Abstract 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. Cancer Prev Res; 8(8); 720–8. ©2015 AACR.

Perspective on this Article from A Phase 2a Study of Topical Perillyl Alcohol Cream for Chemoprevention of Skin Cancer

Supplementary Figure Legends from Activation of the PI3K/Akt/mTOR and MAPK Signaling Pathways in Response to Acute Solar-Simulated Light Exposure of Human Skin

Supplementary Figure 1. Box plot graphs of protein expression in sun-protected skin after 2, 2,5, and 3 MED (x-axis) of SSL-irradiation (SSL) with baseline (green bars), 5 minutes (orange bars), 1 hour (blue bars), 5 hours (red bars), and 24 hours (grey bars) post SSL on the y-axis. Supplementary Figure 2. Box plot graphs of protein expression in sun-protected skin after 2, 2,5, and 3 MED (x-axis) of SSL-irradiation (SSL) with baseline (green bars), 5 minutes (orange bars), 1 hour (blue bars), 5 hours (red bars), and 24 hours (grey bars) post SSL on the y-axis. Supplementary Figure 3. Box plot graphs of protein expression in sun-protected skin after 2, 2,5, and 3 MED (x-axis) of SSL-irradiation (SSL) with baseline (green bars), 5 minutes (orange bars), 1 hour (blue bars), 5 hours (red bars), and 24 hours (grey bars) post SSL on the y-axis.

Schema representing UV-induced signaling, rapamycin and PHT-427-regulated pathways in keratinocytes.

Supplementary Figure S1 from Loss of Inositol Polyphosphate 5-Phosphatase Is an Early Event in Development of Cutaneous Squamous Cell Carcinoma

Solar ultraviolet (sUV) irradiation is a major environmental carcinogen that can cause inflammation and skin cancer. The costs and morbidity associated with skin cancer are increasing, and therefore identifying molecules that can help prevent skin carcinogenesis is important. In this study, we identified the p53-related protein kinase (PRPK) as a novel oncogenic protein that is phosphorylated by the T-LAK cell-originated protein kinase (TOPK). Knockdown of TOPK inhibited PRPK phosphorylation and conferred resistance to solar-simulated light (SSL)-induced skin carcinogenesis in mouse models. In the clinic, acute SSL irradiation significantly increased epidermal thickness as well as total protein and phosphorylation levels of TOPK and PRPK in human skin tissues. We identified two PRPK inhibitors, FDA-approved rocuronium bromide (Zemuron®) or betamethasone 17-valerate (Betaderm®) that could attenuate TOPK-dependent PRPK signaling. Importantly, topical application of either rocuronium bromide or betamethasone decreased SSL-induced epidermal hyperplasia, neovascularization, and cutaneous squamous cell carcinoma (cSCC) development in SKH1 (Crl: SKH1-Hrhr) hairless mice by inhibiting PRPK activation, and also reduced expression of the proliferation and oncogenesis markers, COX-2, cyclin D1, and MMP-9. This study is the first to demonstrate that targeting PRPK could be useful against sUV-induced cSCC development.

Abstract Cutaneous squamous cell carcinoma (cuSCC) is the second most common skin cancer, for which long term UV exposure and chronic wounding are the dominant risk factors. Despite these clinically established connections, little is understood about the early molecular response of human skin to UV exposure and its connection to acute wounding and cuSCC. Thus, our goal is to find common and specific signatures driven by UV-exposure and wounding as a means of developing new approaches for treating and preventing cuSCC. Here, we perform integrated analyses of proteomic, RNA-seq and miR-seq on 3 datasets: (1) UV-unexposed and acute UV-exposed human skin, (2) public dataset on acute wound healing and (3) our previously published dataset on normal skin and cuSCC from humans. We find that biological signatures and processes regulated by acute UV exposure and wounding has profound similarity. miR-seq data shows that miR-223, miR-132 and miR-142 are significantly upregulated in both acute events. Combined gene set enrichment analysis shows that G-protein-coupled-receptors (GPCRs) pathways are upregulated, possibly through Gαi activation. While ECM remodeling is significantly enriched in all three datasets, gene expression regulated by PPARα is suppressed. Interestingly, upregulation of matrisome components is observed among all three datasets. This suggests that these changes are important early events that regulated by both UV-exposure and wounding which eventually can promote cuSCC initiation. Thus, our findings suggest that these common signatures can be potentially validated as chemopreventive targets for cuSCC. Citation Format: Tran N. Nguyen, Kimal Rajapakshe, Stanislav Avdieiev, Courtney Nicholas, Vida Chitsazzadeh, Eric Welsh, Bin Fang, John Koomen, Cristian Coarfa, Janine Einspahr, Kenneth Y. Tsai. A proteome-transcriptome-miRnome integrated analysis identifies similarity between UV-exposed skin and wounding skin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 406.

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.

of bone morphogenetic protein receptor 2 promoter is an important mechanism of the penetrance in heritable pulmonary arterial hypertension patients [abstract]. Am J Respir Crit Care Med 2014; 189:A3639. 7. Hamid R, Cogan JD, Hedges LK, Austin E, Phillips JA III, Newman JH, Loyd JE. Penetrance of pulmonary arterial hypertension is modulated by the expression of normal BMPR2 allele. Hum Mutat 2009;30: 649–654. 8. Killen SA, Kunic J, Wang L, Lewis A, Levy BP, Ackerman MJ, George AL Jr. SCN5A allelic expression imbalance in African-Americans heterozygous for the common variant p.Ser1103Tyr. BMC Med Genet 2010;11:74. 9. Voutsinas GE, Stavrou EF, Karousos G, Dasoula A, Papachatzopoulou A, Syrrou M, Verkerk AJ, van der Spek P, Patrinos GP, Stöger R, et al. Allelic imbalance of expression and epigenetic regulation within the alpha-synuclein wild-type and p.Ala53Thr alleles in Parkinson disease. Hum Mutat 2010;31: 685–691. 10. Sa S, Gu M, Chappell J, Shao NY, Ameen M, Elliott KA, Li D, Grubert F, Li CG, Taylor S, et al. iPSC model of pulmonary arterial hypertension reveals novel gene expression and patient specificity. Am J Respir Crit Care Med 2017;195:930–941.

Ultraviolet radiation is an important etiologic factor in skin cancer and there is a need to better understand how solar light affects signal transduction pathways in human skin after both acute doses of SSL and chronic exposure. We previously evaluated activation of proteins within PI3K and MAPK pathways by IHC in sun-protected skin after acute solar simulated light (SSL) (Cancer Prev Res 2015 8:720-728). We next evaluated proteins by IHC in buttock skin and in skin with varying degrees of solar damage and matched actinic keratosis (AK). Data are presented as % positive area ± standard deviation and sample number (N) with the goal of 50/group. IHC for Akt (S473) was 4.5% ± 4.3 (N=27), 9.4% ± 7.0 (N=19), 5.0% ± 6.0 (N=35). mTOR (S2448) was 1.8% ± 3.3 (N=25), 2.9% ± 3.4 (N=18), 15.4% ± 13.5 (N=34). p-S6 (Ser389) was 6.0% ± 4.5 (N=24), 19.8% ± 13.2 (N=21), 45.7% ± 12.6 (N=33). p-4EBP1 (Thr37/46) was 3.5% ± 4.2 (N=24), 46.9% ± 20.9 (N=20), 52.51% ± 9.1 (N=34). PCNA was 7.9% ± 3.7 (N=25), 12.9% ± 4.0 (N=18), 26.8% ± 9.7 (N=34) for normal skin, sun damaged skin, and AK. Because skin is exposed daily to low dose UV, the investigation of signaling pathway alterations that result from acute exposures of normal skin may have significance to skin carcinogenesis. Although chronic exposure is necessary to acquire the critical combination of gene mutations and altered cell signaling in skin for the development of UV-induced SCC, we propose that the study of acute effects of UV may serve as a model for investigation of the effects of SSL on this complex array of signal transduction pathways that are also likely involved in UV-induced carcinogenesis. Here we demonstrate increased expression for p-mTOR, p-S6, p-4EBP1, and PCNA in skin with evidence of increasing sun damage.

Abstract The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced nonmelanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared with those that receive traditional immunosuppression. However, systemic rapamycin use can lead to significant adverse events. Here, we explored the use of topical rapamycin as a chemopreventive agent in the context of solar-simulated light (SSL)-induced skin carcinogenesis. In SKH-1 mice, topical rapamycin treatment decreased tumor yields when applied after completion of 15 weeks of SSL exposure compared with controls. However, applying rapamycin during SSL exposure for 15 weeks, and continuing for 10 weeks after UV treatment, increased tumor yields. We also examined whether a combinatorial approach might result in more significant tumor suppression by rapamycin. We validated that rapamycin causes increased Akt (S473) phosphorylation in the epidermis after SSL, and show for the first time that this dysregulation can be inhibited in vivo by a selective PDK1/Akt inhibitor, PHT-427. Combining rapamycin with PHT-427 on tumor prone skin additively caused a significant reduction of tumor multiplicity compared with vehicle controls. Our findings indicate that patients taking rapamycin should avoid sun exposure, and that combining topical mTOR inhibitors and Akt inhibitors may be a viable chemoprevention option for individuals at high risk for cutaneous SCC. Cancer Prev Res; 9(3); 215–24. ©2016 AACR.

Cutaneous exposure to solar ultraviolet (UV) radiation is a major causative factor in skin carcinogenesis, and improved molecular strategies for efficacious chemoprevention of nonmelanoma skin cancer (NMSC) are urgently needed. Toll‐like receptor 4 (TLR4) signaling has been shown to drive skin inflammation, photoimmunosuppression, and chemical carcinogenesis. Here we have examined the feasibility of genetic and pharmacological antagonism targeting cutaneous TLR4 for the suppression of UV‐induced NF‐κB and AP‐1 signaling in keratinocytes and mouse skin. Using immunohistochemical and proteomic microarray analysis of human skin, we demonstrate for the first time that a significant increase in expression of TLR4 occurs in keratinocytes during the progression from normal skin to actinic keratosis, also detectible during further progression to squamous cell carcinoma. Next, we demonstrate that siRNA‐based genetic TLR4 inhibition blocks UV‐induced stress signaling in cultured keratinocytes. Importantly, we observed that resatorvid (TAK‐242), a molecularly targeted clinical TLR4 antagonist, blocks UV‐induced NF‐κB and MAP kinase/AP‐1 activity and cytokine expression (Il‐6, Il‐8, and Il‐10) in cultured keratinocytes and in topically treated murine skin. Taken together, our data reveal that pharmacological TLR4 antagonism can suppress UV‐induced cutaneous signaling, and future experiments will explore the potential of TLR4‐directed strategies for prevention of NMSC.

Cutaneous exposure to solar ultraviolet (UV) radiation is a major causative factor in skin carcinogenesis, and improved molecular strategies for efficacious chemoprevention of non-melanoma skin cancer are urgently needed. Inflammatory signaling through TLR4 (Toll-like receptor 4) has been shown to drive skin inflammation, photoimmunosuppression and chemical carcinogenesis. Here we test the hypothesis that TLR4 is a major mediator and therapeutic target in skin photocarcinogenesis. In human skin, TLR4 is strongly expressed in the basal layer of normal epidermis and tissue microarray staining indicates that expression is significantly upregulated in cutaneous squamous cell carcinomas (p<0.05). In vitro results indicate that TLR4 strongly contributes to UV-induced cell responses which regulate proliferation, apoptosis and inflammation. Inhibition of TLR4 signaling in HaCaT keratinocytes using three different agents - resatorvid (TAK-242), ST-2824 and carbenoxolone – all significantly blocked UV-induced AP-1 luciferase reporter activity compared to vehicle control. This inhibition was reproduced using NFκB luciferase assays with resatorvid in mouse keratinocytes. Inhibition of TLR4 transcript levels using two different siRNAs also resulted in significantly reduced NFκB signaling after UV treatment. Western blots using lysates from primary keratinocytes in culture and from mouse skin both indicate that treatment with resatorvid dramatically blocks UV-induced phosphorylation of p38 and NFκB (p65). UV-dependent upregulation of the mRNA of cytokines such as Il-6, Il-8 (primary keratinocytes) and Il-10 (in vivo epidermis) are significantly blocked in the presence of resatorvid. We conclude that TLR4 is an active contributor to UV-induced tumorigenic signaling in the skin, and we are carrying forward studies testing resatorvid as a chemopreventive agent in mouse studies.

Prevention of nonmelanoma skin cancers remains a health priority due to high costs associated with this disease. Diclofenac and difluoromethylornithine (DFMO) have demonstrated chemopreventive 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 the 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 with 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 chemopreventive effects. More significant effects may be observed in subjects with greater baseline cutaneous damage. Cancer Prev Res; 9(2); 128–34. ©2015 AACR. See related article by Tsai and Hawk, p. 125

Laboratory studies suggest that vitamin D (VD) supplementation inhibits skin carcinogenesis. However, epidemiologic studies report mixed findings in the association between circulating VD levels and skin cancer risk. We conducted a clinical study to determine whether oral cholecalciferol supplementation would exert direct bioactivity in human skin through modulation of the VD receptor (VDR). We enrolled 25 individuals with serum 25-hydroxyvitamin-D levels <30 ng/mL and with skin photodamage to take 50,000 IU of cholecalciferol biweekly for 8 to 9 weeks. Then, we obtained baseline and end-of-study skin biopsies from photodamaged (PD) and photoprotected (PP) skin, and from benign nevi (BN) and tested for mRNA expression of VDR and cytochrome P450-24 (CYP24), and markers of keratinocytic differentiation. High-dose cholecalciferol supplementation significantly elevated circulating levels of 25-hydroxyvitamin-D (P < 0.0001) and 1,25-dihydroxyvitamin-D (P < 0.0001). VDR expression in PD- and PP-skin showed minimum changes after supplementation. CYP24 expression in PD- and PP-skin was increased after supplementation by 186%, P = 0.08, and 134%, P = 0.07, respectively. In BNs from 11 participants, a trend for higher VDR and CYP24 expression was observed (average of 20%, P = 0.08, and 544%, P = 0.09, respectively). Caspase-14 expression at the basal layer in PD skin samples was the only epidermal differentiation marker that was significantly increased (49%, P < 0.0001). High-dose cholecalciferol supplementation raised serum VD metabolite levels concurrently with CYP24 mRNA and caspase-14 levels in the skin. Our findings of significant variability in the range of VDR and CYP24 expression across study samples represent an important consideration in studies evaluating the role of VD as a skin cancer chemopreventive agent. Cancer Prev Res; 8(6); 563–9. ©2015 AACR.

OBJECTIVE:To develop a quantitative histopathology algorithm to predict which patients with cutaneous squamous cell carcinoma (cSCC) were likely to experience recurrence or metastases.STUDY DESIGN:This retrospective study of cSCC lesions compared patients with aggressive disease (n = 40) and those with nonaggressive disease (n = 35). Based on a previous study using nuclear karyometry, we determined that aggressive lesions had a high proportion of a specific nuclear phenotype. The proportion of those nuclei was used to derive an aggressiveness score for each lesion. The mean age of patients was similar in both groups, as were the locations of index lesions.RESULTS:The mean aggressiveness scorefor cases with aggressive lesions was 0.60 ± 0.21 and was 0.28 ± 0.35 for those with nonaggressive lesions. The overall accuracy in properly characterizing lesions was 72%. The area under the receiver operating characteristic curve was 0.80 ± 0.05. In general, the aggressive nuclear phenotype is represented by elevated levels of chromatin clumps and short linear segments of dark chromatin/intense pixels.CONCLUSION:These data suggest that discriminant functions may be utilized to distinguish between aggressive and nonaggressive lesions at the time of diagnosis.

Solar ultraviolet irradiation is an environmental carcinogen that causes skin cancer. Caspase-7 is reportedly expressed at reduced levels in many cancers. The present study was designed to examine the role of caspase-7 in solar-simulated light (SSL)-induced skin cancer and to elucidate its underlying molecular mechanisms. Our study revealed that mice with genetic deficiency of caspase-7 are highly susceptible to SSL-induced skin carcinogenesis. Epidermal hyperplasia, tumor volume and the average number of tumors were significantly increased in caspase-7 knockout (KO) mice compared with SKH1 wild-type mice irradiated with SSL. The expression of cell proliferation markers, such as survivin and Ki-67, was elevated in SSL-irradiated skin of caspase-7 KO mice compared with those observed in SSL-exposed wild-type SKH1 mouse skin. Moreover, SSL-induced apoptosis was abolished in skin from caspase-7 KO mice. Two-dimensional gel electrophoresis, followed by matrix-assisted laser desorption/ionization-time-of-flight analysis of skin tissue lysates from SSL-irradiated SKH1 wild-type and caspase-7 KO mice revealed an aberrant induction of keratin-17 in caspase-7 KO mice. Immunohistochemical analysis of skin tumors also showed an increase of keratin-17 expression in caspase-7 KO mice compared with SKH1 wild-type mice. The expression of keratin-17 was also elevated in SSL-irradiated caspase-7 KO keratinocytes as well as in human basal cell carcinomas. The in vitro caspase activity assay showed keratin-17 as a substrate of caspase-7, but not caspase-3. Overall, our study demonstrates that genetic loss of caspase-7 promotes SSL-induced skin carcinogenesis by blocking caspase-7-mediated cleavage of keratin-17.

Abstract Experimental studies suggest that vitamin D (VD) plays an important role in skin carcinogenesis. In humans, epidemiologic studies have reported mixed findings in the association between circulating vitamin D levels and skin cancer risk. We conducted a pilot clinical study to determine whether oral VD supplementation would exert any bioactivity in human skin. Methods: The study accrued twenty-five healthy individuals with serum 25-hydroxyvitamin D levels <30 ng/mL and with moderate to severe photodamage on the forearms. Participants took 50,000 IU of VD3 capsules twice a week for 8-9 weeks. Baseline and end-of study skin biopsies were obtained from photodamaged (PD) and photoprotected (PP) skin, and benign nevi (BN), when available, for assessment of changes in putative biomarkers of VD activity. Biomarkers evaluated include the mRNA expression of vitamin D receptor (VDR) and cytochrome P450 24 (CYP24) in keratinocytes and available BN. In addition, molecular markers of keratinocytic differentiation (caspase 14 and loricrin protein expression), epidermal thickness, serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were assessed. Results: High dose VD supplementation significantly elevated the circulating levels of 25-hydroxyvitamin D from 21.6 ± 5.2 to 70.5 ± 18.2 ng/mL (p < 0.0001) and 1,25-dihydroxyvitamin D from 31.1 ± 12.4 to 51.4 ± 13.5 pg/mL (p < 0.0001). VDR expression in PD- and PP-skin showed minimum changes after VD supplementation. CYP24 expression in PD- and PP-skin showed a non-statistically significant increase after VD supplementation (average of 186% increase, p = 0.08, and 134% increase, p=0.07, respectively). Higher VDR and CYP24 expression was observed in BNs collected at post-intervention than that at baseline from eleven participants, but the difference did not reach statistical significance (average of 20% higher, p = 0.08, and 544% higher, p= 0.09, respectively). The large inter-subject variation in VDR and CYP24 expression may have limited the statistical evaluation. The epidermal differentiation markers did not change significantly after VD supplementation with the exception of a 49% increase (p< 0.0001) in caspase 14 expression at the basal layer in PD skin samples. When epidermal thickness was analyzed, the only significant change was identified when the analysis was stratified by the baseline median thickness. Samples with baseline thickness below or equal to the median exhibited a significant increase in thickness at the end of the intervention. Conclusion: The study showed that following effective oral supplementation based on VD serum levels, subtle indicators of increased keratinocytic differentiation and CYP24 activation can be observed. Future studies evaluating the role of VD as a skin cancer chemopreventive agent with biomarker modulation as an endpoint should be considered before larger intervention studies are implemented in at risk populations. Citation Format: Clara Curiel-Lewandrowski, Jean Tang, Janine Einspahr, Yira Bermudez, Chiu-Hsieh Hsu, Melika Rezaee, Alex Lee, Joe Tangrea, Howard Parnes, David Alberts, H-H. Sherry Chow. Pilot study on the bioactivity of vitamin D in the skin after oral supplementation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3248. doi:10.1158/1538-7445.AM2014-3248