bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II Study of the Mammalian Target of Rapamycin Inhibitor Everolimus (RAD001) in Patients with Relapsed or Refractory Hematologic Malignancies
Authors: Yee Karen W.L. , Zeng Zhihong , Konopleva Marina , Verstovsek Srdan , Ravandi Farhad , Ferrajoli Alessandra , Thomas Deborah , Wierda William , Apostolidou Efrosyni , Albitar Maher , O'Brien Susan , Andreeff Michael , Giles Francis J. 
Published: September 2006

Abstract
Purpose: Everolimus (RAD001, Novartis), an oral derivative of rapamycin, inhibits the mammalian target of rapamycin (mTOR), which regulates many aspects of cell growth and division. A phase I/II study was done to determine safety and efficacy of everolimus in patients with relapsed or refractory hematologic malignancies.
Experimental Design: Two dose levels (5 and 10 mg orally once daily continuously) were evaluated in the phase I portion of this study to determine the maximum tolerated dose of everolimus to be used in the phase II study.
Results: Twenty-seven patients (9 acute myelogenous leukemia, 5 myelodysplastic syndrome, 6 B-chronic lymphocytic leukemia, 4 mantle cell lymphoma, 1 myelofibrosis, 1 natural killer cell/T-cell leukemia, and 1 T-cell prolymphocytic leukemia) received everolimus. No dose-limiting toxicities were observed. Grade 3 potentially drug-related toxicities included hyperglycemia (22%), hypophosphatemia (7%), fatigue (7%), anorexia (4%), and diarrhea (4%). One patient developed a cutaneous leukocytoclastic vasculitis requiring a skin graft. One patient with refractory anemia with excess blasts achieved a major platelet response of over 3-month duration. A second patient with refractory anemia with excess blasts showed a minor platelet response of 25-day duration. Phosphorylation of downstream targets of mTOR, eukaryotic initiation factor 4E-binding protein 1, and/or, p70 S6 kinase, was inhibited in six of nine patient samples, including those from the patient with a major platelet response.
Conclusions: Everolimus is well tolerated at a daily dose of 10 mg daily and may have activity in patients with myelodysplastic syndrome. Studies of everolimus in combination with therapeutic agents directed against other components of the phosphatidylinositol 3-kinase/Akt/mTOR pathway are warranted.
Signal Transducers and Activators of Transcription 3 Pathway Activation in Drug-Resistant Ovarian Cancer
Authors: Duan Zhenfeng , Foster Rosemary , Bell Debra A. , Mahoney Jennifer , Wolak Kathryn , Vaidya Ami , Hampel Constanze , Lee Hang , Seiden Michael V. 
Published: September 2006

Abstract
Purpose: One of the major obstacles in the treatment of ovarian cancer is the development of multidrug resistance. Recent evidence shows that high-grade ovarian cancer often shows activation of the signal transducers and activators of transcription 3 (Stat3) pathway with subsequent transcription of genes that support tumor growth and survival. Less studied is the role of the Stat3 pathway in acquired drug resistance. There is no information on Stat3 expression in chemotherapy naïve ovarian cancer as compared with tumors collected later in the natural history of the disease. To further clarify the significance of Stat3 activation in ovarian cancer, here we investigated the Stat3 expression and activation in ovarian cancer and ovarian cancer multidrug resistance cell lines.
Experimental Design: Western blotting, electrophoretic mobility shift assay, luciferase assays, ELISA assay, and real-time reverse transcription-PCR determined interleukin-6 and Stat3 pathway expression and activation in cell lines. Stat3 expression in ovarian cancer tissue microarray was evaluated by immunohistochemistry.
Results: Activated (phosphorylated) Stat3 is overexpressed in most paclitaxel-resistant ovarian cancer cells. Inhibition of Stat3 activation results in significant decreases in paclitaxel resistance and enhanced apoptosis. Drug-resistant recurrent tumors have significantly greater phosphorylated Stat3 (pStat3) expression as compared with matched primary tumors. Tumors with associated inflammatory cell infiltrates also have a higher proportion of cells staining intensely for nuclear phosphorylated Stat3 as compared with tumors without inflammatory infiltrates, consistent with paracrine activation of the Stat3 pathway by immune-mediated cytokines.
Conclusions: These data support the hypothesis that interruption of Stat3 signaling could reverse resistance to paclitaxel and perhaps other chemotherapy agents in human cancer.
Differential Expression of Neuronal Genes Defines Subtypes of Disseminated Neuroblastoma with Favorable and Unfavorable Outcome
Authors: Fischer Matthias , Oberthuer André , Brors Benedikt , Kahlert Yvonne , Skowron Matthias , Voth Harald , Warnat Patrick , Ernestus Karen , Hero Barbara , Berthold Frank 
Published: September 2006

AbstractPurpose: Identification of molecular characteristics of spontaneously regressing stage IVS and progressing stage IV neuroblastoma to improve discrimination of patients with metastatic disease following favorable and unfavorable clinical courses.Experimental Design: Serial analysis of gene expression profiles were generated from five stage IVS and three stage IV neuroblastoma. Differential expression of candidate genes was evaluated by real-time quantitative reverse transcription-PCR in 76 pretreatment tumor samples (stage IVS n = 27 and stage IV n = 49). Gene expression-based outcome prediction was determined by Prediction Analysis for Microarrays using 38 tumors as a training set and 38 tumors as a test set.Results: Comparison of serial analysis of gene expression profiles from stage IV and IVS neuroblastoma revealed ∼500 differentially expressed transcripts. Genes related to neuronal differentiation were observed more frequently in stage IVS tumors as determined by associating transcripts to Gene Ontology annotations. Forty-one candidate genes were evaluated by quantitative reverse transcription-PCR and 18 were confirmed to be differentially expressed (P ≤ 0.001). Classification of patients according to expression patterns of these 18 genes using Prediction Analysis for Microarrays discriminated two subgroups with significantly differing event-free survival (96 ± 6% versus 40 ± 8% at 3 years; P &lt; 0.0001) and overall survival (100% versus 72 ± 7% at 3 years; P = 0.0003). This classifier was the only independent covariate marker in a multivariate analysis considering the variables stage, age, MYCN amplification, and gene signature.Conclusions: Spontaneously regressing and progressing metastatic neuroblastoma differ by specific gene expression patterns, indicating distinct levels of neuronal differentiation and allowing for an improved risk estimation of children with disseminated disease.
A Molecular Diagnostic Test for Distinguishing Lung Adenocarcinoma from Malignant Mesothelioma Using Cells Collected from Pleural Effusions
Authors: Holloway Andrew J. , Diyagama Dileepa S. , Opeskin Ken , Creaney Jenette , Robinson Bruce W.S. , Lake Richard A. , Bowtell David D.L. 
Published: September 2006

Abstract
Purpose: Patients with malignant mesothelioma or adenocarcinoma of the lung often present with respiratory complications associated with a malignant pleural effusion. Distinguishing between these malignancies is frequently problematic, as many of the clinical, cytologic, and histologic features of the diseases overlap. Following cytologic analysis of pleural effusions, subsequent confirmatory tissue biopsies involve increased patient morbidity and expense. We have therefore designed a gene expression–based test to classify the primary tumor causing a malignant pleural effusion, using cells collected from the effusion itself.
Experimental Design: We have used microarray data for 190 lung adenocarcinomas and 33 malignant mesotheliomas to identify genes differentially expressed between the two diseases. Genes expressed in normal mesothelial cells were removed, allowing the development of a PCR-based test to measure the expression of genes that discriminate between mesothelioma and lung adenocarcinoma from cytology specimens.
Results: Applying an real-time PCR–based assay involving 17 genes to 13 independent samples from biopsy-proven malignant mesothelioma and lung adenocarcinomas resulted in the correct identification of all samples.
Conclusions: We have developed a test that is able to distinguish between lung adenocarcinoma and mesothelioma in cells collected from pleural effusions.
Vascular Endothelial Growth Factor Signaling Pathways: Therapeutic Perspective
Authors: Kowanetz Marcin , Ferrara Napoleone 
Published: September 2006

Abstract
The establishment of a vascular supply is one of the earliest and most important events occurring during embryonic development. Growth and maturation of a functional vascular network are complex and still incompletely understood processes involving orchestrated activation of vascular progenitors in the early stages of embryonic development followed by vasculogenesis and angiogenesis. These processes require a tightly regulated activation of several growth factors and their receptors. The role of vascular endothelial growth factors (VEGF) and their receptors has been studied extensively due to their prominent role during blood vessel formation. Mice deficient in various VEGF ligands or receptors show serious defects in vascular formation and maturation. Moreover, members of the VEGF family are involved in other significant biological processes, including lymphangiogenesis, vascular permeability, and hematopoiesis. Importantly, VEGF is released by tumor cells and induces tumor neovascularization. It is now well established that the VEGF axis represents an important target for antitumor therapy. Aberrant VEGF signaling is also a feature of several other pathologic conditions, such as age-related macular degeneration and rheumatoid arthritis.
Mitochondrial DNA sequence variation in single cells from leukemia patients
Authors: Yao Yong-Gang , Ogasawara Yoji , Kajigaya Sachiko , Molldrem Jeffrey J. , Falcão Roberto P. , Pintão Maria-Carolina , McCoy J. Philip , Rizzatti Edgar Gil , Young Neal S. 
Published: September 2006

AbstractA high frequency of mtDNA somatic mutation has been observed in many tumors as well as in aging tissues. In this study, we analyzed the mtDNA control region sequence variation in 3534 single normal cells and individual blasts from 18 patients with leukemia and 10 healthy donors, to address the mutation process in leukemic cells. We found significant differences in mtDNA sequence, as represented by the number of haplotypes and the mean number of cells with each nonaggregate haplotype in a population of cells, in patients compared to controls. Patients with similar clinical leukemia types, particularly acute myeloid leukemia (AML), did not show a uniform pattern of sequence variation in single blasts. Some patients at relapse presented a complex shift of major haplotypes in single cells. Four patients showed high frequencies of cells containing mutations 189, 260, 16150, and 16488, respectively, as a result of clonal expansion and could be considered as potential markers for their respective disease progression. To our knowledge, this is the first large-scale study of mtDNA variation in single malignant cells. Our results suggest that the somatic mutation process in leukemia is complex, leading to diverse levels of genetic alterations due to either intrinsic aspects of leukemia pathophysiology or chemotherapy effects.
Continuous in vivo infusion of interferon-gamma (IFN-γ) enhances engraftment of syngeneic wild-type cells in Fanca–/– and Fancg–/– mice
Authors: Si Yue , Ciccone Samantha , Yang Feng-Chun , Yuan Jin , Zeng Daisy , Chen Shi , van de Vrugt Henri J. , Critser John , Arwert Fre , Haneline Laura S. , Clapp D. Wade 
Published: September 2006

AbstractFanconi anemia (FA) is a heterogeneous genetic disorder characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of FA complementation types allows the potential of using gene transfer technology to introduce functional cDNAs as transgenes into autologous stem cells and provide a cure for the BM failure in FA patients. However, strategies to enhance the mobilization, transduction, and engraftment of exogenous stem cells are required to optimize efficacy prior to widespread clinical use. Hypersensitivity of Fancc–/– cells to interferon-gamma (IFN-γ), a nongenotoxic immune-regulatory cytokine, enhances engraftment of syngeneic wild-type (WT) cells in Fancc–/– mice. However, whether this phenotype is of broad relevance in other FA complementation groups is unresolved. Here we show that primitive and mature myeloid progenitors in Fanca–/– and Fancg–/– mice are hypersensitive to IFN-γ and that in vivo infusion of IFN-γ at clinically relevant concentrations was sufficient to allow consistent long-term engraftment of isogenic WT repopulating stem cells. Given that FANCA, FANCC, and FANCG complementation groups account for more than 90% of all FA patients, these data provide evidence that IFN-γ conditioning may be a useful nongenotoxic strategy for myelopreparation in FA patients.
JAK2V617F: prevalence in a large Chinese hospital population
Authors: Xu Xuesong , Zhang Qi , Luo Jian , Xing Shu , Li Qingshan , Krantz Sanford B. , Fu Xueqi , Zhao Zhizhuang Joe 
Published: September 2006

AbstractRecently, the JAK2V617F mutation was found in patients with myeloproliferative disorders (MPDs), including most with polycythemia vera (PV). The mutant JAK2 has increased kinase activity, and it was shown to be pathogenic in mouse models. Herein, we analyzed blood samples randomly collected from a clinical laboratory. Surprisingly, as many as 37 samples from a total of 3935 were found positive for the JAK2 mutation. However, only one of these samples had blood test results indicative for probable PV, but several had nonhematologic diseases. On average, samples with the mutation had normal red cell counts but significantly higher white blood cell and platelet counts, although most were within the normal range. The data suggest that the JAK2V617F mutation is apparently much more common than MPDs. Its occurrence may be a prelude to full blood cell abnormalities and other diseases, but it cannot by itself diagnose MPDs.
Role of phosphatidylinositol 3′-kinase/AKT pathway in diffuse large B-cell lymphoma survival
Authors: Uddin Shahab , Hussain Azhar R. , Siraj Abdul K. , Manogaran Pulicat S. , Al-Jomah Naif A. , Moorji Azadali , Atizado Valerie , Al-Dayel Fouad , Belgaumi Asim , El-Solh Hassan , Ezzat Adnan , Bavi Prashant , Al-Kuraya Khawla S. 
Published: September 2006

AbstractPhosphatidylinositol 3′-kinase (PI3K) is a key player in cell-growth signaling in a number of lymphoid malignancies, but its role in diffuse large B-cell lymphoma (DLBCL) has not been fully elucidated. Therefore, we investigated the role of the PI3K/AKT pathway in a panel of 5 DLBCL cell lines and 100 clinical samples. Inhibition of PI3K by a specific inhibitor, LY294002, induced apoptosis in SUDHL4, SUDHL5, and SUDHL10 (LY-sensitive) cells, whereas SUDHL8 and OCI-LY19 (LY-resistant) cells were refractory to LY294002-induced apoptosis. AKT was phosphorylated in 5 of 5 DLBCL cell lines and inhibition of PI3K caused dephosphorylation/inactivation of constitutively active AKT, FOXO transcription factor, and GSK3 in LY-sensitive cell lines. In addition, there was a decrease in the expression level of inhibitory apoptotic protein, XIAP, in the DLBCL cell lines sensitive to LY294002 after treatment. However, no effect was observed in XIAP protein levels in the resistant DLBCL cell lines following LY294002 treatment. Finally, using immunohistochemistry, p-AKT was detected in 52% of DLBCL tumors tested. Furthermore, in univariate analysis, high p-AKT expression was associated with short survival. In multivariate analysis, this correlation was no longer significant. Altogether, these results suggest that the PI3K/AKT pathway may be a potential target for therapeutic intervention in DLBCL.
Long-term outcome of patients given transplants of mobilized blood or bone marrow: a report from the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation
Authors: Schmitz Norbert , Eapen Mary , Horowitz Mary M. , Zhang Mei-Jie , Klein John P. , Rizzo J. Douglas , Loberiza Fausto R. , Gratwohl Alois , Champlin Richard E. 
Published: September 2006

Abstract
We previously compared outcomes after allogeneic peripheral-blood stem cell (PBSC) and bone marrow (BM) transplantation in 706 patients with leukemia. We obtained long-term follow up on 413 of 491 patients who were alive at the time of the initial report: 141 PBSC and 272 BM recipients. Chronic graft-versus-host disease (GVHD) was more frequent after PBSC compared to BM transplantation (RR 1.65, P < .001) yet relapse rates were similar in both groups. Leukemia-free survival rates were higher after PBSC than BM transplantation for patients with advanced chronic myeloid leukemia (33% versus 25%) but lower for those in first chronic phase (41% versus 61%) due to higher rates of late transplant-related mortality. Leukemia-free survival was similar after PBSC and BM transplantation for acute leukemia. These data represent the early experience with PBSC grafts. Long-term outcomes in recipients of more recent transplants are required to better evaluate the role of PBSC grafts relative to BM transplantation.
WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus–truncated CXCR4
Authors: Kawai Toshinao , Choi Uimook , Cardwell Lanise , DeRavin Suk See , Naumann Nora , Whiting-Theobald Narda L. , Linton Gilda F. , Moon Jaehyun , Murphy Philip M. , Malech Harry L. 
Published: September 2006

AbstractWHIM(warts, hypogammaglobulinemia, recurrent bacterial infection, and myelokathexis) syndrome is a rare immunodeficiency caused in many cases by autosomal dominant C-terminal truncation mutations in the chemokine receptor CXCR4. A prominent and unexplained feature of WHIM is myelokathexis (hypercellularity with apoptosis of mature myeloid cells in bone marrow and neutropenia). We transduced healthy human CD34+ peripheral blood–mobilized stem cells (PBSCs) with retrovirus vector encoding wild-type (wt) CXCR4 or WHIM-type mutated CXCR4 and studied these cells ex vivo in culture and after engraftment in a nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse xenograft model. Neither wt CXCR4 nor mutated CXCR4 transgene expression itself enhanced apoptosis of neutrophils arising in transduced PBSC cultures even with stimulation by a CXCR4 agonist, stromal cell–derived factor-1 (SDF-1 [CXCL12]). Excess wt CXCR4 expression by transduced human PBSCs enhanced marrow engraftment, but did not affect bone marrow (BM) apoptosis or the release of transduced leukocytes into PB. However, mutated CXCR4 transgene expression further enhanced BM engraftment, but was associated with a significant increase in apoptosis of transduced cells in BM and reduced release of transduced leukocytes into PB. We conclude that increased apoptosis of mature myeloid cells in WHIM is secondary to a failure of marrow release and progression to normal myeloid cell senescence, and not a direct effect of activation of mutated CXCR4.
Phosphotyrosine profiling identifies the KG-1 cell line as a model for the study of FGFR1 fusions in acute myeloid leukemia
Authors: Gu Ting-Lei , Goss Valerie L. , Reeves Cynthia , Popova Lana , Nardone Julie , MacNeill Joan , Walters Denise K. , Wang Yi , Rush John , Comb Michael J. , Druker Brian J. , Polakiewicz Roberto D. 
Published: September 2006

Abstract
The 8p11 myeloproliferative syndrome (EMS) is associated with translocations that disrupt the FGFR1 gene. To date, 8 fusion partners of FGFR1 have been identified. However, no primary leukemia cell lines were identified that contain any of these fusions. Here, we screened more than 40 acute myeloid leukemia cell lines for constitutive phosphorylation of STAT5 and applied an immunoaffinity profiling strategy to identify tyrosine-phosphorylated proteins in the KG-1 cell line. Mass spectrometry analysis of KG-1 cells revealed aberrant tyrosine phosphorylation of FGFR1. Subsequent analysis led to the identification of a fusion of the FGFR1OP2 gene to the FGFR1 gene. Small interfering RNA (siRNA) against FGFR1 specifically inhibited the growth and induced apoptosis of KG-1 cells. Thus, the KG-1 cell line provides an in vitro model for the study of FGFR1 fusions associated with leukemia and for the analysis of small molecule inhibitors against FGFR1 fusions.
STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation
Authors: Verga Falzacappa Maria Vittoria , Vujic Spasic Maja , Kessler Regina , Stolte Jens , Hentze Matthias W. , Muckenthaler Martina U. 
Published: September 2006

Abstract
Hepcidin is a key iron-regulatory hormone produced by the liver. Inappropriately low hepcidin levels cause iron overload, while increased hepcidin expression plays an important role in the anemia of inflammation (AI) by restricting intestinal iron absorption and macrophage iron release. Its expression is modulated in response to body iron stores, hypoxia, and inflammatory and infectious stimuli involving at least in part cytokines secreted by macrophages. In this study we established and characterized IL6-mediated hepcidin activation in the human liver cell line Huh7. We show that the proximal 165 bp of the hepcidin promoter is critical for hepcidin activation in response to exogenously administered IL6 or to conditioned medium from the monocyte/macrophage cell line THP-1. Importantly, we show that hepcidin activation by these stimuli requires a STAT3 binding motif located at position –64/–72 of the promoter. The same STAT binding site is also required for high basal-level hepcidin mRNA expression under control culture conditions, and siRNA-mediated RNA knockdown of STAT3 strongly reduces hepcidin mRNA expression. These results identify a missing link in the acute-phase activation of hepcidin and establish STAT3 as a key effector of baseline hepcidin expression and during inflammatory conditions.