atoms",
"(mean",
"deviation",
"=",
"0.042",
"A˚",
").",
"Both",
"N",
"atoms",
"are",
"sp2",
"hybridized,",
"lying",
"0.0413",
"(9)",
"and",
"0.067",
"(1)",
"A˚",
"out",
"of",
"the",
"planes",
"defined",
"by",
"the",
"three",
"C",
"atoms",
"bonded",
"to",
"them.",
"The",
"absolute",
"configuration",
"was",
"determined,",
"based",
"on",
"resonant",
"scattering",
"of",
"light",
"atoms",
"in",
"Cu",
"K",
"radiation.",
"Related",
"literature",
"For",
"synthesis",
"and",
"chemical",
"interest,",
"see:",
"Oguz",
"(2003);",
"Oguz",
"et",
"al.",
"(2001).",
"For",
"a",
"similar",
"structure,",
"see:",
"Valle",
"et",
"al.",
"(1989).",
"For",
"absolute",
"configuration",
"parameters,",
"see:",
"Hooft",
"et",
"al.",
"(2008).",
"Experimental",
"Crystal",
"data",
"C24H42N2O7",
"Mr",
"=",
"470.6",
"Monoclinic,",
"C2",
"a",
"=",
"27.282",
"(3)",
"A˚",
"b",
"=",
"9.4315",
"(10)",
"A˚",
"c",
"=",
"11.5884",
"(10)",
"A˚",
"=",
"110.729",
"(1)",
"Data",
"collection",
"Bruker",
"Kappa",
"APEXII",
"CCD",
"diffractometer",
"Absorption",
"correction:",
"multi-scan",
"(SADABS;",
"Sheldrick,",
"2004)",
"Tmin",
"=",
"0.800,",
"Tmax",
"=",
"0.878",
"Refinement",
"R[F",
"2",
">",
"2",
"(F",
"2)]",
"=",
"0.026",
"wR(F",
"2)",
"=",
"0.071",
"S",
"=",
"1.01",
"4844",
"reflections",
"310",
"parameters",
"1",
"restraint",
"organic",
"compounds",
"V",
"=",
"2788.7",
"(5)",
"A˚",
"3",
"Z",
"=",
"4",
"Cu",
"K",
"radiation",
"=",
"0.67",
"mm",
"1",
"T",
"=",
"86",
"K",
"0.35",
"0.25",
"0.20",
"mm",
"10823",
"measured",
"reflections",
"4844",
"independent",
"reflections",
"4782",
"reflections",
"with",
"I",
">",
"2",
"(I)",
"Rint",
"=",
"0.023",
"H-atom",
"parameters",
"constrained",
"max",
"=",
"0.19",
"e",
"A˚",
"3",
"min",
"=",
"0.12",
"e",
"A˚",
"3",
"Absolute",
"structure:",
"Flack",
"(1983),",
"2174",
"Friedel",
"pairs",
"Flack",
"parameter:",
"0.02",
"(10)",
"Data",
"collection:",
"APEX2",
"(Bruker,",
"2006);",
"cell",
"refinement:",
"APEX2;",
"data",
"reduction:",
"APEX2;",
"program(s)",
"used",
"to",
"solve",
"structure:",
"SHELXS97",
"(Sheldrick,",
"2008);",
"program(s)",
"used",
"to",
"refine",
"structure:",
"SHELXL97",
"(Sheldrick,",
"2008);",
"molecular",
"graphics:",
"ORTEP-3",
"for",
"Windows",
"(Farrugia,",
"1997);",
"software",
"used",
"to",
"prepare",
"material",
"for",
"publication:",
"WinGX",
"(Farrugia,",
"1999).",
"We",
"are",
"grateful",
"to",
"Dr",
"Umut",
"Oguz",
"for",
"providing",
"the",
"crys-",
"talline",
"sample.",
"Supplementary",
"data",
"and",
"figures",
"for",
"this",
"paper",
"are",
"available",
"from",
"the",
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] | [
"Research",
"|",
"Children’s",
"Health",
"Lead",
"Exposure",
"and",
"Behavior",
"among",
"Young",
"Children",
"in",
"Chennai,",
"India",
"Ananya",
"Roy,1",
"David",
"Bellinger,2,3",
"Howard",
"Hu,1,2,4",
"Joel",
"Schwartz,2,4",
"Adrienne",
"S.",
"Ettinger,1,2,4",
"Robert",
"O.",
"Wright,2,4,5",
"Maryse",
"Bouchard,2",
"Kavitha",
"Palaniappan,6",
"and",
"Kalpana",
"Balakrishnan",
"6",
"1Department",
"of",
"Environmental",
"Health",
"Sciences,",
"University",
"of",
"Michigan",
"School",
"of",
"Public",
"Health,",
"Ann",
"Arbor,",
"Michigan,",
"USA;",
"2Depart-",
"ment",
"of",
"Environmental",
"Health,",
"Harvard",
"School",
"of",
"Public",
"Health,",
"Boston,",
"Massachusetts,",
"USA;",
"3Department",
"of",
"Neurology,",
"Children’s",
"Hospital",
"Boston,",
"Boston,",
"Massachusetts,",
"USA;",
"4Channing",
"Laboratory,",
"Brigham",
"and",
"Women’s",
"Hospital,",
"Boston,",
"Massachusetts,",
"USA;",
"5Department",
"of",
"Medicine,",
"Children’s",
"Hospital",
"Boston,",
"Boston,",
"Massachusetts,",
"USA;",
"6Department",
"of",
"Environmental",
"Health",
"Engineering,",
"Sri",
"Ramachandra",
"Medical",
"College",
"and",
"Research",
"Institute,",
"Chennai,",
"Tamil",
"Nadu,",
"India",
"Bdnuorgkca",
":",
"Lead",
"exposure",
"has",
"long",
"been",
"associated",
"with",
"deficits",
"in",
"IQ",
"among",
"children.",
"However,",
"few",
"studies",
"have",
"assessed",
"the",
"impact",
"of",
"lead",
"on",
"specific",
"domains",
"of",
"behavior",
"and",
"cognition.",
"o",
"Bjectiv",
":",
"We",
"evaluated",
"the",
"associations",
"between",
"lead",
"and",
"different",
"domains",
"of",
"neurobehavior",
"and",
"their",
"relative",
"sensitivity",
"to",
"lead.",
"Msdohte",
":",
"We",
"determined",
"blood",
"lead",
"levels",
"using",
"a",
"LeadCare",
"instrument",
"in",
"756",
"children",
"3–7",
"years",
"of",
"age",
"attending",
"pre-",
"and",
"elementary",
"schools",
"in",
"Chennai,",
"India.",
"Anxiety,",
"social",
"problems,",
"inatten-",
"tion,",
"hyperactivity,",
"and",
"attention",
"deficit",
"hyperactivity",
"disorder",
"(ADHD),",
"as",
"well",
"as",
"executive",
"function",
"were",
"assessed",
"in",
"children",
"by",
"their",
"schoolteachers",
"using",
"Conners’",
"Teacher",
"Rating",
"Scales-39,",
"Conners’",
"ADHD/Diagnostic",
"and",
"Statistical",
"Manual",
"for",
"Mental",
"Disorders,",
"4th",
"Edition",
"Scales",
"(CADS),",
"and",
"the",
"Behavior",
"Rating",
"Inventory",
"of",
"Executive",
"Function",
"questionnaires,",
"with",
"higher",
"scores",
"denoting",
"worse",
"behavior.",
"Analyses",
"were",
"carried",
"out",
"using",
"multivariate",
"generalized",
"estimating",
"equations",
"with",
"com-",
"parisons",
"of",
"outcome",
"Z-scores",
"to",
"assess",
"the",
"relative",
"strengths",
"of",
"the",
"associations",
"between",
"log-blood",
"lead",
"and",
"the",
"different",
"domains",
"of",
"behavior.",
"r",
"tluse",
":",
"Mean",
"blood",
"lead",
"level",
"was",
"11.4",
"±",
"5.3",
"µg/dL.",
"Blood",
"lead",
"was",
"associated",
"with",
"higher",
"anxiety",
"(β",
"=",
"0.27,",
"p",
"=",
"0.01),",
"social",
"problems",
"(β",
"=",
"0.20,",
"p",
"=",
"0.02),",
"and",
"higher",
"scores",
"in",
"the",
"ADHD",
"index",
"(β",
"=",
"0.17;",
"p",
"=",
"0.05).",
"The",
"effect",
"estimate",
"was",
"highest",
"for",
"global",
"executive",
"function",
"(β",
"=",
"0.42;",
"p",
"<",
"0.001).",
"c",
"onclusi",
":",
"Higher",
"blood",
"lead",
"levels",
"in",
"this",
"population",
"of",
"young",
"children",
"is",
"associated",
"with",
"increased",
"risk",
"of",
"neurobehavioral",
"deficits",
"and",
"ADHD,",
"with",
"executive",
"function",
"and",
"attention",
"being",
"particularly",
"vulnerable",
"domains",
"to",
"the",
"effects",
"of",
"lead.",
"k",
"ey",
"words",
":",
"ADHD,",
"anxiety,",
"blood",
"lead,",
"children,",
"executive",
"function,",
"India,",
"sociability.",
"Environ",
"Health",
"Perspect",
"117:1607–1611",
"(2009).",
"doi:10.1289/ehp.0900625",
"available",
"via",
"http://dx.doi.org/",
"[Online",
"26",
"June",
"2009]",
"The",
"removal",
"of",
"lead",
"from",
"sources",
"in",
"the",
"environment,",
"such",
"as",
"gasoline",
"and",
"residential",
"paint,",
"have",
"resulted",
"in",
"declines",
"in",
"blood",
"lead",
"levels",
"in",
"many",
"countries",
"[Centers",
"for",
"Disease",
"Control",
"and",
"Prevention",
"(CDC)",
"1997,",
"2005a].",
"In",
"India,",
"leaded",
"gasoline",
"was",
"phased",
"out",
"in",
"early",
"2001.",
"Nichani",
"et",
"al.",
"(2006)",
"reported",
"that",
"37%",
"of",
"children",
"in",
"Mumbai",
"in",
"2002",
"had",
"blood",
"lead",
"levels",
">",
"10",
"µg/dL,",
"the",
"CDC",
"level",
"of",
"concern",
"for",
"blood",
"lead",
"(CDC",
"2005b),",
"down",
"from",
"60%",
"in",
"1997.",
"Other",
"studies",
"describe",
"continued",
"elevations",
"in",
"blood",
"lead",
"levels",
"among",
"children",
"in",
"other",
"parts",
"of",
"the",
"country",
"(Ahamed",
"et",
"al.",
"2006;",
"Bellinger",
"et",
"al.",
"2005).",
"Many",
"studies",
"have",
"shown",
"that",
"lead",
"exposure",
"is",
"associated",
"with",
"significant",
"defi-",
"cits",
"in",
"intelligence",
"quotient",
"(IQ)",
"of",
"children",
"(Lanphear",
"et",
"al.",
"2005).",
"However,",
"IQ",
"is",
"a",
"global",
"construct",
"of",
"cognition,",
"and",
"fewer",
"studies",
"have",
"assessed",
"the",
"impact",
"of",
"lead",
"on",
"specific",
"domains",
"of",
"behavior",
"and",
"cognition,",
"such",
"as",
"executive",
"function",
"(Canfield",
"et",
"al.",
"2003,",
"2004;",
"Froehlich",
"et",
"al.",
"2007),",
"attention",
"(Bellinger",
"et",
"al.",
"1994;",
"Stiles",
"and",
"Bellinger",
"1993),",
"and",
"internaliz-",
"ing",
"behaviors.",
"Recent",
"evidence",
"suggests",
"that",
"increased",
"lead",
"exposure",
"is",
"associated",
"with",
"atten-",
"tion",
"deficit",
"hyperactivity",
"disorder",
"(ADHD)",
"(Braun",
"et",
"al.",
"2006;",
"Nigg",
"2008)",
"and",
"conduct",
"disorder",
"(Needleman",
"et",
"al.",
"2002;",
"Nevin",
"2000).",
"Currently,",
"relatively",
"little",
"is",
"known",
"about",
"the",
"shape",
"of",
"the",
"dose–response",
"relationships",
"or",
"the",
"relative",
"sensitivity",
"of",
"behavioral",
"domains",
"to",
"lead",
"toxicity.",
"Only",
"one",
"study",
"has",
"reported",
"on",
"the",
"relationship",
"between",
"lead",
"exposure",
"and",
"behav-",
"ior,",
"as",
"well",
"as",
"other",
"cognitive",
"outcomes",
"among",
"children",
"in",
"India",
"(Bellinger",
"et",
"al.",
"2005).",
"The",
"objective",
"of",
"this",
"study",
"was",
"to",
"explore",
"the",
"associations",
"between",
"lead",
"and",
"specific",
"neurobehavioral",
"outcomes",
"such",
"as",
"ADHD-",
"like",
"behaviors,",
"executive",
"function,",
"and",
"inter-",
"nalizing",
"problems",
"(anxiety",
"and",
"sociability)",
"in",
"a",
"cohort",
"of",
"children",
"3–7",
"years",
"of",
"age",
"in",
"Chennai,",
"India.",
"In",
"addition,",
"we",
"investigated",
"the",
"shape",
"of",
"the",
"dose–response",
"relationships",
"and",
"the",
"relative",
"sensitivity",
"of",
"the",
"different",
"behavioral",
"outcomes",
"to",
"lead",
"exposure.",
"Methods",
"Study",
"population.",
"This",
"cross-sectional",
"study",
"of",
"814",
"children",
"was",
"carried",
"out",
"during",
"2005–2006",
"in",
"Chennai,",
"India.",
"Four",
"traffic",
"and",
"industry",
"zones",
"were",
"selected",
"on",
"the",
"basis",
"of",
"industrial",
"zoning",
"information",
"provided",
"by",
"the",
"Tamil",
"Nadu",
"State",
"Pollution",
"Control",
"Board",
"and",
"the",
"Chennai",
"traffic",
"police",
"department.",
"Children",
"3–7",
"years",
"of",
"age",
"were",
"recruited",
"from",
"12",
"schools",
"(three",
"schools",
"within",
"each",
"zone).",
"Informed",
"consent",
"was",
"obtained",
"from",
"each",
"child’s",
"primary",
"caregiver.",
"Venous",
"blood",
"was",
"collected",
"from",
"each",
"child,",
"and",
"questionnaires",
"Environmental",
"Health",
"Perspectives",
"•",
"volume",
"117",
"|",
"number",
"10",
"|",
"October",
"2009",
"were",
"administered",
"in",
"Tamil",
"(the",
"regional",
"lan-",
"guage)",
"to",
"the",
"teachers",
"and",
"primary",
"caregivers",
"(usually",
"the",
"mothers)",
"of",
"the",
"children.",
"A",
"semi-",
"quantitative",
"food",
"frequency",
"questionnaire",
"was",
"used",
"to",
"assess",
"nutritional",
"status.",
"Information",
"was",
"collected",
"on",
"a",
"family’s",
"average",
"monthly",
"income,",
"educational",
"attainment",
"and",
"occupa-",
"tion",
"of",
"the",
"parents,",
"and",
"type",
"of",
"housing.",
"Data",
"on",
"family",
"size,",
"maternal",
"age",
"at",
"birth",
"of",
"child,",
"and",
"child’s",
"age,",
"birth",
"weight,",
"and",
"birth",
"rank",
"were",
"also",
"collected.",
"This",
"investigation",
"was",
"conducted",
"as",
"part",
"of",
"a",
"collaborative",
"study",
"between",
"the",
"Harvard",
"School",
"of",
"Public",
"Health",
"(HSPH),",
"Boston,",
"Massachusetts",
"(USA),",
"and",
"Sri",
"Ramachandra",
"Medical",
"College",
"and",
"Research",
"Institute",
"(SRMC),",
"Chennai,",
"India,",
"on",
"lead",
"genetics",
"and",
"neurotoxicity.",
"The",
"study",
"was",
"approved",
"by",
"institutional",
"review",
"boards",
"at",
"HSPH,",
"SRMC,",
"the",
"University",
"of",
"Michigan,",
"and",
"the",
"Indian",
"Council",
"for",
"Medical",
"Research,",
"New",
"Delhi,",
"India,",
"and",
"complied",
"with",
"U.S.",
"federal",
"and",
"Indian",
"regulations",
"and",
"laws",
"regarding",
"research",
"on",
"human",
"subjects.",
"Blood",
"lead",
"measurement.",
"Blood",
"was",
"col-",
"lected",
"from",
"the",
"cubital",
"vein",
"of",
"each",
"child",
"into",
"lead-free",
"tubes",
"(royal",
"blue",
"top",
"tubes",
"#369736;",
"Becton-Dickinson,",
"Franklin",
"Lakes,",
"NJ,",
"USA)",
"by",
"a",
"trained",
"phlebotomist",
"during",
"a",
"school",
"day.",
"The",
"blood",
"was",
"transferred",
"to",
"the",
"laboratory",
"at",
"SRMC,",
"and",
"blood",
"lead",
"was",
"measured",
"using",
"Anodic",
"Stripping",
"Voltammetry",
"by",
"a",
"LeadCare",
"Analyzer",
"(ESA",
"Laboratories,",
"Chelmsford,",
"MA,",
"USA),",
"which",
"is",
"a",
"well-validated",
"field",
"instru-",
"ment",
"with",
"sensitivity",
"of",
"1",
"µg/dL",
"blood",
"lead",
"(Shannon",
"and",
"Rifai",
"1997).",
"Duplicates",
"and",
"controls",
"were",
"run",
"with",
"every",
"20",
"samples,",
"every",
"new",
"batch,",
"and",
"kit",
"lot.",
"Fifty-eight",
"children",
"Address",
"correspondence",
"to",
"A.",
"Roy,",
"University",
"of",
"Michigan",
"School",
"of",
"Public",
"Health,",
"Department",
"of",
"Environmental",
"Health",
"Sciences,",
"109",
"South",
"Observatory",
"St.,",
"Building",
"1,",
"Ann",
"Arbor,",
"MI",
"48109",
"USA.",
"Telephone:",
"(617)",
"642-1376.",
"Fax:",
"(734)",
"936-",
"7283.",
"E-mail:",
"aroyk@umich.edu",
"This",
"study",
"was",
"supported",
"by",
"U.S.",
"National",
"Institutes",
"of",
"Health",
"(NIH)",
"grants",
"1R03TW005914",
"and",
"R01ES007821.",
"This",
"work",
"was",
"carried",
"out",
"as",
"a",
"part",
"of",
"the",
"Sc.D.",
"thesis",
"of",
"A.R.",
"at",
"the",
"Harvard",
"School",
"of",
"Public",
"Health,",
"where",
"she",
"was",
"supported",
"by",
"the",
"training",
"core",
"of",
"NIH",
"P42-ES05947.",
"The",
"contents",
"of",
"this",
"study",
"are",
"solely",
"the",
"responsi-",
"bility",
"of",
"the",
"authors",
"and",
"do",
"not",
"necessarily",
"represent",
"the",
"official",
"views",
"of",
"the",
"NIH.",
"The",
"authors",
"declare",
"they",
"have",
"no",
"competing",
"financial",
"interests.",
"Received",
"28",
"January",
"2009;",
"accepted",
"26",
"June",
"2009.",
"1607"
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] | [
"Takuma",
"et",
"al.",
"World",
"Journal",
"of",
"Surgical",
"Oncology",
"2011,",
"9:153",
"http://www.wjso.com/content/9/1/153",
"C",
"A",
"S",
"E",
"R",
"E",
"P",
"O",
"R",
"T",
"WORLD",
"JOURNAL",
"OF",
"SURGICAL",
"ONCOLOGY",
"Open",
"Access",
"Main-duct",
"intraductal",
"papillary",
"mucinous",
"adenoma",
"of",
"the",
"pancreas",
"Kensuke",
"Takuma1,",
"Terumi",
"Kamisawa1*,",
"Taku",
"Tabata1,",
"Masanao",
"Kurata2,",
"Goro",
"Honda2",
"and",
"Shin-ichiro",
"Horiguchi3",
"Abstract",
"Background:",
"The",
"prevalence",
"of",
"carcinoma",
"in",
"main-duct",
"intraductal",
"papillary",
"mucinous",
"neoplasm",
"(IPMN)",
"is",
"high,",
"and",
"surgical",
"resection",
"is",
"recommended",
"for",
"all",
"patients",
"with",
"a",
"main-duct",
"IPMN.",
"Results:",
"A",
"main-duct",
"IPMN",
"with",
"typical",
"imagings",
"including",
"protruding",
"lesions",
"in",
"the",
"dilated",
"main",
"pancreatic",
"duct",
"was",
"resected,",
"but",
"the",
"histology",
"was",
"intraductal",
"papillary",
"mucinous",
"adenoma",
"of",
"the",
"pancreas.",
"Discussion:",
"It",
"has",
"been",
"reported",
"that",
"the",
"presence",
"of",
"mural",
"nodules",
"and",
"dilatation",
"of",
"MPD",
"are",
"significantly",
"higher",
"in",
"malignant",
"IPMNs.",
"The",
"presented",
"case",
"had",
"protruding",
"lesions",
"in",
"the",
"dilated",
"main",
"pancreatic",
"duct",
"on",
"endoscopic",
"ultrasonography,",
"but",
"the",
"histology",
"was",
"adenoma.",
"Conclusion:",
"Preoperative",
"distinction",
"between",
"benign",
"and",
"malignant",
"IPMNs",
"is",
"difficult.",
"Keywords:",
"intraductal",
"papillary",
"mucinous",
"neoplasm,",
"main",
"duct,",
"mural",
"nodule,",
"IPMN",
"Background",
"Intraductal",
"papillary",
"mucinous",
"neoplasm",
"(IPMN)",
"of",
"the",
"pancreas",
"is",
"a",
"distinct",
"entity",
"characterized",
"by",
"intraductal",
"papillary",
"growth",
"and",
"thick",
"mucus",
"secretion.",
"Copious",
"mucous",
"fills",
"the",
"main",
"and",
"branch",
"pancreatic",
"ducts",
"and",
"causes",
"ductal",
"dilation.",
"Thus,",
"IPMNs",
"of",
"the",
"pancreas",
"are",
"being",
"diagnosed",
"with",
"increasing",
"frequency",
"by",
"radiologic",
"findings.",
"IPMNs",
"are",
"pathologically",
"classified",
"into",
"two",
"types",
"based",
"on",
"site",
"of",
"tumor",
"involvement,",
"that",
"is,",
"main-duct",
"type",
"or",
"branch",
"type.",
"The",
"histology",
"is",
"classified",
"into",
"intraductal",
"adenocarcinoma,",
"intraductal",
"adenoma,",
"and",
"hyperplasia.",
"It",
"has",
"been",
"suggested",
"that",
"these",
"lesions",
"have",
"the",
"capacity",
"to",
"progress",
"from",
"hyperplasia",
"to",
"adenoma,",
"to",
"noninvasive",
"car-",
"cinoma,",
"and",
"ultimately",
"to",
"invasive",
"carcinoma.",
"The",
"preva-",
"lence",
"of",
"carcinoma",
"in",
"main-duct",
"IPMN",
"is",
"as",
"high",
"as",
"60%",
"[1]",
"to",
"92%",
"[2],",
"and",
"international",
"consensus",
"guidelines",
"[3]",
"recommend",
"surgical",
"resection",
"for",
"all",
"patients",
"with",
"a",
"main-",
"duct",
"IPMN.",
"In",
"preoperative",
"diagnosis,",
"it",
"is",
"evaluated",
"the",
"existence",
"of",
"mural",
"nodule",
"increase",
"the",
"risk",
"of",
"malignancy",
"[3-5].",
"Whereas,",
"there",
"are",
"various",
"unanswered",
"problems",
"about",
"the",
"conditions",
"of",
"main-duct",
"type",
"IPMNs.",
"It",
"is",
"*",
"Correspondence:",
"kamisawa@cick.jp",
"1Departments",
"of",
"Internal",
"Medicine,",
"Tokyo",
"Metropolitan",
"Komagome",
"Hospital,",
"Tokyo,",
"Japan",
"Full",
"list",
"of",
"author",
"information",
"is",
"available",
"at",
"the",
"end",
"of",
"the",
"article",
"unknown",
"whether",
"all",
"IPMNs",
"have",
"malignant",
"potential",
"or",
"what",
"the",
"time",
"course",
"of",
"progression",
"may",
"be.",
"Case",
"presentation",
"A",
"56-year-old",
"man",
"presented",
"with",
"mild",
"abdominal",
"pain.",
"Physical",
"examination",
"and",
"laboratory",
"data",
"were",
"unremark-",
"able.",
"Abdominal",
"symptoms",
"were",
"relieved",
"with",
"conservative",
"medical",
"management",
"within",
"a",
"few",
"days.",
"Abdominal",
"ultra-",
"sonography",
"showed",
"dilation",
"of",
"the",
"main",
"pancreatic",
"duct",
"(MPD).",
"Subsequent",
"computed",
"tomography",
"scan",
"showed",
"dilatation",
"of",
"the",
"MPD",
"and",
"several",
"small",
"cysts",
"in",
"the",
"pancreatic",
"tail,",
"with",
"no",
"findings",
"of",
"mural",
"nodules,",
"mass",
"formation,",
"metastasis,",
"or",
"lymph",
"node",
"swelling.",
"Magnetic",
"resonance",
"cholangiopancreatography",
"(MRCP)",
"showed",
"an",
"irregular",
"dilatation",
"(10",
"mm)",
"of",
"the",
"MPD",
"of",
"the",
"tail",
"[Figure",
"1].",
"On",
"duodenoscopy,",
"mucin",
"was",
"secreted",
"from",
"a",
"patulous",
"orifice",
"of",
"the",
"papilla",
"of",
"Vater.",
"On",
"endoscopic",
"retrograde",
"pancreatography,",
"a",
"filling",
"defect",
"equivalent",
"to",
"mucus",
"was",
"shown",
"in",
"the",
"dilated",
"MPD.",
"Cytological",
"examination",
"of",
"the",
"pancreatic",
"fluid",
"was",
"negative,",
"and",
"CEA",
"level",
"in",
"the",
"pan-",
"creatic",
"fluid",
"was",
"2.3",
"ng/ml.",
"Endoscopic",
"ultrasonography",
"(EUS)",
"revealed",
"hyperplastic",
"or",
"polypoid",
"growth",
"of",
"the",
"epithelial",
"layer",
"and",
"hyperechoic",
"ductal",
"margin",
"of",
"the",
"irre-",
"gularly",
"dilated",
"MPD",
"[Figure",
"2].",
"Under",
"a",
"diagnosis",
"of",
"main-",
"duct",
"IPMN,",
"laparoscopy-assisted",
"distal",
"pancreatectomy",
"was",
"performed.",
"Cut",
"surface",
"of",
"the",
"resected",
"specimen",
"©",
"2011",
"Takuma",
"et",
"al;",
"licensee",
"BioMed",
"Central",
"Ltd.",
"This",
"is",
"an",
"Open",
"Access",
"article",
"distributed",
"under",
"the",
"terms",
"of",
"the",
"Creative",
"Commons",
"Attribution",
"License",
"(http://creativecommons.org/licenses/by/2.0),",
"which",
"permits",
"unrestricted",
"use,",
"distribution,",
"and",
"reproduction",
"in",
"any",
"medium,",
"provided",
"the",
"original",
"work",
"is",
"properly",
"cited."
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