bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combining Milatuzumab with Bortezomib, Doxorubicin, or Dexamethasone Improves Responses in Multiple Myeloma Cell Lines
Authors: Stein Rhona , Smith Mitchell R. , Chen Susan , Zalath Maria , Goldenberg David M. 
Published: April 2009

AbstractPurpose: The humanized anti-CD74 monoclonal antibody, milatuzumab, is in clinical evaluation for the therapy of multiple myeloma (MM). The ability of milatuzumab to increase the efficacy of bortezomib, doxorubicin, and dexamethasone was examined in three human CD74+ MM cell lines, CAG, KMS11, KMS12-PE, and one CD74-MM cell line, OPM-2.Experimental Design: Activity of milatuzumab as a monotherapy and combined with the drugs was evaluated by studying in vitro cytotoxicity, signaling and apoptotic pathways, and in vivo therapeutic activity in severe combined immunodeficient (SCID) mouse models of MM.Results: Given as a monotherapy, cross-linked milatuzumab, but not milatuzumab alone, yielded significant antiproliferative effects in CD74+ cells. The combination of cross-linked milatuzumab with bortezomib, doxorubicin, or dexamethasone caused more growth inhibition than either cross-linked milatuzumab or drug alone, producing significant reductions in the IC50 of the drugs when combined. Efficacy of combined treatments was accompanied by increased levels of apoptosis measured by increases of activated caspase-3 and hypodiploid DNA. Both milatuzumab and bortezomib affect the nuclear factor-κB pathway in CAG MM cells. In CAG- or KMS11-SCID xenograft models of disseminated MM, milatuzumab more than doubled median survival time, compared with up to a 33% increase in median survival with bortezomib but no significant benefit with doxorubicin. Moreover, combining milatuzumab and bortezomib increased survival significantly compared with either treatment alone.Conclusions: The therapeutic efficacies of bortezomib, doxorubicin, and dexamethasone are enhanced in MM cell lines when given in combination with milatuzumab, suggesting testing these combinations clinically.
Sarcopenia as a Determinant of Chemotherapy Toxicity and Time to Tumor Progression in Metastatic Breast Cancer Patients Receiving Capecitabine Treatment
Authors: Prado Carla M.M. , Baracos Vickie E. , McCargar Linda J. , Reiman Tony , Mourtzakis Marina , Tonkin Katia , Mackey John R. , Koski Sheryl , Pituskin Edith , Sawyer Michael B. 
Published: April 2009

Abstract
Purpose: Body composition has emerged as an important prognostic factor in cancer patients. Severe depletion of skeletal muscle (sarcopenia) and, hence, of overall lean body mass may represent an occult condition in individuals with normal or even high body weight. Sarcopenia has been associated with poor performance status, 5-fluorouracil toxicity, and shortened survival in cancer patients. Here, we prospectively studied patients with metastatic breast cancer receiving capecitabine treatment in order to determine if sarcopenia was associated with a higher incidence of toxicity and a shorter time to tumor progression (TTP).
Experimental Design: Fifty-five women with metastatic breast cancer resistant to anthracycline and/or taxane treatment were included. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured by computerized tomography, and sarcopenia was defined using a previously published cutoff point. Toxicity was assessed after cycle 1 of treatment, and TTP was determined prospectively.
Results: Approximately 25% of patients were classified as sarcopenic, and this feature was seen in normal weight, overweight, and obese individuals. Toxicity was present in 50% of sarcopenic patients, compared with only 20% of nonsarcopenic patients (P = 0.03), and TTP was shorter in sarcopenic patients (101.4 days; confidence interval, 59.8-142.9) versus nonsarcopenic patients (173.3 days; confidence interval, 126.1-220.5; P = 0.05).
Conclusion: Sarcopenia is a significant predictor of toxicity and TTP in metastatic breast cancer patients treated with capecitabine. Our results raise the potential use of body composition assessment to predict toxicity and individualize chemotherapy dosing.
Overexpression and Mislocalization of the Chromosomal Segregation Protein Separase in Multiple Human Cancers
Authors: Meyer Rene , Fofanov Viacheslav , Panigrahi AnilK. , Merchant Fatima , Zhang Nenggang , Pati Debananda 
Published: April 2009

Abstract
Purpose: Separase, an endopeptidase, plays a pivotal role in chromosomal segregation by separating sister chromatids during the metaphase to anaphase transition. Using a mouse mammary tumor model we have recently shown that overexpression of Separase induces aneuploidy and tumorigenesis (Zhang et al., Proc Natl Acad Sci 2008;105:13033). In the present study, we have investigated the expression level of Separase across a wide range of human tumors.
Experimental Design: To examine the expression levels and localization of Separase in human tumors, we have performed immunofluorescence microscopy using human Separase antibody and tumor tissue arrays from osteosarcoma, colorectal, breast, and prostate cancers with appropriate normal controls.
Results: We show that Separase is significantly overexpressed in osteosarcoma, breast, and prostate tumor specimens. There is a strong correlation of tumor status with the localization of Separase into the nucleus throughout all stages of the cell cycle. Unlike the normal control tissues, where Separase localization is exclusively cytoplasmic in nondividing cells, human tumor samples show significantly higher number of resting cells with a strong nuclear Separase staining. Additionally, overexpression of Separase transcript strongly correlates with high incidence of relapse, metastasis, and lower 5-year overall survival rate in breast and prostate cancer patients.
Conclusion: These results further strengthen our hypothesis that Separase might be an oncogene, whose overexpression induces tumorigenesis, and indicates that Separase overexpression and aberrant nuclear localization are common in many tumor types and may predict outcome in some human cancers.
MicroRNA Expression Ratio Is Predictive of Head and Neck Squamous Cell Carcinoma
Authors: Avissar Michele , Christensen Brock C. , Kelsey Karl T. , Marsit Carmen J. 
Published: April 2009

Abstract
Purpose: The involvement of microRNAs in cancer and their potential as biomarkers of diagnosis and prognosis are becoming increasingly appreciated. We sought to identify microRNAs altered in head and neck squamous cell carcinoma (HNSCC) and to determine whether microRNA expression is predictive of disease.
Experimental Design: RNA isolated from fresh-frozen primary tumors, fresh-frozen nondiseased head and neck epithelial tissues, and HNSCC cell lines was profiled for the expression of 662 microRNAs by microarray. The microRNAs that were both differentially expressed on the array and by quantitative reverse transcription-PCR were subsequently validated by quantitative reverse transcription-PCR using a total of 99 HNSCC samples and 14 normal epithelia.
Results: A marked difference in microRNA expression pattern was observed between tumors and cell lines. Eighteen microRNAs were significantly altered in their expression between normal tissues and tumors. Four of these microRNAs were validated in the larger sample series, and each showed significant differential expression (P &lt; 0.0001). Furthermore, an expression ratio of miR-221:miR-375 showed a high sensitivity (0.92) and specificity (0.93) for disease prediction.
Conclusions: These data suggest that cultured tumor cell lines are inappropriate for microRNA biomarker identification and that the pattern of microRNA expression in primary head and neck tissues is reflective of disease status, with certain microRNAs exhibiting strong predictive potential. These results indicate that miR-221 and miR-375 should be evaluated further as diagnostic biomarkers because they may hold utility in defining broadly responsive prevention and treatment strategies for HNSCC.
The supportive and palliative care needs of Australian families of children who die from cancer
Authors: Monterosso L , Kristjanson LJ , Phillips MB 
Published: April 2009

Objective To identify the perceptions of parents of children who died from cancer regarding the palliative and supportive care they received in hospital and in community settings. Method Face-to-face or telephone questionnaires. Setting Tertiary paediatric oncology centres in Western Australia, New South Wales, Queensland and Victoria. Participants 69 parents. Results Parents indicated the need for clear and honest information about their child’s condition and prognosis throughout the trajectory of illness. Parents also required access to, and advice from, multidisciplinary health professionals when caring for their child at home. Parents preferred to care for their child at home wherever possible throughout the palliative care trajectory of their child’s cancer and were well supported by immediate and extended family and friends. However, many families were affected emotionally and financially by the burden of caring for their child with incurable cancer. Families required financial and practical assistance with providing care from their child. Parents wanted and needed more practical resources and information to assist with the management of their child’s nutrition and pain, as well as for the support of their other children. Conclusion Care for children and their families should be coordinated by a multidisciplinary team in consultation with children and their families, and should be linked and integrated with the treating hospital in collaboration with community services.
Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome
Authors: Bosticardo Marita , Marangoni Francesco , Aiuti Alessandro , Villa Anna , Grazia Roncarolo Maria 
Published: April 2009

AbstractWiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency caused by mutations in the gene encoding for WASP, a key regulator of signaling and cytoskeletal reorganization in hematopoietic cells. Mutations in WASP result in a wide spectrum of clinical manifestations ranging from the relatively mild X-linked thrombocytopenia to the classic full-blown WAS phenotype characterized by thrombocytopenia, immunodeficiency, eczema, and high susceptibility to developing tumors and autoimmune manifestations. The life expectancy of patients affected by severe WAS is reduced, unless they are successfully cured by bone marrow transplantation from related identical or matched unrelated donors. Because many patients lack a compatible bone marrow donor, the administration of WAS gene–corrected autologous hematopoietic stem cells could represent an alternative therapeutic approach. In the present review, we focus on recent progress in understanding the molecular and cellular mechanisms contributing to the pathophysiology of WAS. Although molecular and cellular studies have extensively analyzed the mechanisms leading to defects in T, B, and dendritic cells, the basis of autoimmunity and thrombocytopenia still remains poorly understood. A full understanding of these mechanisms is still needed to further implement new therapeutic strategies for this peculiar immunodeficiency.
Regulation of Hoxb4 induction after neurulation by somite signal and neural competence
Authors: Amirthalingam Gayana S , Howard Sara , Alvarez Susana , de Lera Angel R , Itasaki Nobue 
Published: April 2009

Abstract

Background
While the body axis is largely patterned along the anterior-posterior (A-P) axis during gastrulation, the central nervous system (CNS) shows dynamic changes in the expression pattern of Hox genes during neurulation, suggesting that the CNS refines the A-P pattern continuously after neural tube formation. This study aims at clarifying the role of somites in up-regulating Hoxb4 expression to eventually establish its final pattern and how the neural tube develops a competence to respond to extrinsic signals.

Results
We show that somites are required for the up-regulation of Hoxb4 in the neural tube at the level of somites 1 to 5, the anterior-most domain of expression. However, each somite immediately adjacent to the neural tube is not sufficient at each level; planar signaling is additionally required particularly at the anterior-most segments of the expression domain. We also show that the dorsal side of the neural tube has a greater susceptibility to expressing Hoxb4 than the ventral region, a feature associated with dorsalization of the neural tube by BMP signals. BMP4 is additionally able to up-regulate Hoxb4 ventrally, but the effect is restricted to the axial levels at which Hoxb4 is normally expressed, and only in the presence of retinoic acid (RA) or somites, suggesting a role for BMP in rendering the neural tube competent to express Hoxb4 in response to RA or somite signals.

Conclusion
In identifying the collaboration between somites and neural tube competence in the induction of Hoxb4, this study demonstrates interplay between A-P and dorsal-ventral (D-V) patterning systems, whereby a specific feature of D-V polarity may be a prerequisite for proper A-P patterning by Hox genes.
Adenomatous polyposis coli-mediated control of β-catenin is essential for both chondrogenic and osteogenic differentiation of skeletal precursors
Authors: Miclea Razvan L , Karperien Marcel , Bosch Cathy AJ , van der Horst Geertje , van der Valk Martin A , Kobayashi Tatsuya , Kronenberg Henry M , Rawadi Georges , Akçakaya Pinar , Löwik Clemens WGM , Fodde Riccardo , Wit Jan Maarten , Robanus-Maandag Els C 
Published: April 2009

AbstractBackgroundDuring skeletogenesis, protein levels of β-catenin in the canonical Wnt signaling pathway determine lineage commitment of skeletal precursor cells to osteoblasts and chondrocytes. Adenomatous polyposis coli (Apc) is a key controller of β-catenin turnover by down-regulating intracellular levels of β-catenin.ResultsTo investigate whether Apc is involved in lineage commitment of skeletal precursor cells, we generated conditional knockout mice lacking functionalApcinCol2a1-expressing cells. In contrast to other models in which an oncogenic variant of β-catenin was used, our approach resulted in the accumulation of wild type β-catenin protein due to functional loss of Apc. Conditional homozygousApcmutant mice died perinatally showing greatly impaired skeletogenesis. All endochondral bones were misshaped and lacked structural integrity. Lack of functional Apc resulted in a pleiotropic skeletal cell phenotype. The majority of the precursor cells lackingApcfailed to differentiate into chondrocytes or osteoblasts. However, skeletal precursor cells in the proximal ribs were able to escape the noxious effect of functional loss of Apc resulting in formation of highly active osteoblasts. Inactivation of Apc in chondrocytes was associated with dedifferentiation of these cells.ConclusionOur data indicate that a tight Apc-mediated control of β-catenin levels is essential for differentiation of skeletal precursors as well as for the maintenance of a chondrocytic phenotype in a spatio-temporal regulated manner.
Immunostaining with D2–40 improves evaluation of lymphovascular invasion, but may not predict sentinel lymph node status in early breast cancer
Authors: Britto Anna V , Schenka André A , Moraes-Schenka Natália G , Alvarenga Marcelo , Shinzato Júlia Y , Vassallo José , Ward Laura S 
Published: April 2009

Abstract

Background
Sentinel lymph node (SLN) biopsy is a widely used diagnostic procedure in the management of early breast cancer. When SLN is free of metastasis, complete axillary dissection may be skipped for staging in clinically N0 patients, allowing a more conservative procedure. Histological tumor features that could reliably predict SLN status have not yet been established. Since the degree of tumor lymphangiogenesis and vascularization may theoretically be related to the risk of lymph node metastasis, we sought to evaluate the relationship between lymph vessel invasion (LVI), lymphatic microvascular density (LVD), microvascular density (MVD) and VEGF-A expression, with SLN status and other known adverse clinical risk factors.

Methods
Protein expression of D2–40, CD34, and VEGF-A was assessed by immunohistochemistry on paraffin-embedded sections of primary breast cancer specimens from 92 patients submitted to SLN investigation. The presence of LVI, the highest number of micro vessels stained for D2–40 and CD34, and the protein expression of VEGF-A were compared to SLN status, clinicopathological features and risk groups.

Results
LVI was detected in higher ratios by immunostaining with D2–40 (p < 0.0001), what would have changed the risk category from low to intermediate in four cases (4.3%). There was no association between LVI and other angiogenic parameters determined by immunohistochemistry with SLN macrometastases, clinical features or risk categories.

Conclusion
Assessment of LVI in breast carcinoma may be significantly increased by immunostaining with D2–40, but the clinical relevance of altering the risk category using this parameter may not be advocated according to our results, neither can the use of LVI and LVD as predictors of SLN macrometastasis in early breast cancer.
Identification and characterization of Ca2+-activated K+ channels in granulosa cells of the human ovary
Authors: Traut Matthias H , Berg Dieter , Berg Ulrike , Mayerhofer Artur , Kunz Lars 
Published: April 2009

Abstract

Background
Granulosa cells (GCs) represent a major endocrine compartment of the ovary producing sex steroid hormones. Recently, we identified in human GCs a Ca2+-activated K+ channel (KCa) of big conductance (BKCa), which is involved in steroidogenesis. This channel is activated by intraovarian signalling molecules (e.g. acetylcholine) via raised intracellular Ca2+ levels. In this study, we aimed at characterizing 1. expression and functions of KCa channels (including BKCa beta-subunits), and 2. biophysical properties of BKCa channels.

Methods
GCs were obtained from in vitro-fertilization patients and cultured. Expression of mRNA was determined by standard RT-PCR and protein expression in human ovarian slices was detected by immunohistochemistry. Progesterone production was measured in cell culture supernatants using ELISAs. Single channels were recorded in the inside-out configuration of the patch-clamp technique.

Results
We identified two KCa types in human GCs, the intermediate- (IK) and the small-conductance KCa (SK). Their functionality was concluded from attenuation of human chorionic gonadotropin-stimulated progesterone production by KCa blockers (TRAM-34, apamin). Functional IK channels were also demonstrated by electrophysiological recording of single KCa channels with distinctive features. Both, IK and BKCa channels were found to be simultaneously active in individual GCs. In agreement with functional data, we identified mRNAs encoding IK, SK1, SK2 and SK3 in human GCs and proteins of IK and SK2 in corresponding human ovarian cells. Molecular characterization of the BKCa channel revealed the presence of mRNAs encoding several BKCa beta-subunits (beta2, beta3, beta4) in human GCs. The multitude of beta-subunits detected might contribute to variations in Ca2+ dependence of individual BKCa channels which we observed in electrophysiological recordings.

Conclusion
Functional and molecular studies indicate the presence of active IK and SK channels in human GCs. Considering the already described BKCa, they express all three KCa types known. We suggest that the plurality and co-expression of different KCa channels and BKCa beta-subunits might allow differentiated responses to Ca2+ signals over a wide range caused by various intraovarian signalling molecules (e.g. acetylcholine, ATP, dopamine). The knowledge of ovarian KCa channel properties and functions should help to understand the link between endocrine and paracrine/autocrine control in the human ovary.
A controlled trial of value-based insurance design – The MHealthy: Focus on Diabetes (FOD) trial
Authors: Spaulding Alicen , Fendrick A Mark , Herman William H , Stevenson James G , Smith Dean G , Chernew Michael E , Parsons Dawn M , Bruhnsen Keith , Rosen Allison B 
Published: April 2009

Abstract

Background
Diabetes affects over 20 million Americans, resulting in substantial morbidity, mortality, and costs. While medications are the cornerstone of secondary prevention, many evidence-based therapies are underutilized, and patients often cite out-of-pocket costs as the reason. Value-based insurance design (VBID) is a 'clinically sensitive' refinement to benefit design which links patient cost-sharing to therapy value; the more clinically beneficial (and valuable) a therapy is for a patient, the lower that patient's cost-sharing should be. We describe the design and implementation of MHealthy: Focus on Diabetes (FOD), a prospective, controlled trial of targeted co-payment reductions for high value, underutilized therapies for individuals with diabetes.

Methods
The FOD trial includes 2,507 employees and dependents with diabetes insured by one large employer. Approximately 81% are enrolled in a single independent-practice association model health maintenance organization. The control group includes 8,637 patients with diabetes covered by other employers and enrolled in the same managed care organization. Both groups received written materials about the importance of adherence to secondary prevention therapies, while only the intervention group received targeted co-payment reductions for glycemic agents, antihypertensives, lipid-lowering agents, antidepressants, and diabetic eye exams. Primary outcomes include medication uptake and adherence. Secondary outcomes include health care utilization and expenditures. An interrupted time series, control group design will allow rigorous assessment of the intervention's impact, while controlling for unrelated temporal trends. Individual patient-level baseline data are presented.

Discussion
To our knowledge, this is the first prospective controlled trial of co-payment reductions targeted to high-value services for high-risk patients. It will provide important information on feasibility of implementation and effectiveness of VBID in a real-world setting. This program has the potential for broad dissemination to other employers and insurers wishing to improve the value of their health care spending.