Posted by rob on September 21, 2004 under Uncategorized | 
By Jennifer Bails
TRIBUNE-REVIEW
Tuesday, September 21, 2004
Unlike Disney’s Nemo or Charlie the Tuna, the thousands of zebra fish that live in the University of Pittsburgh’s Biomedical Science Tower South don’t have cute names.
In fact, an advanced degree in molecular genetics would come in handy when trying to make sense of how scientists classify their hordes of black-and-white striped fish.
Glomus absent M3612, No isthmus, GFP-Lin 1 — these are just a few of the zebra fish strains researchers at the University of Pittsburgh School of Medicine hope will help them identify genes involved in human disease and understand how people develop from the moment sperm fertilizes egg.
Zebra fish are becoming increasingly popular among scientists — joining the menagerie of so-called model organisms, such as fruit flies and mice — to address questions that can’t be studied easily in humans.
Last year, Pitt’s medical school jumped in by constructing the city’s first large-scale zebra fish facility, which can hold about 3,100 tanks and 10,000 fish the size of a pinkie. It is a not-so-dry run for the even bigger, $1.5 million zebra fish system the university plans to erect in the life sciences research center under construction on Fifth Avenue in Oakland.
By spring, the center should house one of the largest zebra fish facilities in the United States, with about 10,000 tanks containing more than 350,000 fish.
“For any large university interested in being on the cutting edge of developmental research, a large zebra fish facility is definitely an asset,” said Heather Stickney, a biologist who works in one of the nation’s foremost zebra fish labs, at the Stanford School of Medicine in California.
“In many ways, zebra fish are ideal to work with,” Stickney said. “They have a lot of the benefits of invertebrate organisms like worms and flies, but they are genetically much closer to humans.”
The University of Pittsburgh School of Medicine has recruited five leading zebra fish researchers from prestigious labs at Harvard University and the National Institutes of Health.
These efforts are part of an initiative led by the medical school dean, Dr. Arthur Levine, to make Pitt a hub for zebra fish research, which started at the University of Oregon in the early 1970s and has been making a splash ever since.
“Over the last decade, there has been a growing realization amongst developmental biologists and geneticists that the zebra fish is an unusually useful model for exploring the molecular basis of development,” said Levine, who helped to launch a zebra fish facility at the NIH in the early 1990s.
More than 1,000 researchers worldwide now work with zebra fish as a model organism. By the end of next year, this rising star of science will become the third vertebrate to have its genome sequenced, together with the human and the mouse.
So why are scientists so enamored with a tropical aquarium fish you can buy at the local pet store for 60 cents?
One advantage of zebra fish is that, unlike mice, they can be kept together in high densities in a small space, said Neil Hukriede, an assistant professor of molecular genetics and biochemistry who came to Pitt from the NIH almost two years ago.
Designed by research associate Paul Ulanch, an aquarium hobbyist, Pitt’s current fish rooms resemble a well-stocked library — only instead of books, the shelves are lined with clear plastic containers teeming with fish.
Grouped according to size and genetic makeup, the fish are fed a combination of brine shrimp and flake food, usually twice a day. Their water quality and light exposure are regulated to create the perfect conditions for frequent spawning.
Slight changes in temperature, salt concentration or pH trigger an electronic alarm that sends researchers scrambling to make sure the labyrinthine network of water purifiers, filters and pumps is working properly.
Aside from saving space, zebra fish also make useful models because they have backbones. As a result, they are more likely to share genetic similarities with humans than the invertebrate fruit fly, Hukriede said. This means that most zebra fish genes have a human counterpart, or homolog, with a similar function, he said.
But to developmental biologists, the true beauty of the zebra fish lies in its transparent embryos, which grow outside the mother’s body instead of in a uterus. Scientists can watch under a microscope as the cells of the embryo divide to form a recognizable fish within the first 24 hours of life.
To find out what genes orchestrate the stages of early development, scientists treat male zebra fish with a chemical that induces mutations in their sperm cell DNA. Then they breed the fish, examine the embryos in later generations for visible malformations, and pinpoint the gene responsible. The next step is to see whether the human version of this gene is mutated in people afflicted by disease.
“The ultimate promise (of zebra fish research) is knowledge that will lead to sufficient understanding of human disease and disorders such that we may be able to prevent them,” Levine said.
For example, Hukriede is trying to determine how mutations in two zebra fish genes affect vertebrate kidney development, which could lead to new treatments other than kidney dialysis and organ transplant.
Nearby, in the medical school’s ophthalmology department, assistant professor Xiangyun Wei is identifying gene mutations that affect the development of the zebra fish retina.
“If we know the principles of how retinal cells organize, we might in the future be able to engineer an artificial retina,” Wei said.
Dr. Nathan Bahary, an oncologist at the University of Pittsburgh Medical Center, is trying to create a mutant strain of zebra fish that has chronic myelogenous leukemia — a cancer of the bone marrow that results when white blood cells divide uncontrollably. It is associated with mutations in a gene called ABL1, which has a homolog in zebra fish. Bahary hopes to make his fish leukemic by inducing this particular mutation in their DNA.
These fish could be used to test the effectiveness of potential cancer treatments simply by adding the drugs to the tank water, Bahary said.
Bahary also is using zebra fish to study the development of blood and the gut, to determine how to halt the spread of cancer and to search for new treatments for inflammatory bowel disease.
“It’s such a good model for so many different things,” said Bahary, who is also an assistant professor of molecular genetics and biochemistry.
Zebra fish research is still in its early stages compared with work on the fruit fly and mouse. But Pitt’s new facility should position the university’s medical school as a leader in the nascent field.
“This has been a useful scientific adventure for others in the world, and it certainly should be for us,” Levine said.
Jennifer Bails can be reached at jbails@tribweb.com or (412) 320-7991.
http://pittsburghlive.com/x/tribune-review/health/s_253315.html
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Oktoberfest visitors ride in a roller coaster in front of Munich’s landmark Frauenkirche
Posted by rob on September 20, 2004 under Uncategorized |
Two models cross each other on the catwalk as they show an outfit by designer Ronit Zilkha during her Spring/Summer 2005 show at the London fashion week in London.
Posted by rob on September 19, 2004 under Uncategorized |
Effects of the tyrosine kinase inhibitor Imatinib mesylate (STI571) on bone marrow features in patients with chronic myelogenous leukemia.
Preliminary data are available about bone marrow (BM) changes in patients with chronic myeloid leukemia (CML) who received the molecularly targeted and highly effective tyrosine kinase inhibitor Imatinib mesylate (STI571). This review is focused on a systematic assessment of BM features detectable at different stages of CML (stable, accelerated, blastic) following long-term (more than 10 months) treatment. By applying enzyme- and immunohistochemistry including monoclonal antibodies visualizing proliferating cell nuclear antigen (PCNA) and apoptosis (anti-apostatin), a more elaborate insight into alterations affecting hematopoiesis and the stroma compartment was gained. In patients with stable-phase CML therapy resulted in a significant reduction in cellularity, neutrophil granulopoiesis and number of megakaryocytes, accompanied by a retrieval of erythroid precursors. In patients with Imatinib as the only treatment morphometric analysis of CD61+ megakaryopoiesis was in keeping with a significant decrease in maturation defects implying a lesser amount of atypical micromegakaryocytes almost consistent with normalization. Moreover, a reduction of the initially enhanced (CD34+) microvessel density was detectable associated with a decrease in luminal distension. Regression of marked to moderate myelofibrosis was recognizable in about 70% of patients especially in the accelerated and blastic phases. The amount of myeloblasts, CD34+ progenitor cells and lysozyme-expressing immature myelomonocytic cells declined with treatment, but recurred in about 19% of patients that developed a leukemic relapse after 21+/-6 months of therapy. Data on proliferative activity and apoptosis in general supported in vitro findings concerning the inhibitory effect of this agent on growth associated with a tendency for stimulated apoptosis, at least in responding patients.
http://www.hubmed.org/display.cgi?issn=02133911&uids=15375771
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Clinical Studies of Antisense Oligonucleotides for Cancer Therapy.
Until now, the clinical demise of cancer has relied on surgical resection and the inhibition of tumor cell proliferation using ionizing radiation or chemotherapeutic drugs designed to perturb DNA synthesis or the mitotic event. The development of cytotoxic agents has resulted in improvements in the treatment of leukemia, lymphoma, testicular cancer, and many other solid tumor types. Hormone-based drugs have also been useful for breast and prostate cancers. Although much success has been achieved, cytotoxic modalities walk the therapeutic tightrope of toxicities to normal tissues vs cancer cells, and drug resistance is generally present de novo or develops with treatment. Over the last decade or so, more attention has been focused on different therapeutic approaches. These include the development of monoclonal antibodies (MAbs) to specifically target cancer cells, and small molecule-inhibitors of cell-signaling pathways that have been linked to oncogenesis or maintenance of the malignant phenotype. For example, the former approach has seen the development and licensing of Herceptin(R) (trastuzumab; Genentech/Roche), a humanized MAb that targets erbB2/HER2, a receptor tyrosine kinase that is overexpressed in some 30% of breast cancers and has shown promising clinical activity when used in combination with other drugs for the treatment of metastatic breast cancer. Promising small-molecule inhibitors of cell-signaling pathways include Gleevec trade mark (STI571, imitanib mesylate; Novartis) and Iressa trade mark (ZD1839, gefitinib; AstraZeneca). Gleevec is a small-molecule inhibitor (a phenylaminopyridine) of the tyrosine kinase encoded by the abl gene. In chronic myelogenous leukemia (CML), a chromosomal translocation forms the Philadelphia chromosome that expresses a bcr/abl gene resulting in the expression of a constitutively active Abl tyrosine kinase. Gleevec has shown excellent clinical activity against CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Gleevec is not uniquely selective for inhibition of Abl tyrosine kinase and has additional inhibitory activities against the c-Kit receptor tyrosine kinase and the platelet-derived growth factor receptor tyrosine kinase. Resistance to Gleevec characterized by overexpression or mutations in the bcr/abl gene is now emerging.
http://www.hubmed.org/display.cgi?issn=15431894&uids=15375314
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Correlation between CXCR4 and Homing or Engraftment of Acute Myelogenous Leukemia.
http://www.hubmed.org/display.cgi?issn=00085472&uids=15375005
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Blocking the Raf/MEK/ERK Pathway Sensitizes Acute Myelogenous Leukemia Cells to Lovastatin-Induced Apoptosis.
The statin family of drugs are well-established inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase and are used clinically in the control of hypercholesterolemia. Recent evidence, from ourselves and others, shows that statins can also trigger tumor-specific apoptosis by blocking protein geranylgeranylation. We and others have proposed that statins disrupt localization and function of geranylgeranylated proteins responsible for activating signal transduction pathways essential for the growth and/or survival of transformed cells. To explore this further, we have investigated whether the mitogen-activated protein kinase (MAPK) signaling cascades play a role in regulating statin-induced apoptosis. Cells derived from acute myelogenous leukemia (AML) are used as our model system. We show that p38 and c-Jun NH(2)-terminal kinase/stress-activated kinase MAPK pathways are not altered during lovastatin-induced apoptosis. By contrast, exposure of primary and established AML cells to statins results in significant disruption of basal extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Addition of geranylgeranyl PP(i) reverses statin-induced loss of ERK1/2 phosphorylation and apoptosis. By establishing and evaluating the inducible Raf-1:ER system in AML cells, we show that constitutive activation of the Raf/MAPK kinase (MEK)/ERK pathway significantly represses but does not completely block lovastatin-induced apoptosis. Our results strongly suggest statins trigger apoptosis by regulating several signaling pathways, including the Raf/MEK/ERK pathway. Indeed, down-regulation of the Raf/MEK/ERK pathway potentiates statin-induced apoptosis because exposure to the MEK1 inhibitor PD98059 sensitizes AML cells to low, physiologically achievable concentrations of lovastatin. Our study suggests that lovastatin, alone or in combination with a MEK1 inhibitor, may represent a new and immediately available therapeutic approach to combat tumors with activated ERK1/2, such as AML.
http://www.hubmed.org/display.cgi?issn=00085472&uids=15374955
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Some 31,000 students, faculty and alumni of the Polytechnic University of the Philippines create a “human rainbow” in a move to boost the image of the school and a bid to set a new record for world’s largest human rainbow in the Guiness Book of World Records.
Posted by rob on September 18, 2004 under Uncategorized |
A road lies covered by sand and many homes are completely missing after Hurricane Ivan hit Naverre Beach, Florida
Posted by rob on September 17, 2004 under Uncategorized |
Diosgenin induces cell cycle arrest and apoptosis in human leukemia K562 cells with the disruption of Ca(2+) homeostasis.
PURPOSE. Diosgenin is a steroidal sapogenin with estrogenic and antitumor properties. In order to elucidate the mechanism of its antiproliferative activity, we investigated its effects on the cell cycle and apoptosis in human chronic myelogenous leukemia K562 cells. METHODS. Cell viability was assessed via an MTT assay. Apoptosis was investigated in terms of nuclear morphology, DNA fragmentation, and phosphatidylserine externalization. Cell cycle analysis was performed via PI staining and flow cytometry (FCM). Western blotting and immunofluorescence methods were used to determine the levels of p53, cell cycle-related proteins and Bcl-2 family members. FCM was also used to estimate the changes in mitochondrial membrane potential (MMP), intracellular Ca(2+) concentration and reactive oxygen species (ROS) generation. RESULTS. Cell cycle analysis showed that diosgenin caused G(2)/M arrest independently of p53. The levels of cyclin B1 and p21(Cip1/Waf1) were decreased, whereas cdc2 levels were increased. Subsequent apoptosis was demonstrated with the dramatic activation of caspase-3. A dramatic decline in intracellular Ca(2+) concentration was observed as an initiating event in the process of cell cycle arrest and apoptosis, which was followed by the hyperpolarization and depolarization of MMP. Generation of ROS was observed in the progression of apoptosis. The antiapoptotic Bcl-2 and Bcl-x(L) proteins were downregulated, whereas the proapoptotic Bax was upregulated. CONCLUSIONS. Diosgenin inhibits K562 cell proliferation via cell cycle G(2)/M arrest and apoptosis, with disruption of Ca(2+) homeostasis and mitochondrial dysfunction playing vital roles.
http://www.hubmed.org/display.cgi?issn=03445704&uids=15372201
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CD25 Indicates the Neoplastic Phenotype of Mast Cells: A Novel Immunohistochemical Marker for the Diagnosis of Systemic Mastocytosis (SM) in Routinely Processed Bone Marrow Biopsy Specimens.
The diagnosis of systemic mastocytosis (SM) is based primarily on the histologic and immunohistochemical evaluation of a bone marrow trephine biopsy specimen. Although mast cell (MC) specific antigens like tryptase and chymase are detectable in routinely processed tissue, no immunohistochemical markers that can be used to discriminate between normal and neoplastic MCs are yet available. We have investigated the diagnostic value of an antibody against CD25 for the immunohistochemical detection of MCs in bone marrow sections in 73 patients with SM and 75 control cases (reactive marrow, n = 54; myelogenous neoplasms, n = 21) and correlated the results with the presence of c-kit mutations. While MCs in almost all patients with SM (72 of 73) expressed CD25, none of the control samples contained CD25-positive MCs. Irrespective of the SM subtype, most of neoplastic MCs expressed CD25. In 3 patients with advanced MC disease, pure populations of neoplastic MCs were obtained and found to express CD25 mRNA by RT-PCR analysis. In addition, all patients with CD25-positive MCs contained c-kit mutations, while all control cases exhibited wild type c-kit. CD25 therefore appears to be a reliable immunohistochemical marker for the discrimination of neoplastic from normal/reactive MCs, with potential as a diagnostic tool in SM.
http://www.hubmed.org/display.cgi?issn=01475185&uids=15371947
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p14(ARF), p15(INK4b) and p16(INK4a) Methylation Status in Chronic Myelogenous Leukemia.
The INK4 family of proteins p15(INK4b), p14(ARF) and p16(INK4a) function as cell cycle inhibitors where they are involved in the inhibition of G1 phase progression. Methylation of the p15(INK4b) promoter never seems to occur in solid tumors but is a major gene silencing mechanism in hematological malignancies. p14(ARF) and p16(INK4a) promoter methylation often occurs in solid tumors but also in leukemias and lymphomas. In chronic myelogenous leukemia (CML), only a few reports have been published regarding INK4 methylation and the results of the literature are discordant. Thus clearly, more works on large series have to be performed independently.
http://www.hubmed.org/display.cgi?issn=10428194&uids=15370242
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Central Nervous System Relapse in Two Patients with Chronic Myelogenous Leukemia in Myeloid Blastic Phase on Imatinib Mesylate Therapy.
We report two patients with Philadelphia (Ph) chromosome positive chronic myelogenous leukemia (CML) in myeloid blastic phase that developed central nervous system disease while on imatinib mesylate therapy. Patient 1 presented with CML in myeloid blastic phase and responded to imatinib, cytarabine, and idarubicin-based treatment achieving complete cytogenetic remission in the marrow, but developed myeloid blasts in his cerebrospinal fluid (CSF) during treatment. Patient 2 developed CML myeloid blastic phase after initially being in hematologic and cytogenetic remission with imatinib treatment. He represented with an extramedullary mass at the base of his skull and CSF involvement. Both patients were treated with intrathecal chemotherapy and received craniospinal irradiation to clear the spinal fluid of disease. Both patients have undergone related allogeneic stem cell transplant and are in complete hematologic remission; one is in complete cytogenetic remission, the other is too early to evaluate. Central nervous system involvement with myeloid blasts is previously unreported for patients with CML in blastic phase on imatinib and warrants cautious observation and vigilance in these patients.
http://www.hubmed.org/display.cgi?issn=10428194&uids=15370215
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Birds silhouetted by the evening sun sit along electric wires at the village of Tyazhino, some 50 km (31 miles) from the capital Moscow.
Posted by rob on September 16, 2004 under Uncategorized |
Comparison of two new classifications for pediatric myelodysplastic and myeloproliferative disorders.
BACKGROUND: The category, cytology, cytogenetics (CCC) system for myelodysplastic syndrome (MDS) and the pediatric WHO system for MDS/myeloproliferative disorder (MPD) have recently been proposed to characterize these diseases in pediatrics. OBJECTIVE: We compare the CCC and pediatric WHO systems against each other and against the French, American, British (FAB) and adult WHO classifications in order to determine which more accurately classifies these diseases and predicts outcome. METHODS: An 18-year retrospective review identified patients less than 18 years of age meeting CCC and/or pediatric WHO criteria for the diagnosis of MDS or MPD. Resolution, stability, progression, and death in the subcategories of each system were compared. RESULTS: Twenty-eight patients were included in the study. Pediatric WHO: 17 patients met criteria, 10 died. Eight developed acute myelogenous leukemia (AML) (seven died), one juvenile myelomonocytic leukemia (JMML) (died), one chronic myelomonocytic leukemia (CMML) (currently in relapse), two died of complications, two responded to BMT, three have stable disease, one resolved. Eleven patients were not classifiable by the pediatric WHO system, one of which progressed to AML and died. CCC: 26 patients met criteria, 9 died. Nine developed AML (8 died), 1 died of complications, 10 responded to treatment (BMT and/or chemotherapy). Four are stable without treatment, two resolved. Two patients with MPD were not classifiable by the CCC system. CONCLUSIONS: Both the pediatric WHO and CCC systems are better able to classify MDS in children than the adult WHO and FAB classifications. The pediatric WHO system is more exclusive. Children meeting these criteria are more likely to progress to AML or death. The restrictive nature of the pediatric WHO system was unable to classify one case of fatal MDS. The CCC system is more inclusive and can stratify patients into a neutral or poor prognosis based upon outcome. However, the CCC system ignores those diseases with a myeloprolifferative component. This resulted in two cases of MPD that were unclassifiable by the CCC system. One of these patients died, the other is currently in relapse. Copyright 2004 Wiley-Liss, Inc.
http://www.hubmed.org/display.cgi?issn=15455009&uids=15368549
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Inhibition of bcr-abl and/or c-abl gene expression by small interfering, double-stranded RNAs.
BACKGROUND: Short, 21-mer, double-stranded/small interfering RNAs (ds/siRNAs) were designed to target bcr-abl mRNA in chronic myelogenous leukemia (CML) with a potential also to target c-abl mRNA. METHODS: ds/siRNAs were transfected into bcr-abl-positive K-562 cells (derived from blast-crisis) or bcr-abl-negative/c-abl-positive Jurkat cells (derived from acute lymphoblastic leukemia) using lipofectamine. ds/siRNAs intracellular uptake was detected by fluorescent confocal microscopy using fluorescein-labeled ds/siRNAs. The treatment was performed over 6 days with repetitive siRNA transfections. Efficiency of the siRNAs was determined 24 hours after single siRNA transfection and 6 days after repetitive siRNA transfections. RESULTS: Two of the designed ds/siRNAs decreased the target mRNA levels markedly (determined by reverse transcriptase-polymerase chain reaction analysis) and bcr-abl/c-abl oncoproteins (determined by flow cytometry using Fluor-488-labeled, anti-c-abl antibody as well as by Western blot analysis). These sequences also inhibited protein tyrosine kinase activity significantly and suppressed cell proliferation. One of the three selected ds/siRNAs expressed only slight effects on the bcr-abl/c-abl mRNA in K-562 cells (but not on the oncoprotein level), on protein tyrosine kinase activity, and on cell proliferation. The combination of the three ds/siRNA constructs provoked stronger decreases in bcr-abl/c-abl mRNAs and their respective oncoproteins and produced the strongest suppression of cell proliferation. CONCLUSIONS: The cross-talk between siRNA interference of bcr-abl oncogene and the expression of several apoptotic/antiapoptotic factors, cell proliferation factors, and other oncogenes exists and it was determined by microarray analysis in K-562 cells that were treated over 6 days. Cancer 2004. Copyright 2004 American Cancer Society.
http://www.hubmed.org/display.cgi?issn=0008543X&uids=15368327
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Gefitinib reverses breast cancer resistance protein-mediated drug resistance.
Breast cancer resistance protein (BCRP) is an ATP binding cassette transporter that confers resistance to a series of anticancer agents such as 7-ethyl-10-hydroxycamptothecin (SN-38), topotecan, and mitoxantrone. In this study, we evaluated the possible interaction of gefitinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, with BCRP. BCRP-transduced human epidermoid carcinoma A431 (A431/BCRP) cells acquired cellular resistance to gefitinib, suggesting that BCRP could be one of the determinants of gefitinib sensitivity in a certain sort of cells. Next, the effect of gefitinib on BCRP-mediated drug resistance was examined. Gefitinib reversed SN-38 resistance in BCRP-transduced human myelogenous leukemia K562 (K562/BCRP) or BCRP-transduced murine lymphocytic leukemia P388 (P388/BCRP) cells but not in these parental cells. In addition, gefitinib sensitized human colon cancer HT-29 cells, which endogenously express BCRP, to SN-38. Gefitinib increased intracellular accumulation of topotecan in K562/BCRP cells and suppressed ATP-dependent transport of estrone 3-sulfate, a substrate of BCRP, in membrane vesicles from K562/BCRP cells. These results suggest that gefitinib may overcome BCRP-mediated drug resistance by inhibiting the pump function of BCRP. Furthermore, P388/BCRP-transplanted mice treated with combination of irinotecan and gefitinib survived significantly longer than those treated with irinotecan alone or gefitinib alone. In conclusion, gefitinib is shown to interact with BCRP. BCRP expression in a certain sort of cells is supposed to be one of the determinants of gefitinib sensitivity. Gefitinib inhibits the transporter function of BCRP and reverses BCRP-mediated drug resistance both in vitro and in vivo.
http://www.hubmed.org/display.cgi?issn=15357163&uids=15367706
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Extreme leucocytosis and splenomegaly in metastasised melanoma.
A 63-year-old woman presented to the internist with fatigue, cough, low-grade fever, splenomegaly and leucocytosis up to 130 x 10(9)/l. Although a diagnosis of chronic myelogenous leukaemia was initially entertained, she turned out to have a metastasised melanoma. The differential diagnosis and workup is discussed, as well as potential mechanisms by which the tumour could have induced the leucocytosis, such as the production of G-CSF or similar mediators, and the prognostic significance of this phenomenon.
http://www.hubmed.org/display.cgi?issn=03002977&uids=15366701
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