Kenzie Burks

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Rapid monoisotopic cisplatin based barcoding for multiplexed mass cytometry

Scientific Reports, 2017

Mass cytometry presents an exceptional opportunity to interrogate the biology of highly heterogen... more Mass cytometry presents an exceptional opportunity to interrogate the biology of highly heterogeneous cell populations, owing to the ability to collect highly parametric proteomic data at a single cell level. However, sample-to-sample variability, due to antibody staining and/or instrument sensitivity, can introduce substantial artifacts into the data, which can in turn lead to erroneous conclusions. This variability can be eliminated by sample barcoding which enables samples to be pooled, stained and run simultaneously. Existing mass cytometry barcoding approaches require time intensive labeling, reduce the number of biologically meaningful parameters and/or rely on expensive reagents. We present an approach utilizing monoisotopic cisplatin to perform cell barcoding that does not require cell permeabilization, can be completed in 10 minutes and can be utilized in combination with existing barcoding techniques to greatly increase the number of samples which can be multiplexed to imp...

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Nursing quality care indicators for elderly patients who have suffered stroke

This study aimed to identify nursing quality care indicators for elderly patients who have suffer... more This study aimed to identify nursing quality care indicators for elderly patients who have suffered from stroke. The study consisted of two phases. In the beginning, focus group and semi structured interview were used to identify the perception of nursing quality care of the elderly patients suffering from stroke, their families, the physicians, and the nurses. The seventyfive care indicators of six nursing quality care aspects were emerged. Subsequently three-round Delphi study were used to find the 36 experts consensus regarding the important, the feasibility, and the face validity of the care indicators. For the result of the Delphi study, the number of pre-determined care indicators in each round was 75, 45 and 27. After round three, the twenty-five quality care indicators under six quality care aspects emerged. They were managing patient unit (5 indicators), nursing staff qualification (2 indicators), nursing care activity, (5 indicators), encouraging family participation in pa...

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Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia

Clinical cancer research : an official journal of the American Association for Cancer Research, 2001

Sodium phenylbutyrate (PB) is an aromatic fatty acid with cytostatic and differentiating activity... more Sodium phenylbutyrate (PB) is an aromatic fatty acid with cytostatic and differentiating activity against malignant myeloid cells (ID(50), 1-2 mM). Higher doses induce apoptosis. Patients with myelodysplasia (n = 11) and acute myeloid leukemia (n = 16) were treated with PB as a 7-day continuous infusion repeated every 28 days in a Phase I dose escalation study. The maximum tolerated dose was 375 mg/kg/day; higher doses led to dose-limiting reversible neurocortical toxicity. At the maximum tolerated dose, PB was extremely well tolerated, with no significant toxicities; median steady-state plasma concentration at this dose was 0.29 +/- 0.16 mM. Although no patients achieved complete or partial remission, four patients achieved hematological improvement (neutrophils in three, platelet transfusion-independence in one). Other patients developed transient increases in neutrophils or platelets and decrements in circulating blasts. Monitoring of the percentage of clonal cells using centrome...

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900 Multipotent Mesenchymal Stromal Cells (MSC) - Evolving Role in Cancer and Leukemia Therapy

Clinical Lymphoma, Myeloma & Leukemia, 2011

... Michael Andreeff; Venkata Lokesh Battula; Rui-yu Wang; Ye Chen; Xiaoyan Ling; Rodrigo Jacamo;... more

SAT-509 Sudden Onset of Malabsorption

Journal of the Endocrine Society, 2020

Celiac disease (CD) is an immune-mediated enteropathy caused by a reaction to gliadin which respo... more Celiac disease (CD) is an immune-mediated enteropathy caused by a reaction to gliadin which responds to a restriction to dietary gluten. It has been traditionally recognized in children and young adults, although, recently, detection in the elderly population has increased. CD occurs in 2–5% of patients with autoimmune hypothyroidism, and is more prevalent in this group than in the general population An 82-year-old Caucasian woman with primary hypothyroidism and a BMI of 16 is referred to our endocrinology clinic for help with the management of hypothyroidism. She had a history of well controlled hypothyroidism on weight-dosed levothyroxine for many years until several months prior when she developed sudden onset of diarrhea and weight loss. Since then, her thyroid function tests showed an elevated TSH despite medication adherence. Her levothyroxine dose was steadily increased to 300 mcg daily and yet, her TSH still remained elevated. Laboratory work up was done which revealed eleva...

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Radiation with STAT3 Blockade Triggers Dendritic Cell–T cell Interactions in the Glioma Microenvironment and Therapeutic Efficacy

Clinical Cancer Research, 2020

Purpose: Patients with central nervous system (CNS) tumors are typically treated with radiotherap... more Purpose: Patients with central nervous system (CNS) tumors are typically treated with radiotherapy, but this is not curative and results in the upregulation of phosphorylated STAT3 (p-STAT3), which drives invasion, angiogenesis, and immune suppression. Therefore, we investigated the combined effect of an inhibitor of STAT3 and whole-brain radiotherapy (WBRT) in a murine model of glioma. Experimental Design: C57BL/6 mice underwent intracerebral implantation of GL261 glioma cells, WBRT, and treatment with WP1066, a blood–brain barrier–penetrant inhibitor of the STAT3 pathway, or the two in combination. The role of the immune system was evaluated using tumor rechallenge strategies, immune-incompetent backgrounds, immunofluorescence, immune phenotyping of tumor-infiltrating immune cells (via flow cytometry), and NanoString gene expression analysis of 770 immune-related genes from immune cells, including those directly isolated from the tumor microenvironment. Results: The combination of...

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CXCR4 expression and biologic activity in acute myeloid leukemia are dependent on oxygen partial pressure

Blood, 2009

The CXCR4/SDF-1 axis has been studied extensively because of its role in development and hematopo... more The CXCR4/SDF-1 axis has been studied extensively because of its role in development and hematopoiesis. In acute myeloid leukemia (AML), elevated expression of CXCR4 has been shown to correlate with shortened survival. Hy-poxia increases CXCR4 in several tumor models, but the impact of reduced O(2) partial pressure (pO(2)) on expression and biologic function of CXCR4 in AML is unknown. We determined pO(2) in bone marrows of AML patients as 6.1% (+/-1.7%). At this pO(2), CXCR4 surface and total expression were up-regulated within 10 hours in leukemic cell lines and patient samples as shown by Western blotting, fluorescence-activated cell sorting, and microscopy. Interestingly, hypoxic cells failed to internalize CXCR4 in response to SDF-1, and upon reoxygenation at 21% O(2), surface and total expression of CXCR4 rapidly decreased independent of adenosine triphosphate or proteasome activity. Instead, increased pO(2) led to alteration of lipid rafts by cholesterol depletion and structu...

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Disruption of Wnt/β-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3-Mutant Acute Myeloid Leukemia

Clinical Cancer Research, 2018

Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are ... more Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKI) are used clinically to treat FLT3-mutated AML patients, but with limited efficacy. We investigated the antileukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3-mutant AML. Experimental Design: Wnt/β-catenin signaling was inhibited by the β-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, Western blot, RT-PCR, and CyTOF. Results: We found significantly higher β-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone marrow–resident leukemic cel...

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Ataxia-telangiectasia mutated interacts with Parkin and induces mitophagy independent of kinase activity. Evidence from mantle cell lymphoma

Haematologica, 2020

Ataxia telangiectasia mutated (ATM), a critical DNA damage sensor with protein kinase activity, i... more Ataxia telangiectasia mutated (ATM), a critical DNA damage sensor with protein kinase activity, is frequently altered in human cancers including mantle cell lymphoma. Loss of ATM protein is linked to accumulation of nonfunctional mitochondria and defective mitophagy in both murine thymocytes and in ataxia-telangiectasia cells. However, the mechanistic role of ATM kinase in cancer cell mitophagy is unknown. Here, we provide evidence that FCCP-induced mitophagy in mantle cell lymphoma and other cancer cell lines is dependent on ATM but independent of its kinase function. While Granta-519 mantle cell lymphoma cells possess single copy kinase-dead ATM and are resistant to FCCP-induced mitophagy, both Jeko-1 and Mino cells are ATMproficient and induce mitophagy. Stable knockdown of ATM in Jeko-1 and Mino cells conferred resistance to mitophagy and was associated with reduced ATP production, oxygen consumption, and increased mitochondrial reactive oxygen species. ATM interacts with the E3...

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$Research paper thumbnail of High-dose topotecan with granulocyte-colony stimulating factor in fluoropyrimidine-refractory colorectal cancer: a phase II and pharmacodynamic study$

High-dose topotecan with granulocyte-colony stimulating factor in fluoropyrimidine-refractory colorectal cancer: a phase II and pharmacodynamic study

Annals of oncology : official journal of the European Society for Medical Oncology, 1998

PURPOSE The premise for this study was that topotecan (TPT) resistance in preclinical studies is ... more PURPOSE The premise for this study was that topotecan (TPT) resistance in preclinical studies is associated with low level expression of the p-glycoprotein (Pgp) multi-drug transporter conferred by the multi-drug resistant (MDR) phenotype, which might be overcome in clinical practice by administering moderately (2.3-fold) higher doses of TPT that have shown to be feasible with granulocyte colony-stimulating factor (G-CSF) support. This phase II study evaluated the anti-tumor activity of TPT administered at its highest possible solid tumor dose with G-SCF in patients with fluoropyrimidine-refractory advanced colorectal carcinoma. The study also sought to identify pharmacodynamic (PD) determinants of both activity and toxicity. PATIENTS AND METHODS TPT was administered as a 30-minute infusion daily for five days every three weeks at a dose of 3.5 mg/m2/day to patients with advance colorectal carcinoma who developed progressive disease either during treatment with fluoropyrimidine-base...

PD-1 Levels Correlate With Lymph Node Positivity in Patients With Squamous Cell Carcinoma of the Cervix

International Journal of Radiation Oncology Biology Physics, 2014

A phase II "window" study of topotecan in untreated patients with high risk adult acute lymphoblastic leukemia

Clinical cancer research : an official journal of the American Association for Cancer Research, 1998

To further evaluate the activity of topotecan (TPT) in acute leukemia, TPT was administered (2.1 ... more To further evaluate the activity of topotecan (TPT) in acute leukemia, TPT was administered (2.1 mg/m2/day for 5 days by continuous i.v. infusion) to adult patients with previously untreated acute lymphoblastic leukemia (ALL) with high-risk features (13 patients) or relapsed ALL (1 patient). Patients achieving a partial response or significant hematological improvement received a second course. All patients subsequently received standard treatment for ALL. Because complete response was achieved in only 1 of 14 patients, the study was terminated prematurely. An additional patient achieved minimal response, and a third patient normalized her hemogram despite ongoing leukemia in the marrow. Overall, six patients had significant hematological improvement (normalization of platelet and/or absolute neutrophil count). Two patients expired due to infections during induction chemotherapy. The primary nonhematological toxicities were mucositis and diarrhea. Exposure to TPT did not appear to i...

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A nursing practice model for chronic illness

Rehabilitation nursing : the official journal of the Association of Rehabilitation Nurses, 1999

As the 21st century approaches, one very important issue for nursing is the increased prevalence ... more As the 21st century approaches, one very important issue for nursing is the increased prevalence of chronic conditions such as arthritis. Self-management is one way that individuals can cope with the uncertainty and many changes chronic illness brings. The purpose of this article is to describe a nursing model that addresses the need for enhanced self-management skills and the rehabilitation nurse's role in this process. The model is based on the concept of intentional action and uses Orem's (1995) self-care deficit nursing theory as its conceptual structure. The expected outcomes of care for clients are effective self-management skills and subsequently improved health status and quality of life. The model will be useful in the design of rehabilitation nursing research as well as in the planning of care for individuals with chronic illness.

The Transcriptomic Landscape of Mismatch Repair-Deficient Intestinal Stem Cells

Cancer Research, 2021

The transcriptomic and proteomic profile of MMR-deficient intestinal stem cells displays a unique... more The transcriptomic and proteomic profile of MMR-deficient intestinal stem cells displays a unique set of genes with potential roles as biomarkers of cancer initiation and early progression. Lynch syndrome is the most common cause of hereditary colorectal cancer and is secondary to germline alterations in one of four DNA mismatch repair (MMR) genes. Here we aimed to provide novel insights into the initiation of MMR-deficient (MMRd) colorectal carcinogenesis by characterizing the expression profile of MMRd intestinal stem cells (ISC). A tissue-specific MMRd mouse model (Villin-Cre;Msh2LoxP/LoxP) was crossed with a reporter mouse (Lgr5-EGFP-IRES-creERT2) to trace and isolate ISCs (Lgr5+) using flow cytometry. Three different ISC genotypes (Msh2-KO, Msh2-HET, and Msh2-WT) were isolated and processed for mRNA-seq and mass spectrometry, followed by bioinformatic analyses to identify expression signatures of complete MMRd and haplo-insufficiency. These findings were validated using qRT-PCR...

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Postprandial Hypoglycemia: Complication of Peptic Ulcer Surgery

The American journal of medicine, 2017

OBJECTIVE Billroth II procedures (gastrojejunostomy with vagotomy) are seldom performed now but w... more OBJECTIVE Billroth II procedures (gastrojejunostomy with vagotomy) are seldom performed now but were popular before the advent of histamine 2 receptor blockers and proton pump inhibitors. Such procedures can be a cause of late postprandial hypoglycemia. METHODS We performed a formal evaluation and discussion of postprandial hypoglycemia. RESULTS We present a case of an 85-year-old man who presented to the endocrinology clinic with symptoms of "fainting spells after large meals." The patient previously had extensive evaluations by a neurologist and a cardiologist. Because of the history of Billroth II surgery and the description of his fainting spells, a 5-hour glucose tolerance test was performed in the clinic using the foods that uniformly resulted in symptoms. This confirmed that the late dumping syndrome with associated hypoglycemia was the cause of his spells. CONCLUSIONS Late dumping syndrome manifesting with hypoglycemia should be considered in the workup of patients...

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Abstract PO-014: Interleukin 17 induced- neutrophil extracellular traps (NETs) mediate resistance to checkpoint blockade in pancreatic cancer

Cancer Research, 2020

Pancreatic ductal adenocarcinoma (PDAC) continues to be an aggressive disease with an immunosuppr... more Pancreatic ductal adenocarcinoma (PDAC) continues to be an aggressive disease with an immunosuppressive tumor microenvironment, which is recalcitrant to most therapies. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, has been implicated in initiation of pancreatic premalignant lesions but its role in invasive PDAC has not been widely explored. We hypothesized that IL-17 triggers and sustains immunosuppression during PDAC. We employed pharmacological and genetic strategies to inhibit IL-17/IL-17RA signaling axis and characterized the tumor microenvironment with RNA sequencing, mass & flow cytometry and quantitative multiplex immunofluorescence. Our analysis revealed that IL-17 signaled through tumor cells to recruit neutrophils into the tumor microenvironment and spatially exclude cytotoxic CD8 T cells. Furthermore, IL-17 signaling in tumor cells triggered neutrophils to form extracellular traps (NETs), a primary mechanism mediating PDAC immunosuppression. Genetic or phar...

The Novel Tryptamine Derivative JNJ-26854165 Induces Wild-Type p53- and E2F1-Mediated Apoptosis in Acute Myeloid and Lymphoid Leukemias

Molecular Cancer Therapeutics, 2010

The development of small-molecule activators of p53 is currently focused on malignancies containi... more The development of small-molecule activators of p53 is currently focused on malignancies containing a wild-type p53 genotype, which is present in most leukemias. JNJ-26854165 is one such p53-activating agent, but its mechanism of action remains to be elucidated. Here, we report the effects of JNJ-26854165 in acute leukemias. JNJ-26854165 treatment induced p53-mediated apoptosis in acute leukemia cells with wild-type p53, in which p53 rapidly drives transcription-independent apoptosis followed by activation of a transcription-dependent pathway. JNJ-26854165 accelerated the proteasome-mediated degradation of p21 and antagonized the transcriptional induction of p21 by p53. Interestingly, JNJ-26854165 induced S-phase delay and upregulated E2F1 expression in p53 mutant cells, resulting in apoptosis preferentially of S-phase cells. E2F1 knockdown blocked apoptosis induced by JNJ-26854165 in p53 mutant cells. Apoptotic activity of JNJ-26854165 against primary acute leukemia cells was maint...

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Antileukemia Effects of Notch-Mediated Inhibition of Oncogenic PLK1 in B-Cell Acute Lymphoblastic Leukemia

Molecular Cancer Therapeutics, 2019

In B-cell acute lymphoblastic leukemia (B-ALL), activation of Notch signaling leads to cell-cycle... more In B-cell acute lymphoblastic leukemia (B-ALL), activation of Notch signaling leads to cell-cycle arrest and apoptosis. We aimed to harness knowledge acquired by understanding a mechanism of Notch-induced cell death to elucidate a therapeutically viable target in B-ALL. To this end, we identified that Notch activation suppresses Polo-like kinase 1 (PLK1) in a B-ALL–specific manner. We identified that PLK1 is expressed in all subsets of B-ALL and is highest in Philadelphia-like (Ph-like) ALL, a high-risk subtype of disease. We biochemically delineated a mechanism of Notch-induced PLK1 downregulation that elucidated stark regulation of p53 in this setting. Our findings identified a novel posttranslational cascade initiated by Notch in which CHFR was activated via PARP1-mediated PARylation, resulting in ubiquitination and degradation of PLK1. This led to hypophosphorylation of MDM2Ser260, culminating in p53 stabilization and upregulation of BAX. shRNA knockdown or pharmacologic inhibit...

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267 Familial Cases of Mast Cell Disease

Journal of Investigative Medicine, 2005

Elevated mast cell numbers have been implicated in a wide range of clinical conditions, from alle... more Elevated mast cell numbers have been implicated in a wide range of clinical conditions, from allergic rhinitis and asthma to systemic mastocytosis. Familial etiologies for mast cell disease have been suggested including defects in c-kit regulation. Purpose To evaluate a family with multiple presentations of probable mast cell disease. Methods A case review of a family cohort is presented. Summary The index case, a 26-year-old Caucasian male, was initially followed at our institution for reversible airway obstruction as a young child. He was lost to follow-up, returning to the allergy/immunology clinic at the age of 18 years with fixed airway obstruction and severe, steroid-dependent asthma, as well as allergic rhinitis, GER, dilated cardiomyopathy of unknown etiology, and sleep apnea. Due to the refractory nature of his disease,and his continued decline on aggressive medical therapy, he underwent extensive evaluation, ultimately including endobronchial and open lung biopsies. Prior ...

Abstract 2679: Immuno-oncology panel optimization for imaging mass cytometry and digital image analysis of tumor tissues

Tumor Biology, 2020

Introduction: Imaging mass cytometry (IMC) enables highly multiplexed assessment of more than 30 ... more Introduction: Imaging mass cytometry (IMC) enables highly multiplexed assessment of more than 30 proteins at a time for the quantification of cell phenotypes within the tumor microenvironment of formaldehyde fixed-paraffin embedded (FFPE) tumor tissue. This methodology provides a deep understanding of the immune-contexture while preserving their spatial information in regards to malignant cells. We report a detailed workflow for optimization of a 27-plex immune-oncology (IO) panel, immune-phenotyping, and spatial analysis of tumor tissue. Methods: IO-panel includes 27 antibodies targeting lymphoid (CD3e, CD4, CD8a, CD19, CD45RO, LAG3, ICOS, Granzyme-B), myeloid (CD11b, CD14, CD33, CD68, CSF1R, IDO-1), immune-regulatory (HLA-DR, OX-40, VISTA, TIM-3, CD73, B7-H3), epithelial (Cytokeratin), proliferative (Ki-67), and constitutive (GAPDH, NaKATPase, Vimentin, aSMA, Histone H3) markers that were selected by singlet automated chromogenic immunohistochemistry (IHC) staining. BSA-free formulation from the same clones of antibodies were isotope-metal conjugated and manual indirect immunofluorescence (IF) staining was used to confirm the stability of metal-tagged antibodies. The optimization by singlet-IF and multiplexed-IMC staining was performed with normal and malignant tissues (4mm core TMA with tonsil, placenta, prostate, breast carcinoma, ovarian carcinoma, and endometrioid carcinoma tissues). All images from IHC (HALO software), indirect IF (InForm software), and IMC (MCD viewer software) slides were evaluated by two pathologists. Cell densities and spatial analysis of a breast carcinoma core was performed using HALO software. Results: All antibodies included in the panel were individually optimized by IHC under the same protocol conditions. A significant correlation of optimal antibody concentrations where observed across the different staining techniques (IHC vs IF, r=0.51; IHC vs IMC, r= 0.54; IF vs IMC, r=0.992; all p values &lt;0.01). The breast carcinoma core (total area=0.308mm2) was segmented into epithelial (area=0.216 mm2) and stroma (area=0.092mm2) compartments by digital image analysis. Individual cell segmentation was obtained with based on iridium nuclei signal (total cells=2420). Automated immune-phenotyping showed 20 different cell phenotypes with a predominance of malignant cells expressing B7-H3 (120.1 cells/mm2) and T-lymphocytes expressing LAG3 (3.2 cells/mm2). The average distance between proliferative cytotoxic T-lymphocytes to malignant cells (MCs) was higher when MCs were proliferating (22.94 μm, and 55.4 μm, respectively). Conclusions: IMC is a powerful platform for highly multiplexed detection of protein and cell phenotypes quantification in FFPE samples. Our developed IMC panel and digital image analysis of tissues allow the quantification of immune cells and spatial analysis of the tumor tissue microenvironment. Citation Format: Pedro Rocha, Luisa Solis, Edwin Parra, Ou Shi, Barbara Mino, Vidya C. Sinha, Amanda Rinkenbaugh, Auriole Tamegnon, Mak Duncan, Wei Lu, Mei Jiang, Lakshimi Kakarala, Jared K. Burks, Helen Piwnica-Worms, Cara Haymacker, Michael Teztlaff, Ignacio Wistuba, Alejandro Francisco-Cruz. Immuno-oncology panel optimization for imaging mass cytometry and digital image analysis of tumor tissues [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2679.

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