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STOKOL LABORATORY
 

Research
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Publications
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People
 

My lab philosophy

Practice high-quality research with repeatable data, be thorough, take responsibility for yourself, be respectful and considerate of others, and HAVE FUN (with lots of coffee and chocolate - 2 research necessities!!).


Research
 

I concentrate on two different research areas, which are the exploration into the mechanisms of thrombosis in animals and mechanisms of cancer metastasis in humans and animals. These two research areas are linked by a common theme of hemostasis, i.e. I am specifically looking at the role of coagulation in thrombosis and cancer metastasis.

Thrombosis in animals

Thrombosis is a serious complication of various diseases in animals, including sepsis, neoplasia, cardiac disease and inflammation. When thrombi develop in blood vessels, the tissues supplied by these vessels undergo hypoxic injury, causing cell death, organ dysfunction and even failure. The consequence of this tissue damage can be devastating to the patient, resulting in prolonged illness and even death. Thrombi are thought to form through three major pathways called Virchows's triad: endothelial injury, abnormalities in blood flow (stasis) and hypercoagulability. Hypercoagulability, which is defined as an abnormally activated coagulation cascade, is the research focus in my laboratory. I am particularly interested in the role of tissue factor (coagulation factor III or tissue thromboplastin) in mediating hypercoagulability and, consequently, thrombosis in animals.
Fibrinclot
Figure 1: Tissue factor, in complex with factor FVIIa (FVIIa), activates factor X (FX). FXa, in the presence of calcium and factor V, cleaves prothrombin to thrombin. Thrombin amplifies its own production by activating coagulation factors (factor FIX) and cofactors (factor VIII, factor V) of the intrinsic and common pathways. This generates a large burst of thrombin, which then cleaves fibrinogen to fibrin and activates factor XIII, which crosslinks fibrin forming an insoluble fibrin clot.

Tissue factor is the main trigger of the complex coagulation cascade. It is a transmembrane protein that is constitutively expressed on the surface of fibroblasts and smooth muscles, which underly the endothelium in blood vessels. The coagulation cascade is normally activated when endothelial cells are injured. This injury exposes extravascular tissue factor to its circulating ligand, plasma factor VII (FVII). Once bound to tissue factor, FVII becomes activated and together the two proteins form an enzymatic complex, which binds to and activates another coagulation factor, factor X (FX). FX is the lead protein of the common pathway of coagulation, whose end-result is the generation of the potent enzyme, thrombin from prothrombin (factor II). Thrombin is the ultimate enzyme responsible for clot or thrombus formation, since it is directly responsible for converting fibrinogen into fibrin, which forms the basis of thrombi (Figure 1).
In disease conditions, tissue factor may be aberrantly expressed on endothelium, circulating monocytes or cancer cells. This aberrant tissue factor expression is the current focus of my research studies into mechanisms of thrombosis in animals. I am investigating the thrombosis pathogenesis in two diseases in animals:

  1. Immune-mediated hemolytic anemia (IMHA) in dogs.
    Dogs with this hematologic disorder develop severe anemia when their body starts to destroy its own erythrocytes. During this disease, thrombi form in multiple blood vessels, such as the lungs. This thrombosis is a major cause of death in dogs with IMHA.
  2. Herpes virus myeloencephalopathy in horses.
    Some horses infected with equine herpes virus type-1 develop a severe neurologic syndrome characterized by paresis, paralysis and recumbency. Thrombosis in spinal cord vessels is a characteristic pathologic feature of this disorder and contributes to the spinal cord injury and clinical signs seen in affected horses.

Both of these studies are currently supported by grants funded by the Morris Animal Foundation.

Cancer metastasis
channels
Figure 2: Endothelial cells grown within a fabricated microfluidic channel (arrowheads). The endothelial cells are confluent within the channel as shown by linear red immunostaining of vascular-endothelial cadherin (arrows), a marker of inter-endothelial junctions.

My interest in this area arose from my professional diagnostic service responsibilities, in which I frequently make a diagnosis of cancer from aspirates of tissues of animals. My desire to understand the biology of cancer and to help animals led to this research focus in my laboratory. I am studying the role of tissue factor in cancer metastasis in humans and animals. Tissue factoris upregulated in cancer cells and is thought to be a marker of oncogenic transformation. Activation of coagulation, with thrombus formation, is a common consequence of cancer in people. To facilitate my studies on how tissue factor helps cancer cells metastasize, I have established a collaboration with the Department of Biomedical Engineering at Cornell University. We have developed a unique microfluidic device, consisting of small (<70 um) semi-cylindrical "vascular" channels fabricated into a synthetic transparent polymer. Endothelial cells can be grown within the channels and can be exposed to fluid shear forces, similar to what they experience in blood (Figure 2). We are using this device to explore how cancer cells interact with endothelial cells to form metastatic tumors as well as to answer specific questions related to endothelial biology in the microvasculature. These studies are supported by Consolidated grants from the College of Veterinary Medicine and a Nanobiotechnology Center grant from Cornell University.

Clinical pathology-related research

I am a veterinary clinical pathologist and am dedicated to advancing my field through investigative studies. Anything clinical pathology-related is fair research game, as can be seen from my varied research publications. My main clinical pathologic interests are hemostatic disorders and hematopoietic neoplasia.

cytology images
Panel A: Wright's-stained smear of a bone marrow aspirate from a dog with acute megakaryocytic leukemia. Most of the cells in the aspirate are abnormal megakaryocytes (red arrows). Panel B: Wright's stained smear of a bone marrow aspirate from a dog with Leishmania. A macrophage containing Leishmania amastigotes is visible in the center (red arrow). Panel C: Bone marrow smear from a cat with acute lymphoid leukemia. The marrow is dominated by large blasts, with only a few small lymphocytes (L). Normal hematopoietic cells were absent.

 

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Publications

2006-current

  1. Stokol T, Daddona JL, Choi B (2010) Heat-inactivated fetal bovine serum inhibits lipopolysaccharide-induced tissue factor expression in feline leukocytes. Am J Vet Res. 71:623-629.
  2. Wagner B, Stokol T, Ainsworth DM (2010) Induction of interleukin-4 production in neonatal IgE(+) cells after crosslinking of maternal IgE. Dev Comp Immunol. 34:436-444.
  3. Ospina PA, Nydam DV, Stokol T, Overton TR (2010) Associations of elevated nonesterified fatty acids and beta-hydroxybutyrate concentrations with early lactation reproductive performance and milk production in transition dairy cattle in the northeastern United States. J Dairy Sci. 93:1596-1603.
  4. Ospina PA, Nydam DV, Stokol T, Overton TR (2010) Evaluation of nonesterified fatty acids and beta-hydroxybutyrate concentrations in transition dairy cattle in the northeastern United States: Critical thresholds for prediction of clinical diseases. J Dairy Sci 93:546-554.
  5. Angle CT, Wakshlag JJ, Gillete RL, Stokol T, Geske S, Adkins TO, Gregor C (2009) Hematologic, serum biochemical and cortisol changes associated with anticipation of exercise and short duration high-intensity exercise in sled dogs. Vet Clin Pathol. 38:370-374.
  6. Schaefer D, Priest H, Stokol T, Goldstein R, Belcher N (2009) Anticoagulant-dependent in vitro hemagglutination in a cat. Vet Clin Pathol. 38:194-200.
  7. Ledbetter EC, Landry MP, Stokol T, Kern TJ and Messick JB (2009) Brucella canis endophthalmitis in 3 dogs: clinical features, diagnosis, and treatment. Vet. Ophthalmol. 12:183-191.
  8. Stokol T, Divers TJ, Worobey J, McDonough SP (2009) Cerebrospinal fluid findings in cattle with central nervous system disorders: A retrospective study of 102 cases (1990-2008). Vet Clin Pathol. 38:103-12.
  9. Gold J, Warren AL, French TW, Stokol T (2008) What is your diagnosis? Biopsy impression smear of a hepatic mass in a yearling Thoroughbred filly. Vet Clin Pathol. 37:339-343.
  10. Stokol T, Gold J, Johnson A, Ainsworth D (2008) What is your diagnosis? Pleural fluid from a Thoroughbred filly with pneumonia. Vet Clin Pathol. 37:237-241.
  11. Stokol T, Brooks MB, Rush JE, Rishniw M, Erb H, Rozanski E, Kraus MS, Gelzer AR (2008) Hypercoagulability in cats with cardiomyopathy. J Vet Intern Med 22:546-552.
  12. Dereszynski DM, Center SA, Randolph JF, Brooks MB, Hadden AG, Palyada KS, McDonough SP, Messick J, Stokol T, Bischoff KL, Gluckman S, Sanders SY (2008) Clinical and clinicopathologic features of dogs that consumed foodborne hepatotoxic aflatoxins: 72 cases (2005-2006) J Am Vet Med Assoc. 232:1329-1337.
  13. Camp JP, Stokol T, Shuler M (2008) Fabrication of a multiple-diameter branched network of microvascular channels with semi-circular cross-sections using xenon difluoride etching. Biomed Microdevices. 10:179-186.
  14. Flory A, Rassnick K, Stokol T, Scrivani P, Erb H (2007) The impact of stage migration in dogs with lymphoma. J Vet Intern Med. 21: 1041-1047.
  15. Stokol T, Erb HN (2007) A comparison of platelet parameters in EDTA- and citrate-anticoagulated blood in dogs. Vet Clin Pathol. 36:148-154.
  16. Borges A, Divers T, Stokol T, Mohammed H (2007) Evaluation of serum iron and plasma fibrinogen concentrations as indicators of systemic inflammatory diseases in horses - Retrospective study 2003-2005”. J Vet Intern Med. 21:489-494.
  17. Thoesen MS, Vanden Berg-Foels WS, Stokol T, Rassnick KM, Jacobson MS, Kevy SV, Todhunter RJ (2006) Use of a centrifugation-based, point-of-care device for production of canine autologous bone marrow and platelet concentrates. Am J Vet Res. 67:1655-1661.
  18. Stokol T, Nydam D (2006) Effect of hemolysis on nonesterified fatty acid and beta-hydroxybutyrate concentrations in dairy cows. J Vet Diagn Invest. 18:466-469.
  19. Gardner RB, Hart KA, Stokol T, Divers TJ, Flaminio MJBF (2006) Fell pony syndrome in a pony in North America. J Vet Intern Med. 20:198-203.


People in the laboratory

Current laboratory members

Christine DeLeonardis
Wee Ming Yeo PhD: Postdoctoral associate
Sara Che: Graduate student


Christine

Christine DeLeonardis - Research assistant

 

 

Sara

Sara Che - Graduate student extraordinaire!

Sara, who hails from north of the border (Canada) started in the lab in August 2010 and hit the ground running!

 

Wee Ming

Wee Ming Yeo - Postdoctoral Associate

Wee Ming is a PhD from the National University of Singapore. He is doing great work in the lab with equine herpes virus and is also introducing us to exotic fruits like Durian (see below).

 

   

Previous summer veterinary students/under-graduate students

Cornell leadership program
Sean Llewellyn, Atlantic Veterinary College, Prince Edward Island (2005)
Onno Burgfeind, Free University of Berlin (2006)
Boran Choi, Seoul National University, Republic of Korea (2007)
Jakob Trimpert, Free University of Berlin, Germany (2009)
Eliza Smith, University of Queensland, Australia (2010)

Qatar Howard Hughes students/Nanobiotechnology Center summer students
Vijaytha Rathnam (2007)
Felicia Lew (2008)

Lamya Mubayed (2009)
Mohamed Al Hajri (2010)

Previous research assistants/Masters students

Masters of Engineering students
Albert Chan (2006)
Rebecca Moy (2007)
Daniel Lee (2009)
Dhruv Desai (2010)
David Post (2010)

Research assistants
Leanna Doherty (2006-2007)
Sridhar Patel (2005-2007)
Rajiv Perinbasekar (2007-2008)
Alexander Fe (2008-2009)

Previous post-doctoral associates
James Camp (2006-2007)