387 results on '"DiGiovanni J"'
Search Results
2. Constitutive activation and targeted disruption of signal transducer and activator of transcription 3 (Stat3) in mouse epidermis reveal its critical role in UVB-induced skin carcinogenesis
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Kim, D J, Angel, J M, Sano, S, and DiGiovanni, J
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- 2009
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3. Forced expression of a constitutively active form of Stat3 in mouse epidermis enhances malignant progression of skin tumors induced by two-stage carcinogenesis
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Chan, K S, Sano, S, Kataoka, K, Abel, E, Carbajal, S, Beltran, L, Clifford, J, Peavey, M, Shen, J, and DiGiovanni, J
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- 2008
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4. Sulforaphane induces phase II detoxication enzymes in mouse skin and prevents mutagenesis induced by a mustard gas analog
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Abel, E. L., Boulware, S., Fields, T., McIvor, E., Powell, K. L., DiGiovanni, J., Vasquez, K. M., and MacLeod, M. C.
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- 2013
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5. 7.15 - Genetic Determinants of Cancer Susceptibility
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Angel, J.M. and DiGiovanni, J.
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- 2018
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6. Loggerhead turtle Caretta caretta density and abundance in Chesapeake Bay and the temperate ocean waters of the southern portion of the Mid-Atlantic Bight
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Barco, SG, Burt, ML, DiGiovanni Jr, RA, Swingle, WM, and Williard, AS
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Zoology ,QL1-991 ,Botany ,QK1-989 - Abstract
We conducted aerial surveys of sea turtles in 2011 and 2012, incorporating corrections for perception and availability bias in Chesapeake Bay and near-shore continental shelf waters of the Mid-Atlantic Bight off the US states of Virginia and Maryland. Results of these surveys and ancillary research to determine surface times for loggerhead turtles provide us with a new baseline population estimate for turtles in the region. Prior surveys were conducted in Chesapeake Bay in the mid-1980s and early 2000s, and in ocean waters in the late 1970s and early 1980s. Although comparison of density estimates not corrected for availability between prior surveys and this effort suggests that the population of sea turtles, especially loggerhead turtles, is higher than previous estimates, differences between surveys may be the result of survey methodologies and cannot be assumed to be true changes in density. Surface time for availability corrections was calculated using dive summaries from satellite telemetry on 27 loggerhead turtles tracked between 2011 and 2015. We calculated stratified seasonal availability corrections for bay and ocean waters based on assumed differences in turtle behavior and water clarity between the 2 habitats. For each habitat, we provided seasonal corrections for 3 detection depth bins (shallow, moderate, and deep) to account for differences in sub-surface detection ranges. Differences and trends toward differences among availability corrections underscore the need to better understand the many variables that affect surface time for sea turtles in temperate waters, and the effect that availability has on abundance and density estimates.
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- 2018
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7. Genetics of Skin Tumor Promotion.
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Angel, J.M. and DiGiovanni, J.
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- 1999
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8. Lack of effect of a 60 Hz magnetic field on biomarkers of tumor promotion in the skin of SENCAR mice.
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DiGiovanni, J, Johnston, DA, Rupp, T, Sasser, LB, Anderson, LE, Morris, JE, Miller, DL, Kavet, R, and Walborg, EF
- Abstract
It has been proposed that extremely low frequency magnetic fields may enhance tumorigenesis through a co-promotional mechanism. This hypothesis has been further tested using the two-stage model of mouse skin carcinogenesis, i.e. 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced promotion of skin carcinogenesis in mice initiated by a single subcarcinogenic dose of 7,12-dimethylbenz[a]anthracene. Experimentation utilized three different doses of TPA within its dose-response range (0.85, 1.70 or 3.40 nmol) and examined the following early biomarkers of tumor promotion after 1, 2 and 5 weeks of promotion: increases in epidermal thickness and the labeling index of epidermal cells, induction of epidermal ornithine decarboxylase activity and down-regulation of epidermal protein kinase C activity. Mice exposed to a 60 Hz magnetic field having a flux density of 2 mT for 6 h/day for 5 days/week were compared with mice exposed to an ambient magnetic field. Within the sensitivity limits of the biomarker methodology and the exposure parameters employed, no consistent, statistically significant effects indicative of promotion or co-promotion by the magnetic field were demonstrated. [ABSTRACT FROM PUBLISHER]
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- 1999
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9. Mechanism-based cancer prevention approaches: targets, examples, and the use of transgenic mice.
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Hursting, Stephen D., Slaga, Thomas J., Fischer, Susan M., DiGiovanni,, John, Phang, James M., Hursting, S D, Slaga, T J, Fischer, S M, DiGiovanni, J, and Phang, J M
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CHEMICAL carcinogenesis ,CANCER prevention - Abstract
Humans are exposed to a wide variety of carcinogenic insults, including endogenous and man-made chemicals, radiation, physical agents, and viruses. The ultimate goal of carcinogenesis research is to elucidate the processes involved in the induction of human cancer so that interventions may be developed to prevent the disease, either in the general population or in susceptible subpopulations. Progress to date in the carcinogenesis field, particularly regarding the mechanisms of chemically induced cancer, has revealed several points along the carcinogenesis pathway that may be amenable to mechanism-based prevention strategies. The purpose of this review is to examine the basic mechanisms and stages of chemical carcinogenesis, with an emphasis on ways in which preventive interventions can modify those processes. Possible ways of interfering with tumor initiation events include the following: i) modifying carcinogen activation by inhibiting enzymes responsible for that activation or by direct scavenging of DNA-reactive electrophiles and free radicals; ii) enhancing carcinogen detoxification processes by altering the activity of the detoxifying enzymes; and iii) modulating certain DNA repair processes. Possible ways of blocking the processes involved in the promotion and progression stages of carcinogenesis include the following: i) scavenging of reactive oxygen species; ii) altering the expression of genes involved in cell signaling, particularly those regulating cell proliferation, apoptosis, and differentiation; and iii) decreasing inflammation. In addition, the utility for mechanism-based cancer prevention research of new animal models that are based on the overexpression or inactivation of specific cancer-related genes is examined. [ABSTRACT FROM AUTHOR]
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- 1999
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10. Lack of a co-promoting effect of a 60 Hz magnetic field on skin tumorigenesis in SENCAR mice.
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Sasser, LB, Anderson, LE, Morris, JE, Miller, DL, Walborg, EF, Kavet, R, Johnston, DA, and DiGiovanni, J
- Abstract
It has been proposed that extremely low frequency (ELF) magnetic fields may enhance tumorigenesis through a co-promotional mechanism. This hypothesis has been further tested using the two-stage model of mouse skin carcinogenesis, i.e. 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced promotion of skin tumors in mice initiated by a single subcarcinogenic dose of 7,12-dimethylbenz[a]anthracene. Experimentation described herein utilized the SENCAR mouse and examined the effect of a magnetic field on skin tumor promotion induced by three different doses of TPA within its dose-response range, i.e. 0.85, 1.70 or 3.40 nmol, administered twice per week. SENCAR mice (56/treatment group) were exposed to a 60 Hz magnetic field having a flux density of 2 mT for 6 h/day for 5 days/week and compared with mice exposed to the ambient magnetic field. Tumor incidence and multiplicity were monitored weekly for 23 weeks of TPA promotion. Statistical evaluation of the effects of the magnetic field on tumor incidence and multiplicity did not reveal any statistically significant effects; thus, within the sensitivity limits imposed by the animal model and the exposure parameters employed, no promotional or co-promotional effect of a 2 mT magnetic field on skin tumor development in SENCAR mice could be demonstrated. [ABSTRACT FROM PUBLISHER]
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- 1998
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11. Papillomas at high risk for malignant progression arising both early and late during two-stage carcinogenesis in SENCAR mice.
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DuBowski, A, Johnston, DA, Rupp, T, Beltran, L, Conti, CJ, and DiGiovanni, J
- Abstract
The current study was designed to further establish that most papillomas produced in SENCAR mice during two-stage skin carcinogenesis are, in fact, premalignant lesions and to specifically determine the malignant conversion potential of papillomas that arise at different times during the carcinogenesis process. A method was established to physically map and monitor the lifespan of all papillomas produced in SENCAR mice during the course of an initiation-promotion experiment using DMBA as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. The results from these experiments showed that in groups of mice initiated with either 0.5 or 2.0 μg DMBA, long-term (60 weeks) treatment with TPA yielded a significantly higher number of SCCs compared to short-term treatment (7 weeks). Papillomas that emerged after 11 weeks and thereafter in all treatment groups had the ability to progress to SCCs. The median conversion time for all papillomas in all groups was 26 weeks. When corrected for median conversion time, papillomas that emerged in week 11 and thereafter in all treatment groups had similar or greater conversion ratios compared to those that emerged within the first 10 weeks. Interestingly, the median conversion time was significantly shorter (18 versus 27 weeks, respectively; P <0.0002) for papillomas that emerged in week 11 and thereafter compared to those that emerged at or prior to 10 weeks for all groups. The data in this study demonstrate that papillomas arising throughout a two-stage carcinogenesis protocol in SENCAR mice progress to SCCs. Many papillomas that arise later in two-stage carcinogenesis protocols do not have sufficient time to allow for conversion and should be excluded from the analyses. Furthermore, another novel finding of the current study was the observation that papillomas arising later in the two-stage protocol (>11 weeks) progressed to SCCs at a faster rate than those that arose earliest in the protocol. [ABSTRACT FROM PUBLISHER]
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- 1998
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12. Analysis of two inbred strains of mice derived from the SENCAR stock with different susceptibility to skin tumor progression.
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Stern, MC, Gimenez-Conti, IB, Budunova, I, Coghlan, L, Fischer, SM, DiGiovanni, J, Slaga, TJ, and Conti, CJ
- Abstract
The SENCAR stock of mice has proved to be a useful model in dissecting out the multistage nature as well as the critical mechanisms involved in skin tumorigenesis. This outbred stock was selectively bred to be susceptible to initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). In order to obtain mice more suitable for genetic analyses of tumor susceptibility and tissue transplantation studies, several inbred lines of mice were derived from the SENCAR stock. One of these lines, the SSIN mice, has a higher susceptibility to tumor promotion compared to the SENCAR stock but is very resistant to tumor progression. On the other hand, the SENCAR B/Pt mice, derived also from the outbred stock, not only have a tumor promotion susceptibility almost identical to the SSIN mice, but they also have a high susceptibility to tumor progression. In order to understand the nature of the phenotypic differences between these two inbred lines we have characterized them using several parameters and markers that are associated with the progression of papillomas to squamous cell carcinoma (SCC). In this sense we analysed the tumor multiplicity and SCC incidence, and the expression of markers of progression and cell cycle related proteins in papillomas derived from both strains. Our results showed that while both strains have a similar papilloma multiplicity and incidence the SENCAR B/Pt mice have 67% incidence of SCC, compared to 0% in the SSIN. SENCAR B/Pt papillomas at 30 weeks of promotion have a higher and aberrant expression of K13, and loss of connexin 26. TGF-β1 was found to be over-expressed in the suprabasal and superficial cells in the SENCAR B/Pt papillomas, while it was only expressed in the superficial cell layer in those derived from SSIN. The SENCAR B/Pt papillomas also showed an enlarged proliferative compartment with overexpression of cyclin D1 and PCNA as seen by immunohistochemistry and Western blot. [ABSTRACT FROM PUBLISHER]
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- 1998
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13. Effect of naturally occurring coumarins on the formation of epidermal DNA adducts and skin tumors induced by benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene in SENCAR mice.
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Cai, Y, Kleiner, H, Johnston, D, Dubowski, A, Bostic, S, Ivie, W, and DiGiovanni, J
- Abstract
Several naturally occurring coumarins previously found to be potent inhibitors of mouse hepatic ethoxyresorufin-O-deethylase (EROD) and/or pentoxyresorufin-O-dealkylase (PROD) were examined for their effects on formation of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) DNA adducts in mouse epidermis, as well as, their effects on skin tumor initiation by these polycyclic aromatic hydrocarbons (PAH). Bergamottin, a potent inhibitor of hepatic EROD, given topically 5 min prior to an initiating dose of B[a]P, significantly decreased total covalent binding of B[a]P to DNA in a dose-dependent manner 24 h after treatment. A dose of 400 nmol bergamottin reduced covalent binding of B[a]P by 72%. Coriandrin, at a dose of 400 nmol also significantly reduced total covalent binding of B[a]P by 59%. In addition, formation of the major (+)anti-B[a]P-diol epoxide-N2-dGuo adduct was selectively reduced by both of these coumarins. In contrast, bergamottin and coriandrin did not significantly decrease covalent binding of DMBA to epidermal DNA at doses of either 400 nmol or 800 nmol. Imperatorin and isopimpinellin, which are more potent inhibitors of hepatic PROD activity, significantly reduced overall binding of DMBA to epidermal DNA by 67% and 52%, respectively, when applied at doses of 400 nmol. These two coumarins also inhibited B[a]P-DNA adduct formation at similar doses but to a lesser extent. Imperatorin at a dose of 400 nmol dramatically decreased formation of covalent DNA adducts derived from both the anti and syn diol epoxides of DMBA. Bergamottin was a potent inhibitor of tumor initiation by B[a]P while coriandrin was less effective in this regard. Imperatorin was an effective inhibitor of skin tumor initiation by DMBA and also inhibited complete carcinogenesis by this PAH. At dose levels higher than those effective against DMBA, imperatorin also inhibited tumor initiation by B[a]P. The results demonstrate that several naturally occurring coumarins possess the ability to block DNA adduct formation and tumor initiation by PAHs such as B[a]P and DMBA. The mechanism for reduced DNA adduct formation and tumor initiation appears to involve inhibition of the P450s involved in the metabolic activation of these hydrocarbons. Finally, the differential effects of certain coumarins on B[a]P vs DMBA DNA adduct formation and tumor initiation may be useful for dissecting the role of specific cytochromes P450 in their metabolic activation. [ABSTRACT FROM PUBLISHER]
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- 1997
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14. Analysis of 7-methylbenz[a]anthracene-DNA adducts formed in SENCAR mouse epidermis by 32P-postlabeling.
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Baer-Dubowska, W, Vulimiri, S V, Harvey, R G, Cortez, C, and DiGiovanni, J
- Abstract
The present study has analysed the DNA adducts formed in SENCAR mouse epidermis following topical application of 7-methylbenz[a]anthracene (7-MBA). Mice were treated with 400 nmol of 7-MBA, which represents an initiating dose of this hydrocarbon for SENCAR mice. DNA adducts were analysed 24 h after topical application of the hydrocarbon by 32P-postlabeling coupled with either HPLC analysis or an improved TLC procedure giving better resolution of DNA adducts through the use of a D6 solvent [isopropanol:4N NH4OH (1:1)] following D5. Twenty-four hours after topical application of 400 nmol 7-MBA, the level of total covalent binding was 0.37 +/- 0.07 pmol/mg DNA as determined by 32P-postlabeling. This level of binding correlated well with the relative tumor initiating activity of this hydrocarbon compared to 7,12-dimethylbenz[a]anthracene (6.4 +/- 0.01 pmol/mg DNA) and dibenz[a,j]anthracene (0.03 +/- 0.01 pmol/mg DNA). Analysis of the 32P-labeled 3',5'-diphosphodeoxyribonucleosides by HPLC and TLC revealed the presence of deoxyguanosine (dGuo) and deoxyadenosine (dAdo) adducts formed from both the anti- and syn-bay-region diol-epoxides of 7-MBA (anti- and syn-7-MBADEs). The major DNA adduct derived from 7-MBA in mouse epidermis was tentatively identified as (+) anti-7-MBADE-trans-N2-dGuo. In addition, a minor dGuo adduct derived from the bay-region syn-diol-epoxide of 7-MBA was detected as well as a minor dAdo adduct from this diol-epoxide. Another minor dAdo adduct was also detectably present which arose from either the anti- or syn-diol epoxide. Furthermore, several unidentified DNA adducts were present in both HPLC and TLC chromatograms of DNA samples from 7-MBA-treated mice. These results are discussed in terms of the role of specific 7-MBA-DNA adducts in tumor initiation by this hydrocarbon. [ABSTRACT FROM PUBLISHER]
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- 1997
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15. Inhibitory effects of naturally occurring coumarins on the metabolic activation of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene in cultured mouse keratinocytes.
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Cai, Y, Baer-Dubowska, W, Ashwood-Smith, M, and DiGiovanni, J
- Abstract
Several naturally occurring coumarins to which humans are routinely exposed have been previously found to be potent inhibitors and inactivators of cytochrome P450 (P450) 1A1-mediated monooxygenase in both murine hepatic microsomes and in a reconstituted system using purified human P450 1A1 [Cai et al. (1993) Chem. Res. Toxicol., 6, 872-879 and Cai et al. (1996) Chem. Res. Toxicol., 9, 729-736]. In the present study, several of these coumarins were investigated for their inhibitory effects on the metabolism and metabolic activation of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) in cultured mouse keratinocytes. Initial analysis of B[a]P metabolism in cultured keratinocytes showed that imperatorin, isoimperatorin, coriandrin, and bergamottin, at concentrations of 2 nM equal with B[a]P, reduced the formation of water-soluble metabolites of B[a]P by 33% to 57%. Bergamottin and coriandrin were the most potent inhibitors of the compounds examined. HPLC analysis of organic solvent-soluble metabolites of B[a]P indicated that all the coumarins tested significantly reduced the formation of individual B[a]P metabolites (including phenols, diols and tetraols). However, the greatest effect was on the formation of B[a]P tetraols. Additional experiments determined the ability of selected coumarins to block covalent binding of B[a]P and DMBA to DNA in keratinocytes. Bergamottin preferentially inhibited the binding of B[a]P to DNA by 56%, while coriandrin preferentially inhibited the binding of DMBA to DNA by 48%. Notably, analysis of individual DNA adducts formed from B[a]P and DMBA indicated that both bergamottin and coriandrin specifically inhibited the formation of anti diol-epoxide DNA adducts derived from both hydrocarbons. The preferential inhibitory effect of bergamottin and coriandrin on the formation of anti diol-epoxide adducts derived from DMBA was further confirmed by separation of anti- and syn-diol-epoxide-DNA adducts using immobilized boronate chromatography. The current study demonstrates that certain naturally occurring coumarins inhibited metabolic activation of B[a]P and DMBA in cultured mouse keratinocytes and specifically inhibited the formation of DNA adducts derived from the anti diol-epoxide diastereomers from either hydrocarbon. The current data also suggest that certain naturally occurring coumarins may possess anticarcinogenic activity toward polycyclic aromatic hydrocarbons. [ABSTRACT FROM PUBLISHER]
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- 1997
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16. CANCER BIOLOGY: Regression and progression characteristics of papillomas induced by chrysarobin in SENCAR mice.
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Battalora, M.St J., Conti, C.J., Aldaz, C.M., Slaga, T.J., Johnston, D.A., and DiGiovanni, J.
- Abstract
The present study was designed to test the effects of a free radical generating tumor promoter, chrysarobin (1, 8-dihydroxy-3-methyl-9-anthrone), on the growth and progression of papillomas generated in the skin of SENCAR mice. In the first set of experiments, papillomas were generated by initiation with 6.4 μg of 7, 12-dimethyl-benz[a]anthracene (DMBA) followed by promotion with once-weekly applications of 52.8 μg chrysarobin for 10 weeks. The fate of individual papillomas was then monitored for a 20 week interval following cessation of promoter treatment Five weeks after the cessation of chrysarobin treatment, the papilloma response reached a maximum of 13.2 papillomas/mouse. By the end of the 20 week interval 19% and 18% of the papillomas had regressed or coalesced respectively. A three-stage treatment protocol was also utilized to test the ability of chrysarobin to enhance the progression of pre-existing papillomas to squamous cell carcinomas (SCCs). In stage I, mice were initiated with 0, 5 μg of DMBA. In stage II, mice were promoted with twice-weekly applications of 1 or 2 μg of 12-O-tetra-decanoylphorbol-13-acetate (TPA) for 15 weeks. Then, in stage III, mice were treated with acetone, TPA (1 or 2 μg), chrysarobin (52.8 μg) or benzoyl peroxide (BzPo; 20 mg) for the next 45 weeks. The mean number of papillomas per mouse at plateau was very similar for all groups. The carcinoma incidence was also similar for all groups regardless of the treatment protocol used, as was the mean number of carcinomas per mouse. The ratio of papillomas that converted to SCCs in mice treated with chrysarobin during stage III was not significantly different from the acetone controls or any of the other treatment groups (P > 0.05, Kruskal- Wallis analysis). In addition, BzPo did not enhance the progression of papillomas to SCCs under the current experimental conditions. Collectively, the results indicate that papillomas promoted by chrysarobin have growth properties similar to those promoted by TPA under similar experimental conditions. Furthermore, despite its ability to generate free radical intermediates, chrysarobin does not enhance the malignant progression of pre-existing papillomas induced by TPA treatment. [ABSTRACT FROM PUBLISHER]
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- 1996
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17. Further studies on the influence of initiation dose on papilloma growth and progression during two-stage carcinogenesis in SENCAR mice.
- Author
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DiGiovanni, J., Walker, S.E., Aldaz, C.M., Slaga, T.J., and Conti, C.J.
- Abstract
The present study was designed to further evaluate the growth and progression of papillomas to squamous cell carcinomas (SCCs) in groups of animals receiving initiating doses of 7,12-dimethylbenz[]anthracene (DMBA) producing relatively low papilloma yields following long term promotion (60 weeks) with 12--tetradecanoylphorbol-13-acetate (TPA). For comparison, groups of animals were initiated with various doses of DMBA and then promoted with mezerein (MEZ), benzoyl peroxide (BzPo) and chrysarobin (CHRY). Following initiation, groups of female SENCAR mice received the following promoter doses: TPA (1.0 or 2.0 μg per mouse); MEZ (2.0 μg per mouse); BzPo (20.0 mg per mouse); and CHRY (52.8 μg per mouse). The maximum papilloma to SCC conversion ratio obtained with TPA in the current study was 0.32. This value was in the range of maximum conversion ratios obtained with the other compounds: MEZ, 0.40; CHRY, 0.32 and BzPo, 0.19. In general, the highest papilloma to SCC conversion ratios observed with TPA as the promoter were obtained in groups that received the lowest doses of DMBA and had relatively low papilloma burdens. A comparison of papilloma to SCC conversion in groups of mice promoted with TPA, MEZ or CHRY and having similar papilloma yields, revealed very similar conversion ratios. Comparison of the BzPo group with a similar papilloma yield indicated that the conversion ratio was slightly lower with this promoter. The present results indicate that in mice promoted with TPA and having relatively low papilloma numbers, a larger proportion of these papillomas progress to SCCs during continued promoter treatment. Furthermore, the results suggest that papillomas behave similarly in their ability to progress to SCCs regardless of the promoter used when comparing groups of mice with similar tumor numbers. The data are discussed in terms of possible mechanisms for the observed results. [ABSTRACT FROM PUBLISHER]
- Published
- 1993
18. DBA/2 mice are as sensitive as SENCAR mice to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate.
- Author
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DiGiovanni, J., Prichett, W. P., Decina, P. C., and Diamond, L.
- Abstract
Mice of the inbred strain DBA/2 responded to a two-stage, initiation-promotion tumorigenesis protocol when high initiating doses (400 nmol/mouse) of 7,12-dimethylbenz[a]- anthracene were utilized. They also responded when N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was used as the initiating agent. The tumor response in both cases was characterized by a rapid rate of tumor development with the maximal tumor responses reached on or before the 15th week of promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). When DBA/2 mice were compared with SENCAR mice for promotion sensitivity following initiation with MNNG, the two mouse stocks responded with a nearly identical tumor response. C57BL/6 mice were essentially resistant to TPA promotion regardless of the initiator or the dose of initiator used. A preliminary study was conducted to determine how susceptibility to tumor promotion by TPA was inherited in F mice derived from DBA/2 (sensitive) and C57BL/6 (resistant) parents. The B6D2F mice were as sensitive as the DBA/2 parent, suggesting that susceptibility in these two inbred mouse strains is inherited as an autosoma1 dominant trait. The results show that these two inbred mouse strains may provide a model system for studying genetic factors controlling susceptibility to phorbol ester skin tumor promotion. [ABSTRACT FROM PUBLISHER]
- Published
- 1984
19. Tumor promoting activity of 1,8-dihydroxy-3-methyl-9-anthrone (chrysarobin) in female SENCAR mice.
- Author
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DiGiovanni, J. and Boutwell, R.K.
- Abstract
Purified 1,8-dihydroxy-3-methyl-9-anthrone or chrysarobin was found to be an effective skin tumor-promoter in SENCAR mice, although, at the dose used, it was ˜43-fold less active than 12-O-tradecanoylphorbol-13-acetate (TPA). When non-promoting doses of chrysarobin were applied 30 min prior to each application of TPA, a marked potentiation in the promoting response to TPA was observed. Chrysarobin will provide a valuable tool for studying the mechanism of action of anthracene-derived mouse skin tumor promoters. [ABSTRACT FROM PUBLISHER]
- Published
- 1983
20. Comparison of the tumor-initiating activity of 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene in female SENCAR and CD-1 mice1.
- Author
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DiGiovanni, J., Slaga, T.J., and Boutwell, R.K.
- Abstract
The derivation of mice resistant and susceptible to skin tumorigenesis using the initiation-promotion regimen is described. Dose-response relationships for tumor-initiating activities of 7,12-dimethylbenz[a]-anthracene (DMBA) and benzo[a]pyrene (BP) in the susceptible line (SENCAR) are presented. A single topical dose of either 0.1, 1.0, 10 or 100 nmol DMBA, followed one week later by twice weekly applications of 8.5 nmol 12–0-tetradecanoylphorbol-13-acetate (TPA) for 19 weeks, produced 0, 3.3, 4.9 and 23.1 papillomas per mouse, respectively. Single topical initiating doses of either 50, 100 or 200 nmol BP produced 1.7, 3.8 or 7.8 papillomas per mouse, respectively, after 28 weeks of promotion with 8.5 nmol TPA. SENCAR mice were compared with CD-1 mice for the initiating activity of DMBA and BP. Initiating doses of 0.1, 1.0, 10 and 100 nmol DMBA produced 0.6, 3.8, 7.0 and 24 papillomas per mouse, respectively, in SENCAR mice and in CD-1 mice produced 0, 0.2, 3.0 and 5.6 papillomas per mouse, respectively, after 25 weeks of promotion with TPA. With BP as the initiator, 10, 50, 100 and 200 nmol doses produced 0.9, 1.6, 3.8 and 8.3 papillomas per mouse, respectively, in SENCAR mice and in CD-1 mice produced 0.1, 0.7,1.8 and 3.8 papillomas per mouse, respectively, after 25 weeks of promotion with TPA. SENCAR mice were compared with CD-1 mice for possible differences in the oxidative metabolism of DMBA using epidermal homogenates as the enzyme source. Basal levels of monooxygenase activity toward DMBA were similar in both mouse stocks. Epidermal monooxygenase activities following pre-treatment with inducers including DMBA, 3-methylcholanthrene, dibenz[a,c]anthracene, Aroclor 1254 and 2,3,7,8-tetrachlorodibenzo-p-dioxin, also were quite similar in both mouse stocks. High-pressure liquid chromatographic profiles of ethyl acetate/ acetone (2:1) extractable metabolites revealed a close similarity in the patterns as well as the rates of formation of specific metabolites. Metabolites of DMBA tentatively identified based on cochromato-graphy with purified reference standards included phenols, 12-hydroxymethyl-7-methylbenz[a]anthracene, 7-hydroxymethyl-12-methylbenz[a]antnracene, 7,12-dihydroxymethylbenz[a]anthracene, (±)-trans-8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz[a]anthracene and (±)-trans-5,6-dihydro-5,6-dihydroxy-7,12-dimethylbenz[a]anthracene. The results suggested that differences in oxidative metabolism of DMBA were not responsible for the differences in sensitivity to tumor-initiation between SENCAR and CD-1 mice. [ABSTRACT FROM PUBLISHER]
- Published
- 1980
21. Biotransformation of 7,12-dimethylbenz [a] anthracene by mouse epidermal cells in culture.
- Author
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DiGiovanni, J., Viaje, A., Fischer, S., Slaga, T.J., and Boutwell, R.K.
- Abstract
The formation of cell- and medium-associated metabolites of 7,12-dimethylbenz[a]anthracene (DMBA) by primary mouse epidermal cells was examined using high-pressure liquid chromatography. Cells were cultured in the presence of C DMBA for various time periods prior to harvesting. Ethyl acetate/acetone (2:1) extractable metabolites found associated with cells cochromatographed with 7-hydroxymethyl-12-methylbenz[a]anthracene (7-OHM-12-MBA), 12-hydroxymethyl-7-methylbenz[a]anthracene (12-OHM-7-MBA), (±)-trans-3,4-dihydro-3,4-dihydroxy-7, 12-dimethylbenz[a]anthracene ((±)-trans-DMBA-3, 4-diol) and phenols. The major metabolite(s) found within cells cochromatographed with DMBA-phenol(s). Ethyl acetate/acetone extractable metabolites found in the medium cochromatographed with 7-OHM-12-MBA, 12-OHM-7-MBA, (±)-trans-DMBA-3,4-diol, (±)-trans-8,9-dihydro-8,9-dihydroxy-7, 12-dimethylbenz[a]anthracene ((± -trans-DMBA-8,9-diol) and phenols. The major ethyl acetate/acetone soluble metabolite found in the medium cochromatographed with (±)-trans-DMBA- 8,9-diol. This metabolite is rapidly excreted unchanged from the cells into the medium. In addition, primary epidermal cells rapidly converted C DMBA to water soluble metabolites that could not be extracted from the medium with ethyl acetate/acetone. Approximately 50% of these water soluble metabolites were extractable with organic solvent upon treatment of the medium with β-glucuronidase. Phenolic metabolite(s) represented 75–85% of the total β-glucuronidase releasable material. The results indicated that primary mouse epidermal cells in culture rapdly converted DMBA to a variety of hydroxylated products some of which were conjugated with glucuronic acid. In addition, the formation of (±)-trans-DMBA-3,4-diol and its retention within the cells provides additional support for an important role for this metabolite in carcinogenesis by DMBA. [ABSTRACT FROM PUBLISHER]
- Published
- 1980
22. Intragastric mefloquine is absorbed rapidly in patients with cerebral malaria
- Author
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Chanthavanich, P., Looareesuwan, S., Nicholas White, Warrell, D. A., Warrell, M. J., Digiovanni, J. H., and Bredow, J.
- Subjects
parasitic diseases - Abstract
Mefloquine has proved effective in chloroquine- and quinine-resistant falciparum malaria, but it cannot be given parenterally. We have measured the absorption of mefloquine hydrochloride suspension (mean 15.6, range 9.7-28.6 mg/kg) given by nasogastric tube to 19 cerebral malaria patients already receiving intravenous quinine. Absorption was rapid with both dose schedules used; mean absorption half-times were 1.5 and 1.8 hr, and plasma mefloquine concentrations exceeded 200 ng/g within 3 hr of completing administration in all but one exceptionally ill patient who died 40 hr later. Steady state plasma concentrations over 7 days ranged from 300 to 1,050 (mean 561) ng/g. Bioavailability of mefloquine suspension in cerebral malaria therefore appears to be adequate for treatment in all but the most severely ill patients. Although intragastric mefloquine cannot now be recommended as an alternative to intravenous quinine for the treatment of severe chloroquine-resistant falciparum malaria, this situation could change if quinine resistance increases further.
- Published
- 1985
23. 405 km of repeaterless transmission at 5 Gb/s utilizing a post-amplifier and a remotely preamplified receiver with forward error correction.
- Author
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Alphonsus, J.E.J., Hansen, P.B., Eskildsen, L., Truxal, D.A., Grubb, S.G., DiGiovanni, J., Strasser, T.A., and Beck, E.C.
- Published
- 1995
- Full Text
- View/download PDF
24. C57BL/6 mice are resistant to tumor promotion by full thickness skin wounding.
- Author
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DiGiovanni, J., S.Bhatt, T., and E.Walker, S.
- Abstract
The present study demonstrates that C57BL/6 mice, previously shown to be relatively resistant to skin tumor promotion by phorbol esters as well as several other classes of tumor promoters, are resistant to skin tumor promotion by full thickness skin wounding. Two separate experiments were performed comparing female SENCAR and C57BL/6 mice for their sensitivity to skin tumor promotion by skin wounding following initiation with 7,12-dimethylbenz[a]-anthracene (DMBA). In the first experiment, groups of mice were initiated with 25 nmol DMBA and then received full thickness skin wounds in the initiated skin 2 weeks later. Neither SENCAR nor C57BL/6 mice developed skin tumors during the 26 weeks following initial wounding. However, these groups were rewounded in week 27 and 14 weeks later the SENCAR mice had developed a significant tumor response (0.75 papillomas per mouse, 55% incidence). At this time, the C57BL/6 mice still did not have a tumor response significantly different from the acetone-initiated controls. A second experiment was performed using a 100 nmol initiating dose of DMBA. Fifteen weeks after initial wounding in this experiment, the group of SENCAR mice had 0.76 papillomas per mouse (41% incidence) whereas no tumors were present in the group of C57BL/6 mice, even 31 weeks after the initial wounding. The results demonstrate that C57BL/6 mice are resistant to an endogenous skin tumor promotion mechanism and strongly support a link between skin tumor promotion by several classes of chemical promoters and full thickness wounding. [ABSTRACT FROM PUBLISHER]
- Published
- 1993
25. A May-December wedding finally puts a brake on the oldest Rolling Stone.
- Author
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Freeman, P. and DiGiovanni, J.
- Subjects
- WYMAN, Bill, 1936-
- Abstract
Reports on the recent marriage of Rolling Stones bassist Bill Wyman, 52, and Mandy Smith, 18, who met when she was only 13. The two had a private civil ceremony, followed three days later by a church wedding.
- Published
- 1989
26. Effects of the tropical ginger compound,1’-acetoxychavicol acetate, against tumor promotion in K5.Stat3C transgenic mice
- Author
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Batra Vinita, Syed Zanobia, Gill Jennifer N, Coburn Malari A, Adegboyega Patrick, DiGiovanni John, Mathis J, Shi Runhua, Clifford John L, and Kleiner-Hancock Heather E
- Subjects
NF-κB ,Stat3 ,Squamous cell carcinoma ,Carcinogenesis ,TPA ,Tropical ginger ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The purpose of the current study was to determine whether a tropical ginger derived compound 1’-acetoxychavicol acetate (ACA), suppresses skin tumor promotion in K5.Stat3C mice. In a two-week study in which wild-type (WT) and K5.Stat3C mice were co-treated with either vehicle, ACA, galanga extract, or fluocinolone acetonide (FA) and tetradecanoyl phorbol acetate (TPA), only the galanga extract and FA suppressed TPA-induced skin hyperproliferation and wet weight. None of these agents were effective at suppressing p-Tyr705Stat3 expression. However, ACA and FA showed promising inhibitory effects against skin tumorigenesis in K5.Stat3C mice. ACA also suppressed phospho-p65 NF-κB activation, suggesting a potential mechanism for its action.
- Published
- 2012
- Full Text
- View/download PDF
27. Active Stat3 is required for survival of human squamous cell carcinoma cells in serum-free conditions
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DiGiovanni John, Syson-Chan Keith, Roberts Jennifer N, Cheepala Satish, Yin Weihong, and Clifford John L
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Squamous cell carcinoma (SCC) of the skin is the most aggressive form of non-melanoma skin cancer (NMSC), and is the single most commonly diagnosed cancer in the U.S., with over one million new cases reported each year. Recent studies have revealed an oncogenic role of activated signal transducer and activator of transcription 3 (Stat3) in many human tumors, especially in those of epithelial origin, including skin SCC. Stat3 is a mediator of numerous growth factor and cytokine signaling pathways, all of which activate it through phosphorylation of tyrosine 705. Results To further address the role of Stat3 in skin SCC tumorigenesis, we have analyzed a panel of human skin-derived cell lines ranging from normal human epidermal keratinocytes (NHEK), to non-tumorigenic transformed skin cells (HaCaT), to highly tumorigenic cells (SRB1-m7 and SRB12-p9) and observed a positive correlation between Stat3 phosphorylation and SCC malignancy. We next determined the role of Stat3 activity in cell proliferation and viability under serum-free culture conditions. This was accomplished by suppressing Stat3 activity in the SRB12-p9 cells through stable expression of a dominant negative acting form of Stat3β, which contains a tyrosine 705 to phenylalanine mutation (S3DN). The S3DN cells behaved similar to parental SRB12-p9 cells when cultured in optimal growth conditions, in the presence of 10% fetal calf serum. However, unlike the SRB12-p9 cells, S3DN cells underwent apoptotic cell death when cultured in serum-free medium (SFM). This was evidenced by multiple criteria, including accumulation of sub-G1 particles, induced PARP cleavage, and acquisition of the characteristic morphological changes associated with apoptosis. Conclusion This study provides direct evidence for a role for Stat3 in maintaining cell survival in the conditions of exogenous growth factor deprivation produced by culture in SFM. We also propose that delivery of the S3DN gene or protein to tumor cells could induce apoptosis and/or sensitize those cells to the apoptotic effects of cancer therapeutic agents, raising the possibility of using S3DN as an adjunct for treatment of skin SCC.
- Published
- 2006
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28. The role of anthralin in mouse skin tumour promotion.
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Boutwell, R. K., Hoel, M. J., and Digiovanni, J.
- Subjects
SKIN tumors ,COCARCINOGENESIS ,CARCINOGENESIS ,DERMATOLOGIC agents ,DERMATOPHARMACOLOGY ,DERMATOLOGY ,MEDICINE - Abstract
Examines the role of anthralin in mouse skin tumor promotion. Determination of the epidermal ornithine decarboxylase activity; Establishment of the time-dependency of anthralin treatment relative to the time of application of the inducing agent; Evidence that anthralin does not interfere with the assay for ornithine decarboxylase.
- Published
- 1981
- Full Text
- View/download PDF
29. ChemInform Abstract: Synthesis of the Tumorigenic 3,4-Dihydrodiol Metabolites of Dibenz-(a,j)anthracene and 7,14-Dimethyldibenz(a,j)anthracene.
- Author
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HARVEY, R. G., CORTEZ, C., SAWYER, T. W., and DIGIOVANNI, J.
- Published
- 1988
- Full Text
- View/download PDF
30. Despite her stunning success in best-seller land, Rosamunde Pilcher's heart is still in the...
- Author
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Hubbard, K. and DiGiovanni, J.
- Subjects
- PILCHER, Rosamunde, 1924-2019
- Abstract
Profiles author Rosamunde Pilcher, 65, who turned from writing romance novels to more substantial books, the best-selling `The Shell Seekers,' and her latest `September.' Career; Personal life in Scotland; Background.
- Published
- 1990
31. Kay Kent died the way she lived--as a mirror of Marilyn Monroe.
- Author
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Dougherty, M. and DiGiovanni, J.
- Subjects
- KENT, Kay
- Abstract
Talks about Kay Kent, a Marilyn Monroe impersonator, who recently committed suicide at age 25, with sleeping pills and vodka in her bedroom, just like her idol who died in 1962.
- Published
- 1989
32. Effects of pretreatment with 2,3,7,8-tetrachlorodibenzo- p-dioxin on the capacity of hepatic and extrahepatic mouse tissues to convert procarcinogens to mutagens for Salmonella typhimurium auxotrophs
- Author
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DiGiovanni, J., Berry, D.L., Slaga, T.J., Jones, A.H., and Juchau, M.R.
- Published
- 1979
- Full Text
- View/download PDF
33. ChemInform Abstract: Biologically Active Dihydrodiol Metabolites of Polycyclic Aromatic Hydrocarbons Structurally Related to the Potent Carcinogenic Hydrocarbon 7,12-Dimethylbenz(a)anthracene.
- Author
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HARVEY, R. G., CORTEZ, C., SUGIYAMA, T., ITO, Y., SAWYER, T. W., and DIGIOVANNI, J.
- Published
- 1988
- Full Text
- View/download PDF
34. Tumor-initiating ability of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDC) and arochlor 1254 in the two-stage system of mouse skin carcinogenesis
- Author
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Juchau, M. R., Berry, D. L., Slaga, T. J., DiGiovanni, J., and Viaje, A.
- Subjects
CANCER research ,CARCINOGENS ,MICE ,SKIN ,TOXICOLOGY - Published
- 1977
35. Obesity increases genomic instability at DNA repeat-mediated endogenous mutation hotspots.
- Author
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Kompella P, Wang G, Durrett RE, Lai Y, Marin C, Liu Y, Habib SL, DiGiovanni J, and Vasquez KM
- Subjects
- Animals, Humans, Mice, Repetitive Sequences, Nucleic Acid genetics, Male, Mice, Inbred C57BL, Female, Burkitt Lymphoma genetics, DNA genetics, DNA metabolism, Obesity genetics, Genomic Instability, Mice, Transgenic, Mutation, DNA Repair genetics, DNA Damage genetics
- Abstract
Obesity is associated with increased cancer risk, yet the underlying mechanisms remain elusive. Obesity-associated cancers involve disruptions in metabolic and cellular pathways, which can lead to genomic instability. Repetitive DNA sequences capable of adopting alternative DNA structures (e.g., H-DNA) stimulate mutations and are enriched at mutation hotspots in human cancer genomes. However, it is not known if obesity impacts DNA repeat-mediated endogenous mutation hotspots. We address this gap by measuring mutation frequencies in obese and normal-weight transgenic reporter mice carrying either a control human B-DNA- or an H-DNA-forming sequence (from a translocation hotspot in c-MYC in Burkitt lymphoma). Here, we discover that H-DNA-induced DNA damage and mutations are elevated in a tissue-specific manner, and DNA repair efficiency is reduced in obese mice compared to those on the control diet. These findings elucidate the impact of obesity on cancer-associated endogenous mutation hotspots, providing mechanistic insight into the link between obesity and cancer., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
36. Impact of Weight Management on Obesity-Driven Biomarkers of Prostate Cancer Progression.
- Author
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Bechtel MD, Michel C, Srinivasan P, Chalise P, Parker WP, Mirza M, Thrasher B, Gibbs HD, DiGiovanni J, and Hamilton-Reeves J
- Subjects
- Male, Humans, Prostate, Quality of Life, Adipose Tissue, Obesity complications, Obesity therapy, Biomarkers, Body Weight, Weight Loss, Leptin, Prostatic Neoplasms therapy
- Abstract
Purpose: Excess body and visceral fat increase the risk of death from prostate cancer (PCa). This phase II study aimed to test whether weight reduction by > 5% total body weight counteracts obesity-driven PCa biomarkers., Materials and Methods: Forty men scheduled for prostatectomy were randomized into intervention (n = 20) or control (n = 20) arms. Intervention participants followed a weight management program for 4 to 16 weeks before and 6 months after surgery. Control participants received standardized educational materials. All participants attended visits at baseline, 1 week before surgery, and 6 months after surgery. Circulating immune cells, cytokines, and chemokines were evaluated. Weight loss, body composition/distribution, quality of life, and nutrition literacy were assessed. Prostate tissue samples obtained from biopsy and surgery were analyzed., Results: From baseline to surgery (mean = 5 weeks), the intervention group achieved 5.5% of weight loss (95% CI, 4%-7%). Compared to the control, the intervention also reduced insulin, total cholesterol, LDL cholesterol, leptin, leptin:adiponectin ratio, and visceral adipose tissue. The intervention group had reduced c-peptide, plasminogen-activator-inhibitor-1, and T cell count from baseline to surgery. Myeloid-derived suppressor cells were not statistically different by group. Intervention group anthropometrics improved, including visceral and overall fat loss. No prostate tissue markers changed significantly. Quality of life measures of general and emotional health improved in the intervention group. The intervention group maintained or kept losing to a net loss of 11% initial body weight (95% CI, 8%-14%) at the study end., Conclusions: Our study demonstrated improvements in body composition, PCa biomarkers, and quality of life with a weight management intervention.
- Published
- 2024
- Full Text
- View/download PDF
37. Novel two-tiered screening approach identifies synergistic combinations of natural compounds for prostate cancer prevention and treatment.
- Author
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Friedman CA, Saha A, Lavender Hackman G, Lu X, Lodi A, Tiziani S, and DiGiovanni J
- Subjects
- Male, Humans, Animals, Mice, Early Detection of Cancer, Cell Cycle Proteins, Cell Line, Cell Survival, Cell Line, Tumor, Prostatic Neoplasms drug therapy, Prostatic Neoplasms prevention & control, Glycyrrhetinic Acid, Neoplasms, Second Primary
- Abstract
Prostate cancer (PCa) is the second most common cancer type among American men and it is estimated that in 2023, 34,700 men will die from PCa. Since it can take a considerable amount of time for the disease to progress to clinically evident cancer, there is ample opportunity for effective chemopreventive strategies to be applied for the successful management of PCa progression. In the current study, we have developed a two-tiered metabolomics-based screen to identify synergistic combinations of phytochemicals for PCa chemoprevention. This involves an initial screen for ATP depletion in PCa cells followed by a targeted screen for blocking glutamine uptake in the same cells. One of the phytochemical combinations (enoxolone [ENO] + silibinin [SIL]), identified via this screen, was examined for effects on PCa cell survival, oncogenic signaling and tumor growth in vivo. This combination was found to synergistically reduce cell survival, colony formation and cell cycle progression of PCa cell lines to a greater extent than either agent alone. The combination of ENO and SIL also synergistically reduced tumor growth when administered ad libitum through the diet in a HMVP2 allograft PCa tumor model. Treatment with the combination also significantly reduced STAT3 and mTORC1 signaling pathways in mouse and human PCa cells while significantly reducing levels of critical cell cycle regulatory proteins, contributing to the synergistic inhibition of tumor growth observed. Collectively, the current results demonstrate a novel approach to identifying synergistic combinations of phytochemicals for chemoprevention of PCa and possibly other cancers., (© 2024 Wiley Periodicals LLC.)
- Published
- 2024
- Full Text
- View/download PDF
38. Phase 1 clinical trial evaluating safety, bioavailability, and gut microbiome with a combination of curcumin and ursolic acid in lipid enhanced capsules.
- Author
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Liss MA, Dursun F, Hackman GL, Gadallah MI, Saha A, Friedman CA, Rathore AS, Chandra P, White JR, Tiziani S, and DiGiovanni J
- Abstract
As screening strategies employ better biomarkers and genetics to identify individuals at an increased risk of prostate cancer, there are currently no chemotherapeutic prevention strategies. With any chemoprevention strategy, the population will be younger and healthier; therefore, they will be less tolerant of side effects. This study translated findings from screening a natural product library and pre-clinical evaluation of curcumin (CURC) in combination with ursolic acid (UA) in prostate cancer models. After manufacturing capsules for each compound, 18 subjects were enrolled. The study used a 3 × 3 phase 1 clinical trial to evaluate CURC (1200 mg/day) and UA (300 mg/day) alone and in combination over a 2-week period with endpoints of safety, bioavailability, and microbiome alterations. After enrolling six subjects in each arm, we found no grade 3 or 4 events and only minor changes in the safety laboratory values. In the pooled analysis of groups, we noted a statistically significant difference between median serum levels of UA when administered alone vs administered in the combination (2.7 ng/mL vs 43.8 ng/mL, p = 0.03). Individuals receiving the combination also had a favorable impact on gut microbiome status and a reduction in "microbiome score" predictive of prostate cancer risk., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michael Liss has patent #WO2023091668A1 issued to John DiGiovanni., (© 2024 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.)
- Published
- 2024
- Full Text
- View/download PDF
39. Human mitochondrial uncoupling protein 3 functions as a metabolite transporter.
- Author
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De Leonardis F, Ahmed A, Vozza A, Capobianco L, Riley CL, Barile SN, Di Molfetta D, Tiziani S, DiGiovanni J, Palmieri L, Dolce V, and Fiermonte G
- Subjects
- Humans, Uncoupling Protein 1 genetics, Uncoupling Protein 2, Uncoupling Protein 3, Ion Channels, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism
- Abstract
Since its discovery, a major debate about mitochondrial uncoupling protein 3 (UCP3) has been whether its metabolic actions result primarily from mitochondrial inner membrane proton transport, a process that decreases respiratory efficiency and ATP synthesis. However, UCP3 expression and activity are induced by conditions that would seem at odds with inefficient 'uncoupled' respiration, including fasting and exercise. Here, we demonstrate that the bacterially expressed human UCP3, reconstituted into liposomes, catalyses a strict exchange of aspartate, malate, sulphate and phosphate. The R282Q mutation abolishes the transport activity of the protein. Although the substrate specificity and inhibitor sensitivity of UCP3 display similarity with that of its close homolog UCP2, the two proteins significantly differ in their transport mode and kinetic constants., (© 2023 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
- Published
- 2024
- Full Text
- View/download PDF
40. Effects of curcumin and ursolic acid in prostate cancer: A systematic review.
- Author
-
Besasie BD, Saha A, DiGiovanni J, and Liss MA
- Subjects
- Male, Humans, Ursolic Acid, NF-kappa B metabolism, NF-kappa B pharmacology, Signal Transduction, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-akt pharmacology, Apoptosis, Curcumin pharmacology, Triterpenes pharmacology, Prostatic Neoplasms
- Abstract
The major barriers to phytonutrients in prostate cancer therapy are non-specific mechanisms and bioavailability issues. Studies have pointed to a synergistic combination of curcumin (CURC) and ursolic acid (UA). We investigate this combination using a systematic review process to assess the most likely mechanistic pathway and human testing in prostate cancer. We used the PRISMA statement to screen titles, abstracts, and the full texts of relevant articles and performed a descriptive analysis of the literature reviewed for study inclusion and consensus of the manuscript. The most common molecular and cellular pathway from articles reporting on the pathways and effects of CURC ( n = 173) in prostate cancer was NF-κB ( n = 25, 14.5%). The most common molecular and cellular pathway from articles reporting on the pathways and effects of UA ( n = 24) in prostate cancer was caspase 3/caspase 9 ( n = 10, 41.6%). The three most common molecular and cellular pathway from articles reporting on the pathways and effects of both CURC and UA ( n = 193) in prostate cancer was NF-κB ( n = 28, 14.2%), Akt ( n = 22, 11.2%), and androgen ( n = 19, 9.6%). Therefore, we have identified the potential synergistic target pathways of curcumin and ursolic acid to involve NF-κB, Akt, androgen receptors, and apoptosis pathways. Our review highlights the limited human studies and specific effects in prostate cancer., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Published
- 2024
- Full Text
- View/download PDF
41. Inducible Keratinocyte Specific FGFR2 Deficiency Inhibits UVB-Induced Signaling, Proliferation, Inflammation, and Skin Carcinogenesis.
- Author
-
Thakur M, Rho O, Khandelwal A, Nathan CO, and DiGiovanni J
- Subjects
- Animals, Female, Male, Mice, Carcinogenesis genetics, Cell Proliferation, Inflammation metabolism, Keratinocytes metabolism, Mice, Transgenic, Receptor, Fibroblast Growth Factor, Type 2 genetics, Receptor, Fibroblast Growth Factor, Type 2 metabolism, Tamoxifen, Ultraviolet Rays adverse effects, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell metabolism, Skin Neoplasms genetics, Skin Neoplasms prevention & control
- Abstract
A potential role for fibroblast growth factor receptor 2 (FGFR2) in cutaneous squamous cell carcinoma (cSCC) has been reported. To demonstrate the specific role of FGFR2 in UVB-induced skin carcinogenesis and development of cSCC, we generated a keratinocyte specific, tamoxifen inducible mouse model of FGFR2 deficiency. In this mouse model, topical application of 4-hydroxy tamoxifen led to the induction of Cre recombinase to delete FGFR2 in epidermal keratinocytes of both male and female transgenic mice. Analysis of epidermal protein lysates isolated from FGFR2 deficient mice exposed to UVB showed significant reductions of phospho-FGFR (pFGFR; Y653/654) and phospho-fibroblast growth factor receptor substrate 2α as well as downstream effectors of mTORC1 signaling. Phosphorylation of signal transducer and activators of transcription 1/3 was significantly reduced as well as levels of IRF-1, DUSP6, early growth response 1, and PD-L1 compared to the control groups. Keratinocyte-specific ablation of FGFR2 also significantly inhibited epidermal hyperproliferation, hyperplasia, and inflammation after exposure to UVB. Finally, keratinocyte-specific deletion of FGFR2 significantly inhibited UVB-induced cSCC formation. Collectively, the current data demonstrate an important role of FGFR2 in UVB-induced oncogenic signaling as well as development of cSCC. In addition, the current preclinical findings suggest that inhibition of FGFR2 signaling may provide a previously unreported strategy to prevent and/or treat UVB-induced cSCC., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
42. Enzymatic depletion of l-Met using an engineered human enzyme as a novel therapeutic strategy for melanoma.
- Author
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Wilder CS, Chiou J, Battenhouse A, Saha A, Chen Z, Kim E, Gadallah MI, Tiziani S, Georgiou G, Stone E, and DiGiovanni J
- Subjects
- Humans, Animals, Mice, G2 Phase Cell Cycle Checkpoints, Apoptosis, Cell Line, Tumor, Melanoma drug therapy, Melanoma genetics, Melanoma pathology, Skin Neoplasms drug therapy, Skin Neoplasms genetics, Skin Neoplasms metabolism
- Abstract
Many cancers, including melanoma, have a higher requirement for l-methionine in comparison with noncancerous cells. In this study, we show that administration of an engineered human methionine-γ-lyase (hMGL) significantly reduced the survival of both human and mouse melanoma cells in vitro. A multiomics approach was utilized to identify global changes in gene expression and in metabolite levels with hMGL treatment in melanoma cells. There was considerable overlap in the perturbed pathways identified in the two data sets. Common pathways were flagged for further investigation to understand their mechanistic importance. In this regard, hMGL treatment induced S and G2 phase cell cycle arrest, decreased nucleotide levels, and increased DNA double-strand breaks suggesting an important role for replication stress in the mechanism of hMGL effects on melanoma cells. Further, hMGL treatment resulted in increased cellular reactive oxygen species levels and increased apoptosis as well as uncharged transfer RNA pathway upregulation. Finally, treatment with hMGL significantly inhibited the growth of both mouse and human melanoma cells in orthotopic tumor models in vivo. Overall, the results of this study provide a strong rationale for further mechanistic evaluation and clinical development of hMGL for the treatment of melanoma skin cancer and other cancers., (© 2023 Wiley Periodicals LLC.)
- Published
- 2023
- Full Text
- View/download PDF
43. Obesity and prostate cancer - microenvironmental roles of adipose tissue.
- Author
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Saha A, Kolonin MG, and DiGiovanni J
- Subjects
- Male, Humans, Adipocytes metabolism, Adipocytes pathology, Obesity complications, Obesity metabolism, Neovascularization, Pathologic, Adipose Tissue metabolism, Adipose Tissue pathology, Prostatic Neoplasms pathology
- Abstract
Obesity is known to have important roles in driving prostate cancer aggressiveness and increased mortality. Multiple mechanisms have been postulated for these clinical observations, including effects of diet and lifestyle, systemic changes in energy balance and hormonal regulation and activation of signalling by growth factors and cytokines and other components of the immune system. Over the past decade, research on obesity has shifted towards investigating the role of peri-prostatic white adipose tissue as an important source of locally produced factors that stimulate prostate cancer progression. Cells that comprise white adipose tissue, the adipocytes and their progenitor adipose stromal cells (ASCs), which proliferate to accommodate white adipose tissue expansion in obesity, have been identified as important drivers of obesity-associated cancer progression. Accumulating evidence suggests that adipocytes are a source of lipids that are used by adjacent prostate cancer cells. However, results of preclinical studies indicate that ASCs promote tumour growth by remodelling extracellular matrix and supporting neovascularization, contributing to the recruitment of immunosuppressive cells, and inducing epithelial-mesenchymal transition through paracrine signalling. Because epithelial-mesenchymal transition is associated with cancer chemotherapy resistance and metastasis, ASCs are considered to be potential targets of therapies that could be developed to suppress cancer aggressiveness in patients with obesity., (© 2023. Springer Nature Limited.)
- Published
- 2023
- Full Text
- View/download PDF
44. Cysteine depletion sensitizes prostate cancer cells to agents that enhance DNA damage and to immune checkpoint inhibition.
- Author
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Saha A, Zhao S, Kindall A, Wilder C, Friedman CA, Clark R, Georgiou G, Stone E, Kidane D, and DiGiovanni J
- Subjects
- Male, Humans, Cysteine pharmacology, Cysteine therapeutic use, Immune Checkpoint Inhibitors therapeutic use, Reactive Oxygen Species metabolism, Cystine genetics, Cystine therapeutic use, Androgens, Cell Line, Tumor, DNA Damage, DNA, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Cysts drug therapy
- Abstract
Background: Prostate Cancer (PCa) represents one of the most commonly diagnosed neoplasms in men and is associated with significant morbidity and mortality. Therapy resistance and significant side effects of current treatment strategies indicate the need for more effective agents to treat both androgen-dependent and androgen-independent PCa. In earlier studies, we demonstrated that depletion of L-cysteine/cystine with an engineered human enzyme, Cyst(e)inase, increased intracellular ROS levels and inhibited PCa growth in vitro and in vivo. The current study was conducted to further explore the mechanisms and potential combinatorial approaches with Cyst(e)inase for treatment of PCa., Methods: DNA single strand breaks and clustered oxidative DNA damage were evaluated by alkaline comet assay and pulsed field gel electrophoresis, respectively. Neutral comet assay and immunofluorescence staining was used to measure DNA double strand breaks. Cell survival and reactive oxygen species level were measured by crystal violet assay and DCFDA staining, respectively. Western blot was used to determine protein expression. FACS analyses were preformed for immune cell phenotyping. Allograft and xenograft tumor models were used for assessing effects on tumor growth., Results: PCa cells treated with Cyst(e)inase lead to DNA single and double strand breaks resulted from clustered oxidative DNA damage (SSBs and DSBs). Cyst(e)inase in combination with Auranofin, a thioredoxin reductase inhibitor, further increased intracellular ROS and DNA DSBs and synergistically inhibited PCa cell growth in vitro and in vivo. A combination of Cyst(e)inase with a PARP inhibitor (Olaparib) also increased DNA DSBs and synergistically inhibited PCa cell growth in vitro and in vivo without additional ROS induction. Knockdown of BRCA2 in PCa cells increased DSBs and enhanced sensitivity to Cyst(e)inase. Finally, Cyst(e)inase treatment altered tumor immune infiltrates and PD-L1 expression and sensitized PCa cells to anti-PD-L1 treatment., Conclusions: The current results demonstrate the importance of oxidative DNA damage either alone or in combination for Cyst(e)inase-induced anticancer activity. Furthermore, cysteine/cystine depletion alters the tumor immune landscape favoring enhanced immune checkpoint inhibition targeting PD-L1. Thus, combinatorial approaches with Cyst(e)inase could lead to novel therapeutic strategies for PCa., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
45. Twist1 as a target for prevention of cutaneous squamous cell carcinoma.
- Author
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Wang T, Rho O, Eguiarte-Solomon F, and DiGiovanni J
- Subjects
- Animals, Mice, Cell Line, Tumor, Cell Proliferation genetics, Epithelial-Mesenchymal Transition genetics, Gene Expression Regulation, Neoplastic, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell prevention & control, Carcinoma, Squamous Cell metabolism, Skin Neoplasms genetics, Skin Neoplasms prevention & control, Skin Neoplasms pathology, Twist-Related Protein 1 genetics, Twist-Related Protein 1 metabolism
- Abstract
Cutaneous squamous cell carcinoma (cSCC) represents an important clinical problem requiring novel approaches for both prevention and treatment. The transcription factor, Twist-related protein 1 (Twist1), has been identified as having a key mechanistic role in the development and progression of cSCC. Studies in relevant mouse models of cSCC have shown that Twist1 regulates epithelial-mesenchymal transition (EMT) and stemness driving progression and metastasis of cSCC. In addition, further research has shown that Twist1 regulates the balance between keratinocyte proliferation and differentiation and therefore impacts earlier stages of cSCC development. Through use of keratinocyte specific Twist1 knockout models, a role for this gene in keratinocyte stem cell homeostasis has been revealed. As a transcription factor, Twist1 regulates a large number of genes both in a positive, as well as a negative manner across several interdependent pathways. Studies in keratinocyte specific knockout models have shown that Twist1 upregulates the expression of genes involved in proliferation, stemness, and EMT while downregulating the expression of genes associated with differentiation. Furthermore, a number of compounds, including naturally occurring compounds, have been identified that target Twist1 and can block its effects in cancer cells and in keratinocytes in vivo. Collectively, the current understanding of Twist1 function in cSCC development and progression suggests that it represents a potential target for prevention and treatment of cSCC., (© 2022 Wiley Periodicals LLC.)
- Published
- 2023
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46. Inhibition of Fibroblast Growth Factor Receptor Attenuates UVB-Induced Skin Carcinogenesis.
- Author
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Thakur MA, Khandelwal AR, Gu X, Rho O, Carbajal S, Kandula RA, DiGiovanni J, and Nathan CO
- Subjects
- Mice, Animals, Receptors, Fibroblast Growth Factor metabolism, Proto-Oncogene Proteins c-akt metabolism, STAT3 Transcription Factor metabolism, Ultraviolet Rays adverse effects, TOR Serine-Threonine Kinases metabolism, Mechanistic Target of Rapamycin Complex 1 metabolism, Carcinogenesis, RNA, Messenger, Carcinoma, Squamous Cell genetics, Skin Neoplasms etiology, Skin Neoplasms prevention & control, Skin Neoplasms pathology
- Abstract
Altered fibroblast GF receptor (FGFR) signaling has been shown to play a role in a number of cancers. However, the role of FGFR signaling in the development and progression of UVB-induced cutaneous squamous cell carcinoma remains unclear. In this study, the effect of UVB radiation on FGFR activation and its downstream signaling in mouse skin epidermis was examined. In addition, the impact of FGFR inhibition on UVB-induced signaling and skin carcinogenesis was also investigated. Exposure of mouse dorsal skin to UVB significantly increased the phosphorylation of FGFRs in the epidermis as well as the activation of downstream signaling pathways, including protein kinase B/mTOR, signal transducers and activators of transcription, and MAPK. Topical application of the pan-FGFR inhibitor AZD4547 to mouse skin before exposure to UVB significantly inhibited FGFR phosphorylation as well as mTORC1, signal transducer and activator of transcription 3, and MAPK activation (i.e., phosphorylation). Moreover, AZD4547 pretreatment significantly inhibited UVB-induced epidermal hyperplasia and hyperproliferation and reduced the infiltration of mast cells and macrophages into the dermis. AZD4547 treatment also significantly inhibited mRNA expression of inflammatory genes in the epidermis. Finally, mice treated topically with AZD4547 before UVB exposure showed decreased cutaneous squamous cell carcinoma incidence and increased survival rate. Collectively, the current data support the hypothesis that inhibition of FGFR in the epidermis may provide a new strategy to prevent and/or treat UVB-induced cutaneous squamous cell carcinoma., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
47. CXCR4 and CXCR7 signaling promotes tumor progression and obesity-associated epithelial-mesenchymal transition in prostate cancer cells.
- Author
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Ahn S, Saha A, Clark R, Kolonin MG, and DiGiovanni J
- Subjects
- Animals, Cell Line, Tumor, Chemokine CXCL12 genetics, Chemokine CXCL12 metabolism, Epithelial-Mesenchymal Transition, Histone Demethylases metabolism, Histones, Male, Mice, Obesity genetics, Prostate pathology, Receptors, CXCR4 metabolism, Prostatic Neoplasms pathology, Receptors, CXCR
- Abstract
Obesity is associated with increased prostate cancer (PCa) progression and higher mortality, however, the mechanism(s) remain still unclear. Here, we investigated signaling by the ASC-secreted chemokine CXCL12 in a mouse allograft model of PCa and in HiMyc mice in the context of diet-induced obesity. Treatment of mice with CXCR4 antagonist inhibited CXCL12-induced signaling pathways, tumor growth and EMT in HMVP2 allograft tumors. Similar results were obtained following prostate epithelium-specific deletion of CXCR4 in HiMyc mice. We also show that CXCR4 signaling regulates expression of JMJD2A histone demethylase and histone methylation which is modulated by AMD3100. Importantly, treatment with a CXCR7 antagonist also inhibited allograft tumor growth and EMT. The current results demonstrate that both CXCR4 and CXCR7 play an important role in cancer progression and establish CXCL12 signaling pathways, activated in obesity, as potential targets for PCa intervention. In addition, other factors secreted by ASCs, may also contribute to cancer aggressiveness in obesity., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2022
- Full Text
- View/download PDF
48. White adipose tissue-derived factors and prostate cancer progression: mechanisms and targets for interventions.
- Author
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Saha A, Hamilton-Reeves J, and DiGiovanni J
- Subjects
- Adipose Tissue metabolism, Chemokine CXCL12, Humans, Male, Obesity metabolism, Adipose Tissue, White metabolism, Prostatic Neoplasms metabolism
- Abstract
Obesity represents an important risk factor for prostate cancer, driving more aggressive disease, chemoresistance, and increased mortality. White adipose tissue (WAT) overgrowth in obesity is central to the mechanisms that lead to these clinical observations. Adipose stromal cells (ASCs), the progenitors to mature adipocytes and other cell types in WAT, play a vital role in driving PCa aggressiveness. ASCs produce numerous factors, especially chemokines, including the chemokine CXCL12, which is involved in driving EMT and chemoresistance in PCa. A greater understanding of the impact of WAT in obesity-induced progression of PCa and the underlying mechanisms has begun to provide opportunities for developing interventional strategies for preventing or offsetting these critical events. These include weight loss regimens, therapeutic targeting of ASCs, use of calorie restriction mimetic compounds, and combinations of compounds as well as specific receptor targeting strategies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
- Full Text
- View/download PDF
49. Metabolomics-based phenotypic screens for evaluation of drug synergy via direct-infusion mass spectrometry.
- Author
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Lu X, Hackman GL, Saha A, Rathore AS, Collins M, Friedman C, Yi SS, Matsuda F, DiGiovanni J, Lodi A, and Tiziani S
- Abstract
Drugs used in combination can synergize to increase efficacy, decrease toxicity, and prevent drug resistance. While conventional high-throughput screens that rely on univariate data are incredibly valuable to identify promising drug candidates, phenotypic screening methodologies could be beneficial to provide deep insight into the molecular response of drug combination with a likelihood of improved clinical outcomes. We developed a high-content metabolomics drug screening platform using stable isotope-tracer direct-infusion mass spectrometry that informs an algorithm to determine synergy from multivariate phenomics data. Using a cancer drug library, we validated the drug screening, integrating isotope-enriched metabolomics data and computational data mining, on a panel of prostate cell lines and verified the synergy between CB-839 and docetaxel both in vitro (three-dimensional model) and in vivo . The proposed unbiased metabolomics screening platform can be used to rapidly generate phenotype-informed datasets and quantify synergy for combinatorial drug discovery., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)
- Published
- 2022
- Full Text
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50. NUAK family kinase 2 is a novel therapeutic target for prostate cancer.
- Author
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Fu W, Zhao MT, Driver LM, Schirmer AU, Yin Q, You S, Freedland SJ, DiGiovanni J, Drewry DH, and Macias E
- Subjects
- Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Male, Protein Serine-Threonine Kinases, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics
- Abstract
Current advancements in prostate cancer (PC) therapies have been successful in slowing PC progression and increasing life expectancy; however, there is still no curative treatment for advanced metastatic castration resistant PC (mCRPC). Most treatment options target the androgen receptor, to which many PCs eventually develop resistance. Thus, there is a dire need to identify and validate new molecular targets for treating PC. We found NUAK family kinase 2 (NUAK2) expression is elevated in PC and mCRPC versus normal tissue, and expression correlates with an increased risk of metastasis. Given this observation and because NUAK2, as a kinase, is actionable, we evaluated the potential of NUAK2 as a molecular target for PC. NUAK2 is a stress response kinase that also plays a role in activation of the YAP cotranscriptional oncogene. Combining pharmacological and genetic methods for modulating NUAK2, we found that targeting NUAK2 in vitro leads to reduction in proliferation, three-dimensional tumor spheroid growth, and matrigel invasion of PC cells. Differential gene expression analysis of PC cells treated NUAK2 small molecule inhibitor HTH-02-006 demonstrated that NUAK2 inhibition results in downregulation of E2F, EMT, and MYC hallmark gene sets after NUAK2 inhibition. In a syngeneic allograft model and in radical prostatectomy patient derived explants, NUAK2 inhibition slowed tumor growth and proliferation rates. Mechanistically, HTH-02-006 treatment led to inactivation of YAP and the downregulation of NUAK2 and MYC protein levels. Our results suggest that NUAK2 represents a novel actionable molecular target for PC that warrants further exploration., (© 2021 Wiley Periodicals LLC.)
- Published
- 2022
- Full Text
- View/download PDF
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