Showing papers by "Oregon Health & Science University published in 2003"
Newcastle University1, University of Chicago2, Novartis3, University of Bologna4, University of Barcelona5, Erasmus University Rotterdam6, University of Mainz7, Heidelberg University8, Royal Adelaide Hospital9, Medical University of Vienna10, Aarhus University11, University of Paris12, University of Bordeaux13, University of British Columbia14, Uppsala University15, University of Basel16, Imperial College London17, University of Texas MD Anderson Cancer Center18, Katholieke Universiteit Leuven19, Oregon Health & Science University20
TL;DR: Imatinib was superior to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed chronic-phase CML and was better tolerated than combination therapy.
Abstract: Background Imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase, produces high response rates in patients with chronic-phase chronic myeloid leukemia (CML) who have had no response to interferon alfa. We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML. Methods We randomly assigned 1106 patients to receive imatinib (553 patients) or interferon alfa plus low-dose cytarabine (553 patients). Crossover to the alternative group was allowed if stringent criteria defining treatment failure or intolerance were met. Patients were evaluated for hematologic and cytogenetic responses, toxic effects, and rates of progression. Results After a median follow-up of 19 months, the estimated rate of a major cytogenetic response (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome) at 18 months was 87.1 percent (95 percent confidence interval, 84.1 to 90.0) in the imatinib group and 34.7 percent (95 perce...
3,399 citations
TL;DR: Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression, suggesting KIT and PDGFra mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.
Abstract: Most gastrointestinal stromal tumors (GISTs) have activating mutations in the KIT receptor tyrosine kinase, and most patients with GISTs respond well to Gleevec, which inhibits KIT kinase activity. Here we show that approximately 35% (14 of 40) of GISTs lacking KIT mutations have intragenic activation mutations in the related receptor tyrosine kinase, platelet-derived growth factor receptor alpha (PDGFRA). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Thus, KIT and PDGFRA mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.
2,249 citations
TL;DR: Data suggest that the MELD score is able to accurately predict 3-month mortality among patients with chronic liver disease on the liver waiting list and can be applied for allocation of donor livers.
2,225 citations
TL;DR: With a heightened awareness of these issues, informaticians can educate, design systems, implement, and conduct research in such a way that they might be able to avoid the unintended consequences of these subtle silent errors.
1,739 citations
Massachusetts Institute of Technology1, University of California, Riverside2, University of Oregon3, University of Edinburgh4, Celera Corporation5, Texas A&M University6, University of New Mexico7, University of Colorado Denver8, University of Kansas9, University of Florida10, Hebrew University of Jerusalem11, University of Düsseldorf12, Rockefeller University13, Technische Universität München14, University of Kentucky15, University of Texas at Austin16, J. Craig Venter Institute17, University of California, Berkeley18, University of California, Los Angeles19, Sapienza University of Rome20, Flinders University21, Ohio State University22, University of Arizona23, University of Missouri–Kansas City24, Dartmouth College25, University of Leeds26, California State Polytechnic University, Pomona27, Oregon Health & Science University28
TL;DR: A high-quality draft sequence of the N. crassa genome is reported, suggesting that RIP has had a profound impact on genome evolution, greatly slowing the creation of new genes through genomic duplication and resulting in a genome with an unusually low proportion of closely related genes.
Abstract: Neurospora crassa is a central organism in the history of twentieth-century genetics, biochemistry and molecular biology. Here, we
report a high-quality draft sequence of the N. crassa genome. The approximately 40-megabase genome encodes about 10,000
protein-coding genes—more than twice as many as in the fission yeast Schizosaccharomyces pombe and only about 25% fewer
than in the fruitfly Drosophila melanogaster. Analysis of the gene set yields insights into unexpected aspects of Neurospora biology
including the identification of genes potentially associated with red light photobiology, genes implicated in secondary metabolism,
and important differences in Ca21 signalling as compared with plants and animals. Neurospora possesses the widest array of
genome defence mechanisms known for any eukaryotic organism, including a process unique to fungi called repeat-induced
point mutation (RIP). Genome analysis suggests that RIP has had a profound impact on genome evolution, greatly slowing the
creation of new genes through genomic duplication and resulting in a genome with an unusually low proportion of closely related
genes.
1,659 citations
TL;DR: It is concluded that hepatocytes derived form bone marrow arise from cell fusion and not by differentiation of haematopoietic stem cells.
Abstract: Evidence suggests that haematopoietic stem cells might have unexpected developmental plasticity, highlighting therapeutic potential. For example, bone-marrow-derived hepatocytes can repopulate the liver of mice with fumarylacetoacetate hydrolase deficiency and correct their liver disease. To determine the underlying mechanism in this murine model, we performed serial transplantation of bone-marrow-derived hepatocytes. Here we show by Southern blot analysis that the repopulating hepatocytes in the liver were heterozygous for alleles unique to the donor marrow, in contrast to the original homozygous donor cells. Furthermore, cytogenetic analysis of hepatocytes transplanted from female donor mice into male recipients demonstrated 80,XXXY (diploid to diploid fusion) and 120,XXXXYY (diploid to tetraploid fusion) karyotypes, indicative of fusion between donor and host cells. We conclude that hepatocytes derived form bone marrow arise from cell fusion and not by differentiation of haematopoietic stem cells.
1,588 citations
TL;DR: Using electrophysiological recordings, ghrelin stimulated the activity of arcuate NPY neurons and mimicked the effect of NPY in the paraventricular nucleus of the hypothalamus (PVH), thus representing a novel regulatory circuit controlling energy homeostasis.
1,578 citations
TL;DR: Systematically titrating bedtime basal insulin added to oral therapy can safely achieve 7% HbA(1c) in a majority of overweight patients with type 2 diabetes, thus reducing a leading barrier to initiating insulin.
Abstract: OBJECTIVE —To compare the abilities and associated hypoglycemia risks of insulin glargine and human NPH insulin added to oral therapy of type 2 diabetes to achieve 7% HbA 1c . RESEARCH DESIGN AND METHODS —In a randomized, open-label, parallel, 24-week multicenter trial, 756 overweight men and women with inadequate glycemic control (HbA 1c >7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily, titrated using a simple algorithm seeking a target fasting plasma glucose (FPG) ≤100 mg/dl (5.5 mmol/l). Outcome measures were FPG, HbA 1c , hypoglycemia, and percentage of patients reaching HbA 1c ≤7% without documented nocturnal hypoglycemia. RESULTS —Mean FPG at end point was similar with glargine and NPH (117 vs. 120 mg/dl [6.5 vs. 6.7 mmol/l]), as was HbA 1c (6.96 vs. 6.97%). A majority of patients (∼60%) attained HbA 1c ≤7% with each insulin type. However, nearly 25% more patients attained this without documented nocturnal hypoglycemia (≤72 mg/dl [4.0 mmol/l]) with glargine (33.2 vs. 26.7%, P CONCLUSIONS —Systematically titrating bedtime basal insulin added to oral therapy can safely achieve 7% HbA 1c in a majority of overweight patients with type 2 diabetes with HbA 1c between 7.5 and 10.0% on oral agents alone. In doing this, glargine causes significantly less nocturnal hypoglycemia than NPH, thus reducing a leading barrier to initiating insulin. This simple regimen may facilitate earlier and effective insulin use in routine medical practice, improving achievement of recommended standards of diabetes care.
1,474 citations
Shimane University1, University of Freiburg2, University of Manitoba3, University of Kentucky4, University of Marburg5, St. Michael's Hospital6, Baylor College of Medicine7, University of Illinois at Urbana–Champaign8, Scripps Health9, Oregon Health & Science University10, Tulane University11, Mayo Clinic12, Michigan State University13, University of Göttingen14, Max Planck Society15, University of California, Los Angeles16, Rutgers University17, Seton Hall University18
TL;DR: This scale meets performance criteria for a brief, patient completed instrument that can be used to assess RLS severity for purposes of clinical assessment, research, or therapeutic trials and supports a finding that RLS is a relatively uniform disorder in which the severity of the basic symptoms is strongly related to their impact on the patient's life.
1,439 citations
TL;DR: A human ortholog of Sir2p, sirtuin type 2 (SIRT2), is a predominantly cytoplasmic protein that colocalizes with microtubules and is established as a bona fide tubulin deacetylase.
1,434 citations
Johns Hopkins University1, Auckland University of Technology2, University of South Florida3, Oregon Health & Science University4, University of Florida5, Texas Woman's University6, University of California, Los Angeles7, University of Washington8, New York City Department of Health and Mental Hygiene9, Covance10, Mount Sinai St. Luke's and Mount Sinai Roosevelt11
TL;DR: There are identifiable risk factors for intimate partner femicides and they include perpetrator's access to a gun and previous threat with a weapon, perpetrator's stepchild in the home, and estrangement, especially from a controlling partner.
Abstract: Objectives. This 11-city study sought to identify risk factors for femicide in abusive relationships. Methods. Proxies of 220 intimate partner femicide victims identified from police or medical examiner records were interviewed, along with 343 abused control women. Results. Preincident risk factors associated in multivariate analyses with increased risk of intimate partner femicide included perpetrator’s access to a gun and previous threat with a weapon, perpetrator’s stepchild in the home, and estrangement, especially from a controlling partner. Never living together and prior domestic violence arrest were associated with lowered risks. Significant incident factors included the victim having left for another partner and the perpetrator’s use of a gun. Other significant bivariate-level risks included stalking, forced sex, and abuse during pregnancy. Conclusions. There are identifiable risk factors for intimate partner femicides.
TL;DR: Continuous insulin infusion eliminates the incremental increase in in-hospital mortality after coronary artery bypass grafting associated with diabetes, and should become the standard of care for glycometabolic control in patients with diabetes undergoing coronary arteries bypass surgery.
National Institutes of Health1, University of British Columbia2, University of Nebraska Medical Center3, University of Oslo4, University of Barcelona5, University of Würzburg6, Oregon Health & Science University7, University of Arizona8, University of Rochester9, Fred Hutchinson Cancer Research Center10
TL;DR: Gene expression profiling strongly supported a relationship between PMBL and Hodgkin lymphoma: over one third of the genes that were more highly expressed in PMBL than in other DLBCLs were also characteristically expressed in Hodgkinymphoma cells.
Abstract: Using current diagnostic criteria, primary mediastinal B cell lymphoma (PMBL) cannot be distinguished from other types of diffuse large B cell lymphoma (DLBCL) reliably. We used gene expression profiling to develop a more precise molecular diagnosis of PMBL. PMBL patients were considerably younger than other DLBCL patients, and their lymphomas frequently involved other thoracic structures but not extrathoracic sites typical of other DLBCLs. PMBL patients had a relatively favorable clinical outcome, with a 5-yr survival rate of 64% compared with 46% for other DLBCL patients. Gene expression profiling strongly supported a relationship between PMBL and Hodgkin lymphoma: over one third of the genes that were more highly expressed in PMBL than in other DLBCLs were also characteristically expressed in Hodgkin lymphoma cells. PDL2, which encodes a regulator of T cell activation, was the gene that best discriminated PMBL from other DLBCLs and was also highly expressed in Hodgkin lymphoma cells. The genomic loci for PDL2 and several neighboring genes were amplified in over half of the PMBLs and in Hodgkin lymphoma cell lines. The molecular diagnosis of PMBL should significantly aid in the development of therapies tailored to this clinically and pathogenetically distinctive subgroup of DLBCL.
TL;DR: The insulin-like growth factor (IGF) family of ligands, binding proteins and receptors is an important growth factor system involved in both the development of the organism and the maintenance of normal function of many cells of the body.
TL;DR: The addition of enfuvirtide to an optimized antiretroviral and immunologic benefit through 24 weeks in patients who had previously received multiple antireTroviral drugs and had multidrug-resistant HIV-1 infection.
Abstract: Background The T-20 vs. Optimized Regimen Only Study 1 (TORO 1) was a randomized, open-label, phase 3 study of enfuvirtide (T-20), a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor. Methods Patients from 48 sites in the United States, Canada, Mexico, and Brazil with at least six months of previous treatment with agents in three classes of antiretroviral drugs, resistance to drugs in these classes, or both, and with at least 5000 copies of HIV-1 RNA per milliliter of plasma were randomly assigned in a 2:1 ratio to receive enfuvirtide plus an optimized background regimen of three to five antiretroviral drugs or such a regimen alone (control group). The primary efficacy end point was the change in the plasma HIV-1 RNA level from base line to week 24. Results A total of 501 patients underwent randomization, and 491 received at least one dose of study drug and had at least one measurement of plasma HIV-1 RNA after treatment began. The two groups were balanced in terms of the median base-line HIV-1...
TL;DR: It is found that more than 90% of volunteers vaccinated 25–75 years ago still maintain substantial humoral or cellular immunity (or both) against vaccinia, the virus used to vaccinate against smallpox.
Abstract: Although naturally occurring smallpox was eliminated through the efforts of the World Health Organization Global Eradication Program, it remains possible that smallpox could be intentionally released. Here we examine the magnitude and duration of antiviral immunity induced by one or more smallpox vaccinations. We found that more than 90% of volunteers vaccinated 25-75 years ago still maintain substantial humoral or cellular immunity (or both) against vaccinia, the virus used to vaccinate against smallpox. Antiviral antibody responses remained stable between 1-75 years after vaccination, whereas antiviral T-cell responses declined slowly, with a half-life of 8-15 years. If these levels of immunity are considered to be at least partially protective, then the morbidity and mortality associated with an intentional smallpox outbreak would be substantially reduced because of pre-existing immunity in a large number of previously vaccinated individuals.
TL;DR: The in vivo efficacy of SU11248 (20 mg/kg/d) dramatically regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model and prolongs survival in the bone marrow engraftment model, suggesting that further exploration of SU 11248 activity in AML patients is warranted.
TL;DR: It is reported that BDNF is expressed at high levels in the ventromedial hypothalamus (VMH) where its expression is regulated by nutritional state and by MC4R signaling, and this results show that MC 4R signaling controls BDNF expression in the VMH.
Abstract: The melanocortin-4 receptor (MC4R) is critically involved in regulating energy balance, and obesity has been observed in mice with mutations in the gene for brain-derived neurotrophic factor (BDNF). Here we report that BDNF is expressed at high levels in the ventromedial hypothalamus (VMH) where its expression is regulated by nutritional state and by MC4R signaling. In addition, similar to MC4R mutants, mouse mutants that expresses the BDNF receptor TrkB at a quarter of the normal amount showed hyperphagia and excessive weight gain on higher-fat diets. Furthermore, BDNF infusion into the brain suppressed the hyperphagia and excessive weight gain observed on higher-fat diets in mice with deficient MC4R signaling. These results show that MC4R signaling controls BDNF expression in the VMH and support the hypothesis that BDNF is an important effector through which MC4R signaling controls energy balance.
TL;DR: Evidence is described that Vif binds APOBEC3G and induces its rapid degradation, thus eliminating it from cells and preventing its incorporation into HIV-1 virions, providing promising approaches for drug discovery.
Abstract: The viral infectivity factor (Vif) encoded by HIV-1 neutralizes a potent antiviral pathway that occurs in human T lymphocytes and several leukemic T-cell lines termed nonpermissive, but not in other cells termed permissive. In the absence of Vif, this antiviral pathway efficiently inactivates HIV-1. It was recently reported that APOBEC3G (also known as CEM-15), a cytidine deaminase nucleic acid-editing enzyme, confers this antiviral phenotype on permissive cells. Here we describe evidence that Vif binds APOBEC3G and induces its rapid degradation, thus eliminating it from cells and preventing its incorporation into HIV-1 virions. Studies of Vif mutants imply that it contains two domains, one that binds APOBEC3G and another with a conserved SLQ(Y/F)LA motif that mediates APOBEC3G degradation by a proteasome-dependent pathway. These results provide promising approaches for drug discovery.
TL;DR: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study, and did not improve parkinsonism, possibly because GDNF did not reach the target tissues—putamen and substantia nigra.
Abstract: Objective: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. Background: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. Methods: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 μg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 μg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson’s Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. Results: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. “On” and “off” total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 μg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 μg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. Conclusions: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues—putamen and substantia nigra.
TL;DR: Fanconi anaemia is a rare genetic cancer-susceptibility syndrome that is characterized by congenital abnormalities, bone-marrow failure and cellular sensitivity to DNA crosslinking agents, and the FA proteins could be involved in the cell-cycle checkpoint and DNA-repair pathways.
Abstract: Fanconi anaemia (FA) is a rare genetic cancer-susceptibility syndrome that is characterized by congenital abnormalities, bone-marrow failure and cellular sensitivity to DNA crosslinking agents. Seven FA-associated genes have recently been cloned, and their products were found to interact with well-known DNA-damage-response proteins, including BRCA1, ATM and NBS1. The FA proteins could therefore be involved in the cell-cycle checkpoint and DNA-repair pathways. Recent studies implicate the FA proteins in the process of repairing chromosome defects that occur during homologous recombination, and disruption of the FA genes results in chromosome instability--a common feature of many human cancers.
TL;DR: It is shown that there are only a few points within laparoscopic cholecystectomy where the complication-causing errors occur, which suggests that focused training to heighten vigilance might be able to decrease the incidence of bile duct injury.
Abstract: Bile duct injuries are the main serious technical complication of laparoscopic cholecystectomy. 1,2 Data are insufficient to determine precisely the frequency of bile duct injuries, but a reasonable estimate is one in 1,000 cases. 2 A decade ago, as the technique of laparoscopic cholecystectomy was first being learned by otherwise fully trained, practicing surgeons, the injury rate was noted to be greater during an individual’s first dozen cases than in subsequent ones. 2 This learning curve contribution is now much less important, for surgical residents learn the procedure under direct supervision of more experienced surgeons.
Surgeons have always analyzed their technical complications for insights that might be translated into improved performance. In the past the information available from such reviews could rarely go much beyond a tabulation of results. An understanding of the root causes of technical complications remained elusive. This report takes analysis of technical complications to greater depths, for it integrates the findings of videotapes of operations involving bile duct injuries, operative notes dictated after the operation had been completed but before an injury had become apparent, and conceptual tools of human factors research and the cognitive science of human error.
TL;DR: It is shown that teriparatide treatment results in an increase in bone mineral density and is a potentially useful therapy for osteoporosis in men.
Abstract: Teriparatide [rhPTH(1-34)] increases bone mineral density and reduces the risk of vertebral fracture in women. We randomized 437 men with spine or hip bone mineral density more than 2 SD below the young adult male mean to daily injections of placebo, teriparatide 20 microg, or teriparatide 40 microg. All subjects also received supplemental calcium and vitamin D. The study was stopped after a median duration of 11 months because of a finding of osteosarcomas in rats in routine toxicology studies. Biochemical markers of bone formation increased early in the course of therapy and were followed by increases in indices of osteoclastic activity. Spine bone mineral density was greater than in placebo subjects after 3 months of teriparatide therapy, and by the end of therapy it was increased by 5.9% (20 microg) and 9.0% (40 microg) above baseline (p < 0.001 vs. placebo for both comparisons). Femoral neck bone mineral density increased 1.5% (20 microg; p = 0.029) and 2.9% (40 microg; p < 0.001), and whole body bone mineral content increased 0.6% (20 microg; p = 0.021) and 0.9% (40 microg;p = 0.005) above baseline in the teriparatide subjects. There was no change in radial bone mineral density in the teriparatide groups. Bone mineral density responses to teriparatide were similar regardless of gonadal status, age, baseline bone mineral density, body mass index, smoking, or alcohol intake. Subjects experienced expected changes in mineral metabolism. Adverse events were similar in the placebo and 20-microg groups, but more frequent in the 40-microg group. This study shows that teriparatide treatment results in an increase in bone mineral density and is a potentially useful therapy for osteoporosis in men.
TL;DR: Bowel preparation is inadequate for almost a quarter of patients undergoing colonoscopy, and results suggest that inadequate preparation quality only hinders detection of smaller lesions, while having negligible impact on detection of larger lesions.
TL;DR: Patients with atypical disease who had PANK2 mutations were more likely to have prominent speech-related and psychiatric symptoms than patients with classic disease or mutation-negative patients with attypical disease.
Abstract: Background Hallervorden–Spatz syndrome is an autosomal recessive disorder characterized by dystonia, parkinsonism, and iron accumulation in the brain. Many patients with this disease have mutations in the gene encoding pantothenate kinase 2 (PANK2); these patients are said to have pantothenate kinase–associated neurodegeneration. In this study, we compared the clinical and radiographic features of patients with Hallervorden–Spatz syndrome with and without mutations in PANK2. Methods One hundred twenty-three patients from 98 families with a diagnosis of Hallervorden–Spatz syndrome were classified on the basis of clinical assessment as having classic disease (characterized by early onset with rapid progression) or atypical disease (later onset with slow progression). Their genomic DNA was sequenced for PANK2 mutations. Results All patients with classic Hallervorden–Spatz syndrome and one third of those with atypical disease had PANK2 mutations. Whereas almost all mutations in patients with atypical disease ...
TL;DR: It is demonstrated that FKN preferentially mediates arrest and migration of CD16+ monocytes and suggested that recruitment of this proinflammatory monocyte subset to vessel walls via the CX3CR1-FKN pathway may contribute to vascular and tissue injury during pathological conditions.
Abstract: CD16 � monocytes represent 5‐10% of peripheral blood monocytes in normal individuals and are dramatically expanded in several pathological conditions including sepsis, human immunodeficiency virus 1 infection, and cancer. CD16 � monocytes produce high levels of proinflammatory cytokines and may represent dendritic cell precursors in vivo. The mechanisms that mediate the recruitment of CD16 � monocytes into tissues remain unknown. Here we investigate molecular mechanisms of CD16 � monocyte trafficking and show that migration of CD16 � and CD16 � monocytes is mediated by distinct combinations of adhesion molecules and chemokine receptors. In contrast to CD16 � monocytes, CD16 � monocytes expressed high CX3CR1 and CXCR4 but low CCR2 and CD62L levels and underwent efficient transendothelial migration in response to fractalkine (FKN; FKN/CX3CL1) and stromal-derived factor 1 � (CXCL12) but not monocyte chemoattractant protein 1 (CCL2). CD16 � monocytes arrested on cell surface‐expressed FKN under flow with higher frequency compared with CD16 � monocytes. These results demonstrate that FKN preferentially mediates arrest and migration of CD16 � monocytes and suggest that recruitment of this proinflammatory monocyte subset to vessel walls via the CX3CR1-FKN pathway may contribute to vascular and tissue injury during pathological conditions.
TL;DR: The QOLS is a valid instrument for measuringquality of life across patient groups and cultures and is conceptually distinct from health status or other causal indicators of quality of life.
Abstract: The Quality of Life Scale (QOLS), created originally by American psychologist John Flanagan in the 1970's, has been adapted for use in chronic illness groups. This paper reviews the development and psychometric testing of the QOLS. A descriptive review of the published literature was undertaken and findings summarized in the frequently asked questions format. Reliability, content and construct validity testing has been performed on the QOLS and a number of translations have been made. The QOLS has low to moderate correlations with physical health status and disease measures. However, content validity analysis indicates that the instrument measures domains that diverse patient groups with chronic illness define as quality of life. The QOLS is a valid instrument for measuring quality of life across patient groups and cultures and is conceptually distinct from health status or other causal indicators of quality of life.
TL;DR: The data suggest that PHF9 has a crucial role in the Fanconi anemia pathway as the likely catalytic subunit required for monoubiquitination of FANCD2.
Abstract: Fanconi anemia is a recessively inherited disease characterized by congenital defects, bone marrow failure and cancer susceptibility. Cells from individuals with Fanconi anemia are highly sensitive to DNA-crosslinking drugs, such as mitomycin C (MMC). Fanconi anemia proteins function in a DNA damage response pathway involving breast cancer susceptibility gene products, BRCA1 and BRCA2 (refs. 1,2). A key step in this pathway is monoubiquitination of FANCD2, resulting in the redistribution of FANCD2 to nuclear foci containing BRCA1 (ref. 3). The underlying mechanism is unclear because the five Fanconi anemia proteins known to be required for this ubiquitination have no recognizable ubiquitin ligase motifs. Here we report a new component of a Fanconi anemia protein complex, called PHF9, which possesses E3 ubiquitin ligase activity in vitro and is essential for FANCD2 monoubiquitination in vivo. Because PHF9 is defective in a cell line derived from an individual with Fanconi anemia, we conclude that PHF9 (also called FANCL) represents a novel Fanconi anemia complementation group (FA-L). Our data suggest that PHF9 has a crucial role in the Fanconi anemia pathway as the likely catalytic subunit required for monoubiquitination of FANCD2.
University of California, Irvine1, Oregon Health & Science University2, Merck & Co.3, University of Virginia4, Harvard University5, Thomas Jefferson University6, Yale University7, Astellas Pharma8, University of Wisconsin-Madison9, University of Ulm10, University of California, San Francisco11, University of Würzburg12, Rosalind Franklin University of Medicine and Science13, Vanderbilt University14, Osaka University15, Centre national de la recherche scientifique16, California Institute of Technology17, Stony Brook University18, Washington University in St. Louis19, King's College London20, New York University21, University of Utah22, Chiba University23, Max Planck Society24, Colorado State University25, University of California, Santa Barbara26, University of Tulsa27
TL;DR: An overview of the molecular relationships among the voltage-gated potassium channels and a standard nomenclature for them is derived from the IUPHAR Compendium of Voltage-Gated Ion Channels as mentioned in this paper.
Abstract: This summary article presents an overview of the molecular relationships among the voltage-gated potassium channels and a standard nomenclature for them, which is derived from the IUPHAR Compendium of Voltage-Gated Ion Channels.1 The complete Compendium, including data tables for each member of the potassium channel family can be found at http://www.iuphar-db.org/iuphar-ic/.