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Hire Dr. Johny E.

United States

USD 80 /hr

Freelance Clinical Cancer Research; Expert in Uro-Oncology; Inflammation, prostatic Hyperplasia, and Prostate Cancer

Profile Summary

Inflammation and Prostate Carcinogenesis Synopsis Research Report Principal Investigator: Johny E. Elkahwaji Department of Internal Medicine-Section of Medical Oncology and Hematology In the last decade, advanced cancer research has pointed out several cancer-causing factors including spontaneous replication errors in DNA, endogenous and exogenous carcinogenic substances, irradiation such ultraviolet and transduction of viral oncogenes, and infection/inflammation. The role of infection/inflammation in the initiation and progression of cancer has been an area of intense scientific interest and usually considered from the perspective that persistent inflammation in the context of chronic infection or tissue injury might promote cell transformation through DNA damage or that tumor cells produce pro-inflammatory factors that derive chronic inflammation and tumor growth. In 2000, approximately 20% of all cancer deaths were attributable to inflammatory reactions due to chronic infections caused by infectious agents (bacterial, viral, microbial, etc.). In the set of prostate cancer (CaP), chronic prostatic inflammation is increasingly often discussed as a critical component of tumor carcinogenesis by generating a pathologically conducive microenvironment that may favor the initiation and progression of cancer. A sustained inflammatory microenvironment provides a constant supply of a variety of reactive nitrogen and oxygen species, reactive aldehydes, cytokines, chemokines and growth factors, which can alter crucial biological processes responsible of maintaining normal cellular homeostasis, leading to genomic instability and the risk of CaP development. Several key observations have supported the postulated relationship: First, most epithelial malignancies, including the prostate, are accompanied by overexpression of cyclooxygenase 2 (COX-2), an inducible enzyme responsive to cytokines, growth factors, oncogenes, or tumor promoters during inflammation or cancer. Its rapid induction results in enhanced synthesis of prostanoids at the tumor site with several procarcinogenic effects including direct stimulation of tumor growth and inhibition of immune surveillance. Second, the common genetic and epigenetic instabilities in CaP include a strong representation of genes involved in inflammation such phosphatase and tensin analog protein (PTEN), macrophage scavenger receptor (MSR-1), Ribonuclease L (RNAse-L), and Toll receptor 4 (TLR-4). Third, the inflammatory mediators such as interleukin (IL)-1 and 6, tumor necrosis factor (TNF)-alpha, and prostanoids which all play a role in prostatic inflammation, have all been implicated as growth promoters in CaP. Finally, proliferative inflammatory atrophy (PIA), areas of epithelial proliferation associated with chronic inflammation, has been found closely associated with areas of prostatic intraepithelial neoplasia (PIN) and CaP. Based on these key observations, it is becoming clear that inflammation plays an important role in cancer initiation, progression, and metastasis. It induces the release of a variety of cytokines and chemokines that alert the vasculature to release inflammatory cells and factors into the tissue milieu, thereby causing oxidative damage, DNA mutations and deletions, and other changes in the microenvironment, making it more conducive to cell transformation, increased cell survival and proliferation. We postulated that chronic inflammation and the inflammatory network are inter-related and that the chronic inflammatory response associated with persistent bacterial infection and inflammation results in a reactive epithelial hyperplasia and severe dysplasia that could evolve into a neoplastic process. The postulated causal relationship between inflammation and cancer is provocative and exciting; however, a detailed molecular profiling of human prostatic inflammation has not been well characterized, in part due to lack of adequate models, tissue banking, and state of the art tissue microarray techniques. I have conducted some preliminary studies showing that C3H/HeOuJ inbred male mice inoculated intra-urethrally with uropathogenic E. coli develop acute prostate infections that evolve into chronic bacterial prostatitis associated with reactive hyperplasia and progressive dysplasia mimicking a prostatic intraepithelial neoplasia and carcinoma in situ. Furthermore, the inflammatory state generated during the chronic inflammation induces the phosphoinositide-3 kinase (PI3K) pathway and that activation of PI3K pathway signaled by Akt phosphorylation and PTEN suppression occurs during the reactive hyperplasia and severe dysplasia in vivo. My ultimate goal is to use the new mouse model of chronic bacterial prostatitis: 1. To examine the effects of chronic bacterial inflammation on the prostate epithelium 2. To characterize the immunobiology of prostate inflammation in response to bacterial infection and examine how the chronic inflammatory states in response to infection will resolve when the infecting bacteria are cleared after antibiotic treatment 3. To evaluate the link of chronic inflammatory states to prostate carcinogenesis by determining the origin and time-course of the reactive hyperplasia and characterizing the appearance of reactive and severe dysplasia 4. To determine whether activation of PI3K/Akt/mTOR pathway is necessary for the progression of reactive hyperplasia to severe dysplasia and carcinoma in situ associated with chronic prostatic inflammation. Furthermore, my translational research interest includes the construction of high-density tissue microarray (HDTMA) of human prostate and kidney specimens, using a robotic ATA-27 tissue microarray, to provide a high-throughput gene expression analysis and molecular profiling in a complex picture of a cellular state by determining whether genes are turned off or on in the cell, or their expression level, for tens of thousands of genes at a specific time for a specific biological sample. Such expression analysis could be performed on tumors, normal tissue, and many other types of samples and will set the stage to identify possible candidate gene where their proteins profiling is over/under-expressed at the early stage of the disease. One example of gene expression analysis will be to compare the gene expression levels between normal and cancerous tissue with or without inflammation and to identify genes that are differentially expressed only in the disease state. Not only this information will be used as a potential molecular diagnostic, but it will also direct new research to enlighten our basic understanding of these disease states. We have evaluated the expression of β-catenin as a field biomarker for prostate cancer. We observed that the normal acini (figure 2A) of the control gland exhibited bright, specific labeling. Normal appearing acini (figure 2B) and cancerous acini (figure 2C) of the cancer-bearing gland exhibited intermediate and low-level labeling, respectively. These data suggest that reduced expression of β-catenin in normal-appearing acini of a cancerous gland relative to the normal-appearing acini of matched controls is a potential field marker for CaP in biopsies that miss existing cancer nodules. The observed sensitivities and specificities qualify the marker as a potentially significant contributor to a small panel of field markers and support the feasibility of applying the TMA and quantitative fluorescence microscopy (QFM) to the development of such a panel. Also in the setting of a pilot study, we performed a quantitative analysis for oxidative DNA injury using the same section of the constructed TMA (benign prostatic hyperplasia versus prostate carcinoma). We observed that the genomic DNA damage measured by QFM was more pronounced in CaP specimens as compared to BPH (figure 3). This observation confirmed De Marzo and his colleagues’ hypothesis that genomic alterations become permanent in the genomes of proliferating epithelial cells and thus provide a mechanism for prostate carcinogenesis. My group’s focus is to collect more retrospective archived prostate tissues (IRB approval number: IRB # 115-07-EX) from the Department of Pathology and Microbiology at the UNMC to generate a high-density TMA using the robotic ATA-27 purchased by the University of Nebraska Foundation Grant (PI: Elkahwaji). This HDTMA will be used to evaluate the correlation between the inflammatory mediators and repeated bouts of oxidative injury to the human prostatic epithelium and areas of prostatic inflammation and whether this correlation is similar in patients with and without CaP. We anticipate that results generated in my lab using the UN foundation funds will allow Urologists and Clinical Oncologists to use TMA-identified markers to better diagnose patients with cancer and estimate their responsiveness to a given therapy, avoid the trial and error process of finding the most effective prescription based on a patient’s symptoms, and avoid the patient of some or all adverse reactions, side effects, and ingestion of medicines that would have no therapeutic effect. Treatment would be faster, safer, and more effective. Better still, people could manage their health and mitigate their known risks for developing certain conditions. Also, this novel molecular diagnostic technology will benefit the public health in terms of accuracy, efficacy, safety, and speed and will have an impact on the disease management and prevention, quality of life, and health care spending. Finally, this TMA will amplify the scarce resource, have an experimental uniformity, decrease assay volume, and does not destroy the original block for diagnosis. Also, it will provide a rapid assessment of prognosis-based subsets in a variety of tumor markers that cannot be attained by pathologist-based techniques and will better discern subtle differences in staining intensity which will distinguish novel prognostic associations with patient survival and outcome. Numerous UNMC and Eppley Cancer Center investigators research interests involve the understanding of the pathobiology and pathogenesis of cancer including breast cancer, lymphoma, and prostate cancer; therefore, these funds will help my group to develop this HDTMA on campus and to foster a very productive collaborative environment in experimental and clinical oncology, to identify specific alterations and will provide molecular targets for early detection, prevention and cancer targeted therapies. Furthermore, the HDTMA will be of great value when shared with many researchers not only in cancer, but also in many other areas including obesity/diabetes, cardiovascular and neurodegenerative diseases, immunology, and organ transplant.

Subject Matter Expertise

• ★ Hematology-Oncology
• ☆ Microarrays
• ☆ Mutagenesis
• ☆ Kinases
• ☆ Surveillance Systems
• ☆ Antibiotic Development
• ☆ Urology & Nephrology
• ☆ Tissue Microarray
• ☆ Cancer Research
• ☆ Carcinogenesis
• ☆ Hypothesis

Services

• Writing
• Research

Writing Clinical Trial Documentation, Technical Writing, Newswriting

Research Fact Checking, Gray Literature Search, Systematic Literature Review, Secondary Data Collection

Work Experience

Scientific Medical Reviewer

Cactus CRM

March 2018 - Present

Clinical Coordinator

NEX Medical Solutions

July 2017 - Present

Clinical Investigator

Novartis

July 2010 - Present

Assistant Professor of Medical Oncology and Director of the Uro-oncology Research Program

University of Nebraska Medical Center-Nebraska Medicine

July 2007 - Present

Assistant Professor of Urologic Surgery

University of Nebraska Medical Center-Nebraska Medicine

June 2006 - July 2007

Education

Post-Doctorate (Urology & Uro-Oncology)

University of Wisconsin-UW Hospital & Clinics

June 2001 - June 2004

Masters (MS)

Medical School Lariboisiere-St Louis, France

August 2002 - August 2003

Post-Doctorate (Transplant Immunology & Transplant Surgery)

University of Wisconsin-UW Hospital & Clinics

December 1999 - June 2001

Doctorate (PhD) (Clinical Pharmacology)

University of Pierre & Marie Curie, France

August 1993 - August 1998

Doctorate (Medicine/MD)

University of Paris, France

September 1986 - August 1993

Certifications

• Certification details not provided.

Publications

JOURNAL ARTICLE

(2012). The role of inflammatory mediators in the development of prostatic hyperplasia and prostate cancer . Research and reports in urology.

(2009). Chronic bacterial inflammation induces prostatic intraepithelial neoplasia in mouse prostate . British journal of cancer.

Richardson T, McCanse W, Casale GP, Huang D, Tian J, Elkahwaji JE, Lele S, Hemstreet GP(2009). Tissue-based quantification of 8-hydroxy-2'-deoxyguanosine in human prostate biopsies using quantitative fluorescence imaging analysis . Urology.

Hopkins WJ, Elkahwaji J, Kendziorski C, Moser AR, Briggs PM, Suhs KA(2009). Quantitative trait loci associated with susceptibility to bladder and kidney infections induced by Escherichia coli in female C3H/HeJ mice . The Journal of infectious diseases.

(2007). Quantitative fluorescence imaging analysis for cancer biomarker discovery: application to beta-catenin in archived prostate specimens . Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

Wagenlehner FM, Elkahwaji JE, Algaba F, Bjerklund-Johansen T, Naber KG, Hartung R, Weidner W(2007). The role of inflammation and infection in the pathogenesis of prostate carcinoma . BJU international.

(2007). Vaginal mucosal vaccine for recurrent urinary tract infections in women: results of a phase 2 clinical trial . The Journal of urology.

Bjorling DE, Elkahwaji JE, Bushman W, Janda LM, Boldon K, Hopkins WJ, Wang ZY(2007). Acute acrolein-induced cystitis in mice . BJU international.

Elkahwaji JE, Zhong W, Hopkins WJ, Bushman W(2007). Chronic bacterial infection and inflammation incite reactive hyperplasia in a mouse model of chronic prostatitis . The Prostate.

Elkahwaji JE, Ott CJ, Janda LM, Hopkins WJ(2005). Mouse model for acute bacterial prostatitis in genetically distinct inbred strains . Urology.

(2003). Rapamycin antagonizes cyclosporin A- and tacrolimus (FK506)-mediated augmentation of linker for activation of T cell expression in T cells . International immunology.

Uehling DT, Hopkins WJ, Elkahwaji JE, Schmidt DM, Leverson GE(2003). Phase 2 clinical trial of a vaginal mucosal vaccine for urinary tract infections . The Journal of urology.

Cho CS, Elkahwaji J, Chang Z, Scheunemann TL, Manthei ER, Hamawy MM(2003). Modulation of the electrophoretic mobility of the linker for activation of T cells (LAT) by the calcineurin inhibitors CsA and FK506: LAT is a potential substrate for PKC and calcineurin signaling pathways . Cellular signalling.

(2003). Inheritance of susceptibility to induced Escherichia coli bladder and kidney infections in female C3H/HeJ mice . The Journal of infectious diseases.

Tinel M, Elkahwaji J, Robin MA, Fardel N, Descatoire V, Haouzi D, Berson A, Pessayre D(1999). Interleukin-2 overexpresses c-myc and down-regulates cytochrome P-450 in rat hepatocytes . The Journal of pharmacology and experimental therapeutics.