bluuebunny/crossref_metadata_2025_split huggingface dataset:
Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells
Authors: Dowdy Sean C. , Jiang Shujuan , Zhou X. Clare , Hou Xiaonan , Jin Fan , Podratz Karl C. , Jiang Shi-Wen 
Published: November 2006

Abstract
The use of histone deacetylase (HDAC) inhibitors has shown promise for a variety of malignancies. In this investigation, we define the activity of this class of inhibitors in combination with traditional cytotoxic chemotherapy in endometrial cancer cells. Significant reductions in growth were observed in Ark2 and KLE endometrial cancer cells following treatment with paclitaxel, doxorubicin, carboplatin, or the HDAC inhibitor trichostatin A (TSA). However, only combined treatment with TSA/paclitaxel caused synergistic inhibition of cell growth. This combination also resulted in significant changes in cell morphology. Using cell cycle analysis, nuclear staining, and Western blot analysis for poly(ADP-ribose) polymerase and caspase-9 degradation products, TSA/paclitaxel showed the most dramatic activation of the apoptotic cascade. These effects were also observed when the HDAC inhibitors HDAC inhibitor-1 or oxamflatin were substituted for TSA. The anticancer properties of paclitaxel are known to result in part from inhibition of microtubule depolymerization, which results in apoptosis. We show that TSA administration also stabilizes microtubules via α-tubulin acetylation. Furthermore, using Western blot and immunohistochemical analysis, treatment with TSA/paclitaxel led to a significant increase in acetylated tubulin and microtubule stabilization. These effects were confirmed in a mouse xenograft model. Moreover, TSA/paclitaxel resulted in a 50% reduction in tumor weight compared with either agent alone. This study provides in vivo evidence of nonhistone protein acetylation as one possible mechanism by which HDAC inhibitors reduce cancer growth. The TSA/paclitaxel combination seems to hold promise for the treatment of serous endometrial carcinoma and other malignancies with limited sensitivity to paclitaxel. [Mol Cancer Ther 2006;5(11):2767–76]
Potentiation of radiation sensitivity in breast tumor cells by the vitamin D3 analogue, EB 1089, through promotion of autophagy and interference with proliferative recovery
Authors: DeMasters Gerald , Di Xu , Newsham Irene , Shiu Robert , Gewirtz David A. 
Published: November 2006

Abstract
1,25-Dihydroxyvitamin D3 and vitamin D3 analogues, such as EB 1089, potentiate the response to ionizing radiation in breast tumor cells. The current studies address the basis for this interaction by evaluating DNA damage and repair, the effect of interference with reactive oxygen generation, the involvement of p53 and caspase-3, signaling through c-myc, as well as the induction of senescence and multiple modes of cell death. EB 1089 failed to increase the extent of radiation-induced DNA damage or to attenuate the rate of DNA repair. The reactive oxygen scavengers N-acetyl-l-cysteine and reduced glutathione failed to protect the cells from the promotion of cell death by EB 1089 and radiation. Whereas MCF-7 cells expressing caspase-3 showed significant apoptosis with radiation alone as well as with EB 1089 followed by radiation, EB 1089 maintained its ability to confer susceptibility to radiation-induced cell killing, in large part by interference with proliferative recovery. In contrast, in breast tumor cells lacking p53, where radiation promoted extensive apoptosis and the cells failed to recover after radiation treatment, EB 1089 failed to influence the effect of radiation. EB 1089 treatment interfered with radiation-induced suppression of c-myc; however, induction of c-myc did not prevent senescence by radiation alone or radiation-induced cell death promoted by EB 1089. EB 1089 did not increase the extent of micronucleation, indicative of mitotic catastrophe, induced by radiation alone. However, EB 1089 did promote extensive autophagic cell death in the irradiated cells. Taken together, these studies suggest that the effect of EB 1089 treatment on the radiation response is related in part to enhanced promotion of autophagic cell death and in part to interference with the proliferative recovery that occurs with radiation alone in p53 wild-type breast tumor cells. [Mol Cancer Ther 2006;5(11):2786–97]
In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in phase I clinical trials
Authors: DePinto Wanda , Chu Xin-Jie , Yin Xuefeng , Smith Melissa , Packman Kathryn , Goelzer Petra , Lovey Allen , Chen Yingsi , Qian Hong , Hamid Rachid , Xiang Qing , Tovar Christian , Blain Roger , Nevins Tom , Higgins Brian , Luistro Leopoldo , Kolinsky Kenneth , Felix Bernardo , Hussain Sazzad , Heimbrook David 
Published: November 2006

Abstract
The cyclin-dependent protein kinases are key regulators of cell cycle progression. Aberrant expression or altered activity of distinct cyclin-dependent kinase (CDK) complexes results in escape of cells from cell cycle control, leading to unrestricted cell proliferation. CDK inhibitors have the potential to induce cell cycle arrest and apoptosis in cancer cells, and identifying small-molecule CDK inhibitors has been a major focus in cancer research. Several CDK inhibitors are entering the clinic, the most recent being selective CDK2 and CDK4 inhibitors. We have identified a diaminopyrimidine compound, R547, which is a potent and selective ATP-competitive CDK inhibitor. In cell-free assays, R547 effectively inhibited CDK1/cyclin B, CDK2/cyclin E, and CDK4/cyclin D1 (Ki = 1–3 nmol/L) and was inactive (Ki &gt; 5,000 nmol/L) against a panel of &gt;120 unrelated kinases. In vitro, R547 effectively inhibited the proliferation of tumor cell lines independent of multidrug resistant status, histologic type, retinoblastoma protein, or p53 status, with IC50s ≤ 0.60 μmol/L. The growth-inhibitory activity is characterized by a cell cycle block at G1 and G2 phases and induction of apoptosis. R547 reduced phosphorylation of the cellular retinoblastoma protein at specific CDK phosphorylation sites at the same concentrations that induced cell cycle arrest, suggesting a potential pharmacodynamic marker for clinical use. In vivo, R547 showed antitumor activity in all of the models tested to date, including six human tumor xenografts and an orthotopic syngeneic rat model. R547 was efficacious with daily oral dosing as well as with once weekly i.v. dosing in established human tumor models and at the targeted efficacious exposures inhibited phosphorylation of the retinoblastoma protein in the tumors. The selective kinase inhibition profile and the preclinical antitumor activity of R547 suggest that it may be promising for development for use in the treatment of solid tumors. R547 is currently being evaluated in phase I clinical trials. [Mol Cancer Ther 2006;5(11):2644–58]
Mithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites
Authors: Lee Tae-Jin , Jung Eun Mi , Lee Jung Tae , Kim Shin , Park Jong-Wook , Choi Kyeong Sook , Kwon Taeg Kyu 
Published: November 2006

Abstract
Mithramycin A is a DNA-binding antitumor agent, which has been clinically used in the therapies of several types of cancer and Paget's disease. In this study, we investigated the combined effect of mithramycin A and tumor necrosis factor-α–related apoptosis-inducing ligand (TRAIL) on apoptosis of cancer cells. In Caki renal cancer cells, which are resistant to TRAIL, cotreatment with subtoxic doses of mithramycin A and TRAIL resulted in a marked increase in apoptosis. This combined treatment was also cytotoxic to Caki cells overexpressing Bcl-2 but not to normal mesengial cells. Moreover, apoptosis by the combined treatment with mithramycin A and TRAIL was dramatically induced in various cancer cell types, thus offering an attractive strategy for safely treating malignant tumors. Mithramycin A–stimulated TRAIL-induced apoptosis was blocked by pretreatment with the broad caspase inhibitor zVAD-fmk or Crm-A overexpression, showing its dependence on caspases. We found that mithramycin A selectively down-regulated XIAP protein levels in various cancer cells. Luciferase reporter assay and the chromatin immunoprecipitation assay using the XIAP promoter constructs show that mithramycin A down-regulates the transcription of XIAP gene through inhibition of Sp1 binding to its promoter. Although XIAP overexpression significantly attenuated apoptosis induced by mithramycin A plus TRAIL, suppression of XIAP expression by transfection with its small interfering RNA prominently enhanced TRAIL-induced apoptosis. We present here for the first time that mithramycin A–induced suppression of XIAP transcription plays a critical role in the recovery of TRAIL sensitivity in various cancer cells. [Mol Cancer Ther 2006;5(11):2737–46]
Did Second Isaiah write Lamentations iii?
Authors: Middlemas Jill 
Published: November 2006

AbstractIn recent years, textual analyses of Lamentations have increasingly noted correspondences with Isaiah xl-lv. The alignment of the two has resulted in various proposals about influence with the recent work of Patricia Willey noticeable in its claim that the Lamentations iii geber provided the paradigm for the Suffering Servant figure of the third and fourth songs (Isa. lii, liii-liv). This article considers this discussion anew with the intent to ascertain the provenance of the Lamentations geber and his relationship to Second Isaiah. After a close analysis of some of the more persuasive correspondences between the two figures, it becomes clear that the geber fits uncomfortably in the book of Lamentations. Furthermore, his persona functions as a corrective to the responses to disaster found so prominently outside of chapter iii. The parenetic section which follows the geber's lament in vv. 22-39 defines the sufferer and uses his experience to teach sanctioned views of the deity and the human person. Bearing in mind the way the geber acts to admonish and teach in Lamentations leads to the view that the suffering figure has more commonality with images and thought stemming from the Golah community. The paper explores the implications for understanding a Golah view placed at the heart of Lamentations for interpreting the material.
Dancing for God or the Devil: Pentecostal Discourse on Popular Dance in Kinshasa
Authors: Pype Katrien 
Published: November 2006

AbstractThis article studies the dance poetics and politics of Christians in contemporary Kinshasa. For Kinois (inhabitants of Kinshasa), dance is one of the most important technologies to get in touch with an invisible Other, the divine or the occult. In sermons, and other modes of instruction, spiritual leaders inform their followers about the morality of songs and dances. These discourses reflect pentecostal thought, and trace back the purity of specific body movements to the choreography's source of inspiration. As the specific movements of so-called sacred dances borrow from a wide array of cultural worlds, ranging from traditional ritual dances and popular urban dance to biblical tales, the religious leaders state that not just the body movements, but also the space where people dance and the accompanying songs, define the Christian or pagan identity of the dancer. Therefore, both the reflections upon dance movements and the dance events within these churches will be discussed as moments in the construction of a Christian community.
Disorders of Neutrophil Number and Function
Authors: Newburger Peter E. 
Published: November 2006

AbstractThis review of disorders of neutrophil number and function will discuss important research advances in the field and then provide a clinical diagnostic approach. The focus will be on two recent clinical developments in the field of phagocyte disorders. First, an important natural history study from the Severe Chronic Neutropenia International Registry has recently quantitated the incidence and risk factors for death from sepsis and for progression to myelodysplastic syndrome and acute myeloid leukemia in a large cohort of severe chronic neutropenia patients, many of whom were followed 10 or more years on treatment with granulocyte colony-stimulating factor. Second, in the past year, a multinational group has announced successful gene therapy of two adults with chronic granulomatous disease, the most common disorder of neutrophil function. However, monitoring of retroviral insertion sites revealed expansion of the multiclonal population of gene-modified cells, raising concerns about eventual leukemogenesis. The review also provides a pragmatic approach to the evaluation of a patient with a suspected disorder of neutrophil number or function.
Tumor-Specific Genetic Lesions and Their Influence on Therapy in Pediatric Acute Lymphoblastic Leukemia
Authors: Downing James R. , Mullighan Charles G. 
Published: November 2006

Abstract
Pharmacogenomics has traditionally focused on the identification of inherited genetic differences that influence a patient’s response to a specific therapeutic agent. These differences can range from inherited variability in the genes that affect drug absorption, distribution, intracellular transport, metabolism, and elimination, to variability in the genes that encode either the target of the drug or components of the pathway affected by the drug. The main goal of pharmacogenomics is to improve our understanding of how these variations, either individually or collectively, influence the therapeutic response. The genetic differences inherent within cancer cells constitute the other major variable in a patient’s ultimate response to therapy. In this review, we provide an overview of high-throughput genomic methods that can be used to identify genetic lesions within cancer cells. These efforts will ultimately allow the identification of the full complement of genetic lesions that underlie the establishment and maintenance of the leukemic clone. The identification of these lesions should provide the bases for defining the molecular “Achilles heels” against which new targeted therapies can be developed.
Evolving View of the In-Vivo Kinetics of Chronic Lymphocytic Leukemia B Cells
Authors: Chiorazzi Nicholas , Ferrarini Manlio 
Published: November 2006

AbstractB-cell chronic lymphocytic leukemia (B-CLL) has long been considered a disease of “accumulation,” due to a presumed defect in programmed cell death. Recent data, however, suggest that B-CLL cells are born at a normal to an accelerated rate, with the rate of proliferation varying among patients. In addition, differences in birth rates, activation state, and inducibility appear to exist among subpopulations of cells within individual leukemic clones. The extent to which such dissimilarities influence clinical course and outcome is still unclear. This review examines the evidence supporting the existence of a proliferative compartment in B-CLL and the role that proliferating cells might play in the progression and evolution of this disease.
Controversies in Follicular Lymphoma: “Who, What, When, Where, and Why?” (Not Necessarily in That Order!)
Authors: Czuczman Myron S. 
Published: November 2006

AbstractFollicular lymphoma (FL) is the most common subtype of indolent lymphoma. Specific “facts” about FL that were generated by past research and have been passed down as dogma to a majority of practicing oncologists over the past 20 to 30 years that need to be revisited, include: (1) do not initiate therapy soon after diagnosis in asymptomatic, advanced-stage patients since it does not change outcome; (2) initiate therapy with single-agent oral alkylators when intervention needed and “save” more aggressive combination chemotherapy for “later” since the standard chemotherapy regimen used did not seem to impact survival; (3) FL is an incurable disease and palliation of symptoms was an acceptable approach to the expected pattern of repeated relapses; (4) transformation of FL is independent of the type or timing of therapies received by a patient; (5) median overall survival (OS) for FL patients is 8–10 years. Although the heterogeneity of FL will never change, we are developing the scientific tools to identify and better understand the biologic and genetic features associated with its clinical variability. In the current exciting era of targeted therapies (e.g., rituximab, radioimmunoconjugates) and novel treatment approaches demonstrating an improvement in treatment outcomes (e.g., disease-free survival and OS), our old beliefs and historically accepted dogma need to be retested and revitalized. The optimal combination(s) of old and new agents and the optimal timing of when to initiate and how to sequence specific therapies will require data from well-designed clinical trials that should include important correlative laboratory studies.
Pathobiology of Peripheral T-cell Lymphomas
Authors: Jaffe Elaine S. 
Published: November 2006

AbstractPeripheral T-cell lymphomas (PTLs) are uncommon, accounting for fewer than 10% of all non-Hodgkin lymphomas. Success in therapy of the PTLs has lagged behind that of aggressive B-cell lymphomas, and most PTLs have a poor prognosis. The molecular pathogenesis of most PTLs is also poorly understood. In the WHO classification, clinical features, in conjunction with morphological and immunophenotypic criteria, are relied on to define most disease entities.Functionally, T-cell lymphomas are related to the two major arms of the immune system, the innate and adaptive immune systems. NK cells and T cells of the innate immune system recognize antigen in the absence of MHC antigens and are involved in mucosal immunity. The lymphomas derived from these cells often involve cutaneous and mucosal sites. The expression of cytotoxic molecules in these lymphomas may predispose to apoptosis by tumor cells and normal bystander cells. Hepatosplenic T-cell lymphoma is a systemic disease derived from functionally immature innate effector cells, most often of γδ T-cell origin. In contrast, most nodal T-cell lymphomas belong to the adaptive immune system.Angioimmunoblastic T-cell lymphoma (AILT) is mostly likely derived from follicular helper T-cells (TFH), a finding that explains many of its pathological and clinical features. Studies of these neoplasms may assist in further unraveling the functional diversity of their normal counterparts.
ITP in the 21st Century
Authors: Beardsley Diana S. 
Published: November 2006

Abstract
Immune (or idiopathic) thrombocytopenic purpura (ITP) is commonly encountered by the practicing hematologist. Clinical management decisions have traditionally been guided by individual training and past experience. Input from the literature has been more from observational reports of case series than from scientific results of hypothesis-driven research. Practice guidelines and several surveys of clinical hematology practice have highlighted important questions in the field, and in the past 5 to 10 years both clinical and laboratory investigations have produced valuable new information. Thrombopoietin levels are normal or only slightly increased in ITP, and stimulation of thrombopoiesis appears to be a promising new therapeutic approach in clinical trials. Chronic, refractory ITP in children or adults remains a challenge for the hematologist. It is this group that has the greatest risk of serious bleeding, particularly among the elderly. The anti-B–cell monoclonal antibody, anti-CD20, has shown benefit in phase I/II clinical trials in patients who had failed a number of previous therapeutic modalities. The standard for clinical research into therapy for ITP has become evidence-based medicine, and more prospective, randomized clinical trials are being completed by multi-institutional study groups.
Red Cell Exchange in Sickle Cell Disease
Authors: Swerdlow Paul S. 
Published: November 2006

Abstract
Red cell exchange transfusions remain an effective but possibly underutilized therapy in the acute and chronic treatment of sickle cell disease. In sickle cell disease, increased blood viscosity can cause complications when the hemoglobin exceeds 10 g/dL even if this is due to simple transfusion. Red cell exchange can provide needed oxygen carrying capacity while reducing the overall viscosity of blood. Acute red cell exchange is useful in acute infarctive stroke, in acute chest and the multi-organ failure syndromes, the right upper quadrant syndrome, and possibly priapism. Neither simple or exchange transfusions are likely to hasten resolution of an acute pain episode.
Platelets: Testing, Dosing and the Storage Lesion—Recent Advances
Authors: Kaufman Richard M. 
Published: November 2006

Abstract
The demand for platelet transfusions continues to grow. Several complementary approaches that may help meet this demand in the future are reviewed. First, platelet bacterial testing is beginning to allow the extension of platelet storage beyond 5 days. Studies are also underway aimed at better preserving viability and function during ex vivo platelet storage: additive solutions and other approaches are being developed to try to negate the “platelet storage lesion.” Finally, new approaches to dosing platelets may help extend the limited supply.
Induction of Fetal Hemoglobin in the Treatment of Sickle Cell Disease
Authors: Fathallah Hassana , Atweh George F. 
Published: November 2006

Abstract
Reactivation of fetal hemoglobin (HbF) expression is an important therapeutic option in patients with hemoglobin disorders. In sickle cell disease (SCD), an increase in HbF inhibits the polymerization of sickle hemoglobin and the resulting pathophysiology. Hydroxyurea, an inducer of HbF, has already been approved for the treatment of patients with moderate and/or severe SCD. Recent clinical trials with other pharmacological inducers of HbF, such as butyrate and decitabine, have shown considerable promise. In this chapter, we highlight the important clinical trials with pharmacological inducers of HbF, discuss their mechanisms of action and speculate about the future of this therapeutic approach in the treatment of patients with SCD.
Immune Thrombocytopenic Purpura of Childhood
Authors: Nugent Diane J. 
Published: November 2006

Abstract
Immune mediated thrombocytopenia (ITP) is a common manifestation of autoimmune disease in children. Although patients often present with bruises, petechiae, and some mucosal bleeding, the incidence of life-threatening hemorrhage is rare (0.2–0.9%) but can be fatal when presenting in vital organs. A wide range of therapeutic regimens are currently in use, including observation alone, as the majority of children recover within 4–6 months regardless of treatment. A growing understanding of the pathophysiology of acute ITP in children has not impacted the controversy surrounding treatment, but has clarified the mechanism of action of the most frequently used agents in chronic ITP. Newer monoclonal antibodies such as Rituxan have proved very useful in chronic or refractory ITP and studies are ongoing to determine the best regimens using this form of immune modulation. Splenectomy and newer agents to boost platelet production are also under study in chronic ITP. Neonates may also have a form of immune thrombocytopenia with extensive bruising and thrombocytopenia called neonatal alloimmune thrombocytopenic purpura (NATP). Rather than autoantibodies, the platelet destruction is secondary to transplacental maternal IgG alloantibodies. During pregnancy mothers may become sensitized to platelet membrane antigens present on fetal platelets. These antibodies may result in serious bleeding, including intracranial hemorrhage in the perinatal period. Once identified, these mothers may require treatment during future pregnancies to minimize serious bleeding in the fetus and neonate. Treatment in utero and immediately following delivery is focused on restoring neonatal platelets to a safe level and preventing life-threatening bleeding.