bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single cell cultures of Drosophila neuroectodermal and mesectodermal central nervous system progenitors reveal different degrees of developmental autonomy
Authors: Lüer Karin , Technau Gerhard M 
Published: August 2009

Abstract
Background
The Drosophila embryonic central nervous system (CNS) develops from two sets of progenitor cells, neuroblasts and ventral midline progenitors, which behave differently in many respects. Neuroblasts derive from the neurogenic region of the ectoderm and form the lateral parts of the CNS. Ventral midline precursors are formed by two rows of mesectodermal cells and build the CNS midline. There is plenty of evidence that individual identities are conferred to precursor cells by positional information in the ectoderm. It is unclear, however, how far the precursors can maintain their identities and developmental properties in the absence of normal external signals.

Results
To separate the respective contributions of autonomous properties versus extrinsic signals during their further development, we isolated individual midline precursors and neuroectodermal precursors at the pre-mitotic gastrula stage, traced their development in vitro, and analyzed the characteristics of their lineages in comparison with those described for the embryo. Although individually cultured mesectodermal cells exhibit basic characteristics of CNS midline progenitors, the clones produced by these progenitors differ from their in situ counterparts with regard to cell numbers, expression of molecular markers, and the separation of neuronal and glial fate. In contrast, clones derived from individually cultured precursors taken from specific dorsoventral zones of the neuroectoderm develop striking similarities to the lineages of neuroblasts that normally delaminate from these zones and develop in situ.

Conclusion
This in vitro analysis allows for the first time a comparison of the developmental capacities in situ and in vitro of individual neural precursors of defined spatial and temporal origin. The data reveal that cells isolated at the pre-mitotic and pre-delamination stage express characteristics of the progenitor type appropriate to their site of origin in the embryo. However, presumptive neuroblasts, once specified in the neuroectoderm, exhibit a higher degree of autonomy regarding generation of their lineages compared to mesectodermal midline progenitors.
Antigen delivery by α2-macroglobulin enhances the cytotoxic T lymphocyte response
Authors: Bowers Edith V , Horvath Jeffrey J , Bond Jennifer E , Cianciolo George J , Pizzo Salvatore V 
Published: August 2009

Abstractα-2M*-mediated antigen delivery leads to cross-presentation and improved cell-mediated immunity, suggesting that α-2M* may have applications for vaccines based on weakly immunogenic subunits.α2M* targets antigens to APCs for rapid internalization, processing, and presentation. When used as an antigen-delivery vehicle, α2M* amplifies MHC class II presentation, as demonstrated by increased antibody titers. Recent evidence, however, suggests that α2M* encapsulation may also enhance antigen-specific CTL immunity. In this study, we demonstrate that α2M*-delivered antigen (OVA) enhances the production of specific in vitro and in vivo CTL responses. Murine splenocytes expressing a transgenic TCR specific for CTL peptide OVA257–264 (SIINFEKL) demonstrated up to 25-fold greater IFN-γ and IL-2 secretion when treated in vitro with α2M*-OVA compared with soluble OVA. The frequency of IFN-γ-producing cells was increased ∼15-fold, as measured by ELISPOT. Expansion of the OVA-specific CD8+ T cell population, as assayed by tetramer binding and [3H]thymidine incorporation, and OVA-specific cell-mediated cytotoxicity, as determined by a flow cytometric assay, were also enhanced significantly by α2M*-OVA. Furthermore, significant CTL responses were observed at antigen doses tenfold lower than those required with OVA alone. Finally, we also observed enhanced humoral and CTL responses by naïve mice following intradermal immunization with α2M*-OVA. These α2M*-OVA-immunized mice demonstrated increased protection against a s.c.-implanted, OVA-expressing tumor, as demonstrated by delayed tumor growth and prolonged animal survival. The observation that α2M*-mediated antigen delivery elicits specific CTL responses suggests the cross-presentation of antigen onto MHC class I. These results support α2M* as an effective antigen-delivery system that may be particularly useful for vaccines based on weakly immunogenic subunits or requiring dose sparing.
Phase II Study of Sunitinib Administered in a Continuous Once-Daily Dosing Regimen in Patients With Cytokine-Refractory Metastatic Renal Cell Carcinoma
Authors: Escudier Bernard , Roigas Jan , Gillessen Silke , Harmenberg Ulrika , Srinivas Sandhya , Mulder Sasja F. , Fountzilas George , Peschel Christian , Flodgren Per , Maneval Edna Chow , Chen Isan , Vogelzang Nicholas J. 
Published: August 2009

Purpose Sunitinib has demonstrated antitumor activity in metastatic renal cell carcinoma (mRCC) when given at 50 mg/d on a 4-weeks-on 2-weeks-off regimen. Herein, we report results of an open-label, multicenter phase II mRCC study of sunitinib administered on a continuous once-daily dosing regimen. Patients and Methods Eligibility criteria included histologically proven mRCC with measurable disease, failure of one prior cytokine regimen, and good performance status. Patients were randomly assigned to a sunitinib starting dose of 37.5 mg/d in the morning (AM) or evening (PM). RECIST-defined objective response rate (ORR) was the primary end point. Secondary end points included progression-free survival (PFS), overall survival (OS), adverse events (AEs), and quality-of-life measures. Results One hundred seven patients were randomly assigned to AM (n = 54) or PM (n = 53) dosing and on study for a median 8.3 months. Eighty-three patients discontinued, 65 due to disease progression and 16 because of AEs; two patients withdrew consent. Dosing was reduced to 25 mg/d in 46 patients (43%) due to grade 3/4 AEs. The most common grade 3 treatment-related AEs were asthenia/fatigue (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%), and anorexia (8%). ORR was 20% with a 7.2-month median response duration. Median PFS and OS were 8.2 and 19.8 months, respectively, at median follow-up of 26.4 months. Efficacy, tolerability, and quality-of-life results were similar between patients dosed in the AM or PM. Conclusion Sunitinib 37.5 mg, administered on a continuous once-daily dosing regimen, has a manageable safety profile as second-line mRCC therapy, providing flexible dosing, which can be explored in combination studies.
Phase II-I-II Study of Two Different Doses and Schedules of Pralatrexate, a High-Affinity Substrate for the Reduced Folate Carrier, in Patients With Relapsed or Refractory Lymphoma Reveals Marked Activity in T-Cell Malignancies
Authors: O'Connor Owen A. , Horwitz Steven , Hamlin Paul , Portlock Carol , Moskowitz Craig H. , Sarasohn Debra , Neylon Ellen , Mastrella Jill , Hamelers Rachel , MacGregor-Cortelli Barbara , Patterson Molly , Seshan Venkatraman E. , Sirotnak Frank , Fleisher Martin , Mould Diane R. , Saunders Mike , Zelenetz Andrew D. 
Published: August 2009

Purpose To determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma. Patients and Methods Pralatrexate, initially given at a dose of 135 mg/m2 on an every-other-week basis, was associated with stomatitis. A redesigned, weekly phase I/II study established an MTD of 30 mg/m2 weekly for six weeks every 7 weeks. Patients were required to have relapsed/refractory disease, an absolute neutrophil greater than 1,000/μL, and a platelet count greater than 50,000/μL for the first dose of any cycle. Results The every-other-week, phase II experience was associated with an increased risk of stomatitis and hematologic toxicity. On a weekly schedule, the MTD was 30 mg/m2 weekly for 6 weeks every 7 weeks. This schedule modification resulted in a 50% reduction in the major hematologic toxicities and abrogation of the grades 3 to 4 stomatitis. Stomatitis was associated with elevated homocysteine and methylmalonic acid, which were reduced by folate and vitamin B12 supplementation. Of 48 assessable patients, the overall response rate was 31% (26% by intention to treat), including 17% who experienced complete remission (CR). When analyzed by lineage, the overall response rates were 10% and 54% in patients with B- and T-cell lymphomas, respectively. All eight patients who experienced CR had T-cell lymphoma, and four of the six patients with a partial remission were positron emission tomography negative. The duration of responses ranged from 3 to 26 months. Conclusion Pralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma.
Pre-Emptive Treatment With Rituximab of Molecular Relapse After Autologous Stem Cell Transplantation in Mantle Cell Lymphoma
Authors: Andersen Niels S. , Pedersen Lone B. , Laurell Anna , Elonen Erkki , Kolstad Arne , Boesen Anne Marie , Pedersen Lars M. , Lauritzsen Grete F. , Ekanger Roald , Nilsson-Ehle Herman , Nordström Marie , Fredén Susanne , Jerkeman Mats , Eriksson Mikael , Väärt Jaan , Malmer Beatrice , Geisler Christian H. 
Published: August 2009

Purpose Minimal residual disease (MRD) is predictive of clinical progression in mantle-cell lymphoma (MCL). According to the Nordic MCL-2 protocol we prospectively analyzed the efficacy of pre-emptive treatment using rituximab to MCL patients in molecular relapse after autologous stem cell transplantation (ASCT). Patients and Materials MCL patients enrolled onto the study, who had polymerase chain reaction (PCR) detectable molecular markers and underwent ASCT, were followed with serial PCR assessments of MRD in consecutive bone marrow and peripheral blood samples after ASCT. In case of molecular relapse with increasing MRD levels, patients were offered pre-emptive treatment with rituximab 375 mg/m2 weekly for 4 weeks. Results Of 160 MCL patients enrolled, 145 underwent ASCT, of whom 78 had a molecular marker. Of these, 74 were in complete remission (CR) and four had progressive disease after ASCT. Of the CR patients, 36 underwent a molecular relapse up to 6 years (mean, 18.5 months) after ASCT. Ten patients did not receive pre-emptive treatment mainly due to a simultaneous molecular and clinical relapse, while 26 patients underwent pre-emptive treatment leading to reinduction of molecular remission in 92%. Median molecular and clinical relapse-free survival after pre-emptive treatment were 1.5 and 3.7 years, respectively. Of the 38 patients who remain in molecular remission for now for a median of 3.3 years (range, 0.4 to 6.6 years), 33 are still in clinical CR. Conclusion Molecular relapse may occur many years after ASCT in MCL, and PCR based pre-emptive treatment using rituximab is feasible, reinduce molecular remission, and may prevent clinical relapse.
Follicular Lymphoma International Prognostic Index 2: A New Prognostic Index for Follicular Lymphoma Developed by the International Follicular Lymphoma Prognostic Factor Project
Authors: Federico Massimo , Bellei Monica , Marcheselli Luigi , Luminari Stefano , Lopez-Guillermo Armando , Vitolo Umberto , Pro Barbara , Pileri Stefano , Pulsoni Alessandro , Soubeyran Pierre , Cortelazzo Sergio , Martinelli Giovanni , Martelli Maurizio , Rigacci Luigi , Arcaini Luca , Di Raimondo Francesco , Merli Francesco , Sabattini Elena , McLaughlin Peter , Solal-Céligny Philippe 
Published: August 2009

Purpose The aim of the F2 study was to verify whether a prospective collection of data would enable the development of a more accurate prognostic index for follicular lymphoma (FL) by using parameters which could not be retrospectively studied before, and by choosing progression-free survival (PFS) as principal end point. Patients and Methods Between January 2003 and May 2005, 1,093 patients with a newly diagnosed FL were registered and 942 individuals receiving antilymphoma therapy were selected as the study population. The variables we used for score definition were selected by means of bootstrap resampling procedures on 832 patients with complete data. Procedures to select the model that would minimize errors were also performed. Results After a median follow-up of 38 months, 261 events for PFS evaluation were recorded. β2-microglobulin higher than the upper limit of normal, longest diameter of the largest involved node longer than 6 cm, bone marrow involvement, hemoglobin level lower than 12 g/dL, and age older than 60 years were factors independently predictive for PFS. Using these variables, a prognostic model was devised to identify three groups at different levels of risk. The 3-year PFS rate was 91%, 69%, and 51% for patients at low, intermediate, and high risk, respectively (log-rank = 64.6; P < .00001). The 3-year survival rate was 99%, 96%, and 84% for patients at low, intermediate, and high risk, respectively (P < .0001). Conclusion Follicular Lymphoma International Prognostic Index 2 is a simple prognostic index based on easily available clinical data and may represent a promising new tool for the identification of patients with FL at different risk in the era of immunochemotherapy.
Pomalidomide Is Active in the Treatment of Anemia Associated With Myelofibrosis
Authors: Tefferi Ayalew , Verstovsek Srdan , Barosi Giovanni , Passamonti Francesco , Roboz Gail J. , Gisslinger Heinz , Paquette Ronald L. , Cervantes Francisco , Rivera Candido E. , Deeg H. Joachim , Thiele Juergen , Kvasnicka Hans M. , Vardiman James W. , Zhang Yanming , Bekele B. Nebiyou , Mesa Ruben A. , Gale Robert P. , Kantarjian Hagop M. 
Published: August 2009

Purpose Thalidomide and lenalidomide can alleviate anemia in myelofibrosis. However, their value is undermined by their respective potential to cause peripheral neuropathy and myelosuppression. We therefore evaluated the safety and therapeutic activity of another immunomodulatory drug, pomalidomide. Methods In a phase II randomized, multicenter, double-blind, adaptive design study, four treatment arms were evaluated: pomalidomide (2 mg/d) plus placebo, pomalidomide (2 mg/d) plus prednisone, pomalidomide (0.5 mg/d) plus prednisone, and prednisone plus placebo. Pomalidomide was administered for up to 12 28-day treatment cycles. Prednisone (30 mg/d) was given in a tapering dose schedule during the first three cycles. Response was assessed by International Working Group criteria. Results Eighty-four patients with myelofibrosis-associated anemia were randomly assigned to the aforementioned treatment arms: 22, 19, 22, and 21, respectively. Response in anemia was documented in 20 patients, including 15 who became transfusion independent. Response rates in the four treatment arms were 23% (95% CI, 5% to 41%), 16% (95% CI, 0% to 33%), 36% (95% CI, 16% to 56%), and 19% (95% CI, 2% to 36%). The corresponding figures for patients receiving ≥ 3 cycles of treatment (n = 62) were 38%, 23%, 40%, and 25%. Response to pomalidomide with or without prednisone was durable (range, 3.2 to 16.9+ months) and significantly better in the absence of leukocytosis (37% v 8%; P = .01); JAK2V617F or cytogenetic status did not affect response. Grade ≥ 3 toxicities were infrequent and included (in each treatment arm) neutropenia (9%; 16%; 5%; 5%), thrombocytopenia (14%; 16%; 9%; 5%), and thrombosis (9%; 5%; 0%; 0%). Conclusion Pomalidomide therapy at 0.5 or 2 mg/d with or without an abbreviated course of prednisone is well tolerated in patients with myelofibrosis and active in the treatment of anemia.
Phase II, Multicenter, Uncontrolled Trial of Single-Agent Sorafenib in Patients With Relapsed or Refractory, Advanced Non–Small-Cell Lung Cancer
Authors: Blumenschein George R. , Gatzemeier Ulrich , Fossella Frank , Stewart David J. , Cupit Lisa , Cihon Frank , O'Leary James , Reck Martin 
Published: August 2009

Purpose Sorafenib is an oral multikinase inhibitor that targets the Ras/Raf/MEK/ERK mitogenic signaling pathway and the angiogenic receptor tyrosine kinases, vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor β. We evaluated the antitumor response and tolerability of sorafenib in patients with relapsed or refractory, advanced non–small-cell lung cancer (NSCLC), most of whom had received prior platinum-based chemotherapy. Patients and Methods This was a phase II, single-arm, multicenter study. Patients with relapsed or refractory advanced NSCLC received sorafenib 400 mg orally twice daily until tumor progression or an unacceptable drug-related toxicity occurred. The primary objective was to measure response rate. Results Of 54 patients enrolled, 52 received sorafenib. The predominant histologies were adenocarcinoma (54%) and squamous cell carcinoma (31%). No complete or partial responses were observed. Stable disease (SD) was achieved in 30 (59%) of the 51 patients who were evaluable for efficacy. Four patients with SD developed tumor cavitation. Median progression-free survival (PFS) was 2.7 months, and median overall survival was 6.7 months. Patients with SD had a median PFS of 5.5 months. Major grades 3 to 4, treatment-related toxicities included hand-foot skin reaction (10%), hypertension (4%), fatigue (2%), and diarrhea (2%). Nine patients died within a 30-day period after discontinuing sorafenib, and one patient experienced pulmonary hemorrhage that was considered drug related. Conclusion Continuous treatment with sorafenib 400 mg twice daily was associated with disease stabilization in patients with advanced NSCLC. The broad activity of sorafenib and its acceptable toxicity profile suggest that additional investigation of sorafenib as therapy for patients with NSCLC is warranted.
Predictive Capacity of Three Comorbidity Indices in Estimating Mortality After Surgery for Colon Cancer
Authors: Hines Robert B. , Chatla Chakrapani , Bumpers Harvey L. , Waterbor John W. , McGwin Gerald , Funkhouser Ellen , Coffey Christopher S. , Posey James , Manne Upender 
Published: August 2009

Purpose Although, for patients with cancer, comorbidity can affect the timing of cancer detection, treatment, and prognosis, there is little information relating to the question of whether the choice of comorbidity index affects the results of studies. Therefore, to compare the association of comorbidity with mortality after surgery for colon cancer, this study evaluated the Adult Comorbidity Evaluation-27 (ACE-27), the National Institute on Aging (NIA) and National Cancer Institute (NCI) Comorbidity Index, and the Charlson Comorbidity Index (CCI). Patients and Methods The study population consisted of colon cancer patients (N = 496) who underwent surgery at the University of Alabama at Birmingham Hospital from 1981 to 2002. Hazard ratios (HRs) with 95% CIs were obtained using the method of Cox proportional hazards for the three comorbidity indices in predicting overall and colon cancer–specific mortality. The point estimates obtained for comorbidity and other risk factors across the three models were compared. Results For each index, the highest comorbidity burden was significantly associated with poorer overall survival (ACE-27: HR = 1.63; 95% CI, 1.24 to 2.15; NIA/NCI: HR = 1.83; 95% CI, 1.29 to 2.61; CCI: HR = 1.46; 95% CI, 1.14 to 1.88) as well as colon cancer–specific survival. For the other risk factors, there was little variation in the point estimates across the three models. Conclusion The results obtained from these three indices were strikingly similar. For patients with severe comorbidity, all three indices were statistically significant in predicting shorter survival after surgery for colon cancer.
Practical approach to dependence modelling using copulas
Authors: Dutfoy A , Lebrun R 
Published: August 2009

Modelling the stochastic dependence between random inputs of a system is of uttermost importance for a sensible evaluation of its reliability. Most of the time, this modelling is made using some linear correlation coefficients. The current paper underlines the potential pitfalls of such an approach and gives a short introduction to the concept of copula, which appears to be the exact concept of stochastic dependence from a theoretical point of view. From a practical point of view, the identification of the copula of a multi-dimensional random vector can be challenging. After a short presentation of the concept of measure of association, the current paper introduces the new concept of dependence information as a multi-scalar synthesis of the copula. Thanks to several numerical simulations, it proposes first practical rules to select a copula for the dependence modelling, based on specific dependence information and the expected reliability level of the system under study.
Toward defining materials chemistry (IUPAC Technical Report)
Authors: Day Peter , Interrante Leonard V. , West Anthony R. 
Published: August 2009

AbstractThis report describes the results of a Project whose goals were to "assemble, collate and disseminate information about the scope of the newly-emerging discipline of materials chemistry, leading to an authoritative definition of the subject within the family of chemical sciences" and further, as a corollary, "to recommend to IUPAC how this new discipline might best be represented within the IUPAC structure". The history and current status of the research and teaching, only recently labeled as "materials chemistry", is described. This field has become one of the major growth sectors in pure and applied chemistry and now accounts for a significant fraction of all publications in the chemical sciences, based on measures such as journal citations and submitted papers and journals that are devoted entirely or in part to this subject. Nonetheless, there is still considerable confusion about what does, and does not, fall within the scope of "materials chemistry", and there is no consensus regarding a definition for the subject. After examining existing definitions for "chemistry" and "materials science" and considering prior attempts to define the subject, the following working definition for "materials chemistry" was suggested: "Materials chemistry comprises the application of chemistry to the design, synthesis, characterization, processing, understanding and utilisation of materials, particularly those with useful, or potentially useful, physical properties." In conclusion, the report suggests that IUPAC consider elevating this field from its current Subdivision status to that of "a cross-divisional Committee that would work with all the current IUPAC Divisions to develop and co-sponsor new projects, in the area of chemical education, nomenclature, terminology, health and safety, etc., that will increase the recognition of the current and future importance of this field to the international chemistry community".
Spatiotemporal Delivery Strategies for Promoting Musculoskeletal Tissue Regeneration
Authors: Guldberg Robert E 
Published: August 2009

Abstract
A primary regenerative medicine strategy is to stimulate or augment endogenous repair mechanisms that promote functional restoration of damaged or degenerated tissues. There is increasing evidence that maximizing the potency of tissue regenerative therapies will require design and development of delivery approaches that provide controlled spatiotemporal release of key signaling molecules. Guidance on which factors to deliver and the timing of delivery is emerging from advances in understanding of critical pathways involved in the development of integrated musculoskeletal tissues. A broad range of biomaterials-based deployment technologies are becoming available that allow controlled spatial presentation and release kinetics of biological cues. The purpose of this perspective article is to review promising spatiotemporal delivery strategies designed to promote functional tissue regeneration with an emphasis on vascularized bone repair.