Posted by rob on January 20, 2006 under Uncategorized | 
Schittenhelm MM, Shiraga S, Schroeder A, Corbin AS, Griffith D, Lee FY, Bokemeyer C, Deininger MW, Druker BJ, Heinrich MC
Cancer Res. 2006 Jan 1; 66(1): 473-81
Activating mutations of the activation loop of KIT are associated with certain human neoplasms, including the majority of patients with systemic mast cell disorders, as well as cases of seminoma, acute myelogenous leukemia (AML), and gastrointestinal stromal tumors (GISTs). The small-molecule tyrosine kinase inhibitor imatinib mesylate is a potent inhibitor of wild-type (WT) KIT and certain mutant KIT isoforms and has become the standard of care for treating patients with metastatic GIST. However, KIT activation loop mutations involving codon D816 that are typically found in AML, systemic mastocytosis, and seminoma are insensitive to imatinib mesylate (IC50 > 5-10 micromol/L), and acquired KIT activation loop mutations can be associated with imatinib mesylate resistance in GIST. Dasatinib (formerly BMS-354825) is a small-molecule, ATP-competitive inhibitor of SRC and ABL tyrosine kinases with potency in the low nanomolar range. Some small-molecule SRC/ABL inhibitors also have potency against WT KIT kinase. Therefore, we hypothesized that dasatinib might inhibit the kinase activity of both WT and mutant KIT isoforms. We report herein that dasatinib potently inhibits WT KIT and juxtamembrane domain mutant KIT autophosphorylation and KIT-dependent activation of downstream pathways important for cell viability and cell survival, such as Ras/mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and Janus-activated kinase/signal transducers and activators of transcription. Furthermore, dasatinib is a potent inhibitor of imatinib-resistant KIT activation loop mutants and induces apoptosis in mast cell and leukemic cell lines expressing these mutations (potency against KIT D816Y >> D816F > D816V). Our studies suggest that dasatinib may have clinical efficacy against human neoplasms that are associated with gain-of-function KIT mutations.
Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies.
Posted by rob on under Uncategorized |
Porter D, Levine JE
Semin Hematol. 2006 Jan ; 43(1): 53-61
Although dramatically effective for relapsed chronic myelogenous leukemia (CML), successful donor leukocyte infusion (DLI) remains limited primarily by inadequate responses for patients with diseases other than CML and by toxicity related to graft-versus-host disease (GVHD). Acute GVHD grades 2 to 4 follows 34% to 47% of infusions and chronic GVHD occurs in 33% to 61% of cases. Strategies to reduce the incidence and severity of GVHD while preserving the graft-versus-leukemia (GVL) effect, such as low-dose DLI, depletion of GVHD effector cells, and tumor-specific DLI, are reviewed.
Graft-versus-host disease and graft-versus-leukemia after donor leukocyte infusion.
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Adrián FJ, Ding Q, Sim T, Velentza A, Sloan C, Liu Y, Zhang G, Hur W, Ding S, Manley P, Mestan J, Fabbro D, Gray NS
Nat Chem Biol. 2006 Jan 15;
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl-transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism.
Allosteric inhibitors of Bcr-abl-dependent cell proliferation.
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Guerzoni C, Bardini M, Mariani SA, Ferrari-Amorotti G, Neviani P, Panno ML, Zhang Y, Martinez R, Perrotti D, Calabretta B
Blood. 2006 Jan 17;
Translational regulation by oncogenic proteins may be a rapid and efficient mechanism to modulate gene expression. We report here the identification of the C/EBPbeta gene as a target of translational regulation in myeloid precursor cells transformed by the BCR/ABL oncogene. Expression of C/EBPbeta was repressed in 32D-BCR/ABL cells and reinduced by STI571 via a mechanism requiring expression of the CUG-repeat RNA binding protein CUGBP1 and the integrity of the CUG-rich intercistronic region of c/ebpbeta mRNA. Constitutive expression or conditional activation of wild-type C/EBPbeta induced differentiation and inhibited proliferation of 32D-BCR/ABL cells in vitro and in mice, but a DNA-binding deficient C/EBPbeta mutant had no effect. The proliferation-inhibitory effect of C/EBPbeta was, in part, mediated by the C/EBPbeta- induced GADD45alpha gene. Since expression of C/EBPbeta (and C/EBPalpha) is low in the aggressive blast crisis (BC) stage of chronic myelogenous leukemia (CML) and is inversely correlated with BCR/ABL tyrosine kinase levels, these findings point to the therapeutic potential of restoring C/EBP activity in CML-BC and, perhaps, other types of acute leukemia.
Inducible activation of C/EBP{beta}, a gene negatively regulated by BCR/ABL, inhibits proliferation and promotes differentiation of BCR/ABL-expressing cells.
Posted by rob on January 19, 2006 under Uncategorized |
BY BILL CAHIR
January 15, 2006
Newhouse News Service
WASHINGTON — One of the great winners in the congressional sweepstakes
of 2005 was — no drum roll needed — the pharmaceutical industry.
While it is rare for most lobbies to achieve any of their goals in just
one year, drugmakers got virtually everything they wanted in 2005.
Congress resisted changes to the prescription drug benefit for Medicare
recipients, such as the Republican Study Committee’s plan to delay its
launch.
Lawmakers calling themselves fiscal conservatives, such as U.S. Rep.
Jeff Flake, R-Ariz., had hoped to save up to $38 billion by either
stalling or killing the drug-coverage program.
The Arizona lawmaker “was disappointed that, rather than setting
spending priorities, Congress decided to move forward with a new
universal drug entitlement that’s just not fiscally sustainable,”
Matthew Specht, a spokesman for Flake, said in an e-mail note.
Lawmakers also ignored proposals to toughen the Medicare initiative by
authorizing the government to bargain for the lowest possible prices.
U.S. Rep. Jo Ann Emerson, R-Mo., has drafted a bill that would authorize
the U.S. Health and Human Services Department to engage in price
negotiations with drug manufacturers, pharmacies and sponsors of
Medicare prescription drug plans.
Emerson’s proposal is languishing in the House Ways and Means
Subcommittee on Health, where no action is expected. A related measure
sponsored by U.S. Sen. Debbie Stabenow, D-Mich., has stalled before the
Senate Finance Committee.
Drugmakers gave $18.1 million to federal candidates in 2004, the cycle
during which the current crop of lawmakers was elected, according to the
nonpartisan Center for Responsive Politics. Two-thirds of the money went
to Republicans.
“The drug companies have a record of getting this Republican Congress to
do their bidding,” said U.S. Rep. Henry Waxman, D-Calif.
Billy Tauzin, top lobbyist for the Pharmaceutical Research and
Manufacturers Association, in an interview, said drugmakers were
supporting the launch of the Medicare drug benefit, but resisting
changes to its current design.
“The fact is that too many people are uninsured in this country,” said
Tauzin, a Louisiana Republican who headed the House Energy and Commerce
Committee before retiring from politics. “Any program that can help
provide coverage to Americans is important to us. Medicare coverage is
obviously extremely important.”
On another front, makers of prescription drugs, vaccines and medical
devices in 2005 won sweeping federal immunity from lawsuits.
Congress included the liability provisions in a defense-spending bill,
blocking litigation against drug and vaccine manufacturers and device
makers. Lawmakers also provided $3.79 billion to spend on avian flu
inoculations.
The lawsuit-protection provision bars lawsuits against any company that
manufactures a product used in response to a disease or disorder deemed
a public health emergency by the secretary of Health and Human Services.
The bill did not define what would constitute an emergency, but allowed
the Bush administration to determine what would constitute a product
responding to an epidemic or a pandemic.
Public Citizen, a watchdog group frequently critical of the prescription
drug industry, claims the 45-page section blocking lawsuits against
drug, vaccine and medical-device makers prevents lawsuits even in cases
involving any allegedly tainted, defective or deceptively labeled products.
The cost of any defective medicine, vaccine or medical device “all falls
on the back of the victims,” said Jillian Aldebron, a civil-justice
lawyer for Public Citizen. “It won’t come out of the pockets of anyone
who is responsible for any gross negligence, any reckless actions.”
Tauzin defended the new provisions protecting U.S. companies from
lawsuits related to allegedly defective drugs, vaccines or medical
devices. He claimed that few vaccines are made in the United States
today, partly because of the threat from frivolous lawsuits.
The no-lawsuits provision represents “a step in the right direction, but
look, we still face a huge problem here,” Tauzin said.
“The sad truth is, we’re down to one (vaccine) manufacturing facility in
this country now,” Tauzin said. “If there is a limited supply of
vaccines or a limited supply of anti-virals, what country do you think
is going to have first access to them? It’s the country where they’re
made. If we’re not that country, that’s not in our national interest.”
On another front, Congress in 2005 did not pass legislation that would
authorize consumers in the United States to purchase low-cost
pharmaceuticals from Canada or other nations with price controls.
If the drug industry has become a punching bag for watchdog groups and
some lawmakers, Tauzin hopes to address that public-relations problem
with a more vigorous charity campaign.
Tauzin said that drugmakers had added 1.2 million people to the roster
of a program, the Partnership for Prescription Assistance, through which
low-income people receive free or discounted medicines. Somewhere
between 4 million and 6 million people are enrolled, according to Tauzin.
Members of the Pharmaceutical Research and Manufacturers Association
also have adopted a new advertising code of conduct, which emphasizes
greater education and training of physicians about new medicines. But it
does not prevent direct-to-consumer advertising of new drugs, as Senate
Majority Leader Bill Frist, R-Tenn., had proposed.
Jan. 15, 2006
Newhouse A1
Posted by rob on January 18, 2006 under Uncategorized |
MELBOURNE, Australia and MENLO PARK, Calif., Jan. 17
/PRNewswire-FirstCall/ — ChemGenex Pharmaceuticals Limited (Nasdaq: CXSP)
today announced that the United States Patent and Trademark Office (USPTO) has
issued a patent covering its lead drug Ceflatonin(R) (homoharringtonine). The
patent is entitled “Treatment of chronic myelogenous leukemia, resistant or
intolerant to ST1571, involving homoharringtonine alone or combined with other
agents” and has been issued as U.S. patent number 6,987,103.
The patent covers the use of Ceflatonin in the treatment of chronic
myeloid leukemia (CML) and Ph-positive acute lymphocytic leukemia (ALL) in
patients who are intolerant or resistant to imatinib (Gleevec(R)). In addition
to covering the use of Ceflatonin as a single agent, the patent also covers
use in combination with a range of drugs including cytarabine, interferon
alpha, Gleevec, farnesyl transferase inhibitors (FTI’s) and nucleoside
analogs, in patients who are resistant to Gleevec.
“This is the third issued patent covering Ceflatonin, including claims
covering formulations, synthesis and uses,” said Greg Collier, Ph.D., chief
executive officer of ChemGenex. “This most recent patent provides long-term
protection for use in CML, our initial indication. To date, we have filed 9
other patents covering a range of claims related hematologic malignancies, but
also for potential use in solid tumors.”
Ceflatonin is currently being evaluated in chronic myeloid leukemia (CML),
myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Two separate
phase 2/3 clinical trials are planned to begin in the first half of 2006. The
first study will be in patients with a specific bcr-abl point mutation (T315I)
bcr-abl and the second in patients failing imatinib and dasatinib.
About Ceflatonin(R)
Ceflatonin(R) (sHHT) is a new, well-tolerated inducer of apoptosis in
phase 2/3 clinical trials in chronic myeloid leukemia (CML) patients who have
developed resistance to Gleevec(R). Initial approval will be sought in
patients who have developed Gleevec(R) resistance and in patients resistant to
abl-kinase inhibitors (T315I mutation positive), including Gleevec(R) and
experimental kinase inhibitors. Additional studies in chronic myeloid
leukemia, myelodysplastic syndrome and acute myeloid leukemia are intended to
broaden the near-term market potential of the drug.
NOTE: Gleevec(R) is a registered trademark of the Novartis
Pharmaceuticals Corporation.
About ChemGenex Pharmaceuticals Limited (http://www.chemgenex.com)
ChemGenex Pharmaceuticals is a pharmaceutical development company
dedicated to improving the lives of patients by developing therapeutics in the
areas of oncology, diabetes, obesity, and depression. ChemGenex harnesses the
power of genomics for target discovery and validation, and in clinical trials
to develop more individualized therapeutic outcomes. ChemGenex’s lead
compound, Ceflatonin(R), is currently in phase 2/3 clinical trials for
leukemia and Quinamed(R) is in phase 2 clinical trials for prostate, breast
and ovarian cancers. The company has a significant portfolio of anti-cancer,
diabetes, obesity and depression programs, several of which have been
partnered with international pharmaceutical companies. ChemGenex currently
trades on the Australian Stock Exchange under the symbol “CXS” and on NASDAQ
under the symbol “CXSP.”
Safe Harbor Statement
Certain statements made herein that use the words “estimate,” “project,”
“intend,” “expect,” “believe,” and similar expressions are intended to
identify forward-looking statements within the meaning of the US Private
Securities Litigation Reform Act of 1995. These forward-looking statements
involve known and unknown risks and uncertainties which could cause the actual
results, performance or achievements of the company to be materially different
from those which may be expressed or implied by such statements, including,
among others, risks or uncertainties associated with the development of the
company’s technology, the ability to successfully market products in the
clinical pipeline, the ability to advance promising therapeutics through
clinical trials, the ability to establish our fully integrated technologies,
the ability to enter into additional collaborations and strategic alliances
and expand current collaborations and obtain milestone payments, the
suitability of internally discovered genes for drug development, the ability
of the company to meet its financial requirements, the ability of the company
to protect its proprietary technology, potential limitations on the company’s
technology, the market for the company’s products, government regulation in
Australia and the United States, changes in tax and other laws, changes in
competition and the loss of key personnel. These statements are based on our
management’s current expectations and are subject to a number of uncertainties
that could change the results described in the forward-looking statements.
Investors should be aware that there are no assurances that results will not
differ from those projected.
SOURCE ChemGenex Pharmaceuticals Limited
Web Site: http://www.chemgenex.com
ChemGenex Granted U.S. Patent on Ceflatonin(R)’s Use for Treatment of Gleevec(R)-Resistant Patients With CML and Ph-Positive ALL
Posted by rob on January 15, 2006 under Uncategorized |
Guo X, Zhang J, Fu X, Wei Q, Lu Y, Li Y, Yin G, Mao Y, Xie Y, Rui Y, Ying K
Front Biosci. 2006 May 1; 11: 1924-31
Camptothecin (CPT) is a potent inhibitor of DNA topoisomerase I with a wide spectrum of anti-tumor activity. Relatively little information is available regarding the relation of known topoisomerase-mediated DNA damage with other intracellular pathways. To gain an insight into the intracellular molecular mechanisms of Topoisomerase I inhibitor camptothecin-mediated DNA damage leading to cell death, we used a high-density cDNA microarray to assess sensitive early gene expression profiles in SGC7901 (gastric cancer), Hela (cervical adenocarcinoma), K562 (chronic myelogenous leukemia) and HL60 (promyelocytic leukemia) tumor cells stimulated with camptothecin for 1 h at the concentrations of GI50 (50 % growth inhibition after 24 h of treatment). Analysis of the differentially expressed genes obtained 29 response genes common to all four cell lines. Moreover, these cell lines also shared the direction of regulation. Most of these common response genes were functionally related to cell proliferation or apoptosis, and some of them were involved in ATM (ataxia-telangiectasia mutated) and ATR (ATM-and Rad3 related) checkpoint pathways, JNK (c-Jun N-terminal kinase) pathway, the survival phosphatidylinositol (PI) 3 kinase-Akt-dependent pathway, mitochondrial cell death pathway, endoplasmic reticulum (ER)-related cell death pathway, and to ubiquitin/proteasome dependent protein degradation pathway. The data provides evidence for a linkage between topoisomerase-mediated DNA damage and intracellular signaling events, which may facilitate our understanding of the camptothecin mediated molecular mechanisms of action.
Analysis of common gene expression patterns in four human tumor cell lines exposed to camptothecin using cDNA microarray: identification of topoisomerase-mediated DNA damage response pathways.
Posted by rob on under Uncategorized |
Gyulai Z, Balog A, Borbényi Z, Mándi Y
Acta Microbiol Immunol Hung. 2005; 52(3-4): 463-75
Myelodysplastic syndrome (MDS) is a family of clonal disorders characterized by dyshematopoiesis and susceptibility to acute myelogenous leukemia. Tumor necrosis factor-a (TNF-alpha) and transforming growth factor-beta (TGF-beta) are cytokines that play key roles in the pathogenesis of MDS. There have been several reports on the presence of genetic polymorphisms in the DNA sequence encoding the leader sequence of the TGF-beta protein, and in the -308 promoter region of TNF-alpha. The association between TNF-alpha and TGF-beta1 gene polymorphism and the susceptibility to MDS and the progression of the disease was investigated. As compared with healthy control subjects (n = 74), patients with MDS (n = 55) showed no significant deviations in genotype or allele frequencies of TNF-alpha. Similarly, there were no differences in the distribution of TNF-alpha genotypes between the MDS patients with only anemia (mild group) and those with bi- or pancytopenia (severe group). On the other hand the TT homozygosity at codon 10 in exon 1 of TGF-beta1 gene was associated with a severe degree of cytopenia [95% CI OR = 4.889, p = 0.0071]. These findings suggest that the investigated genetic polymorphisms do not predispose to the development of MDS, but that TGF-beta1 gene polymorphism may affect the disease progression.
Genetic polymorphisms in patients with myelodysplastic syndrome.
Posted by rob on under Uncategorized |
Huang Y, Li WJ, Wei CX, Zhou Z, Nie B
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2005 Dec ; 13(6): 959-63
To investigate the expression of HoxA(10) mRNA in acute leukemia patients and its significanse, HoxA(10) level was detected by reverse transcription polymerase chain reaction (RT-PCR) in 50 patients with acute leukemias, 7 healthy volunteers and 3 patients with ITP (idiopathic thrombocytopenic purpura). The regularity of the expression of HoxA(10) gene in acute leukemia and the relationship between HoxA(10) level and the prognosis of leukemia was explored. The results showed that HoxA(10) was expressed in all types of acute myelogenous leukemia; HoxA(10) message was also observed in acute lymphoblastic leukemia patients and part of control groups. 3 normal donors were found not to express HoxA(10). The level of HoxA(10) mRNA of acute myelogenous leukemia patients was significantly higher than that of acute lymphoblastic leukemia patients and controls (P [Expression of HoxA(10) in Acute Leukemia and Its Significance.]
Posted by rob on under Uncategorized |
Bojesen SE, Ammerpohl O, Weinhäusl A, Haas OA, Mettal H, Bohle RM, Borkhardt A, Fuchs U
Br J Cancer. 2006 Jan 10;
We report the isolation of the 5′ flanking region of GRAF (GTPase regulator associated with the focal adhesion kinase), previously described as a putative tumour suppressor gene of acute myelogenous leukaemia and myelodysplastic syndrome, and demonstrate its promoter activity in reporter gene assays. Two putative protein-binding sites are identified of which one was sensitive to CpG methylation. The suppressed GRAF expression could be restored in leukaemia cell lines by treatment with a demethylating agent and an inhibitor of histone deacetylases. In contrast to normal tissues, which tested negative for GRAF promoter methylation, 11 of 29 (38%) bone marrow samples from patients with acute myeloid leukaemia or myelodysplastic syndrome were positive.British Journal of Cancer advance online publication, 10 January 2006; doi:10.1038/sj.bjc.6602939.
Characterisation of the GRAF gene promoter and its methylation in patients with acute myeloid leukaemia and myelodysplastic syndrome.
Posted by rob on under Uncategorized |
Senel S, Kaya E, Aydogdu I, Erkurt MA, Kuku I
Rheumatol Int. 2006 Jan 11; 1-5
We report four patients with rheumatic disease (RD) and chronic myelogenous leukemia (CML). In two patients with Behcet’s disease (BD) and rheumatoid arthritis (RA), CML developed after RD, in two patients with diffuse cutaneous systemic sclerosis and spondyloarthropathy, RD was diagnosed after CML. A variety of interactions have been described between hematological malignancies and RD. Nevertheless, few cases of RD have been documented associated with CML. It is unclear whether the development of CML in patients with RD and RD development after CML occurs by chance alone, is due to the underlying disease, or is facilitated by drugs. Whatever the cause is, it should be kept in mind that CML may develop in the course of RD and RD may be seen in CML patients.
Rheumatic diseases and chronic myelogenous leukemia, presentation of four cases and review of the literature.
Posted by rob on under Uncategorized |
Qin YZ, Liu YR, Li JL, Ruan GR, Zhu HH, Jiang Q, Fu JY, Lu Y, Chang Y, Li LD, Huang XJ, Chen SS, Qiu JY
Zhonghua Yi Xue Za Zhi. 2005 Nov ; 85(45): 3186-9
OBJECTIVE: To evaluate ABL tyrosine kinase point mutations in imatinib treated chronic myelogenous leukemia (CML) patients. METHODS: A total of 45 bone marrow samples from 30 CML patients were included in this work. The patients were in accelerated/blast phase (AP/BP) or late-chronic phase (CP) at the start of imatinib and usually showed resistance to imatinib. ABL kinase domain of BCR-ABL allele was amplified by nested reverse transcriptase-polymerase chain reaction technique, followed by direct sequencing and sequence homologous analyzing. RESULTS: The ABL point mutation was detected in 13 of 30 patients, 12 of them had progressed to advanced phase, The other patient who was in late chronic phase showed point mutation when she was at 45(th) months of imatinib treatment, but she was still in complete cytogenetic remission at 50(th) months and is doing well. 4 patients had Glu255Lys mutation and 4 had Gly250Glu, the other types of mutation were Phe359Cys, Glu355Gly, Met244Val, Tyr253His and Asp276Gly, each was tested in one patient. 11/12 patients who progressed to advanced disease and showed point mutation were collected samples in advanced stage, 8 patients showed homozygote mutation, and 3 patients had a mixture of wild and mutant type. In advanced stage patients, mutations were detected in a median of 5 months (ranged 0.5 approximately 30 months), it appeared much ealier than that in late CP patients (25.5 months, ranged 11 approximately 45months, P [Analysis of ABL tyrosine kinase point mutations in imatinib treated chronic myelogenous leukemia patients.]
Posted by rob on January 14, 2006 under Uncategorized |
Advances in treatment of chronic myeloid leukaemia
The results from five studies highlighting new advances in the treatment of chronic myeloid leukemia ( CML ) – a slow-progressing, malignant bone marrow cancer – have been presented at the 47th Annual Meeting of the American Society of Hematology.
” The survival rate for leukemia has improved in the past two decades, thanks to new agents designed to treat patients,” said Brian J. Druker, Oregon Health and Science University, Portland, Ore. ” Continued research will only strengthen our understanding of the disease and support the therapeutic potential of current and developing treatments for chronic myeloid leukemia.”
Chronic myeloid leukemia is usually diagnosed by finding a specific chromosomal abnormality called the Philadelphia chromosome ( Ph chromosome ).
The Ph chromosome is the result of translocation – a genetic chromosomal abnormality – between the long arms of chromosomes 9 and 22.
The result is that part of the BCR ( breakpoint cluster region ) gene from chromosome 22 is fused with part of the ABL ( abelson leukemia virus ) gene on chromosome 9.
The translocation takes place in a single bone marrow cell and, through the process of cell division and expansion, results in leukemia, the rapid growth of abnormal white blood cells in the bone marrow, blood, and body tissues.
The discovery of the Ph chromosome marked the first genetic abnormality consistently associated with a particular form of cancer.
In addition to chronic myeloid leukemia Ph chromosome can also be found in some cases of acute lymphoblastic leukemia ( ALL ) and acute myeloid leukemia ( AML ).
Imatinib ( Gleevec/Glivec ), which blocks the abnormal protein driving the overproduction of abnormal white blood cells, has become a standard therapy for patients not undergoing stem cell transplantation. It is now demonstrating continued control and reduction in levels of remaining disease in chronic phase CML ( CML- CP ) patients. However, a number of patients have developed resistance to this treatment because their cancer cells are able to mutate and adapt.
As a result, treatment options for patients with chronic myeloid leukemia continue to expand. Various studies of potential new treatments for chronic myeloid leukemia yield positive results in patients whose disease is resistant to Imatinib.
Both Dasatinib and AMN107 have been shown to be effective in treating patients with chronic myeloid leukemia whose disease has progressed on Imatinib.
Continuing reduction in level of residual disease after four years in patients with chronic myeloid leukemia in chronic phase responding to first-line Imatinib in the IRIS Study
A recent report updated results of molecular monitoring of patients in the International Randomized Interferon vs. STI 571 ( IRIS ) study that prospectively compared Imatinib therapy with Interferon-alfa plus Cytarabine.
The IRIS study was initiated in June 2000, and demonstrated that after one year of Imatinib treatment, an estimated 40 percent of CML-CP patients taking 400 mg per day achieved a major molecular response ( MMR ), defined as substantial reduction in BCR-ABL levels.
This particular analysis assessed the level of BCR-ABL transcripts after approximately four years of Imatinib treatment and showed continuing reduction in transcript levels.
The analysis was based on 101 patients who achieved complete cytogenetic response ( CCyR ) within one year, received first-line treatment for at least 24 months, and had blood collected for measuring transcript numbers at one year and four years after starting treatment.
Results are expressed as a log reduction from a standardized baseline value for untreated patients. This means they are expressed as transcript copy numbers, with a one-log reduction equivalent to a fall from 100 to 10, and a two-log reduction a fall from 100 to one.
At one year, BCR-ABL transcript levels fell by at least three logs in 46 percent of the 101 patients. At the most recent measurement, at or after 44 months from start of study, 75 percent of patients demonstrated a reduction of at least three logs. Of these patients, more than half had already had a three-log reduction at year one, whereas 49 percent had not.
Conversely, eight of the 47 patients with three-log reduction at one year had log reductions greater than three at four years.
At the one- and four-year points, 20 percent and 36 percent of patients, respectively, achieved four-log reductions.
” The results are gratifying and show that patients in complete cytogenetic response who had an ‘adequate’ reduction in their BCR-ABL transcript levels at one year have a good chance at achieving a much greater reduction after four years of Imatinib treatment,” said John M. Goldman, National Heart, Lung, and Blood Institute ( NHLBI ), Bethesda.” This is an important observation because it means that Imatinib continues for at least four years to reduce the quantity of residual disease and so promises to offer patients with chronic phase chronic myeloid leukemia very substantial prolongation of essentially normal life, compared with previous therapies.”
Control of residual disease in Imatinib treated chronic myeloid leukemia patients with peptide vaccinations: two years follow up of CMLVAX100 Trial
In the past five years, the body of data concerning Imatinib has defined its role as an effective first-line therapy for CML-CP patients. However, the persistence of disease in most patients, together with the evidence that discontinuation of Imatinib inevitably results in a rapid loss of response, suggests that the cure for CML is unlikely using Imatinib alone.
Researchers from the University of Siena ( Italy ), looked at the anti-tumor effect of a vaccine ( CMLVAX100 ) targeting the BCR-ABL genes and how it reduced remaining disease in some patients with chronic myeloid leukemia who have reached a maximum response to Imatinib.
After a median time of 24 months of Imatinib treatment, a group of 21 patients showing different degrees of persistent residual disease started vaccinations with CMLVAX100.
Vaccine treatment plans included six vaccinations at two-week intervals.
In patients who responded to treatment, additional boosts of vaccine were provided every four to six months.
To date, 18 of the 21 patients have completed the immunization regimen, eight of whom received four additional boosts of vaccine.
After six vaccinations, six patients with persisting, progressing disease reached a complete response, with three of them achieving an undetectable level of BCR-ABL transcript.
In addition, three patients starting vaccinations with persistent molecular disease further reduced their BCR-ABL level, with one reaching molecular negativity.
This suggests that CMLVAX100 works effectively with Imatinib in CML-CP patients with persistent minimal residual disease.
Of the eight patients who underwent four additional boosts of vaccine, one reached a complete molecular response, five maintained the response obtained after immunization, and two patients ( who previously achieved an undetectable level of BCR-ABL transcript ) lost the complete molecular response ( CMR ), but maintained CCyR. This suggests that while beneficial, a six-month interval between boosts could be too long to maintain efficient immune control on residual leukemia cells.
” Although the number of patients who participated in the trial is small, this is a very important study,” said Monica Bocchia, University of Siena. ” Researchers have been attempting to develop cancer vaccines for decades, and results in chronic myeloid leukemia patients are a very encouraging step forward.”
Dasatinib ( BMS-354825 ) in patients with chronic myeloid leukaemia and Philadelphia chromosome- positive acute lymphoblastic leukemia who are resistant or intolerant to Imatinib: update of a phase I study
Imatinib resistance in chronic myeloid leukemia and Philadelphia ( Ph ) chromosome positive acute lymphoblastic leukemia ( Ph + ALL ) is frequently associated with BCR-ABL mutations that interfere with the ability of Imatinib to inhibit BCR-ABL overproduction.
Dasatinib ( BMS-354825 ) is a novel, oral, multi-targeted kinase inhibitor which targets BCR-ABL and SRC protein kinases.
The SRC protein is a signaling protein that specializes in messages that control the growth of cells. The drug is 325-fold more potent than Imatinib in cells transduced with normal BCR-ABL genes, and has demonstrated preclinical activity against 18 of 19 imatinib-resistant BCR-ABL mutants.
In an update of a phase I, dose-escalating study initiated in November 2003, researchers from the University of California, Los Angeles ( UCLA ) School of Medicine and The University of Texas M. D. Anderson Cancer Center looked at the use of Dasatinib in Imatinib-resistant or intolerant patients with chronic myeloid leukemia in late chronic phase ( CP ), accelerated phase ( AP ), myeloid blast crisis ( MBC ), or lymphoid blast crisis ( LBC )/Ph+ ALL.
Data are available for 82 patients ( 40 CP, 10 AP, 22 MBC, 10 LBC/Ph+ ALL ).
The 40 CP patients, with five years median duration of chronic myeloid leukemia, were treated with 15 to 180 mg of Dasatinib either once daily ( QD ) or twice daily ( BID ) for a median of 13 months.
The rate of complete hematologic response ( CHR ) in CP patients was 93 percent, while major cytogenetic responses ( McyR ) were observed in 45 percent and CCyR in 35 percent.
In advanced disease, 44 patients have been treated with Dasatinib ( 70 to 240 mg BID ) for a median of 37 months.
The rate of major hematologic response ( MHR ) is 81 percent in AP, 61 percent in MBC, and 70 percent in LBC/Ph+ ALL.
The complete response rate is 45 percent in AP, 70 percent in LBC/Ph+ ALL, and 35 percent in MBC.
The overall rates of MCyR and CCyR in advanced disease were 43 percent and 25 percent, respectively. Cytogenetic responses were seen in patients with a wide spectrum of BCR-ABL mutations, as well as in patients with minimal or no prior cytogenetic response with Imatinib. Responses were durable in CP and AP patients, but relapses have occurred in the MBC and LBC/Ph+ ALL cohorts, often due to dasatinib-resistant BCR-ABL mutations.
” These data support the therapeutic potential of Dasatinib in chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia patients who are Imatinib-resistant or intolerant,” said Charles Sawyers, Jonsson Cancer Center, UCLA School of Medicine, Los Angeles.” We are encouraged by the results and are looking forward to seeing the results from ongoing phase II studies to confirm the effects of Dasatinib in patients with all phases of the disease.”
Efficacy of Dasatinib ( BMS-354825 ) in patients with chronic phase Philadelphia chromosome-positive chronic myeloid leukemia resistant or intolerant to Imatinib: first results of the CA180013 START-C phase II study
After three years of Imatinib therapy, hematologic relapse occurs in seven percent of newly-diagnosed chronic myeloid leukemia patients and 20 percent of CML chronic phase patients after failure to respond to current standard therapy.
This is mostly associated with BCR-ABL mutations and/or clonal evolution – the development of chromosomal mutations that occurs in untreated chronic myeloid leukemia and leads to progression of the disease.
A previous phase I, dose-escalating study provided early evidence for the safety and efficacy of Dasatinib in Imatinib-resistant or intolerant patients with CML-CP.
This study ( START-C [CA180013] ), carried out by a multinational group of 75 investigators, is a follow-up on the use of Dasatinib in CP Imatinib resistant or intolerant patients.
A total of 394 patients were recruited to this phase II, open-label study.
To date, data from 186 patients are available for analysis. Imatinib resistance ( n=127 ) or intolerance ( n=59 ) was defined as a failure to respond to Imatinib at maximum tolerated doses or the occurrence of BCR-ABL mutations associated with virtual insensitivity to Imatinib.
Dasatinib was administered to patients at 70 mg BID, based on phase I data and optimal inhibition of BCR-ABL activity from biomarker analysis.
Dose escalation to 90 mg BID was permitted in patients lacking response, and dose reductions to 50 and 40 mg BID were allowed in the event of intolerance.
Complete blood counts were obtained weekly for the first 12 weeks, while bone marrow was collected every three months.
Median time from diagnosis of chronic myeloid leukemia was 63.8 months. Prior therapy included Imatinib in 100 percent Hydroxyurea or Anagrelide in 86 percent, and Interferon alpha in 70 percent of patients.
Approximately 54 percent of patients received Imatinib for more than three years.
Within the first six months, 90 percent of patients reached a complete hematologic response ( 87 percent resistant patients, 97 percent intolerant patients ), and 45 percent achieved a major cytogenetic response (
Interim results of Phase II Dasatinib studies in advanced disease were also presented.
Of the myeloid blast crisis patients resistant to Imatinib ( n=68 ), 31 percent reached a major hematologic response, and 29 percent achieved a major cytogenetic response.
Of the accelerated phase patients resistant to Imatinib ( n=99 ), 59 percent achieved a major hematologic response and 31 percent a major cytogenetic response.
” Despite the short follow-up, significant improvements of hematologic and cytogenetic responses were seen in pretreated chronic myeloid leukemia patients in all phases of the disease, which further supports the activity of Dasatinib in BCR-ABL positive leukemia,” said Andreas Hochhaus, University of Heidelberg, Mannheim ( Germany ). ” This is very encouraging news for patients and should be viewed as a step forward in the treatment of chronic myeloid leukemia .”
AMN107, a novel aminopyrimidine inhibitor of BCR-ABL, has significant activity in Imatinib-resistant chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoid leukaemia
AMN107 is an investigational oral compound which inhibits the activity of specific proteins, including BCR-ABL and 32 of 33 mutant forms of protein responsible for the development of chronic myeloid leukemia.
It is 10- to 50-fold more potent than Imatinib against BCR-ABL-expressing cell lines, including most Imatinib-resistant BCR-ABL mutants.
In research led by The University of Texas M.D. Anderson Cancer Center in Houston and the University of Frankfurt, Germany, 119 patients with Imatinib-resistant chronic myeloid leukemia in blast crisis ( BC ), AP, CP, or Ph+ ALL were treated with AMN107.
Initial daily doses ranged from 50 mg QD to 1,200 mg QD, and 400 mg BID to 600 mg BID.
Dose escalations occurred in 48 of the 69 patients in the once daily groups, and one patient in the 400 mg BID group escalated to 600 mg BID.
As of June 15, 2005, patients had been treated for a median of 120 days.
AMN107 was well-tolerated, and the most common drug-related adverse events were constipation, nausea, and vomiting.
Among CML patients who harbored a BCR-ABL mutation prior to treatment, 60 percent achieved a hematologic response and 41 percent achieved a cytogenetic response.
In addition, 72 percent of chronic myeloid leukemia patients who had no BCR-ABL mutation prior to taking AMN107 achieved a hematologic response, and 59 percent achieved a cytogenetic response.
Ph+ ALL patients who harbored a mutation prior to treatment with AMN107 saw a 33 percent response rate.
” AMN107 was shown to have significant activity in patients with advanced Imatinib-resistant chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia,” said Hagop M. Kantarjian, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. ” Current therapies, though effective, still have many limitations, and new treatment options with proven safety and efficacy can only benefit this patient population.”
Source: American Society of Hematology, 2005
XagenaMedicine2005
Advances in treatment of chronic myeloid leukaemia
Posted by rob on January 13, 2006 under Uncategorized |
By Lisa Arkin
Published: Friday, January 13, 2006
Should Eugene parents have the right to learn how much cancer-causing benzene is in the air near their children?
That will be the question when the Eugene City Council decides whether to add gas stations and petroleum product distributors to the list of industrial facilities that must report under Eugene’s toxics right-to-know law.
Studies from France, England, China and the United States all confirm the same fact: Benzene, present in gasoline fumes (as well as in the manufacture of some paints, plastics and pesticides) is clearly established as causing cancer in humans. Exposure to benzene has been linked previously to leukemia in adults, but recent research has made the link to children.
France’s national research institute recently published a study of 280 children younger than 15 diagnosed with acute leukemia, a cancer of the blood and bone marrow. Two-thirds of these children were 2 years old to 6 years old when diagnosed.
When compared with children not diagnosed with leukemia, the study found that children living near gas stations were four times more likely to have contracted leukemia. These children were seven times more likely to contract acute myelogenous leukemia. Children living for longer periods near a gas station experienced higher rates of leukemia.
Another study in England tracking 22,458 children who died from leukemia or solid cancers found that higher rates of childhood cancer are associated with living near distributors and industrial users of petroleum pro- ducts.
Eugene’s toxics right-to-know law, passed by citizens in 1996, requires manufacturers that yearly use 2,640 pounds of hazardous substances to report annually in April their inputs and outputs of these toxics. You can read the reports for the past seven years at www.ci.eugene.or.us/toxics.
Last March, the City Council directed the Toxics Board to prepare a list of additional categories of businesses that use more than 2,640 pounds of hazardous substances per year. The board determined that gas stations, petroleum product distributors and possibly manufacturers with fewer than 10 employees (which currently do not report) use these large quantities of hazardous substances in Eugene. The City Council now will determine whether to add them to the reporting program.
How much would reporting cost each Eugene gas station? The yearly program fee for a gas station with five full-time employees would be approximately $155. Since each gas station sells approximately 1.1 million gallons of gasoline, this might add a bit more than one ten-thousandths of 1 cent to the cost of a gallon of gas. In other words, should gas stations choose to pass this cost on to consumers, we would pay one additional penny for every 10,000 gallons of gas.
What about the costs of filling out the report? Gas stations can quickly produce the annual report by using a state-approved formula that allows each gas station to automatically calculate escapes of their gasoline into the air based on quantity of gas sold.
If the station has a spill, it might have additional outputs to air or to surface water. Two formulas exist: One formula is for gas stations that use stage one vapor control equipment, and another for those that don’t.
What is stage one vapor control equipment? This is a system of valves and gaskets inside the hoses of delivery trucks and the underground gas tanks. The equipment creates a vacuum that recaptures fumes that would otherwise leak to the air when filling the tank. A gas station can easily reduce its gasoline vapors by requiring trucks that fill the station’s underground tanks to use this system.
A 1978 law requires each gas station in the Portland metropolitan area, Salem and Medford with an underground tank capacity of 1,500 gallons to install vapor control equipment. As a result, gasoline delivery trucks have installed the equipment to do business in these three metropolitan areas.
However, equipment to control noxious fumes is not required in other cities, including Eugene.
Currently, Oregon’s gas stations do not report their yearly gas use and emissions to any government agency, and don’t track their releases of benzene. Wouldn’t you like to have the right to know how much benzene your local gas station is releasing?
Hopefully, when it votes on this issue, the Eugene City Council will keep in mind the image of a 2-year-old child with leukemia. That’s who the community’s right-to-know law is for – our children.
Lisa Arkin is executive director of the Oregon Toxics Alliance.
The Register-Guard, Eugene, Oregon, USA: “The
Posted by rob on under Uncategorized |
After the Yahoo group was deleted yesterday we tried to set up the CML group on our own server. We ran into problems with the software trying to set up on the CMLHope.Com server. After working with the hosting company engineer we found that because of the size of the list it causes a lag in the message delivery of several hours.We have tried 2 server software packages so far and neither will work well for large lists since they are designed for much smaller lists.
Since that is the case we will use the Google group instead since it can easily handle large numbers of subscribers and message traffic. For those who are not on the CMLHope you can join by sending an email to
CMLHOPE-subscribe@googlegroups.com
or by clicking on the link on the web site at http://cmlhope.com
Rob
Posted by rob on under Uncategorized |
Yahoo has deleted the CML (Chronic Myelogenous Leukemia) group which I established in 1998. The group, all of its archives, and 10 year history were destroyed by Yahoo. They also did the same to all of my business and real estate groups which destroyed another 10 to 15 years of my life’s work and disrupted communications for about 15,000 individuals and firms in the real estate and capital markets.
As some of you know I started having problems about a year ago with Yahoo when they deleted my Yahoo ID. At that time I lost access to bank records and other business and financial accounts which were linked to my Yahoo ID. I then got another Yahoo ID and had the same thing happen again. The second time I was banned from the very groups that I own on Yahoo including the CML group. When the problems began with Yahoo about a year ago I managed to keep the group going under the Yahoo ID of a friend who had been added as a moderator. In each of the previous incidents there were apparently claims that Yahoo’s Terms Of Service was violated even though there was not a shred of evidence to support that. Yahoo apparently will take action based on false and malicious complaints and there is essentually nothing that can be done about it.
The only response Yahoo would make today is the meaningless “Have a nice day!” drivel below which once again hides behind non-existent TOS complaints and Yahoo’s all encompassing power to terminate any group and person they do not like.
| From: Yahoo! Groups <groups-abuse@cc.yahoo-inc.com> |
Mailed-By: cc.yahoo-inc.com |
Reply-To: Yahoo! Groups <groups-abuse@cc.yahoo-inc.com>
Date: Jan 12, 2006 7:40 PM
Yahoo! may, in appropriate circumstances and in its sole discretion,
terminate Groups that appear to have violated the Yahoo! Terms of
Service (TOS). In some cases, Groups may be deleted by an Owner or
Moderator. You may want to contact the owner or moderator(s) regarding
your concern.
Please feel free to visit the Yahoo! Terms of Service at:
http://docs.yahoo.com/info/terms/
Thank you again for contacting Yahoo! Customer Care.
Have a nice day!
Regards,
Kirk Morrison
Yahoo! Customer Care
http://www.yahoo.com/
When the problems started with Yahoo a year ago I set up the CMLHope and CML Newswire web sites and a new CML group on Googlegroups. Those remain open and will not be affected by the action taken by Yahoo. We will not start another group on Yahoo, their conduct over the past year makes it clear they are not a realiable facility to use especially for a group such as the CML group where the lives of other people are at stake.
In addition to the group on Google we will start using a new CML group on the CMLHope mail server. By using our own server we will be able to continue with a CML group that is free from harassment and intimidation and is safe for our members. Those who want to join either of our groups can do so by sending an email to the addresses below and I will try to send out an email later to all of our members to add them to the CML@CMLHOPE.COM group if I can locate all of the old addresses.
CML-SUBSCRIBE@CMLHOPE.COM
CMLHOPE-SUBSCRIBE@GOOGLEGROUPS.COM
If anyone is unable to successfully subscribe contact me and I will add you to the group.
It has been a sad experience for me the past year to see so much of what I have done destroyed. When the problems started a year ago I tried the best I could to keep the CML group on Yahoo operating and to try to set up alternative sites that would not be subject to harassment and intimidation. It is unfortunate that 10 years of history are now down the drain but there is nothing that can be done about it.
Rob
Posted by rob on January 11, 2006 under Uncategorized |
In an upcoming G&D paper, Dr. Albert Baldwin and colleagues (UNC School of Medicine) lend new insight into an alternate mechanism of p53 inactivation in tumor cells. The researchers found that the putative oncoprotein Bcl-3, which is expressed in some leukemias and solid tumors, potently suppresses p53 activation through a mechanism that involves the controlled upregulation of Hdm2 gene expression.
Additionally, they found that Bcl-3 is activated by DNA damage and is required for p53 to control Hdm2 gene expression. Thus the normal function of Bcl-3 appears to be to limit p53 activation and to suppress apoptosis. Constitutive expression of Bcl-3 in cancer, therefore, subverts the normal regulation of the p53 tumor suppressor mechanism leading to oncogenic potential.
Oncogenic role for Bcl-3
Posted by rob on January 8, 2006 under Uncategorized |
That trip to Europe I’ve always craved finally happened on Thursday.
About the institute
The Oklahoma Blood Institute has about 650 employees statewide, most of them phlebotomists who join the staff after high school and get on-the-job training.
“Unfortunately, those are the ones that find better hours and sometimes better pay at a hospital, so we may have constant turnover,” said Dr. Jim Smith, associate medical director. But since the recruitment pool for highly trained nurses and lab technologists is smaller, OBI does everything it can to keep those employees, he said.
As part of the National Marrow Donor Program, OBI gets some funds from that organization to support processing for each person who signs up — about $50 per person. No funding is available to support personnel working on the program, so those fees are absorbed into OBI’s $60 million annual budget. Still, Smith wishes the institute had a full-time recruiter for the marrow donor program to help build a bigger base.
For more information about the marrow donor program, call 297-5619.
It wasn’t exactly as I imagined it would be. This wasn’t a business or leisure trip but more like a goodwill tour with a European destination, so I was never concerned about how the U.S. dollar stacked up against the Euro, where I’d be staying or how I’d get there. In fact, I didn’t take up much space at all, cuddled all the way in a 9-by-12 cooler.
It was a trip about 10 weeks in the making — seven years if you count when I reluctantly put my name on the National Bone Marrow Registry. Back then I was responding to a plea from a recruiter after she said the registry had few minority donor prospects. So imagine my surprise when I got a call from the registry’s Washington office saying I was one of five possible matches for someone who needed a bone marrow transplant. That preceded the first of four trips to the Oklahoma Blood Institute for more tests.
The initial OBI results showed I was a match to someone’s immunological white cell marker. It was a perfect match, I’m told. And Friday, I met her — a 12-year-old girl with chronic myelogenous leukemia who lives somewhere in Europe.
Over the past few weeks I’ve learned so much about the business of blood and the miracles the folks at the Oklahoma Blood Institute and the marrow donor program help to facilitate.
The institute is not for profit, but operates as a business nonetheless. Personnel include nurses, phlebotomists, doctors and administrators who ensure the safety not only of the state’s blood supply but also of donors.
As someone who is squeamish about needles, this was not an environment I found appealing. In fact, I’d never even donated blood, avoiding all the donor drives at work and church. But Sherri Ellis and Angie Powell could stick you, and you’d still be waiting to feel the prick. And doctors such as Jim Smith talk to patients in soothing tones that erase any preconceived fears.
Ellis is a registered nurse and hemapheresis practitioner. Powell is a phlebotomist and apheresis technician. The unfamiliar terms in both titles refer to the women’s specialties in operating machines that separate blood into various components.
Together Ellis and Powell — with medical oversight from Smith — comprise the staff for the institute’s marrow donor program. They work regular 8 a.m. to 5 p.m. hours most days, but every two to four weeks may have to show up earlier, as they did at 5:30 a.m. Thursday to prepare me for a date two hours later with Dr. George Selby at OU Medical Center.
Selby, a urologist, has been doing marrow extractions since the early 1990s. I met him about six weeks earlier to talk about the entire process and for a physical. Selby is a charmer who leaves you feeling comfortable about your decision to have his bone-piercing needles enter your pelvic area.
He said the out-patient process was fairly quick — about 30 to 45 minutes — followed by a recovery period that involved how long a patient takes to recover from the effects of anesthesia and when my marrow will replace itself — that happens within weeks. And of course my pelvic area will be sore, he said.
He wasn’t kidding. Even my 5-year-old Labrador, Patch, sensed my discomfort when I got home, whimpering and pawing to get in my bed during the night.
But the pain wasn’t unbearable and definitely worth the effort to save a child’s life. Selby says there’s an 80 percent chance of success with a marrow transplant that matches. That’s encouraging odds, and I hope that 12-year-old likes me.
I’m still not sure exactly how much of me went to Europe though.
“They take less than 10 percent, so you’re never at risk, and particularly in your case, they didn’t need to take the amount they normally would because the recipient is so small,” Powell said.
I still intend to see all of Europe, but I’ll pay my own way on the next trip.
Business Editor Clytie Bunyan can be reached at 475-3284 and cbunyan@oklahoman.com.
NewsOK.com | Powered by The Oklahoman and NEWS 9
Posted by rob on under Uncategorized |
Ma X, Ruan G, Wang Y, Li Q, Zhu P, Qin YZ, Li JL, Liu YR, Ma D, Zhao H
Clin Cancer Res. 2005 Dec 15; 11(24 Pt 1): 8592-9
PURPOSE: Chronic myelogenous leukemia (CML) is a disease characterized cytogenetically by the presence of the Philadelphia chromosome. Recent studies suggested that altered PDCD5 expression may have significant implications in CML progression. The aim of this study was to identify single-nucleotide polymorphisms (SNP) within the programmed cell death 5 (PDCD5) promoter region and show their functional relevance to PDCD5 expression as well as their genetic susceptibility to CML. EXPERIMENTAL DESIGN: One hundred twenty-nine CML subjects and 211 healthy controls were recruited for identification of SNPs and subsequent genetic analysis. Luciferase reporter assays were carried out to show the functional significance of the SNPs located in the promoter region to PDCD5 expression. Real-time quantitative PCR and Western blot analysis were done to determine the expression differences of PDCD5 in CML patients with different genotypes. RESULTS: Two SNPs were identified within the PDCD5 promoter. They are -27A>G and -11G>A (transcription start site as position 1), respectively. The complete linkage disequilibrium was found between these two polymorphisms. The frequencies of -27G+/-11A+ genotype and -27G/-11A allele were significantly higher in CML patients than in healthy controls (genotype: 26.36% versus 11.85%, chi2=11.75, PHubMed Abstracts
