bluuebunny/crossref_metadata_2025 huggingface dataset:
A Survey on Additively Manufactured Nanocomposite Biomaterial for Orthopaedic Applications
Authors: Gowtham S. , Kumar T.Ch. Anil , Devi N. S. M. P. Latha , Chakravarthi M. Kalyan , Pradeep Kumar S. , Karthik R. , Anandaram Harishchander , Kumar N. Manoj , Ramaswamy Kiran
Published: June 2022

The sturdy demands in orthopaedics are not yet fulfilled, in both bone replacement and joint substitution and also in other repairs of bone defects. Metals are used for bone repair and replacement for a long period of time instead of biomaterial. Most of the countries are still now practising bone replacement with metals like titanium and stainless steel only due to the lag of technology advancement. A lot of research and development paves the way to composite biomaterial, as it is evolving in the domain of treatment of orthopaedics. There was massive research undergoing in the biomaterial field recently, and various methods of fabrication have been tested and implemented. Nanocomposites provide a higher surface‐to‐volume ratio, surface chemistry and nanoscale reinforcement, flexible production techniques, good corrosion and erosion resistance, and cheaper costs. The nanocomposite biomaterials were intended for biomedical purposes. Because of the intricacy of biological structures (tissue or organ) and additive manufacturing techniques for tissue engineering, scaffolding has wide scope for instant remedies in bone implant. The design restrictions and physical attributes of fast prototyping structures are then evaluated in terms of input factors like design elements, material choices, and additive manufacturing processing parameters. As a result of this survey, the needs and application importance of additively manufactured implants for the regeneration of various biomaterial types as well as the attempts undertaken to mitigate their medical impairment are suggested.
Damage Characteristics of Uniaxial Compressed Concrete Embedded Different Aging Rubber by 3D Mesoscale Model
Authors: Yu Shuo , Cao Miaofeng , Liu Changbao , Jin Hao
Published: June 2022

Rapid development of the automobile industry has brought the disposal problem of waste rubber tires. Mixing waste rubber tires into concrete can not only solve environmental problems but also improve the mechanical properties of concrete. Rubber aging is one of the main factors to affect the mechanical properties of rubberized concrete. Therefore, an FEM model of rubberized concrete in mesoscale is established in this paper. The influence of rubber aging on the uniaxial compression damage of rubberized concrete is u;studied. The results show that (1) the elastic modulus and compressive strength of rubberized concrete are negatively correlated with the aging level and content of rubber and positively correlated with the particle size of rubber. (2) After uniaxial compression of concrete enters the softening section, the crack resistance of concrete is positively correlated with the aging level and content of rubber and negatively correlated with the particle size of rubber. (3) Compared with the elastic modulus, the compressive strength of rubberized concrete is more sensitive to the change of parameters of rubber, that is, the change range of the compressive strength of rubberized concrete is always greater than the change range of its elastic modulus, when the aging level, content, and particle size of rubber change.
Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition
Authors: Goudar Ranjit K. , Shi Qing , Hjelmeland Mark D. , Keir Stephen T. , McLendon Roger E. , Wikstrand Carol J. , Reese Elizabeth D. , Conrad Charles A. , Traxler Peter , Lane Heidi A. , Reardon David A. , Cavenee Webster K. , Wang Xiao-Fan , Bigner Darell D. , Friedman Henry S. , Rich Jeremy N.
Published: June 2022

Malignant gliomas are highly lethal tumors that display striking genetic heterogeneity. Novel therapies that inhibit a single molecular target may slow tumor progression, but tumors are likely not dependent on a signal transduction pathway. Rather, malignant gliomas exhibit sustained mitogenesis and cell growth mediated in part through the effects of receptor tyrosine kinases and the mammalian target of rapamycin (mTOR). AEE788 is a novel orally active tyrosine kinase inhibitor that decreases the kinase activity associated with the epidermal growth factor receptor and, at higher concentrations, the vascular endothelial growth factor receptor 2 (kinase domain region). RAD001 (everolimus) is an orally available mTOR inhibitor structurally related to rapamycin. We hypothesized that combined inhibition of upstream epidermal growth factor receptor and kinase domain region receptors with AEE788 and inhibition of the downstream mTOR pathway with RAD001 would result in increased efficacy against gliomas compared with single-agent therapy. In vitro experiments showed that the combination of AEE788 and RAD001 resulted in increased rates of cell cycle arrest and apoptosis and reduced proliferation more than either agent alone. Combined AEE788 and RAD001 given orally to athymic mice bearing established human malignant glioma tumor xenografts resulted in greater tumor growth inhibition and greater increases in median survival than monotherapy. These studies suggest that simultaneous inhibition of growth factor receptor and mTOR pathways offer increased benefit in glioma therapy.
Gene expression changes induced by green tea polyphenol (−)-epigallocatechin-3-gallate in human bronchial epithelial 21BES cells analyzed by DNA microarray
Authors: Vittal Ragini , Selvanayagam Zachariah E. , Sun Yi , Hong Jungil , Liu Fang , Chin Khew-Voon , Yang Chung S.
Published: June 2022

Many studies suggest green tea is a cancer chemopreventive agent. This effect has been attributed to its major constituent (−)-epigallocatechin-3-gallate (EGCG). EGCG is also observed to have cytotoxic anticancer effects, especially when used in combination with certain chemotherapeutic agents. The biochemical actions of EGCG in chemoprevention and anticancer effects have been studied; however, the mechanisms of action are not clearly understood. We show here by expression genomics the effects of EGCG (25 μmol/L) in the Ha-ras gene transformed human bronchial epithelial 21BES cells. We found induction of temporal changes in gene expression and the coalescence of specific genetic pathways by EGCG. In this experimental system, hydrogen peroxide (H2O2) was produced. By treating cells with EGCG in the presence or absence of catalase, we further distinguished gene expression changes that are mediated by H2O2 from those that are H2O2 independent. Many genes and cellular pathways, including genes of the transforming growth factor-β signaling pathway, were H2O2 dependent because the effects were abolished by catalase. Gene expression changes that were not affected by catalase included those of the bone morphogenetic protein signaling pathway, peptidylprolyl isomerase (cyclophilin)–like 2, alkylated DNA repair enzyme alkB, polyhomeotic-like 2, and homeobox D1. We show further that EGCG and H2O2 differentially transactivated the bone morphogenetic protein and the transforming growth factor-β response element promoter reporters, respectively, thus confirming results from DNA microarray analysis. The elucidation of gene expression changes between H2O2-dependent and H2O2-independent responses helps us better understand the cancer chemopreventive and anticancer actions of EGCG.
Topoisomerase-IIα expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel
Authors: Durbecq Virginie , Paesmans Marianne , Cardoso Fatima , Desmedt Christine , Di Leo Angelo , Chan Stephen , Friedrichs Kay , Pinter Tamas , Van Belle Simon , Murray Elizabeth , Bodrogi István , Walpole Euan , Lesperance Bernard , Korec Stefan , Crown John , Simmonds Peter , Perren Thimothy J. , Leroy Jean-Yves , Rouas Ghizlane , Sotiriou Christos , Piccart Martine , Larsimont Denis
Published: June 2022

Purpose: The predictive value of topoisomerase-IIα (topo-II) has been evaluated in advanced breast cancer patients randomly treated with single-agent doxorubicin or docetaxel. Experimental design: Primary tumor samples from patients enrolled in a randomized, phase III clinical trial comparing single-agent doxorubicin (75 mg/m2 q3wks) with docetaxel (100 mg/m2 q3wks) were collected and topo-II status was evaluated by immunohistochemistry (clone KiS1). Results: Topo-II status was evaluated in 108 samples, 55 (51%) in the doxorubicin arm and 53 (49%) in the docetaxel arm. An increment of 10% in cells expressing topo-II is associated with a statistically significant odds ratio (OR; 95% confidence interval) of 1.09 (1.03–1.15; P = 0.002) for overall response to doxorubicin versus 1.002 (0.94–1.07; P = 0.95) in the docetaxel arm. With increasing topo-II, the favorable OR for overall response to docetaxel compared with doxorubicin decreases to become not significant in patients with topo-II tumor content >10%. In a multivariate analysis, (a) HER-2 status seems positively correlated with overall response to chemotherapy (OR, 2.34; 95% confidence interval, 0.87–6.27; P = 0.09). (b) Overall response to doxorubicin is significantly lower than overall response to docetaxel (OR, 0.17; 95% confidence interval, 0.04–0.64; P = 0.009) but with a significant interaction term for doxorubicin-treated patients with topo-II tumor content >10% (OR, 8.31; 95% confidence interval, 1.86–37.03; P = 0.05). Conclusions: (a) Topo-II overexpression confers a higher probability of response in the doxorubicin arm only. (b) Despite being a small retrospective study, this study is in line with previously reported studies and the hypotheses raised are now being tested in a prospective neoadjuvant trial.
Genistein potentiates inhibition of tumor growth by radiation in a prostate cancer orthotopic model
Authors: Hillman Gilda G. , Wang Yu , Kucuk Omer , Che Mingxin , Doerge Daniel R. , Yudelev Mark , Joiner Michael C. , Marples Brian , Forman Jeffrey D. , Sarkar Fazlul H.
Published: June 2022

Objective: We have shown previously that pretreatment with genistein potentiated cell killing induced by radiation in human PC-3 prostate carcinoma cell line in vitro. We tested this approach in vivo using an orthotopic prostate carcinoma model of PC-3 cells in nude mice. Methods: Established prostate tumors were pretreated with p.o. genistein at a dose of 5 mg/d for 2 days followed by tumor irradiation with 5 Gy photons. One day after radiation, genistein was resumed and given every other day for 4 weeks. Results: Genistein combined with radiation caused a significantly greater inhibition of primary tumor growth (87%) compared with genistein (30%) or radiation (73%) alone. The number of metastatic lymph nodes was also significantly decreased following genistein and radiation. Paradoxically, genistein alone increased the size of lymph nodes associated with heavy tumor infiltration. Genistein-treated prostate tumors were large with necrosis, apoptotic cells, and giant cells and have a lower proliferation index than in control tumors. Following radiation, areas of tumor destruction replaced by fibrotic tissue and inflammatory cells as well as giant cells were observed, which are typical of radiation effect. After radiation and genistein treatment, an increase in giant cells, apoptosis, inflammatory cells, and fibrosis was observed with decreased tumor cell proliferation consistent with increased tumor cell destruction. Long-term therapy with genistein after prostate tumor irradiation significantly increased survival. Conclusions: Genistein combined with prostate tumor irradiation led to a greater control of the growth of the primary tumor and metastasis to lymph nodes than genistein or radiation alone, resulting in greater survival.
Targeting tumor microvessels using doxorubicin encapsulated in a novel thermosensitive liposome
Authors: Chen Qing , Tong Sheng , Dewhirst Mark W. , Yuan Fan
Published: June 2022

Liposomal drugs accumulate only in perivascular regions in tumors after i.v. injection. Thus, they cannot kill tumor cells in deeper tissue layers. To circumvent this problem, we investigated effects of doxorubicin (DOX) encapsulated in a lysolecithin-containing thermosensitive liposome (LTSL) on tumor microcirculation because damaging microvessels would stop nutrient supply to deeper tumor cells. We used LTSL-DOX in combination with hyperthermia to treat a human squamous carcinoma xenograft (FaDu) implanted in dorsal skinfold chambers in nude mice. Before the treatment, the RBC velocity in tumors was 0.428 ± 0.037 mm/s and the microvascular density was 3.93 ± 0.44 mm/mm2. At 24 hours after the treatment, they were reduced to 0.003 ± 0.003 mm/s and 0.86 ± 0.27 mm/mm2, respectively. The same treatment, however, caused only 32% decrease in the RBC velocity and no apparent change in microvascular networks in normal s.c. tissues over the same period. LTSL and LTSL-DOX alone had no effect on tumor microcirculation, and LTSL plus hyperthermia caused only a transient decrease in the RBC velocity in tumors. At 24 hours after treatments, tumor microcirculation in all these control experiments was insignificantly different from that before the treatments. We also examined apoptosis of cells in tumors at different time points after LTSL-DOX plus hyperthermia treatment and observed few apoptotic cells in tumor microvessels. In conclusion, the rapid release of DOX during hyperthermia could make the drug to shutdown tumor blood flow while have only minor effects on normal microcirculation in s.c. tissues.
Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts
Authors: Fry David W. , Harvey Patricia J. , Keller Paul R. , Elliott William L. , Meade MaryAnne , Trachet Erin , Albassam Mudher , Zheng XianXian , Leopold Wilbur R. , Pryer Nancy K. , Toogood Peter L.
Published: June 2022

PD 0332991 is a highly specific inhibitor of cyclin-dependent kinase 4 (Cdk4) (IC50, 0.011 μmol/L) and Cdk6 (IC50, 0.016 μmol/L), having no activity against a panel of 36 additional protein kinases. It is a potent antiproliferative agent against retinoblastoma (Rb)-positive tumor cells in vitro, inducing an exclusive G1 arrest, with a concomitant reduction of phospho-Ser780/Ser795 on the Rb protein. Oral administration of PD 0332991 to mice bearing the Colo-205 human colon carcinoma produces marked tumor regression. Therapeutic doses of PD 0332991 cause elimination of phospho-Rb and the proliferative marker Ki-67 in tumor tissue and down-regulation of genes under the transcriptional control of E2F. The results indicate that inhibition of Cdk4/6 alone is sufficient to cause tumor regression and a net reduction in tumor burden in some tumors.
Biological impediments to monoclonal antibody–based cancer immunotherapy
Authors: Christiansen Jason , Rajasekaran Ayyappan K.
Published: June 2022

The ability of antibodies to exploit antigenic differences between normal and malignant tissues and to exact a variety of antitumor responses offers significant advantages to conventional forms of therapy. Several monoclonal antibodies (mAb) have already proved to be relatively well tolerated and effective for the treatment of many different malignant diseases. However, mAbs must overcome substantial obstacles to reach antigens presented on target cells to be of therapeutic value. Intravenously administered antibodies must avoid host immune response and contend with low or heterogeneous expression of antigen on tumor cells. Antibodies must also overcome significant physical barriers en route to a solid tumor mass, including the vascular endothelium, stromal barriers, high interstitial pressure, and epithelial barriers. Here we review the application and evolution of mAbs as effective forms of treatment, with particular attention to the barriers and impediments to successful treatment and discuss strategies to overcome these barriers and improve the efficacy of mAb-based therapy.
Different proteome pattern of epidermal growth factor receptor–positive colorectal cancer cell lines that are responsive and nonresponsive to C225 antibody treatment
Authors: Skvortsov Sergej , Sarg Bettina , Loeffler-Ragg Judith , Skvortsova Ira , Lindner Herbert , Werner Ott Helmut , Lukas Peter , Illmensee Karl , Zwierzina Heinz
Published: June 2022

The monoclonal antibody C225 directed against the epidermal growth factor receptor (EGFR) blocks downstream mitogenic signaling and is effective in patients with advanced colorectal cancer. Clinical data, however, suggest the presence of primary and secondary resistance mechanisms that are hardly understood. To define proteins involved in EGFR-triggered growth regulation and potential resistance mechanisms, we characterized the proteome profile of two colorectal cancer cell lines with a high expression of functional EGFR but a different response to treatment with C225. In Caco-2 and HRT-18, a complete saturation of EGFR was achieved after incubation with C225; whereas Caco-2 showed inhibition of proliferation, growth of HRT-18 was not suppressed. Using two-dimensional electrophoresis and subsequent mass spectrometry, we identified 14 proteins differentially expressed in both cell lines. All proteins are involved in metabolic pathways and malignant growth. Expression of enzymes such as ubiquitin carboxyl-terminal hydrolase isozyme 1, glutathione S-transferase P, and chloride intracellular channel protein 1 does not seem to interfere with the antiproliferative effect of anti-EGFR antibody. On the other hand, expression of proteins such as fatty acid binding protein and heat shock protein 27 might constitute strong antiapoptotic effects contributing to the nonresponse of HRT-18 to C225 treatment. Proteome-based investigations can help us better understand the complex protein interactions involved in EGFR signaling and its blockage by therapeutic monoclonal antibodies.
Highly efficient delivery of p16 antitumor peptide into aggressive leukemia/lymphoma cells using a novel transporter system
Authors: Kondo Eisaku , Seto Masao , Yoshikawa Kazuhiro , Yoshino Tadashi
Published: June 2022

Molecular targeting of hematopoietic malignancies has been generally hindered by technological obstacles to gene delivery in the neoplastic cells. The development of peptide delivery systems based on protein transduction domains has recently gained attention as a means of potentially overcoming these impediments. Here, we present a novel peptide transporter system that increases the efficiency of peptide delivery more than 10 times compared with the previous methods. The transporter, Wr-T, has an enlarged hydrophobic pocket consisting of triple tryptophan-rich domains fused with nine d-enantiomer polyarginines (r9) via Gly-Pro-Gly spacer, which serves to augment delivery of a cargo peptide. Wr-T–mediated transport of p16INK4a functional peptide dramatically inhibits growth of highly aggressive leukemia/lymphomas by up to 80% through restoration of p16 function. The Wr-T system thus represents a highly effective approach to cargo peptide delivery with the potential for substantially developing p16 peptide–based therapy for hematopoietic malignancies.
Camptothecin- and etoposide-induced apoptosis in human leukemia cells is independent of cell death receptor-3 and -4 aggregation but accelerates tumor necrosis factor–related apoptosis-inducing ligand–mediated cell death
Authors: Bergeron Stephane , Beauchemin Myriam , Bertrand Richard
Published: June 2022

During camptothecin- and etoposide (VP-16)-induced apoptosis in HL-60 cells, the expression level of cell death receptor-3 (DR3), cell death receptor-4 (DR4), and FAS remained mostly unchanged, whereas the expression of silencers of death domain (SODD) and FLICE inhibitory proteins, inhibitors of the cell death receptor signaling pathways, decreased substantially. By indirect immunofluorescence and immunoperoxidase imaging and with gel filtration column chromatography, we observed rapid aggregation at the cell surface and the appearance of high molecular weight protein complexes primarily involving DR3, and DR3 and DR4 after camptothecin and VP-16 treatment, respectively. Both drugs failed to rapidly promote FAS aggregation in these cells. The high expression level of SODD or of dominant negative forms of FADD (FADD-DN) and DAP3 (DAP3-DN), or of NH 2-terminal deletion mutant of TRADD (TRADD-ND) achieved by transient transfection experiments, did not impair the kinetics of apoptosis after camptothecin and VP-16 treatment in HL-60 and U937 cells. Taken together, these observations suggested that camptothecin and VP-16 induced rapid aggregation of DR4 and DR3, but paradoxically, the importance of these events in signaling apoptosis is uncertain, because the kinetics of apoptosis were unaffected, even in the presence of a high expression level of SODD, FADD-DN, TRADD-ND, and DAP3-DN. However, camptothecin or VP-16 treatment in combination with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) substantially accelerated kinetics of apoptosis than treatment with camptothecin, VP-16, or TRAIL alone. In contrast, cotreatment of camptothecin or VP-16 with TWEAK or TL1A did not facilitate apoptosis in HL60 cells. These findings suggest that DR4 aggregation mediated by camptothecin or VP-16 could represent a mean that accelerates TRAIL-induced apoptosis.
Enhanced efficacy of therapy with antisense BCL-2 oligonucleotides plus anti-CD20 monoclonal antibody in scid mouse/human lymphoma xenografts
Authors: Smith Mitchell R. , Jin Fang , Joshi Indira
Published: June 2022

Monoclonal anti-CD20 antibody (rituximab) is active, but not curative, therapy for B-cell non-Hodgkin's lymphoma. BCL-2 is an antiapoptotic protein whose expression is dysregulated in most indolent B-cell malignancies. Antisense oligonucleotides (AS-ODNs) that down-regulate BCL-2 expression induce apoptosis and chemosensitize B-cell lymphoma cells. We hypothesized that BCL-2 down-regulation by AS-ODNs would sensitize cells to rituximab and improve therapeutic results. There is enhanced apoptosis and reduction in cell numbers when DoHH2 cells are treated in vitro with rituximab plus BCL-2 AS-ODNs, compared with either agent alone. There is little in vitro effect on WSU-FSCCL cells by rituximab, AS-ODNs that down-regulate BCL-2 by targeting the immunoglobulin portions of the BCL-2-immunoglobulin fusion molecule, or a combination of the two. The combination is more effective than either agent alone in clearing DoHH2 cells from ascites in scid mice. Combination therapy with AS-BCL-2-ODNs and rituximab significantly prolongs survival in both the DoHH2 and WSU-FSCCL models. With higher and repeated doses, this combination could be curative. We conclude that the combination of rituximab and antisense-mediated down-regulation of BCL-2 has enhanced activity against human lymphoma, prolongs survival, and could cure mice bearing human lymphoma. This merits investigation in clinical trials.
Cytochrome P450 enzymes: Novel options for cancer therapeutics
Authors: McFadyen Morag C. E. , Melvin William T. , Murray Graeme I.
Published: June 2022

The concept of overexpression of individual forms of cytochrome P450 enzymes in tumor cells is now becoming well recognized. Indeed, a growing body of research highlights the overexpression of P450s, particularly CYP1B1, in tumor cells as representing novel targets for anticancer therapy. The purpose of this review is to outline the novel therapeutic options and opportunities arising from both enhanced endogenous expression of cytochrome P450 in tumors and cytochrome P450-mediated gene therapy.
Proteasome-mediated degradation of cell division cycle 25C and cyclin-dependent kinase 1 in phenethyl isothiocyanate-induced G2-M-phase cell cycle arrest in PC-3 human prostate cancer cells
Authors: Xiao Dong , Johnson Candace S. , Trump Donald L. , Singh Shivendra V.
Published: June 2022

Phenethyl isothiocyanate (PEITC), a constituent of many cruciferous vegetables, offers significant protection against cancer in animals induced by a variety of carcinogens. The present study demonstrates that PEITC suppresses proliferation of PC-3 cells in a dose-dependent manner by causing G2-M-phase cell cycle arrest and apoptosis. Interestingly, phenyl isothiocyanate (PITC), which is a structural analogue of PEITC but lacks the -CH2 spacers that link the aromatic ring to the -N=C=S group, neither inhibited PC-3 cell viability nor caused cell cycle arrest or apoptosis. These results indicated that even a subtle change in isothiocyanate (ITC) structure could have a significant impact on its biological activity. The PEITC-induced cell cycle arrest was associated with a >80% reduction in the protein levels of cyclin-dependent kinase 1 (Cdk1) and cell division cycle 25C (Cdc25C; 24 h after treatment with 10 μm PEITC), which led to an accumulation of Tyr15 phosphorylated (inactive) Cdk1. On the other hand, PITC treatment neither reduced protein levels of Cdk1 or Cdc25C nor affected Cdk1 phosphorylation. The PEITC-induced decline in Cdk1 and Cdc25C protein levels and cell cycle arrest were significantly blocked on pretreatment of PC-3 cells with proteasome inhibitor lactacystin. A 24 h exposure of PC-3 cells to 10 μm PEITC, but not PITC, resulted in about 56% and 44% decrease in the levels of antiapoptotic proteins Bcl-2 and Bcl-XL, respectively. However, ectopic expression of Bcl-2 failed to alter sensitivity of PC-3 cells to growth inhibition or apoptosis induction by PEITC. Treatment of cells with PEITC, but not PITC, also resulted in cleavage of procaspase-3, procaspase-9, and procaspase-8. Moreover, the PEITC-induced apoptosis was significantly attenuated in the presence of general caspase inhibitor and specific inhibitors of caspase-8 and caspase-9. In conclusion, our data indicate that PEITC-induced cell cycle arrest in PC-3 cells is likely due to proteasome-mediated degradation of Cdc25C and Cdk1, and ectopic expression of Bcl-2 fails to confer resistance to PEITC-induced apoptosis. Furthermore, the results of the present study point toward involvement of both caspase-8- and caspase-9-mediated pathways in apoptosis induction by PEITC.
The novel estrogen 17α-20Z-21-[(4-amino)phenyl]-19-norpregna-1,3,5(10),20-tetraene-3,17β-diol induces apoptosis in prostate cancer cell lines at nanomolar concentrations in vitro
Authors: Mobley James A. , L'Esperance James O. , Wu Mengchu , Friel Carolyn J. , Hanson Robert H. , Ho Shuk-Mei
Published: June 2022

Prostate cancer remains the number one cause of noncutaneous cancer, with 220,900 new cases predicted for the year 2003 alone. Of the more promising classes of compounds studied thus far for the treatment of prostate cancer, estrogens of various types have consistently exhibited antitumor activities both in vitro and in vivo. For this reason, we have synthesized and screened a library of unique 17α/11β modified 17β-estradiol (E2) analogues designed for estrogen receptor β (ER-β) specificity and a potential for cytotoxic activity directed toward prostate cancer cells. From this library, the novel compound 17α-20Z-21-[(4-amino)phenyl]-19-norpregna-1,3,5(10),20-tetraene-3,17β-diol (APVE2) was identified as the primary lead, found to induce a high level (>90%) of cell death through an apoptotic mechanism, with an EC50 of 1.4, 2.7, and 16 nm in the LNCaP, PC3, and DU145 cell lines, respectively. APVE2 was found to bind to ER-β, albeit weakly, with an EC50 of 250 nm and a binding activity of 6.2% relative to E2, nearly two orders of magnitude less than the concentration required to induce apoptosis. APVE2 bound preferentially to ER-β by 7-fold over ER-α, and did not induce growth in the MCF-7 cell line, thus indicating that it is not a classical ER agonist. Furthermore, the cytotoxic actions of APVE2 were not reversed by co-treatment with a 50-fold excess E2. In summary, a novel 17 modified estrogen APVE2 was identified as a lead compound, capable of inducing apoptosis in three prostate cancer cell lines at low nanomolar concentrations, through a mechanism inconsistent with an ER-mediated mechanism.
Abstract A02: A case for re-examination of the contribution of nitro-PAHs to combustion-product carcinogenesis
Authors: Blackburn Gary
Published: June 2022

One of the most studied compounds in all of cancer research is the environmental carcinogen benzo[a]pyrene (BaP). There is little doubt that BaP and its PAH congeners are the principal carcinogens in products like coal tar pitch, a category 1 IARC carcinogen. However, their concentrations in other complex hydrocarbon mixtures, like uncracked petroleum oils, are too low to account for their overall carcinogenic potency (that is, discounting contributory factors like tumor promotion and cumulative mutagenic insult). Nonetheless, the potent carcinogenicity of BaP and other four- and five-ring PACs has made reducing the release of these compounds into the environment from their principal endogenous source, petroleum, a major goal of health and safety regulation. Similar efforts to minimize the levels of the same PAHs pyrosynthesized and released into the atmosphere by the combustion of carbon fuels, have, however, faced a far greater challenge, given the immensity of that release on a daily basis. Moreover, the regulatory focus on parent, largely unsubstituted, PAHs has led to a de-emphasis on other potential contributors to the carcinogenicity of complex hydrocarbon mixtures, which in the case of the combustion products studied here, include their nitro-PAH derivatives. There are valid reasons for this de-emphasis. But there are also grounds to believe that a re-examination of the nitro-PAH role in combustion product carcinogenesis is warranted. Among them are the demonstration by Rosenkranz et al. (Science 1980;209:1039-43) that one such compound, 1,8-dinitropyrene (DNP), induces over one million mutations per microgram in the Ames Test, and the Iwagawa et al. report (Carcinogenesis 1989;10:1285-90) that its isomer 1,6-DNP, when injected directly into the lungs of rats, exhibited three times the carcinogenic potency of BaP similarly introduced. The present report demonstrates that extracts of soot or ash from a variety of sources, including wood, liquified petroleum gas, and the burnt ends of cigarettes, contain an extremely potent Ames Test mutagen that, when fractionated by HPLC, coelutes with authentic DNP. These results would seem to be inconsistent with the known low activities in lung tissue of the nitroreductase required for DNP’s activation to its ultimate carcinogenic form. But one possible explanation for that apparent discrepancy is that populations of bacteria resident in the lung—many species of which are as nitroreductase-proficient as the Salmonella strains used in Ames testing—may be largely responsible for that activation.

Citation Format: Gary Blackburn. A case for re-examination of the contribution of nitro-PAHs to combustion-product carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A02.
Abstract A16: Environmental exposure to persistent organic pollutants (POPs) and primary colorectal cancer risk: A case-cohort study in a community-based perspective cohort
Authors: Kim Jinsun , Park Eun Young , Kim Byungmi , Lim Min Kyung , Oh Jin-Kyoung
Published: June 2022

Background: Recent studies suggest that the low-dose environmental exposure of persistent organic pollutants (POPs) may develop prostate cancer or breast cancer based on prospective cohort study design. This study investigates a relationship between environmental exposures to POPs and the development of colorectal cancer (CRC) in the general population.

Methods: We conducted a case-cohort study based on the Korean National Cancer Center Community Cohort, which included 16,304 adults who enrolled from 1993 to 2010 and followed by 2016 for the cancer incidence. We included 104 CRC cases and 235 adults in a subcohort and assessed their serum lipid-adjusted levels of 19 organochlorine pesticides (OCPs) and 32 polychlorinated biphenyls (PCBs). Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for determining the association between POPs and risk of CRC were estimated using logistic regression analyses, controlling for following covariates: age, sex, education, physical activity, meat consumption, vegetable/fruit consumption, drinking, smoking, obesity, pesticides use experience, and residential areas.

Results: Natural log-transformed cis-heptachlor epoxide and p,p’-DDD were significantly associated with increased risk of CRC [ORcis-heptachlor epoxide = 1.29, 95% CI: 1.03-1.62; ORp,p’-DDD = 1.63, 95% CI: 1.11-2.41] and increased ORs were also estimated for the highest versus lowest tertiles of these two metabolites [ORcis-heptachlor epoxide = 2.64, 95% CI: 1.24-5.6, p-trend = 0.021; ORp,p’-DDD = 3.51, 95% CI: 1.58-7.78, p-trend = 0.004]. Also, there was a significant association between natural log-transformed PCB 52 and risk of CRC (ORPCB 52 = 1.54, 95% CI: 1.06-2.24).

Conclusion: Higher exposure to POPs, such as cis-heptachlor epoxide, p,p’-DDD, and PCB 52, was associated with the elevated risk of CRC. Our findings from a community-based prospective cohort provide evidence on the relationship between environmental exposure of POPs and CRC in the general population.

Citation Format: Jinsun Kim, Eun Young Park, Byungmi Kim, Min Kyung Lim, Jin-Kyoung Oh. Environmental exposure to persistent organic pollutants (POPs) and primary colorectal cancer risk: A case-cohort study in a community-based perspective cohort [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A16.
Abstract A42: The search for new targets for mitigation of metal toxicity based on molecular pathways of action: A case study using cadmium and iron
Authors: Mudipalli Anuradha
Published: June 2022

Cadmium is a nonessential heavy metal, ubiquitous in nature with a long half-life in human beings. It is widely used in various industrial applications such as toy and jewelry making and is one of the key constituents of tobacco and cigarette smoke. Cadmium, both at occupational and environmental levels, has been implicated in the causation of cancerous and noncancerous health outcomes. In comparison, iron is an essential metal and is a constituent of hemoglobin and many vital enzymes and proteins and plays a pivotal role in human health. However, increased consumption of iron from fortified diets and iron supplements presents opportunities for exposure to supraphysiologic iron concentrations and toxicity. Additionally, hereditary iron disorders (thalassemia, hereditary hemochromatosis), other disease conditions such as cancer and kidney diseases, and certain environmental exposures (e.g., steel-welding fumes, asbestos, and air pollution) could also lead to iron toxicity with disturbed homeostasis mechanisms affecting intracellular and systemic regulation of iron. Chelation therapy has traditionally been used to mitigate the toxicity of metals. This talk will present the results of systematic reviews and analyses for both cadmium and iron toxicity and highlight the diverse molecular pathways by which these metals can elicit toxic effects. Using the examples of cadmium and iron, I will discuss some recent advances in our understanding of the molecular mechanisms of metal toxicity and how this information can be used to identify novel targets for toxicity mitigation. (The views expressed in this abstract are those of the author and do not necessarily reflect the views or policies of EPA.)

Citation Format: Anuradha Mudipalli. The search for new targets for mitigation of metal toxicity based on molecular pathways of action: A case study using cadmium and iron [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A42.
Abstract A47: PFOA and zeranol exposure during puberty affects the transcriptomic profile of the rat mammary gland
Authors: Dang Nhi M. , Su Yanrong , Santucci-Pereira Julia , Russo Jose
Published: June 2022

Background: Perfluorooctanoic acid (PFOA) and zeranol (Zer) are known as endocrine-disrupting chemicals (EDCs); however, their potential either alone or in combination of increasing the susceptibility to breast cancer is still not fully understood. Here, we hypothesize that pubertal exposure to these EDCs has an impact on the transcriptomic profile of the mammary glands, which explains the less differentiated phenotype and increased susceptibility to carcinogenesis when challenged with a chemical carcinogens like DMBA.

Methods: Female Sprague-Dawley rats at 21 days of age were assigned to four groups and received daily gavage for three weeks with PFOA and Zer alone or in combination. A control group received only sesame oil. At 50 days and 100 days of age (d50 and d100, respectively) the animals were euthanized and the mammary glands were collected, the RNA was extracted, and a RNA-seq library was constructed and sequenced.

Results: We detected differentially expressed genes (DEGs, absolute fold change > 2 and FDR p< 0.05) at d50 by PFOA 136 (106 up- and 30 downregulated), Zer 394 (370 up and 24 down), and PFOA+Zer 630 (244 up and 386 down); and at d100, PFOA 74 DEGs (23 up and 51 down), Zer 405 (11 up and 394 down), and PFOA+Zer 669 (98 up and 571 down). Zer and PFOA+Zer caused the remarkable number of genes with expression alteration at both of two endpoints. Gene ontology enrichment analyses revealed that zeranol affects immune response at d50 but is majorly associated with tissue development at d100, whereas PFOA affects cell development at d50 but is mainly related to morphogenesis at d100. Meanwhile, PFOA+Zer is associated with metabolic process at both of two endpoints. KEGG pathway analysis demonstrated that PFOA+Zer’s effects at both d50 and d100 were notably mediated through PI3K-Akt and PPAR signaling pathways.

Conclusion: A relevant and significant finding is that each compound induces a different transcriptomic profile and changes its biologic effects between day 50 and day 100 of age, and when both compounds are administered together the transcriptomic profile differs from that induced by each individual one. The major EDCs affected pathways are PI3K-Akt and PPAR signaling, indicating that the long-term damaging effect of the combination of EDCs explains the less differentiated phenotype and its higher susceptibility to develop mammary cancer when challenged with a chemical carcinogen. (This work was supported by the NIEHS/NCI grant U01ES026130 and NCI/NIH Cancer Center Support Grant P30-CA006927.)

Citation Format: Nhi M. Dang, Yanrong Su, Julia Santucci-Pereira, Jose Russo. PFOA and zeranol exposure during puberty affects the transcriptomic profile of the rat mammary gland [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A47.
Abstract A51: Mechanistic pathways for breast carcinogens can highlight early effects as predictive endpoints for chemical safety testing: Case studies for ionizing radiation and for in utero exposure to estrogens such as DES
Authors: Helm Jessica , Hindman Andrea , Rudel Ruthann A.
Published: June 2022

Knowledge about established breast carcinogens can support improved 21st-century toxicologic testing by identifying key mechanistic events. To clarify mechanisms, we developed adverse outcome pathways (AOPs) for two well-established breast carcinogens: ionizing radiation (IR) and the pharmaceutical hormone diethylstilbestrol (DES). The AOP for ionizing radiation includes these elements: IR increases production of reactive oxygen and nitrogen species (RONS), and directly and indirectly causes DNA damage. DNA damage leads to mutations and proliferation, leading to increased breast cancer. RONS also increases inflammation, contributing to direct and indirect effects (effects in cells not directly reached by IR) via positive feedback to RONS, and separately increases breast cancer risk through increased proliferation of cells and increased tumor growth and invasion. Estrogen and progesterone also influence the risk of breast cancer from ionizing radiation, as does developmental stage. For in utero estrogens like DES, the AOP links gestational estrogen exposure to transcriptional activity that promotes altered signaling between the epithelial and stromal tissue compartments, leading to disrupted development, including altered tensional homeostasis and tissue architecture, inflammation, and altered cellular differentiation. These key events lead to several adverse outcomes at the tissue and organ level that increase susceptibility to breast cancer, including altered density, structure, and hormone sensitivity along with hyperplasia. Epigenetic alterations are a cellular-level outcome that propagates gestational estrogen exposure to later-life risk through cellular memory that directs ER-mediated gene expression and altered mammary development. Increased susceptibility to breast cancer follows from these adverse outcomes. Dose-response and developmental timing of exposure are discussed in both AOPs. These AOPs provide a framework for evaluating the potential for mechanistically similar stressors—e.g., genotoxicants/RONS-inducers may act like IR, or estrogenic chemicals in utero may act like DES—to affect breast cancer risk.

Citation Format: Jessica Helm, Andrea Hindman, Ruthann A. Rudel. Mechanistic pathways for breast carcinogens can highlight early effects as predictive endpoints for chemical safety testing: Case studies for ionizing radiation and for in utero exposure to estrogens such as DES [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A51.
Abstract A54: Case-based causality: An application of artificial intelligence to environmental carcinogenesis
Authors: Weed Douglas L.
Published: June 2022

Determining whether environmental exposures cause cancer is a complex and often controversial issue, involving epidemiologic and toxicologic studies and a family of methods discussed and debated for decades. These methods include the general scientific method, study design and statistical methods, and research synthesis methods—sometimes called “weight of evidence” methods—such as the systematic narrative review, meta-analysis, and criteria-based methods of causation. These methods have been applied to a wide range of topics involving environmental (and occupational and lifestyle) exposures as well as a wide variety of specific cancers. The purpose of this project is to bring a method from artificial intelligence (AI)—Case-Based Reasoning (CBR)—to bear on the issue of environmental causes of cancer. Case-Based Reasoning is an AI method that capitalizes upon past experience to solve current problems. In terms of the search for causes of disease, CBR (renamed Case-Based Causality) is a method that uses bodies of evidence from past examples of known causal relationships to inform the determination of causality for a body of evidence associated with an exposure-disease relationship under investigation. CBR is typically described at its conceptual level in terms of 5 “Rs”: Representation, Retrieval, Reuse, Revision, and Retention. Each “R” can be interpreted in terms of the causation issue in epidemiology and public health. “Representation,” for example, is the collection, description, summarization, and interpretation of a body of evidence regarding an exposure and a disease—what is basically provided by a high-quality systematic narrative review, which may include a meta-analysis. In this presentation, the 5 “Rs” of Case-Based Causality (CBC) will be described and applied to current issues in environmental carcinogenesis. In addition, the relationship of CBC to existing methods of causal inference will be noted as well as the links between CBC and the concept of reliability, i.e., the extent to which current methods of causal inference provide reproducible results. Fundamentally, Case-Based Causality is a method for examining whether a body of evidence under investigation can be considered causal by examining the extent to which its characteristics are similar to bodies of evidence from known (i.e., established) causal relationships.

Citation Format: Douglas L. Weed. Case-based causality: An application of artificial intelligence to environmental carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A54.
Abstract IA13: Key characteristics of carcinogens
Authors: Smith Martyn T.
Published: June 2022

The key characteristics (KCs) of human carcinogens were recently introduced as the basis of a uniform approach for searching, organizing, and evaluating mechanistic evidence to support cancer hazard identification (Smith et al., 2016; Guyton et al., 2018). The KCs comprise the properties of known human carcinogens, including their ability to be genotoxic, be immunosuppressive, or modulate receptor-mediated effects. Established human carcinogens commonly exhibit one or more of these characteristics, and therefore, data on these characteristics can provide independent evidence of carcinogenicity when human data are lacking. Such data can also help in interpreting the relevance and importance of findings of cancer in animals and in humans. In its 2017 report, “Using 21st Century Science to Improve Risk-Related Evaluations,” the NRC recently opined that the KCs approach “avoids a narrow focus on specific pathways and hypotheses and provides for a broad, holistic consideration of the mechanistic evidence.” They further suggested that key characteristics be developed for other endpoints, such as endocrine disruption and reproductive toxicity, and efforts in this regard are approaching completion and publication. The KC approach therefore holds great potential to improve hazard identification and risk assessment but still needs to be further developed, especially in regard to its integration with the hallmarks of cancer and its potential for helping analyze the toxic effects of untested chemicals and chemical mixtures in cell culture and experimental animals. Unfortunately, the current Tox21 and Toxcast repertoire of assays is mostly lacking in relevance to the KCs, as are most clinical biomarkers. Approaches to developing a new set of high-throughput tests and biomarkers (a CarciCAST) will be described along with a discussion of the use of the key characteristics approach in hazard identification and risk assessment instead of, or as well as, the current MOA/AOP approach.

References

Guyton KZ, Rusyn I, Chiu WA, Corpet DE, van den Berg M, Ross MK, et al. Application of the key characteristics of carcinogens in cancer hazard identification. Carcinogenesis 2018;39:614-22; doi:10.1093/carcin/bgy031.

Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, et al. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 2016;124:713-21; doi:10.1289/ehp.1509912.

Citation Format: Martyn T. Smith. Key characteristics of carcinogens [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA13.