bluuebunny/crossref_metadata_2025_split huggingface dataset:
Particle detection in rare gas solid crystals: a feasibility experimental study—exploring new ways for dark matter searches
Authors: Guarise Marco 
Published: June 2022

AbstractThis article reviews the experimental activity that has been carried out within the INFN DEMIURGOS research and development (R &D) project. This R &D concerns the study of possible innovative experimental approaches for the detection of low-energy-releases of feeble interacting particles within the matter. Possible applications could be the direct investigation of Dark Matter candidates. The idea behind the proposed scheme is to exploit rare gas solid crystals both pure and doped, combined with the in-vacuum single electron detection technology. In pure materials, the signal can be the charge produced directly during the ionization. Laser-assisted processes can instead be used to probe low-energy-releases in doped materials. Both these mechanisms should lead to a detectable electronic signal triggered by the incoming particle. In such a way, energy threshold ranging from meV to tens of eV could in principle be reached, opening-up the possibility to probe theoretically, well-motivated regions of unexplored electroweak parameter-space and thus test the existence of light Dark Matter candidates. The activity presented here has been performed to understand the mechanisms at the basis of the proposed detection scheme and possible showstopper. The experimental investigations refer to the research and development phases about: the crystal growing techniques and the corresponding set-up, the electrons’ extraction from rare gas crystals to the vacuum environment, and finally the spectroscopic studies on atomic species embedded into rare gas matrices.
Muscle-targetedinterleukin-12gene therapy of orthotopic hepatocellular carcinoma in mice usingin vivoelectrosonoporation
Authors: Yamashita Yo-ichi , Shimada Mitsuo , Minagawa Ryosuke , Tsujita Eiji , Harimoto Norifumi , Tanaka Shinji , Shirabe Ken , Miyazaki Jun-ichi , Maehara Yoshihiko 
Published: June 2022

AbstractWe developed a new potent nonviral gene transfer method into mouse muscles in vivo named “electrosonoporation.” We tried in this report to treat murine orthotopic hepatocellular carcinoma (HCC) by muscle-targeted mouse interleukin-12 (mIL-12) gene transfer using in vivo electrosonoporation. I.m. administration of the mIL-12 gene with electrosonoporation elevated serum IL-12 and IFN-γ and significantly prolonged the survival periods with both growth inhibition of orthotopic HCC and inhibition of spontaneous lung metastasis. The IL-12 gene therapy reduced the number of microvessels and induced more Mac-1-positive cells into HCC. These results show that muscle-targeted mIL-12 gene therapy for orthotopic HCC using in vivo electrosonoporation is very efficient and is thus promising for further clinical trial.
Modulation of p53 in 7,12-dimethylbenz[a]anthracene–induced skin tumors by diallyl sulfide in Swiss albino mice
Authors: Arora Annu , Siddiqui Imtiaz A. , Shukla Yogeshwer 
Published: June 2022

Abstract
Allium vegetables have been shown to have beneficial health effects against several chronic diseases including cancer. Diallyl sulfide (DAS), an organosulfur compound present in garlic, is well known for its chemopreventive properties in several tumor models. The pharmacologic role of DAS in prevention and treatment of cancer is well documented in the literature, but its molecular mechanism of action is not yet well defined. In the present study, modulation in p53 expression by topical application of DAS was recorded in 7,12-dimethylbenz[a]anthracene (DMBA)–induced skin tumors in Swiss albino mice. Western blot analysis and immunohistochemical protein detection, combined with multivariable flow cytometry, show that DAS application induces the expression of the wild-type (wt) p53 and down-regulates the expression of mutant (mut) p53. Immunoblotting analysis of tumors showed significant increase in levels of wtp53 by DAS application, whereas for mutp53 the DMBA-induced levels of protein were found to reduce to near normal levels with DAS application. The quantitative analysis of immunostained skin/tumor sections using image analysis and quantitative stereology showed 66.6% and 54.2% increases in wtp53 levels and 53.4% and 44.3% decreases in mutp53 levels in animals where DAS was applied 1 hour prior to or 1 hour after DMBA application, respectively. Flow cytometric analysis further confirmed modulation of wtp53 and mutp53 protein in DAS-supplemented tumors. The increase in the expression of wt tumor suppressor gene protein p53 was accompanied by elevation of the levels of cyclin-dependent kinase inhibitor p21/waf1. The percentage increase in the levels of p21/waf1 was found to be 72.9% and 61.3%, respectively, in DAS-supplemented groups before and after administration. These results thus show that DAS is a potential chemopreventive agent capable of modulating and regulating the tumor suppressor p53 along with its downstream effective molecule, p21/waf1. Thus, DAS can be a potential chemopreventive agent against skin tumor development.
A humanized monoclonal antibody to carcinoembryonic antigen, labetuzumab, inhibits tumor growth and sensitizes human medullary thyroid cancer xenografts to dacarbazine chemotherapy
Authors: Stein Rhona , Goldenberg David M. 
Published: June 2022

Abstract
A variety of observations have shown that carcinoembryonic antigen (CEA) is associated with growth and metastasis of cancers, including correlation of CEA serum levels with poor clinical outcome, mediation of cell-cell adhesion by CEA, and involvement of CEA in the immune recognition of tumors and apoptotic pathways. The purpose of this study was to investigate the effect that an anti-CEA monoclonal antibody (MAb) may have on the growth of medullary thyroid cancer (MTC), a CEA-expressing tumor, alone and in combination with chemotherapy. Antitumor effects were evaluated in a nude mouse-human MTC xenograft model. Using the TT MTC cell line grown s.c., we compared tumor growth in untreated mice with that of mice given the humanized anti-CEA MAb labetuzumab or an isotype-matched control MAb. The effects of time of administration post-tumor injection, MAb dose response, specificity of response, and combination with dacarbazine (DTIC) chemotherapy were studied. The humanized anti-CEA MAb, labetuzumab, has direct, specific, antitumor effects in this model, without conjugation to a cytotoxic agent. In addition, labetuzumab sensitizes these tumor cells to chemotherapy with an effective drug in this model, DTIC, without increased toxicity. Significant delays in tumor growth were caused by the MAb therapy or chemotherapy alone; however, the combination of these agents was significantly more effective than either agent given as a monotherapy or use of an irrelevant MAb in this model. The superiority of the combined modality treatment argues for the integration of CEA MAb therapy into chemotherapeutic regimens for MTC management and possibly other CEA-expressing neoplasms.
A therapeutic model for advanced endometrial cancer: Systemic progestin in combination with local adenoviral-mediated progesterone receptor expression
Authors: Dai Donghai , Albitar Lina , Nguyen Tan , Laidler Laura L. , Singh Meenakshi , Leslie Kimberly K. 
Published: June 2022

Abstract
Cancer of the uterine endometrium is a frequent gynecologic malignant disease for which few therapeutic options are available for advanced disease. Progesterone is the normal female hormone that limits growth and proliferation of endometrial cancers; however, progesterone receptors are frequently down-regulated, leading to treatment failures. The current studies explored the effectiveness of adenoviral-mediated progesterone receptor gene transduction in combination with progestin therapy in mouse xenograft models. Pretreatment of cells with progesterone receptor–encoding adenovirus and progestin inhibited the development of s.c. tumors in athymic mice. In the i.p. xenograft model, replacement of both isoforms of progesterone receptor, PRA and PRB, in combination with progestin treatment resulted in a significant 2.6-fold increase in overall survival time compared with control animals. These studies indicate that when progesterone receptor levels are maintained, progestin therapy is effective in limiting tumor growth. Future therapeutic regimens targeted at enhancing progesterone receptor expression have the potential to improve outcomes in women with endometrial cancer.
AG490 inhibits G1-S traverse in BALB/c-3T3 cells following either mitogenic stimulation or exogenous expression of E2F-1
Authors: Savell Jason , Ma Yihong , Morrow Kristin S. , Jove Richard , Olashaw Nancy , Moseley Pope L. , Cress W. Douglas , Wharton Walker 
Published: June 2022

Abstract
AG490, a member of the tryphostin family of protein kinase inhibitors, repressed G0-G1 traverse in BALB/c-3T3 cells. While the early induction of STAT activity was repressed by AG490, extracellular signal-regulated kinase (ERK) activation was unaffected and a pattern of gene expression suggested that cells exited G0 in the presence of the inhibitor. Although AG490 did not alter the induction of cyclin D1 protein, neither cyclin D1- nor cyclin D3-associated kinase activity was observed in growth-inhibited cells. Surprisingly, p130 was partially phosphorylated, and E2F3A protein was expressed in mitogen-stimulated AG490-treated cells despite the lack of cyclin D-associated kinase activity. These data suggest that AG490 inhibits a cellular pathway required for mid-G0-G1 traverse that is located after the induction of early processes potentially mediated by E2F (although independent of cyclin D-associated kinase activity) but before the late G1 increase in E2F-dependent transcription. Infection of AG490-treated cells with an E2F-1 adenovirus caused the induction of cyclin A, but could not overcome the drug-induced cell cycle arrest that was coincident with the repression of cyclin-dependent kinase 2 (cdk2)-associated kinase activation. We conclude that cdk2-associated kinase activity is modulated by a cellular process repressed by AG490. Furthermore, this cdk2-associated kinase activity is required for G0-G1 traverse in some role other than the regulation of E2F-dependent transcription.
The nuclear factor κB inhibitor parthenolide restores ICI 182,780 (Faslodex; fulvestrant)–induced apoptosis in antiestrogen-resistant breast cancer cells
Authors: Riggins Rebecca B. , Zwart Alan , Nehra Ruchi , Clarke Robert 
Published: June 2022

Abstract
The molecular mechanisms underlying the acquisition of resistance to the antiestrogen Faslodex are poorly understood, although enhanced expression and activity of nuclear factor κB (NFκB) have been implicated as a critical element of this phenotype. The purpose of this study was to elucidate the mechanism by which NFκB up-regulation contributes to Faslodex resistance and to determine whether pharmacologic inhibition of NFκB by the small molecule parthenolide could restore Faslodex-mediated suppression of cell growth. Basal expression of multiple NFκB-related molecules in MCF7-derived LCC1 (antiestrogen-sensitive) and LCC9 (antiestrogen-resistant) breast cancer cells was determined, and cells were treated with Faslodex or parthenolide. The effect of these drugs either singly or in combination was assessed by cell proliferation, estrogen receptor (ER)–dependent transcriptional activation, cell cycle analysis, and apoptosis assays. Expression of the p65 NFκB subunit and the upstream NFκB regulator IκB kinase γ/NFκB essential modulator were increased in the resistant MCF7/LCC9 cells (P = 0.001 and 0.04, respectively). Whereas MCF7/LCC9 cells were unresponsive to Faslodex alone, parthenolide effectively inhibited MCF7/LCC9 cell proliferation and the combination of Faslodex and parthenolide resulted in a 4-fold synergistic reduction in cell growth (P = 0.03). This corresponded to a restoration of Faslodex-induced apoptosis (P = 0.001), with no observable changes in ER-dependent transcription or cell cycle phase distribution. Because parthenolide has shown safety in Phase I clinical trials, these findings have direct clinical relevance and provide support for the design of clinical studies combining antiestrogens and parthenolide in ER-positive breast cancer.
Development of a high-throughput screen for inhibitors of replication protein A and its role in nucleotide excision repair
Authors: Andrews Brooke J. , Turchi John J. 
Published: June 2022

Abstract
The heterotrimeric protein, replication protein A (RPA), is essential for DNA repair and replication. RPA is a viable target in the treatment of cancer as many chemotherapeutic agents act by blocking DNA replication. Furthermore, inhibition of RPA could prove useful in treating cancers that have acquired resistance to DNA damaging agents through enhanced DNA repair mechanisms as has been observed with certain platinum-resistant carcinomas. In an effort to identify inhibitors of RPA, we employed a novel fluorescent reporter and established a homogeneous high-throughput screening assay to measure RPA's DNA binding activity. Using this assay, we have screened a collection of small molecules and determined the effect they have on the RPA-DNA interaction. Of the 2000 compounds screened, 79 scored positive for inhibition of RPA binding activity. Secondary screenings were performed using an electrophoretic mobility shift assay; of the 79 compounds, 9 scored positive and were further characterized in titration experiments to determine the most potent inhibitor, resulting in several compounds showing an IC50 in the low micromolar range. Fluorescence polarization analyses were also performed to determine the mechanism of inhibition for each compound. Validation of the inhibitory activity of selected compounds was verified using in vitro nucleotide excision repair (NER) catalyzed excision of a single cisplatin lesion in a duplex DNA. The identification and use of RPA inhibitors may aid in inhibiting NER activity that could potentially circumvent resistance to certain chemotherapeutic agents as well as be useful in the characterization of RPA and its interaction with DNA.
Epigenetic regulation of O6-methylguanine-DNA methyltransferase gene expression by histone acetylation and methyl-CpG binding proteins
Authors: Danam Rebecca P. , Howell Sherie R. , Brent Thomas P. , Harris Linda C. 
Published: June 2022

Abstract
Transcriptional silencing of the DNA repair gene, O6-methylguanine-DNA methyltransferase (MGMT) in a proportion of transformed cell lines is associated with methylated CpG hotspots in the MGMT 5′ flank. The goal of the study was to evaluate the mechanism by which CpG methylation of theMGMT promoter region influenced silencing of the gene. Analysis of histone acetylation status in two regions of the promoter using chromatin immunoprecipitation assay showed that a higher level of histone acetylation was associated with expression in three MGMT-expressing cell lines (HeLa CCL2, HT29, and Raji) compared with three MGMT-silenced cell lines (HeLa S3, BE, and TK6). To determine how the modulation of CpG methylation and histone acetylation influenced MGMT expression, we exposed the cells to 5-aza-2′deoxycytidine (5-Aza-dC), inhibitor of DNA methylation, which strongly up-regulated MGMT expression in three MGMT-silenced cell lines whereas trichostatin A, inhibitor of histone deacetylase, weakly induced MGMT. However, combined treatment with 5-Aza-dC and trichostatin A significantly up-regulated MGMT RNA expression to a greater extent than in cells treated with either agent alone suggesting that histone deacetylation plays a role in MGMT silencing but that CpG methylation has a dominant effect. Consistent with enhanced MGMT expression, 5-Aza-dC increased the association of acetylated histone H3 and H4 bound to the MGMT promoter. Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT.
Involvement of base excision repair in response to therapy targeted at thymidylate synthase
Authors: Li Li , Berger Sondra H. , Wyatt Michael D. 
Published: June 2022

Abstract
Thymidylate synthase (TS) is an important target of several classes of chemotherapeutic agents. Although the precise mechanism of cytotoxicity in thymidylate deprivation remains obscure, uracil misincorporation and DNA strand breaks are recognized as important events during thymidylate deprivation. Base excision repair (BER) plays a primary role in removing damaged or modified bases from the genome, including uracil. Because of uracil misincorporation, BER is hypothesized to play a role in the cellular response to thymidylate deprivation. In this study, we used murine embryo fibroblasts wild-type or homozygous null for DNA polymerase β (β-pol), which plays a central role in BER. We found that, compared with wild-type, β-pol null cells were resistant to the toxic effects of raltitrexed (Tomudex, ZD1694), a folate inhibitor of TS. There was little difference in TS levels or in TS-ligand complex formation between the cell lines. Furthermore, cells deficient in XRCC1, a scaffold protein for the final steps of BER, were also modestly resistant to raltitrexed compared with XRCC1-proficient cells. Cell cycle analysis revealed that the responses of the wild-type and β-pol null cells were similar during drug exposure. However, following drug removal, the β-pol null cells appeared to resume cell cycle progression more rapidly than the wild-type cells. The results suggest that BER plays a role in modulating the toxic effects of TS inhibitors, and that this role occurs during recovery from TS inhibition.
p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas
Authors: Qin Jian-Zhong , Stennett Lawrence , Bacon Patricia , Bodner Barbara , Hendrix Mary J.C. , Seftor Richard E.B. , Seftor Elisabeth A. , Margaryan Naira V. , Pollock Pamela M. , Curtis Amy , Trent Jeffrey M. , Bennett Frank , Miele Lucio , Nickoloff Brian J. 
Published: June 2022

Abstract
Once melanoma metastasizes, no effective treatment modalities prolong survival in most patients. This notorious refractoriness to therapy challenges investigators to identify agents that overcome melanoma resistance to apoptosis. Whereas many survival pathways contribute to the death-defying phenotype in melanoma, a defect in apoptotic machinery previously highlighted inactivation of Apaf-1, an apoptosome component engaged after mitochondrial damage. During studies involving Notch signaling in melanoma, we observed a γ-secretase tripeptide inhibitor (GSI; z-Leu-Leu-Nle-CHO), selected from a group of compounds originally used in Alzheimer's disease, induced apoptosis in nine of nine melanoma lines. GSI only induced G2-M growth arrest (but not killing) in five of five normal melanocyte cultures tested. Effective killing of melanoma cells by GSI involved new protein synthesis and a mitochondrial-based pathway mediated by up-regulation of BH3-only members (Bim and NOXA). p53 activation was not necessary for up-regulation of NOXA in melanoma cells. Blocking GSI-induced NOXA using an antisense (but not control) oligonucleotide significantly reduced the apoptotic response. GSI also killed melanoma cell lines with low Apaf-1 levels. We conclude that GSI is highly effective in killing melanoma cells while sparing normal melanocytes. Direct enhancement of BH3-only proteins executes an apoptotic program overcoming resistance of this lethal tumor. Identification of a p53-independent apoptotic pathway in melanoma cells, including cells with low Apaf-1, bypasses an impediment to current cytotoxic therapy and provides new targets for future therapeutic trials involving chemoresistant tumors.
Abstract A17: In utero DDT exposure and breast density in early menopause by maternal history of breast cancer
Authors: McDonald Jasmine A. , Cirillo Piera M. , Tehranifar Parisa , Krigbaum Nickilou Y. , Engman Natalie , Cohn Barbara A. , Terry Mary Beth 
Published: June 2022

Abstract
Studies examining intrauterine environmental exposures and breast cancer risk are challenged by the long induction period between exposure and breast cancer development. One strategy to address this challenge is to examine the relationship between exposures and intermediate markers of breast cancer risk. Mammographic breast density (MBD) is considered an intermediate marker for breast cancer—having mostly dense breasts is associated with nearly a 4-fold increase in breast cancer as compared with having mostly fatty breasts. Here we examined the relation between intrauterine dichlorodiphenyltrichloroethane (DDT) exposure (o,p’-DDT, p,p’-DDT, and p,p’-DDE) to MBD in midlife. We focused our analyses on o,p’-DDT exposure when mutually adjusted for p,p’-DDE given our previous report of a positive association between intrauterine o,p’-DDT exposure and daughters’ breast cancer (BC) risk. We estimated associations of early postpartum serum DDTs with MBD in 224 daughters of women in the Child Health and Development Studies pregnancy cohort whose mothers did not develop BC (MBCa-negative) and 156 daughters whose mothers did develop BC (MBCa-positive). In MBCa-positive daughters, highest relative to lowest quartile of o,p’-DDT exposure was associated with a 17-unit higher dense area (95% CI= 2.6-31.2; Ptrend=0.01); associations persisted after adjusting for p,p’-DDT. MBD, an important intermediate marker of BC risk, may be affected by intrauterine DDT exposures; MBCa status may modify the association.
Citation Format: Jasmine A. McDonald, Piera M. Cirillo, Parisa Tehranifar, Nickilou Y. Krigbaum, Natalie Engman, Barbara A. Cohn, Mary Beth Terry. In utero DDT exposure and breast density in early menopause by maternal history of breast cancer [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 A17.