The Experts below are selected from a list of 291 Experts worldwide ranked by ideXlab platform
Herbert Chen - One of the best experts on this subject based on the ideXlab platform.
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chrysin suppresses achaete scute Complex like 1 and alters the neuroendocrine phenotype of carcinoids
Cancer Gene Therapy, 2015Co-Authors: Yash R Somnay, Herbert Chen, Barbara Zarebczan Dull, Jacob Eide, Renata JaskulasztulAbstract:Carcinoids are neuroendocrine neoplasms that cause significant morbidity and mortality and for which few effective therapies are available. Given the recent identification of the anticancer flavonoid chrysin, we sought to investigate its therapeutic potential in carcinoids. Here we report chrysin’s ability to modulate the Achaete-Scute Complex-like 1 (ASCL1), a neuroendocrine-specific transcription factor highly implicated in the malignant phenotype of carcinoids and other neuroendocrine cancers. Moreover, we elucidate the role of ASCL1 in carcinoid growth and bioactivity. Treatment of two carcinoid cell lines (BON and H727) with varying chrysin concentrations suppressed cell proliferation, while reducing expression of ASCL1 and the neuroendocrine biomarker chromogranin A (CgA), demonstrated by western blotting. Propidium iodide and phycoerythrin AnnexinV/7-aminoactinomycin D staining and sorting following chrysin treatment revealed S/G2 phase arrest and apoptosis, respectively. This was corroborated by chrysin-induced cleavage of caspase-3 and poly ADP-ribose polymerase and activation of p21Waf1/Cip1. Furthermore, direct ASCL1 knockdown with an ASCL1-specific small interfering RNA inhibited CgA and synaptophysin expression as well as carcinoid proliferation, while also reducing cyclin B1 and D1 and increasing p21Waf1/Cip1 and p27Kip1 expression, suggesting an arrest of the cell cycle. Collectively, these findings warrant the deliberation of targeted ASCL1 suppression by chrysin or other agents as a therapeutic approach for carcinoid management.
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Hesperetin, a potential therapy for carcinoid cancer.
American journal of surgery, 2011Co-Authors: Barbara Zarebczan, Muthusamy Kunnimalaiyaan, Scott N. Pinchot, Herbert ChenAbstract:Abstract Background The investigators' laboratory has demonstrated that the Notch1 signaling pathway acts as a tumor suppressor in carcinoid tumors. The aim of this study was to examine hesperetin, a flavonoid, as a potential Notch1 activator and carcinoid tumor suppressor. Methods A high-throughput drug screen revealed hesperetin as a Notch1 activator. Human gastrointestinal carcinoid (BON) cell growth after hesperetin treatment was assessed with a 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide assay. Western blots were used to measure neuroendocrine tumor markers, human Achaete-Scute Complex-like 1, and chromogranin A. Notch1 expression was measured using western blot analysis and real-time polymerase chain reaction. Results Hesperetin induced cell death in a dose-dependent manner and reduced Achaete-Scute Complex-like 1 and chromogranin A expression, with a concomitant rise in Notch1 levels. It also induced Notch1 messenger ribonucleic acid, indicating regulation at the transcriptional level. Conclusion Hesperetin induces Notch1 expression in carcinoid cells, subsequently suppressing tumor cell proliferation and bioactive hormone production. This provides evidence for further study into hesperetin as a potential treatment for carcinoid cancer.
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Notch in the development of thyroid C-cells and the treatment of medullary thyroid cancer.
American journal of translational research, 2010Co-Authors: Mackenzie R. Cook, Herbert ChenAbstract:The Notch pathway plays an important role in the normal development of neuroendocrine cells, including the calcitonin producing C-cells of the thyroid. This effect has been elucidated to be mediated through modulation of Achaete-Scute Complex Like 1 (ASCL1), a transcription factor associated with poor prognosis in neuroendocrine cancer. Medullary thyroid cancer (MTC) is one of the neuroendocrine cancers derived from the thyroid C-cells. The Notch pathway has been shown to be inactive in MTC which may lead to altered expression of ASCL1. Artificial induction of Notch signaling in MTC cells can suppress ASCL1 expression, the cell growth as well as hormone secreting potential. Pharmacological activation of the Notch pathway also successfully suppresses the tumor growth in an animal model, which sheds light on the targeted therapy of Notch as a potential treatment for intractable MTC.
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Xanthohumol inhibits the neuroendocrine transcription factor Achaete-Scute Complex-like 1, suppresses proliferation, and induces phosphorylated ERK1/2 in medullary thyroid cancer.
American journal of surgery, 2010Co-Authors: Mackenzie R. Cook, Herbert Chen, Jie Luo, Mary A. Ndiaye, Muthusamy KunnimalaiyaanAbstract:Abstract Background Achaete-Scute Complex-like 1 (ASCL1) is a transcription factor important in the malignant development of medullary thyroid cancer (MTC). Activation of Raf-1 signaling is associated with ASCL1 suppression and growth inhibition. Xanthohumol, a natural compound, has recently been shown to have anticancer properties. We thus hypothesized that xanthohumol would suppress growth by activating Raf-1 signaling, thus altering the malignant phenotype of MTC. Methods Human MTC cells were treated with xanthohumol (0–30 μmol/L) for up to 6 days. Proliferation was measured by a methylthiazolyldiphenyl-tetrazolium bromide (MTT) colorimetric assay. Western blot analysis was performed for ASCL1 and markers of Raf-1 pathway activation. Results Treatment of MTC cells with xanthohumol resulted in a dose dependent inhibition of growth. Additionally, induction of phosphorylated ERK1/2 and a reduction of ASCL1 protein was noted. Conclusions Xanthohumol is a potent Raf-1 activator in MTC cells. This compound suppresses MTC growth, alters the malignant phenotype, and warrants further preclinical study.
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Review Article Notch in the development of thyroid C-cells and the treatment of medullary thyroid cancer
2010Co-Authors: Mackenzie R. Cook, Herbert ChenAbstract:The Notch pathway plays an important role in the normal development of neuroendocrine cells, including the calcitonin producing C-cells of the thyroid. This effect has been elucidated to be mediated through modulation of Achaete-Scute Complex Like 1 (ASCL1), a transcription factor associated with poor prognosis in neuroendocrine can- cer. Medullary thyroid cancer (MTC) is one of the neuroendocrine cancers derived from the thyroid C-cells. The Notch pathway has been shown to be inactive in MTC which may lead to altered expression of ASCL1. Artificial induction of Notch signaling in MTC cells can suppress ASCL1 expression, the cell growth as well as hormone secreting potential. Pharmacological activation of the Notch pathway also successfully suppresses the tumor growth in an animal model, which sheds light on the targeted therapy of Notch as a potential treatment for intractable MTC.
Pat Simpson - One of the best experts on this subject based on the ideXlab platform.
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The achaete‐scute Complex in Diptera: patterns of noncoding sequence evolution
Journal of evolutionary biology, 2015Co-Authors: Bárbara Negre, Pat SimpsonAbstract:The Achaete-Scute Complex (AS-C) has been a useful paradigm for the study of pattern formation and its evolution. Achaete-Scute genes have duplicated and evolved distinct expression patterns during the evolution of cyclorraphous Diptera. Are the expression patterns in different species driven by conserved regulatory elements? If so, when did such regulatory elements arise? Here, we have sequenced most of the AS-C of the fly Calliphora vicina (including the genes achaete, scute and lethal of scute) to compare noncoding sequences with known cis-regulatory sequences in Drosophila. The organization of the Complex is conserved with respect to Drosophila species. There are numerous small stretches of conserved noncoding sequence that, in spite of high sequence turnover, display binding sites for known transcription factors. Synteny of the blocks of conserved noncoding sequences is maintained suggesting not only conservation of the position of regulatory elements but also an origin prior to the divergence between these two species. We propose that some of these enhancers originated by duplication with their target genes.
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the achaete scute Complex in diptera patterns of noncoding sequence evolution
Journal of Evolutionary Biology, 2015Co-Authors: Bárbara Negre, Pat SimpsonAbstract:The Achaete-Scute Complex (AS-C) has been a useful paradigm for the study of pattern formation and its evolution. Achaete-Scute genes have duplicated and evolved distinct expression patterns during the evolution of cyclorraphous Diptera. Are the expression patterns in different species driven by conserved regulatory elements? If so, when did such regulatory elements arise? Here, we have sequenced most of the AS-C of the fly Calliphora vicina (including the genes achaete, scute and lethal of scute) to compare noncoding sequences with known cis-regulatory sequences in Drosophila. The organization of the Complex is conserved with respect to Drosophila species. There are numerous small stretches of conserved noncoding sequence that, in spite of high sequence turnover, display binding sites for known transcription factors. Synteny of the blocks of conserved noncoding sequences is maintained suggesting not only conservation of the position of regulatory elements but also an origin prior to the divergence between these two species. We propose that some of these enhancers originated by duplication with their target genes.
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Evolution of the Achaete-Scute Complex in insects: convergent duplication of proneural genes.
Trends in genetics : TIG, 2009Co-Authors: Bárbara Negre, Pat SimpsonAbstract:Proneural genes encode transcriptional activators of the basic Helix–loop–helix class that are involved in neuronal specification and differentiation. We have used the recent availability of genome sequences of multiple distant insect species to study the evolution of a family of proneural genes, the achaete - scute genes, and to examine their genomic organization and evolution. We document independent evolution of multiple copies of Achaete-Scute homologues and argue that this might have contributed to morphological diversity in Diptera and Lepidoptera.
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Gene duplication at the Achaete-Scute Complex and morphological Complexity of the peripheral nervous system in Diptera.
Trends in genetics : TIG, 2002Co-Authors: Nick Skaer, Daniela Pistillo, Jean-michel Gibert, Pietro Liò, Corinna Wülbeck, Pat SimpsonAbstract:The number of Achaete-Scute genes increased during insect evolution, particularly in the Diptera lineage. Sequence comparison indicates that the four Achaete-Scute genes of Drosophila result from three independent duplication events. After duplication, the new genes acquired individual expression patterns but, in Drosophila, their products can compensate for one another, which raises the question: why retain all four genes? The Complexity of the spatial expression of these genes on the notum increased in the lineage leading to the higher Diptera, allowing the development of stereotyped bristle patterns. This probably coincided in time with gene duplication events, raising the possibility that an increase in gene copy number might have provided the flexibility necessary for more Complex transcriptional regulation.
Douglas W Ball - One of the best experts on this subject based on the ideXlab platform.
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Achaete-Scute Complex Homologue 1 Regulates Tumor-Initiating Capacity in Human Small Cell Lung Cancer
Cancer research, 2009Co-Authors: Tianyun Jiang, Brendan J Collins, Barry D. Nelkin, Ning Jin, David N. Watkins, Malcolm V. Brock, William Matsui, Douglas W BallAbstract:The basic helix-loop-helix transcription factor Achaete-Scute Complex homologue 1 (ASCL1) is essential for the development of normal lung neuroendocrine cells as well as other endocrine and neural tissues. Small cell lung cancer (SCLC) and non-SCLC with neuroendocrine features express ASCL1, where the factor may play a role in the virulence and primitive neuroendocrine phenotype of these tumors. In this study, RNA interference knockdown of ASCL1 in cultured SCLC resulted in inhibition of soft agar clonogenic capacity and induction of apoptosis. cDNA microarray analyses bolstered by expression studies, flow cytometry, and chromatin immunoprecipitation identified two candidate stem cell marker genes, CD133 and aldehyde dehydrogenase 1A1 (ALDH1A1), to be directly regulated by ASCL1 in SCLC. In SCLC direct xenograft tumors, we detected a relatively abundant CD133(high)-ASCL1(high)-ALDH1(high) subpopulation with markedly enhanced tumorigenicity compared with cells with weak CD133 expression. Tumorigenicity in the CD133(high) subpopulation depended on continued ASCL1 expression. Whereas CD133(high) cells readily reconstituted the range of CD133 expression seen in the original xenograft tumor, CD133(low) cells could not. Our findings suggest that a broad range of SCLC cells has tumorigenic capacity rather than a small discrete population. Intrinsic tumor cell heterogeneity, including variation in key regulatory factors such as ASCL1, can modulate tumorigenicity in SCLC.
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regulation of neuroendocrine differentiation in gastrointestinal carcinoid tumor cells by notch signaling
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Eric K Nakakura, Muthusamy Kunnimalaiyaan, Virote Sriuranpong, Kornel E Schuebel, Michael Borges, Brendan J Collins, Herbert Chen, Barry D. Nelkin, Edward C. Hsiao, Douglas W BallAbstract:Context: Gastrointestinal (GI) carcinoid tumors elaborate serotonin and other vasoactive substances, causing the carcinoid syndrome. Based on developmental biology data, we hypothesized that basic helix-loop-helix transcription factors, including Achaete-Scute Complex homolog-like 1 (Ascl1)/hASH1, and the Notch signaling pathway might regulate the neuroendocrine phenotype in GI carcinoids. Objective: The aim of this study was to evaluate expression of developmental transcription factors and Notch signaling components in GI carcinoids and model their interaction in a relevant GI carcinoid cell line. Design: Fourteen GI carcinoid tumor specimens, five paired adjacent normal tissues, fetal tissues, and tumor cell lines were analyzed by RT-PCR and immunoblot. BON carcinoid cells were further analyzed after Notch overexpression for neuroendocrine marker expression, serotonin production, and growth. Setting: The study was conducted in an academic referral center. Patients or Other Participants: Deidentified arc...
Sung-hwan Park - One of the best experts on this subject based on the ideXlab platform.
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achaete scute Complex homologue 2 accelerates the development of sjogren s syndrome like disease in the nod shiltj mouse
Immunology Letters, 2017Co-Authors: Sung-min Kim, Jeong-eun Kwon, Jin-sil Park, Hyeon-beom Seo, Kyungah Jung, Young-mee Moon, Jennifer Lee, Seung-ki Kwok, Mi-la Cho, Sung-hwan ParkAbstract:Abstract Achaete-Scute Complex homologue 2 (Ascl2) has been reported to induce the differentiation and activation of follicular helper T (TFH) cells, which are essential for development of Sjogren’s syndrome (SS). This study examined whether Ascl2 plays a role in the development of SS. NOD/ShiLtJ mice were injected with an Ascl2-overexpression vector, and the infiltration of lymphocytes into salivary and lacrimal glands was assessed. The expression of inflammatory cytokines and chemoattractants for T or B cells was measured. The activation of TFH cells was assessed using a specific marker of TFH cells. Ascl2 level was also measured in SS patients. Overexpression of Ascl2 increased the expression of C-X-C chemokine receptor type 5 (CXCR5) in both salivary and lacrimal glands (p
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Achaete-Scute Complex homologue 2 accelerates the development of Sjögren's syndrome-like disease in the NOD/ShiLtJ mouse.
Immunology letters, 2017Co-Authors: Sung-min Kim, Jeong-eun Kwon, Jin-sil Park, Hyeon-beom Seo, Kyungah Jung, Young-mee Moon, Jennifer Lee, Seung-ki Kwok, Mi-la Cho, Sung-hwan ParkAbstract:Abstract Achaete-Scute Complex homologue 2 (Ascl2) has been reported to induce the differentiation and activation of follicular helper T (TFH) cells, which are essential for development of Sjogren’s syndrome (SS). This study examined whether Ascl2 plays a role in the development of SS. NOD/ShiLtJ mice were injected with an Ascl2-overexpression vector, and the infiltration of lymphocytes into salivary and lacrimal glands was assessed. The expression of inflammatory cytokines and chemoattractants for T or B cells was measured. The activation of TFH cells was assessed using a specific marker of TFH cells. Ascl2 level was also measured in SS patients. Overexpression of Ascl2 increased the expression of C-X-C chemokine receptor type 5 (CXCR5) in both salivary and lacrimal glands (p
Muthusamy Kunnimalaiyaan - One of the best experts on this subject based on the ideXlab platform.
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XN regulates the Akt pathway and associated with an increase in DR5 expression.
2019Co-Authors: Samuel Engelsgjerd, Selvi Kunnimalaiyaan, Emad Kandil, Clark T. Gamblin, Muthusamy KunnimalaiyaanAbstract:A. Notch signaling is minimally active in NGP, SK-N-AS, and SH-SY-5Y, as evidenced by minimal expression of Notch intracellular Domain1, whereas there is increased expression of Achaete-Scute Complex-like1 (ASCL1), a downstream target of Notch signaling. B. Inhibition of Akt pathway by XN treatment was observed by reduction in phosphorylation of Akt (ser473) as early as 6 hrs. This was associated with a reduction in CyclinD1. C. NB cell line, SK-N-AS was treated with indicated concentrations of XN for 6–24 hours’ time points and lysates were prepared. Western blot analysis of the lysates shows a time-dependent increase in DR5 expression following XN treatment. GAPDH was used as loading control. D. DR5 gene expression increases with XN treatment in a dose-dependent fashion in quantitative RT PCR analysis. GAPDH was used as a control and for normalization. * p
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Hesperetin, a potential therapy for carcinoid cancer.
American journal of surgery, 2011Co-Authors: Barbara Zarebczan, Muthusamy Kunnimalaiyaan, Scott N. Pinchot, Herbert ChenAbstract:Abstract Background The investigators' laboratory has demonstrated that the Notch1 signaling pathway acts as a tumor suppressor in carcinoid tumors. The aim of this study was to examine hesperetin, a flavonoid, as a potential Notch1 activator and carcinoid tumor suppressor. Methods A high-throughput drug screen revealed hesperetin as a Notch1 activator. Human gastrointestinal carcinoid (BON) cell growth after hesperetin treatment was assessed with a 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide assay. Western blots were used to measure neuroendocrine tumor markers, human Achaete-Scute Complex-like 1, and chromogranin A. Notch1 expression was measured using western blot analysis and real-time polymerase chain reaction. Results Hesperetin induced cell death in a dose-dependent manner and reduced Achaete-Scute Complex-like 1 and chromogranin A expression, with a concomitant rise in Notch1 levels. It also induced Notch1 messenger ribonucleic acid, indicating regulation at the transcriptional level. Conclusion Hesperetin induces Notch1 expression in carcinoid cells, subsequently suppressing tumor cell proliferation and bioactive hormone production. This provides evidence for further study into hesperetin as a potential treatment for carcinoid cancer.
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Xanthohumol inhibits the neuroendocrine transcription factor Achaete-Scute Complex-like 1, suppresses proliferation, and induces phosphorylated ERK1/2 in medullary thyroid cancer.
American journal of surgery, 2010Co-Authors: Mackenzie R. Cook, Herbert Chen, Jie Luo, Mary A. Ndiaye, Muthusamy KunnimalaiyaanAbstract:Abstract Background Achaete-Scute Complex-like 1 (ASCL1) is a transcription factor important in the malignant development of medullary thyroid cancer (MTC). Activation of Raf-1 signaling is associated with ASCL1 suppression and growth inhibition. Xanthohumol, a natural compound, has recently been shown to have anticancer properties. We thus hypothesized that xanthohumol would suppress growth by activating Raf-1 signaling, thus altering the malignant phenotype of MTC. Methods Human MTC cells were treated with xanthohumol (0–30 μmol/L) for up to 6 days. Proliferation was measured by a methylthiazolyldiphenyl-tetrazolium bromide (MTT) colorimetric assay. Western blot analysis was performed for ASCL1 and markers of Raf-1 pathway activation. Results Treatment of MTC cells with xanthohumol resulted in a dose dependent inhibition of growth. Additionally, induction of phosphorylated ERK1/2 and a reduction of ASCL1 protein was noted. Conclusions Xanthohumol is a potent Raf-1 activator in MTC cells. This compound suppresses MTC growth, alters the malignant phenotype, and warrants further preclinical study.
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Phosphatidylinositol 3-Kinase-Akt Signaling in Pulmonary Carcinoid Cells
Journal of the American College of Surgeons, 2009Co-Authors: Susan C. Pitt, Herbert Chen, Muthusamy KunnimalaiyaanAbstract:Background In several types of cancer, upregulation of phosphatidylinositol 3-kinase (PI3K)-Akt signaling facilitates tumor cell growth and inhibits apoptosis. Previous reports demonstrated that this pathway promotes growth, survival, and chemotherapy resistance in non-small cell and small cell lung cancer cells. But the importance of PI3K-Akt signaling has not been explored in pulmonary carcinoids. In this study, our objective was to establish the role of the PI3K-Akt signal transduction pathway in pulmonary carcinoid cells. Study Design Human pulmonary carcinoid NCI-H727 cells were treated with LY294002 (0 to 100 μM), a well-known PI3K inhibitor, or transfected with Akt1 small interfering RNA (75 nM). Cellular proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for up to 8 days. Western blot analysis was performed for expression of active, phosphorylated Akt (pAkt), total Akt, Akt1, and the neuroendocrine markers chromogranin A and Achaete-Scute Complex-like1. Results Treatment of NCI-H727 cells with LY294002 significantly reduced tumor cell growth (85.3%). Similarly, Akt1 small interfering RNA transfection led to diminished tumor cell proliferation (31.3%). A dose-dependent decrease in chromogranin A and Achaete-Scute Complex-like1 production was observed with both PI3K inhibition and Akt1 RNA interference. Expression of Akt1 was reduced at all time points by transient Akt1 small interfering RNA transfection. Conclusions The PI3K-Akt pathway plays a role in both tumor cell growth and neuroendocrine hormone secretion in human pulmonary carcinoid cells. Inhibition of Akt1, PI3K-Akt signaling, or a downstream mediator of this pathway may provide therapeutic approaches for patients with pulmonary carcinoid tumors.
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regulation of neuroendocrine differentiation in gastrointestinal carcinoid tumor cells by notch signaling
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Eric K Nakakura, Muthusamy Kunnimalaiyaan, Virote Sriuranpong, Kornel E Schuebel, Michael Borges, Brendan J Collins, Herbert Chen, Barry D. Nelkin, Edward C. Hsiao, Douglas W BallAbstract:Context: Gastrointestinal (GI) carcinoid tumors elaborate serotonin and other vasoactive substances, causing the carcinoid syndrome. Based on developmental biology data, we hypothesized that basic helix-loop-helix transcription factors, including Achaete-Scute Complex homolog-like 1 (Ascl1)/hASH1, and the Notch signaling pathway might regulate the neuroendocrine phenotype in GI carcinoids. Objective: The aim of this study was to evaluate expression of developmental transcription factors and Notch signaling components in GI carcinoids and model their interaction in a relevant GI carcinoid cell line. Design: Fourteen GI carcinoid tumor specimens, five paired adjacent normal tissues, fetal tissues, and tumor cell lines were analyzed by RT-PCR and immunoblot. BON carcinoid cells were further analyzed after Notch overexpression for neuroendocrine marker expression, serotonin production, and growth. Setting: The study was conducted in an academic referral center. Patients or Other Participants: Deidentified arc...
