bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hematopoietic stem-cell gene therapy of hemophilia A incorporating a porcine factor VIII transgene and nonmyeloablative conditioning regimens
Authors: Ide Lucienne M. , Gangadharan Bagirath , Chiang Kuang-Yueh , Doering Christopher B. , Spencer H. Trent 
Published: June 2007

Abstract
Insufficient expression of factor VIII (fVIII) is a major hurdle in the development of successful nucleic acid treatments for hemophilia. However, we recently showed that under myeloablative and reduced-intensity total body irradiation (TBI) conditioning, transplantation of hematopoietic stem cells (HSCs) transduced with recombinant retroviruses containing B domain–deleted porcine fVIII (BDDpfVIII) sequences provides curative fVIII levels in a hemophilia A mouse model. In the current study, we tested BDDpfVIII activity after nonmyeloablative conditioning with busulfan, cyclophosphamide, or fludarabine and immunosuppressive agents CTLA4-Ig + anti-CD40L or anti-(murine)thymocyte serum (ATS). ATS is similar in action to anti-(human)thymocyte globulin (ATG), which is used clinically with busulfan in bone marrow transplantations to increase donor cell engraftment. Mice conditioned with busulfan + ATS and that received a transplant of BDDpfVIII-transduced stem-cell antigen 1-positive cells exhibited moderate levels of donor cell chimerism (between 20% and 60%) and achieved sustained fVIII levels more than 1 U/mL. Similar results were observed in mice preimmunized with human fVIII and conditioned with 5 Gy TBI + ATS or busulfan + ATS. These data demonstrate that it is possible to achieve sufficient fVIII expression after transplantation of BDDpfVIII-transduced HSCs following low-toxicity pretransplantation conditioning with targeted immunosuppression, potentially even in the context of preexisting inhibitors.
Nonhemolytic antigen loss from red blood cells requires cooperative binding of multiple antibodies recognizing different epitopes
Authors: Zimring James C. , Cadwell Chantel M. , Chadwick Traci E. , Spitalnik Steven L. , Schirmer David A. , Wu Tao , Parkos Charles A. , Hillyer Christopher D. 
Published: June 2007

AbstractTransfusion of crossmatch-incompatible red blood cells (RBCs) can result in antibody-mediated hemolysis. However, in some patients, crossmatch-incompatible RBCs lose the incompatible antigen from their surface, and then circulate normally (“antigen loss”). Although antigen loss has been reported in the settings of autoimmune hemolytic anemia and transfusion of crossmatch-incompatible RBCs, mechanistic understanding of this phenomenon is limited. Using an in vivo murine model of antigen loss, we report that, unlike polyclonal antisera, monoclonal antibodies did not induce antigen loss. However, the combination of 2 monoclonal antibodies that recognized separate epitopes on the same antigen induced antigen loss. This was not due to an increased number of Fc domains bound to the cell surface, because antigen loss still occurred when combining intact monoclonal IgG and F(ab′)2 fragments recognizing different epitopes. Together, these data lead to the hypothesis that antigen-antibody crosslinking is required for nonhemolytic antigen loss to occur.
Virulence phenotypes of low-passage clinical isolates of Nontypeable Haemophilus influenzae assessed using the chinchilla laniger model of otitis media
Authors: Buchinsky Farrel J , Forbes Michael L , Hayes Jay D , Shen Kai , Ezzo Suzanne , Compliment James , Hogg Justin , Hiller N Luisa , Hu Fen Ze , Post J Christopher , Ehrlich Garth D 
Published: June 2007

Abstract

Background
The nontypeable Haemophilus influenzae (NTHi) are associated with a spectrum of respiratory mucosal infections including: acute otitis media (AOM); chronic otitis media with effusion (COME); otorrhea; locally invasive diseases such as mastoiditis; as well as a range of systemic disease states, suggesting a wide range of virulence phenotypes. Genomic studies have demonstrated that each clinical strain contains a unique genic distribution from a population-based supragenome, the distributed genome hypothesis. These diverse clinical and genotypic findings suggest that each NTHi strain possesses a unique set of virulence factors that contributes to the course of the disease.

Results
The local and systemic virulence patterns of ten genomically characterized low-passage clinical NTHi strains (PittAA – PittJJ) obtained from children with COME or otorrhea were stratified using the chinchilla model of otitis media (OM). Each isolate was used to bilaterally inoculate six animals and thereafter clinical assessments were carried out daily for 8 days by blinded observers. There was no statistical difference in the time it took for any of the 10 NTHi strains to induce otologic (local) disease with respect to any or all of the other strains, however the differences in time to maximal local disease and the severity of local disease were both significant between the strains. Parameters of systemic disease indicated that the strains were not all equivalent: time to development of the systemic disease, maximal systemic scores and mortality were all statistically different among the strains. PittGG induced 100% mortality while PittBB, PittCC, and PittEE produced no mortality. Overall Pitt GG, PittII, and Pitt FF produced the most rapid and most severe local and systemic disease. A post hoc determination of the clinical origins of the 10 NTHi strains revealed that these three strains were of otorrheic origin, whereas the other 7 were from patients with COME.

Conclusion
Collectively these data suggest that the chinchilla OM model is useful for discriminating between otorrheic and COME NTHi strains as to their disease-producing potential in humans, and combined with whole genome analyses, point the way towards identifying classes of virulence genes.
Symptom burden among patients with Renal Cell Carcinoma (RCC): content for a symptom index
Authors: Harding Gale , Cella David , Robinson Don , Mahadevia Parthiv J , Clark Jason , Revicki Dennis A 
Published: June 2007

Abstract

Background
Renal cell carcinoma (RCC) has multiple symptoms stemming from disease and treatments. There are few validated scales for evaluating RCC symptoms.

Methods
A national cross-sectional study of adult RCC patients was conducted from October to December 2003 to define patient-reported RCC symptomology. Participants were asked open-ended questions regarding their signs and symptoms and completed an 86-item pilot questionnaire of physical and psychological symptoms. Patients were asked to rate the relevancy and clarity of each pilot question using a 5-point Likert scale. Subsequent open-ended caregiver interviews and a provider panel relevance ranking contributed additional information.

Results
The average age of the participants (n = 31) was 55 years; 55% of patients were male, 74% had attended college, and 97% were Caucasian. The five most frequent symptoms among localized-stage patients (n = 14) were irritability (79%), pain (71%), fatigue (71%), worry (71%), and sleep disturbance (64%). Among metastatic patients (n = 17), the five most frequent symptoms were fatigue (82%), weakness (65%), worry (65%), shortness of breath (53%), and irritability (53%). More than 50% of localized and metastatic-stage patients reported pain, weakness, fatigue, sleep disturbance, urinary frequency, worry, and mood disorders as being moderately to highly relevant.

Conclusion
A brief, self-administered RCC Symptom Index was created that captures the relevant signs and symptoms of both localized and metastatic patients. Pending additional content validation, the Index can be used to assess the signs and symptoms of RCC and the clinical benefit resulting from RCC treatment.
Null Effect of Antidepressants on the Astrocytes-Mediated Proliferation of Hippocampal Progenitor Cells in vitro
Authors: Ko Hyoung-Gon , Lee Sung Joong , Son Hyeon , Kaang Bong-Kiun 
Published: June 2007

Background: It is well known that antidepressants increase neurogenesis in the dentate gyrus of the hippocampus. The increase of neurogenesis might contribute to the behavioral effects of antidepressants. However, the mechanism by which antidepressants increase hippocampal neurogenesis is largely unknown. It has been recently reported that astroglia induce the neurogenesis of the hippocampal neural progenitor cells (NPCs). Therefore, we hypothesized that antidepressants may act on astrocytes, and this in turn induces neurogenesis of NPCs. Results: To examine this hypothesis, we used two co-culture systems, i.e., a contact-independent Banker culture and a contact-dependent overlay co-culture. In both of these systems, in comparison with naïve astrocytes, antidepressant-treated astrocytes did not further increase the proliferation of NPCs. Conclusion: These results suggest that astrocytes increase the proliferation of hippocampal NPCs, however, this may not be directly involved in the antidepressant-induced proliferation of NPCs.
Prognostic Factors for Survival in Adult Patients With Recurrent Glioma Enrolled Onto the New Approaches to Brain Tumor Therapy CNS Consortium Phase I and II Clinical Trials
Authors: Carson Kathryn A. , Grossman Stuart A. , Fisher Joy D. , Shaw Edward G. 
Published: June 2007

Purpose Prognostic factor analyses have proven useful in predicting outcome in patients with newly diagnosed malignant glioma. Similar analyses in patients with recurrent glioma could affect the design and conduct of clinical trials substantially. Patients and Methods Between 1995 and 2002, 333 adults with recurrent gliomas were enrolled onto 10 phase I or II trials of systemic or local therapy. The studies had similar inclusion criteria and were conducted within the New Approaches to Brain Tumor Therapy CNS Consortium. Ninety-three percent of the patients have died. Cox proportional hazards (PH) regression and recursive partitioning analysis (RPA) were performed to identify prognostic factors. Results Factors associated with an increased risk of death were increased age, lower Karnofsky performance score (KPS), initial and on-study histologies of glioblastoma multiforme (GBM), corticosteroid use, shorter time from original diagnosis to recurrence, and tumor outside frontal lobe. The final PH model included initial histology of GBM (relative risk [RR] = 2.01), 10-year increase in age (RR = 1.23), KPS less than 80 (RR = 1.54), and corticosteroid use (RR = 1.49). RPA resulted in seven classes. Median survival time was poorest in non-GBM patients with KPS less than 80 or GBM patients, age ≥ 50 years, corticosteroid use (4.4 months; 95% CI, 3.6 to 5.4 months); median survival was best in patients with initial histology other than GBM with KPS ≥ 80 and tumor confined to the frontal lobe (25.7 months; 95% CI, 18.7 to 52.5), and was 7.0 months (95% CI, 6.2 to 8.0 months) for all patients. Conclusion Initial histology, age, KPS, and corticosteroid use are prognostic for survival in recurrent glioma patients. To allow comparisons across phase II trials, enrollment criteria may need to be restricted.
Leuprorelin Acetate Every-3-Months Depot Versus Cyclophosphamide, Methotrexate, and Fluorouracil As Adjuvant Treatment in Premenopausal Patients With Node-Positive Breast Cancer: The TABLE Study
Authors: Schmid Peter , Untch Michael , Kossé Valentin , Bondar Grigorij , Vassiljev Leonid , Tarutinov Valerie , Lehmann Ute , Maubach Lutz , Meurer Juergen , Wallwiener Diethelm , Possinger Kurt 
Published: June 2007

Purpose Ovarian suppression with luteinizing hormone–releasing hormone (LHRH) agonists is an effective adjuvant treatment for premenopausal women with estrogen receptor (ER) –positive breast cancer. Whereas monthly LHRH agonist therapy has been well established, the value of every-3-months (3-monthly) formulations is unclear. Patients and Methods This randomized phase III trial was performed to compare the 3-monthly depot LHRH agonist leuprorelin acetate (LAD-3M; n = 299) and chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF; n = 300) in pre- or perimenopausal patients with ER-positive, node-positive breast cancer. Results With a median follow-up of 5.8 years, recurrence-free survival was similar for patients treated with LAD-3M or CMF (hazard ratio [HR], 1.19; 95% CI, 0.94 to 1.51; P = .15). There was no substantial heterogeneity in the relative treatment effect among subgroups defined by age, progesterone receptor (PR) status, nodal status, hormone levels, or menstrual recovery after treatment. Exploratory overall survival analysis favored LAD-3M (HR, 1.50; 95% CI, 1.13 to 1.99; P = .005). Chemotherapy-related adverse effects such as nausea, vomiting, and alopecia were more common with CMF, whereas symptoms of estrogen suppression such as hot flushes and sweating were initially more pronounced with LAD-3M. Conclusion The 3-monthly depot LHRH-agonist leuprorelin acetate is an effective adjuvant treatment in premenopausal patients with hormone receptor–positive, node-positive breast cancer that is not inferior to CMF.
Meta-Analyses of Chemotherapy for Locally Advanced and Metastatic Pancreatic Cancer
Authors: Sultana Asma , Smith Catrin Tudur , Cunningham David , Starling Naureen , Neoptolemos John P. , Ghaneh Paula 
Published: June 2007

Purpose There are a large number of randomized controlled trials involving chemotherapy in the management of advanced pancreatic cancer. Several chemotherapeutic agents, either alone or in combination with other chemotherapy or novel agents, have been used. The aim of these meta-analyses was to examine the different therapeutic approaches, and the comparisons examined were as follows: chemotherapy versus best supportive care; fluorouracil (FU) versus FU combination chemotherapy; gemcitabine versus FU; and gemcitabine versus gemcitabine combination chemotherapy. Methods Relevant trials were identified by searching databases, trial registers, and conference proceedings. The primary end point was overall survival. Results One hundred thirteen randomized controlled trials were identified, of which 51 trials involving 9,970 patients met the inclusion criteria. Chemotherapy improved survival compared with best supportive care (hazard ratio [HR] = 0.64; 95% CI, 0.42 to 0.98). FU-based combination chemotherapy did not result in better overall survival compared with FU alone (HR = 0.94; 95% CI, 0.82 to 1.08). There was insufficient evidence of a survival difference between gemcitabine and FU, but the wide CI includes clinically important differences in both directions, making a clear conclusion difficult (HR = 0.75; 95% CI, 0.42 to 1.31). Survival was improved after gemcitabine combination chemotherapy compared with gemcitabine alone (HR = 0.91; 95% CI, 0.85 to 0.97). Conclusion There was a significant survival benefit for chemotherapy over best supportive care and gemcitabine combinations over gemcitabine alone. This supports the use of gemcitabine-based combination chemotherapy in the treatment of advanced pancreatic cancer.
Intratumoral Balance of Regulatory and Cytotoxic T Cells Is Associated With Prognosis of Hepatocellular Carcinoma After Resection
Authors: Gao Qiang , Qiu Shuang-Jian , Fan Jia , Zhou Jian , Wang Xiao-Ying , Xiao Yong-Sheng , Xu Yang , Li Yi-Wei , Tang Zhao-You 
Published: June 2007

Purpose To investigate the prognostic value of tumor-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in hepatocellular carcinoma (HCC) patients after resection. Patients and Methods CD3+, CD4+, CD8+, Foxp3-positive, and granzyme B-positive TILs were assessed by immunohistochemistry in tissue microarrays containing HCC from 302 patients. Prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff. Results CD3+, CD4+, CD8+ TILs were associated with neither overall survival (OS) nor disease-free survival (DFS). The presence of low intratumoral Tregs in combination with high intratumoral activated CD8+ cytotoxic cells (CTLs), a balance toward CTLs, was an independent prognostic factor for both improved DFS (P = .001) and OS (P < .0001). Five-year OS and DFS rates were only 24.1% and 19.8% for the group with intratumoral high Tregs and low activated CTLs, compared with 64.0% and 59.4% for the group with intratumoral low Tregs and high activated CTLs, respectively. Either intratumoral Tregs alone (P = .001) or intratumoral activated CTLs (P = .001) alone is also an independent predictor for OS. In addition, high Tregs density was associated with both absence of tumor encapsulation (P = .032) and presence of tumor vascular invasion (P = .031). Conclusion Tregs are associated with HCC invasiveness, and intratumoral balance of regulatory and cytotoxic T cells is a promising independent predictor for recurrence and survival in HCC. A combination of depletion of Tregs and concomitant stimulation of effector T cells may be an effective immunotherapy to reduce recurrence and prolong survival after surgery.
Prognostic Significance of 99mTc Hynic-rh-Annexin V Scintigraphy During Platinum-Based Chemotherapy in Advanced Lung Cancer
Authors: Kartachova Marina , van Zandwijk Nico , Burgers Sjaak , van Tinteren Harm , Verheij Marcel , Valdés Olmos Renato Alfredo 
Published: June 2007

Purpose The purpose of this study was to evaluate if sequential 99mTc Hynic-rh- annexin V scintigraphy (TAS) can predict outcome in patients with advanced lung cancer, shortly after the start of platinum-based chemotherapy. Patients and Methods In 16 consecutive chemotherapy-naive patients with advanced stage non–small-cell lung cancer scheduled for platinum-based chemotherapy, TAS was performed before and within 48 hours after the start of therapy. Chemotherapy-induced changes in tumor annexin V uptake, calculated as maximum count per pixel and expressed as percentage to baseline value, were compared with treatment response determined according to Response Evaluation Criteria in Solid Tumors. Results A significant correlation (r2 = 0.86; P = .0001) was found between annexin V metabolic changes and treatment outcome. All patients with notably increased annexin V tumor uptake showed complete or partial response. Less prominently increased or decreased uptake correlated with stable or progressive disease. Conclusion TAS is a promising test to predict tumor response in patients with advanced lung cancer early in the course of platinum-based chemotherapy.
UGT1A1Promoter Genotype Correlates With SN-38 Pharmacokinetics, but Not Severe Toxicity in Patients Receiving Low-Dose Irinotecan
Authors: Stewart Clinton F. , Panetta John C. , O'Shaughnessy Melinda A. , Throm Stacy L. , Fraga Charles H. , Owens Thandranese , Liu Tiebin , Billups Catherine , Rodriguez-Galindo Carlos , Gajjar Amar , Furman Wayne L. , McGregor Lisa M. 
Published: June 2007

PurposeTo study the association between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity as well as irinotecan disposition in pediatric patients with solid tumors receiving low-dose, protracted irinotecan (15 to 75 mg/m2daily for 5 days for 2 consecutive weeks).Patients and MethodsSeventy-four patients on five institutional clinical trials received irinotecan (15 to 75 mg/m2) daily intravenously or orally for 5 days for 2 consecutive weeks. Genomic DNA was genotyped for UGT1A1*28, and patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the UGT1A1 promoter region. Patients were evaluated for gastrointestinal and hematologic toxicity, as well as baseline and maximal serum bilirubin levels. Toxicity and pharmacokinetic results were evaluated during courses 1 and 2 of irinotecan therapy.ResultsThe frequencies of 6/6, 6/7, and 7/7 genotypes were 27 (36.5%), 36 (48.6%), and 9 (12.2%) of 74 patients, respectively. Patients with 7/7 genotype had a statistically greater baseline total bilirubin than patients with 6/6 or 6/7 genotype (P = .005). UGT1A1*28 genotype was not associated with grade 3 and 4 neutropenia (P = .21 for course 1; P = .23 for course 2) or diarrhea (P = .176 for course 1; P = .87 for course 2). However, patients with the 7/7 genotype tended to have higher SN-38 area under the plasma time-concentration curve (AUC) values and lower SN-38G/SN-38 AUC ratios.ConclusionSevere toxicity was not increased in pediatric patients with the 7/7 genotype when treated with a low-dose protracted schedule of irinotecan. Therefore, UGT1A1 genotyping is not a useful prognostic indicator of severe toxicity for patients treated with this irinotecan dosage and schedule.
Phase II Study of Erlotinib in Advanced Non–Small-Cell Lung Cancer After Failure of Gefitinib
Authors: Cho Byoung Chul , Im Chong-Kun , Park Moo-Suk , Kim Se Kyu , Chang Joon , Park Jong Pil , Choi Hye Jin , Kim Yu Jin , Shin Sang-Joon , Sohn Joo Hyuk , Kim Hoguen , Kim Joo Hang 
Published: June 2007

PurposeThis study was designed to evaluate the efficacy and toxicity of erlotinib in patients with advanced non–small-cell lung cancer (NSCLC) who experienced disease progression after treatment with gefitinib.Patients and MethodsThe study included stage IIIB/IV recurrent or metastatic NSCLC patients who received two or three prior chemotherapy regimens and showed progressive disease within 4 months of gefitinib therapy discontinuation. Patients received erlotinib 150 mg/d until disease progression or unacceptable toxicity. Epidermal growth factor receptor (EGFR) mutations and other genetic abnormalities were analyzed from available tumor samples.ResultsPatient and disease characteristics (N = 21) included median age 56 years; number of prior chemotherapy regimens (three; n = 11); female sex (n = 11); adenocarcinoma (n = 15); and never-smoker status (n = 11). Among the 17 patients with tumor samples available, EGFR mutations were detected in five. The disease control rate (DCR) and response rate (RR) for all patients were 28.6% and 9.5%, respectively. The median duration of disease control was 125 days. The median time to progression and overall survival were 60 days and 158 days, respectively. Patients who had stable disease (SD) while receiving gefitinib showed significantly higher DCR (75% v 17.6% in non-SD patients; P = .050) and RR (50.0% v 0% in non-SD patients; P = .029). Among 17 patients with biomarker results available, those lacking EGFR mutations who had SD while receiving gefitinib showed significantly higher DCR and RR.ConclusionErlotinib seems to be a potential therapeutic option for the treatment of advanced NSCLC patients with wild-type EGFR who had SD while receiving gefitinib.