bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconi anemia
Authors: Pulliam-Leath Anna C. , Ciccone Samantha L. , Nalepa Grzegorz , Li Xiaxin , Si Yue , Miravalle Leticia , Smith Danielle , Yuan Jin , Li Jingling , Anur Praveen , Orazi Attilio , Vance Gail H. , Yang Feng-Chun , Hanenberg Helmut , Bagby Grover C. , Clapp D. Wade 
Published: July 2010

AbstractFanconi anemia (FA) is an inherited chromosomal instability syndrome characterized by bone marrow failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). Eight FA proteins associate in a nuclear core complex to monoubiquitinate FANCD2/FANCI in response to DNA damage. Additional functions have been described for some of the core complex proteins; however, in vivo genetic proof has been lacking. Here we show that double-mutant Fancc−/−;Fancg−/− mice develop spontaneous hematologic sequelae including bone marrow failure, AML, MDS and complex random chromosomal abnormalities that the single-mutant mice do not. This genetic model provides evidence for unique core complex protein function independent of their ability to monoubiquitinate FANCD2/FANCI. Importantly, this model closely recapitulates the phenotypes found in FA patients and may be useful as a preclinical platform to evaluate the molecular pathogenesis of spontaneous bone marrow failure, MDS and AML in FA.
An adult uterine hemangioblast: evidence for extramedullary self-renewal and clonal bilineage potential
Authors: Sun Zhuo , Zhang Yuemei , Brunt Keith R. , Wu Jun , Li Shu-Hong , Fazel Shafie , Weisel Richard D. , Keating Armand , Li Ren-Ke 
Published: July 2010

AbstractStem cells exhibit long-term self-renewal by asymmetric division and multipotent differentiation. During embryonic development, cell fate is determined with predictable orientation, differentiation, and partitioning to form the organism. This includes the formation of a hemangioblast from which 2 derivative cell clusters commit to either a hematopoietic or an endothelial lineage. Frequently, it is not clear whether tissue resident stem cells in the adult originate from the bone marrow. Here, we show that blast colony-forming cells exhibiting bilineage (hematopoietic and vascular) potential and long-term self-renewal originate from the uterus in the mouse. This is the first in vitro and in vivo evidence of an adult hemangioblast retained from development in the uterus. Our findings offer new understanding of uterine cell renewal and turnover and may provide insights and opportunities for the study of stem cell maintenance.
A transgenic mouse model demonstrates a dominant negative effect of a point mutation in the RPS19 gene associated with Diamond-Blackfan anemia
Authors: Devlin Emily E. , DaCosta Lydie , Mohandas Narla , Elliott Gene , Bodine David M. 
Published: July 2010

AbstractDiamond Blackfan anemia (DBA) is an inherited erythroblastopenia associated with mutations in at least 8 different ribosomal protein genes. Mutations in the gene encoding ribosomal protein S19 (RPS19) have been identified in approximately 25% of DBA families. Most of these mutations disrupt either the translation or stability of the RPS19 protein and are predicted to cause DBA by haploinsufficiency. However, approximately 30% of RPS19 mutations are missense mutations that do not alter the stability of the RPS19 protein and are hypothesized to act by a dominant negative mechanism. To formally test this hypothesis, we generated a transgenic mouse model expressing an RPS19 mutation in which an arginine residue is replaced with a tryptophan residue at codon 62 (RPS19R62W). Constitutive expression of RPS19R62W in developing mice was lethal. Conditional expression of RPS19R62W resulted in growth retardation, a mild anemia with reduced numbers of erythroid progenitors, and significant inhibition of terminal erythroid maturation, similar to DBA. RNA profiling demonstrated more than 700 dysregulated genes belonging to the same pathways that are disrupted in RNA profiles of DBA patient cells. We conclude that RPS19R62W is a dominant negative DBA mutation.
Association of obesity risk SNPs in PCSK1with insulin sensitivity and proinsulin conversion
Authors: Heni Martin , Haupt Axel , Schäfer Silke A , Ketterer Caroline , Thamer Claus , Machicao Fausto , Stefan Norbert , Staiger Harald , Häring Hans-Ulrich , Fritsche Andreas 
Published: July 2010

Abstract

Background
Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene PCSK1, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs) within this gene, rs6232 and rs6235, are associated with obesity. We studied whether these SNPs influence the prediabetic traits insulin resistance, β-cell dysfunction, or glucose intolerance.

Methods
We genotyped 1498 German subjects for SNPs rs6232 and rs6235 within PCSK1. The subjects were metabolically characterized by oral glucose tolerance test with glucose, insulin, proinsulin, and C-peptide measurements. A subgroup of 512 subjects underwent a hyperinsulinemic-euglycemic clamp.

Results
The minor allele frequencies were 25.8% for SNP rs6235 and 6.0% for rs6232. After adjustment for sex and age, we found no association of SNPs rs6235 and rs6232 with BMI or other weight-related traits (all p ≥ 0.07). Both minor alleles, adjusted for sex, age, BMI and insulin sensitivity were associated with elevated AUCproinsulin and AUCproinsulin/AUCinsulin (rs6235: padditive model ≤ 0.009, effect sizes 8/8%, rs6232: pdominant model ≤ 0.01, effect sizes 10/21%). Insulin secretion was not affected by the variants (different secretion parameters, all p ≥ 0.08). The minor allele of SNP rs6232 was additionally associated with 15% higher OGTT-derived and 19% higher clamp-derived insulin sensitivity (pdom ≤ 0.0047), 4.5% lower HOMAIR (pdom = 0.02) and 3.5% lower 120-min glucose (pdom = 0.0003) independently of BMI and proinsulin conversion. SNP rs6235 was not associated with parameters of glucose metabolism.

Conclusions
Like rare mutations in PCSK1, the more common variants tested determine glucose-stimulated proinsulin conversion, but not insulin secretion. In addition, rs6232, encoding the amino acid exchange N221D, influences insulin sensitivity and glucose homeostasis.
Synuclein gamma predicts poor clinical outcome in colon cancer with normal levels of carcinoembryonic antigen
Authors: Liu Caiyun , Dong Bin , Lu Aiping , Qu Like , Xing Xiaofang , Meng Lin , Wu Jian , Eric Shi Y , Shou Chengchao 
Published: July 2010

Abstract

Background
Synuclein gamma (SNCG), initially identified as a breast cancer specific gene, is aberrantly expressed in many different malignant tumors but rarely expressed in matched nonneoplastic adjacent tissues. In this study, we investigated the prognostic potential of SNCG in colon cancer particularly in the patients with normal carcinoembryonic antigen (CEA) levels.

Methods
SNCG levels were assessed immunohistochemically in cancer tissues from 229 colon adenocarcinoma patients with a mean follow-up of 44 months. Correlations between SNCG levels and clinicopathologic features, preoperative serum CEA level, and clinical outcome were analyzed statistically using SPSS.

Results
SNCG levels in colon adenocarcinoma were closely associated with intravascular embolus and tumor recurrence but independent of preoperative serum CEA levels. SNCG expression was an independent prognostic factor of a shorter disease-free survival (DFS) and overall survival (OS) (P < 0.0001). Multivariate analysis revealed that both tissue SNCG and serum CEA were independent prognostic factors of DFS (P = 0.001, <0.0001, respectively) for 170 patients with colon adenocarcinomas. Importantly, SNCG remained a prognostic determinant of DFS and OS (P = 0.001, 0.002) for 97 patients with normal preoperative serum CEA level.

Conclusions
Our results suggest for the first time that SNCG is a new independent predicator for poor prognosis in patients with colon adenocarcinoma, including those with normal CEA levels. Combination of CEA with SNCG improves prognostic evaluation for patients with colon adenocarcinoma.
A single amino acid substitution of the human immunodeficiency virus type 1 capsid protein affects viral sensitivity to TRIM5α
Authors: Kuroishi Ayumu , Bozek Katarzyna , Shioda Tatsuo , Nakayama Emi E 
Published: July 2010

Abstract

Background
Human immunodeficiency virus type 1 (HIV-1) productively infects only humans and chimpanzees but not Old World monkeys, such as rhesus and cynomolgus (CM) monkeys. To establish a monkey model of HIV-1/AIDS, several HIV-1 derivatives have been constructed. We previously reported that efficient replication of HIV-1 in CM cells was achieved after we replaced the loop between α-helices 6 and 7 (L6/7) of the capsid protein (CA) with that of SIVmac239 in addition to the loop between α-helices 4 and 5 (L4/5) and vif. This virus (NL-4/5S6/7SvifS) was supposed to escape from host restriction factors cyclophilin A, CM TRIM5α, and APOBEC3G. However, the replicative capability of NL-4/5S6/7SvifS in human cells was severely impaired.

Results
By long-term cultivation of human CEMss cells infected with NL-4/5S6/7SvifS, we succeeded in rescuing the impaired replicative capability of the virus in human cells. Sequence analysis of the CA region of the adapted virus revealed a G-to-E substitution at the 116th position of the CA (G116E). Introduction of this substitution into the molecular DNA clone of NL-4/5S6/7SvifS indeed improved the virus' replicative capability in human cells. Although the G116E substitution occurred during long-term cultivation of human cells infected with NL-4/5S6/7SvifS, the viruses with G116E unexpectedly became resistant to CM, but not human TRIM5α-mediated restriction. The 3-D model showed that position 116 is located in the 6th helix near L4/5 and L6/7 and is apparently exposed to the protein surface. The amino acid substitution at the 116th position caused a change in the structure of the protein surface because of the replacement of G (which has no side chain) with E (which has a long negatively charged side chain).

Conclusions
We succeeded in rescuing the impaired replicative capability of NL-4/5S6/7SvifS and report a mutation that improved the replicative capability of the virus. Unexpectedly, HIV-1 with this mutation became resistant to CM TRIM5α-mediated restriction.
Gene expression profiling in circulating endothelial cells from systemic sclerosis patients shows an altered control of apoptosis and angiogenesis that is modified by iloprost infusion
Authors: Tinazzi Elisa , Dolcino Marzia , Puccetti Antonio , Rigo Antonella , Beri Ruggero , Valenti Maria Teresa , Corrocher Roberto , Lunardi Claudio 
Published: July 2010

Abstract
Introduction
Circulating endothelial cells are increased in patients affected by systemic sclerosis (SSc) and their number strongly correlates with vascular damage. The effects of iloprost in systemic sclerosis are only partially known. We aimed at studying the gene expression profile of circulating endothelial cells and the effects of iloprost infusion and gene expression in patients with systemic sclerosis.

Methods
We enrolled 50 patients affected by systemic sclerosis, 37 patients without and 13 patients with digital ulcers. Blood samples were collected from all patients before and 72 hours after either a single day or five days eight hours iloprost infusion. Blood samples were also collected from 50 sex- and age-matched healthy controls. Circulating endothelial cells and endothelial progenitors cells were detected in the peripheral blood of patients with systemic sclerosis by flow cytometry with a four-colour panel of antibodies. Statistical analysis was performed with the SPSS 16 statistical package.Circulating endothelial cells were then isolated from peripheral blood by immunomagnetic CD45 negative selection for the gene array study.

Results
The number of both circulating endothelial cells and progenitors was significantly higher in patients affected by systemic sclerosis than in controls and among patients in those with digital ulcers than in patients without them. Circulating endothelial cells and progenitors number increased after iloprost infusion. Gene array analysis of endothelial cells showed a different transcriptional profile in patients compared to controls. Indeed, patients displayed an altered expression of genes involved in the control of apoptosis and angiogenesis. Iloprost infusion had a profound impact on endothelial cells gene expression since the treatment was able to modulate a very high number of transcripts.

Conclusions
We report here that circulating endothelial cells in patients with systemic sclerosis show an altered expression of genes involved in the control of apoptosis and angiogenesis. Moreover we describe that iloprost infusion has a strong effect on endothelial cells and progenitors since it is able to modulate both their number and their gene expression profile.
Citrullinated vimentin as an important antigen in immune complexes from synovial fluid of rheumatoid arthritis patients with antibodies against citrullinated proteins
Authors: Van Steendam Katleen , Tilleman Kelly , De Ceuleneer Marlies , De Keyser Filip , Elewaut Dirk , Deforce Dieter 
Published: July 2010

Abstract
Introduction
Rheumatoid arthritis (RA) is an inflammatory disease, which results in destruction of the joint. The presence of immune complexes (IC) in serum and synovial fluid of RA patients might contribute to this articular damage through different mechanisms, such as complement activation. Therefore, identification of the antigens from these IC is important to gain more insight into the pathogenesis of RA. Since RA patients have antibodies against citrullinated proteins (ACPA) in their serum and synovial fluid (SF) and since elevated levels of citrullinated proteins are detected in the joints of RA patients, citrullinated antigens are possibly present in IC from RA patients.

Methods
IC from serum of healthy persons, serum of RA patients and IC from synovial fluid of RA patients and Spondyloarthropathy (SpA) patients were isolated by immunoprecipitation. Identification of the antigens was performed by SDS-PAGE, mass spectrometry and immunodetection. The presence of citrullinated proteins was evaluated by anti-modified citrulline (AMC) staining.

Results
Circulating IC in the serum of RA patients and healthy controls contain fibrinogenβ and fibronectin, both in a non-citrullinated form. Additionally, in IC isolated from RA SF, fibrinogenγ and vimentin were identified as well. More importantly, vimentin and a minor portion of fibrinogenβ were found to be citrullinated in the isolated complexes. Moreover these citrullinated antigens were only found in ACPA+ patients. No citrullinated antigens were found in IC from SF of SpA patients.

Conclusions
Citrullinated fibrinogenβ and citrullinated vimentin were found in IC from SF of ACPA+ RA patients, while no citrullinated antigens were found in IC from SF of ACPA- RA patients or SpA patients or in IC from serum of RA patients or healthy volunteers. The identification of citrullinated vimentin as a prominent citrullinated antigen in IC from SF of ACPA+ RA patients strengthens the hypothesis that citrullinated vimentin plays an important role in the pathogenesis of RA.
Disclosing a Diagnosis of Cancer: Where and How Does It Occur?
Authors: Figg William D. , Smith Erika K. , Price Douglas K. , English Bevin C. , Thurman Paul W. , Steinberg Seth M. , Emanuel Ezekiel 
Published: July 2010

PurposeWhile disclosing a cancer diagnosis to a patient is common practice, how it is disclosed and the impact it has on the patient are poorly understood. We examined how cancer diagnoses were first given to patients and the impact of different aspects of disclosure on patient satisfaction.Patients and MethodsWe provided a self-administered questionnaire to a total of 460 oncology patients of the National Cancer Institute (NCI) being treated at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD.ResultsOf the 437 patients who completed the survey, 54% were told their diagnosis in-person in the physician's office, 18% by phone, and 28% in the hospital. Forty-four percent of patients reported discussions of 10 minutes or fewer, 53% reported discussions lasting longer than 10 minutes, and 5% could not remember. Treatment options were not discussed for 31% of those who could clearly remember. Higher mean satisfaction scores were associated with diagnoses revealed in person rather than over the phone (68.2 ± 1.6 v 47.2 ± 3.7), diagnoses revealed in a personal setting rather than an impersonal setting (68.9 ± 1.6 v 55.7 ± 2.8), discussions lasting longer than 10 minutes rather than fewer than 10 minutes (73.5 ± 1.9 v 54.1 ± 2.4), and inclusion of treatment options rather than exclusion (72.0 ± 1.9 v 50.7 ± 3.2; P < .001 for each aspect).ConclusionPhysicians should disclose a cancer diagnosis in a personal setting, discussing the diagnosis and treatment options for a substantial period of time whenever possible.
Pain and Emotional Well-Being Outcomes in Southwest Oncology Group–Directed Intergroup Trial S0205: A Phase III Study Comparing Gemcitabine Plus Cetuximab Versus Gemcitabine As First-Line Therapy in Patients With Advanced Pancreas Cancer
Authors: Moinpour Carol M. , Vaught Nancy L. , Goldman Bryan , Redman Mary W. , Philip Philip A. , Millwood Barbara , Lippman Scott M. , Seay Thomas E. , Flynn Patrick J. , O'Reilly Eileen M. , Rowland Kendrith M. , Wong Ralph P. , Benedetti Jacqueline , Blanke Charles D. 
Published: July 2010

Purpose S0205 was a randomized clinical trial that compared the therapeutic impact of gemcitabine versus gemcitabine plus cetuximab. Study results for patient-reported health-related quality of life (HRQL) outcomes are reported. Patients and Methods Patients completed the Brief Pain Inventory and a measure of emotional well-being (each measured on a 0 to 10 scale) at baseline and at weeks 5, 9, 13, and 17 postrandom assignment. Worst pain status was classified as palliated (worst pain scores < 5 maintained for 2 consecutive cycles) or not palliated (remaining patients) and tested with a χ2 test. Change in emotional well-being and worst pain (exploratory analysis) were assessed over 17 weeks using generalized estimating equations with inverse probability of censoring weights. Results Seven hundred twenty of 766 enrolled patients contributed baseline HRQL data. The two treatment arms did not differ statistically in the percentage of patients with successful worst pain palliation. Longitudinal analyses showed significantly improved emotional well-being for patients on both arms by weeks 13 and 17 (P < .01 and P < .001). An exploratory longitudinal analysis of worst pain showed significant decreases at all time points for both arms (P < .01 and P < .001). Significant treatment arm differences for either worst pain or emotional well-being were not observed at any of the assessment times. Conclusion We observed palliated pain and improved well-being for patients on this trial. However, these improvements were similar in both treatment arms, suggesting that the addition of cetuximab did not contribute to improvement in these HRQL outcomes.
T-Cell–Depleted Reduced-Intensity Transplantation Followed by Donor Leukocyte Infusions to Promote Graft-Versus-Lymphoma Activity Results in Excellent Long-Term Survival in Patients With Multiply Relapsed Follicular Lymphoma
Authors: Thomson Kirsty J. , Morris Emma C. , Milligan Don , Parker Anne N. , Hunter Ann E. , Cook Gordon , Bloor Adrian J.C. , Clark Fiona , Kazmi Majid , Linch David C. , Chakraverty Ronjon , Peggs Karl S. , Mackinnon Stephen 
Published: July 2010

Purpose Follicular lymphoma (FL) is an indolent disorder that is treatable but considered incurable with chemotherapy alone. The curative potential of allogeneic transplantation using conventional myeloablative conditioning has been demonstrated, but this approach is precluded in the majority of patients with FL because of excessive toxicity. Thus, reduced-intensity conditioning regimens are being explored. Patients and Methods This study reports the outcome of 82 consecutive patients with FL who underwent transplantation using fludarabine, melphalan, and alemtuzumab for in vivo T-cell depletion. Patients were heavily pretreated, having received a median of four lines of prior therapy, and 26% had experienced treatment failure with previous autologous transplantation. Median patient age was 45 years, and 52% of patients received stem cells from unrelated donors. Results With a median follow-up time of 43 months, the nonrelapse mortality was 15% at 4 years (8% for sibling and 22% for unrelated donor transplantations), acute grade 2 or 3 graft-versus-host disease (GVHD) occurred in 13%, and the incidence of extensive chronic GVHD was only 18%. Although relapse risk was 26%, this was significantly reduced where mixed chimerism had been converted to full donor chimerism by the use of donor lymphocyte infusion (DLI; P = .03). In addition, 10 (77%) of 13 patients given DLI for relapse after transplantation experienced remission, with nine of these responses being sustained. Current progression-free survival at 4 years was 76% for the whole cohort (90% for those with sibling donors and 64% for those with unrelated donors). Conclusion The excellent long-term survival with associated low rates of GVHD and the frequency and durability of DLI responses make this an extremely encouraging strategy for the treatment and potential cure of FL.
Somatic Mutations in BRCA1 and BRCA2 Could Expand the Number of Patients That Benefit From Poly (ADP Ribose) Polymerase Inhibitors in Ovarian Cancer
Authors: Hennessy Bryan T.J. , Timms Kirsten M. , Carey Mark S. , Gutin Alexander , Meyer Larissa A. , Flake Darl D. , Abkevich Victor , Potter Jennifer , Pruss Dmitry , Glenn Pat , Li Yang , Li Jie , Gonzalez-Angulo Ana Maria , McCune Karen Smith , Markman Maurie , Broaddus Russell R. , Lanchbury Jerry S. , Lu Karen H. , Mills Gordon B. 
Published: July 2010

Purpose The prevalence of BRCA½ mutations in germline DNA from unselected ovarian cancer patients is 11% to 15.3%. It is important to determine the frequency of somatic BRCA½ changes, given the sensitivity of BRCA-mutated cancers to poly (ADP ribose) polymerase-1 (PARP1) inhibitors and platinum analogs. Patients and Methods In 235 unselected ovarian cancers, BRCA½ was sequenced in 235, assessed by copy number analysis in 95, and tiling arrays in 65. 113 tumors were sequenced for TP53. BRCA½ transcript levels were assessed by quantitative polymerase chain reaction in 220. When available for tumors with BRCA½ mutations, germline DNA was sequenced. Results Forty-four mutations (19%) in BRCA1 (n = 31)/BRCA2 (n = 13) were detected, including one homozygous BRCA1 intragenic deletion. BRCA½ mutations were particularly common (23%) in high-grade serous cancers. In 28 patients with available germline DNA, nine (42.9%) of 21 and two (28.6%) of seven BRCA1 and BRCA2 mutations were demonstrated to be somatic, respectively. Five mutations not previously identified in germline DNA were more commonly somatic than germline (four of 11 v one of 17; P = .062). There was a positive association between BRCA1 and TP53 mutations (P = .012). BRCA½ mutations were associated with improved progression-free survival (PFS) after platinum-based chemotherapy in univariate (P = .032; hazard ratio [HR] = 0.65; 95% CI, 0.43 to 0.98) and multivariate (P = .019) analyses. BRCA½ deficiency, defined as BRCA½ mutations or expression loss (in 24 [13.3%] BRCA½–wild-type cancers), was present in 67 ovarian cancers (30%) and was also significantly associated with PFS in univariate (P = .026; HR = 0.67; 95% CI, 0.47 to 0.96) and multivariate (P = .008) analyses. Conclusion BRCA½ somatic and germline mutations and expression loss are sufficiently common in ovarian cancer to warrant assessment for prediction of benefit in clinical trials of PARP1 inhibitors.