James A Warneke

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Courses

Scholarly Contributions

Books

• Marian, M., Thomson, C., Esser, M., & Warneke, J. A. (1996). Surgery: Nutrition Handbook. New York, NY: Chapman and Hall.

Chapters

• Warneke, J. A., & Rose, J. (2016). Soft Tissue Sarcoma And Skin. In Surgery Review Illustrated(pp 717-735). Cenveo Publisher Services.
• Warneke, J. A. (2013). Surgical Oncology. In In Essentials of General Surgery(pp 505-546). Philadelphia, PA and Baltimore, MA: Lippincott Williams & Wilkins.
• Lang, N., Stone, M., de Gara, C., & Warneke, J. A. (2006). Surgical Oncology: Malignant Diseases of the Skin, the Lymphatics, and Soft Tissue. In In Essentials of General Surgery(pp 491-518). Philadelphia, PA and Baltimore, MA: Lippincott Williams & Wilkins.
• Bradford, C., Neal, D., & Warneke, J. A. (1996). Laparoscopic Surgery. In In NMS Surgery (National Medical Series for Independent Study)(pp 577-602). Media, PA: Williams and Wilkins.
• Warneke, J. A., & Moritz, M. (1996). Problems in General Surgery. In In National Medical Series for Independent Study(pp 27-50). Media, Pennsylvania: Williams and Wilkins.
• Warneke, J. A., & Hunter, T. (1994). Common Surgical Procedures. In In Radiologic Guide to Medical Devices and Foreign Bodies(pp 329-347). St. Louis, MO: Mosby-Year Book, Inc.
• Warneke, J. A., Hunter, T., & Bragg, D. (1994). Medical Devices and Foreign Bodies Associated with Surgery. In In Radiologic Guide to Medical Devices and Foreign Bodies; Mosby Year Book, Inc; St. Louis, MO(pp 307-328). St. Louis, MO: Mosby-Year Book, Inc.

Journals/Publications

• Einspahr, J. G., Curiel-Lewandrowski, C., Calvert, V. S., Stratton, S. P., Alberts, D. S., Warneke, J., Hu, C., Saboda, K., Wagener, E. L., Dickinson, S., Dong, Z., Bode, A. M., & PetricoinIII, E. F. (2017). Protein activation mapping of human sun-protected epidermis after an acute dose of erythemic solar simulated light. NPJ precision oncology, 1.
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  Ultraviolet radiation is an important etiologic factor in skin cancer and a better understanding of how solar stimulated light (SSL) affects signal transduction pathways in human skin which is needed in further understanding activated networks that could be targeted for skin cancer prevention. We utilized Reverse Phase Protein Microarray Analysis (RPPA), a powerful technology that allows for broad-scale and quantitative measurement of the activation/phosphorylation state of hundreds of key signaling proteins and protein pathways in sun-protected skin after an acute dose of two minimal erythema dose (MED) of SSL. RPPA analysis was used to map the altered cell signaling networks resulting from acute doses of solar simulated radiation (SSL). To that end, we exposed sun-protected skin in volunteers to acute doses of two MED of SSL and collected biopsies pre-SSL and post-SSL irradiation. Frozen biopsies were subjected to laser capture microdissection (LCM) and then assessed by RPPA. The activation/phosphorylation or total levels of 128 key signaling proteins and drug targets were selected for statistical analysis. Coordinate network-based analysis was performed on specific signaling pathways that included the PI3k/Akt/mTOR and Ras/Raf/MEK/ERK pathways. Overall, we found early and sustained activation of the PI3K-AKT-mTOR and MAPK pathways. Cell death and apoptosis-related proteins were activated at 5 and 24 h. Ultimately, expression profile patterns of phosphorylated proteins in the epidermal growth factor receptor (EGFR), AKT, mTOR, and other relevant pathways may be used to determine pharmacodynamic activity of new and selective topical chemoprevention agents administered in a test area exposed to SSL to determine drug-induced attenuation or reversal of skin carcinogenesis pathways.
• Glazer, E. S., Bartels, P. H., Lian, F., Kha, S. T., Morgan, S. S., da Silva, V. D., Yozwiak, M. L., Bartels, H. G., Cranmer, L. D., de Oliveira, J. K., Alberts, D. S., Warneke, J. A., & Krouse, R. S. (2016). Quantitative histopathology identifies patients with thin melanomas who are at risk for metastases. Melanoma research, 26(3), 261-6. doi:10.1097/CMR.0000000000000236
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  This small exploratory study was designed to test the hypothesis that thin melanoma lesions contain nuclei of two similar phenotypes, in different proportions. In lesions likely to progress to metastatic disease, one of these phenotypes predominates. Histopathological sections from 18 cases of thin melanomas which did not progress to metastasis, and from 10 cases which did progress were imaged and digitized at high resolution, with a total of 2084 and 1148 nuclei, respectively, recorded. Five karyometric features were used to discriminate between nuclei from indolent and from potentially metastatic lesions. For each case, the percentage of nuclei classified by the discriminant function as having come from a potentially metastatic lesion was determined and termed as case classification criterion. Standard histopathological criteria, such as ulceration and high mitotic index, indicated in this material the need for intensive therapy for only one of the 10 participants, as compared with 7/10 identified correctly by the karyometric measure. Using a case classification criterion threshold of 40%, the overall accuracy was 86% in the test set. The proportion of nuclei of an aggressive phenotype may lend itself as an effective prognostic clue for thin melanoma lesions. The algorithm developed in this training set appears to identify those patients at high risk for metastatic disease, and demonstrates a basis for a further study to assess the utility of prognostic clues for thin melanomas.
• Raoof, M., Nelson, R. A., Nfonsam, V., Warneke, J. A., & Krouse, R. (2016). Prognostic significance of lymph node yield in ypN0 rectal cancer. British Journal of Surgery, 103(12), 1731-1737.
• Bermudez, Y., Stratton, S. P., Curiel-Lewandrowski, C., Warneke, J., Hu, C., Bowden, G. T., Dickinson, S. E., Dong, Z., Bode, A. M., Saboda, K., Brooks, C. A., Petricoin, E. F., Hurst, C. A., Alberts, D. S., & Einspahr, J. G. (2015). Activation of the PI3K/Akt/mTOR and MAPK Signaling Pathways in Response to Acute Solar-Simulated Light Exposure of Human Skin. Cancer prevention research (Philadelphia, Pa.), 8(8), 720-8.
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  The incidence of skin cancer is higher than all other cancers and continues to increase, with an average annual cost over $8 billion in the United States. As a result, identifying molecular pathway alterations that occur with UV exposure to strategize more effective preventive and therapeutic approaches is essential. To that end, we evaluated phosphorylation of proteins within the PI3K/Akt and MAPK pathways by immunohistochemistry in sun-protected skin after acute doses of physiologically relevant solar-simulated ultraviolet light (SSL) in 24 volunteers. Biopsies were performed at baseline, 5 minutes, 1, 5, and 24 hours after SSL irradiation. Within the PI3K/Akt pathway, we found activation of Akt (serine 473) to be significantly increased at 5 hours while mTOR (serine 2448) was strongly activated early and was sustained over 24 hours after SSL. Downstream, we observed a marked and sustained increase in phospho-S6 (serine 235/S236), whereas phospho-4E-BP1 (threonines 37/46) was increased only at 24 hours. Within the MAPK pathway, SSL-induced expression of phospho-p38 (threonine 180/tyrosine 182) peaked at 1 to 5 hours. ERK 1/2 was observed to be immediate and sustained after SSL irradiation. Phosphorylation of histone H3 (serine 10), a core structural protein of the nucleosome, peaked at 5 hours after SSL irradiation. The expression of both p53 and COX-2 was increased at 5 hours and was maximal at 24 hours after SSL irradiation. Apoptosis was significantly increased at 24 hours as expected and indicative of a sunburn-type response to SSL. Understanding the timing of key protein expression changes in response to SSL will aid in development of mechanistic-based approaches for the prevention and control of skin cancers.
• Jeter, J. M., Curiel-Lewandrowski, C., Stratton, S. P., Myrdal, P. B., Warneke, J. A., Einspahr, J. G., Bartels, H., Yozwiak, M., Bermudez, Y., Hu, C., Bartels, P., & Alberts, D. S. (2015). Phase IIB Randomized Study of Topical Difluoromethylornithine and Topical Diclofenac on Sun-Damaged Skin of the Forearm. Cancer Prevention Research, 9(2), 128-34. doi:0.1158/1940-6207.CAPR-15-0232
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  Prevention of nonmelanoma skin cancers remains a health priority due to high costs associated with this disease. Diclofenac and difluoromethylornithine (DFMO) have demonstrated chemopreventative efficacy for cutaneous squamous cell carcinomas. We designed a randomized study of the combination of DFMO and diclofenac in the treatment of sun-damaged skin. Individuals with visible cutaneous sun damage were eligible. Subjects were randomized to one of three groups: topical DFMO applied twice daily, topical diclofenac applied daily, or DFMO plus diclofenac. The treatment was limited to an area on the left forearm, and the duration of use was 90 days. We hypothesized that combination therapy would have increased efficacy compared to single-agent therapy. The primary outcome was change in karyometric average nuclear abnormality (ANA) in the treated skin. Individuals assessing the biomarkers were blinded regarding the treatment for each subject. A total of 156 subjects were randomized; 144 had baseline and end-of-study biopsies, and 136 subjects completed the study. The ANA unexpectedly increased for all groups, with higher values correlating with clinical cutaneous inflammation. Nearly all of the adverse events were local cutaneous effects. One subject had cutaneous toxicity that required treatment discontinuation. Significantly more adverse events were seen in the groups taking diclofenac. Overall, the study indicated that the addition of topical DFMO to topical diclofenac did not enhance its activity. Both agents caused inflammation on a cellular and clinical level, which may have confounded the measurement of chemopreventative effects. More significant effects may be observed in subjects with greater baseline cutaneous damage.
• Nielsen, V. G., Matika, R. W., Ley, M. L., Waer, A. L., Gharagozloo, F., Kim, S., Nfonsam, V. N., Ong, E. S., Jie, T., Warneke, J. A., & Steinbrenner, E. B. (2014). Tissue-type plasminogen activator-induced fibrinolysis is enhanced in patients with breast, lung, pancreas and colon cancer. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, 25(3), 248-53.
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  Although cancer-mediated changes in hemostatic proteins unquestionably promote hypercoagulation, the effects of neoplasia on fibrinolysis in the circulation are less well defined. The goals of the present investigation were to determine if plasma obtained from patients with breast, lung, pancreas and colon cancer was less or more susceptible to lysis by tissue-type plasminogen activator (tPA) compared to plasma obtained from normal individuals. Archived plasma obtained from patients with breast (n = 18), colon/pancreas (n = 27) or lung (n = 19) was compared to normal individual plasma (n = 30) using a thrombelastographic assay that assessed fibrinolytic vulnerability to exogenously added tPA. Plasma samples were activated with tissue factor/celite, had tPA added, and had data collected until clot lysis occurred. Additional, similar samples had potato carboxypeptidase inhibitor added to assess the role played by thrombin-activatable fibrinolysis inhibitor in cancer-modulated fibrinolysis. Rather than inflicting a hypofibrinolytic state, the three groups of cancers demonstrated increased vulnerability to tPA (e.g. decreased time to lysis, increased speed of lysis, decreased clot lysis time). However, hypercoagulation manifested as increased speed of clot formation and strength compensated for enhanced fibrinolytic vulnerability, resulting in a clot residence time that was not different from normal individual thrombi. In sum, enhanced hypercoagulability associated with cancer was in part diminished by enhanced fibrinolytic vulnerability to tPA.
• Nielsen, V. G., Nfonsam, V. N., Matika, R. W., Ong, E. S., Jie, T., Warneke, J. A., & Steinbrenner, E. B. (2014). Colon and pancreas tumors enhance coagulation: role of hemeoxygenase-1. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, 25(5), 435-8. doi:10.1097/MBC
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  Colon and pancreatic cancer are associated with significant thrombophilia. Colon and pancreas tumor cells have an increase in hemeoxygenase-1 (HO-1) activity, the endogenous enzyme responsible for carbon monoxide production. Given that carbon monoxide enhances plasmatic coagulation, we determined if patients undergoing resection of colon and pancreatic tumors had an increase in endogenous carbon monoxide and plasmatic hypercoagulability. Patients with colon (n = 17) and pancreatic (n = 10) tumors were studied. Carbon monoxide was determined by the measurement of carboxyhemoglobin (COHb). A thrombelastographic method to assess plasma coagulation kinetics and formation of carboxyhemefibrinogen (COHF) was utilized. Nonsmoking patients with colon and pancreatic tumors had abnormally increased COHb concentrations of 1.4 ± 0.9 and 1.9 ± 0.7%, respectively, indicative of HO-1 upregulation. Coagulation analyses comparing both tumor groups demonstrated no significant differences in any parameter; thus the data were combined for the tumor groups for comparison with 95% confidence interval values obtained from normal individuals (n = 30) plasma. Seventy percent of tumor patients had a velocity of clot formation greater than the 95% confidence interval value of normal individuals, with 53% of this hypercoagulable group also having COHF formation. Further, 67% of tumor patients had clot strength that exceeded the normal 95% confidence interval value, and 56% of this subgroup had COHF formation. Finally, 63% of all tumor patients had COHF formation. Future investigation of HO-1-derived carbon monoxide in the pathogenesis of colon and pancreatic tumor-related thrombophilia is warranted.
• Curiel-Lewandrowski, C., Speetzen, L. S., Cranmer, L., Warneke, J. A., & Loescher, L. J. (2011). Multiple primary cutaneous melanomas in Li-Fraumeni syndrome. Archives of Dermatology, 147(2), 248-50.
• Sosman, J. A., Moon, J., Tuthill, R. J., Warneke, J. A., Vetto, J. T., Redman, B. G., Liu, P. Y., Unger, J. M., Flaherty, L. E., & Sondak, V. K. (2011). A phase 2 trial of complete resection for stage IV melanoma: results of Southwest Oncology Group Clinical Trial S9430. Cancer, 117, 4740-4706. doi:10.1002/cncr.26111
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  On the basis of retrospective experience at individual centers, it appears that patients with stage IV melanoma who undergo complete resection have a favorable outcome compared with patients with disseminated stage IV disease. The Southwest Oncology Group (SWOG) performed a prospective trial in patients with metastatic melanoma who were enrolled before complete resection of their metastatic disease and provided prospective outcomes in the cooperative group setting.
• Houdek, M. T., Warneke, J. A., Pollard, C. M., Lindgren, E. A., & Taljanovic, M. S. (2010). Giant epidermal cyst of the gluteal region. Radiology case reports, 5(4), 476.
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  Epidermal cysts are common, benign, intradermal or subcutaneous, typically asymptomatic masses, ranging from 1 to 4 cm in size. They may occur anywhere in the body, with a predilection for the face, neck, and trunk. Transformation to squamous-cell carcinoma is rare. We present a case of a 61-year-old male patient with a large, growing mass in his posterior left gluteal region. Given the concern for a malignancy, he was referred to a surgical oncologist. Magnetic resonance imaging (MRI) without contrast was performed due to poor renal function and revealed a large cystic mass in the left gluteal subcutaneous soft tissues that was subsequently excised. Pathological examination revealed an epidermal inclusion cyst that measured 17.8 × 13.18 × 5.8 cm. To our knowledge, this is the largest epidermal inclusion cyst reported in the English literature.
• Jensen, V., Prasad, A. R., Smith, A., Raju, M., Warneke, J., Wendel, C. S., Schmelz, M., Leyva, W., & Krouse, R. S. (2010). Prognostic criteria for squamous cell cancer of the skin. The Journal of surgical research, 159(1), 509-16.
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  Non-well-differentiated cutaneous squamous cell carcinomas may display a more aggressive behavior. It is important to better define prognostic criteria for these tumors.
• Stratton, S. P., Alberts, D. S., Einspahr, J. G., Sagerman, P. M., Warneke, J. A., Curiel-Lewandrowski, C., Myrdal, P. B., Karlage, K. L., Nickoloff, B. J., Brooks, C., Saboda, K., Yozwiak, M. L., Krutzsch, M. F., Hu, C., Lluria-Prevatt, M., Dong, Z., Bowden, G. T., & Bartels, P. H. (2010). A phase 2a study of topical perillyl alcohol cream for chemoprevention of skin cancer. Cancer Prevention Research, 3, 160-9.
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  The chemopreventive and antitumor properties of perillyl alcohol (POH) that were studied preclinically indicate that topical POH inhibits both UVB-induced murine skin carcinogenesis (squamous cell tumor models) and 7,12-dimethylbenz(a)anthracene-induced murine melanoma (transgenic models involving tyrosinase-driven Ras). A previous phase 1 clinical trial in participants with normal-appearing skin showed that topical POH cream was well tolerated at a dose of 0.76% (w/w). Here, we performed a 3-month, double-blind, randomized, placebo-controlled phase 2a trial of two different doses of topical POH in individuals with sun-damaged skin. Participants applied POH cream twice daily to each dorsal forearm. Baseline and end-of-study biopsies were taken from each participant to evaluate whether the topical application of POH was effective in reversing actinic damage as evidenced by normalization of quantitative skin histopathologic scores and change in nuclear chromatin pattern as measured by karyometric analysis. There was a borderline reduction in the histopathologic score of the lower-dose POH group compared with the placebo (P = 0.1), but this was not observed in the high-dose group. However, in the high-dose group, a statistically significant reduction in the proportion of nuclei deviating from normal was observed by the use of karyometric analysis (P < 0.01). There was no statistical significance shown in the lower-dose group. No changes were observed in p53 expression, cellular proliferation (by proliferating cell nuclear antigen expression), or apoptosis in either treatment group compared with the placebo group. These results suggest that whereas our karyometric analyses can detect a modest effect of POH in sun-damaged skin, improved delivery into the epidermis may be necessary.
• Foote, J. A., Ranger-Moore, J. R., Einspahr, J. G., Saboda, K., Kenyon, J., Warneke, J., Miller, R. C., Goldman, R., Xu, M., Roe, D. J., & Alberts, D. S. (2009). Chemoprevention of human actinic keratoses by topical DL-alpha-tocopherol. Cancer Prevention Research, 2(4), 394-400.
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  Prior research shows that topical application of free, nonfatty acid-conjugated vitamin E (DL-alpha-tocopherol) prevents skin cancer in mice, as well as immunosuppression induced by UVB radiation. This study investigated the chemopreventive potential of DL-alpha-tocopherol in humans through monitoring surrogate end point biomarkers in sun-damaged skin. Contralateral arms of healthy human volunteers with actinic keratoses (AK) were randomly assigned to receive either 12.5% DL-alpha-tocopherol or placebo in a crème base for 6 months. Changes in number of AKs, levels of p53 protein expression, proliferating cell nuclear antigen, and polyamines were assessed along with skin and systemic vitamin E levels. Following treatment, plasma concentration levels of DL-alpha-tocopherol were unchanged, but skin levels were highly elevated (P < 0.001). Levels of p53 and proliferating cell nuclear antigen did not change significantly, whereas number of AKs declined insignificantly in both placebo and treatment arms. Regression models showed significant decreases in putrescine, spermidine, spermine, and total polyamine concentrations following treatment. Topically applied DL-alpha-tocopherol was substantially absorbed in skin, but the 6-month application did not significantly reduce numbers of preexisting AKs on moderately to severely sun-damaged forearms. Increases in polyamine synthesis are expected during tumor initiation and promotion; conversely, the significant reductions in polyamine levels resulting from the topical DL-alpha-tocopherol application are consistent with reductions in tumorigenesis potential. Topical tocopherol did not normalize established sun-induced lesions, but DL-alpha-tocopherol-induced reductions in polyamine metabolism are consistent with the inhibition of skin squamous cell carcinogenesis as seen in previous human trials and animal models.
• Loescher, L. J., Crist, J. D., Cranmer, L., Curiel-Lewandrowski, C., & Warneke, J. A. (2009). Melanoma high-risk families' perceived health care provider risk communication. Journal of cancer education: The official journal of the American Association for Cancer Education, 24(4), 301-7.
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  Families with a melanoma history are at risk of melanoma. Melanoma survival improves when people are aware of their risk and ways to modify it. We explored at-risk families' perceived risk communication from healthcare providers.
• Bedogni, B., Warneke, J. A., Nickoloff, B. J., Giaccia, A. J., & Powell, M. B. (2008). Notch 1 is an effector of Akt and hypoxia in melanoma development. The Journal of clinical investigation, 118(11), 3660-70.
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  Melanomas are highly aggressive neoplasms resistant to most conventional therapies. These tumors result from the interaction of altered intracellular tumor suppressors and oncogenes with the microenvironment in which these changes occur. We previously demonstrated that physiologic skin hypoxia contributes to melanomagenesis in conjunction with Akt activation. Here we show that Notch1 signaling is elevated in human melanoma samples and cell lines and is required for Akt and hypoxia to transform melanocytes in vitro. Notch1 facilitated melanoma development in a xenograft model by maintaining cell proliferation and by protecting cells from stress-induced cell death. Hyperactivated PI3K/Akt signaling led to upregulation of Notch1 through NF-kappaB activity, while the low oxygen content normally found in skin increased mRNA and protein levels of Notch1 via stabilization of HIF-1alpha. Taken together, these findings demonstrate that Notch1 is a key effector of both Akt and hypoxia in melanoma development and identify the Notch signaling pathway as a potential therapeutic target in melanoma treatment.
• Einspahr, J. G., Bowden, G. T., Alberts, D. S., McKenzie, N., Warneke, J., Saboda, K., Salasche, S., Ranger-Moore, J., Curiel-Lewandrowski, C., Nagle, R. B., Nickoloff, B. J., Brooks, C., Dong, Z., & Stratton, S. P. (2008). Cross-validation of murine UV signal transduction pathways in human skin. Photochemistry and photobiology, 84(2), 463-76.
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  Acute UVB irradiation of mouse skin results in activation of phospatidyinositol-3 (PI-3) kinase and mitogen-activated protein kinase (MAPK) pathways leading to altered protein phosphorylation and downstream transcription of genes. We determined whether activation of these pathways also occurs in human skin exposed to 4x minimal erythemic dose of UVB in 23 volunteers. Biopsies were taken prior to, at 30 min, 1 and 24 h post-UVB. In agreement with mouse studies, the earliest UV-induced changes in epidermis were seen in phospho-CREB (two- and five-fold at 30 min and 1 h) and in phospho-MAPKAPK-2 (three-fold at both 30 min and 1 h). At 1 h, phospho-c-JUN and phospho-p38 were increased five- and two-fold, respectively. Moreover, phospho-c-JUN and phospho-p38 were further increased at 24 h (12- and six-fold, respectively). Phospho-GSK-3beta was similarly increased at all time points. Increases in phospho-p53 (12-fold), COX-2 (four-fold), c-FOS (14-fold) and apoptosis were not seen until 24 h. Our data suggest that UVB acts through MAPK p38 and PI-3 kinase with phosphorylation of MAPKAPK-2, CREB, c-JUN, p38, GSK-3beta and p53 leading to marked increases in c-FOS, COX-2 and apoptosis. Validation of murine models in human skin will aid in development of effective skin cancer chemoprevention and prevention strategies.
• Stratton, S. P., Warneke, J. A., Saboda, K. L., Myrdal, P. B., Gupta, A., McKenzie, N. E., Brooks, C., Salasche, S. J., Ranger-Moore, J., Bozzo, P. D., Blanchard, J., Einspahr, J. G., Dorr, R. T., Levine, N., & Alberts, D. S. (2008). Phase 1 study of topical perillyl alcohol cream for chemoprevention of skin cancer. Nutrition and cancer, 60(3), 325-30.
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  Perillyl alcohol (POH) is a natural product derived from plants such as cherry and lavendin. Previous studies have indicated that topical POH inhibits ultraviolet (UV) B-induced skin carcinogenesis in vivo, and it may be an effective chemopreventive agent for skin cancer. We performed a 1-mo, first-in-man, Phase 1 trial of topically administered POH cream in human subjects. Endpoints included safety and evaluation of any histopathological changes in skin after 1 mo use of POH cream. We randomized 25 subjects with normal, healthy skin with little or no sun damage and no history of skin cancer in a double-blind fashion to receive topical POH (0.76% wt/wt) on 1 forearm with placebo cream applied to the other forearm twice daily for 30 days. Subjects were monitored for toxicity, and a 4 mm punch biopsy in the treated area was performed at the end of study for histopathological evaluation. The topical cream was well tolerated. No serious cutaneous toxicities, systemic toxicities, or histopathological abnormalities were observed. A total of 8 subjects (32%) reported mild adverse events possibly or probably related to use of cream including reversible appearance of 1 to 2 small papules. However, there was no significant difference between lesions appearing on the POH treated forearm vs. the placebo-treated forearm.
• Einspahr, J. G., Thomas, T. L., Saboda, K., Nickolof, B. J., Warneke, J., Curiel-Lewandrowski, C., Ranger-Moore, J., Duckett, L., Bangert, J., Fruehauf, J. P., & Alberts, D. S. (2007). Expression of vascular endothelial growth factor in early cutaneous melanocytic lesion progression. Cancer, 110(11), 2519-27.
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  A considerable body of evidence supports the concept that a significant number of cutaneous malignant melanomas progress through a precursor lesion or dysplastic melanocytic nevi (DN). Tumor angiogenesis likely plays a critical role in early development of melanoma, and intermediate biomarkers of angiogenesis could be useful as chemoprevention and prognostic markers.
• Korde, V. R., Bonnema, G. T., Warneke, J. A., Xu, W., Krishnamurthy, C., Ranger-Moore, J., Saboda, K., Slayton, L. D., Salasche, S. J., Alberts, D. S., & Barton, J. K. (2007). Using optical coherence tomography to evaluate skin sun damage and precancer. Lasers in surgery and medicine, 39(9), 687-95.
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  Optical coherence tomography (OCT) is a depth resolved imaging modality that may aid in identifying sun damaged skin and the precancerous condition actinic keratosis (AK).
• Bernstein, H., Prasad, A., Warneke, J. A., Holubec, H., Bernstein, C., Payne, C. M., Ramsey, L., Dvorakova, K., Wilson, M., & Garewal, H. (2006). Reduced Pms2 expression in non-neoplastic flat mucosa from patients with colon cancer correlates with reduced apoptosis competence. Applied immunohistochemistry & molecular morphology : AIMM / official publication of the Society for Applied Immunohistochemistry, 14(2), 166-72.
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  Pms2 protein is a component of the DNA mismatch repair complex responsible both for post-replication correction of DNA nucleotide mispairs and for early steps in apoptosis. Germline mutations in DNA mismatch repair genes give rise to hereditary non-polyposis colon cancer, which accounts for about 4% of colon cancers. However, little is known about the expression of mismatch repair proteins in relation to sporadic colon cancer, which accounts for the great majority of colon cancers. Multiple samples were taken from the non-neoplastic flat mucosa of colon resections from patients with no colonic neoplasia, a tubulovillous adenoma, or an adenocarcinoma. Expression of Pms2 was assessed using semiquantitative immunohistochemistry. Apoptosis was assessed in polychrome-stained epoxy sections using morphologic criteria. Samples from patients without colonic neoplasia had moderate to strong staining for Pms2 in cell nuclei at the base of crypts, while samples from 2 of the 3 colons with a tubulovillous adenoma, and from 6 of the 10 colons with adenocarcinomas, showed reduced Pms2 expression. Samples from patients with an adenocarcinoma that had reduced Pms2 expression also exhibited reduced apoptosis capability in nearby tissue samples, evidenced when this paired tissue was stressed ex vivo with bile acid. Reduced Pms2 expression in the colonic mucosa may be an early step in progression to colon cancer. This reduction may cause decreased mismatch repair, increased genetic instability, and/or reduced apoptotic capability. Immunohistochemical determination of reduced Pms2 expression, upon further testing, may prove to be a promising early biomarker of risk of progression to malignancy.
• Einspahr, J. G., Xu, M., Warneke, J., Saboda, K., Ranger-Moore, J., Bozzo, P., Duckett, L., Goldman, R., Lin, P., Buckmeier, J., & Alberts, D. S. (2006). Reproducibility and expression of skin biomarkers in sun-damaged skin and actinic keratoses. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 15(10), 1841-8.
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  To explore p53 and proliferating cell nuclear antigen (PCNA) expression and polyamine content as biomarkers in skin cancer chemoprevention trials, we evaluated their expression in early stages of UV-induced squamous cell tumorigenesis.
• Shi, J., Kahle, A., Hershey, J. W., Honchak, B. M., Warneke, J. A., Leong, S. P., & Nelson, M. A. (2006). Decreased expression of eukaryotic initiation factor 3f deregulates translation and apoptosis in tumor cells. Oncogene, 25(35), 4923-36.
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  The eukaryotic initiation factor 3f (eIF3f) is the p47 subunit of the multi-subunit eIF3 complex. eIF3 plays an important role in translation initiation. In the present study, we investigate the biological function of eIF3f in translation and apoptosis in tumor cells. We demonstrated for the first time that eIF3f is downregulated in most human tumors using a cancer profiling array and confirmed by real-time reverse transcription PCR in melanoma and pancreatic cancer. Overexpression of eIF3f inhibits cell proliferation and induces apoptosis in melanoma and pancreatic cancer cells. Silencing of eIF3f protects melanoma cells from apoptosis. We further investigated the biological function of eIF3f. In vitro translation studies indicate that eIF3f is a negative regulator of translation and that the region between amino acids 170 and 248 of eIF3f is required for its translation regulatory function. Ectopic expression of eIF3f inhibits translation and overall cellular protein synthesis. Ribosome profile and ribosomal RNA (rRNA) fragmentation assays revealed that eIF3f reduces ribosomes, which may be associated with rRNA degradation. We propose that eIF3f may play a role in ribosome degradation during apoptosis. These data provide critical insights into the cellular function of eIF3f and in linking translation initiation and apoptosis.
• Hess, L. M., Saboda, K., Malone, D. C., Salasche, S., Warneke, J., & Alberts, D. S. (2005). Adherence assessment using medication weight in a phase IIb clinical trial of difluoromethylornithine for the chemoprevention of skin cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 14(11 Pt 1), 2579-83.
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  Adherence is a common and essential measurement in clinical trials. This study evaluates the association between participant self-reported study diary records and the weight of the medication vessel at each study visit, in the setting of a phase IIb topical chemoprevention trial.
• Holubec, H., Payne, C. M., Bernstein, H., Dvorakova, K., Warneke, J. A., Bernstein, C., Waltmire, C. N., & Garewal, H. (2005). Assessment of apoptosis by immunohistochemical markers compared to cellular morphology in ex vivo-stressed colonic mucosa. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society, 53(2), 229-35.
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  Apoptosis competence is central to the prevention of cancer. Frequency of apoptotic cells, after a sample of colonic tissue is stressed, can be used to gauge apoptosis competence and, thus, possible susceptibility to colon cancer. The gold standard for assessment of apoptosis is morphological evaluation, but this requires an experienced microscopist. Easier-to-use immunohistochemical markers of apoptosis, applicable in archived paraffin-embedded tissue, have been commercially developed. Potentially useful apoptosis markers include cleaved cytokeratin-18 (c-CK18), cleaved caspase-3 (c-cas-3), cleaved lamin A (c-lam-A), phosphorylated histone H2AX (gammaH2AX), cleaved poly(ADP ribose) polymerase (c-PARP), and translocation of apoptosis-inducing factor (AIF). When tissue samples from freshly resected colon segments were challenged ex vivo with the bile acid deoxycholate, approximately 50% of goblet cells became apoptotic by morphologic criteria. This high level of morphologic apoptosis allowed quantitative comparison with the usefulness and specificity of immunohistochemical markers of apoptosis. The antibody to c-CK18 was almost as useful and about as specific as morphology for identifying apoptotic colonic epithelial cells. Antibodies to c-cas-3, c-lam-A, and gammaH2AX, though specific for apoptotic cells, were less useful. The antibody to c-PARP, though specific for apoptotic cells, had low usefulness, and the antibody to AIF was relatively nonspecific, under our conditions.
• Payne, C. M., Holubec, H., Bernstein, C., Bernstein, H., Warneke, J., Dvorak, K., Green, S. B., Wilson, M., Dall'Agnol, M., Dvorakova, B., & Garewal, H. (2005). Crypt-restricted loss and decreased protein expression of cytochrome C oxidase subunit I as potential hypothesis-driven biomarkers of colon cancer risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 14(9), 2066-75.
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  There is an increasing demand for the development of intermediate biomarkers to assess colon cancer risk. We previously determined that a live cell bioassay, which assesses apoptosis resistance in the nonneoplastic colonic mucosa, detects approximately 50% of patients with colon cancer. A hypothesis-driven biomarker that reflects apoptosis resistance in routine formalin-fixed, paraffin-embedded tissue would be easier to use. Cytochrome c oxidase is a critical enzyme that controls mitochondrial respiration and is central to apoptosis. We did an immunohistochemical study of cytochrome c oxidase subunit I expression in 46 colonic mucosal samples from 16 patients who had undergone a colonic resection. These included five patients without evidence of colonic neoplasia (three normal and two diverticulitis), three patients with tubulovillous adenomas, and eight patients with colonic adenocarcinomas. Analysis of aberrancies in expression of cytochrome c oxidase subunit I showed that, compared with nonneoplasia, the patients with neoplasia had a higher mean incidence of crypts having decreased expression (1.7 versus 22.8, P = 0.03) and a higher mean incidence having crypt-restricted loss (0.6 versus 3.2, P = 0.06). The percentage with segmented loss was low and was similar in the two groups. Combining these results, the mean % normal (i.e., with none of the three types of abnormality) was 96.7 in nonneoplasia versus only 73.2 in patients with neoplasia (P = 0.02). It should be noted that a defect in cytochrome c oxidase subunit I immunostaining was not detected in all biopsy samples from each patient for whom some abnormality was found, indicating a "patchiness" in the cytochrome c oxidase subunit I field defect. As a result of this "patchiness," the increased variability in the incidence of crypt-restricted loss of cytochrome c oxidase subunit I expression was a statistically significant feature of the neoplasia group. Crypt-restricted loss of cytochrome c oxidase subunit I has not been previously reported in colonic mucosa and is presumably the result of a crypt-restricted stem cell mutation. Decreased cytochrome c oxidase subunit I expression also significantly correlated with apoptosis resistance, a factor known to contribute to carcinogenesis. The results suggest, however, that aberrant cytochrome c oxidase subunit I expression may be a better biomarker than loss of apoptosis competence for increased colon cancer risk.
• Alberts, D., Ranger-Moore, J., Einspahr, J., Saboda, K., Bozzo, P., Liu, Y., Xu, X. C., Lotan, R., Warneke, J., Salasche, S., Stratton, S., Levine, N., Goldman, R., Islas, M., Duckett, L., Thompson, D., Bartels, P., & Foote, J. (2004). Safety and efficacy of dose-intensive oral vitamin A in subjects with sun-damaged skin. Clinical cancer research : an official journal of the American Association for Cancer Research, 10(6), 1875-80.
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  Previously, we reported the results of a Phase III, placebo-controlled trial in 2297 randomized participants with moderately severe actinic keratoses wherein 25000 IU/day vitamin A caused a 32% risk reduction in squamous cell skin cancers. We hypothesized that dose escalation of vitamin A to 50000 or 75000 IU/day would be both safe and more efficacious in skin cancer chemoprevention.
• Barton, J. K., Gossage, K. W., Xu, W., Ranger-Moore, J. R., Saboda, K., & Warneke, J. A. (2003). Investigating sun-damaged skin and actinic keratosis with optical coherence tomography: a pilot study. Technology in cancer research & treatment, 2(6), 525-35.
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  Actinic Keratosis (AK) arises from sun-damaged skin and is the first clinical manifestation in the multistep process of skin carcinogenesis to invasive squamous cell carcinoma. Thus, it is an ideal target for chemopreventive efforts. Noninvasive measures of AK severity are needed to assess the efficacy of chemoprevention agents. We performed a pilot study on 20 participants to investigate the OCT appearance of sun-protected skin of the upper inner arm as well as sun-damaged skin and early AKs of the dorsal forearms, and to determine if features or quantitative measures in Optical Coherence Tomography (OCT) images could be used to reliably differentiate between these categories. OCT images of upper inner arm (normal appearing skin) showed skin layers and features (stratum corneum, epidermis, dermis, blood vessels) seen in previous studies; additionally in this participant group the subcutaneous fat layer was usually identified. Sun-damaged skin was characterized by increased signal in the epidermis and rapid attenuation of light. AKs were diverse in appearance but frequently characterized by high surface reflection, the presence of a low-signal band in the stratum corneum, and heterogeneous appearance in the epidermis/dermis. Significant differences were found between skin categories using measures of stratum corneum and epidermal/dermal depths and intensities. The presence of a dark band in the stratum corneum was 79% sensitive and 100% specific for AK. This study indicates that OCT holds promise as a useful technique for identifying and characterizing AKs and monitoring their response to chemoprevention agents.
• Romagnolo, D. F., Chirnomas, R. B., Ku, J., Warneke, J., Jeffy, B. D., & Payne, C. M. (2003). Deoxycholate, an endogenous tumor promoter and DNA damaging agent, modulates BRCA-1 expression in apoptosis-sensitive epithelial cells: loss of BRCA-1 expression in colonic adenocarcinomas. Nutrition and cancer, 46(1), 82-92.
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  Deoxycholate, a bile salt present at high levels in the colonic lumen of individuals on a high-fat diet, is a promoter of colon cancer. Deoxycholate also causes DNA damage. BRCA-1 functions in repair of DNA and in induction of apoptosis. We show that, when cultured cells of colonic origin are exposed to deoxycholate at different concentrations, BRCA-1 expression is induced at a low noncytotoxic concentration (10 microM) but is strongly inhibited at higher cytotoxic concentrations ( > or =100 microM). Indication of phosphorylation of BRCA-1 by deoxycholate (100 microM) at a lower dose was seen by Western blot analysis, whereas, at a higher dose, deoxycholate (200 and 300 microM) caused a complete loss of BRCA-1 expression. We show that BRCA-1 is substantially lower in colon adenocarcinomas from five patients compared with associated non-neoplastic colon tissue from the same patients, suggesting that the loss of BRCA-1 expression contributes to the malignant phenotype. In the non-neoplastic colon tissue, BRCA-1 was localized to the nongoblet cells. Our results imply that reduced expression of BRCA-1 may be associated with carcinoma of the colon.
• Wiese, F. W., Thompson, P. A., Warneke, J., Einspahr, J., & Alberts, D. S. (2003). Variation in cyclooxygenase expression levels within the colorectum. Molecular carcinogenesis, 37(1), 25-31.
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  The positive association of decreased risk of colorectal cancer with nonsteroidal antiinflammatory drug (NSAID) use, combined with the observation that cyclooxygenase(COX)-2 is present in a majority of colorectal tumors, has led to the proposed use of isozyme-specific COX inhibitors as preventive agents in polyp and tumor formation in the colon. However, the exact biochemical mechanisms and disease stage at which reduced risk is mediated remain somewhat controversial, in part because of the complex biochemical changes that occur during the progression from aberrant crypt to polyp to tumor. In this study, COX-1 and COX-2 protein expression levels were determined in sets of tumor and normal colon tissue. Changes were characterized in COX-1 and COX-2 expression within individuals, in relation to such factors as sex, tumor grade, and location in the colorectum. COX-1 expression levels were found to be significantly reduced in tumors compared to matched normal tissues (Dunn's method, P < 0.05). Additionally, COX-1 expression was decreased in stage T3 tumors as compared to stage T2 tumors (Student's t-test, P = 0.009). Similar to previous reports, COX-2 protein expression was present in 73% of the tumors studied and appeared to be independent of tumor grade and sex. Interestingly, decreased COX-2 expression correlated with tumor occurrence in rectal mucosa (Wilcoxon two-sample test, P < 0.05). These results warrant further investigation, especially the identification of determinants that would predict which populations would be most responsive to COX-2 inhibition as a means of colorectal cancer chemoprevention.
• Bernstein, H., Holubec, H., Warneke, J. A., Garewal, H., & Earnest, D. L. (2002). Patchy field defects of apoptosis resistance and dedifferentiation in flat mucosa of colon resections from colon cancer patients. Annals of surgical oncology, 9(5), 505-17.
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  Abnormal areas in normal-appearing flat colonic mucosa (field defects) may predispose individuals to colon cancer. Markers of field defects would indicate cancer risk.
• Einspahr, J. G., Nelson, M. A., Saboda, K., Warneke, J., Bowden, G. T., & Alberts, D. S. (2002). Modulation of biologic endpoints by topical difluoromethylornithine (DFMO), in subjects at high-risk for nonmelanoma skin cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 8(1), 149-55.
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  More than one million new skin cancers are diagnosed yearly in the United States creating the need for effective primary and chemopreventive strategies to reduce the incidence, morbidity, and mortality associated with skin cancer. Skin chemoprevention trials often focus on subjects at high risk of nonmelanoma skin cancers and include biological endpoints like number of actinic keratoses (AK) and measures of cell proliferation, apoptosis, and p53 expression and/or mutation. Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, suppresses increased polyamine synthesis and inhibits tumors in models of skin carcinogenesis. Thus, DFMO is a good candidate chemopreventive agent in humans at increased risk of NMSC. We reported previously results of a randomized, placebo-controlled trial of topical DFMO in 48 participants with AK. In this study there was a significant reduction in the number of AK (23.5%; P = 0.001) and the polyamine, spermidine (26%, P = 0.04; Alberts, D. S. et al. Cancer Epidemiol. Biomark. Prev., 9: 1281-2186, 2000). In skin biopsies from the same study, we demonstrate that topical DFMO significantly reduces the percentage of p53-positive cells (22%; P = 0.04); however, there were no significant changes in proliferating cell nuclear antigen or apoptotic indices, or in the frequency of p53 mutations (25% at baseline, 21% after placebo, and 26% after DFMO). We conclude that inhibition of the premalignant AK lesions as well as a reduction in the expression of p53 and in spermidine concentrations may serve as surrogate endpoint biomarkers of DFMO and possibly other topically administered skin cancer chemopreventive agents.
• Alberts, D. S., Dorr, R. T., Einspahr, J. G., Warneke, J. A., Aickin, M., & Saboda, K. (2009). Chemoprevention of human actinic keratoses by topical 2-(Difluoromethyl)-dl-ornithine. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 9(12), 1281-6.
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  Alpha-2-(Difluoromethyl)-dl-ornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, has been shown to suppress skin carcinogenesis in murine models after oral or topical administration. We designed a randomized, placebo-controlled study using a topical hydrophilic ointment formulation with or without 10% (w/w) DFMO. Forty-eight participants with moderate-severe actinic keratoses (AKs) on their forearms (i.e., at least 10 well-circumscribed lesions on the lateral surface) completed a 1-month run-in on placebo ointment. Before randomization, all lateral forearm AKs were circled, counted, photographed, and skin biopsies were obtained for DFMO and polyamine levels. Then participants were randomized to receive DFMO ointment on the right versus the left forearm and placebo hydrophilic ointment on the contralateral forearm twice daily for 6 months. DFMO was not detected in the blood of any subject, and there were no systemic toxicities. None of a subsample of 17 placebo forearms had measurable concentrations of DFMO, whereas 13 of the corresponding DFMO-treated forearms had high DFMO skin levels. As compared with placebo, the 6-month DFMO treatment caused a 23.5% reduction in the number of AKs (P = 0.001) as well as significant suppression of AK biopsy spermidine levels (26%; P = 0.04). Seven of the 48 (14.6%) participants experienced severe (2; 4.2%) or moderate (5; 10.4%) inflammatory reactions on their DFMO-treated arms which required dosing modification. Topical DFMO for 6 months can reduce the number of AK lesions and skin spermidine concentrations in high-risk participants and deserves additional study as a skin cancer chemopreventive agent.
• Einspahar, J., Alberts, D., Warneke, J. A., Bozzo, P., & Basye, J. (1999). Relationship between p53 mutation, expression, and apoptosis in UV-induced human skin carcinogenesis. Neoplasia, 1(5), 468-75.
• Payne, C. M., Crowley, C., Warneke, J., Washo-Stultz, D., Briehl, M., & Bernstein, H. (1998). The stress-response proteins poly(ADP-ribose) polymerase and NF-kappaB protect against bile salt-induced apoptosis. Cell Death and Differentiation, 5(7), 623-36.
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  Bile salts induce apoptosis and are implicated as promoters of colon cancer. The mechanisms by which bile salts produce these effects are poorly understood. We report that the cytotoxic bile salt, sodium deoxycholate (NaDOC), activates the key stress response proteins, NF-kappaB and poly(ADP-ribose) polymerase (PARP). The activation of NF-kappaB and PARP, respectively, indicates that bile salts induce oxidative stress and DNA damage. The pre-treatment of cells with specific inhibitors of these proteins [pyrrolidine dithiocarbamate (NF-kappaB inhibitor) and 3-aminobenzamide (PARP inhibitor)] sensitizes cells to the induction of apoptosis by NaDOC, indicating that these stress response pathways are protective in nature. Colon cancer risk has been reported to be associated with resistance to apoptosis. We found an increase in activated NF-kappaB at the base of human colon crypts that exhibit apoptosis resistance. This provides a link between an increased stress response and colon cancer risk. The implications of these findings with respect to apoptosis and to colon carcinogenesis are discussed.
• Gause, P. R., Lluria-Prevatt, M., Keith, W. N., Balmain, A., Linardopolous, S., & Warneke, J. (1997). Chromosomal and genetic alterations of 7,12-dimethylbenz[a]anthracene-induced melanoma from TP-ras transgenic mice. Molecular carcinogenesis, 20(1), 78-87.
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  The TP-ras transgenic mouse line expresses an activated human T24 Ha-ras gene with a mutation in codon 12, regulated by a mouse tyrosinase promoter. The transgene is expressed in melanocytes of the skin, eyes, and brain. The mice develop cutaneous melanoma when treated with 7,12-dimethylbenz[a]anthracene. Cell lines have been generated from the cutaneous tumors and metastatic lesions. By using fluorescence in situ hybridization with mouse whole chromosome paints, the cell lines were characterized for chromosomal abnormalities. Key findings in the tumor cells included translocations of chromosome 4 and alterations in chromosome 6. One tumor cell line contained a double translocation involving chromosomes 3 and 6. To extend the results of the chromosome 4 painting, Southern analysis of the p15INK4B, p16INK4A, and p19INK4D genes was performed. Our data indicated that there were homozygous and partial allelic deletions and polymorphisms in the region of chromosome 4 containing these genes, resulting in the absence or reduced expression of the p16 product. These findings are similar to those reported for human melanoma, and the TP-ras transgenic mouse may therefore be a valuable model for studying novel strategies for melanoma prevention and treatment.
• Stopeck, A., Hersh, E., Akporiaye, E., Grogan, T., Unger, E., & Warneke, J. A. (1997). Phase I Study of direct gene transfer of an allogenic histocompatibility antigen, HLA-B7, in patients with metastatic melanoma.. Journal of Clinical Oncology, 15(1), 341-9.
• Berggren, M., Gallegos, A., Gasdaska, J. R., Gasdaska, P. Y., Warneke, J., & Powis, G. (1996). Thioredoxin and thioredoxin reductase gene expression in human tumors and cell lines, and the effects of serum stimulation and hypoxia. Anticancer research, 16(6B), 3459-66.
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  Thioredoxin and thioredoxin reductase are redox proteins that have been implicated in the control of cell proliferation and transformation. We report the levels and activity of these proteins and their mRNAs in human primary tumors and tumor cell lines. Half of human primary colorectal carcinomas (5/10) examined had increased thioredoxin mRNA, of 3- to over 100-fold, compared to adjacent normal colonic mucosa from the same subject. Thioredoxin reductase protein and activity were increased an average of 2-fold in human colorectal tumors compared to normal mucosa. A number of human hematologic and solid tumor cell lines were studied and showed a 10-fold range of thioredoxin mRNA and a 23-fold range of thioredoxin reductase mRNA. Increased proliferation and hypoxia are factors that might contribute to the increased expression in solid tumors. We found that serum stimulation of growth arrested MCF-7 breast cancer cells caused a 59% increase in thioredoxin mRNA and a 62% increase in thioredoxin reductase mRNA by 24 hours. Exposure of HT-20 colon cancer cells to hypoxia resulted in a 14-fold increase in thioredoxin mRNA by 16 hours, and a transient 4-fold increase in thioredoxin reductase mRNA at 1 hour that had returned to control levels by 8 hours. Cancer cells were found to release thioredoxin into the medium at rates between 1 to 2 pmole/10(6) cells/3 hours. The rate of secretion was not, however, related to cellular-levels of thioredoxin. The results of the study show that the expression of thioredoxin and thioredoxin reductase are increased several fold in some human solid tumors compared to normal tissue. Secretion of thioredoxin, which is known to have a direct growth stimulating activity, by human tumor cells might lead to the stimulation of cancer cell growth.
• Warneke, J., Berger, R., Johnson, C., Stea, D., & Villar, H. (1996). Lumpectomy and radiation treatment for invasive lobular carcinoma of the breast. American journal of surgery, 172(5), 496-500.
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  Large studies have shown a similar outcome when comparing mastectomy with lumpectomy and external beam radiation therapy in the treatment of infiltrating ductal carcinoma. However, this has not been studied extensively for invasive lobular carcinoma. We studied the pattern of recurrence and overall survival of patients treated with lumpectomy and radiation for either invasive lobular carcinoma (ILC) or combined invasive lobular carcinoma/invasive ductal carcinoma (ILC/IDC) of the breast.
• Fox, K. A., Mularski, R. A., Sarfati, M. R., Brooks, M. E., Warneke, J. A., Hunter, G. C., & Rappaport, W. D. (1995). Aspiration pneumonia following surgically placed feeding tubes. American journal of surgery, 170(6), 564-6; discussion 566-7.
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  The enteral route is preferred in surgical patients requiring nutritional support; however, controversy surrounds the choice of location of feeding tube placement. Although jejunostomy has been commonly accepted as superior to gastrostomy for long-term nutritional support because of an assumed lower risk of aspiration pneumonia, recent studies suggest that reevaluation of common practices of surgical tube placement is warranted.
• Hall, K. A., Peters, B., Smyth, S. H., Warneke, J. A., Rappaport, W. D., Putnam, C. W., & Hunter, G. C. (1995). Abdominal wall hernias in patients with abdominal aortic aneurysmal versus aortoiliac occlusive disease. American journal of surgery, 170(6), 572-5; discussion 575-6.
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  This study was undertaken to determine the incidence of ventral incisional hernias (VIHs) and inguinal hernias (IHs) in patients with abdominal aortic aneurysmal (AAA) versus those with aortoiliac occlusive disease (AIOD).
• Warneke, J., Grossklaus, D., Davis, J., Stea, B., & Bebb, G. (1995). Influence of local treatment on the recurrence rate of ductal carcinoma in situ. Journal of the American College of Surgeons, 180(6), 683-8.
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  Screening mammography has resulted in a significant increase in the diagnosis of ductal carcinoma in situ (DCIS). The role of breast conservation therapy and the long-term recurrence rate are still controversial. This article compares mastectomy, wide excision alone, and wide excision with radiation as treatments for DCIS.
• Hersh, E., Akporiaye, E., Harris, D., Stopeck, A., Warneke, J. A., & Unger, E. (1994). Phase I study of immunotherapy of malignant melanoma by direct gene transfer. Human Gene Therapy, 5(11), 1371-84.
• Rappaport, W. D., Gordon, P., Warneke, J. A., Neal, D., & Hunter, G. C. (1994). Contraindications and complications of laparoscopic cholecystectomy. American family physician, 50(8), 1707-11, 1714.
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  Laparoscopic cholecystectomy is a commonly performed procedure for the removal of symptomatic gallstones. Compared with open cholecystectomy, laparoscopic cholecystectomy is associated with less postoperative pain, earlier discharge from the hospital and a more rapid recovery. However, there are specific contraindications to the procedure, including empyema of the gallbladder, gangrenous cholecystitis, coagulopathy, portal hypertension and peritonitis. Complications from laparoscopic cholecystectomy include common duct injury, bleeding, bile leakage and wound infection. An understanding of these issues allows the family physician to more appropriately select patients for laparoscopic removal of the gallbladder.
• Sarfati, M. R., Fox, K. A., Warneke, J. A., Fajardo, L. L., Hunter, G. C., & Rappaport, W. D. (1994). Stereotactic fine-needle aspiration cytology of nonpalpable breast lesions: an analysis of 258 consecutive aspirates. American journal of surgery, 168(6), 529-31; discussion 531-2.
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  The role of stereotactic fine-needle aspiration cytology (SFNAC) in the diagnosis of nonpalpable breast lesions is poorly defined.
• Marian, M., Rappaport, W., Cunningham, D., Thompson, C., Esser, M., Warneke, J., Williams, F., & Hunter, G. (1993). The failure of conventional methods to promote spontaneous transpyloric feeding tube passage and the safety of intragastric feeding in the critically ill ventilated patient. Surgery, gynecology & obstetrics, 176(5), 475-9.
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  Nasoenteral tube feedings are often recommended in critically ill patients when gastrointestinal tract function is intact. Conventional methods of placement include turning the patient on the right side and the use of drugs that stimulate peristalsis to promote transpyloric passage. A prospective study was initially performed to assess the success of conventional methods used to promote transpyloric feeding tube placement in patients requiring assisted ventilation admitted to the Surgical Intensive Care Unit (SICU) (Part I of the study). In 68 critically ill ventilated patients, placement of nasoduodenal feeding tubes was attempted. Successful transpyloric placement was achieved in only ten patients. There was no correlation between age, gender, admitting diagnosis, time of tube placement and successful placement. The second part of the study was initiated to assess the safety of nasogastric feeding in critically ill ventilated patients. Forty-two patients admitted to the SICU were considered candidates for gastrointestinal tract feeding and were fed through the gastric route. Twenty-five patients reached enteral feeding goal rate within 72 hours, while 34 patients achieved goal rate by five days. Eight patients required total parenteral nutrition to meet nutritional needs because of an inability to achieve adequate nutritional support enterally. There were 11 complications noted in ten patients, including one episode of aspiration pneumonia. The presence of complications was not related to age, gender, admitting diagnosis, infusion method or type of formula used. Duodenal intubation using conventional methods in critically ill ventilated patients is unsuccessful in most patients. Nasogastric feeding in this group of patients can be safely administered in selected instances.
• Sanchez-Forgach, E. R., Mamounas, E. P., Warneke, J., Driscoll, D., Blumenson, L. E., & Tsangaris, T. N. (1992). Factors affecting outcome in locally advanced breast cancer. Surgical oncology, 1(5), 347-55.
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  Patients presenting with locally advanced breast cancer (LABC) constitute a diverse group for which a variety of treatment modalities have been instituted. To assess which factors have a direct impact on outcome, we reviewed the medical records of 104 patients diagnosed with stage IIIA, stage IIIB and T3N0M0 breast carcinoma. When considered individually (univariate analysis), clinical stage, pathological stage, oestrogen receptor status and type of therapy were significant predictors for disease-free survival (DFS) and overall survival (OS). However, in a multivariate analysis, only clinical stage was a significant predictor for both DFS and OS, while ER status was a significant predictor for OS. There was a high degree of correlation between clinical and pathological staging. Nearly two-thirds of the patients developed a recurrence by 5 years. Loco-regional recurrence was the site of first recurrence in one-third of the patients by 5 years. The prognosis for patients presenting with LABC is poor, and they should be treated aggressively with loco-regional and systemic multimodality therapy. Although groups of patients with improved outcome could be identified by clinical or pathological staging, no group demonstrated an outcome good enough to be spared from multimodality therapy.
• Verazin, G., Warneke, J. A., Driscoll, D., Karakousis, C., & Petrelli, N. (1992). Resection of lung metastasis from soft tissue sarcomas: A multivariate analysis. Archives of Surgery, 127(12), 1407-11.
• Warneke, J., Petrelli, N., Herrera, L., & Nava, H. (1992). Accuracy of colonoscopy for the detection of colorectal polyps. Diseases of the colon and rectum, 35(10), 981-5.
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  The findings at colonoscopy were compared with the pathologic findings of the surgical specimen in 235 patients who underwent a colon resection for a primary colorectal neoplasm from January 1980 to December 1987 at Roswell Park Cancer Institute. Seven patients (3 percent) were found to have synchronous primary colon carcinomas, and 100 patients (43 percent) were found to have synchronous adenomatous polyps identified by colonoscopy and/or pathology. In patients with polyps 10 mm or greater in diameter, the findings on colonoscopy agreed with the pathology report 96 percent of the time. When polyps of all sizes were included, with many less than 5 mm in diameter, colonoscopy agreed with the pathology in 89 percent of patients. When only the area of the colon resected was used to determine the ability of colonoscopy to locate polyps, 58 percent of polyps of all sizes were located. The majority of the missed polyps were adjacent to a carcinoma. One cecal carcinoma was not seen by colonoscopy because of technical inabilities to reach the cecum. A second carcinoma (20 mm x 17 mm) was not seen at the splenic flexure.
• Rappaport, W. D., & Warneke, J. A. (1989). Subhepatic appendicitis. American family physician, 39(6), 146-8.
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  Intestinal malrotation is a developmental anomaly that occasionally causes an unusual array of symptoms in adults. The delay in diagnosis that is common in patients with malrotation frequently results in a ruptured appendix. Appendicitis should be considered when characteristic signs and symptoms are present, even if the location of abdominal pain is atypical.
• Warneke, J., Petrelli, N. J., & Herrera, L. (1989). Local recurrence after sphincter-saving resection for rectal adenocarcinoma. American journal of surgery, 158(1), 3-5.
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  Local pelvic-perineal recurrences were evaluated in 40 patients who underwent a sphincter-saving resection for rectal adenocarcinoma at Roswell Park Memorial Institute. The length of follow-up was at least 5 years or until death in all but one patient. There were 24 women and 16 men with a median age of 63 years. In 31 patients, the resection was considered to be curative and was considered palliative in the remaining 9 patients. Seven of the 31 patients (23 percent) developed a local recurrence. Two of the seven local recurrences had further resection for curative intent, with one person alive at 88 months. Margins of resection were available in 27 patients. Local recurrence occurred in 4 of 8 patients with distal margins of resection less than 2 cm and in 3 of 19 patients with margins greater than 2 cm. When the lesion was less than 10 cm from the anal verge, local recurrence was more likely to occur than at margins above this level.
• Villar, H., Warneke, J. A., Peck, M., Durie, B., & Bjelland, J. (1987). Role of surgical treatment in the management of complications of the gastrointestinal tract i patients with leukemia. Surgery, Gynecology & Obstetrics, 165(3), 217-22.
• McIntyre, JR, K., Warneke, J. A., Malone, J., & Bernhard, V. (1985). Early experience with an implantable reservoir for intravenous chemotherapy. Arizona Medicine, 42(5), 308-11.
• Putnam, C., Buckley, A., Warneke, J. A., Karrer, F., & Rhenman, B. (1984). The mechanism of hepatoprotection by epsilon aminocaproic acid and putrescine. Surgery, 96(2), 214-22.

Presentations

• Warneke, J. A. (2023, May 9). Melanoma Margins of Wide Excision. The University of Arizona - Division of Dermatology Grand Rounds. Tucson, AZ.
• Warneke, J. A. (2022, October 19). Surgical Management of Cutaneous Malignancies. The University of Arizona - Division of Dermatology Grand Rounds. Tucson, AZ.
• Warneke, J. A. (2018, February). Improving Survival for Melanoma Personalized Treatment. 40th Tucson Hospital Medical Education Program (THMEP) Winter Conference. Telluride, CO: Tucson Hospital Medical Education Program (THMEP).
• Hayman, J., Davuluri, R., & Warneke, J. A. (2016, March 1). Interstitial High-Dose Rate (HDR) Brachytherapy (BRT) Boost of Lower Extremity (LE) Sarcomas: Dosimetry Review and Toxicity Assessment. 2016 at The World Congress of Brachytherapy Conference.
• Raoof, M., Nfonsam, V. N., Warneke, J. A., & Krouse, R. S. (2015, February). Node-negative Rectal Cancer After Neoadjuvant Therapy: How Many Lymph Nodes Should Be Removed?. 10th Annual Academic Surgical Congress. San Diego, CA.
• Glazer, E., Bartels, P., Fangru, L., Morgan, S., da Silva, V., Yozwiak, M., Bartels, H., Cranmer, L., Jefferson, d. O., Alberts, D., Warneke, J. A., & Krouse, R. (2013, February). Quantitative histopathology identifies patients with thin melanomas who are at risk for metastases. Portions of this research were presented at the 2013 Academic Surgical Congress.
• Bermudez, Y., Stratton, S., Bowden, G., Dong, Z., Bode, A., & Warneke, J. A. (2011, April 2-6). Expression profile of phosphorylated proteins from the mTOR and Fyn/RSK2 signaling pathways in solar UV-induced skin carcinogenesis. American Association for Cancer Research 102nd Annual Meeting. Orlando, FL.
• Bermudez, Y., Stratton, S., Bowden, G., Dong, Z., Bode, A., Warneke, J. A., & Curiel-Lewandrowski, C. (2011, May). Crosstalk between UV-induced PI-3 kinase/Akt/mTOR and Fyn/RSK2 signaling pathways: implications in skin carcinogenesis. Society of Investigational Dermatology (SID) Annual Meeting, Phoenix, AZ. Phoenix, AZ.
• Walk, N., & Warneke, J. A. (2011, April). Soft Tissue Zebra: A Case Report of an Extraintestinal Malt Lymphoma. Sourthwestern Surgical Congress. Ko Olina, HI: Sourthwestern Surgical Congress.
• Walling, E., & Warneke, J. A. (2002, April). Should Regression be a Predictive Factor in Deciding Whether Sentinel Lymph Node Biopsy Should be Done with Thin Melanomas. 54th Annual Meeting Southwest Surgical Congress. Coronado, CA: Southwest Surgical Congress.

Poster Presentations

• Gimber, L. H., Oats, S., MacKinnon, L., Taljanovic, M., Warneke, J. A., Seidel, M., & Fayad, L. (2018, March). The postoperative MRI: Is it tumor recurrence or nodular scar?. Society of Skeletal Radiology Annual Meeting. Austin, TX: SSR.
• Einspahr, J., Ranger-Moore, J., Warneke, J. A., Saboda, K., & Bozzo, P. (2005, April). Reproducibility and expression of skin biomarkers in sun-damaged skin. 96th Annual Meeting of the American Association for Cancer Research. Anaheim, CA: American Association for Cancer Research.

Others

• Warneke, J. A., & Raoof, M. (2016, January). Node-negative Rectal Cancer after neoadjuvant therapy: How many Lymph Nodes should be evaluated?.
• Ho, A., & Warneke, J. A. (2013, April 4). Importance of sampling nodes with lower radioactive counts in selective sentinel lymph node dissection for melanoma and the role of lymphoscintigraphy.
• Kang, P., Cranmer, L., Baker, A., Warneke, J. A., Hersh, E., Jeter, J., & Curiel, C. (2013, March 28). Relationship of bleeding to pathologic ulceration in a primary melanoma lesion. American Society of Clinical Oncology.
• Einspahr, J. G., Calvert, V., Alberts, D. S., Curiel-Lewandrowski, C., Warneke, J., Krouse, R., Stratton, S. P., Liotta, L., Longo, C., Pellacani, G., Pellicani, G., Prasad, A., Sagerman, P., Bermudez, Y., Deng, J., Bowden, G. T., & Petricoin, E. F. (2012, March). Functional protein pathway activation mapping of the progression of normal skin to squamous cell carcinoma. Cancer prevention research.
  More info

  Reverse phase protein microarray analysis was used to identify cell signaling derangements in squamous cell carcinoma (SCC) compared with actinic keratosis (AK) and upper inner arm (UIA). We analyzed two independent tissue sets with isolation and enrichment of epithelial cells by laser capture microdissection. Set 1 served as a pilot and a means to identify protein pathway activation alterations that could be further validated in a second independent set. Set 1 was comprised of 4 AK, 13 SCC, and 20 UIA. Set 2 included 15 AK, 9 SCCs, and 20 UIAs. Activation of 51 signaling proteins, known to be involved in tumorigenesis, were assessed for set 1 and showed that the MEK-ERK [mitogen-activated protein (MAP)/extracellular signal-regulated (ERK; MEK)] pathway was activated in SCC compared with AK and UIA, and that epidermal growth factor receptor (EGFR) and mTOR pathways were aberrantly activated in SCC. Unsupervised two-way hierarchical clustering revealed that AK and UIA shared a common signaling network activation architecture while SCC was dramatically different. Statistical analysis found that prosurvival signaling through phosphorylation of ASK and 4EBP1 as well as increased Bax and Bak expression was higher in AK compared with UIA. We expanded pathway network activation mapping in set 2 to 101 key signaling proteins, which corroborated activation of MEK-ERK, EGFR, and mTOR pathways through discovery of a number of upstream and downstream signaling molecules within these pathways to conclude that SCC is indeed a pathway activation-driven disease. Pathway activation mapping of SCC compared with AK revealed several interconnected networks that could be targeted with drug therapy for potential chemoprevention and therapeutic applications.
• Einspahr, J., Stratton, S., McKenzie, N., Alberts, D., & Warneke, J. A. (2007, April). Cross-validation of UVB signal transduction pathways in human skin. Proceedings of the American Association for Cancer Research, Los Angeles, CA.
• Herbst, A., Warneke, J. A., & Villar, H. (2006, April). Pancreatic Metastases From Renal Cell Carcinoma. 8th Annual Meeting The Southwestern Surgical Congress, Kauai, HI.
• Smith, A., Tynan-Cruisnier, G., & Warneke, J. A. (2006, April). Angiosarcoma of the Breast in the Absence of Lymphedema. 58th Annual Meeting Southwest Surgical Congress, Kauai, HI.
• Tynan-Cuisinier, G., Schwartz, S., Smith, A., O'Brien, M., & Warneke, J. A. (2006, April). Management of Bleeding Peristomal Varices. 58th Annual Meeting The Southwestern Surgical Congress.
• Holubec, H., Payne, C., Bernstein, H., & Warneke, J. A. (2003, July). Assessment of Apoptosis Markers in Bile Salt—Stressed Flat Colonic Mucosa of Patients with and without Colon Cancer. 94th Annual Meeting of the American Association for Cancer Research, Washington, DC.
• Holubec, H., Bernstein, H., Bernstein, C., Payne, C., & Warneke, J. A. (2000, April). Flat Colonic Mucosa of Colon Cancer Patients have Field Defects Characterized by Dedifferentiation. 91st Annual Meeting of the American Association for Cancer Research.
• Einspahar, J., Alberts, D., Warneke, J. A., Bozzo, P., & Basye, J. (1999, April). Relationship between p53 mutation, expression, and apoptosis in UV-induced human skin carcinogenesis. Proceedings of the American Cancer Center Research.
• Holubec, H., Payne, C., Bernstein, C., Warneke, J. A., & Garewal, H. (1999, July). Evaluation of the frequency of aberrant crypts and apoptosis resistance in flat colonic mucosa of patients in different risk groups. Proceedings of the American Cancer Center Research.
• Wiese, F., Einspahr, J., Warneke, J. A., Snead, G., & Martinez, E. (1999, September). Variation in Cox-2 expression levels in colorectal tumors by subsite of origin. Proceedings of the American Association for Cancer Research.
• Xu, M., Peng, Y., Goldman, R., Warneke, J. A., & Dorr, R. (1999, April). Photoprotective effect of atocopherol on polyamine metabolism in human skin. American Association for Cancer Research.
• Einspahr, J., Alberts, D., Warneke, J. A., Hart, N., & Bozzo, P. (1997, May). P53, BCL-2 and Apoptosis as Useful Surrogate Endpoint Biomarkers (SEBs) in Human Skin Carcinogenesis. Proceedings of the American Association for Cancer Research.
• O'Neil, P., Hersh, E., McNeil, W., Thomas, T., Leong, S., & Warneke, J. A. (1997, May). Adjuvant therapy of AJCC stages I-III malignant melanoma free of disease after surgery. Proceedings of the American Society of Clinical Oncologists.
• Warneke, J. A., Berger, R., & Villar, H. (1997, March). Breast Conservation for Invasive Lobular Carcinoma. Society of Surgical Oncology 50th Meeting.
• Xu, X., Einspahr, J., Nelson, M., Warneke, J. A., & Alberts, D. (1997, June). Differential Expression of Retinoic Acid Receptor B in Actinic Keratosis, Adjacent Skin and Non Sun-Exposed Skin. American Association for Cancer Research.
• Alberts, D., Warneke, J. A., Dorr, R., Aickin, M., Quinn, J., & Goldman, R. (1996, June). Positive Randomized, Double Blinded, Placebo Controlled Study of Topical Difluoromethylornithine (DFMO) in the Chemoprevention of Skin Cancer. Proceedings of American Society of Clinical Oncologists.
• Hersh, E., Stopeck, A., Harris, D., Akporiaye, E., Warneke, J. A., & Schluter, S. (1996, July). Long-Term Follow-Up and Retreatment Studies on Patients with Metastatic Malignant Melanoma (MM) Treated in a Phase I/II Study of Direct Intratumoral Injection of the HLA-B7/2M Gene (Allovectin-7) in a Cationic Lipid Vector;. Proceedings of the American Society of Clinical Oncologists.
• Hersh, E., Stopeck, A., Warneke, J. A., Brailey, J., & Parker, S. (1996, May). Transfection (T) of tumor cell lines (TCL) and fresh tumor cells (FTC) with plasmid DNA/cationic lipid complexes. Proceedings of the American Association for Cancer Research.
• Stopeck, A., Hersh, E., Warneke, J. A., Unger, E., & Rinehart, J. (1996, May). Results of a Phase I Study of Direct Gene Transfer of Interleukin-2 (IL-2) Formulated with Cationic Lipid Vector, Leuvectin, in Patients with Metastatic Solid Tumors. Proceedings of American Society of Clinical Oncologists.
• Warneke, J. A., Powell, M., Valdivia, L., Salvatore, J., & Kramer, T. (1996, June). Histopathology and Immunology of Pigmented Intraocular Tumors in Transgenic Mice. Proceedings of the American Association for Cancer Research.
• Stopeck, A. T., Hersh, E. M., Akporiaye, E., Grogan, T., Harris, D. T., Unger, E. C., Warneke, J. A., & Kradjian, S. A. (1995, October). Phase I study of immunotherapy of malignant melanoma by direct gene transfer of an allogeneic histocompatibility antigen, HLA-B7. Proceedings of American Society of Clinical Oncologists.
• Stopeck, A., Hersh, E., Akpriaye, E., Grogan, T., Harris, D., & Warneke, J. A. (1995, May). Gene Therapy of Malignant Melanoma (MM) by the Direct Intratumoral Injection of the HLA-B7 Gene in a Cationic Lipid Vector. Society for Biological Therapy.
• Karakousis, C., Warneke, J. A., & Vellez, A. (1990, May). Reconstruction of Abdominal or Chest Wall in Cancer Ablative Surgery. American College of Surgeons 76th Annual Clinical Congress.
• Warneke, J. A., Petrelli, N., Herrera, L., & Nava, H. (1990, May). The Accuracy of Colonoscopy for the Detection of Colorectal Polyps. Proceedings of the Society of Surgical Oncology.