bluuebunny/crossref_metadata_2025 huggingface dataset:
CXCR4 antagonist inhibits stromal cell-derived factor 1-induced migration and invasion of human pancreatic cancer
Authors: Mori Tomohiko , Doi Ryuichiro , Koizumi Masayuki , Toyoda Eiji , Ito Daisuke , Kami Kazuhiro , Masui Toshihiko , Fujimoto Koji , Tamamura Hirokazu , Hiramatsu Kenichi , Fujii Nobutaka , Imamura Masayuki
Published: June 2022

The stromal cell-derived factor-1 (SDF-1)/CXCR4 system is implicated in various instances of cell migration in mammals, including the migration of lymphocytes and the formation of metastases. We have recently synthesized a potent novel CXCR4 antagonist, TN14003. The purpose of this study was to investigate the role of SDF-1/CXCR4 axis in the pancreatic cancer metastasis via cell migration and invasion, and the inhibitory effect of TN14003 on pancreatic cancer cell metastasis. The expression of CXCR4 was detected in six pancreatic cancer cell lines by Western blotting and immunocytochemistry. In migration and invasion assays, SDF-1 stimulated both migration and invasion of cancer cells in a dose-dependent manner. The maximal effect of SDF-1 was observed at 100 ng/ml. SDF-1-induced migration and invasion of cancer cells were completely blocked by 100 nm TN14003. The stimulatory effect of SDF-1 on cancer migration and the inhibitory effect of TN14003 were mediated via the alteration in phosphorylation of mitogen-activated protein kinases. Treatment of cancer cells with 100 ng/ml SDF-1 resulted in a significant increase of actin polymerization, which was reduced by 100 nm TN14003. SDF-1 enhanced cancer cell adhesion to laminin, which was not reversed by TN14003. Taken together, SDF-1/CXCR4 axis is involved in pancreatic cancer metastasis through migration and invasion. The small molecule antagonists against CXCR4 such as TN14003 might be an effective anti-metastatic agent for pancreatic cancer.
Marine natural products as anticancer drugs
Authors: Simmons T. Luke , Andrianasolo Eric , McPhail Kerry , Flatt Patricia , Gerwick William H.
Published: June 2022

The chemical and biological diversity of the marine environment is immeasurable and therefore is an extraordinary resource for the discovery of new anticancer drugs. Recent technological and methodologic advances in structure elucidation, organic synthesis, and biological assay have resulted in the isolation and clinical evaluation of various novel anticancer agents. These compounds range in structural class from simple linear peptides, such as dolastatin 10, to complex macrocyclic polyethers, such as halichondrin B; equally as diverse are the molecular modes of action by which these molecules impart their biological activity. This review highlights several marine natural products and their synthetic derivatives that are currently undergoing clinical evaluation as anticancer drugs.
TNP-470 promotes initial vascular sprouting in xenograft tumors
Authors: Huang Jianzhong , Frischer Jason S. , New Tamara , Kim Eugene S. , Serur Anna , Lee Alice , Kadenhe-Chiwishe Angela , Pollyea Daniel A. , Yokoi Akiko , Holash Jocelyn , Yancopoulos George D. , Kandel Jessica J. , Yamashiro Darrell J.
Published: June 2022

TNP-470 (AGM-1470), an analogue of fumagillin, was one of the first molecules proposed to have antiangiogenic properties. This concept was based on its ability to inhibit both endothelial proliferation in vitro and tumor growth in vivo in a number of xenograft models. Yet, subsequent investigations indicated that the biochemical activities associated with TNP-470 are not selective for endothelial cells. Moreover, recent evidence suggests that this agent inhibits tumor growth in vivo, but without a corresponding decrease in angiogenesis. Therefore, we performed a detailed comparison of TNP-470 to a validated antiangiogenic agent, a VEGF inhibitor termed VEGF-Trap, using a xenograft model of Wilms tumor. Treatment with TNP-470 for 5 weeks significantly suppressed xenograft growth (83%). Surprisingly, this inhibition was not associated with a decrease in angiogenesis, but instead with an increase in tiny neovessels. To determine whether this was a direct effect of TNP-470 on tumor vessels, we examined its effect in a short-term assay using large tumors with established vasculature. In contrast to treatment with VEGF-Trap, which led to rapid vessel regression and tumor hypoxia, tumors exposed to TNP-470 for 1 day displayed increased capillary sprouting, with significantly increased microvessel density, vessel length, and branch points. TNP-470 did not induce tumor hypoxia as demonstrated by minimal pimonidazole staining and VEGF expression. TNP-470 did, however, cause a marked increase in apoptosis of tumor cells. Our results indicate that the antitumor effects of TNP-470 cannot be attributed to prevention of neoangiogenesis, but instead to its direct action on tumor cells.
Sensitivity to gefitinib (Iressa, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation
Authors: Ono Mayumi , Hirata Akira , Kometani Takuro , Miyagawa Miho , Ueda Shu-ichi , Kinoshita Hisafumi , Fujii Teruhiko , Kuwano Michihiko
Published: June 2022

Gefitinib (Iressa, ZD1839), a quinazoline tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR), is approved for patients with advanced non-small cell lung cancer (NSCLC) in several countries including Japan. However, the mechanism of drug sensitivity to gefitinib is not fully understood. In this study, we examined the molecular basis of sensitivity to gefitinib using nine human lung cancer cell lines derived from NSCLC. PC9 was the most sensitive to gefitinib of the nine NSCLC cell lines when assayed either by colony formation or MTS assays. The various cell lines expressed different levels of EGFR, HER2, HER3, and HER4, but there was no correlation between levels of EGFR and/or HER2 expression and drug sensitivity. Phosphorylation of EGFR, protein kinase B/AKT (Akt), and extracellular signal-regulated kinase (ERK) 1/2 was inhibited by much lower concentration of gefitinib in PC9 cells than in the other eight cell lines under exponential growing conditions. About 80% of cell surface EGFR in PC-9 was internalized within 10 min, whereas only about 30–50% of the cell surface EGFR was internalized in more drug-resistant cell lines in 15–60 min. The present study is the first to demonstrate that sensitivity to growth inhibition by gefitinib in NSCLC cell lines under basal growth condition is associated with dependence on Akt and ERK1/2 activation in response to EGFR signaling for survival and proliferation and also that drug sensitivity may be related to the extent of EGF-induced down-regulation of cell surface EGFR.
Intravenous liposomal delivery of the snake venom disintegrin contortrostatin limits breast cancer progression
Authors: Swenson Stephen , Costa Fritz , Minea Radu , Sherwin Russell P. , Ernst William , Fujii Gary , Yang Dongyun , Markland Francis S.
Published: June 2022

Despite significant research in this area, metastatic breast cancer remains a disease with a poor prognosis. Until an effective therapy is developed, it is imperative that new treatment modalities be investigated. In this report, we describe an effective method for delivery of a novel snake venom disintegrin, contortrostatin (CN), in an orthotopic, xenograft model of human mammary cancer in immunodeficient mice. CN (Mr 13,500) is a homodimeric disintegrin isolated from venom of the Southern Copperhead snake. The homodimer possesses two Arg-Gly-Asp sites, which modulate its interaction with integrins on tumor cells and angiogenic vascular endothelial cells. Although our laboratory has previously described the antitumor activity of CN in a mouse model of human mammary cancer, the method of delivery, daily intratumor injection, was not translatable to clinical application. We now describe a clinically relevant method of administering CN, liposomal delivery (LCN). A unique liposomal system has been designed for i.v. administration of a biologically active protein with full retention of biological activity. Pharmacokinetics, biodistribution, platelet reactivity, and immunogenicity of LCN were determined and compared with similar characteristics of native, unencapsulated CN. There are several advantages to liposomal delivery of CN: (1) LCN has a significantly prolonged circulatory half-life compared with native CN; (2) LCN is passively accumulated in the tumor; (3) LCN has no platelet reactivity; and (4) LCN is not recognized by the immune system. Finally, antiangiogenic activity is an important component of CN's mechanism of antitumor action. We have demonstrated that i.v. delivery of LCN leads to potent antiangiogenic activity in the orthotopic, xenograft human mammary tumor model.
Nitric oxide prodrugs and metallochemotherapeutics: JS-K and CB-3-100 enhance arsenic and cisplatin cytolethality by increasing cellular accumulation
Authors: Liu Jie , Li Chengxiu , Qu Wei , Leslie Elaine , Bonifant Challice L. , Buzard Gregory S. , Saavedra Joseph E. , Keefer Larry K. , Waalkes Michael P.
Published: June 2022

Development of chemotherapeutic resistance is a major cause of pharmacologic failure in cancer treatment. One mechanism of resistance in tumor cells is the overexpression of glutathione S-transferases (GSTs) that serve two distinct roles in the development of drug resistance via the formation of glutathione conjugates with drugs for their cellular efflux, and the inhibition of the mitogen-activated protein kinase pathway. To target GST-based resistance to chemotherapeutics, a series of nitric oxide (NO)-releasing diazeniumdiolates was synthesized and shown to release NO on reaction with GST and/or glutathione. Two diazeniumdiolates, JS-K [O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] and CB-3-100 [O2-(2,4-dinitrophenyl) 1-[4-(N,N-diethylcarboxamido)piperazin-1-yl]diazen-1-ium-1,2-diolate], were studied on their ability in reversing arsenic and cisplatin resistance in a rat liver cell line that is tumorigenic and shows acquired tolerance to arsenic and cisplatin, with overexpression of GSTs. The enhanced cytolethality produced by the NO donors was accompanied by increased accumulation of arsenic and platinum within cells and by enhanced activation of mitogen-activated protein kinase members c-jun-NH-kinase and extracellular signal-regulated kinase. Our data indicate that JS-K and CB-3-100 are promising lead compounds for the possible development of a novel class of adjuvant chemotherapeutic agents potentially capable of reversing arsenic and cisplatin resistance in certain tumor cells.
Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin's lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis
Authors: Jazirehi Ali R. , Bonavida Benjamin
Published: June 2022

Resveratrol (trans-3,4,5-trihydroxystilbene) has received attention for its potential chemopreventive and antitumor effects in experimental systems. Recent evidence suggests that paclitaxel, alone or in combination with other drugs, can be effectively used in the treatment of non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). This study investigated whether resveratrol can sensitize NHL and MM cell lines to paclitaxel-mediated apoptosis and to delineate the underlying molecular mechanism of sensitization. Both resveratrol and paclitaxel negatively modulated tumor cell growth by arresting the cells at the G2-M phase of the cell cycle. Low concentrations of resveratrol exerted a sensitizing effect on drug-refractory NHL and MM cells to apoptosis induced by paclitaxel. Resveratrol selectively down-regulated the expression of antiapoptotic proteins Bcl-xL and myeloid cell differentiation factor-1 (Mcl-1) and up-regulated the expression of proapoptotic proteins Bax and apoptosis protease activating factor-1 (Apaf-1). Paclitaxel down-regulated the expression of Bcl-xL, Mcl-1, and cellular inhibitor of apoptosis protein-1 antiapoptotic proteins and up-regulated Bid and Apaf-1. Combination treatment resulted in apoptosis through the formation of tBid, mitochondrial membrane depolarization, cytosolic release of cytochrome c and Smac/DIABLO, activation of the caspase cascade, and cleavage of poly(adenosine diphosphate-ribose) polymerase. Combination of resveratrol with paclitaxel had minimal cytotoxicity against quiescent and mitogenically stimulated human peripheral blood mononuclear cells. Inhibition of Bcl-xL expression by resveratrol was critical for chemosensitization and its functional impairment mimics resveratrol-mediated sensitization to paclitaxel-induced apoptosis. Inhibition of Bcl-xL expression by resveratrol was due to the inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and diminished activator protein-1-dependent Bcl-xL expression. The findings by resveratrol were corroborated with inhibitors of the ERK1/2 pathway. This study demonstrates that in resistant NHL and MM cell lines resveratrol and paclitaxel selectively modify the expression of regulatory proteins in the apoptotic signaling pathway and the combination, via functional complementation, results in synergistic apoptotic activity.
Maximal apoptosis of renal cell carcinoma by the proteasome inhibitor bortezomib is nuclear factor-κB dependent
Authors: An Jiabin , Sun Yiping , Fisher Myrna , Rettig Matthew B.
Published: June 2022

Advanced renal cell carcinoma (RCC) is resistant to cytotoxic chemotherapy, and immunotherapy has modest activity. Proteasome inhibitors represent a novel class of anticancer agents that have activity across a wide spectrum of tumor types. We investigated the efficacy of the proteasome inhibitor bortezomib (VELCADE, formerly known as PS-341) in RCC and found that bortezomib potently induces apoptosis of RCC cell lines. Blockade of the nuclear factor-κB (NF-κB) pathway is considered a crucial effect in bortezomib-induced apoptosis, but the dependence on NF-κB inhibition for bortezomib-mediated death has not been formally demonstrated. Thus, we also studied the contribution of NF-κB inhibition as a mechanism of bortezomib-induced apoptosis in RCC cells, which display constitutive NF-κB activation. Ectopic expression of the NF-κB family members, p65 (Rel A) and p50 (NF-κB1), markedly reduced bortezomib-induced apoptosis. However, when we used selective genetic and chemical inhibitors of NF-κB, we found that NF-κB blockade was not sufficient to induce apoptosis of RCC cells. Thus, we conclude that maximal bortezomib-induced apoptosis is dependent on its NF-κB inhibitory effect, but NF-κB-independent effects also play a critical role in the induction of apoptosis by bortezomib. This represents the first report to formally demonstrate that bortezomib-induced NF-κB blockade is required to achieve the maximum degree of apoptosis by this drug.
Selenite-induced p53 Ser-15 phosphorylation and caspase-mediated apoptosis in LNCaP human prostate cancer cells
Authors: Jiang Cheng , Hu Hongbo , Malewicz Barbara , Wang Zaisen , Lü Junxuan
Published: June 2022

The issue of p53 requirement for the caspase-mediated apoptosis induced by selenium in a cancer chemoprevention or chemotherapy context has not been critically addressed. We and others have shown that selenite induces apoptotic DNA laddering in the p53-mutant DU145 prostate cancer cells and the p53-null HL60 leukemia cells without the cleavage of poly(ADP-ribose) polymerase (PARP; i.e., caspase-independent apoptosis), whereas selenium compounds leading to the formation of methylselenol induce caspase-mediated apoptosis in these cells. Because selenite induces DNA single strand breaks, and because certain types of DNA damage activate p53, we investigated whether the human LNCaP prostate cancer cells, which contain a wild-type p53, execute selenite-induced apoptosis through caspase pathways. The results showed that exposure of LNCaP cells for 24 hours to lower micromolar concentrations of selenite led to DNA laddering, and to the cleavage of PARP and several pro-caspases. In contrast to this apoptosis sensitivity, LNCaP cells were rather resistant to similar concentrations of the methylselenol precursor methylseleninic acid. Selenite treatment led to a significant increase in p53 phosphorylation on Ser-15 (Ser15P). Time course experiments showed that p53 Ser15P occurred several hours before caspase activation and PARP cleavage. The general caspase inhibitor zVADfmk completely blocked PARP cleavage, and significantly decreased DNA laddering, but did not affect p53 Ser15P. An inhibitor for caspase-8 was equally as protective as that for caspase-9 against the selenite-induced apoptosis. Attenuating p53 by a chemical inhibitor pifithrin-α decreased the selenite-induced p53 Ser15P and led to concordant reductions of PARP cleavage and apoptosis. In summary, selenite-induced p53 Ser15P appeared to be important for activating the caspase-mediated apoptosis involving both the caspase-8 and the caspase-9 pathways in the LNCaP cells.
Polyomavirus middle T–induced mammary intraepithelial neoplasia outgrowths: Single origin, divergent evolution, and multiple outcomes
Authors: Maglione Jeannie E. , McGoldrick Erik T. , Young Lawrence J.T. , Namba Ruria , Gregg Jeffrey P. , Liu Lin , Moghanaki Drew , Ellies Lesley G. , Borowsky Alexander D. , Cardiff Robert D. , MacLeod Carol L.
Published: June 2022

The development of models to investigate the pathobiology of premalignant breast lesions is a critical prerequisite for development of breast cancer prevention and early intervention strategies. Using tissue transplantation techniques, we modified the widely used polyomavirus middle T (PyV-mT) transgenic mouse model of breast cancer to study the premalignant stages of tumorigenesis. Premalignant atypical lesions were isolated from PyV-mT transgenic mice and used to generate two sets of three mammary intraepithelial neoplasia (MIN) outgrowth lines. Investigation of these six unique lines, each of which fulfills the criteria for MIN, has provided new information regarding the biology of PyV-mT-induced neoplasia. Although expression of the PyV-mT transgene was the primary initiating event for all lines, they exhibited different tumor latencies, metastatic potentials, and morphologies. Six distinguishable morphologic patterns of differentiation were identified within the premalignant outgrowths that are likely to represent several tumorigenic pathways. Further, several tumor phenotypes developed from each line and the tumors developing from the six lines had different metastatic potentials. These observations are consistent with the hypothesis that distinct pathways of PyV-mT-initiated neoplastic progression lead to different outcomes with respect to latency and metastasis. The MIN outgrowth lines share several characteristics with precursors of human breast cancer including the observation that gene expression profiles of tumors are more similar to those of the MIN outgrowth line outgrowth from which they developed than to other tumors. These lines provide an opportunity to study the full range of events occurring secondary to PyV-mT expression in the mammary gland.
Monounsaturated Fatty Acids: Key Regulators of Cell Viability and Intracellular Signaling in Cancer
Authors: Scott Julia S. , Nassar Zeyad D. , Swinnen Johannes V. , Butler Lisa M.
Published: June 2022

Cancer cells feature increased macromolecular biosynthesis to support the formation of new organelles and membranes for cell division. In particular, lipids are key macromolecules that comprise cellular membrane components, substrates for energy generation and mediators of inter- and intracellular signaling. The emergence of more sensitive and accurate technology for profiling the “lipidome” of cancer cells has led to unprecedented leaps in understanding the complexity of cancer metabolism, but also highlighted promising therapeutic vulnerabilities. Notably, fatty acids, as lipid building blocks, are critical players in all stages of cancer development and progression and the importance of fatty acid desaturation and its impact on cancer cell biology has been well established. Recent years have seen the reports of new mechanistic insights into the role of monounsaturated fatty acids (MUFA) in cancer, as regulators of cell death and lipid-related cellular signaling. This commentary aims to highlight these diverse roles of MUFAs in cancer cells which may yield new directions for therapeutic interventions involving these important fatty acids.
Abstract A30: Single-cell RNA-sequencing analysis of estrogen and the endocrine-disrupting chemical induced mouse mammary gland reorganization after surgical menopause
Authors: Chen Shiuan , Kanaya Noriko , Chang Gregory , Wu Xiwei , Saeki Kohei , Bernal Lauren , Dynold Timothy , Neuhausen Susan L.
Published: June 2022

Menopause is considered a critical window of susceptibility (WOS) for its sensitivity to endocrine-disrupting chemicals due to decline of endogenous estrogen. Using a surgical menopausal (ovariectomized) mouse model, we assessed how mammary gland tissue was affected by both 17β-estradiol (E2) and polybrominated diphenyl ethers (PBDEs). These endocrine-disrupting chemicals have been used as flame retardants in common household products since the 1970s and are vastly detected in human serum. During physiologically relevant exposure to E2, PBDEs enhanced E2-mediated regrowth of mammary glands with terminal end budlike structures. To better elucidate the effects of E2 and PBDEs, single-cell RNA sequencing (scRNAseq) analysis was performed. In a definitive manner, E2 was found to induce Pgr expression in both Esr1+ and Esr1- cells. We identified PBDE-impacted cell populations, Esr1+/Pgr+ and Esr1-/Pgr+ cells, in both mature luminal epithelial and progenitor cells, as well as the mammary gland population of M2 macrophages. Significantly, scRNAseq data show gene expression differences among cells with differential expression of Esr1 and Pgr. The results help clarify how exposure to both E2 and endocrine-disrupting chemicals like PBDEs after menopause impacts mammary gland structure. Ultimately, the findings advance understanding of how such exposure can increase the risk of developing breast cancer through the expansion of estrogen-responsive cells. (Supported by NIH U01ES026137.)

Citation Format: Shiuan Chen, Noriko Kanaya, Gregory Chang, Xiwei Wu, Kohei Saeki, Lauren Bernal, Timothy Dynold, Susan L. Neuhausen. Single-cell RNA-sequencing analysis of estrogen and the endocrine-disrupting chemical induced mouse mammary gland reorganization after surgical menopause [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 A30.
Abstract A48: Perinatal DDT exposure shortens latency of mouse mammary tumorigenesis
Authors: Ishikawa Tomoko , Tong Jason , Borowsky Alexander , Cardiff Robert , La Merrill Michele
Published: June 2022

The contribution of exposure to the persistent, lipophilic pesticide dichlorodiphenyltrichloroethane (DDT) to breast cancer risk is controversial. A recent report by the International Agency for Research on Cancer (IARC) concluded that no consistent association exists between DDT exposure and breast cancer, yet stressed that there was a lack of existing evidence to allow for the determination of the effects of early-life exposure to DDT. It has been hypothesized that exposure to DDT during critical periods of breast development may increase breast cancer risk. We hypothesized that perinatal DDT exposure would result in shortened latency of spontaneous mammary tumorigenesis and accelerated growth of mammary tumors and increase the incidence of lung metastasis. To test the effect on mammary tumor early progression and growth as well as lung metastasis, C57BL/6J female mice, pregnant as a result of mating with B6.FVB-Tg(MMTV-PyVT)634Mul/LellJ male mice, were administered DDT from gestational day 11.5 to postnatal day 5 to produce circulating levels of DDT in dams within the prenatal range associated with breast cancer in adult daughters. This perinatal DDT exposure significantly accelerated the development of palpable mammary tumors (hazard ratio = 3.7 (95% confidence interval 2.0-6.8; p<0.0001). We also aimed to study possible mechanisms for DDT increasing mammary cancer risk, including alterations in puberty tempo and the presence of breast cancer risk factors associated with impaired metabolism. We found that mice exposed to DDT perinatally had increased terminal end buds in their mammary glands late in puberty (postnatal day 63, p<0.05). Tumor-free mice exposed to DDT perinatally also had significantly elevated circulating glucose levels (p<0.05). The risk of mammary cancer associated with perinatal DDT exposure observed in mice closely mirrors that observed in women previously. Our findings raise the possibility that perinatal DDT exposure may increase risk of breast cancer through its effects on pubertal mammary gland development and/or on glucose homeostasis. Future research to further evaluate whether these effects are mechanisms by which perinatal DDT exposure accelerates breast tumorigenesis is highly warranted.

Citation Format: Tomoko Ishikawa, Jason Tong, Alexander Borowsky, Robert Cardiff, Michele La Merrill. Perinatal DDT exposure shortens latency of mouse mammary tumorigenesis [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 A48.
Abstract IA02: New concepts in precision prevention
Authors: Rebbeck Timothy R.
Published: June 2022

Traditional approaches to cancer prevention and early detection include population approaches that involve legislation, policy, and social change. These approaches have been extremely effective in many areas including limiting tobacco use, implementing cancer preventive vaccination, and population cancer-screening strategies. Despite their success, some cancers are not readily prevented or detected early by these strategies, and alternative approaches that complement population interventions should be considered. Like the advent of precision medicine, precision prevention and early detection can be developed that build on our substantial knowledge of carcinogenic mechanisms, genetic susceptibility, the effects of extreme environmental exposures, and the natural history of cancers from preneoplasia to invasive cancer. These precision strategies aim to identify groups that may experience optimal benefit from interventions with minimal toxicities. Numerous examples of precision prevention currently exist, including the use of preventive surgery in individuals who have inherited a high-penetrance mutation (e.g., BRCA1, BRCA2, APC) or individuals who have been diagnosed with a preneoplastic lesion that may have a molecular profile that can be monitored over time to identify hallmarks of disease progression and provide opportunities for timely intervention. This presentation will provide an overview of precision prevention and early-detection principles as well as examples of targeted interventions that may minimize the cancer burden in defined high-risk groups.

Citation Format: Timothy R. Rebbeck. New concepts in precision prevention [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 IA02.
Abstract IA22: Impact of workplace exposures on cancer disparities
Authors: Demers Paul A.
Published: June 2022

Workplace exposures can have a big impact on cancer disparities. Perhaps the earliest lens through which disparities were examined was through the UK “Registrar-General’s Social Classes,” which were introduced in 1913. These six classes were based on occupation ranging from “professional occupations” to “unskilled occupations” and were predictive of mortality. One can think of these occupational groups representing both education and income, but they also represent power, control, social prestige/status, and mobility, as well as differential exposure to a wide range of workplace carcinogens. While nonoccupational behavioral risk factors could potentially confound the relationship between social class based on occupation and cancer, adjustment for these factors often does not remove associations. For example, in IARC’s Synergy project, a pooled analysis of lung cancer case-control studies, strong associations between Treiman’s Standard International Occupational Prestige Scale and International Socio-Economic Index of Occupational Status remained after adjustment for smoking. In studies of occupational cancer, our focus has most often been on “skilled manual” and “semi-skilled” occupations, because it has been easier to document exposure and their employment by either large companies or unionization facilitates recruitment. Although potentially carcinogenic exposures can occur among a wide range of occupations, the risk is not spread evenly. For example, exposure to common workplace lung carcinogens such as asbestos, diesel exhaust, crystalline silica, nickel, and chromium remains prevalent among workers in construction, transportation, mining, and certain manufacturing and service industries, and very rare among managerial, professional, and sales workers. Although the first occupational chemical carcinogen identified was soot, to which chimney sweeps were exposed as child workers, few studies have focused on the lowest, most vulnerable social class because of difficulties recruiting and other practical challenges. For example, studies of pesticides and cancer have most often recruited farmers and pesticide applicators, and not the more vulnerable farm workers, particularly migrant workers. Other examples of vulnerable groups with potentially carcinogenic exposures are electronic waste, nail salon, and cleaning workers. Further studies of cancer among these vulnerable groups are needed.

Citation Format: Paul A. Demers. Impact of workplace exposures on cancer disparities [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 IA22.
Abstract IA26: Carcinogens in consumer products: How science can inform policy to benefit public health
Authors: Singla Veena , Woodruff Tracey
Published: June 2022

Flame-retardant chemicals have been added to furniture, baby products, electronics, and building materials since the 1970s to meet flammability standards, but their effectiveness is questionable and many are associated with serious health and environmental concerns. Flame-retardant chemicals are associated with health concerns including loss of IQ in children, ADHD, fertility problems, and cancer. Flame retardants do not stay inside products; they migrate out into indoor air and dust and result in human exposure through inhalation, ingestion, and dermal contact. Significant exposure disparities are seen by age, race, and socioeconomic status (SES), with higher flame-retardant levels documented in infants/ toddlers, nonwhite children, and children of lower SES. Exposures to the flame retardants polybrominated diphenyl ethers (PBDEs) are associated with increased risks for testicular cancer, estimated to result in thousands of excess cancer cases in the U.S. population at a cost of over $80 million annually. The phaseout of PBDEs resulted in a large number of halogenated and nonhalogenated chemicals being used as replacement flame retardants, with studies finding almost 50 unique replacement flame retardants in U.S. indoor dust samples alone. A number of these replacement flame retardants, especially chlorinated chemicals, have identified cancer hazards. A recent assessment from the European Chemicals Agency found increased risks of cancer from infants’ exposures to “chlorinated Tris” flame retardants in children’s products and furniture. Chemical policies have generally managed flame retardants through a paradigm of allowing use while conducting an in-depth, quantitative risk assessment of specific chemicals to inform risk management. Risk assessments include studies of human exposures and effects, and if the chemical is found to be harmful, health damages may already have occurred prior to regulatory decisions. However, there is increasing recognition that this paradigm is insufficient to address current chemicals and their exposures before harm or keep pace with the proliferation of new chemicals. This presentation will review policy approaches attempting to address existing and emerging flame retardants and where possible, present data on their effectiveness in reducing chemical risks.

Citation Format: Veena Singla, Tracey Woodruff. Carcinogens in consumer products: How science can inform policy to benefit public health [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 IA26.
Finerenone Reduces Renal RORγt γδ T Cells and Protects against Cardiorenal Damage
Authors: Luettges Katja , Bode Marlies , Diemer Jan Niklas , Schwanbeck Juliane , Wirth Eva K. , Klopfleisch Robert , Kappert Kai , Thiele Arne , Ritter Daniel , Foryst-Ludwig Anna , Kolkhof Peter , Wenzel Ulrich Otto , Kintscher Ulrich
Published: June 2022

Introduction: Chronic activation of the mineralocorticoid receptor (MR) leads to pathological processes like inflammation and fibrosis during cardiorenal disease. Modulation of immunological processes in the heart or kidney may serve as a mechanistic and therapeutic interface in cardiorenal pathologies. In this study, we investigated anti-inflammatory/-fibrotic and immunological effects of the selective nonsteroidal MR antagonists finerenone (FIN) in the deoxycorticosterone acetate (DOCA)-salt model. Methods: Male C57BL6/J mice were uninephrectomized and received a DOCA pellet implantation (2.4 mg/day) plus 0.9% NaCl in drinking water (DOCA-salt) or received a sham operation and were orally treated with FIN (10 mg/kg/day) or vehicle in a preventive study design. Five weeks after the procedure, blood pressure (BP), urinary albumin/creatinine ratio (UACR), glomerular and tubulointerstitial damage, echocardiographic cardiac function, as well as cardiac/renal inflammatory cell content by FACS analysis were assessed. Results: BP was significantly reduced by FIN. FACS analysis revealed a notable immune response due to DOCA-salt exposure. Especially, infiltrating renal RORγt γδ-positive T cells were upregulated, which was significantly ameliorated by FIN treatment. This was accompanied by a significant reduction of UACR in FIN-treated mice. In the heart, FIN reduced DOCA-salt-induced cardiac hypertrophy, cardiac fibrosis and led to an improvement of the global longitudinal strain. Cardiac actions of FIN were not associated with a regulation of cardiac RORγt γδ-positive T cells. Discussion/Conclusion: The present study shows cardiac and renal protective effects of FIN in a DOCA-salt model. The cardiorenal protection was accompanied by a reduction of renal RORγt γδ T cells. The observed actions of FIN may provide a potential mechanism of its efficacy recently observed in clinical trials.
Epithelial Sodium Channel δ Subunit Is Expressed in Human Arteries and Has Potential Association With Hypertension
Authors: Paudel Puja , van Hout Isabelle , Bunton Richard W. , Parry Dominic J. , Coffey Sean , McDonald Fiona J. , Fronius Martin
Published: June 2022

Background:

Elevated expression and increased activity of vascular epithelial sodium channel (ENaC) can result in vascular dysfunction in small animal models. However, there is limited or no knowledge on expression and function of ENaC channels in human vasculature. Hence, this study explored the expression and function of ENaC in human arteries and their association with hypertension.

Methods:

Human internal mammary artery (IMA) and aorta were obtained from cardiovascular patients undergoing coronary artery bypass graft surgery. Expression of the ENaC subunit was analyzed by polymerase chain reaction, Western blot, and immunohistochemistry. ENaC function was observed by patch-clamp electrophysiology in endothelial cells isolated from IMA. Levels of ENaC subunit expression levels were compared between arteries from normotensive, uncontrolled hypertensive, and controlled hypertensive patients.

Results:

For the first time, expression of α, β, γ, and δ was detected at mRNA and protein levels in human IMA and aorta. Single-channel patch-clamp recordings identified both αβγ- and δβγ-like channel conductance in primary endothelial cells isolated and cultured from IMA. Reduced expression of the δ subunit was observed in controlled hypertensive IMA, whereas reduced expression of γ-ENaC was observed in controlled hypertensive aorta.

Conclusions:

These data suggest that functional ENaC channels are expressed in human arteries and their expression levels are associated with hypertension.
Introduction to Nicos Poulantzas, ‘Theory and History: Brief Remarks on the Object of Capital’
Authors: Baasch Kyle
Published: June 2022

In this Introduction I illuminate the importance of Nicos Poulantzas’s participation at a 1967 colloquium in Frankfurt commemorating the 100th anniversary of the publication of Capital. This colloquium is the only published record of a dialogue between a representative of Louis Althusser’s interpretation of Marx and a member of the first generation of the Frankfurt School and thus casts light on the relationship between these two traditions of critical social theory. After contextualising the colloquium and summarising Poulantzas’s paper, I outline some of the elements of the Frankfurt response to the Althusserian interpretation of Marx by referring to Alfred Schmidt’s contribution to the colloquium, including his reaction to Poulantzas’s paper.
Corrections of orthographical error of two Marchantiophyta
Authors: MAJUMDAR SHUVADEEP
Published: June 2022

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Torenia hookeri, a new combination in Asian Linderniaceae and first record of T. godefroyi in the Himalayan hotspot
Authors: PAL AARATRIK , CHOWDHURY MONORANJAN
Published: June 2022

Recent phylogenetic revision distinguishes Torenia from Vandellia by hairy or glabrous ovary and poricidal or septicidal  capsule not extending the length of calyx (vs glabrous ovary and septicidal capsule clearly exceeding the calyx). Our current study showed that Vandellia hookeri exhibits all the characteristics of Torenia, therefore we change the generic treatment of V. hookeri to Torenia. Torenia godefroyi is also recorded from Himalayan Hotspot for the first time.
Committor Functions for Climate Phenomena at the Predictability Margin: The Example of El Niño–Southern Oscillation in the Jin and Timmermann Model
Authors: Lucente Dario , Herbert Corentin , Bouchet Freddy
Published: June 2022

Many atmosphere and climate phenomena lie in the gray zone between weather and climate: they are not amenable to deterministic forecast, but they still depend on the initial condition. A natural example is medium-range forecasting, which is inherently probabilistic because it lies beyond the deterministic predictability time of the atmosphere, but for which statistically significant prediction can be made, which depends on the current state of the system. Similarly, one may ask the probability of occurrence of an El Niño event several months ahead of time. We introduce a quantity that corresponds precisely to this type of prediction problem: the committor function is the probability that an event takes place within a given time window, as a function of the initial condition. We compute it in the case of a low-dimensional stochastic model for El Niño, the Jin and Timmermann model. In this context, we show that the ability to predict the probability of occurrence of the event of interest may differ strongly depending on the initial state. The main result is the new distinction between probabilistic predictability (when the committor function is smooth and probability can be computed, which does not depend sensitively on the initial condition) and probabilistic unpredictability (when the committor function depends sensitively on the initial condition). We also demonstrate that the Jin and Timmermann model might be the first example of a stochastic differential equation with weak noise for which transition between attractors does not follow the Arrhenius law, which is expected based on large deviation theory and generic hypothesis.

Significance Statement

A key problem for atmospheric and climate phenomena is to predict events beyond the time scale over which deterministic weather forecast is possible. In a simple model of El Niño, we demonstrate the existence of two regimes, depending on initial conditions. For initial conditions in the “probabilistic predictability” regime, the system is unpredictable deterministically because of chaos, but the probability of occurrence of the event can still be predicted because it depends only weakly on the initial condition. In the “probabilistic unpredictability” regime, even predicting probabilities is difficult, because the probability depends strongly on initial conditions. These new concepts of probabilistic predictability and unpredictability should be key in understanding the predictability potential for rare events in climate problems, as well as in other complex dynamics.
How Predictable is Short-Term Drought in the Northeastern United States?
Authors: Carrillo Carlos M. , Evans Colin P. , Belcher Brian N. , Ault Toby R.
Published: June 2022

We investigated the predictability (forecast skill) of short-term droughts using the Palmer drought severity index (PDSI). We incorporated a sophisticated data training (of decadal range) to evaluate the improvement of forecast skill of short-term droughts (3 months). We investigated whether the data training of the synthetic North American Multi-Model Ensemble (NMME) climate has some influence on enhancing short-term drought predictability. The central elements are the merged information among PDSI and NMME with two postprocessing techniques. 1) The bias correction–spatial disaggregation (BC-SD) method improves spatial resolution by using a refined soil information introduced in the available water capacity of the PDSI calculation to assess water deficit that better estimates drought variability. 2) The ensemble model output statistic (EMOS) approach includes systematically trained decadal information of the multimodel ensemble simulations. Skill of drought forecasting improves when using EMOS, but BC-SD does not increase the forecast skill when compared with an analysis using BC (low spatial resolution). This study suggests that predictability forecast of drought (PDSI) can be extended without any change in the core dynamics of the model but instead by using the sophisticated EMOS postprocessing technique. We pointed out that using NMME without any postprocessing is of limited use in the suite of model variations of the NMME, at least for the U.S. Northeast. From our analysis, 1 month is the most extended range we should expect, which is below the range of the seasonal scale presented with EMOS (2 months). Thus, we propose a new design of drought forecasts that explicitly includes the multimodel ensemble signal.
Pediatric Antibiotic Stewardship for Community-Acquired Pneumonia: A Pre–Post Intervention Study
Authors: Cohen Herman Avner , Gerstein Maya , Loewenberg Weisband Yiska , Richenberg Yael , Jacobson Eyal , Cohen Moriya , Shkalim Zemer Vered , Machnes Maayan Diti
Published: June 2022

We aimed to investigate the effectiveness of an antibiotic stewardship program (ASP) on antibiotic prescription in children with community-acquired pneumonia (CAP). Antibiotic purchasing data were collected for children aged 3 months to 18 years diagnosed with CAP from November 2016 to April 2017 (pre-intervention period) and from November 2017 to April 2018 (post-intervention period). The intervention was a 1-day seminar for primary care pediatricians on the diagnosis and treatment of CAP in children according to national guidelines. There was a substantial decrease in the use of azithromycin after the intervention. In younger children, there was a 42% decrease, alongside an increased use of amoxicillin ( P < .001). In older children, there was a smaller, non-statistically significant decrease in the use of azithromycin ( P = .45). Our data demonstrate that the implementation of an ASP was associated with a reduction in the use of broad-spectrum antibiotics and macrolides and increased guideline adherence for the safe treatment of CAP.
Importation for comparison as apparatus: Israeli prime ministers and their political strategies of memorialization
Authors: Adams Tracy
Published: June 2022

Politically grappling with history is a constructive act, one that relies on context, structure, and agency, and is also directed at the forging of cultural coherence. In light of the growing transnationalization of commemoration practices, political actors not only rely on national past but also appeal to historical foreign events in political domestic speech. This research focuses on Israel as a case study for theoretical expansion of the political encounter with history and the experience of alterity. Qualitative analysis of Israeli political rhetoric since the 2000s demonstrates how Israeli prime ministers primarily rely on domestic collective memories; when used, events of others are intended to create a sense of shared experience through comparison. ‘Importation for comparison’ is thus the apparatus reflecting how Israeli prime ministers comply with current needs put forth by internal and external challenges in a globalized world. Contributing to the ongoing discussion regarding the nature of identity, this research underlines how referencing to events from abroad is one of the prominent ways in which national self is evaluated, discussed, and negotiated, thus providing a better understanding of how Israeli society imagines itself in relation to others.
“You’ve Got to Be the Medicine to Heal the Community”: Capoeira and the Art of Healing Mind, Body, and Spirit
Authors: Rashid Kamau
Published: June 2022

The African combat arts have been central to the struggle of African people for self-determination. They have been critical as vehicles of resistance, while also serving a number of important social roles such as being a basis for group cohesion, expressing the kinesthetics of African culture, functioning as a venue for various African musical traditions, and—most notably—providing a means for self-protection. One additional and significant role that these arts have taken on is as a means for cultural reclamation for African people and also as healing modalities. This essay explores the latter theme, examining how such healing is enacted through the learning and practice of Capoeira.
Evidence of Decrease in the Prevalence of Dental Caries in New Zealand
Authors: Brown R.H.
Published: June 2022

Evidence of a substantial decrease in dental caries in New Zealand schoolchildren is available from a number of surveys extending over a period of 30 years; the decrease has been particularly apparent over the past five years. Fluoridation of public water supplies and the widespread use of fluoride toothpastes are considered to be having a major influence on caries prevalence. Coinciding with this decrease, and no doubt contributing to it, has been a change of emphasis within the School Dental Service to a more preventive approach.