Pic Of The Day
Posted by rob on August 31, 2004 under Uncategorized | 
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Hundreds of starlings fly over the city of Angers, France, at sunset.
Pic Of The Day
Posted by rob on August 30, 2004 under Uncategorized | Be the First to Comment
Runners take part in the marathon, the last event of the 2004 Olympic Games
Pic Of The Day
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Dancers perform in a symbolic wheat field during the closing ceremony of the Olympic Games
How to Kill Cancer So It Doesn’t Grow Back
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Quest Seems as Elusive as Hercules’s Second Labor
By Rob Stein
Washington Post Staff Writer
Monday, August 30, 2004; Page A13
In Greek mythology, a terrifying swamp monster known as Hydra would regrow two heads for every one lost when one of the serpent’s many necks was severed, making the beast nearly impossible to slay. Modern scientists think they may have discovered why cancer often behaves like Hydra, refusing to die despite every seemingly mortal blow that medicine inflicts upon it.
Current cancer therapies may attack only the equivalent of Hydra’s head — the majority of cancer cells removed by surgery or destroyed by radiation and chemotherapy. Spared is a crucial pool of mutant cells that acts as the source of the malignancy, leaving the cancer able to rise again and again.
According to this theory, which has steadily been gaining credence, the only effective strategy for defeating cancer will be found in treatments that stanch cancer’s ability to regrow, such as what Hercules did when he finally slew the beast of ancient Greece by cauterizing each of the monster’s necks.
In the case of cancer, the solution would lie in stamping out the highly specialized cells, known as cancer stem cells, that appear to give rise to the cancer in the first place. Such cells are largely impervious to current treatments, enabling them to lurk silently until they repeatedly spawn new tumors, either in the same part or in other parts of the body.
“What we’ve been doing is simply making the tumor shrink — leaving the equivalent of the source of the head behind. So it just regrows,” said Michael Clarke, a professor of medicine at the University of Michigan in Ann Arbor, who has found evidence for the existence of breast cancer stem cells. “We need to figure out how to sever the head so it doesn’t grow back.”
In addition to breast cancer, scientists have produced evidence for the existence of cancer stem cells in two leukemias and a variety of brain cancers.
In the most recent evidence, published in the Aug. 12 issue of the New England Journal of Medicine, researchers at Stanford University showed that among the millions of cancerous cells found in patients suffering from chronic myelogenous leukemia, only a small, discrete population had the ability to replenish the cancer.
“We showed that only certain cells have the ability to self-renew,” said Irving Weissman, who directs Stanford’s Institute for Cancer/Stem Cell Biology and Medicine.
These cells appear to have specific characteristics — they are mutant versions of normal stem cells, which are the immature versions of all cells that have been the focus of attention in recent years because of their potential for treating a host of ailments.
It remains unclear how cancer stem cells originate. But they probably arise as a result of genetic defects or exposure to toxins, researchers said.
“Normal stem cells are regulated by the body to make just the amount you need,” Weissman said. “But a cancer stem cell has broken out of that control. It self-renews in an unregulated fashion. Its self-renewal gets way too big.”
Regardless of the cause, scientists are urgently trying to identify cancer stem cells for every type of malignancy.
“We’re going to keep going through each and every human cancer to isolate each of the cancer stem cells and show what their properties are so one can look for new kinds of therapies,” Weissman said.
Identifying the properties of the cancer stem cells could provide crucial information, according to Peter Dirks, a neurosurgeon at the University of Toronto who has found evidence for cancer stem cells in every form of brain cancer he has examined.
Brain cancer tumors that tend to be more aggressive appear to have higher concentrations of cancer stem cells, he said. “We’re trying to apply this to patient prognosis,” Dirks said. “This may identify which tumors are most likely to respond to treatment but then relapse.”
Scientists trying to understand cancer better at a fundamental level should focus their efforts on cancer stem cells, he said.
“A lot of research on cancer involves the whole tumor mass,” Dirks said. “If you study the expression of genes in all those cells you may not be studying the genes that are the most important.”
But perhaps the most important implication is that identifying and understanding cancer stem cells could lead to more potent treatments.
“If you think about the basis for leukemia treatment, generally it is predicated on the idea that leukemia cells grow faster than the normal cells. So that’s what it goes after,” said John E. Dick, a professor of molecular genetics at the University of Toronto, who discovered cancer stem cells for acute myelogenous leukemia.
“But these cells aren’t. These leukemia stem cells are resting. They behave just like a normal stem cell. They sit there and eventually will regrow the leukemia,” Dick said. “It’s critically important to understand these leukemia stem cells so we can target them.
“What we need to be able to do is identify these cancer stem cells to understand their properties so we can begin to be more strategic and kill the cancer at its source, which are these cancer stem cells.”
That is exactly what Craig T. Jordan, a professor of medicine at the University of Rochester, has started to try to do. Jordan has identified a molecular switch involved in cell survival that appears to be unique to leukemia stem cells and absent from normal blood stem cells. “We don’t think normal treatments would hit this target, which is why patients relapse,” he said.
Jordan has begun testing drugs that, at least in the laboratory, appear highly effective at killing leukemia stem cells while sparing healthy stem cells, he said.
“It looks fantastic in the lab. In the laboratory we can very effectively kill the tumor without killing the normal stem cells,” he said.
A preliminary trial involving leukemia patients has begun at the University of Kentucky, Jordan said.
“It’s finally getting to the exciting point,” he said.
© 2004 The Washington Post Company
http://www.washingtonpost.com/wp-dyn/articles/A44941-2004Aug29.html
C-KIT expression in primary cutaneous T-cell lymphomas
Posted by rob on August 29, 2004 under Uncategorized | Be the First to Comment
C-KIT expression in primary cutaneous T-cell lymphomas.
J Cutan Pathol. 2004 Oct ; 31(9): 577-82
Background: Mutations of the stem cell factor receptor C-KIT play a major pathogenetic role in the development of different malignant diseases like human mastocytosis, myeloproliferative disorders, gastrointestinal stromal tumors, acute myelogenous leukemia, and sinonasal lymphomas. Furthermore, the expression of C-KIT has been described in Hodgkin’s disease and nodal CD30(+) anaplastic large cell lymphomas (ALCLs). As it is possible to inhibit C-KIT by innovative kinase inhibitors like STI571, it may be an attractive target for new therapeutical approaches. Therefore, we screened more than 50 different types of cutaneous T-cell lymphomas (TCLs) for the presence of C-KIT. Immunohistochemical stainings were performed on paraffin-embedded tissue sections using a polyclonal rabbit anti-human C-KIT antibody. Naphtol-ASD-chloroacetate esterase (NASDCE)-control stainings were performed on every positive sample to distinguish C-KIT-positive lymphoma cells from C-KIT-positive mast cells. Results: We found weak expression of C-KIT in seven of 18 patients with primary cutaneous CD30(+) ALCL, two of eight patients with primary cutaneous pleomorphic TCL, six of 18 patients suffering from mycosis fungoides, and three of five patients with Sezary’s syndrome. Generally, only a very small population of the lymphoma cells expressed C-KIT. This finding indicates a difference to the systemic variant of CD30(+) ALCL. The potential use of C-KIT targeting new therapeutical approaches is therefore discussed critically, because C-KIT expression is very rare in all investigated types of primary cutaneous lymphoma. Brauns TC, Schultewolter T, Dissemond J, Maschke J, Goos M. C-KIT expression in primary cutaneous T-cell lymphomas.
http://www.hubmed.org/display.cgi?issn=03036987&uids=15330987
Dawn of Aurora kinase inhibitors as anticancer drugs
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Dawn of Aurora kinase inhibitors as anticancer drugs.
Expert Opin Investig Drugs. 2004 Sep ; 13(9): 1199-201
With the current standard chemotherapy regimens only approximately 25% of acute myelogenous leukaemia (AML) patients survive > 5 years. Aurora kinases are overexpressed in many human cancers. VX-680 inhibited Aurora-A, -B, -C and the FMS-like tyrosine kinase-3 with apparent inhibitory constants of 0.6, 18, 4.6 and 30 nM, respectively. In primary leukaemia cells from patients with AML, which were refractory to standard therapies, VX-680 inhibited colony formation. In nude mice, VX-680 markedly reduced human AML tumours. The development of VX-680 for use in AML should continue.
http://www.hubmed.org/display.cgi?issn=17447658&uids=15330750
Erythroid differentiation in K562 chronic myelogenous cells induced by crambescidin 800
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Erythroid differentiation in K562 chronic myelogenous cells induced by crambescidin 800, a pentacyclic guanidine alkaloid.
Anticancer Res. 2004 Jul-Aug ; 24(4): 2325-30
The differentiation induction of K562 chronic myelogenous leukemia (CML) cells by crambescidin 800, a pentacyclic guanidine alkaloid isolated from a marine sponge, was examined. Crambescidin 800 increased hemoglobin production in K562 cells at concentrations of 0.15-1 microM and arrested the cell cycle of K562 cells at the S-phase. The expression of p21 was detected after 24-h treatment with crambescidin 800, and an increase of the expression was observed after 48-h treatment, but there was no remarkable change in the expression level of p27. This evidence indicates that crambescidin 800 induced the differentiation of K562 cells into erythroblasts accompanied by cell cycle arrest at the S-phase. Furthermore, crambescidin 800 induced a morphological change with neurite outgrowth in Neuro 2A cells at a 0.03-0.1 microM concentration.
http://www.hubmed.org/display.cgi?issn=02507005&uids=15330179
Sensitivity to imatinib therapy may be predicted by testing Wilms tumor gene expression and colony growth after a short in vitro incubation
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Sensitivity to imatinib therapy may be predicted by testing Wilms tumor gene expression and colony growth after a short in vitro incubation.
Cilloni D, Messa F, Gottardi E, Fava M, Arruga F, Defilippi I, Carturan S, Messa E, Morotti A, Giugliano E, Rege-Cambrin G, Alberti D, Baccarani M, Saglio G
BACKGROUND: The objective of the current study was to verify the ability to predict response to imatinib therapy using in vitro assays to evaluate the inhibition of Wilms tumor gene (WT1) expression and colony growth after samples obtained from patients with chronic myelogenous leukemia (CML) before the start of treatment were subjected to short-term incubation with imatinib. METHODS: WT1 transcript levels and colony growth in bone marrow (BM) samples from 23 patients with CML that was later identified as being responsive to imatinib and from 13 patients with CML that was later identified as not being responsive to imatinib were evaluated after incubation of these samples with imatinib at a concentration of 1 microM for 18 hours. In addition, real-time quantitative polymerase chain reaction (RQ-PCR) analysis of WT1 expression was performed during follow-up, and the results were analyzed for associations with cytogenetic response and with BCR/ABL transcript levels as determined using RQ-PCR analysis. RESULTS: Before treatment, it was found that WT1 expression was elevated in BM samples obtained from all patients with CML. WT1 expression and colony growth were reduced significantly after an 18-hour incubation with imatinib in samples obtained from patients who were later identified as responders to treatment, but not in samples obtained from patients who did not experience responses to treatment. Inhibition of WT1 expression in vitro was associated with inhibition of imatinib-induced BCR-ABL tyrosine kinase activity, a finding that also has been made in studies involving certain Philadelphia chromosome (Ph)-positive and Ph-negative cell lines. CONCLUSIONS: Inhibition of WT1 transcript levels after a short period of in vitro exposure of pretherapy BM samples to imatinib was correlated with inhibition of colony growth and may represent the basis for an easy test that is capable of predicting the sensitivity of CML to treatment with imatinib for individual patients. Cancer 2004. Copyright 2004 American Cancer Society.
http://www.hubmed.org/display.cgi?issn=0008543X&uids=15329907
Successful allogeneic bone marrow transplantation for acute myelogenous leukemia after drug-induced cardiomyopathy
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Successful allogeneic bone marrow transplantation for acute myelogenous leukemia after drug-induced cardiomyopathy.
Itoh M, Iwai K, Kotone-Miyahara Y, Yamada H, Ohno H, Yamamoto K, Tashima M, Inoko M, Nohara R, Uchiyama T
Tohoku J Exp Med. 2004 Sep ; 204(1): 85-91
Anthracycline derivatives often induce cardiomyopathy. Patients with seriously decreased cardiac function due to chemotherapeutic drugs cannot usually receive allogeneic hematopoietic stem cell transplantation (SCT) for hematologic disorders. We successfully performed allogeneic bone marrow transplantation (BMT) in a patient with severe cardiomyopathy. An 18-year-old woman with relapsed acute myelogenous leukemia had cardiomyopathy due to previous anthracycline administration. She underwent allogeneic BMT from her HLA-identical brother. Her preconditioning regimen was cytosine arabinoside, etoposide, total body irradiation, and high-dose cyclophosphamide. Congestive heart failure (CHF) was not present before BMT. Right heart pressures were monitored by a pulmonary arterial balloon catheter system (Swan-Ganz catheter). After BMT, she had severe CHF, which was controlled using pimobendan and amrinone. Patients with cardiomyopathy can receive allogeneic SCT under strict hemodynamic management.
http://www.hubmed.org/display.cgi?issn=00408727&uids=15329467
High efficacy of imatinib for recurrent gastrointestinal stromal tumor
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High efficacy of imatinib for recurrent gastrointestinal stromal tumor in the jejunum: a case report.
Yokoi K, Tanaka N, Kyouno S, Ishikawa N, Seya T, Shirakawa T, Takahashi Y, Ohaki Y, Yamashita K, Tajiri T
J Nippon Med Sch. 2004 Apr ; 71(2): 114-9
Gastrointestinal stromal tumor is a mesenchymal tumor of the digestive tract. Although there used to be no effective therapy for the tumor, there have been many recent reports on the efficacy of imatinib. We report on a 53-year-old female patient with a primary tumor of the jejunum who underwent 3 operations. As the tumor could not be removed at the 3rd operation, she was given imatinib orally. Results showed significant reduction ratios of the tumor area (83.0%) and volume (92.2%) at 18 months after starting imatinib administration. Also, the mean reduction ratios of the tumor area and volume per month (%/M) after starting imatinib treatment showed remarkable results, especially during the initial 3 weeks: 53.9%/M and 49.5%/M, respectively. Whether imatinib is the first choice of treatment for GIST or not, and what is the appropriate dose and period should be resolved.
http://www.hubmed.org/display.cgi?issn=13454676&uids=15260086
Pic Of The Day
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A boy holds a banner with pictures of some of the 3,000 people killed or disappeared during Augusto Pinochet dictatorship (1973-90) in Santiago during a demonstration celebrating their memory ahead of Monday’s celebration of the International Day of the Disappeared.
Myeloid/natural killer cell blast crisis representing an additional translocation
Posted by rob on August 27, 2004 under Uncategorized | Be the First to Comment
Myeloid/natural killer cell blast crisis representing an additional translocation, t(3;7)(q26;q21) in Philadelphia-positive chronic myelogenous leukemia.
Henzan H, Yoshimoto G, Okeda A, Nagasaki Y, Hirano G, Takase K, Tanimoto T, Miyamoto T, Fukuda T, Nagafuji K, Harada M
Ann Hematol. 2004 Aug 18; ():
We encountered a patient in blast crisis (BC) with chronic myelogenous leukemia (CML) who showed immunophenotypic features similar to those previously described in acute myeloid/natural killer (NK) cell precursor leukemia. The blasts were positive for CD7, CD33, CD34, and CD56. Cytogenetic analysis disclosed a Philadelphia chromosome (Ph) and t(3;7)(q26;q21). Molecular analysis did not detect any EVI1/CDK6 chimeric transcript generated by t(3;7)(q26;q21), but did indicate overexpression of EVI1, which occurs frequently in progression to myeloid BC in CML. Three cases of myeloid/NK cell precursor BC in CML have been reported, but this case is the first to present with Ph and EVI1 abnormality. These observations suggested that a myeloid/NK cell precursor might have been involved in the Ph-positive clone and have been a target for blastic transformation of CML, although EVI1 expression is not specific for transformation to BC from myeloid/NK lineage.
http://www.hubmed.org/display.cgi?issn=09395555&uids=15322764
Pic Of The Day
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A Tibetan pilgrim walks through Jokhang Temple in Lhasa, Tibet, August 13, 2004. The Buddhist temple is the holiest Tibetan shrine and where the Dalai Lama’s throne has been kept empty since he fled China in 1959.
Rs 1.2 lakh: Cost of life?
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In vitro effects of native human acute myelogenous leukemia blasts on fibroblasts and osteoblasts
Posted by rob on August 26, 2004 under Uncategorized | Be the First to Comment
In vitro effects of native human acute myelogenous leukemia blasts on fibroblasts and osteoblasts.
Int J Cancer. 2004 Oct 10; 111(6): 858-67
Bone marrow stromal cells constitute a heterogeneous population, and in the present study we investigated intercellular crosstalk via release of soluble mediators between native human AML blasts and fibroblasts/osteoblasts. Coculture of nonleukemic stromal cells and AML blasts separated by a semipermeable membrane decreased proliferation of the fibroblast line HFL1, and the inhibition was maintained when HFL1 and AML cells were cultured in direct contact. A similar inhibitory effect was observed for osteoblastic sarcoma cell lines (Cal72, SJSA-1) and normal osteoblasts. GM-CSF was released by both nonleukemic cells and a subset of AML blast populations, and increased levels of GM-CSF were detected in AML cocultures with fibroblasts and osteoblastic sarcoma cells when testing AML cell populations with constitutive GM-CSF release. Furthermore, constitutive IL-1beta secretion by AML blasts was detected only for a subset of patients, whereas relatively high levels of IL-1RA were observed for all patients; coculture of AML blasts with HFL1 fibroblasts and osteoblastic sarcoma cells increased IL-1beta levels for patients with constitutive IL-1beta secretion, whereas IL-1RA levels were slightly decreased but still generally higher than IL-1beta levels (tested only for HFL1 fibroblasts). The bidirectional crosstalk between AML blasts and stromal cells with increased release of AML growth factors may be important in leukemogenesis, whereas the decreased stromal cell proliferation combined with the persistent release of IL-1RA may in addition inhibit remaining normal hematopoiesis and thereby contribute to bone marrow failure in AML.
http://www.hubmed.org/display.cgi?issn=00207136&uids=15300797
Switching leukemia cell phenotype between life and death
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Switching leukemia cell phenotype between life and death.
Proc Natl Acad Sci U S A. 2004 Aug 24; ():
Divergent life or death responses of a cell can be controlled by a single cytokine (tumor necrosis factor alpha, TNF) via the signaling pathways that respond to activation of its two receptors (TNFR1 and TNFR2). Here, we show that the choice of life or death can be controlled by manipulation of TNFR signals. In human erythroleukemia patient myeloid progenitor stem cells (TF-1) as well as chronic myelogenous leukemia cells (K562), granulocyte-macrophage colony-stimulating factor primes cells for apoptosis. These death-responsive cells show prolonged TNF stimulation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, but no NF-kappaB transcriptional activity as a consequence of receptor-interacting protein degradation by caspases. Conversely, cells of a proliferative phenotype display antiapoptotic NF-kappaB responses that antagonize c-Jun N-terminal kinase and p38 mitogen-activated protein kinase stress kinase effects. These proliferative effects of TNF are apparently due to enhanced basal expression of the caspase-8/FLICE-inhibitory protein FLIP. Manipulation of the NF-kappaB, c-Jun N-terminal kinase, or p38 mitogen-activated protein kinase signals switches leukemia cells from a proliferative to an apoptotic phenotype; consequently, these highly proliferative cells die rapidly. In addition, sodium salicylate mimics the death phenotype signals and causes selective destruction of leukemia cells. These findings reveal the signaling mechanisms underlying the phenomenon of human leukemia cell life/death switching. Additionally, through knowledge of the signals that control TNF life/death switching, we have identified several therapeutic targets for selectively killing these cells.
http://www.hubmed.org/display.cgi?issn=00278424&uids=15328418
Imatinib as a paradigm of targeted therapies
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Imatinib as a paradigm of targeted therapies.
Adv Cancer Res. 2004; 91(): 1-30
Imatinib (Gleevec) exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of a specific cancer. This article reviews the identification of the BCR-ABL tyrosine kinase as a therapeutic target in chronic myeloid leukemia and the steps in the development of an agent to specifically inactivate this abnormality. The clinical trials results are reviewed along with a description of resistance mechanisms. As imatinib also inhibits the tyrosine kinase activity of KIT and the platelet-derived growth factor receptors, the extension of imatinib to malignancies driven by these kinases will be described. Issues related to clinical trials of molecularly targeted agents are discussed, including patient and dose selection. Last, the translation of this paradigm to other malignancies is explored.
http://www.hubmed.org/display.cgi?issn=0065230X&uids=15327887
Pic Of The Day
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A kayakist trains in the early morning lights prior to the start of the canoeing and kayaking heats for the Athens 2004 Olympic Games
European Union backs protein kinase research under FP6
Posted by rob on August 25, 2004 under Uncategorized | Be the First to Comment
25/08/2004 – The European Union has granted nearly _25 million to two large-scale research projects coordinated by the University of Helsinki in the area of protein kinases, a promising class of new drug targets.
Protein kinases are considered to be the largest druggable target class, with approximately 2 per cent of all genes encoding these key cellular enzymes. Kinases regulate critical pathways involved in cell growth, activation, and death, and have been implicated in a wide range of diseases.
The high specificity of kinases means that drugs that target them can show unprecedented levels of efficacy. For example, Novartis recently launched a new tyrosine kinase-targeting drug for chronic myelogenous leukaemia and a rare form of stomach cancer – Glivec/Gleevec (imatinib) – that has shown unprecedented efficacy.
The objectives of the research project are to do basic research on protein kinases and to develop PK inhibitors and activators by designing and screening natural compounds from the European biosphere and compounds from chemical libraries.
The research consortium plans to combine European expertise on basic research on PKs and rational drug discovery, in order to develop new drug candidates for major diseases like cancer, autoimmune disorders, vascular diseases and degenerative brain diseases. The consortium consists of 23 partners from 11 countries.
The project leaders are professor Raimo Tuominen from the UH’s Faculty of Pharmacy and Academy professor Kari Alitalo from UH’s Molecular and Cancer Biology Laboratory.
An integrated research project lead by Prof Tuominen carrying out basic research into PKs was granted over _15 million alone, making it the largest in EU’s 6th framework programme (FP6’s) for Life sciences, genomics and biotechnology for health.
A biomedical research project lead by Prof Alitalo was granted _9 million and is focusing on the growth and function of the lymphatic vasculature, with a strong emphasis on the discovery of novel regulatory agents.
The lymphatic vasculature is essential for the maintenance of tissue fluid balance and has an essential role in various pathological conditions such as metastasis of cancer.
Recent experiments suggest that inhibition of lymphatic vessel growth in tumours can block metastasis, just as it has been proposed that blocking new blood vessel formation can limit tumour growth.
Novel discoveries in the field could also be applied to the development of new pharmaceuticals for inflammatory and heart diseases, according to the researchers.
Pic Of The Day
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Children of Athens perform during an artistic gymnastic exhibition at the Athens 2004 Olympic Games