480 research outputs found
The efficacy of recombinant thrombopoietin in murine and nonhuman primate models for radiation-induced myelosuppression and stem cell transplantation
Radiation-induced pancytopenia proved to be a suitable model system in
mice and rhesus monkeys for studying thrombopoietin (TPO) target cell
range and efficacy. TPO was highly effective in rhesus monkeys exposed to
the mid-lethal dose of 5 Gy (300 kV x-rays) TBI, a model in which it
alleviated thrombocytopenia, promoted red cell reconstitution, accelerated
reconstitution of immature CD34+ bone marrow cells, and potentiated the
response to growth factors such as GM-CSF and G-CSF. In contrast to the
results in the 5 Gy TBI model, TPO was ineffective following
transplantation of limited numbers of autologous bone marrow or highly
purified stem cells in monkeys conditioned with 8 Gy TBI. In the 5 Gy
model, a single dose of TPO augmented by GM-CSF 24 h after TBI was
effective in preventing thrombocytopenia. The strong erythropoietic
stimulation may result in iron depletion, and TPO treatment should be
accompanied by monitoring of iron status. This preclinical evaluation thus
identified TPO as a potential major therapeutic agent for counteracting
radiation-induced pancytopenia and demonstrated pronounced stimulatory
effects on the reconstitution of immature CD34+ hemopoietic cells with
multilineage potential. The latter observation explains the potentiation
of the hematopoietic responses to G-CSF and GM-CSF when administered
concomitantly. It also predicts the effective use of TPO to accelerate
reconstitution of immature hematopoietic cells as well as possible
synergistic effects in vivo with various other growth factors acting on
immature stem cells and their direct lineage-committed progeny. The
finding that a single dose of TPO might be sufficient for a clinically
significant response emphasizes its potency and is of practical relevance.
The heterogeneity of the TPO response encountered in the various models
used for evaluation points to multiple mechanisms operating on the TPO
response and heterogeneity of its target cells. Mechanistic mouse studies
made apparent that the response of multilineage cells shortly after TBI to
a single administration of TPO is quantitatively more important for
optimal efficacy than the lineage-restricted response obtained at later
intervals after TBI and emphasized the importance of a relatively high
dose of TPO to overcome initial c-mpl-mediated clearance. Further
elucidation of mechanisms determining efficacy might very well result in a
further improvement, e.g., following transplantation of limited numbers of
stem cells. Adverse effects of TPO administration to myelosuppressed or
stem cell transplanted experimental animals were not observed
Dealing with the Inventory Risk. A solution to the market making problem
Market makers continuously set bid and ask quotes for the stocks they have
under consideration. Hence they face a complex optimization problem in which
their return, based on the bid-ask spread they quote and the frequency at which
they indeed provide liquidity, is challenged by the price risk they bear due to
their inventory. In this paper, we consider a stochastic control problem
similar to the one introduced by Ho and Stoll and formalized mathematically by
Avellaneda and Stoikov. The market is modeled using a reference price
following a Brownian motion with standard deviation , arrival rates of
buy or sell liquidity-consuming orders depend on the distance to the reference
price and a market maker maximizes the expected utility of its P&L over a
finite time horizon. We show that the Hamilton-Jacobi-Bellman equations
associated to the stochastic optimal control problem can be transformed into a
system of linear ordinary differential equations and we solve the market making
problem under inventory constraints. We also shed light on the asymptotic
behavior of the optimal quotes and propose closed-form approximations based on
a spectral characterization of the optimal quotes
Identification of numerical chromosome aberrations in archival tumours by in situ hybridization to routine paraffin sections: Evaluation of 23 phaeochromocytomas
We have applied non-isotopic in situ hybridization (ISH) to interphase cell nuclei of 23 phaeochromocytomas (18 primary and 5 metastatic tumours) within routine paraffin-embedded tissue sections. Each tumour was screened for numerical aberrations with a defined alphoid repetitive DNA probe set containing DNA probes specific for chromosomes 1, 7, 15, and Y. Normal adrenal medullas and other normal human cell types served as cytogenetic controls. Preservation of tissue morphology enabled targeted analysis of tumour cells. The presence of numerical chromosome changes in the tumour cells could easily be evaluated by comparing the ISH results of the DNA probes. Numerical abnormalities not previously reported in this neoplasm included overrepresentation of chromosomes 1 and 7, loss of chromosome 15, and both gain and loss of chromosome Y (P values <0.01). The percentage of aneuploid cell nuclei in a tumour correlated well with the percentage of cells in the 4C peak of flow cytometric DNA histograms from these neoplasms. We conclude that interphase ISH can be used for the identification of new and reported cytogenetic changes in tumour cell nuclei within archival tissue sections. This novel procedure also allows for retrospective analysis of previously not karyotyped material
Comparison of the efficacy of early versus late viral proteins in vaccination against SIV.
The immune response against early regulatory proteins of simian- and human immunodeficiency virus (SIV, HIV) has been associated with a milder course of infection. Here, we directly compared vaccination with Tat/Rev versus Pol/Gag. Challenge infection with SIVmac32H (pJ5) suggested that vaccination with Tat/Rev induced cellular immune responses that enabled cynomolgus macaques to more efficiently control SIV replication than the vaccine-induced immune responses against Pol/Gag. Vaccination with Tat/Rev resulted in reduced plasma SIV loads compared with control (P=0.058) or Pol/Gag-vaccinated (P
Ferrets as a novel animal model for studying human respiratory syncytial virus infections in immunocompetent and immunocompromised hosts
Human respiratory syncytial virus (HRSV) is an important cause of severe respiratory tract disease in immunocompromised patients. Animal models are indispensable for evaluating novel intervention strategies in this complex patient population. To complement existing models in rodents and non-human primates, we have evaluated the potential benefits of an HRSV infection model in ferrets (Mustela putorius furo). Nine- to 12-month-old HRSV-seronegative immunocompetent or immunocompromised ferrets were infected with a low-passage wild-type strain of HRSV subgroup A (105 TCID50) administered by intra-tracheal or intra-nasal inoculation. Immune suppression was achieved by bi-daily oral administration of tacrolimus, mycophenolate mofetil, and prednisolone. Throat and nose swabs were collected daily and animals were euthanized four, seven, or 21 days post-infection (DPI). Virus loads were determined by quantitative virus culture and qPCR. We observed efficient HRSV replication in both the upper and lower respiratory tract. In immunocompromised ferrets, virus loads reached higher levels and showed delayed clearance as compared to those in immunocompetent animals. Histopathological evaluation of animals euthanized 4 DPI demonstrated that the virus replicated in the respiratory epithelial cells of the trachea, bronchi, and bronchioles. These animal models can contribute to an assessment of the efficacy and safety of novel HRSV intervention strategies
Intranasal H5N1 vaccines, adjuvanted with chitosan derivatives, protect ferrets against highly pathogenic influenza intranasal and intratracheal challenge
We investigated the protective efficacy of two intranasal chitosan (CSN and TM-CSN) adjuvanted H5N1 Influenza vaccines against highly pathogenic avian Influenza (HPAI) intratracheal and intranasal challenge in a ferret model. Six groups of 6 ferrets were intranasally vaccinated twice, 21 days apart, with either placebo, antigen alone, CSN adjuvanted antigen, or TM-CSN adjuvanted antigen. Homologous and intra-subtypic antibody cross-reacting responses were assessed. Ferrets were inoculated intratracheally (all treatments) or intranasally (CSN adjuvanted and placebo treatments only) with clade 1 HPAI A/Vietnam/1194/2004 (H5N1) virus 28 days after the second vaccination and subsequently monitored for morbidity and mortality outcomes. Clinical signs were assessed and nasal as well as throat swabs were taken daily for virology. Samples of lung tissue, nasal turbinates, brain, and olfactory bulb were analysed for the presence of virus and examined for histolopathological findings. In contrast to animals vaccinated with antigen alone, the CSN and TM-CSN adjuvanted vaccines induced high levels of antibodies, protected ferrets from death, reduced viral replication and abrogated disease after intratracheal challenge, and in the case of CSN after intranasal challenge. In particular, the TM-CSN adjuvanted vaccine was highly effective at eliciting protective immunity from intratrache
An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics
For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types
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