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J D Jackson

Publications and source records attributed to J D Jackson.

At least 19 recordsLinked to original sources
PubMed2005

An ex vivo model of hematopoietic stem cell mobilization.

BACKGROUND: Mobilization of hematopoietic stem cells to the circulation facilitates their collection, thereby providing a non-marrow source of these cells for transplantation. Hematopoietic cytokine administration induces mobilization for most, but not all, donors. Because the underlying biology of mobilization is not well understood, improving the process on a rational basis is difficult. The design of an in vitro mobilization model was pursued to facilitate investigations of the process. METHODS: MS5 murine stromal cell line cells were grown to confluence on microporous transwell membranes. Murine femoral marrow plugs were placed on top of the prepared transwell membranes. The transwells were then seated in wells containing media and hematopoietic growth factors. Cells that were released from the marrow plugs over time and migrated through the stromal layer into the wells were assayed for stem cell/progenitor cell characteristics. RESULTS: Few or no GM-CSF (progenitors) were found in wells containing media alone or media plus mobilizing cytokines after 24 h. After 120 h, the numbers of cells in the cytokine-containing wells increased, as did the numbers of CD34(+) cells. Cells in the wells at the time progenitor cells were most frequent were shown to include side population (SP) hematopoietic stem cells. After 120 h in the presence of cytokines, cells pooled from the wells were transplanted to lethally irradiated mice. Eighty per cent of the transplanted mice survived 30 days or more, demonstrating that radioprotective stem cells were present in the wells. DISCUSSION: An ex vivo model has been designed that may aid investigations of the various steps of stem cell mobilization.

Animals↗
PubMed2001

An integrated process for measuring the physicochemical properties of drug candidates in a preclinical discovery environment.

Automated log P, pK(a), solubility, and chemical stability systems comprise an integrated process that provides early stage physicochemical property data to the discovery research organization. Capillary electrophoresis (CE) techniques are used to experimentally determine pK(a) and log P. Solubility is determined using a quasi-equilibrium approach employing sample quantitation by flow injection analysis with ultraviolet (UV) detection at 256 nm. Chemical stability is assessed by challenging compounds with pH 2, pH 7, pH 12, and 3% hydrogen peroxide solutions overnight, and comparing the chromatographic profiles of the stability challenged solutions to that of a freshly prepared control. Validation of the log P method using a set of drug-like compounds demonstrates that the method yields log P values within +/-0.5 units of literature values. The log P method is valid over the range -0.5-5.0, and the technique is compatible with acidic, neutral, and basic compounds. The pK(a) technique yields results within +/-0.2 units of corresponding values obtained by potentiometric titration over a pK(a) range of 2 to 12. Solubility is reported in a 3-60 microg/mL range, and the results are generally within 20% of values measured by equilibrium solubility techniques. The current level of automation supports the measurement of the physicochemical properties of 100 compounds per week. Physicochemical property data for approximately 2000 compounds have been generated to date.

Automation↗
PubMed2001

Circulating factors may be responsible for murine strain-specific responses to mobilizing cytokines.

OBJECTIVE: To determine if circulating factors influence strain-specific responses to administration of hematopoietic stem-cell mobilizing cytokines, a murine model was employed. METHODS: Plasma aliquots from intact DBA2, Balb/c, and C57Bl/6 mice were injected into intact Balb/c mice prior to delivery of mobilizing cytokines. Control Balb/c mice were injected with mobilizing cytokines alone. Plasma from hemi-body irradiated Balb/c mice, known to inhibit mobilization, was also injected into Balb/c mice. Twenty-four hours later, spleen cells were harvested and assayed for granulocyte-macrophage colony-forming cells (GM-CFC) and high-proliferative-potential colony-forming cells (HPP-CFC). Simultaneously harvested blood aliquots were assayed for CD45(+)/CD34(+) cells using flow cytometric techniques. RESULTS: Mice receiving plasma from any source demonstrated significant inhibition of mobilization of HPP-CFC and GM-CFC to the spleen as compared to mobilized controls; for HPP-CFC, plasma from C57Bl/6 mice was more inhibitory than plasma from Balb/c (p = 0.001) or from DBA2 mice (p = 0.01), while for GM-CFC, plasma from C57Bl/6 mice was more inhibitory than Balb/c plasma but not more inhibitory than DBA2 plasma. Mice injected with plasma from previously irradiated Balb/c mice exhibited the expected HPP-CFC and GM-CFC mobilization inhibition, which was not statistically different from the inhibition seen in animals that received C57Bl/6 plasma. Mobilization of CD34(+)/CD45(+) cells to the blood also appeared to be inhibited by pretreatment with C57Bl/6 plasma, but not DBA2 plasma. CONCLUSION: These data suggest that strain-specific patterns of mobilization may be influenced by a circulating mobilization inhibitor(s).

Animals↗
PubMed2001

Feasibility of interspecies extrapolation in determining the bioequivalence of animal products intended for intramuscular administration.

To examine the validity of extrapolating parenteral product bioequivalence determinations across target animal species, the relative bioavailability of two injectable formulations of ampicillin trihydrate (PolyflexR, a water-based suspension, and Ampi-kel 10R, an oil-based suspension) was examined in calves, sheep and swine. Employing products recognized to be bioinequivalent provided an opportunity to explore potential species-by-formulation interactions. As compared with PolyflexR, Ampi-kel 10R exhibited lower area under the curve (AUC) estimates but higher peak concentrations in all target animal species. Nevertheless, marked interspecies differences were noted in the width and bounds of the confidence intervals about the differences in treatment means. Potential physiological and physico-chemical reasons for these findings are discussed.

Ampicillin↗
PubMed2001

Oligonucleotide enhanced cytotoxicity of Idarubicin for lymphoma cells.

Oligonucleotides offer the potential to manipulate gene expression in targeted cells which might be exploitable for therapeutic benefit. The effects of combining a phosphorothioate oligonucleotide OL(1) p53, which transiently down-regulates p53 levels, with an anthracycline, Idarubicin, on the growth of wild-type p53 WMN gene-expressing lymphoma cells was evaluated. Fluorescent OL(1) p53, was used to demonstrate oligonucleotide uptake and retention by the WMN cells. Uptake was maximal at 24 hours and compared to baseline (0 hours) increasing apoptotic cells were evident in WMN cells treated with OL(1) (1 microM) alone and in combination with Idarubicin (0.2 nM) for 24 to 48 hours. In cells treated with OL(1) p53 and Idarubicin, truncated p53 message of a predicted 201 base pair length based on RNAase H cleavage of the OL(1) p53-p53 mRNA heteroduplex was detected after 7 hours of incubation. The message for p53 was transiently downregulated as detected by RT-PCR analysis at 24 hours, and protein levels transiently reduced at 36 hours, as shown by a quantitative Western blot. Corresponding to these events, the growth of WMN cells ceased after 48 hours in the concurrent presence of OL(1) p53 and Idarubicin and, the lymphoma cells were dead after 72 hours. No reduction in hematopoietic colony forming cell capacity of similarly treated hematopoietic progenitor cells harvested from cytokine-mobilized blood by apheresis was observed. Therefore, synergistic cytotoxicity of Idarubicin for lymphoma cells treated with an oligonucleotide targeting p53 message was demonstrated at oligonucleotide and Idarubicin concentrations which were minimally toxic to hematopoietic progenitor cells. This approach offers new opportunities for purging of lymphoma cells from hematopoietic harvests and systemic lymphoma therapy.

Antibiotics, Antineoplastic↗
PubMed2000

Histone H2A.Z has a conserved function that is distinct from that of the major H2A sequence variants.

Saccharomyces cerevisiae contains three genes that encode members of the histone H2A gene family. The last of these to be discovered, HTZ1 (also known as HTA3), encodes a member of the highly conserved H2A.Z class of histones. Little is known about how its in vivo function compares with that of the better studied genes (HTA1 and HTA2) encoding the two major H2As. We show here that, while the HTZ1 gene encoding H2A.Z is not essential in budding yeast, its disruption results in slow growth and formamide sensitivity. Using plasmid shuffle experiments, we show that the major H2A genes cannot provide the function of HTZ1 and the HTZ1 gene cannot provide the essential function of the genes encoding the major H2As. We also demonstrate for the first time that H2A.Z genes are functionally conserved by showing that the gene encoding the H2A.Z variant of the ciliated protozoan TETRAHYMENA: thermophila is able to rescue the phenotypes associated with disruption of the yeast HTZ1 gene. Thus, the functions of H2A.Z are distinct from those of the major H2As and are highly conserved.

Animals↗
PubMed2000

Immunological properties of mononuclear cells from blood stem cell harvests following mobilization with erythropoietin + G-CSF in cancer patients.

BACKGROUND: Although the recombinant granulocyte colony-stimulating factor (G-CSF) is a good CD34 cell mobilizer, the effects of G-CSF mobilization on the immune effector function of the individual is not always optimal. We studied the functional and phenotypic properties of peripheral blood stem cells (PBSC) collected from 15 cancer patients mobilized with G-CSF plus recombinant erythropoietin (EPO). METHODS: The patients received EPO (300 U/kg) and (G-CSF 1 microg/kg) per day as mobilizing cytokines and an autologous graft product was collected with at least daily apheresis procedures until a target number of CD34 cells and mononuclear cells were obtained. Mononuclear cells from the first four PBSC collections were tested for their natural killer (NK), activated NK and lymphokine activated killer (LAK) cytotoxicity in vitro against K562 and Raji tumor target cells. RESULTS: There was a significant increase in NK, activated NK and LAK cytotoxicity in EPO + G-CSF mobilized cells when compared to mononuclear cells from premobilization blood baseline values. Although there was no increase in CD3+ T cells, there was a significant increase in myeloid cells (CD14+), B-cells (CD20+) and NK cells (CD56+) following mobilization. There was no difference in T cell response to the mitogens PHA and Con-A, but there was an increase in B-cell response to PWM following mobilization. Thus, the combination of EPO + G-CSF not only mobilized hematopoietic precursor cells but also increased the number of immune effector cells in the PBSC collections.

Adult↗
PubMed2000

Pharmacokinetics and in vivo effects of a six-base phosphorothioate oligodeoxynucleotide with anticancer and hematopoietic activities in swine.

A short phosphorothioate oligodeoxynucleotide telomere mimic with the sequence 5'-d(TTAGGG)-3', TAG-6, has been shown to inhibit telomerase activity and have antineoplastic and hematopoietic stimulatory properties. In this study, three immature male domestic swine (weighing approximately 40 kg) were administered 200 mg/m2 of TAG-6 by continuous intravascular infusion at rates of 0.48 +/- 0.07 mg/hr for 14 days to evaluate the pharmacokinetics, toxicity, and tissue distribution. There was considerable variability (both within each animal and across animals) observed in the pharmacokinetic data. The plasma half-life (t1/2 appeared to be short enough that it could be assumed that steady state was attained by at least 96 h after the start of the infusion. The t1/2 estimates for the three pigs were 8.96, 109, and 1.97 h (the long t1/2 for pig 2 may be explained by poor parameter estimation due to the variability). The volume of distribution ranged from 9.80 to 51.8 L (0.3-1.4 L/kg), and plasma clearance estimates ranged from 0.33 to 3.46 L/h (5.5-57.7 ml/min). The average plasma concentrations at steady state were 0.845, 0.933, and 0.178 microg/ml (0.44, 0.49, and 0.093 microM) for the three animals. Nearly 30% of the administered dose was cleared through renal excretion by day 7 postinfusion. The distribution of TAG-6 was primarily to the liver and kidney, but the spleen and thyroid accumulated relatively high concentrations of TAG-6. TAG-6 was metabolized to apparently higher molecular weight products, which were observed in the urine. The size periodicity of these apparently higher molecular weight products was in 6-base intervals, which is consistent with the actions of telomerase. The infusion did not produce significant changes in serum chemistry or circulating blood cells, but a decrease in colony-forming unit-granulocyte-monocyte (CFU-GM) colony formation from BM was observed. These data suggest that TAG-6 may be a very specific pharmacophore.

Animals↗
PubMed2000

Activity of acetyl-Ser-Asp-Lys-Pro (AcSDKP) on human hematopoietic progenitor cells in short-term and long-term bone marrow cultures.

The tetrapeptide acetyl-Ser-Asp-Lys-Pro (AcSDKP) is a potent inhibitor of hematopoietic stem cell proliferation. We examined the effects of AcSDKP on the production of granulocyte-macrophage colony-forming cells (CFU-GM) and high proliferative potential colony-forming cells (HPP-CFC) in human long-term bone marrow (LTBM) cultures and CFU-GM and erythroid burst-forming cells (BFU-e) in short-term liquid cultures. The addition of AcSDKP in short-term bone marrow cultures resulted in a maximum depression of the total number of progenitor cells as well as the number of progenitor cells entering cell cycle following culture with 10(-12) to 10(-14) M AcSDKP and 10(-14) M AcSDKP when exogenous cytokines (GM-CSF, IL-3, or SCF) were added. AcSDKP was added daily to LTBM cultures at various concentrations (10(-8) M to 10(-16) M) for up to 5 weeks. In these LTBM culture studies, AcSDKP inhibited the entry of nonadherent progenitor cells into S phase and decreased the number of nonadherent progenitor cells with peak activity at 10(-12) M. In contrast, AcSDKP had no effect on the number of adherent CFU-GM, HPP-CFC, or cellularity per culture or percent of adherent progenitor cells in S phase. These studies indicate that the concentration of the tetrapeptide is critical to the activity of AcSDKP on human hematopoietic progenitor cells. Furthermore, we report that the presence of cytokines or stromal cells also affects the response of progenitor cells to AcSDKP. These results will aid in determining kinetic properties of AcSDKP for the development of clinical protocols to protect normal human hematopoietic stem and progenitor cells following cycle-specific chemotherapy agents.

Bone Marrow Cells↗
PubMed1999

Persistence with treatment for hypertension in actual practice.

BACKGROUND: Despite the existence of efficacious medications, many patients in actual practice remain with uncontrolled hypertension. Randomized clinical trials, cannot address this issue well given their highly restricted environment. This paper examines persistence with antihypertensive therapy among patients in actual practice. METHODS: Cohort study of patients who received a diagnosis of hypertension and were treated between 1989 and 1994 identified through the Saskatchewan Health databases. Patients with concurrent diagnoses likely to affect initial treatment choice were excluded. The resulting population of 79,591 subjects was grouped into those with established hypertension (52,227 [66%]) and those with newly diagnosed hypertension (27,364 [34%]). The initial antihypertensive prescription, subsequent changes in treatment and persistence with antihypertensive therapy were analysed. RESULTS: Persistence with antihypertensive therapy decreased in the first 6 months after treatment was started and continued to decline over the next 4 years. Of the patients with newly diagnosed hypertension, only 78% persisted with therapy at the end of 1 year, as compared with 97% of the patients with established hypertension (p < 0.001). Among those with newly diagnosed hypertension, older patients were more likely than younger ones to persist, and women were more likely than men to persist (p < 0.001). INTERPRETATION: This analysis of actual practice data indicates that barriers to persistence occur early in the therapeutic course and that achieving successful therapy when treatment is started is important to maintaining long-term persistence.

Adult↗
PubMed1999

Effect of initial drug choice on persistence with antihypertensive therapy: the importance of actual practice data.

BACKGROUND: Rational medical decisions should be based on the best possible evidence. Clinical trial results, however, may not reflect conditions in actual practice. In hypertension, for example, trials indicate equivalent antihypertensive efficacy and safety for many medications, yet blood pressure frequently remains uncontrolled, perhaps owing to poor compliance. This paper examines the effect of initial choice of treatment on persistence with therapy in actual practice. METHODS: The authors examined all outpatient prescriptions for antihypertensive medications filled in Saskatchewan between 1989 and 1994 by over 22,000 patients with newly diagnosed hypertension whose initial treatment was with a diuretic, beta-blocker, calcium-channel blocker or angiotensin-converting-enzyme (ACE) inhibitor. Rates of persistence over the first year of treatment were compared. RESULTS: After 6 months, persistence with therapy was poor and differed according to the class of initial therapeutic agent: 80% for diuretics, 85% for beta-blockers, 86% for calcium-channel blockers and 89% for ACE inhibitors (p < 0.001). These differences remained significant when age, sex and health status in the previous year were controlled for. Changes in the therapeutic regimen were also associated with lack of persistence. INTERPRETATION: A relation not seen in clinical trials--between persistence with treatment and initial antihypertensive medication prescribed--was found in actual practice. This relation also indicates the importance of real-world studies for evidence-based medicine.

Adult↗
PubMed1999

Unmet needs in hypertension: challenges and opportunities.

On the verge of the new millennium, hypertension remains an area of significant unmet medical need. Although progress has been made in the awareness, treatment, and control of hypertension during the last half of the 20th century, recent trends suggest that progress has stalled. Unfavorable trends in awareness and control have been noted by researchers at the Mayo Clinic, in a community that is socioeconomically prosperous with easy access to primary and tertiary medical care. Evidence suggests that a renewed focus on systolic blood pressure and on efforts to maintain compliance will result in better outcomes in populations at risk. Hiatt and Goldman have presented the case for "making medicine more scientific"--that is, understanding how the application of medical care advances can best be applied to benefit population health status. This is the challenge that hypertension control presents in world populations. Aging societies make this challenge an urgent concern.

Blood Pressure↗
PubMed1998

Cell adhesion molecule expression on CD34+ cells in grafts and time to myeloid and platelet recovery after autologous stem cell transplantation.

The relationship between cell adhesion receptor expression on CD34+ cells in stem cell grafts and the time to neutrophil and platelet recovery after autologous stem cell transplantation (ASCT [n = 25]) was studied with granulocyte/monocyte-colony stimulating factor (GM-CSF)-mobilized peripheral blood stem cells (PBSCs) and steady-state bone marrow (BM) harvests. Cell adhesion receptor expression was analyzed using flow cytometry after CD34+ cell enrichment. Significantly higher expression of L-selectin and CD44, and significantly lower expression of VLA-4, LFA-1, ICAM-1, Sialyl Lewis(x), Sialyl Lewis(A), and Thy-1 were observed on PBSCs compared with BM CD34+ cells. The log of the number of reinfused CD34+ cells, colony forming units granulocyte/macrophage (CFU-GM), and CD34+ cells coexpressing VLA-4, VLA-5, LAF-1, Mac-1, LFA-3, or CD38 but not ICAM-1, Sialyl Lewis(x), Sialyl Lewis(A), or Thy-1 correlated with the time required to reach an absolute neutrophil count (ANC) of > or =0.5 x 10(9)/L. In addition, the log of the number of CD34+ L-selectin+ and CD34+CD44+ cells reinfused after ASCT correlated better with the time required to reach an ANC of > or =0.5 x 10(9)/L than did the log of the number of CD34+ cells or CFU-GM reinfused. The log of the number of reinfused CD34+ cells, CFU-GM, and CD34+ cells coexpressing CD44, L-selectin, VLA-5 Mac-1, or CD38, but not VLA-4, LAF-1, ICAM-1, LAF-3, Sialyl Lewis(X), Sialyl Lewis(A), or Thy-1, correlated with the time required to reach a platelet count of >20 x 10(9)/L. Thus, L-selectin or CD44 may play an important role in the homing of progenitors after ASCT. In addition, the higher proportion of CD34+L-selectin+ or CD34+CD44+ cells in leukapheresis products may provide one explanation for the more rapid hematologic reconstitution observed after PBSC transplantation.

Adult↗
PubMed1998

Cell cycle-based purging of lymphoma cells from bone marrow harvests using radioiodinated 5-iodo-2'-deoxyuridine.

Minimal residual disease in lymphoma patients is a major problem in the clinical management of their cancer. High-dose chemotherapy followed by autologous bone marrow transplantation has been used to treat the disease. However, residual lymphoma may be reintroduced along with the marrow if it is present in the bone marrow harvest. In this report we describe results of experiments testing the efficacy of 5-[125I]-iodo-2'-deoxyuridine (125IdU) for purging murine RAW117 large cell lymphoma cells (Joshi et al., Oncology 44, 180-185, 1987; Cancer Res. 47, 3551-3557, 1987) from bone marrow in a relevant animal model. Donor BALB/c mice were injected with murine RAW117 cells and euthanized on day 13, and their bone marrow that had been contaminated with tumor cells was harvested and treated in vitro with 125IdU or nonradioactive 127IdU (control). Nine of 10 mice receiving 127IdU-treated bone marrow contaminated with tumor cells died at an average of 17 days after injection. In comparison, 9 of 10 mice injected with 125IdU-treated bone marrow contaminated with tumor cells were still alive after 82 days. In addition, the 125IdU treatment did not diminish the formation of hematopoietic progenitor cell colonies in normal mouse and human peripheral blood stem cells.

Animals↗