bluuebunny/crossref_metadata_2025 huggingface dataset:
The p65 subunit of nuclear factor-κB is a molecular target for radiation sensitization of human squamous carcinoma cells
Authors: Kim Kyoung M. , Zhang Yin , Kim Bo-Yeon , Jeong Sook J. , Lee Sung A. , Kim Gun-Do , Dritschilo Anatoly , Jung Mira
Published: June 2022

The transcription factor nuclear factor-κB (NF-κB) is activated in response to various stimuli including ionizing radiation. Disruption of NF-κB activation by mutant forms of the NF-κB inhibitor IκB-α or by proteasome inhibitors enhances both sensitivity to radiation and radiation-induced apoptosis. Human squamous carcinoma SCC-35 cells stably expressing a fragment (residues 1 to 84) of human p65 have been shown to exhibit down-regulation of both endogenous p65 mRNA and its protein. The mutant protein also inhibited radiation-induced NF-κB activation by preventing the proteolysis of IκB-α. This resulted in enhancement of cellular radiosensitivity and radiation-induced apoptosis. The NH2-terminal region of p65 is thus a potential molecular target for disruption of NF-κB activation and sensitization of tumors to radiotherapy.
Polyamine catabolism in platinum drug action: Interactions between oxaliplatin and the polyamine analogue N1,N11-diethylnorspermine at the level of spermidine/spermine N1-acetyltransferase
Authors: Hector Suzanne , Porter Carl W. , Kramer Debora L. , Clark Kimberly , Prey Joshua , Kisiel Nicholas , Diegelman Paula , Chen Ying , Pendyala Lakshmi
Published: June 2022

A great deal of experimental evidence connects induction of polyamine catabolism via spermidine/spermine N1-acetyltransferase (SSAT) to antiproliferative activity and apoptosis. Following our initial observation from gene expression profiling that platinum drugs induce SSAT, we undertook this present study to characterize platinum drug induction of SSAT and other polyamine catabolic enzymes and to examine how these responses might be enhanced with the well-known inducer of SSAT and clinically relevant polyamine analogue, N1,N11-diethylnorspermine (DENSPM). The results obtained in A2780 ovarian cancer cells by real-time quantitative RT-PCR and Northern blot analysis show that a 2-hour exposure of A2780 cells to platinum drugs induces expression of SSAT, a second SSAT (SSAT-2), spermine oxidase, and polyamine oxidase in a dose-dependent manner. At equitoxic doses, oxaliplatin is more effective than cisplatin in SSAT induction. The most affected enzyme, SSAT, increased 15-fold in mRNA expression and 2-fold in enzyme activity. When combined with DENSPM to further induce SSAT and to enhance conversion of mRNA to activity, oxaliplatin increased SSAT mRNA 50-fold and activity, 210-fold. Polyamine pools declined in rough proportion to levels of SSAT induction. At pharmacologically relevant oxaliplatin exposure times (20 hours) and drug concentrations (5 to 15 μmol/L), these responses were increased even further. Combining low-dose DENSPM with oxaliplatin produced a greater than additive inhibition of cell growth based on the sulforhodamine-B assay. Taken together, the findings confirm potent induction of polyamine catabolic enzymes, such as SSAT by platinum drugs, and demonstrate that these biochemical responses as well as growth inhibition can be potentiated by co-treatment with the polyamine analogue DENSPM. With appropriate in vitro and in vivo optimization, these findings could lead to clinically relevant therapeutic strategies.
Activation of protein kinase C βII/ε-c-Jun NH2-terminal kinase pathway and inhibition of mitogen-activated protein/extracellular signal-regulated kinase 1/2 phosphorylation in antitumor invasive activity induced by the polymethoxy flavonoid, nobiletin
Authors: Miyata Yoshiki , Sato Takashi , Yano Masamichi , Ito Akira
Published: June 2022

Flavonoids from medicinal plants have been therapeutically administered for cancer therapy. We recently reported that nobiletin (5,6,7,8,3′,4′-hexamethoxy flavone) exhibits novel antitumor invasive activities by suppressing the production of pro-matrix metalloproteinases (proMMPs) and augmenting the expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) in vivo and in vitro. In the present study, intracellular target molecules associated with the actions of nobiletin against tumor invasion were identified. Nobiletin inhibited the phosphorylation of mitogen-activated protein/extracellular signal-regulated kinase (MEK) 1/2, but not the activity of Ras or the phosphorylation of Raf. Moreover, a MEK1/2 inhibitor, U0126, mimicked nobiletin's ability to decrease the production of proMMPs-1 and 9 in human fibrosarcoma HT-1080 cells stimulated by 12-O-tetradecanoyl phorbol-13-acetate (TPA). In addition, neither the activity of phosphatidylinositol 3-kinase (PI3K) nor the phosphorylation of Akt was influenced by nobiletin. However, nobiletin was found to augment the phosphorylation of c-Jun NH2-terminal kinase (JNK), a downstream signal factor of the PI3K-Akt pathway, in TPA-treated HT-1080 cells. A similar augmentation of JNK phosphorylation was observed on treatment with a PI3K inhibitor, LY-294002. Furthermore, nobiletin enhancement of TIMP-1 production in TPA-stimulated HT-1080 cells was found to be diminished by adding a JNK inhibitor, SP600125. Moreover, protein kinase C (PKC) inhibitor experiments showed that PKCβII/ε were associated with the nobiletin-mediated augmentation of JNK phosphorylation. Therefore, these results introduce novel evidence that the antitumor effects of nobiletin are finely regulated by the following intracellular mechanisms: (1) the inhibition of MEK1/2 activity is involved in the suppression of MMP expression and (2) the activation of the novel PKCβII/ε-JNK pathway is associated with the augmentation of TIMP-1 expression.
The DNA double-stranded break repair protein endo-exonuclease as a therapeutic target for cancer
Authors: Chow Terry Y-K. , Alaoui-Jamali Moulay A. , Yeh Chiaoli , Yuen Leonard , Griller David
Published: June 2022

DNA repair mechanisms are crucial for the maintenance of genomic stability and are emerging as potential therapeutic targets for cancer. In this study, we report that the endo-exonuclease, a protein involved in the recombination repair process of the DNA double-stranded break pathway, is overexpressed in a variety of cancer cells and could represent an effective target for developing anticancer drugs. We identify a dicationic diarylfuran, pentamidine, which has been used clinically to treat opportunistic infections and is an inhibitor of the endo-exonuclease as determined by enzyme kinetic assay. In clonogenic and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays as well as in the in vivo Lewis lung carcinoma mouse tumor model, pentamidine is shown to possess the ability to selectively kill cancer cells. The LD50 of pentamidine on cancer cells maintained in vitro is correlated with the endo-exonuclease enzyme activity. Tumor cell that has been treated with pentamidine is reduced in the endo-exonuclease as compared with the untreated control. Furthermore, pentamidine synergistically potentiates the cytotoxic effect of DNA strand break and cross-link-inducing agents such as mitomycin C, etoposide, and cisplatin. In addition, we used the small interfering RNA for the mouse homologue of the endo-exonuclease to down-regulate the level of endo-exonuclease in the mouse myeloma cell line B16F10. Down-regulation of the endo-exonuclease sensitizes the cell to 5-fluorouracil. These studies suggested the endo-exonuclease enzyme as a novel potential therapeutic target for cancer.
Transient adenoviral N-methylpurine DNA glycosylase overexpression imparts chemotherapeutic sensitivity to human breast cancer cells
Authors: Rinne Mikael , Caldwell David , Kelley Mark R.
Published: June 2022

In an effort to improve the efficacy of cancer chemotherapy by intervening into the cellular responses to chemotherapeutic change, we have used adenoviral overexpression of N-methylpurine DNA glycosylase (MPG or ANPG/AAG) in breast cancer cells to study its ability to imbalance base excision repair (BER) and sensitize cancer cells to alkylating agents. Our results show that MPG-overexpressing cells are significantly more sensitive to the alkylating agents methyl methanesulfonate, N-methyl-N′-nitro-N-nitrosoguanidine, methylnitrosourea, dimethyl sulfate, and the clinical chemotherapeutic temozolomide. Sensitivity is further increased through coadministration of the BER inhibitor methoxyamine, which covalently binds abasic or apurinic/apyrimidinic (AP) sites and makes them refractory to subsequent repair. Methoxyamine reduction of cell survival is significantly greater in cells overexpressing MPG than in control cells, suggesting a heightened production of AP sites that, if made persistent, results in increased cellular toxicity. We further explored the mechanism of MPG-induced sensitivity and found that sensitivity was associated with a significant increase in the number of AP sites and/or single-strand breaks in overexpressing cells, confirming a MPG-driven accumulation of toxic BER intermediates. These data establish transient MPG overexpression as a potential therapeutic approach for increasing cellular sensitivity to alkylating agent chemotherapy.
Antitumor activity of ZD6126, a novel vascular-targeting agent, is enhanced when combined with ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, and potentiates the effects of radiation in a human non-small cell lung cancer xenograft model
Authors: Raben David , Bianco Cataldo , Damiano Vincenzo , Bianco Roberto , Melisi Davide , Mignogna Chiara , D'Armiento Francesco Paolo , Cionini Luca , Bianco A. Raffaele , Tortora Giampaolo , Ciardiello Fortunato , Bunn Paul
Published: June 2022

Objective: Targeting the tumor vasculature may offer an alternative or complementary therapeutic approach to targeting growth factor signaling in lung cancer. The aim of these studies was to evaluate the antitumor effects in vivo of the combination of ZD6126, a tumor-selective vascular-targeting agent; ZD1839 (gefitinib, Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor; and ionizing radiation in the treatment of non-small cell lung cancer xenograft model. Methods: Athymic nude mice with established flank A549 human non-small cell lung cancer xenograft model xenografts were treated with fractionated radiation therapy, ZD6126, ZD1839, or combinations of each treatment. ZD6126 (150 mg/kg) was given i.p. the day after each course of radiation. Animals treated with ZD1839 received 100 mg/kg per dose per animal, 5 or 7 days/wk for 2 weeks. Immunohistochemistry was done to evaluate the effects on tumor growth using an anti-Ki67 monoclonal antibody. Effects on tumor-induced vascularization were quantified using an anti–factor VIII–related antigen monoclonal antibody. Results: ZD6126 attenuated the growth of human A549 flank xenografts compared with untreated animals. Marked antitumor effects were observed when animals were treated with a combination of ZD6126 and fractionated radiation therapy with protracted tumor regression. ZD6126 + ZD1839 resulted in a greater tumor growth delay than either agent alone. Similar additive effects were seen with ZD1839 + fractionated radiation. Finally, the addition of ZD6126 to ZD1839 and radiation therapy seemed to further improve tumor growth control, with a significant tumor growth delay compared with animals treated with single agent or with double combinations. Immunohistochemistry showed that ZD1839 induced a marked reduction in A549 tumor cell proliferation. Both ZD1839 and ZD6126 treatment substantially reduced tumor-induced angiogenesis. ZD6126 caused marked vessel destruction through loss of endothelial cells and thrombosis, substantially increasing the level of necrosis seen when combined with radiation therapy. The combination of radiation therapy, ZD6126, and ZD1839 induced the greatest effects on tumor growth and angiogenesis. Conclusion: This first report shows that a selective vascular-targeting agent (ZD6126) + an anti–epidermal growth factor receptor agent (ZD1839) and radiation have additive in vivo effects in a human cancer model. Targeting the tumor vasculature offers an excellent strategy to enhance radiation cytotoxicity. Polytargeted therapy with agents that interfere with both growth factor and angiogenic signaling warrants further investigation.
Inhibition of constitutively activated nuclear factor-κB radiosensitizes human melanoma cells
Authors: Munshi Anupama , Kurland John F. , Nishikawa Takashi , Chiao Paul J. , Andreeff Michael , Meyn Raymond E.
Published: June 2022

Melanoma tumors and cultured cell lines are relatively resistant to the cytotoxic effects of ionizing radiation, thereby limiting the use of radiotherapy for the clinical treatment of melanoma. New strategies for sensitizing melanoma cells therefore deserve examination. In an attempt to identify and target signaling pathways that contribute to radioresistance, we investigated the role of nuclear factor-κB (NF-κB), a transcription factor known to inhibit apoptosis induced by a variety of stimuli and promote radioresistance. Two human metastatic melanoma cell lines, A375 and MeWo, were used to examine the radiosensitizing effects of inhibitors of the NF-κB pathway. Nuclear extracts from these cell lines were tested for active NF-κB using the electrophoretic mobility shift assay. Both melanoma cell lines had constitutively activated NF-κB as observed by electrophoretic mobility shift assay. In an attempt to reverse NF-κB activity, cells were treated either with vehicle alone (DMSO) or with a proteasome inhibitor Z-Leu-Leu-Leu-H (MG132; 10 μmol/L for 2 hours prior to irradiation) that inhibited both constitutive and radiation-induced NF-κB activity. The clonogenic cell survival assay showed that pretreatment with MG132 enhanced tumor cell radiosensitivity with the survival factor at 2 Gy being reduced from 48 ± 0.8% and 48 ± 1.6% in vehicle-treated cells to 27.7 ± 0.32% and 34.3 ± 0.7% in MG132-treated MeWo and A375 cells, respectively. To test the role of NF-κB in radioresistance more directly, MeWo cells were stably transfected with a dominant-negative mutant IκBα construct, which led to the inhibition of both constitutive and radiation-induced NF-κB activity. A modest restoration of radiosensitivity was also observed in the stably transfected MeWo cells with survival factor at 2 Gy values being reduced from 47 ± 0.8% in parental MeWo cells to 32.9 ± 0.7% in stable transfectants. Because constitutively activated mitogen-activated protein kinase kinase (MEK) pathway has been shown to lead to activated NF-κB, we wanted to determine the relative contribution of activated MEK in the human melanoma cells. To test this, MeWo and A375 melanoma cells were exposed to the MEK inhibitor PD184352. Treatment with PD184352 partially reversed NF-κB activity but did not impart radiation sensitivity to these cells. Our results indicate that activated NF-κB may be one of the pathways responsible for the radioresistance of melanoma cells and that strategies for inhibiting its influence may be useful in restoring the radioresponse of melanomas.
Transcriptome analysis of endometrial cancer identifies peroxisome proliferator-activated receptors as potential therapeutic targets
Authors: Holland Cathrine M. , Saidi Samir A. , Evans Amanda L. , Sharkey Andrew M. , Latimer John A. , Crawford Robin A.F. , Charnock-Jones D. Stephen , Print Cristin G. , Smith Stephen K.
Published: June 2022

Endometrial cancer is the most common gynecologic malignancy, frequently arising in association with obesity and diabetes mellitus. To identify gene pathways contributing to endometrial cancer development, we studied the transcriptome of 20 endometrial cancers and 11 benign endometrial tissues using cDNA microarrays. Among the transcript changes identified in endometrial cancer were up-regulation of the nuclear hormone receptors peroxisome proliferator-activated receptors (PPAR) α and γ, whereas retinoid X receptor β was down-regulated. To clarify the contribution of PPARα to endometrial carcinogenesis, we did experiments on cultured endometrial carcinoma cells expressing this transcript. Treatment with fenofibrate, an activating ligand for PPARα, significantly reduced proliferation and increased cell death, suggesting that altered expression of nuclear hormone receptors involved with fatty acid metabolism leads to deregulated cellular proliferation and apoptosis. These results support further investigation of members of the PPAR/retinoid X receptor pathway as novel therapeutic targets in endometrial cancer.
Abstract A13: Papillary thyroid cancer clusters in North Carolina 1997-2017
Authors: Hoffman Kate , Stapleton Heather M.
Published: June 2022

Thyroid cancer is the fastest-increasing cancer in the U.S., and papillary thyroid cancer (PTC) accounts for >80% of incident cases. Data also indicate that the incidence of PTC varies geographically. We investigated associations between residential location and PTC incidence using data from the North Carolina Central Cancer Registry to generate hypotheses about social and environmental factors related to etiology or diagnosis. Analyses included data on 961,111 individuals diagnosed with cancer between 1997 and 2017 (16,468 with PTC). We explored relationships between PTC and residential location at the time of diagnosis. Generalized additive models were used to predict PTC odds across North Carolina while adjusting for individual-level covariates. Cancer patients living in several regions of North Carolina (e.g., areas of the Western Piedmont and the Southern Coast) were up to 200% more likely to be diagnosed with PTC compared with individuals living elsewhere in the state. Patterns were not explained by geographic variation in individual age, sex, or race. We also examined temporal patterns in PTC incidence; these analyses suggest that geographic patterns vary over time and have diminished in recent years. To evaluate whether diagnostic factors explained observed patterns, we evaluated the average tumor size and disease stage in communities identified as having excess odds of PTC. Results of these analyses do not indicate that diagnostic factors are driving spatial patterns; tumor sizes and disease stage in these communities were similar to those in the state as a whole, which would not be expected if diagnostic bias explained variation. Cumulatively, our data suggest that localized environmental factors are influencing geographic distributions of PTC in North Carolina and provide exposure hypotheses for a future large-scale epidemiologic investigation.

Citation Format: Kate Hoffman, Heather M. Stapleton. Papillary thyroid cancer clusters in North Carolina 1997-2017 [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 A13.
Abstract A49: Induction of the lymphomagenic enzyme activation-induced cytidine deaminase (AID) upon in vitro exposure to phenylurea herbicides
Authors: Leeman-Neill Rebecca J. , Basu Uttiya
Published: June 2022

Many studies have drawn associations between pesticide exposures and lymphomagenesis, both in occupational settings and in the general population. The specific compounds responsible for an increased risk of non-Hodgkin lymphoma in pesticide-exposed individuals have not been entirely established. Furthermore, the biologic mechanisms by which pesticides act as lymphomagens are unknown. One mechanism of B-cell genomic instability that plays a role in lymphomas derived from germinal center (GC)-type B cells, including follicular lymphoma, diffuse large B cell lymphoma, and Burkitt lymphoma, is the off-target/aberrant activity of activation-induced cytidine deaminase (AID). AID damages DNA through deamination of cytidine. This occurs on a physiologic basis within GC B cells and is responsible for both class switch recombination (CSR) and somatic hypermutation (SHM). AID can also target nonimmunoglobulin loci, including several proto-oncogenes, resulting in both mutations (aberrant somatic hypermutation; aSHM) and chromosomal translocations. Overexpression of AID has previously been found to increase B-cell genomic instability. In this study, GC-type B cell lines (Ramos, Raji, and CL-01) were treated with pesticides, including herbicides and insecticides from various classes, to determine the effect on AID expression. Real-time RT-PCR was used to determine the degree of AID mRNA expression after chemical treatment. Two representative phenylurea herbicides, linuron and diuron, were found to induce AID expression, in a time- and dose-dependent manner, at concentrations ranging from 50-200 micromolar, with maximal induction of 2- to 6-fold depending on the compound and time point. Additional pesticides that were tested but not found to induce AID expression, at concentrations that were minimally toxic in vitro, included representative organochlorine, organophosphate, phenoxy, and phosphanoglycine pesticides. The findings raise the possibility of increased AID-mediated genomic instability in GC type B cells exposed to phenylurea herbicides. Future studies will investigate the possible link between the observed phenylurea herbicide-related induction of AID, B-cell genomic instability, and lymphomagenesis.

Citation Format: Rebecca J. Leeman-Neill, Uttiya Basu. Induction of the lymphomagenic enzyme activation-induced cytidine deaminase (AID) upon in vitro exposure to phenylurea herbicides [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 A49.
Abstract IA01: The global impact of environmental carcinogenesis and interventions for prevention
Authors: Wild Christopher P.
Published: June 2022

The global burden of cancer is projected to increase markedly over the next two decades, driven by population aging, population growth, and changes in exposure to known risk factors. The greatest percent increases will be in low- and middle-income countries, the majority of which currently do not have the health care infrastructure to meet this challenge. At the same time much is known about the causes of different cancer types worldwide, with the major contribution arising from environmental and behavioral factors. This recognition provides a foundation to counter the projected increases in cancer burden. However, for a number of these risk factors there remains a gap in developing preventive interventions, whereas for others interventions are available but often fail to be implemented in effective programs. In addition, the etiology of a number of common cancer types remains unexplained. Based on the projected cancer burden, the spiraling costs of therapy, and the unavailability of effective treatment in many parts of the world, prevention should be a priority in overall cancer control planning in every country. Similarly, research on cancer prevention (establishing etiology, preventive interventions and their implementation) should be better supported. To progress, cancer prevention must draw upon new knowledge on carcinogenic mechanisms and the associated technology to address knowledge gaps in innovative ways. There is a major opportunity for interdisciplinary prevention research to provide the basis for a reduction in the projected rises in cancer burden worldwide. Translation of knowledge about causes and prevention into observed reductions in cancer rates is a long and hazardous journey. Researchers should become more aware of the inherent hurdles and active opposition that lie in the way of achieving the goals of cancer prevention. Notably, the tactics of vested interests in casting doubt on the scientific evidence base for prevention should be widely disseminated and understood if researchers are to see their efforts bring benefits. Only by combining the evidence base with a well-planned strategy for implementation will the full fruits of cancer prevention research be realized.

Citation Format: Christopher P. Wild. The global impact of environmental carcinogenesis and interventions for 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 IA01.
Abstract IA21: A systems approach to cancer prevention
Authors: Hoppin Polly J. , Kriebel David , Jacobs Molly
Published: June 2022

Cancer prevention research and practice largely focus on three overlapping areas: precision prevention (e.g., genetic, social, and other factors specific to an individual patient), genetics, and health behaviors. All three of these envision the individual patient and her provider as the agents of change. A fourth realm of research and practice with potential to contribute to the primary prevention of cancers targets environmental and social factors over which the individual has little control, but governments, businesses, and communities do. These include environmental carcinogens in consumer products, workplaces, and air and water pollution. For example, flame retardants, dry cleaning solvents, formaldehyde, and diesel exhaust are widespread and often pose disproportionately high risks for people in low-income communities. Historically, laws and regulations have been the primary tools for controlling environmental and workplace contaminants, but despite important successes, significant cancer risks from pollution still occur. This presentation explores two questions based on our recent policy and program research: 1) What does systems analysis tell us about actions that impede and hold promise for reducing exposure to environmental carcinogens at the scale needed? 2) How might a systems approach inform the integration of environmental carcinogen reduction into cancer prevention research and practice? Particularly in the current political climate, system-level interventions that shift dominant narratives about cancer, prioritize interdisciplinary research, and harness market forces deserve prioritization.

Citation Format: Polly J. Hoppin, David Kriebel, Molly Jacobs. A systems approach to cancer 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 IA21.
Abstract IA24: Applying epidemiology to prevention
Authors: Groopman John D.
Published: June 2022

Within the last decade, for the first time in human history, deaths from chronic diseases have exceeded mortality from acute causes worldwide. These chronic diseases encompass a spectrum of cancers, cardiovascular diseases, neurologic diseases, and the emerging consequences of obesity and overnutrition. Further, there are more people today who are cancer survivors as well as people who are afflicted with multiple chronic diseases. This results in an emerging new group of susceptible populations. Since environmental exposures have a profound impact, from the etiology of disease through progression and response to therapeutic and preventive interventions, a new appreciation of the role of environmental health has emerged. This talk will attempt to provide a global perspective on the transitions that have occurred in environmental health over the last 200 years and how these transitions are impacting diverse populations globally. The extraordinary advances in our understanding of the biology of normal development and the molecular progression of disease processes has created unprecedented opportunities for the translation of basic science to therapy and prevention. The need to integrate findings from the biologic, physical, engineering, social, and behavioral sciences, sometimes called convergence, points to an imperative to develop new team science approaches to address the health consequences of environmental exposures. Finally, as it is increasingly recognized that disease outbreaks in one part of the world are no longer isolated from global impacts, there is a need to assure that our next generations of trained scientists have grounding in global collaborations.

Citation Format: John D. Groopman. Applying epidemiology to 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 IA24.
Abstract PR01: Genomic UV-hypersensitive sites as sentinels for personal UV exposure
Authors: Premi Sanjay , Han Lynn , Mehta Sameet , Knight James , Zhao Dejian , Bacchiocchi Antonella , Halaban Ruth , Palmatier Meg A. , Kornacker Karl , Brash Douglas E.
Published: June 2022

The largest risk factor for skin cancers such as melanoma is past sun exposure, so an objective measurement of traces of an individual’s sun history would allow a general practitioner to identify people who should be monitored for early cancer detection. If the genome contains outlier DNA sequences hypersensitive to environmental agents such as ultraviolet light (UV), these would be genomic dosimeters for monitoring personal carcinogen exposure and would facilitate noninvasive measurements on small skin samples. Such DNA sites might also allow UV to drive direct changes in cell physiology rather than acting through rare mutations. New methods, adductSeq and freqSeq, tagged rare UV-induced cyclobutane pyrimidine dimers (CPDs) and provided statistical resolution to quantify rare lesions at single-base resolution across the genome. Primary human melanocytes, but not fibroblasts, carried spontaneous apurinic sites and TG sequence lesions more frequent than UV-induced CPDs. UV exposure revealed hyperhotspots acquiring CPDs up to 200-fold more frequently than the genomic average; these were 20-fold more prevalent in melanocytes. Hyperhotspots were disproportionately located near genes, particularly for RNA-binding proteins, with the most-recurrent hyperhotspots at a fixed position within two motifs. One motif occurred at ETS1 transcription factor binding sites, known to be UV targets, and at sites of mTOR/TOP-tract translation regulation; the second occurred at a sequence that developed delayed CPDs after UV exposure, repaired CPDs slowly, and had accumulated CPDs prior to the experiment. Melanocyte CPD hyperhotspots aligned precisely with recurrent UV signature mutations in individual gene promoters of melanomas and with known cancer drivers. At sunburn levels of UV exposure, every cell would have a hyperhotspot CPD in each of the ~20 cell pathways targeted, rendering CPD hyperhotspots epigenetic marks.

This abstract is also being presented as Poster A28.

Citation Format: Sanjay Premi, Lynn Han, Sameet Mehta, James Knight, Dejian Zhao, Antonella Bacchiocchi, Ruth Halaban, Meg A. Palmatier, Karl Kornacker, Douglas E. Brash. Genomic UV-hypersensitive sites as sentinels for personal UV exposure [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 PR01.
TRUST4 Interrogates the Immune Receptor Repertoire in Oncology and Immunotherapy
Authors: Liu Yuan , Han Leng
Published: June 2022

The immune receptor repertoire is a set of cellular receptors responsible for recognizing foreign antigens. Characterizing the immune receptor repertoire is critical to understanding mechanisms of human adaptive immunity and developing new approaches to cancer immunotherapy. In this issue, Song and colleagues utilize an advanced bioinformatics pipeline on large-scale samples to investigate the diversity of receptor repertoires in tumors and identify factors correlated with favorable outcomes. The result highlights the role of B cells in immunotherapy responses and suggests establishing B cells as biomarkers in future research.

See related article by Song et al., p. 788 (3).
Factors Associated with Severity of Acute Kidney Injury and Adverse Outcomes in Critically Ill Patients with COVID-19
Authors: El Mouhayyar Christopher , Dewald Jonathan , Cabrales Jose , Tighiouart Hocine , Moraco Andrew H. , Jaber Bertrand L. , Balakrishnan Vaidyanathapuram S.
Published: June 2022

Background: Acute kidney injury (AKI) is a well-recognized complication of coronavirus disease 2019 (COVID-19). The short and long-term outcomes of patients who develop AKI have not been well characterized. Methods: In this multicenter retrospective cohort study, we describe the clinical characteristics and outcomes of critically ill adults with severe COVID-19 and AKI. Patient-level variables were extracted from the electronic medical record. Using nadir-to-peak serum creatinine, AKI was defined using the KDIGO definition. Multivariable logistic regression analyses examined factors associated with development of moderate-to-severe (stage 2–3) AKI, severe (stage-3) AKI, and the composite of renal replacement therapy (RRT) or in-hospital death. Results: Among 459 critically ill adults with COVID-19, 371 (80.1%) developed AKI, with 179 (37.9%) developing stage-3 AKI. Male gender, black and Asian/Native American race, lower baseline estimated glomerular filtration rate (eGFR), higher body mass index (BMI), and higher Acute Physiology and Chronic Health Evaluation (APACHE) IV score were more prevalent among patients with severe AKI, as were systemic markers of inflammation. On multivariable analysis, male gender, black and Asian/Native American race, higher APACHE IV score, lower baseline eGFR, and higher BMI (mainly the highest BMI stratum ≥35 kg/m2) were independently associated with higher stages of AKI severity. Male gender, lower baseline eGFR, and higher APACHE IV score were also independently associated with the composite of RRT or in-hospital death. Moderate-to-severe AKI and severe AKI were independently associated with in-hospital death, and there was a significant interaction between BMI and moderate-to-severe AKI for the outcome of in-hospital death. Among 83 (18.1%) patients who required RRT, 27 (32.5%) survived, and 12 (44.4%) remained dialysis-dependent at discharge. At 3 and 6 months, 5 (41.7%) and 4 (33.3%) remained dialysis-dependent, respectively. Conclusions: AKI is common in critically ill adults with COVID-19. Several patient-level risk factors are associated with higher stages of AKI severity. BMI might be an effect modifier of AKI severity for in-hospital death. Among AKI survivors, there is a high rate of short- and long-term dialysis dependence.
Cross-Sectional Analysis of Paronychias in the National Electronic Injury Surveillance System 1999–2018
Authors: Desai Amar D. , Wang Yu , Nadarajah Cajeton Clint , Lipner Shari R.
Published: June 2022

Introduction: Paronychia is the most common hand infection. Prior paronychia studies were limited by small patient numbers. We conducted a national-level analysis over two decades, analyzing demographics, etiologies, and trends in paronychia cases. Methods: We conducted a retrospective analysis of paronychia cases in the 1999–2018 National Electronic Injury Surveillance System database. Sex, race, age, and cause were recorded and compared using χ2, ANOVA, and t tests. Multivariable linear regression analysis assessed changes in age, weight, and sex over time. Results: We analyzed a total of 2,512 cases, with an average age of 27.6 ± 20.6 years, 45.5% females, and 25.6% white and 28.6% black patients. In multivariable linear regression, both age and weight significantly increased over time. Manicuring was the most common etiology (30.9%), increasing in incidence over time and with a higher frequency in adults (p < 0.0001) and females (p < 0.0001). There was a significant decrease in pediatric paronychia cases over time, particularly in 0- to 4-year-olds. Possible limitations include missed paronychia cases or additional non-paronychia cases due to improper coding, infrequent race reporting, and inability to analyze treatments or distinguish between paronychia subtypes. Conclusions: Paronychia cases were associated with increased age and weight over time with different presentations by age. Manicuring represents the largest growing paronychia etiology.
E-book interativo guia prático: revisão sistemática: da ideia à publicação. Construção Colaborativa - 2021
Authors:   Universidade Federal do Rio de Janeiro, Bandeira Ana Maria Bezerra , Costa Claudio ,   Universidade de São Paulo. Faculdade de Odontologia, Arita Emiko Saito ,   Universidade de São Paulo. Faculdade de Odontologia, Munhoz Luciana ,   Universidade de São Paulo. Faculdade de Odontologia, Moreira Lucila M. Y. Akinaga ,   Universidade de São Paulo. Faculdade de Odontologia
Published: June 2022

Diante dos fatos que vivenciamos no ano de 2020, com a pandemia gerada pela Covid-19, de repercussões mundiais, muitas atividades acadêmicas passaram a ser realizadas de forma remota, determinando um crescimento na oferta de cursos de extensão online por diversas Instituições de Ensino Superior. Ao realizar um desses cursos, promovido por um grupo de alunas de doutorado da Universidade de São Paulo que tiveram a iniciativa de compartilhar seus conhecimentos e experiências sobre “Revisão Sistemática: da ideia à submissão”, a organizadora do livro foi inspirada na elaboração de um conteúdo que construído de forma colaborativa pelos alunos cursistas. A motivação principal era incentivar o estudo, a interação, a troca de saberes e o mais importante: produzir um material interativo educacional que reunisse os conceitos aprendidos, assim como dicas, podcasts, vídeos e referências, visando à obtenção de um produto digital para consulta. Os membros da equipe escolheram o conteúdo a ser produzido de acordo com suas expertises sobre o processo de construção de uma revisão sistemática, com o auxílio de ferramentas digitais que permitiam criar, em grupo e online, todo o conteúdo deste livro, focando na produção de materiais de acesso livre e na valorização da ciência aberta.
Separate and Joint Associations of Cardiorespiratory Fitness and Healthy Vascular Aging With Subclinical Atherosclerosis in Men
Authors: Jae Sae Young , Lee Kyung Hyun , Kim Hyun Jeong , Kunutsor Setor K. , Heffernan Kevin S. , Climie Rachel E. , Bunsawat Kanokwan , Kang Mira
Published: June 2022

Background:

Achieving healthy vascular aging (HVA) is important for decelerating age-related cardiovascular disease risk. We evaluated the interplay between HVA, cardiorespiratory fitness (CRF), and subclinical atherosclerosis.

Methods:

We analyzed data on 3722 men who underwent cardiopulmonary exercise testing in a health examination program. HVA was defined as blood pressure <140/90 mm Hg without hypertension and brachial-ankle pulse wave velocity <1266 cm/s. CRF was directly measured by peak oxygen uptake. Subclinical atherosclerosis was defined as coronary artery calcification scores of >0 and ≥100 and a mean carotid artery intima-media thickness (CIMT) >75th percentile for each age group as well as >0.8 mm of CIMT. Separate and joint associations of HVA and CRF with subclinical atherosclerosis were evaluated.

Results:

Each 1 metabolic equivalent increment in CRF was associated with 23% higher odds for having HVA. HVA was associated with lower odds of coronary artery calcification but not CIMT. CRF modified the association between HVA and CIMT>0.8 mm (interaction:
P
=0.01); HVA was associated with lower odds of CIMT>0.8 mm in fit men with no significant association between HVA and CIMT>0.8 mm in unfit men. Compared with no HVA and being unfit, HVA and being fit was associated with lower odds of subclinical atherosclerosis, but there was no significant association between HVA and being unfit with subclinical atherosclerosis.

Conclusions:

HVA and higher CRF are each associated with a lower risk of subclinical atherosclerosis in men. Higher CRF is associated with a higher prevalence of HVA and may modify the association between HVA and subclinical atherosclerosis.
Underdiagnosis and Undertreatment of Modifiable Cardiovascular Risk Factors Among Survivors of Childhood Cancer
Authors: Chow Eric J. , Chen Yan , Armstrong Gregory T. , Baldwin Laura‐Mae , Cai Casey R. , Gibson Todd M. , Hudson Melissa M. , McDonald Aaron , Nathan Paul C. , Olgin Jeffrey E. , Syrjala Karen L. , Tonorezos Emily S. , Oeffinger Kevin C. , Yasui Yutaka
Published: June 2022

Background

Determine the prevalence and predictors associated with underdiagnosis and undertreatment of modifiable cardiovascular disease (CVD) risk factors (hypertension, dyslipidemia, glucose intolerance/diabetes) among adult survivors of childhood cancer at high risk of premature CVD.

Methods and Results

This was a cross‐sectional study of adult‐aged survivors of childhood cancer treated with anthracyclines or chest radiotherapy, recruited across 9 US metropolitan regions. Survivors completed questionnaires and in‐home clinical assessments. The comparator group was a matched sample from the National Health and Nutrition Examination Survey. Multivariable logistic regression estimated the risk (odds ratios) of CVD risk factor underdiagnosis and undertreatment among survivors compared with the National Health and Nutrition Examination Survey. Survivors (n=571; median age, 37.7 years and 28.5 years from cancer diagnosis) were more likely to have a preexisting CVD risk factor than the National Health and Nutrition Examination Survey (n=345;
P
<0.05 for all factors). While rates of CVD risk factor underdiagnosis were similar (27.1% survivors versus 26.1% National Health and Nutrition Examination Survey;
P
=0.73), survivors were more likely undertreated (21.0% versus 13.9%,
P
=0.007; odds ratio, 1.8, 95% CI, 1.2–2.7). Among survivors, the most underdiagnosed and undertreated risk factors were hypertension (18.9%) and dyslipidemia (16.3%), respectively. Men and survivors who were overweight/obese were more likely to be underdiagnosed and undertreated. Those with multiple adverse lifestyle factors were also more likely undertreated (odds ratio, 2.2, 95% CI, 1.1–4.5). Greater health‐related self‐efficacy was associated with reduced undertreatment (odds ratio, 0.5; 95% CI, 0.3–0.8).

Conclusions

Greater awareness of among primary care providers and cardiologists, combined with improving self‐efficacy among survivors, may mitigate the risk of underdiagnosed and undertreated CVD risk factors among adult‐aged survivors of childhood cancer.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03104543.
Natural History of Asymptomatic Moderate Carotid Artery Stenosis in a Large Community-Based Cohort
Authors: Gologorsky Rebecca C. , Lancaster Elizabeth , Tucker Lue-Yen , Nguyen-Huynh Mai N. , Rothenberg Kara A. , Avins Andrew L. , Kuang Hui C. , Chang Robert W.
Published: June 2022

Background:

Moderate carotid artery stenosis is a poorly defined risk factor for ischemic stroke. As such, practice recommendations are lacking. In this study, we describe the long-term risk of stroke in patients with moderate asymptomatic stenosis in an integrated health care system.

Methods:

All adult patients with asymptomatic moderate (50%–69%) internal carotid artery stenosis between 2008 and 2012 were identified, with follow-up through 2017. The primary outcome was acute ischemic stroke attributed to the ipsilateral carotid artery. Stroke rates were calculated using competing risk analysis. Secondary outcomes included disease progression, ipsilateral intervention, and long-term survival.

Results:

Overall, 11 614 arteries with moderate stenosis in 9803 patients were identified. Mean age was 74.2±9.9 years with 51.4% women. Mean follow-up was 5.1±2.9 years. There were 180 ipsilateral ischemic strokes (1.6%) identified (crude annual risk, 0.31% [95% CI, 0.21%–0.41%]), of which thirty-one (17.2%) underwent subsequent intervention. Controlling for death and intervention as competing risks, the cumulative incidence of stroke was 1.2% (95% CI, 1.0%–1.4%) at 5 years and 2.0% (95% CI, 1.7%–2.4%) at 10 years. Of identified strokes, 50 (27.8%) arteries had progressed to severe stenosis or occlusion. During follow-up, there were 17 029 carotid studies performed in 5951 patients, revealing stenosis progression in 1674 (14.4%) arteries, including 1614 (13.9%) progressing to severe stenosis and 60 (0.5%) to occlusion. The mean time to stenosis progression was 2.6±2.1 years. Carotid intervention occurred in 708 arteries (6.1%). Of these, 66.1% (468/708) had progressed to severe stenosis. The overall mortality rate was 44.5%, with 10.5% of patients lost to follow-up.

Conclusions:

In this community-based sample of patients with asymptomatic moderate internal carotid artery stenosis followed for an average of 5 years, the cumulative incidence of stroke is low out to 10 years. Future research is needed to optimize management strategies for this population.
Polygonatum binatifolium, a new species of Polygonatum (Asparagaceae) from Guizhou, China
Authors: ZHU HENG-XING , HUANG FEI-YI , CHEN HONG-YUAN , ZHANG HONG-JING , DAI QIAN-LI , YI SI-RONG
Published: June 2022

Polygonatum binatifolium, from Guizhou, China, is newly described and illustrated. The new species is morphologically most similar to P. cyrtonema in sharing an erect stem, pendulous flowers, glabrous peduncles and pedicels, campanulate, yellowish green perianths, and glabrous, included stamens, but differs by its shorter stems (20–50 cm vs. 50–100 cm), fewer leaves (5–9 vs. 10–15) of which the lowermost two being opposite, fewer flowers (up to 5 vs. up to 14), shorter peduncles (2–5 mm vs. 1–6 cm), shorter filaments (ca. 1.0 mm vs. 3–4 mm) and anthers (1.6–1.9 mm vs. 3.5–4.0 mm), smaller ovary (1.8–2.2 mm vs. 3.0–6.0 mm) and shorter styles (1.5–2.0 mm vs. 1.2–1.5 cm), and smaller berries (5.5–6.5 mm vs. 6–12 mm) and seeds (2.4–3.0 × 2.0–2.4 mm vs. 3.8–5.6 × 2.8–3.6 mm). The species can be categorized as Critically Endangered (CR).
Begonia amparoi (Begoniaceae, section Baryandra) a new species from Linungaw Twin Islands, Surigao del Sur, Mindanao, Philippines
Authors: BLASCO FREDDIE A. , ALEJANDRO GRECEBIO JONATHAN D. , TANDANG DANILO N. , VALES MARIANITA B. , RUBITE ROSARIO R.
Published: June 2022

We describe Begonia amparoi, a new species of Begonia section Baryandra from Linungaw Twin Islands, Mindanao, Philippines. It grows on limestone and has a robust habit, with a thick rhizome and large leaves. Begonia amparoi is currently known only from the type locality in a coastal island forest of Tandag City, Province of Surigao del Sur. Based on IUCN red list criteria, B. amparoi is considered Vulnerable (VU).
Molecular phylogenetics of Sorocea (Moraceae)
Authors: DE MATTOS LETICIA , GAGLIOTI ANDRÉ LUIZ , DA-SILVA PAULO ROBERTO , PEDERNEIRAS LEANDRO CARDOSO , ROMANIUC-NETO SERGIO
Published: June 2022

Sorocea (Moraceae) includes approximately 25 species with a Neotropical distribution and can be recognized by being shrubs to dioecious trees with paired or solitary racemose inflorescences in the leaf axils. The number of species and the phylogenetic position of this genus are divergent according to different studies. In this work, we performed a comprehensive phylogenetic analysis of Sorocea including species after Berg’s study of the genus for the Flora Neotropica. We analysed 42 accessions of Moraceae (34 taxa), including all tribes, being 21 accessions of Sorocea (13 taxa). The phylogenetic analyses were based on plastid (trnL-F) and nuclear (ITS 4-5 and FA16180b) markers using maximum parsimony, maximum likelihood and Bayesian inference. The analyses of the combined data strongly supported the monophyly of Sorocea and its position in the Moreae tribe. The genus can be divided into three major well-supported clades, for which we described novel morphological characteristics. Morphological and phylogenetic analyses suggest the ressurection of S. jureiana, S. klotzschiana, S. racemosa and S. uaupensis as species.