Despite successful primary tumor treatment, the development of pulmonary
metastasis continues to be the most common cause of mortality in osteosarcoma
patients. A conventional drug development path ...requiring drugs to induce
regression of established lesions has not led to improvements for osteosarcoma
patients in over 30 years. Based on our growing understanding of metastasis
biology, it is now reasonable and essential that we focus on developing
therapeutics that target metastatic progression. To advance this agenda a
meeting of key opinion leaders and experts in the metastasis and osteosarcoma
communities was convened in Bethesda Maryland. The goal of this meeting was to
provide a “Perspective” that would establish a preclinical
translational path that could support the early evaluation of potential
therapeutic agents that uniquely target the metastatic phenotype. Although
focused on osteosarcoma the need for this perspective is shared among many
cancer types. The consensus achieved from the meeting included the following:
That the biology of metastatic progression is associated with
metastasis-specific targets/processes that may not influence grossly detectable
lesions; targeting of metastasis-specific processes is feasible; rigorous
preclinical data is needed to support translation of metastasis-specific agents
into human trials where regression of measurable disease is not an expected
outcome; preclinical data should include an understanding of mechanism of
action, validation of pharmacodynamic markers of effective exposure and
response, the use of several murine models of effectiveness, and where feasible
the inclusion of the dog with naturally occurring osteosarcoma to define the
activity of new drugs in the micro-metastatic disease setting.
Abstract 738
Myelodysplastic syndromes (MDS) are characterized by defective hematopoietic stem/progenitor cell maturation, resulting in ineffective hematopoiesis. This group of disorders is ...characterized by cytogenetic abnormalities and approximately 25% of cases progress to acute myeloid leukemia (AML). NPM1 is frequently mutated in AML and translocations involving NPM1 occur in a number of hematopoietic malignancies including MDS. NPM1 heterozygous mice (NPM1 +/−) have been shown to have a MDS-like phenotype. Taken together, these data suggest an important role for NPM1 in the function of hematopoietic stem cells (HSC) and/or committed progenitors. In order to evaluate NPM1 function in early hematopoiesis, we have evaluated NPM1 expression in both the mouse and human hematopoietic systems. Using quantitative RT-PCR, we show that NPM1 expression levels are 2-3-fold higher in normal CD34+ bone marrow progenitor cells compared to total bone marrow in humans. Furthermore, NPM1 expression levels are decreased by ∼50% in 9/37 MDS CD34+ cells when compared to normal controls. Of interest, NPM1 expression is reduced primarily in patients with poor or intermediate prognosis. Consistent with a functional role for NPM1 in HSC, NPM1 +/− mice (developed by gene trapping and obtained from the MMRRC at UC-Davis) contained significantly increased numbers of HSC (Lin-cKit+Sca+CD34-CD150+) within the Lin-cKit+Sca+ population compared to those from the littermate controls (52 ± 2.6% vs,74 ± 12%, p < 0.01). Consistent with prior reports, NPM +/− mice contained significantly fewer mature erythrocytes (Ter119+CD71lo) in the bone marrow compared to WT controls (6.5 ± 1.8% vs 10 ± 0.5% p < 0.01). In order to study NPM +/− HSC function, we tested the ability of these HSCs to form colonies in methylcellulose. NPM1 +/− HSCs formed increased numbers of both CFU-GM and CFU-GEMM colonies and decreased numbers of CFU-E colonies compared to WT HSC. Flow cytometric analysis of pooled day 14 colonies from individual mice revealed a >2 fold increase in cKit+ progenitor cells from NPM1 +/− colonies (2.0 ± 1.0% vs. 0.2 ± 0.2%, p = 0.02), suggesting that the differentiation potential of NPM+/− HSCs is impaired. To characterize HSC function in vivo, equal numbers of double-sorted HSCs from WT and NPM1 +/− mice were transplanted in triplicate into lethally irradiated C57B6 (CD45.2) recipients. Analysis of peripheral blood donor chimerism (CD45.1+CD45.2+) 21 days post-transplantation showed that NPM1 +/− HSC-transplanted recipients exhibited markedly lower granulocyte chimerism than WT HSC recipients (5.5 fold reduction, 2 ± 2% vs. 11 ± 5%, p < 0.01). This finding suggests that although NPM1 +/− mice have increased numbers of HSC, these HSC exhibit either altered myeloid fate decisions or decreased bone marrow homing capacity. We are currently investigating long-term engraftment potential to further elucidate the function of HSC in NPM1 +/− mice in vivo. In aggregate, these data demonstrate a functional role for NPM1 in early myeloid differentiation and strongly suggest that NPM effects may be exerted as early as at the level of the HSC.
Amgen: Equity Ownership; Cellerant Inc.: ; Stem Cells Inc.: Equity Ownership, Founder; U.S. Patent Application 11/528,890 entitled “Methods for Diagnosing and Evaluating Treatment of Blood Disorders.”: Patents & Royalties.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ONYX-015 is an adenovirus that selectively replicates in p53 dysfunctional or mutated malignant cells. We performed a pilot trial to determine the safety and feasibility of treatment with ONYX-015 ...delivered intravenously in patients with advanced malignancy. One cohort of five patients received ONYX-015 once a week for 6 weeks at a dose of 2 x 10(12) particles per infusion in combination with weekly infusions of irinotecan (CPT11, 125 mg per week) and 5-fluorouracil (5FU, 500 mg per week). A second cohort of five patients received the combination of ONYX-015 at a dose of 2 x 10(11) particles per week for 6 weeks in combination with interleukin 2 (IL 2, 1.1 x 10(6) units daily via subcutaneous injection for 5 days each week for 4 weeks). Toxicity attributable to ONYX-015 was limited to transient fever. All patients demonstrated elevations in neutralizing antibody titers within 4 weeks of the infusion of ONYX-015. Serum levels of IL-6, IL-10, tumor necrosis factor-alpha, and interferon-gamma increased within 6 hours of viral infusion, suggesting immune activation. This response was more pronounced in the cohort of patients who received 2 x 10(12) particles per infusion. Two patients demonstrated uptake of viral particles in malignant tissue by quantitative PCR. Electron microscopy confirmed selective cytoplasmic viral particles within malignant cells but not within adjacent normal tissue in a third patient. In conclusion ONYX-015 can be administered safely in combination with CPT11, 5FU or low-dose IL 2 and is able to access malignant tissue following intravenous infusion. Further investigation of ONYX-015, possibly with agents that may modulate replication activity, or duration of virus survival, is indicated.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This article presents the variety of approaches used to conduct evaluations of performance improvement or accreditation systems, while illustrating the complexity of conducting evaluations to inform ...local public health practice. We, in addition, hope to inform the Exploring Accreditation Program about relevant experiences involving accreditation and performance assessment processes, specifically evaluation, as it debates and discusses a national voluntary model. A background of each state is given. To further explore these issues, interviews were conducted with each state's evaluator to gain more in-depth information on the many different evaluation strategies and approaches used. On the basis of the interviews, the authors provide several overall themes, which suggest that evaluation is a critical tool and success factor for performance assessment or accreditation programs.
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BFBNIB, CMK, NMLJ, NUK, PNG, UL, UM, UPUK
56.
Interrupted Life Solinger, Rickie; Johnson, Paula C; Raimon, Martha L ...
12/2009
eBook
Interrupted Lifeis a gripping collection of writings by and about imprisoned women in the United States, a country that jails a larger percentage of its population than any other nation in the world. ...This eye-opening work brings together scores of voices from both inside and outside the prison system including incarcerated and previously incarcerated women, their advocates and allies, abolitionists, academics, and other analysts. In vivid, often highly personal essays, poems, stories, reports, and manifestos, they offer an unprecedented view of the realities of women's experiences as they try to sustain relations with children and family on the outside, struggle for healthcare, fight to define and achieve basic rights, deal with irrational sentencing systems, remake life after prison; and more. Together, these powerful writings are an intense and visceral examination of life behind bars for women, and, taken together, they underscore the failures of imagination and policy that have too often underwritten our current prison system.
Cultivation of
Mycobacterium avium subsp.
paratuberculosis (
M. paratuberculosis) from feces remains the most reliable method to detect infected animals. The purpose of this study was to evaluate a ...broth-based automated system used for cultivation of mycobacteria such as
M. tuberculosis from human hosts, for the detection of
M. paratuberculosis in bovine feces. Bovine feces was spiked with tenfold serial dilutions of
M. paratuberculosis (5×10
5 to 5×10
−1 organisms), then processed with a double-centrifugation technique that included disinfection prior to inoculation into broth tubes. The same pathogen dilution series was also inoculated directly into broth and broth with uninfected processed feces. All of the system signal-positive bottles were identified within 30 days, with the highest concentration of
M. paratuberculosis detected by the system in as few as 8 days. The presence of the pathogen was confirmed with acid-fast staining and an IS
900-based PCR assay when growth of
M. paratuberculosis was indicated by the system. However, some of the signal-negative cultures inoculated with the equivalent of 0.5 organisms tested PCR-positive 56 days post-inoculation, indicating that longer culture periods may lead to detection of small quantities of the organisms. Additionally, it was indicated that the processing step had a detrimental effect on detection of the organism. Comparison of the broth- and Herrold's egg yolk medium (HEYM) solid media-based culture methods with defined check test specimens corroborated the experimental evaluation of this system, indicating that broth-based detection could provide a more rapid assay for
M. paratuberculosis. These results suggest that this automated system could be used to detect this organism in bovine feces, but that new approaches to processing the feces for culture should be explored.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
58.
Children's Emotional and Behavioral Disorders Johnson, Harriette C; Cournoyer, David E; Fisher, Gene A ...
American journal of orthopsychiatry,
July 2000, Volume:
70, Issue:
3
Journal Article
Peer reviewed
In the wake of the neurobiological "revolution," do mental health professionals still assign etiological responsibility for emotional and behavioral disorders to deficient or harmful parenting? This ...study investigated differences in attributions of causality by theoretical orientation, professional discipline, areas of practice, familiarity with parent support groups, and demographic characteristics. Implications for policy, research, and practice are discussed.
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BFBNIB, CEKLJ, FFLJ, FZAB, GIS, IJS, KILJ, NLZOH, NUK, ODKLJ, OILJ, PEFLJ, SBCE, SBMB, UL, UM, UPUK
In nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT), high-dose cytotoxic therapy as the conceptual basis for treating hematopoietic malignancies has been replaced by ...graft-versus-tumor effects. The use of potent pre- and postgrafting immunosuppression derived from preclinical studies has allowed omission of myeloablative cytotoxic therapy without compromising hematopoietic donor cell engraftment. This results in a marked reduction in transplant-related toxicities that makes older or medically infirm patients candidates for this treatment option. This patient group is more representative of the population with cancer and would have been ineligible for conventional HSCT. Initial results in patients with a variety of hematologic malignancies have been encouraging with documented sustained cytogenetic and molecular remissions in a substantial number of sometimes heavily pretreated and previously refractory patients. Even though patients with hematologic malignancies will likely require conversion to full donor hematopoiesis for long-term disease control, a state of mixed hematopoietic chimerism might suffice to "cure" the disease phenotypes in various nonmalignant diseases. Strategies aimed at optimizing peritransplant immunosuppression may eventually eliminate the need for pretransplant total body irradiation, which is relevant for minimizing late toxicities. Enhancing graft-versus-tumor effects by virtue of postgrafting vaccination of recipients against tumor-specific antigens may help to use this transplant approach more effectively in the treatment of solid tumors.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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