bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of autoreactive CD4 T cells using major histocompatibility complex class II dextramers
Authors: Massilamany Chandirasegaran , Upadhyaya Bijaya , Gangaplara Arunakumar , Kuszynski Charles , Reddy Jay 
Published: July 2011

AbstractBackgroundTetramers are useful tools to enumerate the frequencies of antigen-specific T cells. However, unlike CD8 T cells, CD4 T cells - especially self-reactive cells - are challenging to detect with major histocompatibility complex (MHC) class II tetramers because of low frequencies and low affinities of their T cell receptors to MHC-peptide complexes. Here, we report the use of fluorescent multimers, designated MHC dextramers that contain a large number of peptide-MHC complexes per reagent.ResultsThe utility of MHC dextramers was evaluated in three autoimmune disease models: 1) proteolipid protein (PLP) 139-151-induced experimental autoimmune encephalomyelitis in SJL/J (H-2s) mice; 2) myelin oligodendrocyte glycoprotein (MOG) 35-55-induced experimental autoimmune encephalomyelitis in C57Bl/6 (H-2b) mice; and 3) cardiac myosin heavy chain (Myhc)-α 334-352-induced experimental autoimmune myocarditis in A/J (H-2a) mice. Flow cytometrically, we demonstrate that IAs/PLP 139-151, IAb/MOG 35-55 and IAk/Myhc-α 334-352 dextramers detect the antigen-sensitized cells with specificity, and with a detection sensitivity significantly higher than that achieved with conventional tetramers. Furthermore, we show that binding of dextramers, but not tetramers, is less dependent on the activation status of cells, permitting enumeration of antigen-specific cellsex vivo.ConclusionsThe data suggest that MHC dextramers are useful tools to track the generation and functionalities of self-reactive CD4 cells in various experimental systems.
The prevalence, incidence and natural history of primary sclerosing cholangitis in an ethnically diverse population
Authors: Toy Elaine , Balasubramanian Sripriya , Selmi Carlo , Li Chin-Shang , Bowlus Christopher L 
Published: July 2011

Abstract

Background
Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease often associated with inflammatory bowel diseases (IBD). Current epidemiological data are limited to studies of predominantly Caucasian populations. Our aim was to define the epidemiology of PSC in a large, ethnically diverse US population.

Methods
The Northern California Kaiser Permanente (KP) database includes records from over 3 million people and was searched for cases of PSC between January 2000 and October 2006. All identified charts were reviewed for diagnosis confirmation, IBD co-morbidity, and major natural history endpoints.

Results
We identified 169 (101 males) cases fulfilling PSC diagnostic criteria with a mean age at diagnosis of 44 years (range 11-81). The age-adjusted point prevalence was 4.15 per 100,000 on December 31, 2005. The age-adjusted incidence per 100,000 person-years was not significantly greater in men 0.45 (95% CI 0.33 - 0.61) than women 0.37 (95% CI 0.26 - 0.51). IBD was present in 109/169 (64.5%) cases and was significantly more frequent in men than women with PSC (73.3% and 51.5%, respectively, p = 0.005). The cumulative average yearly mortality rate was 1.9%. Age and serum sodium, creatinine and bilirubin at diagnosis and albumin at last entry were identified as significant factors associated with death, liver transplant or cholangiocarcinoma.

Conclusions
The incidence and prevalence of PSC observed in a representative Northern California population are lower compared to previous studies in Caucasian populations and this might reflect differences in the incidence of PSC among various ethnic groups.
Brain-derived neurotrophic factor expression predicts adverse pathological & clinical outcomes in human breast cancer
Authors: Patani Neill , Jiang Wen G , Mokbel Kefah 
Published: July 2011

AbstractIntroductionBrain-derived neurotrophic factor (BDNF) has established physiological roles in the development and function of the vertebrate nervous system. BDNF has also been implicated in several human malignancies, including breast cancer (BC). However, the precise biological role of BDNF and its utility as a novel biomarker have yet to be determined. The objective of this study was to determine the mRNA and protein expression of BDNF in a cohort of women with BC. Expression levels were compared with normal background tissues and evaluated against established pathological parameters and clinical outcome over a 10 year follow-up period.MethodsBC tissues (n = 127) and normal tissues (n = 33) underwent RNA extraction and reverse transcription, BDNF transcript levels were determined using real-time quantitative PCR. BDNF protein expression in mammary tissues was assessed with standard immuno-histochemical methodology. Expression levels were analyzed against tumour size, grade, nodal involvement, TNM stage, Nottingham Prognostic Index (NPI) and clinical outcome over a 10 year follow-up period.ResultsImmuno-histochemical staining revealed substantially greater BDNF expression within neoplastic cells, compared to normal mammary epithelial cells. Significantly higher mRNA transcript levels were found in the BC specimens compared to background tissues (p = 0.007). The expression of BDNF mRNA was demonstrated to increase with increasing NPI; NPI-1 vs. NPI-2 (p = 0.009). Increased BDNF transcript levels were found to be significantly associated with nodal positivity (p = 0.047). Compared to patients who remained disease free, higher BDNF expression was significantly associated with local recurrence (LR) (p = 0.0014), death from BC (p = 0.018) and poor prognosis overall (p = 0.013). After a median follow up of 10 years, higher BDNF expression levels were significantly associated with reduced overall survival (OS) (106 vs. 136 months, p = 0.006). BDNF emerged as an independent prognostic variable in multivariate analysis for disease free survival (DFS) (p = 0.026) and approached significance for OS (p = 0.055).ConclusionBDNF expression was found to be significantly higher in BC specimens compared to normal tissue. Higher transcript levels were significantly associated with unfavourable pathological parameters including nodal positivity and increasing NPI; and adverse clinical outcomes including LR, death from BC, poor prognosis, reduced DFS and OS. BDNF offers utility as a prognostic marker and potential for targeted therapeutic strategies.
The assessment of quality of life in acute cough with the Leicester Cough Questionnaire (LCQ-acute)
Authors: Yousaf Nadia , Lee Kai K , Jayaraman Bhagyashree , Pavord Ian D , Birring Surinder S 
Published: July 2011

Abstract

Introduction
Acute cough has a significant impact on physical and psychosocial health and is associated with an impaired quality of life (QOL). The Leicester Cough Questionnaire (LCQ) is a validated cough-related health status questionnaire designed for patients with chronic cough. The purpose of this study was to validate the LCQ for the assessment of health related QOL in patients with acute cough and determine the clinical minimal important difference (MID).

Methods
10 subjects with cough due to acute upper respiratory tract infection underwent focused interviews to investigate the face validity of the LCQ. The LCQ was also evaluated by a multidisciplinary team. 30 subjects completed the revised LCQ-acute and a cough visual analogue score (VAS: 0-100 mm) within one week of onset of cough and again <2 weeks later and at resolution of cough. The concurrent validity, internal reliability, repeatability and responsiveness of the LCQ-acute were also assessed. Patients also completed a Global Rating of Change Questionnaire that assessed the change in cough severity between visits. The MID was calculated as the change in LCQ-acute score for patients responding to GRCQ category representing the smallest change in health status that patients found worthwhile.

Results
Health status was severely impaired at baseline affecting all domains; median (interquartile range) total LCQ-acute score 13.0 (3.4). All subjects found the LCQ-acute questionnaire acceptable for assessing their cough. Internal reliability of the LCQ-acute was good for all domains and total score, Cronbach's α coefficients >0.9. There was a significant correlation between LCQ-acute and VAS (ρ = -0.48, p = 0.007). The LCQ-acute and its domains were highly responsive to change; effect sizes 1.7-2.3. The MID for total LCQ and VAS were 2.5 and 13 mm respectively.

Conclusion
The LCQ-acute is a brief, simple and valid instrument to assess cough specific health related QOL in patients with acute cough. It is a highly responsive tool suggesting that it will be particularly useful to assess the effect of antitussive therapy.
Population genetics of Glossina palpalis palpalis from central African sleeping sickness foci
Authors: Melachio Trésor Tito Tanekou/TT , Simo Gustave , Ravel Sophie , De Meeûs Thierry , Causse Sandrine , Solano Philippe , Lutumba Pascal , Asonganyi Tazoacha , Njiokou Flobert 
Published: July 2011

Abstract

Background

Glossina palpalis palpalis (Diptera: Glossinidae) is widespread in west Africa, and is the main vector of sleeping sickness in Cameroon as well as in the Bas Congo Province of the Democratic Republic of Congo. However, little is known on the structure of its populations. We investigated G. p. palpalis population genetic structure in five sleeping sickness foci (four in Cameroon, one in Democratic Republic of Congo) using eight microsatellite DNA markers.

Results
A strong isolation by distance explains most of the population structure observed in our sampling sites of Cameroon and DRC. The populations here are composed of panmictic subpopulations occupying fairly wide zones with a very strong isolation by distance. Effective population sizes are probably between 20 and 300 individuals and if we assume densities between 120 and 2000 individuals per km2, dispersal distance between reproducing adults and their parents extends between 60 and 300 meters.

Conclusions
This first investigation of population genetic structure of G. p. palpalis in Central Africa has evidenced random mating subpopulations over fairly large areas and is thus at variance with that found in West African populations of G. p. palpalis. This study brings new information on the isolation by distance at a macrogeographic scale which in turn brings useful information on how to organise regional tsetse control. Future investigations should be directed at temporal sampling to have more accurate measures of demographic parameters in order to help vector control decision.
Complete Surgical Resection Is Curative for Children With Hepatoblastoma With Pure Fetal Histology: A Report From the Children's Oncology Group
Authors: Malogolowkin Marcio H. , Katzenstein Howard M. , Meyers Rebecka L. , Krailo Mark D. , Rowland Jon M. , Haas Joel , Finegold Milton J. 
Published: July 2011

Purpose Children with pure fetal histology (PFH) hepatoblastoma treated with complete surgical resection and minimal adjuvant therapy have been shown to have excellent outcomes when compared with other patients with hepatoblastoma. We prospectively studied the safety and efficacy of reducing therapy in all children with stage I PFH enrolled onto two consecutive studies. Patients and Methods From August 1989 to December 1992, 9 children with stage I PFH were treated on the Intergroup Hepatoblastoma study INT-0098 and were nonrandomly assigned to receive chemotherapy after surgical resection with single-agent bolus doxorubicin for 3 consecutive days. From March 1999 to November 2006, 16 children with stage I PFH enrolled onto Children's Oncology Group Study P9645 were treated with observation after resection. Central confirmation of the histologic diagnosis by a study group pathologist was mandated. The extent of liver disease was assigned retrospectively according to the pretreatment extent of disease (PRETEXT) system and is designated “retro-PRETEXT” to clarify the retrospective group assignment. Results Five-year event-free and overall survival for the 9 patients treated on INT-0098 were 100%. All 16 patients enrolled onto the P9645 study were alive and free of disease at the time of last contact, with a median follow-up of 4.9 years. Retro-PRETEXT for the 21 patients with available data revealed seven patients with stage I disease, 10 patients with stage II disease, and four patients with stage III disease. Conclusion Children with completely resected PFH hepatoblastoma can achieve long-term survival without additional chemotherapy. When feasible, surgical resection of hepatoblastoma at diagnosis, without chemotherapy, can identify children for whom no additional therapy is necessary.
Health-Related Quality of Life During the 10 Years After Diagnosis of Colorectal Cancer: A Population-Based Study
Authors: Jansen Lina , Herrmann Antje , Stegmaier Christa , Singer Susanne , Brenner Hermann , Arndt Volker 
Published: July 2011

Purpose To compare long-term quality of life (QoL) of colorectal cancer survivors with QoL in the general population and investigate changes in QoL of survivors during the 10 years after diagnosis. Patients and Methods Health-related QoL was assessed 1, 3, 5, and 10 years after diagnosis in a population-based cohort starting with 439 patients with colorectal cancer from Saarland, Germany, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. QoL after 5 and 10 years and time course of QoL during the 10 years after diagnosis were compared with controls from the general population of Germany, after controlling for sex and age. Results Overall, 234 and 196 patients were still alive after 5 and 10 years, respectively. Of these survivors, 178 (76%) responded in the 5-year follow-up, 133 (68%) in the 10-year follow-up, and 117 (60%) participated in all follow-ups. Over the entire follow-up, younger survivors (age at diagnosis, < 60 years) reported restrictions in role, social, emotional, and cognitive functioning and specific problems like constipation, diarrhea, fatigue, and insomnia. Older survivors (age at diagnosis, ≥ 70 years) reported comparable or even better QoL than controls within the first 3 to 5 years after diagnosis and comparable to worse QoL 5 to 10 years after diagnosis. Conclusion Although younger survivors continuously reported detriments in various QoL dimensions during the 10-year period after diagnosis, detriments in older survivors became apparent in the long run only.
Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study
Authors: Irvin William J. , Walko Christine M. , Weck Karen E. , Ibrahim Joseph G. , Chiu Wing K. , Dees E. Claire , Moore Susan G. , Olajide Oludamilola A. , Graham Mark L. , Canale Sean T. , Raab Rachel E. , Corso Steven W. , Peppercorn Jeffrey M. , Anderson Steven M. , Friedman Kenneth J. , Ogburn Evan T. , Desta Zeruesenay , Flockhart David A. , McLeod Howard L. , Evans James P. , Carey Lisa A. 
Published: July 2011

Purpose We examined the feasibility of using CYP2D6 genotyping to determine optimal tamoxifen dose and investigated whether the key active tamoxifen metabolite, endoxifen, could be increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism. Patients and Methods One hundred nineteen patients on tamoxifen 20 mg daily ≥ 4 months and not on any strong CYP2D6 inhibiting medications were assayed for CYP2D6 genotype and plasma tamoxifen metabolite concentrations. Patients found to be CYP2D6 extensive metabolizers (EM) remained on 20 mg and those found to be intermediate (IM) or poor (PM) metabolizers were increased to 40 mg daily. Eighty-nine evaluable patients had tamoxifen metabolite measurements repeated 4 months later. Results As expected, the median baseline endoxifen concentration was higher in EM (34.3 ng/mL) compared with either IM (18.5 ng/mL; P = .0045) or PM (4.2 ng/mL; P < .001). When the dose was increased from 20 mg to 40 mg in IM and PM patients, the endoxifen concentration rose significantly; in IM there was a median intrapatient change from baseline of +7.6 ng/mL (−0.6 to 23.9; P < .001), and in PM there was a change of +6.1 ng/mL (2.6 to 12.5; P = .020). After the dose increase, there was no longer a significant difference in endoxifen concentrations between EM and IM patients (P = .84); however, the PM endoxifen concentration was still significantly lower. Conclusion This study demonstrates the feasibility of genotype-driven tamoxifen dosing and demonstrates that doubling the tamoxifen dose can increase endoxifen concentrations in IM and PM patients.
High-Dose Chemotherapy With Autologous Stem-Cell Support As Adjuvant Therapy in Breast Cancer: Overview of 15 Randomized Trials
Authors: Berry Donald A. , Ueno Naoto T. , Johnson Marcella M. , Lei Xiudong , Caputo Jean , Rodenhuis Sjoerd , Peters William P. , Leonard Robert C. , Barlow William E. , Tallman Martin S. , Bergh Jonas , Nitz Ulrike A. , Gianni Alessandro M. , Basser Russell L. , Zander Axel R. , Coombes R. Charles , Roché Henri , Tokuda Yutaka , de Vries Elisabeth G.E. , Hortobagyi Gabriel N. , Crown John P. , Pedrazzoli Paolo , Bregni Marco , Demirer Taner 
Published: July 2011

PurposeAdjuvant high-dose chemotherapy (HDC) with autologous hematopoietic stem-cell transplantation (AHST) for high-risk primary breast cancer has not been shown to prolong survival. Individual trials have had limited power to show overall benefit or benefits within subsets.MethodsWe assembled individual patient data from 15 randomized trials that compared HDC versus control therapy without stem-cell support. Prospectively defined primary end points were relapse-free survival (RFS) and overall survival (OS). We compared the effect of HDC versus control by using log-rank tests and proportional hazards regression, and we adjusted for clinically relevant covariates. Subset analyses were by age, number of positive lymph nodes, tumor size, histology, hormone receptor (HmR) status, and human epidermal growth factor receptor 2 (HER2) status.ResultsOf 6,210 total patients (n = 3,118, HDC; n = 3,092 control), the median age was 46 years; 69% were premenopausal, 29% were postmenopausal, and 2% were unknown menopausal status; 49.5% were HmR positive; 33.5% were HmR negative, and 17% were unknown HmR status. The median follow-up was 6 years. After analysis was adjusted for covariates, HDC was found to prolong relapse-free survival (RFS; hazard ratio [HR], 0.87; 95% CI, 0.81 to 0.93; P < .001) but not overall survival (OS; HR, 0.94; 95% CI, 0.87 to 1.02; P = .13). For OS, no covariates had statistically significant interactions with treatment effect, and no subsets evinced a significant effect of HDC. Younger patients had a significantly better RFS on HDC than did older patients.ConclusionAdjuvant HDC with AHST prolonged RFS in high-risk primary breast cancer compared with control, but this did not translate into a significant OS benefit. Whether HDC benefits patients in the context of targeted therapies is unknown.
Randomized, Phase III Trial of Sequential Epirubicin and Docetaxel Versus Epirubicin Alone in Postmenopausal Patients With Node-Positive Breast Cancer
Authors: Coombes R. Charles , Bliss Judith M. , Espie Marc , Erdkamp Frans , Wals Jacob , Tres Alejandro , Marty Michel , Coleman Robert E. , Tubiana-Mathieu Nicole , den Boer Marinus O. , Wardley Andrew , Kilburn Lucy S. , Cooper Derek , Thomas Marina W.K. , Reise Justine A. , Wilkinson Katie , Hupperets Pierre 
Published: July 2011

Purpose The Docetaxel Epirubicin Adjuvant (DEVA) trial evaluated the efficacy and toxicity of incorporating docetaxel after epirubicin to create a sequential anthracycline-taxane regimen in early breast cancer. Patients and Methods After complete tumor excision, postmenopausal women with node-positive early breast cancer were randomly assigned to either epirubicin 50 mg/m2 on days 1 and 8 every 4 weeks for six cycles (EPI × 6) or three cycles of epirubicin 50 mg/m2 on days 1 and 8 every 4 weeks followed by three cycles of docetaxel 100 mg/m2 on day 1 every 3 weeks (EPI-DOC). A subset of patients also participated in a quality of life (QOL) study. The primary end point was disease-free survival (DFS). Results From 1997 to 2005, 803 patients entered DEVA (EPI × 6, n = 397; EPI-DOC, n = 406). At a median follow-up of 64.7 months (interquartile range, 45.2 to 84.4 months), 198 DFS events had been reported (EPI × 6, n = 114; EPI-DOC, n = 84). The 5-year DFS rates were 72.7% (95% CI, 68.0% to 77.3%) for epirubicin alone and 79.5% (95% CI, 75.2% to 83.8%) for epirubicin followed by docetaxel; evidence of improvement in DFS was observed with EPI-DOC (hazard ratio [HR], 0.68; 95% CI, 0.52 to 0.91; P = .008). One hundred twenty-seven patients have died (EPI × 6, n = 75; EPI-DOC, n = 52); a reduction in deaths was observed with EPI-DOC (HR, 0.66; 95% CI, 0.46 to 0.94; P = .02). The 5-year overall survival rates were 81.8% (95% CI, 77.7% to 85.9%) for epirubicin and 88.9% (95% CI, 85.5% to 92.2%) for epirubicin followed by docetaxel. Assessment of toxicity and QOL showed that EPI-DOC was associated with greater toxicity but with no difference in QOL between arms during follow-up. Conclusion These results suggest, within a relatively small trial, that substitution of docetaxel for epirubicin for the last three cycles of chemotherapy results in improved outcome in postmenopausal women with node-positive, early breast cancer compared with six cycles of epirubicin monotherapy.
Phase I Pharmacokinetic and Pharmacodynamic Study of the Multikinase Inhibitor Sorafenib in Combination With Clofarabine and Cytarabine in Pediatric Relapsed/Refractory Leukemia
Authors: Inaba Hiroto , Rubnitz Jeffrey E. , Coustan-Smith Elaine , Li Lie , Furmanski Brian D. , Mascara Gerard P. , Heym Kenneth M. , Christensen Robbin , Onciu Mihaela , Shurtleff Sheila A. , Pounds Stanley B. , Pui Ching-Hon , Ribeiro Raul C. , Campana Dario , Baker Sharyn D. 
Published: July 2011

Purpose To assess the toxicity, pharmacokinetics, and pharmacodynamics of multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in children with relapsed/refractory leukemia. Patients and Methods Twelve patients with acute leukemia (11 with acute myeloid leukemia [AML]) received sorafenib on days 1 to 7 and then concurrently with cytarabine (1 g/m2) and clofarabine (stratum one: 40 mg/m2, n = 10; stratum two [recent transplantation or fungal infection]: 20 mg/m2, n = 2) on days 8 to 12. Sorafenib was continued until day 28 if tolerated. Two sorafenib dose levels (200 mg/m2 and 150 mg/m2 twice daily) were planned. Sorafenib pharmacokinetic and pharmacodynamic studies were performed on days 7 and 8. Results At sorafenib 200 mg/m2, two of four patients in stratum one and one of two patients in stratum two had grade 3 hand-foot skin reaction and/or rash as dose-limiting toxicities (DLTs). No DLTs were observed in six patients in stratum one at sorafenib 150 mg/m2. Sorafenib inhibited the phosphorylation of AKT, S6 ribosomal protein, and 4E-BP1 in leukemia cells. The rate of sorafenib conversion to its metabolite sorafenib N-oxide was high (mean, 33%; range, 17% to 69%). In vitro, the N-oxide potently inhibited FLT3–internal tandem duplication (ITD; binding constant, 70 nmol/L) and the viability of five AML cell lines. On day 8, sorafenib decreased blast percentages in 10 of 12 patients (median, 66%; range, 9% to 95%). After combination chemotherapy, six patients (three FLT3-ITD and three FLT3 wild-type AML) achieved complete remission, two (both FLT3-ITD AML) had complete remission with incomplete blood count recovery, and one (FLT3 wild-type AML) had partial remission. Conclusion Sorafenib in combination with clofarabine and cytarabine is tolerable and shows activity in relapsed/refractory pediatric AML.