5 research outputs found
In Silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem Cell Transplant Donors and Recipients: Understanding the Quantitative Immuno-biology of Allogeneic Transplantation
Donor T cell mediated graft vs. host effects may result from the aggregate
alloreactivity to minor histocompatibility antigens (mHA) presented by the HLA
in each donor-recipient pair (DRP) undergoing stem cell transplantation (SCT).
Whole exome sequencing has demonstrated extensive nucleotide sequence variation
in HLA-matched DRP. Non-synonymous single nucleotide polymorphisms (nsSNPs) in
the GVH direction (polymorphisms present in recipient and absent in donor) were
identified in 4 HLA-matched related and 5 unrelated DRP. The nucleotide
sequence flanking each SNP was obtained utilizing the ANNOVAR software package.
All possible nonameric-peptides encoded by the non-synonymous SNP were then
interrogated in-silico for their likelihood to be presented by the HLA class I
molecules in individual DRP, using the Immune-Epitope Database (IEDB) SMM
algorithm. The IEDB-SMM algorithm predicted a median 18,396 peptides/DRP which
bound HLA with an IC50 of <500nM, and 2254 peptides/DRP with an IC50 of <50nM.
Unrelated donors generally had higher numbers of peptides presented by the HLA.
A similarly large library of presented peptides was identified when the data
was interrogated using the Net MHCPan algorithm. These peptides were uniformly
distributed in the various organ systems. The bioinformatic algorithm presented
here demonstrates that there may be a high level of minor histocompatibility
antigen variation in HLA-matched individuals, constituting an HLA-specific
alloreactivity potential. These data provide a possible explanation for how
relatively minor adjustments in GVHD prophylaxis yield relatively similar
outcomes in HLA matched and mismatched SCT recipients.Comment: Abstract: 235, Words: 6422, Figures: 7, Tables: 3, Supplementary
figures: 2, Supplementary tables:
Emerging pharmacotherapy for cancer patients with cognitive dysfunction
Advances in the diagnosis and multi-modality treatment of cancer have increased survival rates for many cancer types leading to an increasing load of long-term sequelae of therapy, including that of cognitive dysfunction. The cytotoxic nature of chemotherapeutic agents may also reduce neurogenesis, a key component of the physiology of memory and cognition, with ramifications for the patient's mood and other cognition disorders. Similarly radiotherapy employed as a therapeutic or prophylactic tool in the treatment of primary or metastatic disease may significantly affect cognition. A number of emerging pharmacotherapies are under investigation for the treatment of cognitive dysfunction experienced by cancer patients. Recent data from clinical trials is reviewed involving the stimulants modafinil and methylphenidate, mood stabiliser lithium, anti-Alzheimer's drugs memantine and donepezil, as well as other agents which are currently being explored within dementia, animal, and cell culture models to evaluate their use in treating cognitive dysfunction
In silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem-Cell Transplant Donors and Recipients: Understanding the Quantitative Immunobiology of Allogeneic Transplantation.
Donor T-cell mediated graft versus host (GVH) effects may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA) presented by the human leukocyte antigen (HLA) molecules in each donor-recipient pair undergoing stem-cell transplantation (SCT). Whole exome sequencing has previously demonstrated a large number of non-synonymous single nucleotide polymorphisms (SNP) present in HLA-matched recipients of SCT donors (GVH direction). The nucleotide sequence flanking each of these SNPs was obtained and the amino acid sequence determined. All the possible nonameric peptides incorporating the variant amino acid resulting from these SNPs were interrogated in silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM) and NetMHCpan algorithms. The SMM algorithm predicted that a median of 18,396 peptides weakly bound HLA class I molecules in individual SCT recipients, and 2,254 peptides displayed strong binding. A similar library of presented peptides was identified when the data were interrogated using the NetMHCpan algorithm. The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting a HLA-specific alloreactivity potential