bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes
Authors: Joffre Olivier , Gorsse Nathalie , Romagnoli Paola , Hudrisier Denis , van Meerwijk Joost P. M. 
Published: February 2004

AbstractThymus-derived regulatory T lymphocytes of CD4+CD25+ phenotype regulate a large variety of beneficial and deleterious immune responses and can inhibit lethal graft-versus-host disease in rodents. In vitro, CD4+CD25+ T cells require specific major histocompatibility complex (MHC)/peptide ligands for their activation, but once activated they act in an antigen-nonspecific manner. In vivo, regulatory T cells are also activated in an antigen-specific fashion, but nothing is known about antigen specificity of their suppressor-effector function. Here we show that CD4+CD25+ regulatory T lymphocytes isolated from naive mice and activated in vitro with allogeneic antigen-presenting cells (APCs) induced specific long-term tolerance to bone marrow grafts disparate for major and minor histocompatibility antigens; whereas “target” bone marrow was protected, third-party bone marrow was rejected. Importantly, in mice injected with a mix of target and third-party bone marrows, protection and rejection processes took place simultaneously. These results indicate that CD4+CD25+ regulatory T cells can act in an antigen-specific manner in vivo. Our results suggest that CD4+CD25+ regulatory T cells could in the future be used in clinical settings to induce specific immunosuppression. (Blood. 2004;103:4216-4221)
Combining Gene Expression Profiles and Clinical Parameters for Risk Stratification in Medulloblastomas
Authors: Fernandez-Teijeiro Ana , Betensky Rebecca A. , Sturla Lisa M. , Kim John Y.H. , Tamayo Pablo , Pomeroy Scott L. 
Published: February 2004

Purpose Stratification of risk in patients with medulloblastoma remains a challenge. As clinical parameters have been proven insufficient for accurately defining disease risk, molecular markers have become the focus of interest. Outcome predictions on the basis of microarray gene expression profiles have been the most accurate to date. We ask in a multivariate model whether clinical parameters enhance survival predictions of gene expression profiles. Patients and Methods In a cohort of 55 young patients (whose medulloblastoma samples have been analyzed previously for gene expression profile), associations between clinical and gene expression variables and survival were assessed using Cox proportional hazards models. Available clinical variables included age, stage (ie, the presence of disseminated disease at diagnosis), sex, histologic subtype, treatment, and status. Results Univariate analysis demonstrated expression profiles to be the only significant clinical prognostic factor (P = .03). In multivariate analysis, gene expression profiles predicted outcome independent of other criteria. Clinical criteria did not significantly contribute additional information for outcome predictions, although an exploratory analysis noted a trend for decreased survival of patients with metastases at diagnosis but favorable gene expression profile. Conclusion Gene expression profiling predicts medulloblastoma outcome independent of clinical variables. These results need to be validated in a larger prospective study.
Trastuzumab in the Treatment of Advanced Non-Small-Cell Lung Cancer: Is There a Role? Focus on Eastern Cooperative Oncology Group Study 2598
Authors: Langer Corey J. , Stephenson Patricia , Thor Ann , Vangel Mark , Johnson David H. 
Published: February 2004

Purpose Multiple non–small-cell lung cancer (NSCLC) cell lines and 20% to 50% of pathologic specimens express HER-2/neu, the target of trastuzumab, and HER-2/neu expression has proven to be an independent, unfavorable prognostic factor in resected patients with NSCLC. Trastuzumab, in vitro, has demonstrated growth-inhibiting synergy with platinating agents, and additivity with paclitaxel. The Eastern Cooperative Oncology Group therefore launched a phase II study evaluating combination carboplatin, paclitaxel, and trastuzumab in patients with advanced NSCLC. Materials and Methods Eligibility stipulated the following: measurable tumor, HER-2/neu positivity (1+ to 3+ by Herceptest [Dako Corp, Carpinteria, CA], confirmed by central review), Eastern Cooperative Oncology Group PS 0 to 1, adequate marrow, hepatic and renal function, and left ventricular ejection fraction ≥ 45%. Patients received paclitaxel 225 mg/m2/3 hours, and carboplatin (area under the curve, 6) every 3 weeks, and trastuzumab 4 mg/kg intravenously on day 1, then 2 mg/kg weekly for ≤ 1 year. Results Between August 1999 and May 2000, 139 patients were screened; seven specimens (5%) were indeterminate. Fifty patients (36%) were HER-2/neu negative, 38 (27%) were HER-2/neu 1+, 31 (22%) were 2+, and 13 (9%) were 3+. Fifty-six patients were enrolled; 53 were eligible (22 [42%] were 1+, 23 (43%) were 2+, and eight (15%) were 3+). Thirteen (24.5%) of 52 assessable patients (95% CI, 13.8 to 38.3) responded. The incidence of grade ≥ 3 neutropenia and thrombocytopenia was 57% (34%) and 16% (2%), respectively. Asymptomatic grade ≤ 2 reduction in left ventricular ejection fraction occurred in 7%. Other nonhematologic toxicities, including nausea, fatigue, arthralgias, and peripheral sensory neuropathy, were mild to moderate and matched those expected with carboplatin and paclitaxel alone. Eighteen patients (35%) received maintenance trastuzumab. Median progression-free survival was 3.3 months; median survival was 10.1 months, and 1-year survival rate was 42%. Conclusion Combination paclitaxel, carboplatin, and trastuzumab is feasible. Toxicity appears no worse than cytotoxic therapy alone. Overall survival is similar to historical data using carboplatin and paclitaxel alone. However, patients with 3+ HER-2/neu expression did well in contrast to historical data suggesting potential benefit for trastuzumab in this rare subset of NSCLC. Critical assessment of trastuzumab's role in advanced NSCLC will require phase III trials.
Bilateral Prophylactic Mastectomy Reduces Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group
Authors: Rebbeck Timothy R. , Friebel Tara , Lynch Henry T. , Neuhausen Susan L. , van ’t Veer Laura , Garber Judy E. , Evans Gareth R. , Narod Steven A. , Isaacs Claudine , Matloff Ellen , Daly Mary B. , Olopade Olufunmilayo I. , Weber Barbara L. 
Published: February 2004

Purpose Data on the efficacy of bilateral prophylactic mastectomy for breast cancer risk reduction in women with BRCA1 and BRCA2 (BRCA1/2) mutations are limited, despite the clinical use of this risk-management strategy. Thus, we estimated the degree of breast cancer risk reduction after surgery in women who carry these mutations. Patients and Methods Four hundred eighty-three women with disease-associated germline BRCA1/2 mutations were studied for the occurrence of breast cancer. Cases were mutation carriers who underwent bilateral prophylactic mastectomy and who were followed prospectively from the time of their center ascertainment and their surgery, with analyses performed for both follow-up periods. Controls were BRCA1/2 mutation carriers with no history of bilateral prophylactic mastectomy matched to cases on gene, center, and year of birth. Both cases and controls were excluded for previous or concurrent diagnosis of breast cancer. Analyses were adjusted for duration of endogenous ovarian hormone exposure, including age at bilateral prophylactic oophorectomy if applicable. Results Breast cancer was diagnosed in two (1.9%) of 105 women who had bilateral prophylactic mastectomy and in 184 (48.7%) of 378 matched controls who did not have the procedure, with a mean follow-up of 6.4 years. Bilateral prophylactic mastectomy reduced the risk of breast cancer by approximately 95% in women with prior or concurrent bilateral prophylactic oophorectomy and by approximately 90% in women with intact ovaries. Conclusion Bilateral prophylactic mastectomy reduces the risk of breast cancer in women with BRCA1/2 mutations by approximately 90%.
Clinical, Histopathologic, and Molecular Markers of Prognosis: Toward a New Disease Risk Stratification System for Medulloblastoma
Authors: Gajjar Amar , Hernan Roberto , Kocak Mehmet , Fuller Christine , Lee Youngsoo , McKinnon Peter J. , Wallace Dana , Lau Ching , Chintagumpala Murali , Ashley David M. , Kellie Stewart J. , Kun Larry , Gilbertson Richard J. 
Published: February 2004

Purpose To assess the feasibility of performing central molecular analyses of fresh medulloblastomas obtained from multiple institutions and using these data to identify prognostic markers for contemporaneously treated patients. Materials and Methods Ninety-seven samples of medulloblastoma were collected. Tumor content in samples was judged by frozen section review. Tumor ERBB2 protein and MYCC, MYCN, and TRKC mRNA levels were measured blind to clinical details using Western blotting and real-time polymerase chain reaction, respectively. Histopathologic and clinical review of each case was also performed. All data were subjected to independent statistical analysis. Results Sample acquisition and analysis times ranged from 3 to 6 days. Eighty-six samples contained sufficient tumor for analysis, including 38 classic, 30 nodular desmoplastic, and 18 large-cell anaplastic (LCA) medulloblastomas. Protein and mRNA were extracted from 81 and 49 tumors, respectively. ERBB2 was detected in 40% (n = 32 of 81) of tumors, most frequently in LCA disease (P = .005), and was independently associated with a poor prognosis (P = .031). A combination of clinical characteristics and ERBB2 expression provided a highly accurate means of discriminating disease risk. One hundred percent (n = 26) of children with clinical average-risk, ERBB2-negative disease were alive at 5 years, with a median follow-up of 5.6 years, compared with only 54% for children with average-risk, ERBB2-positive tumors (n = 13; P = .0001). TRKC, MYCC, and MYCN expression and histopathologic subtype were not associated with prognosis in this study. Conclusion Central and rapid molecular analysis of frozen medulloblastomas collected from multiple institutions is feasible. ERBB2 expression and clinical risk factors together constitute a highly accurate disease risk stratification tool.
Transactivation of the Insulin-Like Growth Factor-I Receptor by Angiotensin II Mediates Downstream Signaling from the Angiotensin II Type 1 Receptor to Phosphatidylinositol 3-Kinase
Authors: Zahradka Peter , Litchie Brenda , Storie Ben , Helwer Gail 
Published: February 2004

AbstractAngiotensin II (AngII) activates phosphatidylinositol 3-kinase (PI3-kinase), a known effector of receptor tyrosine kinases. Treatment of smooth muscle cells with AngII has also been shown to promote phosphorylation of various tyrosine kinase receptors. We therefore investigated the relationship between AngII and IGF-I receptor activation in smooth muscle cells with a phosphorylation-specific antibody. Our experiments showed that IGF-I receptor phosphorylation was maximally stimulated within 10 min by AngII. Inclusion of an IGF-I-neutralizing antibody in the culture media did not prevent IGF-I receptor phosphorylation after AngII treatment, which argues that a paracrine/autocrine loop is not required. Furthermore, this process was blocked by losartan and 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP-1), indicating stimulation of IGF-I receptor phosphorylation occurs via AngII type 1 receptor-dependent activation of Src kinase. The functional significance of IGF-I receptor transactivation was examined with selective inhibitors of the IGF-I receptor kinase (AG1024, AG538). When AngII-treated cells were incubated with AG1024 or AG538, phosphorylation of the regulatory p85 subunit of PI3-kinase was blocked. Furthermore, phosphorylation of the downstream factor p70S6K did not occur. In contrast, AG1024 did not prevent MAPK or Src kinase activation by AngII. AG1024 also did not inhibit AngII-dependent cell migration, although this process was blocked by inhibitors of the epidermal growth factor and platelet-derived growth factor receptors. Transactivation of the IGF-I receptor is therefore a critical mediator of PI3-kinase activation by AngII but is not required for stimulation of the MAPK cascade.
Bapx1 regulates patterning in the middle ear: altered regulatory role in the transition from the proximal jaw during vertebrate evolution
Authors: Tucker Abigail S. , Watson Robert P. , Lettice Laura A. , Yamada Gen , Hill Robert E. 
Published: February 2004

The middle ear apparatus is composed of three endochondrial ossicles (the stapes, incus and malleus) and two membranous bones, the tympanic ring and the gonium, which act as structural components to anchor the ossicles to the skull. Except for the stapes, these skeletal elements are unique to mammals and are derived from the first and second branchial arches. We show that, in combination with goosecoid (Gsc), the Bapx1 gene defines the structural components of the murine middle ear.During embryogenesis, Bapx1 is expressed in a discrete domain within the mandibular component of the first branchial arch and later in the primordia of middle ear-associated bones, the gonium and tympanic ring. Consistent with the expression pattern of Bapx1, mouse embryos deficient for Bapx1 lack a gonium and display hypoplasia of the anterior end of the tympanic ring. At E10.5, expression of Bapx1partially overlaps that of Gsc and although Gsc is required for development of the entire tympanic ring, the role of Bapx1 is restricted to the specification of the gonium and the anterior tympanic ring. Thus, simple overlapping expression of these two genes appears to account for the patterning of the elements that compose the structural components of the middle ear and suggests that they act in concert.In addition, Bapx1 is expressed both within and surrounding the incus and the malleus. Examination of the malleus shows that the width, but not the length, of this ossicle is decreased in the mutant mice. In non-mammalian jawed vertebrates, the bones homologous to the mammalian middle ear ossicles compose the proximal jaw bones that form the jaw articulation(primary jaw joint). In fish, Bapx1 is responsible for the formation of the joint between the quadrate and articular (homologues of the malleus and incus, respectively) enabling an evolutionary comparison of the role of a regulatory gene in the transition of the proximal jawbones to middle ear ossicles. Contrary to expectations, murine Bapx1 does not affect the articulation of the malleus and incus. We show that this change in role of Bapx1 following the transition to the mammalian ossicle configuration is not due to a change in expression pattern but results from an inability to regulate Gdf5 and Gdf6, two genes predicted to be essential in joint formation.
Two-Dimensional Mapping of Copper and Zinc in Liver Sections by Laser Ablation–Inductively Coupled Plasma Mass Spectrometry
Authors: Kindness Andrew , Sekaran Chandra N , Feldmann Jörg 
Published: February 2004

AbstractBackground: Metals are not homogeneously distributed in organ tissues. Although most mapping techniques, such as histologic staining methods, have been developed for element imaging on a subcellular level, many suffer from either low precision or poor detection limits. Therefore, small variations in elemental distribution cannot be identified. We developed a method for two-dimensional mapping of trace elements to identify the influence of metabolic zonation by the liver on trace element distribution.Methods: A prepared homogeneous Certified Reference Material (CRM; LGC 7112, pig liver) was used to characterize the laser ablation–inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-MS) in terms of precision. Different isotopes for copper and zinc were monitored, and the use of carbon as an internal standard was investigated to correct for differences in ablation efficiency to identify the most precise mapping technique for liver samples.Results: For the homogeneous CRM, the reproducibility of the copper and zinc signals was ∼3–24% depending on spot size and number of pulses. When carbon was used as an internal standard, the reproducibility was improved significantly. Line scan signals over a length of 1.5 mm were more precise [relative SD (RSD), 1.6–6.1% for copper (63Cu, 65Cu) and zinc (64Zn, 66Zn) depending on the spot size, the scanning speed, and the element]. Thin section of sheep liver achieved precisions of 27–59% (raster scan) and 9–47% (line scan) RSD for copper, whereas the precision for zinc was significantly better: 8–18% (raster scan) and 4–21% (line scan) RSD. Long line scans and two-dimensional element maps of the thin sections revealed the zonation of copper in sheep liver containing extremely low copper concentrations.Conclusion: Elemental mapping of trace elements generated by LA-ICP-MS can be very precise so that small changes in the elemental concentration in the tissue can be detected and nonuniform spatial distribution of the elements in tissues can be established.
Apolipoprotein C-III Isofocusing in the Diagnosis of Genetic Defects in O-Glycan Biosynthesis
Authors: Wopereis Suzan , Grünewald Stephanie , Morava Éva , Penzien Johannes M , Briones Paz , Garcı́a-Silva M Teresa , Demacker Pierre N M , Huijben Karin M L C , Wevers Ron A 
Published: February 2004

AbstractBackground: Defects in the biosynthesis of N-glycans may be found by isoelectric focusing (IEF) of plasma transferrin. No test is available to demonstrate O-glycan biosynthesis defects.Methods: We used isoforms of apolipoprotein C-III (apoC-III) as a marker for the biosynthesis of core 1 mucin type O-glycans. Plasma samples from patients with primary defects and secondary alterations in N-glycan biosynthesis were studied by apoC-III isofocusing.Results: Age-related reference values for apoC-III were determined. Plasma samples from patients with the primary congenital disorders of glycosylation (CDG) types Ia–Ic, Ie, If, IIa, and IId all showed a normal apoC-III isofocusing profile. Plasma from two patients with CDG type IIx were tested: one showed a normal apoC-III distribution, whereas the other showed a hypoglycosylation profile. In plasma from patients with hemolytic uremic syndrome (HUS), a hypoglycosylation profile was obtained.Conclusions: IEF of apoC-III is a rapid and simple technique that may be used as a screening assay for abnormalities in core 1 mucin type O-glycans. Evidence that a patient in this study has a primary genetic defect affecting both N- and O-glycosylation provides the first example of an inborn error of metabolism affecting the biosynthesis of core 1 mucin type O-glycans. Our data narrow the options for the position of the primary defect in this patient down to a step in the biosynthesis, activation, or transfer of galactose or N-acetylneuraminic acid to both N- and O-glycans. Circulating neuraminidase excreted by Streptococcus pneumoniae caused the high percentage of asialo apoC-III in two HUS patients.
Rapid Separation of LDL Subclasses by Iodixanol Gradient Ultracentrifugation
Authors: Davies Ian G , Graham John M , Griffin Bruce A 
Published: February 2004

AbstractBackground: A predominance of small, dense LDL (sdLDL) confers in excess of a threefold increase in coronary heart disease (CHD) risk. The conventional method for the detection of sdLDL, salt density gradient ultracentrifugation (DGUC) has been superseded by more rapid techniques. This report presents novel methodology for the separation of sdLDL by a combination of iodixanol density gradient centrifugation and digital photography.Methods: LDL subclasses were separated in 3 h from prestained plasma on a self-forming density gradient of iodixanol. LDL subclass profiles were generated by digital photography and gel-scan software. Plasma samples from 106 normo- and dyslipidemic individuals were used to optimize the gradient for the resolution of LDL heterogeneity. A subgroup of 47 LDL profiles were then compared with LDL subclasses separated by salt DGUC.Results: The peak density of the predominant LDL band correlated significantly with the relative abundance (as a percentage) of sdLDL as resolved by salt DGUC (P &lt;0.001). As shown previously, LDL isolated at a lighter density in iodixanol compared with salt gradients. A predominance of sdLDL corresponded to a peak density on iodixanol of 1.028 kg/L. This density and the area under the LDL profile lying above this density were sensitive and specific markers for the prediction of a predominance of sdLDL (P &lt;0.001) and showed predictable associations with plasma triglycerides (r = 0.59; P &lt;0.001) and HDL (r = −0.4; P &lt;0.001).Conclusions: This simple method for the detection of sdLDL can differentiate a predominance of sdLDL, is highly reproducible, and can be used preparatively to isolate sdLDL.
Sensitive HPLC-Fluorescence Method for Irinotecan and Four Major Metabolites in Human Plasma and Saliva: Application to Pharmacokinetic Studies
Authors: Poujol Sylvain , Pinguet Frédéric , Malosse Françoise , Astre Cécile , Ychou Marc , Culine Stéphane , Bressolle Françoise 
Published: February 2004

AbstractBackground: We developed gradient HPLC methods for quantification of the antimitotic drug irinotecan (CPT-11) and its four metabolites, SN-38, SN-38 G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC), and 7-ethyl-10-[4amino-1-piperidino]-carbonyloxycamptothecin (NPC), as the sum of the lactone and carboxylate forms, in human plasma and saliva. Camptothecin was used as internal standard.Methods: The sample pretreatment involved protein precipitation with methanol–acetonitrile (50:50 by volume) followed by acidification with hydrochloric acid to convert the lactone ring-opened form into its lactone form, quantitatively. HPLC separation was performed on a Xterra RP18 column. The excitation wavelength was 370 nm, and the emission wavelength was set at 470 nm for the first 24 min and then at 534 nm for the next 4 min. The stabilities of irinotecan and its four metabolites in plasma, saliva, and acidic extracts were also investigated under various conditions.Results: Assays were linear in the tested range of 0.5–1000 μg/L. For the five analytes, limits of quantification were 0.5 μg/L in both matrices. The interassay imprecision (as relative standard deviation) was 3.2–14% in plasma and 2.6–5.6% in saliva. Assay recoveries ranged from 92.8% to 111.2% for plasma and 100.1% to 104.1% for saliva. Mean extraction recovery from plasma or saliva was 90%.Conclusion: The developed assay can be used to determine pharmacokinetic parameters for CPT-11, SN-38, SN-38 G, APC, and NPC in plasma and saliva from patients with metastatic colorectal cancer.