Browsing by Author "Storek, Jan"

Now showing 1 - 7 of 7
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    Allergen-specific T cell quantity in blood is higher in allergic compared to nonallergic individuals
    (BioMed Central, 2011-04-17) Ueno-Yamanouchi, Aito; Khan, Faisal M; Serushago, Bazir; Bowen, Tom; Lu, Cathy; Luider, Joanne; Storek, Jan
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    Anti-leukemic Activity of Anti-thymocyte Globulin
    (2018-09-17) Dabas, Rosy; Storek, Jan; Khan, Faisal Masood; Morris, Don G.; Mahoney, Douglas J.
    Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative therapy for hematologic malignancies. The most frequent indication is acute myeloid leukemia (AML). Relapse and graft-versus-host disease (GVHD) are the major causes of HCT failure. Most immunosuppressive drugs used for GVHD prophylaxis increase relapse, presumably due to inhibiting not only GVHD but also graft-versus-leukemia effect (GVL). Polyclonal rabbit anti-thymocyte globulin (ATG), now widely used for GVHD prophylaxis, is the only immunosuppressive drug reducing GVHD without increasing relapse. The reason for ATG not increasing relapse is not known. We hypothesized that this could be due to an anti-leukemic activity of ATG. I investigated the anti-leukemic activity both in vitro and in vivo (in patients). I first evaluated whether ATG at clinical concentrations kills leukemic blasts in vitro. I showed that ATG does kill leukemic blasts, via complement-dependent cytotoxicity (CDC) and direct induction of apoptosis. Next, I investigated whether ATG kills in vitro not only leukemic blasts but also leukemic stem cells (LSCs). I showed that ATG does kill LSCs, primarily via CDC, however, only at a higher concentration than needed for killing leukemic blasts. In spite of the anti-leukemic activity of ATG in vitro, in vivo ATG has so far been considered not to have an anti-leukemic activity as in 3/3 randomized studies ATG did not reduce relapse. We hypothesized that this could be due to differential effects of ATG pre- versus post-HCT. Specifically, we hypothesized that the direct anti-leukemic effect of ATG is countered by the anti-GVL effect of ATG post- but not pre-HCT. I evaluated associations between pre- versus post-HCT ATG area-under-the-curve (AUC) and relapse. I found that high pre-HCT AUC was associated with a low incidence of relapse. Conversely, there was a trend toward an association between high post-HCT AUC and a high incidence of relapse. The association between pre-HCT AUC and relapse is an indirect evidence for anti-leukemic activity of ATG in vivo. These findings are expected to lead to clinical studies harnessing the anti-leukemic effect of ATG, e.g., by dosing ATG so as to achieve a higher than conventional pre-HCT AUC and a conventional post-HCT AUC. This could lead to decreasing relapse without increasing GVHD which may lead to improved survival.
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    Basophil activation test compared to skin prick test and fluorescence enzyme immunoassay for aeroallergen-specific Immunoglobulin-E
    (BioMed Central, 2012-01-20) Khan, Faisal M.; Ueno-Yamanouchi, Aito; Serushago, Bazir; Bowen, Tom; Lyon, Andrew W.; Lu, Cathy; Storek, Jan
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    Identification of Somatic Mutational Patterns with Biological and Clinical Significance in Solid and Hematological Malignancies
    (2024-01-17) McNeil, Reid Evan; Bose, Pinaki; Khan, Faisal; Storek, Jan; Lynch, Tarah
    Cancers use Darwinian evolution to naturally select for advantageous DNA alterations that allow these malignancies to escape normal biological control mechanisms. Advantageous alterations are known as driver mutations that modify cellular phenotype causing cancer cells to proliferate, invade adjacent tissues, and metastasize to other organs. Even across very different types of cancers, DNA alteration events are an underlying commonality. Using DNA alterations as a lens to analyze cancers can potentially identify cross cancer biomarkers implicated in disease development, progression, prognostication, and therapeutic drug targeting and response. In this MSc thesis, we hypothesis that in squamous cell carcinomas a subtype of alteration called DNA amplification events can modulate tumor biology through gene expression, and that point mutations in myeloid malignancies can predict clinical outcomes like disease relapse after bone marrow transplant. Aim one of my thesis investigated DNA amplifications to identify how they modulate mRNA and protein expression in head and neck and lung SCCs. Using genomic, transcriptomic, and proteomics data we identify amplification driven expression programs with biological and clinical significance in SCCs. Aim two of my thesis investigated point mutation profiles of myeloid malignancies using the Illumina TruSight Tumor (TST) Myeloid sequencing panel and machine learning analysis. Mutational landscape analysis of all myeloid samples annotated for DNA mutations of clinical relevance. Machine learning analysis was used point mutation profiles to predict relapse status of patients after transplant. The main research findings indicated that in SCCs, the 3q22-29 and 11q13 DNA amplifications were the top events in HNSCs and LUSCs. Several genes from 3q22-29 (ABCC5, ALG3, FXR1, TFRC, and RFC4) and 11q13 amplified regions (CTTN, FADD, and PPFIA1) were overexpressed on the mRNA and protein level. These genes were majority expressed in tumoral tissue and cancerous cells, and when overexpressed led to worse patient survival. The 3q22-29 amplified samples were negatively correlated with immune related pathways in the tumor microenvironment. Specifically, TRAIL and IFNG signaling levels were lower in 3q22-29 amplified samples, along with lower levels of immune cell infiltration of natural killer and cytotoxic cells. In myeloid malignancies, point mutations of clinical significance were identified, the most common mutations across 545 AML samples were TET2, ASXL1, and DNMT3A. The TET2 gene modulates DNA methylation levels and mutations to this gene trigger malignant transformation of myeloid progenitor cells and development of cancer. Patients with TET2 mutations can be treated with azacitidine in combination with chemotherapies to increase overall patient survival. The machine learning analysis of mutation profiles of myeloid patients who went through a bone marrow transplant were able to predict relapse status of patients from mutations profiles generated at disease diagnosis. The random forest model was the best performing model (AUC = 0.845) to predict relapse status after transplantation. Altogether, this analysis demonstrated the ability and importance DNA alterations have in diseases like cancer.
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    Synergy of anti-leukemic effects between anti-thymocyte globulin, busulfan, and fludarabine
    (2017-11-30) Yang, Lucy; Dabas, Rosy; Storek, Jan
    Antithymocyte Globulin (ATG) is an anti-GvHD (Graft versus Host Disease) drug that has recently been shown to have anti-leukemic effects. In Alberta, Busulfan and Fludarabine are used to treat acute myeloid leukemia. However, both drugs also lead to the death of healthy cells within the body, especially with increased doses. It would be beneficial to study ways to maintain their effects while decreasing their toxicity, such as synergy with ATG. Different concentrations of ATG were combined with different concentrations of Busulfan and Fludarabine separately to test their effects on pre-conditioned leukemia cell samples from acute myeloid leukemia patients. Cell death was quantified using flow cytometry. The cells from five patients were used and combined into graphs that compared cells dyed by 7AAD (dead cells) between the drugs. In some of the combinations, there appeared to be increased cell death in test tubes with a combination of ATG with Busulfan or ATG with Fludarabine. However, with the use of the Wilcoxon Matched Pairs Test, the difference was deemed not significant. Even though there were no significant differences, it could be due to the low sample size. Furthermore, other concentrations not tested in this experiment could yield better results. If synergy exists between ATG and Busulfan or Fludarabine, the two drugs should be moved up in patients’ conditioning schedules to allow synergism to occur, leading to more cancer cell death with less risk for side effects.
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    Zoster prophylaxis after allogeneic hematopoietic cell transplantation using acyclovir/valacyclovir followed by vaccination
    (American Society of Hematology, 2016) Jamani, Kareem; MacDonald, Judy; Lavoie, Martin; Williamson, Tyler S.; Brown, Christopher B.; Chaudhry, Ahsan; Jimenez-Zepeda, Victor H.; Duggan, Peter; Tay, Jason; Stewart, Douglas; Daly, Andrew; Storek, Jan
    Varicella zoster virus (VZV) disease (usually cutaneous zoster) occurs frequently after hematopoietic cell transplantation (HCT), and postherpetic neuralgia (PHN) results in poor quality of life. The optimal prophylaxis of VZV disease/PHN has not been established. At our center, before 2008, VZV prophylaxis consisted of ∼1 year of post-HCT acyclovir/valacyclovir (“old strategy”), whereas post-2008 prophylaxis consisted of 2 years of acyclovir/valacyclovir followed by immunization using varicella vaccine (“new strategy”). We performed a retrospective study comparing the cumulative incidence of VZV disease and PHN among patients who completed the old strategy (n = 153) vs the new strategy (n = 125). Patients who completed the old strategy had a significantly higher cumulative incidence of VZV disease (33% vs 17% at 5 years, P ≤ .01) and PHN (8% vs 0% at 5 years, P = .02). In conclusion, VZV prophylaxis with 2 years of acyclovir/valacyclovir followed by vaccination appears to result in a low incidence of VZV disease and may eliminate PHN.