The Fluctuating Phenotype of the Lymphohematopoietic Stem Cell with Cell Cycle Transit

The most primitive engrafting hematopoietic stem cell has been assumed to have a fixed phenotype, with changes in engraftment and renewal potential occurring in a stepwise irreversible fashion linked with differentiation. Recent work shows that in vitro cytokine stimulation of murine marrow cells induces cell cycle transit of primitive stem cells, taking 40 h for progression from G0 to mitosis and 12 h for subsequent doublings. At 48 h of culture, progenitors are expanded, but stem cell engraftment is markedly diminished. We have investigated whether this effect on engraftment was an irreversible step or a reversible plastic feature correlated with cell cycle progression. Long-term engraftment (2 and 6 mo) of male BALB/c marrow cells exposed in vitro to interleukin (IL)-3, IL-6, IL-11, and steel factor was assessed at 2–4-h intervals of culture over 24–48 h using irradiated female hosts; the engraftment phenotype showed marked fluctuations over 2–4-h intervals, with engraftment nadirs occurring in late S and early G2. These data show that early stem cell regulation is cell cycle based, and have critical implications for strategies for stem cell expansion and engraftment or gene therapy, since position in cell cycle will determine whether effective engraftment occurs in either setting

Oncology for veterinary teachnicians and nurses

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H2-mismatched transplantation with repetitive cell infusions and CD40 ligand antibody infusions without myeloablation.

Graft rejection and graft-versus-host disease are major problems in mismatched marrow transplants along with toxicity from standard myeloablative host treatments. We have established a tolerization model, using 1 Gy irradiation, which reduces stem cell capacity to < 10% of control while causing minimal myelosuppression, donor antigen pre-exposure (spleen cells), CD40-ligand antibody blockade and high levels of marrow (40 x 106 cells), which allows for stable long-term multilineage engraftment in H2-mismatched murine marrow transplants. We now show that the establishment of 'microchimaerism' (0.5-3.8%) sets the stage for macrochimaerism, with subsequent marrow infusions in H2-mismatched mice with CD40-ligand blockade only. Neither irradiation nor spleen cell exposure were necessary. When 40 x 106 bone marrow cells were infused on weeks 0, 12, 14 and 16, blood engraftment was about seven times the single 40 x 106 control. When marrow cells were given on weeks 0, 3, 4, 5 and 6, engraftment at 24 weeks post transplant was 17.9 +/- 1.2%, compared with 2.7 +/- 0.8% for the single 40 x 106 control (P = 0.009). We have shown stable, long-term multilineage chimaerism and established that the schedule of marrow administration, not the total cell dose, is critical for tolerization. This approach indicates that microchimaerism can tolerize for subsequent marrow infusions and produce macrochimaerism. This strategy could be applied in clinical human transplants

Vincristine chemotherapy trials and pharmacokinetics in tasmanian devils with tasmanian devil facial tumor disease.

Tasmanian Devil Facial Tumor Disease (DFTD) is a transmissible cancer threatening to cause the extinction of Tasmanian Devils in the wild. The aim of this study was to determine the susceptibility of the DFTD to vincristine. Escalating dosage rates of vincristine (0.05 to 0.136 mg/kg) were given to Tasmanian devils in the early stages of DFTD (n = 8). None of these dosage rates impacted the outcome of the disease. A dosage rate of 0.105 mg/kg, a rate significantly higher than that given in humans or domestic animals, was found to the highest dosage rate that could be administered safely. Signs of toxicity included anorexia, vomiting, diarrhea and neutropenia. Pharmacokinetic studies showed that, as with other species, there was a rapid drop in blood concentration following a rapid intravenous infusion with a high volume of distribution (1.96 L/kg) and a relatively long elimination half life (11 h). Plasma clearance (1.8 ml/min/kg) was slower in the Tasmanian devil than in humans, suggesting that pharmacodynamics and not pharmacokinetics explain the Tasmanian devil's ability to tolerate high dosage rates of vincristine. While providing base-line data for the use of vincristine in Tasmanian devils and possibly other marsupials with vincristine susceptible cancers, these findings strongly suggest that vincristine will not be effective in the treatment of DFTD

Retrospective evaluation of clinical outcome after chemotherapy for lymphoma in 15 equids (1991‐2017)

BackgroundPrognosis associated with lymphoma in horses is poorly characterized, and treatment is often palliative. Long-term outcome after chemotherapy for horses with lymphoma is not well documented.ObjectiveTo report long-term outcome of horses with lymphoma treated with chemotherapy.AnimalsFifteen equids.MethodsRetrospective case series. Medical record search and call for cases on the ACVIM listserv for horses treated with chemotherapy for lymphoma.ResultsFifteen cases with adequate data were identified. Complete remission was achieved in 5 horses (33.3%), partial response was achieved in 9 equids (60%), and stable disease was achieved in 1 horse. Overall response rate was 93.3% (14/15). Overall median survival time was 8 months (range, 1-46 months). Nine horses experienced a total of 14 adverse effects attributable to chemotherapy. Adverse effects were graded according to the Veterinary Cooperative Oncology Group common terminology criteria for adverse events grading system (grade 1 alopecia, n = 2; grade 1 neutropenia, n = 2; grade 1 lymphopenia, n = 3; grade 1 lethargy, n = 1; grade 2 neurotoxicity, n = 1; grade 2 colic, n = 1; grade 1 hypersensitivity, n = 1; grade 2 hypersensitivity, n = 2; grade 5 hypersensitivity, n = 1). Higher grade adverse effects most commonly were associated with doxorubicin administration (n = 4), including 1 horse that died 18 hours post-administration.Conclusions and clinical importanceChemotherapy can be used successfully for treatment of horses with lymphoma. Adverse effects, most commonly mild, occurred in approximately two-thirds of treated horses

Median plasma vincristine concentration versus time for Tasmanian devils (n = 6) corrected for a dose of vincristine 0.05 mg/kg.

<p>Median plasma vincristine concentration versus time for Tasmanian devils (n = 6) corrected for a dose of vincristine 0.05 mg/kg.</p

Plasma pharmacokinetic parameters of vincristine in the Tasmanian devil (median data reported corrected for a dose of vincristine 0.05 mg/kg).

<p>Note: AUC_(0-∞); area under the concentration time curve extrapolated to infinity after a dose of vincristine 0.05 mg/kg, CL;clearance, t_½; elimination half-life, V;volume of distribution.</p