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MCL
Terms modified by MCL Selected AbstractsOver-expression of CCL3,,MIP-1, in a blastoid mantle cell lymphoma with hypercalcemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2010Norimichi Hattori Abstract We analyzed a case with the blastoid variant of mantle cell lymphoma (MCL-BV), a rare subtype of B-cell lymphoma, presenting with marked hypercalcemia at diagnosis. Enzyme-linked immunosorbent assay (ELISA) showed elevated serum levels of interleukin-6 (IL-6), tumor necrosis factor-, (TNF-,), macrophage inflammatory protein-1, (MIP-1,), and type I collagen telopeptide, but not parathyroid hormone, calcitriol or parathyroid hormone-related peptide at diagnosis, suggesting local osteoclastic hypercalcemia in this case. By reverse transcription polymerase chain reaction (RT-PCR) analysis, we found predominant expression of mRNA for MIP-1, in addition to those for receptor-activator of nuclear-factor kappa B ligand (RANKL), TNF-,, and IL-6 in lymphoma cells obtained from the patient. Furthermore, recombinant MIP-1, significantly stimulated 3H-thymidine uptake by isolated MCL cells in vitro. Treatment with intravenous fluids, bisphosphonate, and methylprednisolone followed by combination chemotherapy promptly corrects the hypercalcemia and successfully induced complete remission, which was accompanied by a decrease of these cytokines in the serum, including MIP-1,. In the present case, MIP-1,, an osteoclast-activating factor produced by mantle lymphoma cells, may contribute to the development of hypercalcemia. It likely acts through RANKL expression in tumor cells and/or stroma cells, as indicated in multiple myeloma (MM) and adult T-cell leukemia/lymphoma (ATLL). Furthermore, MIP-1, is also involved in the development of an aggressive phenotype on MCL by stimulating proliferation of these lymphoma cells. In summary, the present study demonstrated that MIP-1, is an important factor in the development of both hypercalcemia and an aggressive phenotype in some types of B-cell lymphoma. [source] Quantitative microsatellite analysis to delineate the commonly deleted region 1p22.3 in mantle cell lymphomasGENES, CHROMOSOMES AND CANCER, Issue 10 2006Asha Balakrishnan The molecular pathogenesis of mantle cell lymphomas (MCL), a subset of B-cell non-Hodgkin's lymphomas with a poor prognosis, is still poorly understood. In addition to the characteristic primary genetic alteration t(11;14)(q13;q32), several further genetic changes are present in most cases. One of the most frequent genomic imbalances is the deletion of 1p22.1,p31.1 observed in nearly one-third of MCL cases. This might indicate the presence of tumor suppressor gene(s) in this critical region of deletion. Quantitative microsatellite analysis (QuMA) is a real-time PCR-based method to detect DNA copy number changes. Since QuMA has the resolving power to detect subtle genomic alterations, including homozygous deletions, this may help to identify candidate tumor suppressor genes from deleted regions. To gain more insight into the molecular pathogenesis of MCL, QuMA was performed on genomic DNA from 57 MCL cases. Eight microsatellite loci mapping to the chromosomal region 1p22.3 were analyzed. Losses were observed in 51 of the 57 (,89.5%) samples. Two cases showed a homozygous deletion at the locus containing the gene SH3GLB1, which plays a key role in Bax-mediated apoptosis. Two hotspots with copy number losses were detected at chromosomal localizations 85.4 and 86.6 Mb encompassing BCL10 and CLCA2. Both the genes seem to be attractive candidates to study tumor suppressor function in MCL. This article contains Supplementary material available at http://www.interscience.wiley.com/jpages/1045,2257/suppmat. © 2006 Wiley-Liss, Inc. [source] Application of Direct Push Methods to Investigate Uranium Distribution in an Alluvial AquiferGROUND WATER MONITORING & REMEDIATION, Issue 4 2009Wesley McCall The U.S. EPA 2000 Radionuclide Rule established a maximum contaminant level (MCL) for uranium of 30 µg/L. Many small community water supplies are struggling to comply with this new regulation. At one such community, direct push (DP) methods were applied to obtain hydraulic profiling tool (HPT) logs and install small diameter wells in a section of alluvial deposits located along the Platte River. This work was conducted to evaluate potential sources of elevated uranium in the Clarks, Nebraska drinking water supply. HPT logs were used to understand the hydrostratigraphy of a portion of the aquifer and guide placement of small diameter wells at selected depth intervals. Low-flow sampling of the wells provided water quality parameters and samples for analysis to study the distribution of uranium and variations in aquifer chemistry. Contrary to expectations, the aquifer chemistry revealed that uranium was being mobilized under anoxic and reducing conditions. Review of the test well and new public water supply well construction details revealed that filter packs extended significantly above the screened intervals of the wells. These filter packs were providing a conduit for the movement of groundwater with elevated concentrations of uranium into the supply wells and the community drinking water supply. The methods applied and lessons learned here may be useful for the assessment of unconsolidated aquifers for uranium, arsenic, and many other drinking water supply contaminants. [source] Mantle cell lymphoma with aberrant expression of CD10HISTOPATHOLOGY, Issue 1 2008U Zanetto Aims:, Morphological, immunophenotypic and genetic heterogeneity amongst mantle cell lymphomas (MCLs) can lead to difficulties in diagnosis and management. The aim was to describe the clinical and pathological features of MCLs with aberrant expression of CD10. Methods and results:, Of 17 specimens from 13 patients, 14 expressed CD10 and three (presenting before or after a CD10+ specimen) did not. All expressed cyclin D1 and carried the t(11;14)(q13;q32)/CCND1-IGH translocation. Similar to non-selected MCL patients, most patients had disseminated disease and an adverse clinical course. Five specimens showed pleomorphic blastoid morphology and blastoid transformation was associated with a change in phenotype, including gain or loss of CD10. Additional phenotypic variations likely to cause diagnostic difficulty were present in eight specimens: five were CD5, and five (all CD10+) expressed Bcl-6. One Bcl-6+ case carried a BCL-6 translocation and three others had extra copies of the BCL-6 gene. Sequence analysis of the immunoglobulin heavy chain variable region in five cases showed only one to have low-level somatic mutation, indicating that they did not arise from germinal centre B cells. Conclusions:, Expression of CD10 by MCL is often associated with other variant morphological, immunophenotypic or genetic features, but does not reflect derivation from germinal centre B cells. [source] Unbalanced expression of licensing DNA replication factors occurs in a subset of mantle cell lymphomas with genomic instabilityINTERNATIONAL JOURNAL OF CANCER, Issue 12 2006Magda Pinyol Abstract DNA licensing is a crucial process for chromosome replication control. Deregulation of the licensing factors Cdt1, Cdc6 and the licensing inhibitor geminin has been associated with DNA replication defects and chromosomal instability. We examined the expression of these factors, in mantle cell lymphoma (MCL) and non-neoplastic lymphoid samples, and analysed the potential role of their deregulation in genomic instability. Geminin, Cdt1 and Cdc6 were coordinately expressed in non-neoplastic tissues and most MCL in relationship to the proliferative activity of the cells. However, 6 (18%) tumours showed an unbalanced "licensing signature" characterized by a higher expression of Cdt1 and Cdc6 than the negative regulator geminin. Tumours with this unbalanced signature and p53/p14ARF alterations had significantly higher number of chromosome abnormalities than lymphomas with p53/p14ARF alterations but with a normal licensing signature. No aberrations of Cdct1, Cdc6, and geminin genes were detected in cases with unbalanced licensing. However, tumours with p53/ARF inactivation and unbalanced licensing signature had significantly higher cyclin D1 levels than tumours with normal licensing signature. These results suggest that an unbalanced mRNA expression of licensing regulatory genes may play a role in the pathogenesis of the chromosomal instability of a subset of MCL with inactivation of the p53/p14ARF pathway. © 2006 Wiley-Liss, Inc. [source] Analysis of Aurora-A and hMPS1 mitotic kinases in mantle cell lymphomaINTERNATIONAL JOURNAL OF CANCER, Issue 2 2006Emma Camacho Abstract Aurora-A and hMPS1 are kinases involved in spindle checkpoint and centrosome duplication regulation and whose alterations have been associated with cell transformation and chromosome instability in different tumor models. In this study, we have examined the possible alterations of these genes in 58 mantle cell lymphomas (MCLs) and 4 MCL-related cell lines. Aurora-A was also examined in 46 diffuse large B-cell lymphomas (DLBCLs). Aurora-A and hMPS1 mRNA expression levels were related to tumor proliferative activity. Interestingly, a MCL case with the highest number or chromosomal imbalances also showed an extremely high value of Aurora-A mRNA expression. No Aurora-A gene amplifications were detected in any tumor or cell line, whereas hemizygous hMPS1 gene deletions were observed in 23% of MCLs and 3 of the 4 cell lines. However, no expression alterations or gene mutations were detected in these cases. The Aurora-A proposed cancer susceptibility polymorphic variant (P31I) was observed with a similar frequency in MCL, DLBCL, chronic lymphocytic leukemia and in the 431 healthy controls. However, the 3 MCLs and 4 DLBCLs with the homozygous variant of this polymorphism had particular clinical characteristics with an unusual early-age presentation and second epithelial malignancies in MCL and extranodal origin in DLBCL. These findings indicate that Aurora-A and hMPS1 aberrations are uncommon in aggressive lymphomas but Aurora-A overexpression may contribute to numerical chromosomal alterations in occasional MCL. Although the Aurora-A P31I polymorphic variant is not directly involved in a genetic predisposition to these lymphomas, it may modulate the clinical presentation of these tumors. © 2005 Wiley-Liss, Inc. [source] Quantitation of cytological parameters of malignant lymphocytes using computerized image analysisINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 4 2008S. A. HAMID JAHANMEHR Summary Computerized image analysis may add to morphological evaluation by turning qualitative data into quantitative values. In this study, image analysis program was used to quantitate cytological parameters of lymphocytes in B-cell lymphoproliferative disorders. Chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and B-cell prolymphocytic leukemia (B-PLL) were selected to represent typically small, medium, and large-sized lymphocytes, respectively. Image analysis was performed to determine the morphological parameters. A set of measurements was generated for quantitation of total cell area, cell diameter, cytoplasm area, nuclear area, nuclear/cell ratio, and nuclear density. The quantitated parameters substantiated morphological characteristics of the tumor cells. Comparative assessments demonstrated that CLL, MCL, and PLL can be differentiated by the quantitative descriptors. The results from image analysis may assist in defining morphological criteria and in developing quantitative cell morphology. [source] Synthesis and characterization of temperature-sensitive block copolymers from poly(N -isopropylacrylamide) and 4-methyl-,-caprolactone or 4-phenyl-,-caprolactoneJOURNAL OF APPLIED POLYMER SCIENCE, Issue 3 2010Ren-Shen Lee Abstract This study synthesizes thermally sensitive block copolymers poly(N -isopropylacrylamide)- b -poly(4-methyl-,-caprolactone) (PNIPA- b -PMCL) and poly(N -isopropylacrylamide)- b -poly(4-phenyl-,-caprolactone) (PNIPA- b -PBCL) by ring-opening polymerization of 4-methyl-,-caprolactone (MCL) or 4-phenyl-,-caprolactone (BCL) initiated from hydroxy-terminated poly(N -isopropylacrylamide) (PNIPA) as the macroinitiator in the presence of SnOct2 as the catalyst. This research prepares a PNIPA bearing a single terminal hydroxyl group by telomerization using 2-hydroxyethanethiol (ME) as a chain-transfer agent. These copolymers are characterized by differential scanning calorimetry (DSC), 1H-NMR, FTIR, and gel permeation chromatography (GPC). The thermal properties (Tg) of diblock copolymers depend on polymer compositions. Incorporating larger amount of MCL or BCL into the macromolecular backbone decreases Tg. Their solutions show transparent below a lower critical solution temperature (LCST) and opaque above the LCST. LCST values for the PNIPA- b -PMCL aqueous solution were observed to shift to lower temperature than that for PNIPA homopolymers. This work investigates their micellar characteristics in the aqueous phase by fluorescence spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering (DLS). The block copolymers formed micelles in the aqueous phase with critical micelle concentrations (CMCs) in the range of 0.29,2.74 mg L,1, depending on polymer compositions, which dramatically affect micelle shape. Drug entrapment efficiency and drug loading content of micelles depend on block polymer compositions. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010 [source] GDF-5/7 and bFGF activate integrin ,2-mediated cellular migration in rabbit ligament fibroblastsJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 2 2010Hirokazu Date Abstract Cellular activities responding to growth factors are important in ligament healing. The anterior cruciate ligament (ACL) has poor healing potential compared to the medial collateral ligament (MCL). To assess the differences, we investigated the proliferation, migration, adhesion, and matrix synthesis responding to growth factors in rabbit ACL and MCL fibroblasts. ACL cell proliferation to basic fibroblast growth factor (bFGF), bone morphogenetic protein-2, growth and differentiation factor (GDF)-5, and GDF-7 treatment was similar to that of MCL cells. GDF-5 enhanced Col1a1 expression in ACL and MCL fibroblasts up to 4.7- and 17-fold levels of control, respectively. MCL fibroblasts showed stronger migration activities in response to bFGF and GDF-5 than ACL cells. GDF-5/7 and bFGF also changed the stress fiber formation and cellular adhesion by modulating the distribution of integrin ,2. Functional blocking analyses using anti-integrin ,2 antibodies revealed that cellular migration responding to growth factors depended on the integrin ,2-mediated adhesion on type I collagen. The expression of integrin ,2 was also increased by growth factors in both cells. Our results demonstrate that GDF-5/7 and bFGF stimulate cellular migration by modulating integrin ,2 expression and integrin ,2-dependent adhesion, especially in MCL fibroblasts. These findings suggest that the different healing potential between ACL and MCL may be caused by different cellular behavior in the integrin ,2-mediated cellular migration in response to growth factors. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:225,231, 2010 [source] Periarticular ligament changes following ACL/MCL transection in an ovine stifle joint model of osteoarthritisJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 8 2007Yusei Funakoshi Abstract Anterior cruciate ligament (ACL) injuries often lead to significant functional impairment, and are associated with increased risk for induction of degenerative joint disease. However, few studies have described the effect of ligament transection on the remaining intact knee ligaments. This study sought to determine specifically what impact combined ACL/medial collateral ligament (MCL) transection had on the remaining intact knee ligaments, particularly from the histological, biochemical, and molecular perspectives. Twenty weeks post-ACL/MCL transection, the cut ends of sheep MCLs were bridged by scar, while the posterior cruciate ligaments (PCLs) and lateral collateral ligaments (LCLs) seemed gross morphologically normal. Water content and cell density increased significantly in the MCL scars and the intact PCLs but were unchanged in the LCLs. Collagen fibril diameter distribution was significantly altered in both MCL scar tissue and uninjured PCLs from transected joints. MMP-13 mRNA levels in MCL scars and PCLs from ligament transected joints were increased, while TIMP-1 mRNA levels were significantly decreased in the PCLs only. This study has shown that some intact ligaments in injured joints are impacted by the injury. The joint appears to behave like an integrated organ system, with injury to one component affecting the other components as the "organ" attempts to adapt to the loss of integrity. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:997,1006, 2007 [source] Medial collateral ligament insertion site and contact forces in the ACL-deficient kneeJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 4 2006Benjamin J. Ellis Abstract The objectives of this research were to determine the effects of anterior cruciate ligament (ACL) deficiency on medial collateral ligament (MCL) insertion site and contact forces during anterior tibial loading and valgus loading using a combined experimental-finite element (FE) approach. Our hypothesis was that ACL deficiency would increase MCL insertion site forces at the attachments to the tibia and femur and increase contact forces between the MCL and these bones. Six male knees were subjected to varus,valgus and anterior,posterior loading at flexion angles of ,0° and 30°. Three-dimensional joint kinematics and MCL strains were recorded during kinematic testing. Following testing, the MCL of each knee was removed to establish a stress-free reference configuration. An FE model of the femur,MCL,tibia complex was constructed for each knee to simulate valgus rotation and anterior translation at 0° and 30°, using subject-specific bone and ligament geometry and joint kinematics. A transversely isotropic hyperelastic material model with average material coefficients taken from a previous study was used to represent the MCL. Subject-specific MCL in situ strain distributions were used in each model. Insertion site and contact forces were determined from the FE analyses. FE predictions were validated by comparing MCL fiber strains to experimental measurements. The subject-specific FE predictions of MCL fiber stretch correlated well with the experimentally measured values (R2,=,0.95). ACL deficiency caused a significant increase in MCL insertion site and contact forces in response to anterior tibial loading. In contrast, ACL deficiency did not significantly increase MCL insertion site and contact forces in response to valgus loading, demonstrating that the ACL is not a restraint to valgus rotation in knees that have an intact MCL. When evaluating valgus laxity in the ACL-deficient knee, increased valgus laxity indicates a compromised MCL. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source] Long-term effects of porcine small intestine submucosa on the healing of medial collateral ligament: A functional tissue engineering studyJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 4 2006Rui Liang Abstract Porcine small intestinal submucosa (SIS) was previously shown to enhance the mechanical properties of healing medial collateral ligaments (MCL), and the histomorphological appearance and collagen type V/I ratio were found to be close to those of normal MCL. We hypothesized that at a longer term, 26 weeks, SIS could guide a better organized neo-ligament formation, increasing mechanical properties and increasing collagen fibril diameters mediated by a reduction in collagen type V. A 6 mm gap injury in the right MCL was surgically created in 38 rabbits, while the contralateral intact MCL served as a sham-operated control. In half the animals, a strip of SIS was sutured onto the severed ends. In the other half, no SIS was applied. The cross-sectional area (CSA) was determined with a laser micrometer system. The femur,MCL,tibia complex was mechanically tested in uniaxial tension. Histomorphology was determined through H&E and immunofluorescent staining and transmission electron microscopy (TEM). Sodium-dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) was used to determine collagen type V/I ratio. SIS-treated MCLs displayed a 28% reduction in CSA, a 33% increase in tangent modulus, and a 50% increase in tensile strength compared with the nontreated group (p,<,0.05). TEM showed groups of collagen fibrils with larger diameters in the SIS-treated ligaments in comparison with uniformly small fibrils for the nontreated group. H&E staining showed more densely stained collagen fibers in the SIS-treated group aligned along the longitudinal axis with more interspersed spindle-shaped cells. Immunofluorescent staining showed less collagen type V signals, confirmed by a 5% lower ratio of collagen type V/I compared with the nontreated controls (p,<,0.05). The findings extend the shorter term 12-week results, and support the potential of porcine SIS as a bioscaffold to enhance ligament healing. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source] Medial collateral ligament autografts have increased creep response for at least two years and early immobilization makes this worseJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 2 2002G. M. Thornton Recent evidence has shown that 10,40% of knee joints reconstructed with soft-tissue autografts have a recurrence of abnormal joint laxity over time. One possible explanation is the "stretching out" (or unrecovered creep) of the graft tissue. To test in vitro creep and creep recovery of fresh anatomic ligament autografts in an extra-articular environment, 16 rabbits underwent an orthotopic medial collateral ligament (MCL) autograft procedure to one hindlimb. Three subgroups of animals had either unrestricted cage activity for 1 year (n = 5) or 2 years (n = 5) or pin-immobilization for the first 6 weeks followed by cage activity for the remainder of 1 year (n = 6). Following laxity measurements, to test their creep response, isolated MCL grafts were cyclically and then statically creep tested in vitro at 4.1 MPa, allowed to recover at zero load for 20 min, and finally elongated to failure. Due to differences in cross-sectional area between the grafts and normal MCLs, two normal control groups were tested: stress-matched tested at 4.1 MPa (16.2 N; n = 7) and force-matched tested at 29.1 N (7.1 MPa; n = 6). Ligament grafts had normal laxity but significantly increased creep and decreased creep recovery compared to normal MCLs after 1 and 2 years of healing (p < 0.0004). Graft failure stress was also significantly less than normal (p < 0.0001). Immobilized grafts had significantly greater creep compared to non-immobilized grafts at 1 year of healing (p < 0.05). These results support previous observations concerning material inferiority of fresh anatomic rabbit MCL autografts, but add the concept that such grafts also have increased potential to creep with either slower or incomplete recovery when subjected to low stresses in vitro. Joint and ligament laxities in situ were normal in this model, however, suggesting either that in vivo MCL graft stresses are lower than those used here in vitro or that these tissues have other mechanisms by which they can recover their functional length in vivo. © 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source] ARSENIC IN THE SHALLOW GROUND WATERS OF CONTERMINOUS UNITED STATES: ASSESSMENT, HEALTH RISKS, AND COSTS FOR MCL COMPLIANCE,JOURNAL OF THE AMERICAN WATER RESOURCES ASSOCIATION, Issue 2 2006Navin Kumar C. Twarakavi ABSTRACT: A methodology consisting of ordinal logistic regression (OLR) is used to predict the probability of occurrence of arsenic concentrations in different threshold limits in shallow ground waters of the conterminous United States (CONUS) subject to a set of influencing variables. The analysis considered a number of maximum contaminant level (MCL) options as threshold values to estimate the probabilities of occurrence of arsenic in ranges defined by a given MCL of 3, 5, 10, 20, and 50 ,g/l and a detection limit of 1 ,g/l. The fit between the observed and predicted probability of occurrence was around 83 percent for all MCL options. The estimated probabilities were used to estimate the median background concentration of arsenic in the CONUS. The shallow ground water of the western United States is more vulnerable than the eastern United States. Arizona, Utah, Nevada, and California in particular are hotspots for arsenic contamination. The risk assessment showed that counties in southern California, Arizona, Florida, and Washington and a few others scattered throughout the CONUS face a high risk from arsenic exposure through untreated ground water consumption. A simple cost effectiveness analysis was performed to understand the household costs for MCL compliance in using arsenic contaminated ground water. The results showed that the current MCL of 10 ,g/l is a good compromise based on existing treatment technologies. [source] Oral leishmaniasis in a HIV-positive patient.ORAL DISEASES, Issue 1 2002Report of a case involving the palate Leishmaniasis is a parasitic disease caused by a protozoon (Leishmania), with different clinical forms that are endemic in certain countries. The association of this disease in patients who are seropositive to human immunodeficiency virus (HIV) has recently been described. Leishmaniasis can develop in any stage of HIV infection, although the clinical manifestations , and hence the diagnosis , tend to coincide with the periods of maximum immune depression. We present the case of a HIV-positive, ex-intravenous drug abuser (in stage B2 of the CDC, 1992) with concomitant hepatitis C infection who presented with palatinal pain and bleeding for the past 2 months. Exploration revealed a vegetating tumoration of the hard palate. Hematoxylin-eosin and Giemsa staining of the biopsy confirmed the diagnosis of leishmaniasis. The definitive diagnosis was mucocutaneous leishmaniasis (MCL), for a bone marrow aspirate proved negative, and no further lesions could be established. The patient was treated with meglumine antimoniate (Glucantime), followed by improvement of the lesions. [source] Identification of uniquely expressed transcription factors in highly purified B-cell lymphoma samples,,§AMERICAN JOURNAL OF HEMATOLOGY, Issue 6 2010Ulrika Andréasson Transcription factors (TFs) are critical for B-cell differentiation, affecting gene expression both by repression and transcriptional activation. Still, this information is not used for classification of B-cell lymphomas (BCLs). Traditionally, BCLs are diagnosed based on a phenotypic resemblance to normal B-cells; assessed by immunohistochemistry or flow cytometry, by using a handful of phenotypic markers. In the last decade, diagnostic and prognostic evaluation has been facilitated by global gene expression profiling (GEP), providing a new powerful means for the classification, prediction of survival, and response to treatment of lymphomas. However, most GEP studies have typically been performed on whole tissue samples, containing varying degrees of tumor cell content, which results in uncertainties in data analysis. In this study, global GEP analyses were performed on highly purified, flow-cytometry sorted tumor-cells from eight subgroups of BCLs. This enabled identification of TFs that can be uniquely associated to the tumor cells of chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hairy cell leukemia (HCL), and mantle cell lymphoma (MCL). The identified transcription factors influence both the global and specific gene expression of the BCLs and have possible implications for diagnosis and treatment. Am. J. Hematol., 2010. © 2010 Wiley-Liss, Inc. [source] Immunotherapy with live BCG plus heat killed Leishmania induces a T helper 1-like response in American cutaneous leishmaniasis patientsPARASITE IMMUNOLOGY, Issue 2 2000Maira Cabrera Previous work has shown that American cutaneous leishmaniasis (ACL) patients treated with viable BCG plus heat killed promastigotes of Leishmania amazonensis show the same rate of cure as patients receiving conventional chemotherapy. The treatment is safe and economical, but the immunological correlates of cure have not been examined. In the present study, T cell responses have been analysed in 43 ACL patients, including patient groups sampled before and after therapy, and in 10 endemic controls. Lymphocyte proliferation, interferon (IFN)-, and interleukin (IL)-5 responses to crude antigen (L. amazonensis, MEL; Mycobacterium tuberculosis PPD; M. bovis BCG) stimulation, and serum IL-5 levels, were analysed. In endemic volunteers, proliferative responses to BCG were high and IFN-, responses low. In contrast, localized cutaneous (LCL) and mucocutaneous (MCL) patients showed low proliferative and high IFN-, responses to BCG. Treatment enhanced the IFN-, response and further decreased the proliferative response to BCG, especially in MCL patients. LCL and MCL patients showed an increase in proliferative and IFN-, responses to MEL with treatment, but the response was not exaggerated in MCL patients, either before or after treatment, compared to LCL patients. IL-5 production was low in T cell assays, and > 62% of untreated patients had very low serum IL-5 levels. There were no significant changes in serum IL-5 with treatment. Overall results show enhanced antigen-specific IFN-, responses to the two components of the immunotherapy, live M. bovis BCG and heat killed L. amazonensis, which is consistent with a shift in balance of T cell response towards a T helper 1 response and clinical cure mediated by IFN-,. [source] Morphological spectrum of cyclin D1-positive mantle cell lymphoma: Study of 168 casesPATHOLOGY INTERNATIONAL, Issue 10 2001Yasushi Yatabe Immunostaining for cyclin D1 is essential for reliable diagnosis of mantle cell lymphoma (MCL). However, a small number of cyclin D1-positive lymphomas other than MCL have been encountered. Our goal was to investigate the morphological spectrum of MCL as a disease entity, based on cyclin D1 overexpression. We reviewed 181 biopsy specimens obtained from 168 cases of cyclin D1-positive MCL. Typical findings were the presence of nodular (53.9% of cases) or diffuse (46.1%) histological patterns, containing mantle zone patterns (16.8%), naked germinal centers (33.5%) and perivascular hyaline deposition (83.2%). Unusual findings of residual germinal centers with a mantle cuff (four cases) and follicular colonization (two cases) were seen. High magnification showed a monotonous proliferation of tumor cells with cytological diversity including small (3.0%), intermediate (43.1%), medium (34.1%), medium, large (13.2%) and large (6.6%) cells. Pleomorphic and blastic / blastoid variants were encountered in 9.6 and 7.2% of cases, respectively. Three cases had foci of cells of considerable size, with a moderately abundant pale cytoplasm resembling marginal zone B cells. Two cases showed an admixture of cells which appeared transformed and mimicked the histology of chronic lymphocytic leukemia / small lymphocytic leukemia. In one, neoplastic mantle zones were surrounded by sheets of mature plasma cells, resembling the plasma cell type of Castleman's disease. An admixture of areas characteristic of MCL and of other larger cells, indicating histological progression or a composite lymphoma, were observed in seven cases. In high-grade lesions of five cases, nuclear staining of cyclin D1 was rarely detected. In our experience, cyclin D1 expression was also found in nine lymphomas other than MCL (five plasma cell myelomas, three Hodgkin's disease and one anaplastic large cell lymphoma). The application of cyclin D1 staining prompted us to recognize the broad morphological spectrum of MCL. MCL can be diagnosed with the application of cyclin D1 immunostaining, if careful attention is given to architectural and cytological features. [source] Synergistic antitumor effects of lenalidomide and rituximab on mantle cell lymphoma in vitro and in vivo,AMERICAN JOURNAL OF HEMATOLOGY, Issue 9 2009Liang Zhang Rituximab (RTX), a chimeric anti-CD20 antibody, is associated with direct induction of apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) with clinical efficacy in mantle cell lymphoma (MCL). Lenalidomide (LEN), a novel immunomodulatory agent, sensitizes tumor cells and enhances ADCC. Our study attempted to elucidate the mechanism of LEN-enhanced RTX-mediated cytotoxicity of MCL cells. We found that LEN and RTX induced growth inhibition of both cultured and fresh primary MCL cells. LEN enhanced RTX-induced apoptosis via upregulating phosphorylation of c-Jun N-terminal protein kinases (JNK), Bcl-2, Bad; increasing release of cytochrome-c; enhancing activation of caspase-3, -8, -9 and cleavage of PARP. Meanwhile, LEN activated NK cells and increased CD16 expression on CD56lowCD16+ NK cells. Whole PBMCs but not NK cell-depleted PBMCs treated with LEN augmented 30% of RTX-dependent cytotoxicity. Daily treatment with LEN increased NK cells by 10-folds in SCID mice, and combination of LEN and RTX decreased tumor burden and prolonged survival of MCL-bearing SCID mice. Taken together, our study demonstrates that LEN plus RTX provides a synergistically therapeutic effect on MCL cells by enhancing apoptosis and RTX-dependent NK cell-mediated cytotoxicity and may be an optimal combination in the clinical trial of relapsed or refractory MCL. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source] Integrated modeling environment for statewide assessment of groundwater vulnerability from pesticide use in agriculture,PEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 8 2004Audra Eason Abstract Atrazine, a herbicide widely used for corn production in the Midwest, has been detected in groundwater of several states, and has been identified as a possible human carcinogen. With the widespread use of pesticides in crop production, and the frequent detection of these chemicals in groundwater, large-scale risk assessments would help water resource managers to identify areas that are more susceptible to contamination and implement practices to ameliorate the problem. This paper presents an integrated, visual and interactive system for predicting potential environmental risks associated with pesticide contamination at spatial scales ranging from fields to landscapes and regions. The interactive system extends the predictive ability of the Pesticide Root Zone Model Release 2.0 (PRZM-2) to a landscape and statewide scale through integration with a geographic information system (GIS), graphical user interface and environmental databases. Predictions of statewide (Iowa) vulnerability of groundwater from atrazine leaching below the unsaturated zone were made to demonstrate the utility of the system, and the results were used in risk assessment. In the example application, atrazine fate and transport were evaluated using long-term climatic data (1980,1989) in combination with several environmental databases (eg STATSGO soils database) and exposure risks were expressed in terms of the probability of the predicted pesticide concentrations exceeding the maximum contaminant level (MCL) for drinking water. The results indicate that the predicted pesticide concentrations were significantly lower than the EPA-established MCL. In addition to providing an interactive environment for landscape-level assessment of potential risks from pesticide leaching, the system significantly reduces the time and resources needed to organize and manipulate data for use with PRZM-2, and provides an analytical framework for evaluating groundwater-leaching impacts of pesticide management practices. Copyright © 2004 Society of Chemical Industry [source] Successful ISCR-enhanced bioremediation of a TCE DNAPL source utilizing EHC® and KB-1®REMEDIATION, Issue 3 2010James G. D. Peale Remediation of chlorinated solvent DNAPL sites often meets with mixed results. This can be attributed to the diametrically opposed nature of the impacts, where the disparate dissolved-phase plume is more manageable than the localized, high-concentration source area. A wide range of technologies are available for downgradient plume management, but the relative mass of contaminants in a DNAPL source area generally requires treatment for such technologies to be effective over the long term. In many cases, the characteristics of DNAPL source zones (e.g., depth, soil heterogeneity, structural limitations) limit the available options. The following describes the successful full-scale implementation of in situ chemical reduction (ISCR) enhanced bioremediation of a TCE DNAPL source zone. In this demonstration, concentrations of TCE were rapidly reduced to below the maximum contaminant level (MCL) in less than six months following implementation. The results described herein suggest that ISCR-enhanced bioremediation is a viable remedial alternative for chlorinated solvent source zones. © 2010 Wiley Periodicals, Inc. [source] Pilot-scale evaluation of in situ cometabolic bioremediation of TCE in groundwater using PHOSter® technologyREMEDIATION, Issue 2 2008Karl W. Eggers A study was conducted to evaluate the efficacy of PHOSter® technology for treating groundwater contaminated with trichloroethene (TCE) at Edwards Air Force Base, California. The technology consists of injecting a gaseous mixture of air, methane, and nutrients into groundwater with the objective of stimulating the growth of methanotrophs, a naturally occurring microbial group that is capable of catalyzing the aerobic degradation of chlorinated solvents into nontoxic products. Injection operations were performed at one well for a period of three months. Six monitoring wells were utilized for groundwater and wellhead vapor monitoring and for groundwater and microbial sampling. In the five monitoring wells located within 44 feet of the injection well, the following results were observed: dissolved oxygen concentrations increased to a range between 6 and 8 milligrams per liter (,g/L); the biomass of target microbial groups increased by one to five orders of magnitude; and TCE concentrations decreased by an average of 92 percent, and to below the California primary maximum contaminant level (MCL; 5 micrograms per liter [µg/L]) in the well closest to the injection well. © 2008 Wiley Periodicals, Inc., [source] JNK is constitutively active in mantle cell lymphoma: cell cycle deregulation and polyploidy by JNK inhibitor SP600125,THE JOURNAL OF PATHOLOGY, Issue 1 2009Miao Wang Abstract Mantle cell lymphoma (MCL) is characterized by genetic instability and a poor prognosis. Many blastoid variants are (hypo)tetraploid and have an even worse prognosis. We investigated the role of signalling by mitogen-activated protein kinases (MAPKs) in MCL. As compared to normal tonsil B cells, MCL cells showed higher activation of the JNK MAPK in both an MAPK array and a sandwich ELISA assay. Immunohistochemistry showed overexpression of phospho (p)-JNK (Thr183/Tyr185) in 30 of 37 MCL cases. Inhibition of p-JNK with SP600125 resulted in growth arrest in all four MCL cell lines (Jeko-1, HBL-2, UPN-1, Granta-519), which could be partly reversed by the addition of CD40L and IL-4. Furthermore, SP600125 led to G2/M phase arrest on day 1 and a striking increase in endoreduplication on day 2 and day 3, which was confirmed by karyotype analysis. G2/M arrest was associated with down-regulation of EGR1 and p21 protein expression. SP600125-induced polyploidy could be blocked by the BCL-2 inhibitor YC137. These data suggest that constitutive JNK activity is necessary to promote proliferation and maintain diploidy in MCL. JNK inhibition leads to cell cycle deregulation and endoreduplication, mimicking the tetraploid state seen in a subset of MCL cases. Thus, our data also provide an experimental model to study polyploid MCL cells. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Pai syndrome: First patient with agenesis of the corpus callosum and literature reviewBIRTH DEFECTS RESEARCH, Issue 10 2007Marco Castori Abstract BACKGROUND: Pai syndrome (PS) is a rare regional developmental defect of the face, mainly characterized by the variable association of midline cleft of the upper lip (MCL), duplicated maxillary median frenulum, and midline facial cutaneous and midanterior alveolar process polyps. Its entire clinical spectrum is still poorly delineated and the etiology remains unknown. CASE: We describe a 1-month-old boy presenting with MCL, left nostril hamartomatous mass, midline pedunculated polyp originating from the columella base, midline alveolar cleft, duplication of the upper median frenulum, unilateral persistent papillary membrane, lipoma of the corpus callosum, and additional minor facial dysmorphism. This patient also presents with agenesis of the corpus callosum, which has never been reported in PS. Literature review was carried out comparing clinical data of the 20 previously published patients with those observed in the present case. CONCLUSIONS: The minimum diagnostic criteria for PS has been fixed in one or more hamartomatous nasal polyps plus MCL (with or without cleft alveolus) and/or midanterior alveolar process congenital polyp. Additional common ancillary findings include duplicated median maxillary frenulum, hypertelorism, nasal cleft, midfrontal skin tags, and ocular and CNS structural abnormalities. However, mental retardation is only an occasional feature and seems to be related to coexisting conditions (such as chromosome imbalance). Literature review shows that PS is etiologically heterogeneous, as it may result from chromosome abnormalities and environmental/stochastic events, as well as de novo mutations. Birth Defects Research (Part A) 2007. © 2007 Wiley-Liss, Inc. [source] Phase 2 study of weekly bortezomib in mantle cell and follicular lymphomaBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2009John Gerecitano Summary Twice-weekly bortezomib has proven activity in mantle cell (MCL) and indolent lymphomas. This study explored a weekly schedule of bortezomib in follicular lymphoma (FL) and MCL. Although weekly bortezomib was better tolerated, the overall response rate (ORR) was inferior (18% vs. 50%, P = 0·02) with no complete remissions (CR) (compared with 18% CR for the twice-weekly schedule). Progression-free survival (PFS) was not different. The weekly schedule of bortezomib was less toxic, but yielded fewer and lower quality responses than twice-weekly bortezomib. Given the similar PFS, the weekly schedule may still be appropriate for some patients. [source] High-dose Ara-C and beam with autograft rescue in R-CHOP responsive mantle cell lymphoma patientsBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2009Mars B. Van't Veer Summary Mantle cell lymphoma (MCL) has a dismal outcome when treated with conventional chemotherapy. This single arm phase 2 study evaluated intensive consolidation treatment of patients with newly diagnosed MCL up to the age of 65 years, responsive to R-CHOP (rituximab, cyclophosphamide, oncovin, adriamycin, prednisolone). Endpoints for evaluation were toxicity, failure-free survival (FFS) and overall survival (OS). Eighty-seven patients were treated with three cycles of R,CHOP. Sixty-six patients responded to R-CHOP with at least a partial response, 62 continued protocol treatment with high-dose cytarabine (Ara-C; 2000 mg/m2, bid. over 4 d) and 61 patients received rituximab and stem cell harvest, followed by BEAM (carmustine, etoposide, Ara-C, melphalan) and autologous stem cell rescue. Non-haematological toxicity, grades III and IV, was seen in 8% of the patients after R-CHOP, in 22% after high-dose Ara-C and in 55% after BEAM. The overall response rate was 70% (complete response rate 64%, partial response rate 6%), FFS and OS at 4 years were 36 ± 7% and 66 ± 6%, respectively. The FFS and OS at 4 years from the evaluation after BEAM in the 61 R-CHOP responsive patients was 46 ± 9% and 79 ± 7%, respectively. In conclusion, high-dose Ara-C and BEAM with stem cell rescue in newly diagnosed MCL patients responsive to R-CHOP is a manageable treatment with respect to toxicity. This regimen leads to long-term, but probably not durable, remissions. [source] Integrated genomic and expression profiling in mantle cell lymphoma: identification of gene-dosage regulated candidate genesBRITISH JOURNAL OF HAEMATOLOGY, Issue 2 2008Margit Schraders Summary Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation and several other cytogenetic aberrations, including heterozygous loss of chromosomal arms 1p, 6q, 11q and 13q and/or gains of 3q and 8q. The common intervals of chromosomal imbalance have been narrowed down using array-comparative genomic hybridization (CGH). However, the chromosomal intervals still contain many genes potentially involved in MCL pathogeny. Combined analysis of tiling-resolution array-CGH with gene expression profiling on 11 MCL tumours enabled the identification of genomic alterations and their corresponding gene expression profiles. Only subsets of genes located within given cytogenetic anomaly-intervals showed a concomitant change in mRNA expression level. The genes that showed consistent correlation between DNA copy number and RNA expression levels are likely to be important in MCL pathology. Besides several ,anonymous genes', we also identified various fully annotated genes, whose gene products are involved in cyclic adenosine monophosphate-regulated pathways (PRKACB), DNA damage repair, maintenance of chromosome stability and prevention of rereplication (ATM, ERCC5, FBXO5), energy metabolism (such as genes that are involved in the synthesis of proteins encoded by the mitochondrial genome) and signal transduction (ARHGAP29). Deregulation of these gene products may interfere with the signalling pathways that are involved in MCL tumour development and maintenance. [source] Proliferation predicts failure-free survival in mantle cell lymphoma patients treated with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with rituximab plus high-dose methotrexate and cytarabineCANCER, Issue 5 2009Mar Garcia MD Abstract BACKGROUND: It has been demonstrated that the tumor proliferation index has prognostic significance in patients with mantle cell lymphoma (MCL). Patients in most of studies, however, have been treated with relatively traditional chemotherapy regimens. At the authors' institution, patients with MCL received an aggressive chemotherapy regimen: rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with rituximab plus high-dose methotrexate and cytarabine (R-hyper-CVAD). METHODS: The authors assessed the proliferation rate of MCL using immunohistochemistry and an antibody specific for Ki-67 in 71 untreated patients who subsequently received R-hyper-CVAD. The study group included 59 patients who had classic MCL and 12 patients who had the blastoid variant of MCL. RESULTS: For the entire study group and for the group of patients with classic MCL, a proliferation index of >20% Ki-67-positive cells was correlated significantly with shorter failure-free survival. There was no correlation between the proliferation index and overall survival. CONCLUSIONS: The current results indicated that the proliferation index in patients with MCL predicted prognosis in those who uniformly received the R-hyper-CVAD chemotherapy regimen. Cancer 2009. © 2009 American Cancer Society. [source] Long-term follow-up of autologous stem cell transplantation in patients with diffuse mantle cell lymphoma in first disease remissionCANCER, Issue 12 20032 -microglobulin, The prognostic value of, the tumor score Abstract BACKGROUND The current study was conducted to analyze the long-term results of autologous stem cell transplantation (ASCT) in patients with diffuse mantle cell lymphoma (MCL) in first disease remission. METHODS Thirty-three patients were treated. Thirty-one patients had Ann Arbor Stage III or Stage IV disease. The hyper-CVAD regimen (hyperfractionated intense-dose cyclophosphamide, vincristine, continuous intravenous infusion of doxorubicin, and dexamethasone, alternating with high doses of cytarabine and methotrexate plus leucovorin rescue) was used for cytoreduction before ASCT. Patients were consolidated with high-dose cyclophosphamide (120 mg/kg), total body irradiation, and ASCT. RESULTS At a median follow-up of 49 months, the overall survival and disease-free-survival rates at 5 years were estimated to be 77% and 43%, respectively. Patients whose M. D. Anderson Lymphoma Tumor Score (TS) was , 1 at the time of diagnosis or transplantation experienced longer disease-free survival compared with those whose TS was > 1 (P = 0.02). A ,2 -microglobulin (,2m)level , 3 mg/L at the time of diagnosis or transplantation was also found to be strongly predictive of longer survival (5-year survival rate of 100% vs. 22% in patients with a ,2m level > 3 mg/L) (P = 0.0001). CONCLUSIONS ASCT may prolong the overall survival in a subset of patients with MCL. This improvement has been observed for the most part in patients with low ,2m levels (, 3 mg/L) and TS (, 1). Randomized trials are required to fully assess the benefits of this strategy. Cancer 2003;98:2630,5. © 2003 American Cancer Society. [source] Potential efficacy of the oral histone deacetylase inhibitor vorinostat in a phase I trial in follicular and mantle cell lymphomaCANCER SCIENCE, Issue 1 2010Takashi Watanabe Vorinostat (suberoylanilide hydroxamic acid, SAHA, Zolinza) is a histone deacetylase inhibitor with clinical activity in cutaneous T-cell lymphoma (CTCL). A phase I trial of oral vorinostat was conducted in Japanese patients with malignant lymphoma. Vorinostat 100 or 200 mg was administered twice daily for 14 consecutive days followed by a 1-week rest interval. Of 10 patients enrolled, four had follicular lymphoma (FL), two mantle cell lymphoma (MCL), two diffuse large B-cell lymphoma, and two CTCL (median age, 60 years; median number of prior regimens, 3). Vorinostat was well tolerated up to 200 mg with only one of six patients developing a dose-limiting toxicity (DLT; Grade 3 anorexia/hypokalemia). Common Grade 3 events were reversible neutropenia (30%), thrombocytopenia, and hypermagnesemia (20% each). The median number of treatment cycles was five (range, 1,36); two patients were continuing treatment. The overall response rate was 40%, with two complete responses/unconfirmed (CRu) and one partial response among FL patients and one CRu among MCL patients. One FL patient maintained CRu for 18.0 months. The median time to achieve CRu among the three patients was 8 months. These data suggest that further investigations of vorinostat in non-Hodgkin lymphoma, focusing on FL and MCL, are warranted. (Cancer Sci 2009) [source] | ||||||||||||||||||||||||||||||||||||||||