Posted by rob on July 21, 2005 under Uncategorized | 
Bullinger L, Dã Hner H, Pollack JR
Rev Clin Exp Hematol. 2005 Jun ; 9(1): E2
Myeloid leukemias are clonal hematopoietic stem cell disorders characterized either by proliferation of one or more of the myeloid lineages (chronic myelogenous leukemia) or by clonal expansion of myeloid blasts (acute myeloid leukemia). Over the past several years our knowledge of these hematologic malignancies has increased tremendously. The result is a classification that incorporates morphologic, immunophenotypic, genetic and clinical features in an attempt to define biologically and clinically relevant entities. Nevertheless, in many tumor subtypes the pathogenic event is still unknown. Furthermore, well-defined leukemia subgroups exhibit considerable heterogeneity, arousing the suspicion that several molecularly distinct subtypes might exist within the same cytogenetic category. Therefore, an ideal classification system would ultimately be based on the underlying molecular pathogenesis, but such knowledge is not yet available. However, by surveying the expression levels of thousands of genes in parallel, DNA microarrays have recently contributed to an increasingly refined molecular taxonomy of myeloid disorders. This powerful technology is becoming well established and has been used to diagnosis cancer and predict clinical outcome, to discover novel tumor subclasses, to gain insights into pathogenesis, and to identify new therapeutic targets. While many challenges remain ahead, genomic technologies have already demonstrated tremendous potential. We expect whole genome approaches will significantly contribute to a better understanding of the pathogenesis and result in a refined molecular classification of myeloid leukemias.
Genomics in myeloid leukemias: an array of possibilities.
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Requena L, Kutzner H, Palmedo G, Pascual M, Fernández-Herrera J, Fraga J, García-Díez A, Yus ES
Arch Dermatol. 2005 Jul ; 141(7): 834-42
OBJECTIVE: To describe a series of 41 patients with fresh lesions of Sweet syndrome in which the histopathologic study demonstrated an inflammatory infiltrate mostly composed of histiocytoid mononuclear cells. DESIGN: Histopathologic, immunohistochemical, and cytogenetic studies of the inflammatory infiltrate in a case series of histiocytoid Sweet syndrome. SETTING: University departments of dermatology and a private laboratory of dermatopathology. METHODS: Conventional histopathologic study as well as immunohistochemical investigations were performed using the alkaline phosphatase antialkaline phosphatase technique with a large panel of antibodies. In some cases, fluorescent in situ hybridization studies were performed to investigate the presence of the bcr/abl gene fusion. RESULTS: Immunohistochemical studies demonstrated that most cells of the infiltrate showed immunoreactivity for CD15, CD43, CD45, CD68, MAC-386, HAM56, and lysozyme, which is consistent with a monocytic-histiocytic immunoprofile. However, intense myeloperoxidase reactivity was detected in most of the cells with histiocytic appearance, which raised the possibility of specific cutaneous involvement by myelogenous leukemia. Nevertheless, cytologic peripheral blood examinations, fluorescent in situ hybridization studies to investigate the bcr/abl gene fusion, and follow-up of the patients, taken all together, ruled out this possibility. CONCLUSIONS: This case series demonstrates that some fresh cutaneous lesions of Sweet syndrome are histopathologically characterized by an infiltrate mostly composed of cells that may be misinterpreted as histiocytes, when in fact they are immature myeloid cells. We named this histopathologic variant histiocytoid Sweet syndrome, which should not be mistaken with leukemia cutis or other inflammatory dermatoses that are histopathologically characterized by histiocytes interstitially arranged between collagen bundles of the dermis.
Histiocytoid Sweet syndrome: a dermal infiltration of immature neutrophilic granulocytes.
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Xu R, Dong Q, Yu Y, Zhao X, Gan X, Wu D, Lu Q, Xu X, Yu XF
Leuk Res. 2005 Jul 13;
Gleevec, which is an inhibitor of the bcr/abl tyrosine kinase, has been a remarkable success for the treatment of chronic myelogenous leukemia (CML). However, a significant proportion of patients chronically treated with Gleevec develop resistance. Here we describe the activity of a natural small molecular compound, berbamine from plant Berberis amurensis that can selectively induce cell death of both Gleevec-sensitive and -resistant Ph(+) CML cells. The IC(50) values of berbamine were 8.80mug/ml in Gleevec-sensitive Ph(+) CML cells, 11.34mug/ml in Gleevec-resistant Ph(+) CML cells, and 54.40mug/ml in Ph(-) KG-1 cells, respectively. Similarly, berbamine was also found to display a selective anti-proliferative activity of primary leukemia cells from CML patients, and its IC(50) values were 4.20-10.50mug/ml in primary CML cells, and 185.20mug/ml in normal bone marrow cells, respectively. More importantly, our studies demonstrate that berbamine down-regulates p210bcr/abl oncoprotein level, and induces apoptosis of bcr/abl+ cells through caspase-3-dependent pathway. These data suggest that berbamine might be a novel bcr/abl inhibitor with potent anti-leukemia activity.
Berbamine: A novel inhibitor of bcr/abl fusion gene with potent anti-leukemia activity.
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Terme M, Borg C, Guilhot F, Masurier C, Flament C, Wagner EF, Caillat-Zucman S, Bernheim A, Turhan AG, Caignard A, Zitvogel L
Cancer Res. 2005 Jul 15; 65(14): 6409-17
BCR/ABL fusion gene, encoding a paradigmatic tyrosine kinase involved in chronic myelogenous leukemia (CML), can modulate the expression of genes involved in natural killer (NK) cell target recognition. Recent reports outline the role of allogeneic antileukemic NK effectors in the graft-versus-leukemia effect but the regulation of NK cell activation in the setting of graft-versus-leukemia effect remains unknown. Here we show that dendritic cells derived from monocytes of CML patients are selectively endowed with NK cell stimulatory capacity in vitro. We further show, using a gene transfer approach in mouse bone marrow progenitors, that ABL/ABL is necessary to promote dendritic cell-mediated NK cell activation. The dendritic cell/NK cell cross-talk in ABL/ABL-induced CML seems unique because JunB or IFN consensus sequence binding protein loss of functions, associated with other myeloproliferative disorders, do not promote dendritic cell-mediated NK cell activation. NK cell activation by leukemic dendritic cells involves NKG2D activating receptors and is blocked by imatinib mesylate. Indeed, ABL/ABL translocation enhances the expression levels of the NKG2D ligands on dendritic cells, which is counteracted by imatinib mesylate. Altogether, the clonal ABL/ABL dendritic cells display the unique and selective ability to activate NK cells and may participate in the NK cell control of CML. This study also highlights the deleterious role of imatinib mesylate at the dendritic cell level for NK cell activation.
BCR/ABL Promotes Dendritic Cell-Mediated Natural Killer Cell Activation.
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Jenei V, Jakus J
Orv Hetil. 2005 Jun 12; 146(24): 1293-9
Hungary is among the leading countries in Europe regarding the mortality and incidence of different types of tumours. Therefore, developing effective therapies is especially important in this country. Investigation of tumour formation and progression on the molecular level is required to develop possible therapeutical targets. Such targets can be proteins with tumour suppressor function, which inhibit intracellular signalling processes that under pathophysiological conditions can lead to uncontrolled cell proliferation and tumour formation. Protein e3B1/Abi-1, which belongs to the family of Abl-interactors, was isolated recently as a possible tumour suppressor. As a partner of Abl kinase, its role has been investigated in the development and progression of some types of leukemias, however, more and more experimental data suggest that it is a general suppressor protein. According to the latest results, e3B1/Abi-1 via the Ras small G-protein has an essential role in the regulation of cell proliferation, and via Rac activation it can affect actin remodelling, cell adhesion and migration. Cell proliferation is important in tumour development, while cell adhesion and migration has a role in metastasis formation. The latest results showed deletion of the gene encoding protein e3B1/Abi-1 in prostate cancer, loss of its expression during the progression of some types of leukemias, and there are data on the effect of imatinib mesylate (Gleevec or outside USA Glivec, Novartis), one of the newest drugs in leukemia treatment, on the phosphorylation of e3B1/Abi-1 as well. This report summarizes the data published on protein e3B1/Abi-1, with special interest in practical implications.
[An epidermal growth factor receptor-dependent e3B1/Abi1 protein as a tumor suppressing candidate in cancer]
Posted by rob on July 20, 2005 under Uncategorized |
A family of three huddles under their umbrellas as giant waves whipped up by Typhoon Haitang come crashing outside Taiwan’s northern city of Keelung.
Posted by rob on July 19, 2005 under Uncategorized |
Tourists attempt to catch fish while visiting Lake Rapel, one of South America’s largest artificial lakes, in Punta Verde, Chile.
Posted by rob on July 18, 2005 under Uncategorized |
Bone marrow donor match sought in city
By Michael Valkys
Poughkeepsie Journal
Dozens of people — friends and strangers — turned out Saturday for a bone marrow drive that could help two Dutchess County residents in need of transplants.
Gary Ponico, 36, of LaGrange, and Lynn Dagata-Grist, 39, of Wingdale, await bone marrow transplants. More than 60 people came to Vassar Brothers Medical Center in the City of Poughkeepsie for blood tests to determine if they are a match.
Chris Ponico, Gary’s older brother, said the turnout was heartening.
“We’re trying to get everybody we can,” Chris Ponico said. “We love him very much, and we’re trying to do everything we can for him.”
Gary Ponico has been diagnosed with acute lymphocytic leukemia. He has a rare tissue type and has been unable to find a family member as a match.
Dagata-Grist is a mother of two who was recently diagnosed with chronic myelogenous leukemia.
Patient in Westchester
Gary Ponico has been in Westchester Medical Center in Valhalla for more than a month and could not attend Saturday’s drive. It was held at the The Dyson Center for Cancer Care at Vassar Brothers.
Younger brother Frank Ponico said Gary would have appreciated those who came out on a summer Saturday to help.
“He would say he’s grateful that people are coming down,” Frank Ponico said.
Debbie Chita is Gary’s girlfriend and was also at Vassar Brothers on Saturday.
“It’s very meaningful for us that people came out and showed their support,” Chita said.
She said Gary is holding up well despite his illness.
“He’s definitely holding high spirits,” Chita said of Gary, whom friends described as a big New York Yankees and Billy Joel fan. He works for IBM Corp. in East Fishkill.
Robert Cattau of Pine Bush said Gary was the best man at his wedding. Cattau was at the drive Saturday and said his friend would have done the same for him.
“I’m glad,” Cattau said as he saw those who had shown up for the drive. “It’s a real good turnout.”
Donations and matching funds from the National Marrow Donor Registry Program covered the $65 cost of blood testing for possible donors. Additional donations are still being accepted.
East Fishkill resident Tania Cohen helped organize the drive.
“I figured, let’s try to get some people out here and see what we can do,” Cohen said.
She said time is of the essence.
“Gary needs one as soon as possible,” Cohen said of the transplant procedure. “He’s a great guy.”
Cohen said that even if donors are not found for Ponico and Dagata-Grist, the day was worthwhile.
She said all of Saturday’s donors will have their information sent to a national donor data base, where a match could be found.
“Even if we don’t match them, we could match someone in Minneapolis,” Cohen said. “Maybe we can help somebody else.”
Michael Valkys can be reached at mvalkys@poughkeepsiejournal.com
How to help
For information or to make a contribution to the bone marrow drive, contact Tania Cohen at 845-454-0088 ext. 6.
PoughkeepsieJournal.com – Drive seeks help for 2 ill residents
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A hut is seen on the beach in the southeastern Mexican seaside resort town of Cancun July 17, 2005. Mexico was braced for one of its worst storms in years as violent Hurricane Emily howled toward popular Caribbean resorts around Cancun on Sunday, packing winds of up to 155 mph (250 kph). The second major hurricane of the season, arriving just days after Hurricane Dennis ripped through Cuba and Florida, Emily was due to pass over the tiny Cayman Islands early Sunday and smash into Mexico’s Yucatan Peninsula during the evening.
Posted by rob on July 17, 2005 under Uncategorized |
Slovak freelance fotographer Jakub Sukup is surrounded by sunflower field as he shoots pictures during an assignment, near the village of Vistuk, near the Slovak capital of Bratislava.
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Interactions between the histone deacetylase inhibitor SAHA and the pharmacologic MEK1/2 inhibitor PD184352 were examined in Bcr/Abl+ human leukemia cells. Coadministration of minimally toxic concentrations of SAHA (or sodium butyrate) and PD184352 (or U0126) resulted in a synergistic increase in mitochondrial damage, caspase activation, and apoptosis in K562 and LAMA 84 cells. Similar interactions were observed in CD34(+) cells from two patients with CML and in imatinib mesylate-resistant K562 cells but not in normal human CD34(+) bone marrow cells. These events were associated with a marked increase in ROS generation, inactivation of ERK and Akt, downregulation of p21(CIP1), Bcr/Abl, and cyclin D(1), and activation of JNK. Of these events, ROS generation, ERK inactivation, and cytochrome c/AIF release were largely caspase-independent, whereas the other phenomena displayed varying degrees of caspase-dependence. Using pharmacologic and genetic approaches, generation of ROS, p21(CIP1) downregulation, and inactivation of Akt and MEK were found to play significant functional roles in SAHA/PD184352-mediated lethality, whereas JNK activation and Raf-1 downregulation were determined to represent secondary events. These findings indicate that interruption of the MEK/ERK pathway substantially lowers the threshold for HDAC inhibitor-mediated oxidative injury, mitochondrial dysfunction, and apoptosis, suggesting that this approach warrants further examination in Bcr/Abl+-related malignancies.Leukemia advance online publication, 14 July 2005; doi:10.1038/sj.leu.2403868.
http://www.hubmed.org/display.cgi?uids=16015388
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Patients with chronic myeloid leukemia (CML) can develop extramedullary involvement during the course of the illness. This usually occurs during the accelerated phase or blast crisis. We describe a patient who presented with massive ascites probably due to mesenteric/peritoneal infiltration during chronic phase CML. There was an excellent response to imatinib with a complete cytogenetic response and total disappearance of ascites.
http://www.hubmed.org/display.cgi?uids=16019565
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Imatinib mesylate, a signal transduction inhibitor molecule, has been introduced in the treatment of chronic myelogenous leukemia (CML) since May 2001. By its unique mechanism of action, the drug has revolutionized the management of chronic phase CML. The drug is generally well tolerated. A number of hematological and non-hematological side-effects have been reported. Fatal bone marrow (BM) aplasia has rarely been reported. A 46-year-old women with chronic phase CML was treated with imatinib. Six weeks later she developed severe pancytopenia associated with fever, chest infection and bleeding. A BM biopsy revealed hypoplasia (BM cellularity <?5%). She died of pulmonary mucormycosis. CML patients on imatinib therapy need close monitoring. Those pre-treated with busulfan and interferon-a may be at a higher risk of developing BM aplasia.
http://www.hubmed.org/display.cgi?uids=16019519
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One hundred and ten patients with Philadelphia chromosome (Ph)-positive chronic phase chronic myelogenous leukemia (CML) post-interferon-a failure treated with imatinib mesylate therapy were analyzed for the prognostic significance of marrow reticulin stain-measured fibrosis. The median time from diagnosis was 31 months. Severe reticulin (grade 3?-?4) fibrosis was observed in 67 patients (61%). Patients with severe marrow fibrosis had similar complete cytogenetic response rates with imatinib (67 vs. 58%; P?=?0.45) compared with those with mild?-?moderate fibrosis. The estimated 4 year survival rates (80 vs. 88%; P?=?0.27) and failure-free survival rates (69 vs. 77%; P?=?0.34) were also not different. We conclude that the previously established poor prognostic significance of marrow fibrosis in CML is less relevant with imatinib therapy.
http://www.hubmed.org/display.cgi?uids=16019549
Posted by rob on July 16, 2005 under Uncategorized |
View of one of the corridors of the new hotel ‘Puerta America’ in Madrid during its presentation to the media.
Posted by rob on July 15, 2005 under Uncategorized |
A child bathes at Algeciras Beach in southern Spain on a hot summer day.
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| Measure for Measure: Tracking Treatment Progress in CML |
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When someone has cancer, doctors carefully monitor how well he or she responds to treatment. In chronic myeloid leukemia, the results of various blood and DNA tests act as a barometer for treatment effectiveness, helping doctors and patients determine the next best steps in treatment.
http://healthology.sparklist.com/t/61360/8512763/1016918/0/
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| Understanding CML Therapy: Responses and Side Effects |
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One of the greatest success stories in cancer treatment occurs in people with chronic myeloid leukemia. But treatments don’t always work well in everyone. Learn what can happen.
http://healthology.sparklist.com/t/61360/8512763/438905/0/
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Gotlib J
Acta Haematol. 2005; 114(1): 7-25
Use of the term “idiopathic hypereosinophilic syndrome (HES)” has highlighted our basic lack of understanding of the molecular pathophysiology of eosinophilic disorders. However, over the last 10 years, the study of hypereosinophilia has enjoyed a revival. This interest has been rekindled by two factors: (1) the development of increasingly sophisticated molecular biology techniques that have unmasked recurrent genetic abnormalities linked to eosinophilia, and (2) the successful application of targeted therapy with agents such as imatinib to treat eosinophilic diseases. To date, most of these recurrent molecular abnormalities have resulted in constitutively activated fusion tyrosine kinases whose phenotypic consequence is an eosinophilia-associated myeloid disorder. Most notable among these are rearrangements of platelet-derived growth factor receptors alpha and beta (PDGFRalpha, PDGFRbeta), which define a small subset of patients with eosinophilic chronic myeloproliferative disorders (MPDs) and/or overlap myelodysplastic syndrome/MPD syndromes, including chronic myelomonocytic leukemia. Discovery of the cryptic FIP1L1-PDGFRA gene fusion in cytogenetically normal patients with systemic mast cell disease with eosinophilia or idiopathic HES has redefined these diseases as clonal eosinophilias. A growing list of fibroblast growth factor receptor 1 fusion partners has similarly emerged in the 8p11 myeloproliferative syndromes, which are often characterized by elevated eosinophil counts. Herein the focus is on the molecular gains made in these MPD-type eosinophilias, and the classification and clinicopathological issues related to hypereosinophilic syndromes, including the lymphocyte variant. Success in establishing the molecular basis of a group of once seemingly heterogeneous diseases has now the laid the foundation for establishing a semi-molecular classification scheme of eosinophilic disorders.
Molecular classification and pathogenesis of eosinophilic disorders: 2005 update.
