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Curriculum vitae - rak, janusz
CURRICULUM VITAE – RAK, Janusz
Department of Medicine, Division of Oncology, McMaster University,
Hamilton, Canada. Faculty of Health Sciences,
Graduate Faculty of Hemostasis,
Thrombembolism and Atherosclerosis. McMaster University. Associated Graduate Faculty at the
Department of Biomedical Sciences, University of Guelph. Address.
Henderson Research Centre. Department of Medicine, McMaster University
711 Concession Street, Hamilton, Ontario L8V 1C3
Tel: (905) 527-2299 ext. 43771; Fax:(905) 575-2646, firstname.lastname@example.org Educational background:
L. Hirszfeld Institute of Immunology and Experimental Therapy. Polish Academy of Sciences, Wroclaw, Poland.
1980 - 1981
Regional Comprehensive Cancer Center, Wroclaw. Departments
of Oncology, Oncological Surgery, and Gynecology. Wroclaw . Medical
Academy, Dept of Hematology. Wroclaw. Poland.
Graduate Ph. D. Student
(Doctoral Fellow). Department of Tumor
Immunology. L. Hirszfeld Institute of Immunology and Experimental Therapy. Polish Academy of Sciences. Wroclaw. Poland. Thesis supervisor: Prof. Czeslaw Radzikowski MD, PhD
(part time). Departments of Neonatology and Emergency at
Regional Obstertics and Gynecology Hospital Wroclaw, City of Wroclaw
Medical Emergency Department.
Senior Research Associate
. Department of Tumor Immunology.
L. Hirszfeld Institute of Immunology and Experimental Therapy. Polish Academy of Sciences, Wroclaw. Poland. Head of the Department: Prof. Cz. Radzikowski MD, PhD
. Department of Immunology. Michigan Cancer
Foundation. Detroit. MI. USA. Head of the Laboratory: Fred R. Miller
Ph.D. Head of the Department: Gloria H. Heppner Ph. D.
. Division of Cancer and Cell Biology.
S. Lunefeld Research Institute. Mount Sinai Hospital. Toronto.
. Cancer Research Division. Sunnybrook Health
Science Centre, Toronto, Ontario, Director: Dr Robert S. Kerbel Ph. D.
Ontario, Canada. Head of the Laboratory: Robert S. Kerbel Ph. D.
. Cancer Research Division. Sunnybrook Health
Science Centre, Toronto, Ontario, Director: Dr Robert S. Kerbel Ph. D.
, Cancer Research Division. Sunnybrook Health
Science Centre, Toronto, Ontario, Director: Dr Robert S. Kerbel Ph. D.
Awards, Honors and Memberships:
Department of Medicine Internal Award, McMaster University
American Association for Cancer Research (Full Member)
Graduate Training Award/Doctoral Fellowship
Undergraduate Summer Training Award. Department of Cardiovascular Surgery and Transplantology. Inselspital, University of Bern, Bern, Switzerland.
Fourth Undergraduate Student Award - Medical Physiology Contest - Synapsis Magna . Wroclaw Medical School. Wroclaw, Poland.
Grant support for the last five years:
HRC, start up grant – Linkages between angiogenesis and hemostasis in cancer
Department of Medicine Internal Award – Tissue factor as a putative regulator of VEGF expression
NCIC Terry Fox Grant for New Investigators - Tagreting oncogene driven tumor angiogenesis. Dissecting the role of angiogenesis inhibitors
. Equipment grant- $70,000. Operating grant 100, 000/year
NSERC - The role of solid stress in tumor angiogenesis
CIHR - co-applicant (PI Dr. Brenda Coomber University of Guelph) Vascular dependence, tumor angiogenesis and microenvironment.
Hamilton Health Foundation Research Grant – Atherosclerosis and tumor angiogenesis
NCIC – Scientists Award – Career Award – Targeting oncogene-driven tumor angiogenesis
- app. $71,000/year
NCIC – co-applicant (PI Dr. Brenda Coomber, University of Guelph) Heterogeneous tumor vasculature: implications for therapy and consequences for cancer progression.-
total of app $67,000
Hamilton Health Foundation Research Grant – Oncogene targeting agents as potential regulators of tissue factor expression and modulators of coagulopathy in cancer.
A total of $43,000
CIHR – one year funding after unsuccessful application: Tissue factor in tumor progression and angiogenesis
. – approximately $75,000
OCRN – The roles of tissue factor in malignant glioma (PI Agnes Lee, 6 applicants)
A. Published Refereed Papers:
*1. W. Kalas, S. Gilpin, J. L. Yu, L. May, H. Krchnakova, P. Bornstein & J. Rak
author). Restoration of thrombospondin 1 expression in tumor cells harbouring mutant ras
oncogene by treatment with low doses of doxycycline. Biochem. Biophys, Res. Comm., 2003,
*2. A. Viloria-Petit, L. Miguerol, M. Gertsenstein, J. Yu, C. Sheehan, L. May, C. Lobe, A. Nagy,
R. S. Kerbel & J. Rak
(corresponding author). Contrasting effects of VEGF gene disruption in
embryonic stem cell-derived teratomas versus adult fibrosarcoma cells. EMBO J., 2003, 22, 16,
*3. J. Yu & J. Rak
(corresponding author). Inflammatory and immune cells in tumor angiogenesis
and arteriogenesis. Breast Cancer Research,2003, 3: 83-88
*4. B. Coomber, J. Yu, K. E. Fathers, C. Plumb & J. Rak
. Angiogenesis and the role of
epigenetics in metastasis. Clinical and Experimental Metastasis
, 2003, 20, 215-227.
5. P. Klement, S. Carlsson, J. Rak
, P. Liao, M. Vlasin, A. Stafford, M. Johnston, J.I. Weitz. The
benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis
prevention and bleeding model. Journal of Thrombosis and Haemostasis,2003, 1: 587-594
*6. J. Rak
(corresponding author), J. Yu, R. S. Kerbel & B. Coomber: What oncogenic mutations
have to do with angiogenesis/vascular dependence of tumors. Cancer Res. 2002, 62, 1931-1934.
7. T. Crombet-Ramos, J. Rak
, R. Perez, A. Viloria-Petit. Antiproliferative, antiangiogenic and
proapoptotic activity of h-R3: A humanized anti-EGFR antibody. Int. J. Cancer, 2002, 101: 567-
*8. A. K. Chan, J. Rak
(equal first authorship), L. Berry, P. Liao, M. Vlasin, J. Weitz, P. Klement:
Antithrombin-heparin covalent complex (ATH): a possible alternative to heparin for arterial
thrombosis prevention. Circulation, 2002, 106: 261-265.
9. J. Tran, Z. Master, J. L. Yu, J. Rak
, D. J. Dumont, R. S. Kerbel. A role for survivin in
chemoresistance of endothelial cells mediated by VEGF. Proc. Natl. Acad. Sci. USA, 2002, 7:
J. Yu, J. Rak
, G. Klement, R.S. Kerbel. Vascular endothelial growth factor isoform
expression as a determinant of blood vessel patterning in human melanoma xenografts. Cancer
Res., 2002, 62: 1838-1846.
*11. J. Yu, J. Rak,
B. Coomber, D. Hicklin, R.S. Kerbel. Effect of p53
status on tumor response
to anti-angiogenic therapy. Science, 2002, 295: 1526-1528.
*12. M. Wojtukiewicz, E. Sierko, P. Klement, J. Rak
(corresponding author): The hemostatic
system and angiogenesis in malignancy. Neoplasia 2001, 3, 5, 371-384
13. B. Mayer, G. Klement, M. Kaneko, S. Man, S. Jothy, J. Rak
& R.S. Kerbel. Multicellular
gastric cancer spheroids recapitulate growth pattern and differentiation phenotype
gastric carcinomas. Gastroenterology, 2001, 121: 839-852.
14. A. Viloria-Petit, T. Crombet, S. Jothy, D. Hicklin, P. Bohlen, J. M. Schlaeppi, J. Rak
Kerbel. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking
antibodies in vivo: A role of altered tumor angiogenesis. Cancer Res., 2002, 61: 5090-5101.
15. J. Yu, J. Rak,
P. Carmeliet, A. Nagy, R. S. Kerbel, B. L. Coomber. Heterogeneous vascular
dependence of tumor cell populations. Am. J. Pathology, 2001, 158:1325-1334
16. P. P. Claudio, P. Stiegler, C. M. Howard, C. Bellan, C. Minimo, G. M. Tosi, J. Rak
Kovatich, P. DeFazio, P. Micheli, M. Caputi, L. Leoncini, R. Kerbel, G. G. Giordano, A.
Giordano. Rb2/p130 gene enhanced expression down-regulates vascular endothelial growth
factor expression and inhibits angiogenesis in vivo. Cancer Res.,2001, 61: 462-8.
17. R.S. Kerbel, A. Viloria-Petit, G. Klement, J. Rak
: ‘Accidental’ anti-angiogenic drugs: anti-
oncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as
examples. Eur. J. of Cancer, 2000, 36, 1248-1257.
18. O. Lopez-Ocejo, A. Viloria-Petit, M. Bequet-Romero, J. Rak
, D. Mukhopadhyay, R. S.
Kerbel. Oncogenes and tumor angiogenesis: the HPV-16 E6 oncoprotein activates the vascular
endothelial growth factor (VEGF) gene promoter in a p53 independent manner. Oncogene,2000,
19. G. Klement, S. Baruchel, J. Rak
, S. Man, K. Clark, D. J. Hicklin, P. Bohlen, R. S. Kerbel.
Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained
tumor regression without overt toxicity. J. Clin. Invest 2000, 105: R15-R24.
20. K. Rosen, J. Rak,
J. Jin, T. Leung, R. Kerbel. J. Filmus. Bcl-xL as a mediator of ras-induced
resistance to anoikis. J. Cell Biol.2000, 149: 447-455.
21. J. Rak,
Y. Mitsuhashi, C. Sheehan, A. Tamir, A. Viloria-Petit, J. Filmus, S. Mansour, N.
Ahn, R. S. Kerbel. Oncogenes and tumor angiogenesis: Differential modes of VEGF
upregulation in ras-transformed epithelial cells and fibroblasts. Cancer Research, 2000, 60: 490-
22. J. Rak
(corresponding author), J. Yu, G. Klement, R.S. Kerbel: Oncogenes and angiogenesis.
Signaling three-dimensional tumor growth. J. Invest. Dermatol. 2000, 5, 24-33.
**23. J. Rak
(corresponding author). & G. Klement: Impact of oncogenes and tumor suppressor
genes on deregulation of hemostasis and angiogenesis in cancer. Canc. Metast. Reviews, 2000,
24. J. Tran, J. Rak
, C. Sheehan, S. Saibil, E. LaCasse, R. Korneluk, R. S. Kerbel. Marked
induction of the IAP family anti-apoptotic proteins survivin, and XIAP by VEGF in
endothelial cells. Biophys. Biochem. Res. Comm.1999, 264: 781-788.
25. J. K. Krestow, J. Rak,
J. Filmus, R. S. Kerbel. Functional dissociation of anoikis-like cell
death and activity of stress activated protein kinase. Biophys. Bichem. Res. Comm. 1999, 260:
26. J. Rak
, Y. Mitsuhashi, C. Sheehan, J. Krestow, V. A. Florenes, R. S. Kerbel. Collateral
expression of tumorigenic and angiogenic properties by epithelial cell variants selected for
resistance to anoikis. Neoplasia, 1999, 1: 23-30.
27. M. Feldkamp, N. Lau, J. Rak,
R. S. Kerbel, A. Guha. Normoxic and hypoxic regulation of
vascular endothelial growth factor (VEGF) by astrocytoma cells is mediated by Ras. Int. J.
Cancer, 1999, 81: 118-124.
28. V. A. Florenes, C. Lu, N. Bhattacharya, J. Rak
, C. Sheehan, J. Slingerland, R. S. Kerbel.
Interleukin-6 dependent induction of the cyclin dependent kinase inhibitor p21WAF1/CIP1 is lost
during progression of human malignant melanoma. Oncogene, 1999, 18: 1023-1032
29. L. Bayko, J. Rak
, S. Man, R. Bicknell, N. Ferrara, R. S. Kerbel. The dormant phenotype of
early stage primary human melanoma: termination by overexpression of vascular endothelial
growth factor. Angiogenesis, 1998, 2: 203-217.
30. K. Rosen, J. Rak,
Jin, R. S. Kerbel, M. J. Newman, J. Filmus. Downregulation of the pro-
apoptotic protein Bak is required for the ras-induced transformation of intestinal epithelial cells. Current Biol., 1998, 8: 1331-1334.
31. B. Liebeau-Teilliet, J. Rak
, S. Jothy, O. Illiopoulos, W. Kaelin, R. S. Kerbel. Von Hippel-
Lindau gene mediated growth suppression and induction of differentiation in renal cell
carcinoma cells grown as multicellular tumor spheroids. Cancer Res, 1998,. 58: 4957-4962
32. B. St.Croix, C.Sheehan, J. Rak
, V. A. Florenes, J. Slingerland, R. S. Kerbel. E-cadherin-
dependent growth suppression is mediated by the cyclin-dependent kinase inhibitor p27KIP1. J.
Cell Biol., 1998, 142: 557-571.
33. F. Okada, J. Rak
, B. St.Croix, B. Liebeau, M. Kaya, R.S. Kerbel. Impact of oncogenes on
tumor angiogenesis. K-ras dependent up-regulation of VEGF/VPF is necessary but not sufficient
for tumorigenicity of human colorectal cancer cells. Proc. Natl. Acad. Sci. USA, 1998, 95: 3609-
34. R. S. Kerbel, A. Viloria Petit, F. Okada, J. Rak
: Establishing a link between oncogenes and
tumor angiogenesis. Molecular Medicine, 1998, 4, 286-295.
B. Accepted or In Press Refereed Papers.
*1. J. Rak
(corresponding author) & Joanne L. Yu: Oncogenes and tumor angiogenesis. The
question of ‘vascular supply’ and ‘vascular demand. Seminars in Cancer Biology, 2003, in press.
*2. M. Wojtukiewicz, E. Sierko & J. Rak
: Contribution of the hemostatic system to
angiogenesis in cancer. Invited review, Seminars in Thrombosis and Haemostasis, 2003 in press
*3. J. L. Yu, L. May, P. Klement, J. I. Weitz & J. Rak
(corresponding author): Oncogenes as
putative regulators of tissue factor expression in cancer: Implications for angiogenesis and anti-
cancer therapy. Invited review, Seminars in Thrombosis and Haemostasis, 2003, in press
C. Submitted Refereed Papers:
1. M. Vlasin, P. Liao, J. Rak
, J. I. Weitz, & P. Klement. Paradoxical effects of heparin on
streptokinase-mediated arterial recanalization. Thrombosis Res., 2003, submitted.
D. Published Books and Monographs
*1. J. Rak
: Oncogene Directed Therapies. Humana Press Totowa, NJ, 2003
E. Published Contributions to Collective Work/Book Chapters.
1. J. Rak
: Preface. In Oncogene Directed Therapies, Editor J. Rak, Humana Press Totowa, NJ,
*2. J. Rak
(corresponding author) & R.S. Kerbel: Oncogenes and tumor angiogenesis. In Oncogene
Directed Therapies, Editor J. Rak, Humana Press Totowa, NJ, 2003 171-218.
*3. J. Rak
(corresponding author) & R.S. Kerbel: Prospects and progress in developmen
angiogenic agents. Principles and Practice of Biologic Therapy of Cancer 2002, Eds V. T.
DeVita, S. Hellman, S. A. Rosenberg, 3,2:5-13.
4. J. Rak
and R. Kerbel: Ras regulation of VEGF and angiogenesis. Methods in Enzymology
2001 , 333, 267-283.
5. R.S. Kerbel, A. Viloria-Petit, F. Okada, J. Rak
: The link between oncogenes, signal
transduction therapy and tumor angiogenesis. Chapter 17 in Tumor Angiogenesis and
Microcirculation. Editors: E. E. Voest & P. A. D’Amore, Marcel Dekker, Inc., New York, Basel,
6. S. Dedhar, G. E. Hannigan, J. Rak
, R. S. Kerbel: Chapter 9. The extracellular environment
and cancer. In: Basic Science of Oncology. Ed. : I. Tannock and R. Hill, 197-218, 1998.
F. Articles in Professional Journals Without Peer Review Committee.
& J.I. Weitz: Heparin and angiogenesis: Size matters! Editorial, Arteriosclerosis,
Thrombosis and Vascular Biology, 2003, 23, 1: 1954-1955.
(corresponding author), R. S. Kerbel: Basic fibroblast growth factor and the complexity of
tumor angiogenesis. Exp. Opin. Invest. Drugs,1998, 7, 5, 797-801.
G. Invited Presentations (J. Rak)
Dec. 1, 2003. Abbott Labs. Abbott Park IL. Angiogenic field effect in cancer: the role of
Nov 28, 2003. Prostate Centre, Vancouver General Hospital. The role of angiogenesis inhibitors
in oncogene-driven tumor angiogenesis.
Oct 17, 2003. Meeting of the American Association for Cancer Research, New Directions in the
Angiogenesis Research, Chicago. Oncogenes as Inducers of Tumor Angiogenesis. What Are
the Key Effectors.
Dec 19, 2002. Hamilton Regional Cancer Centre. Investigational New Drugs Meeting. Prospects
and progress in antiangiogenic therapy – the specter of ‘anti-angiogenic drug resistance’.
Dec12, 2002. Henderson Research Centre, McMaster University. The role of VEGF in genetic
and epigenetic tumor angiogenesis.
Oct. 31, 2002. Hamilton Regional Cancer Centre. The role of VEGF in oncogene-driven versus
epigenetic tumor angiogenesis
Sep. 10, 2002. Karmanos Cancer Research Center. Detroit Michigan. Oncogenes as regulators
of tumor angiogenesis and vascular dependence in cancer
Nov 22, 2001. Hamilton Regional Cancer Centre. Oncogenes, angiogenesis and angiogenesis
dependence in cancer.
Nov. 5, 2001
University of Innsbruck, Austria. Departrment of Pediatric Hematology and Oncology.
Genes, tumors and blood vessels. Tumor angiogenesis and vascular dependence
May 11, 2001 Smooth Muscle Research Program Seminar Series, McMaster University: Oncogenes as inducers of tumor angiogenesis
Oct. 17, 2000 Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish
Academy of Sciences, Wroclaw, Poland. Genes and three-dimensional tumor growth geometry.
Oct. 12, 2000 Masaryk University, Oncology Centre, Brno, Czech Republic. Oncogenes,
angiogenesis and angiogenesis dependence
May 25, 2000 Regional Oncology Rounds. Hamilton Regional Cancer Centre. Genetic
Determinants of Tumor Angiogenesis - Therapeutic Implications.
Feb 29, 2000 CTEP Meeting, NCI, National Institutes of Health, Bethesda, MD, USA. Oncogenes and Angiogenesis: Oncogene Function.
Aug 9, 1999 Forty-Eighth Annual Montagna Symposium on the Biology of Skin. “Endothelial
Cells and Angiogenesis: From Benchtop to Bedside”. Snowmass, Colorado. Tumor progression
and angiogenesis: Signal Transduction Inhibitors as Potential Anti-angiogenesis drugs in
Jul 11, 1998 Venezuelan Institute of Scientific Research (IVIC), Carracas, Venezuela,
Department of Tumor Bilogy (Dr Manuel Rieber) Principles of angiogenesis and anti-
angiogenesis. RAS oncogenes as inducers of tumor angiogenesis.
Mar 26, 1997 Harvard Medical School, Children’s Hospital, Boston, MA, USA. Research
Department. Genes and Geometry. Molecular Control of Three-dimensional Tumor Growth
Biology of cancer and cellular transformation. Cell biology. Principles of vascular biology, angiogenesis and vasculogenesis. Graduate teaching in the area of research interest (angiogenesis, vascular disease, cancer)
2003 - McMaster University, MS-733, Vasculogenesis and tissue development (Course Coordinator - Mark Hatton Ph.D.)
2003 - McMaster University, MS-733, Pathological angiogenesis and tumor growth (Course Coordinator - Mark Hatton Ph.D.)
2003 - McMaster University, MS-729, Molecular basis of neoplasia (Course Coordinator – Steve Shaughnessy Ph.D.)
2002 - McMaster University, MS-729, Molecular basis of neoplasia (Course Coordinator – Steve Shaughnessy Ph.D.)
2002 - McMaster University, MS-733, Vasculogenesis and tissue development (Course Coordinator - Mark Hatton Ph.D.)
2002 - McMaster University, MS-733, Pathological angiogenesis and tumor growth (Course Coordinator - Mark Hatton Ph.D.)
2001 - McMaster University, Biochemistry 4EE3 ABB271. Molecular regulation of tumor angiogenesis
2001- McMaster University, MS-733, Vascular Biology Course-Angiogenesis (Course Organized - Mark Hatton Ph.D.)
2000- McMaster University, MS-733, Vascular Biology Course-Angiogenesis (Course Organized - Mark Hatton Ph.D.)
1998 - Faculty and Co-organizer - Special Course: Tumor Progression and Angiogenesis
. University of Zulia, Maracaibo, Venezuela.
2003 – pres. Stephanie Brightwaite – MSc Student
2003 – pres. Chloe Milson – MSc Student 2001-pres.- Halka Krchnakova DVM, PhD Student - International Exchange Program between Henderson Research Centre and Veterinary College in Brno, Czech Republik.
2003-pres. – Vladimir Lhotak, PhD, Henderson Research Centre 2002- pres.- Wojciech Kalas, PhD, Henderson Research Centre 2002-pres.- Joanne Yu, PhD, Henderson Research Centre 2001-2002 – Sander van Leuven MD
C. Suprevisory Committees:
2000-2003 Member of the PhD Student Advisory Committee for Alicia Viloria-Petit, Sunnybrook and Women’s College Health Science Centre, department of Medical Biophysics, University of Toronto, Supervisor, Dr. Robert, S. Kerbel. 2001-pres. Member of the PhD Student Advisory Committee for Claire Plumb, Department of Biomedical Sciences, University of Guelph, Supervisor Dr Brenda Coomber.
2001-pres. Member of the MSci Student Advisory Committee for Kelly Fathers, Department of Biomedical Sciences, University of Guelph, Supervisor Dr Brenda Coomber. 2002-pres. Member of the PhD Student Advisory Committee for Paul Nortcoth, Department of Pathology, McMaster University, Supervisor Dr. Maria Rozakis-Adcock. 2002-pres Member of the PhD Student Advisory Committee for Nisha Anand, Department of Pathology, McMaster University, Supervisor Dr. Jonathan Lee. 2003-pres Member of the MSc Student Advisory Committee for Joanne Kasaboski, Department of Pathology, McMaster University, Supervisor Dr. Steven Shaughnessy. 2003-pres Member of the PhD Student Advisory Committee for Showkat Hoseini, Department of Pathology, McMaster University, Supervisor Dr. Rick Austin. 2003- Member of the MSc Student Advisory Committee for Dan Purcell Department of Pathology, McMaster University, Supervisor Dr. Jonathan Lee
1993-2000 Adjunct advisor for graduate students (Erik Hegman MSci - completed, Liisa Bayko Msci - completed, Kate Krestow MSci - completed, Brad St.Croix PhD - completed, Joanne Yu PhD-expected completion in 2002, Jennifer Tran PhD – expected completion in 2002, Alicia Viloria Petit PhD expected completion in 2002). Department of Medical Biophysics. Department of Pathology, University of Toronto, Sunnybrook Health Science Centre.
2001 – External Examiner – Dr Mihal Vlasin DVM, PhD Student – International Exchange Program between the Hamilton Civic Hospitals Research Centre and Veterinary College Brno, Czech Republik.
2002 – Scientific Examiner (Comprehensive Examination) for the PhD Student Philip Swirski
2002 – External PhD examiner for George Naumov, University of Western Ontario, London (Supervisor - Dr Ann Chambers).
2002 – Scientific Examiner (Comprehensive Examination) for Yingtao Xu, McMaster University, Hamilton (Supervisor - Dr Mazurek)
2002 – External Examiner (PhD Examination) for Alicia Viloria-Petit, Medical Biophysics, University of Toronto (Supervisor Dr R. S. Kerbel).
2002 – External MSc Examiner for Filipe Tiburcio, McMaster University (Supervisor R. M. K. Lee).
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TERRAQUANT. WOUND MANAGEMENT SCIENTIFIC EVIDENCE The clinical trials reported in this section have sound methodologies; at least a control group and all have been published in peer review scientific journals. LLLT produced in vitro increases in cell growth of 140-200% in mouse-derived fibroblasts , rat-derived osteoblasts and rat-derived skeletal muscle cells , and incr