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Rahaju, Pudji, Rio Auricknaga Kintono, Ahmad Dian Wahyudiono, Arif Satria, and Ferry Sandra. "Immunohistochemical Expression of EGFR, NF-kB and Cyclin D1 in Sinonasal Inverted Papilloma and Squamous Cell Carcinoma." Indonesian Biomedical Journal 12, no. 3 (September 5, 2020): 239–44. http://dx.doi.org/10.18585/inabj.v12i3.1172.
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BACKGROUND: Sinonasal inverted papilloma (SIP), a benign epithelial growth in the sinonasal region with epidermoid epithelial transformation, has been known for its invasiveness, recurrency, and its link with malignancy. Meanwhile sinonasal squamous cell carcinoma (SSCC) is an epithelial malignancy on squamous cells from the sinonasal region. Epidermal growth factor receptor (EGFR), Nuclear Factor kB (NF-kB), and Cyclin D1 are factors those might play important role in proliferation of SIP and SSCC. This research was conducted to investigate the expressions of EGFR, NF-kB and Cyclin D1 in SIP and SSCC.METHODS: A cross-sectional study by examining the EGFR, NF-kB, and Cyclin D1 immunohistochemical expressions of SIP and SSCC was conducted. Subjects whose blocks were used in this research, were diagnosed as SIP and SSCC at the Otorhinolaryngology-Head and Neck Surgery Clinic, Dr. Saiful Anwar General Hospital. Samples were selected, processed for inmmunohistochemistry, evaluated and statistical analyzed.RESULTS: Twenty-four SIP and 9 SSCC subjects with their paraffin blocks were selected. Clear immunohistochemical expressions of EGFR, NF-kB, and Cyclin D1 were observed for both SIP and SSCC. Significantly higher immunostaining levels of EGFR (45.6%, p=0.001) and NF-kB (42.2%, p=0.013) were observed in SSCC. Immunostaining levels of EGFR vs. NF-kB were moderately correlated (p=0.03, r=0.437), while the immunostaining levels of NF-kB vs. Cyclin D1 were strongly correlated (p=0.002, r=0.602).CONCLUSION: Expression of EGFR and NF-kB in SSCC were higher than the EGFR and NF-kB expression in SIP, suggesting that EGFR and NF-kB play important role in sinonasal malignancy.KEYWORDS: sinonasal, inverted papilloma, SCC, EGFR, NF-kB, Cyclin D1
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Scartozzi, M., I. Bearzi, C. Pierantoni, A. Mandolesi, F. Loupakis, V. Catalano, R. Berardi, R. Silva, A. Falcone, and S. Cascinu. "Nuclear factor kB (NF-kB) may predict efficacy of cetuximab therapy in EGFR-positive colorectal cancer." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 14036. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14036.
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14036 Background: NF-kB is part of the aberrant activation of the EGFR-downstream signalling pathway in colorectal tumours, which is described to be inhibited by anti-EGFR therapies. Methods: We retrospectively analysed nuclear immunoreactivity for NF-kB with the aim to determine a correlation between NF-kB expression and outcome in terms of response rate and time to progression in EGFR-positive advanced colorectal cancer patients receiving cetuximab and irinotecan. Results: To date 67 patients (40 males and 27 females, median age 62, range 38–78) were analysed. Cetuximab and irinotecan were administered as a second-line in 18 cases (27%) and after = 3 lines of chemotherapy in the remaining 49 patients (63%). Among the 56 patients evaluable for response we observed a partial (PR) or a complete response (CR) in 10 and 1 cases respectively for an overall response rate of 20%. Twenty-seven patients (48%) obtained progressive disease, median time to progression (TTP) was 3,6 months, median overall survival was 16 months. NF-kB was positive in 46 cases (69%). All main clinical characteristics resulted well balanced between NF-kB positive and NF-kB negative patients. Response rate was 6% (2 PR) vs 43% (8 PR and 1 CR) (p= 0.001) in NF-kB positive and NF-kB negative tumours respectively whereas progressive disease was observed in 19 (54%) vs 8 (23%) cases in NF-kB positive and NF-kB negative cases respectively. Median TTP in NF- kB positive patients was 2.9 months versus 6.8 months in the remaining NF-kB negative patients (p= 0.01). Conclusions: Both the difference in median TTP and in response rate seem to confirm that NF-kB may play a crucial role in predicting the efficacy of cetuximab therapy in advanced colorectal tumours. The analysis is ongoing and updated results on an expanded number of cases will be presented. No significant financial relationships to disclose.
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Ashktorab, Hassan, Alfred Johnson, Mohammad Daremipouran, Awana Ferguson, Biniam Kifle, and Duane T. Smoot. "Cross talk between EGFR and NF-kB altered by H. pylori in human gastric epithelial cells." Gastroenterology 124, no. 4 (April 2003): A587—A588. http://dx.doi.org/10.1016/s0016-5085(03)82975-x.
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Shukla, Vinay, Vishal Chandra, Pushplata Sankhwar, Pooja Popli, Jyoti Bala Kaushal, Vijay Kumar Sirohi, and Anila Dwivedi. "Phytoestrogen genistein inhibits EGFR/PI3K/NF-kB activation and induces apoptosis in human endometrial hyperplasial cells." RSC Advances 5, no. 69 (2015): 56075–85. http://dx.doi.org/10.1039/c5ra06167a.
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Hassanein, Sarah Sayed, Sherif Abdelaziz Ibrahim, and Ahmed Lotfy Abdel-Mawgood. "Cell Behavior of Non-Small Cell Lung Cancer Is at EGFR and MicroRNAs Hands." International Journal of Molecular Sciences 22, no. 22 (November 19, 2021): 12496. http://dx.doi.org/10.3390/ijms222212496.
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Lung cancer is a complex disease associated with gene mutations, particularly mutations of Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) and epidermal growth factor receptor (EGFR). Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are the two major types of lung cancer. The former includes most lung cancers (85%) and are commonly associated with EGFR mutations. Several EGFR-tyrosine kinase inhibitors (EGFR-TKIs), including erlotinib, gefitinib, and osimertinib, are effective therapeutic agents in EGFR-mutated NSCLC. However, their effectiveness is limited by the development (acquired) or presence of intrinsic drug resistance. MicroRNAs (miRNAs) are key gene regulators that play a profound role in the development and outcomes for NSCLC via their role as oncogenes or oncosuppressors. The regulatory role of miRNA-dependent EGFR crosstalk depends on EGFR signaling pathway, including Rat Sarcoma/Rapidly Accelerated Fibrosarcoma/Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase 1/2 (Ras/Raf/MEK/ERK1/2), Signal Transducer and Activator of Transcription (STAT), Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-kB), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), Janus kinase 1 (JAK1), and growth factor receptor-bound protein 2 (GRB2). Dysregulated expression of miRNAs affects sensitivity to treatment with EGFR-TKIs. Thus, abnormalities in miRNA-dependent EGFR crosstalk can be used as diagnostic and prognostic markers, as well as therapeutic targets in NSCLC. In this review, we present an overview of miRNA-dependent EGFR expression regulation, which modulates the behavior and progression of NSCLC.
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Berardi, Rossana, Anna Campanati, Azzurra Onofri, Chiara Pierantoni, Irene Conte, Katia Giuliodori, E. Molinelli, Fabiana Marcucci, Annamaria Offidani, and Stefano Cascinu. "A novel approach to manage skin toxicity caused by therapeutic agents targeting epidermal growth factor receptor." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 636. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.636.
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636 Background: Inhibition of EGFR represents an important field in cancer therapy.Skin rash is a common adverse reaction in patients receiving EGFR inhibitors. Nicotinamide has been shown to be an effective treatment for skin inflammation in various conditions, since nicotinamide inhibits IL-8 production through the NF-kB and MAPK pathways in an in vitro keratinocytes/P. acnes model of inflammation. Furthermore green tea polyphenols could be useful in attenuation of solar UVB light-induced oxidative stress-mediated and MAPK-caused skin disorders in humans.In this study we evaluated the effect of nicotinamide and green tea polyphenols on skin toxicity EGFRI related. Methods: Patients with skin toxicity induced by EGFRI were enrolled. They underwent a skin biopsy and skin samples for microbiological analyses at first presentation of skin toxicity (T0). Skin toxicity was assessed with NCI-CTACE,EGFR index and Dermatology Life Quality Index (DLQI) test. Therapy protocol consisted in topical application of moisturizing cream containing green tea polyphenols plus oral administration of nicotinamide 200 mg/die for 12 weeks. Topical application of 1% clindamycin gel and/or systemic administration of minocicline were provided in case of superbacterial infection. All treated patients were monitored for at least 12 weeks (T12), across three time points (T0,T6,T12). Results: 24 colorectal cancer patients receiving anti-EGFR monoclonal antibodies (cetuximab or panitumumab) and developing skin toxicity were treated by a multidisciplinary team including oncologists, dermatologists, a pathologist and a nurse. All the patients experienced a significant reduction of skin toxicity according to the NCI-CTACE and EGFR index (p<0.05). Papulo-pustular eruption and itching significantly improved after 6 weeks of treatment and erythema decreased after 12 weeks. A significative improvement of the global score and of DLQI was evident. No toxicity related to the treatment of skin toxicity was observed. Conclusions: Treatment with nicotinamide and green tea polyphenols represent a novel effective approach to manage skin toxicity caused by EGFRI.
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Foulke-Abel, Jennifer D., Nesrin Hasan, Mark Donowitz, Mary Estes, and Olga Kovbasnjuk. "Su1039 – Human Differentiated Enteroid Monolayers Exhibit Egfr/Mek- and Nf-Kb-Dependent Plasticity in a Model of Intestinal Trauma." Gastroenterology 156, no. 6 (May 2019): S—491—S—492. http://dx.doi.org/10.1016/s0016-5085(19)38093-x.
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Pan, Shaojun, Yuhui Zhang, Mark Huang, Zhoufeng Deng, Amin Zhang, Lijia Pei, Lirui Wang, et al. "Urinary exosomes-based Engineered Nanovectors for Homologously Targeted Chemo-Chemodynamic Prostate Cancer Therapy via abrogating EGFR/AKT/NF-kB/IkB signaling." Biomaterials 275 (August 2021): 120946. http://dx.doi.org/10.1016/j.biomaterials.2021.120946.
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Berardi, R., A. Campanati, A. Onofri, A. Bittoni, C. Pierantoni, K. Giuliodori, G. Ganzetti, M. Scartozzi, A. Offidani, and S. Cascinu. "A novel approach to manage skin toxicity caused by cetuximab and panitumumab." Journal of Clinical Oncology 29, no. 4_suppl (February 1, 2011): 616. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.616.
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616 Background: Inhibition of the EGFR represents one of the most important fields for research and development in cancer therapy. Skin rash has been documented as one of the most common adverse reactions in patients receiving EGFR inhibitors. Several approaches have been attempted to manage skin toxicity. Nicotinamide has been shown to be an effective treatment for skin inflammation in various conditions, since nicotinamide inhibits IL-8 production through the NF-kB and MAPK pathways in an in vitro keratinocytes/P. acnes model of inflammation. Furthermore green tea polyphenols could be useful in attenuation of solar UVB light-induced oxidative stress-mediated and MAPK-caused skin disorders in humans. Methods: Therapy protocol for skin toxicity consisted of: topic applications of green tea and a mostouizer and orally given nicotinamide. Patients were monitored weekly and data regarding skin toxicity (NCI-CTC grade, the Dermatology Life Quality Index (DLQI), a global score evaluating all the parameters) were recorded. Results: Between September 2009 and September 2010, 13 colorectal cancer patients receiving anti-EGFR monoclonal antibodies (cetuximab or panitumumab) and developing skin toxicity, were treated by a multidisciplinary team including oncologists, dermatologists, a pathologist, and a nurse. All the patients experienced a significative eduction of erythema, papulo-pustular rash, paronychia, fissuring, xerosis, and itching. A significative improvement of the global score and of DLQI was evident. No toxicity related to the treatment of skin toxicity was observed. Conclusions: Treatment with nicotinamide, green tea, and moisturizer represents a novel effective approach to manage skin toxicity caused by cetuximab and panitumumab. No significant financial relationships to disclose.
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Cho, Sang Hee, Jo-Heon Kim, Chang-Soo Hong, Eun-Gene Sun, Kyung-Hyun Ryu, Jun Eul Hwang, Woo Kyun Bae, Ik-Joo Chung, and Hyun-Jin Bang. "The role of fibroblast growth factor receptor 4 (FGFR4) signaling in anti-EGFR resistance in colon cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 4060. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.4060.
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4060 Background: Anti-EGFR therapy has been used as a standard treatment for metastatic colon cancer, but the innate resistance is still issues of increasing significance. Fibroblast growth factor receptor 4 (FGFR4) plays an important role in cell proliferation, invasion and anti-apoptosis, through the pathway of MAPK-ERK and PI3K-AKT. We investigated potential crosstalk between FGFR4 and EGFR signaling to identify new resistant mechanism of anti-EGFR therapy and how to overcome it in colon cancer. Methods: RNA-Seq was used to identify the associated signal pathway and down targets induced by FGFR4. Molecular studies including RTK array, RT-qPCR, western blotting were performed to validate the interaction between FGFR4 and EGFR signaling in vitro and in vivo. Next, the effect of FGFR4 in cetuximab resistance was investigated in vitro and in colon cancer patients. Results: FGFR4 overexpression in colon cancer cells activates downstream signaling, such as, PI3K/Akt and RAS/RAF/Erk pathway. Gene Ontology (GO) analysis from RNA-seq revealed that differentially expressed genes (DEGs) altered by expression of FGFR4 were related to biological functions, including cell proliferation, epidermal growth factor receptor signaling, NIK/NF-kB signaling, interferon-gamma signaling, wound healing. RT–qRCR showed that FGFR4 promotes the EGFR and ErbB3 by inducing the expression of EGFR ligands such as AREG, BTC, EREG, HBEGF. In vivo tumorigenesis, we found that FGFR4 promotes tumor growth and high expression of AREG in xenograft tumors. FGFR4 expression reduced the sensitivity to cetuximab in colon cancer cells and synergistic effect was shown when treated with FGFR4 inhibitor with cetuximab. A positive correlation between FGFR4 and AREG expression was observed in cancer, but not in normal tissues and high FGFR4 or AREG expression showed significantly inferior overall survival than low expression in patients treated with cetuximab for metastatic colon cancer. Conclusions: We demonstrated a pivotal mechanism of FGFR4 in colon cancer progression and cetuximab resistance through inducing AREG. Our data point to FGFR4 as a new biomarker to predict cetuximab response and dual targeting of FGFR4 and EGFR may be a promising treatment modality for colon cancer.
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Zou, Wujun, Xiaoyan Hu, and Liang Jiang. "Advances in Regulating Tumorigenicity and Metastasis of Cancer Through TrkB Signaling." Current Cancer Drug Targets 20, no. 10 (November 2, 2020): 779–88. http://dx.doi.org/10.2174/1568009620999200730183631.
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The clinical pathology of various human malignancies is supported by tropomyosin receptor kinase (Trk) B TrkB which is a specific binding receptor of the brain-derived neurotrophic factor (BDNF). TrkB and TrkB fusion proteins have been observed to be over-expressed in many cancer patients. Moreover, these proteins have been observed in multiple types of cells. A few signaling pathways can be modulated by the abnormal activation of the BDNF/TrkB pathway. These signaling pathways include PI3K/Akt pathway, transactivation of EGFR, phospholipase C-gamma (PLCγ) pathway, Ras-Raf-MEK-ERK pathway, Jak/STAT pathway, and nuclear factor kappalight- chain-enhancer of activated B cells (NF-kB) pathway. The BDNF/TrkB pathway, when overexpressed in tumors, is correlated with reduced clinical prognosis and short survival time of patients. Targeting the BDNF/TrkB pathway and the use of Trk inhibitors, such as entrectinib, larotrectinib, etc. are promising methods for targeted therapy of tumors. The present review provides an overview of the role of the TrkB pathway in the pathogenesis of cancer and its value as a potential therapeutic target.
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Rosell, R. R., M. S. Mariacarmela Santarpia, M. S. R. Maria Sanchez Ronco, C. C. Carlota Costa, M. A. M. Miguel Angel Molina-Vila, I. M. Ignacio Magri, S. V. Santiago Viteri, A. G. Amaya Gasco, N. M. Nuria Mederos, and M. T. Miquel Taron. "9142 POSTER MRNa Levels and Genetic Status of Genes Involved in the Epidermal Growth Factor Receptor (EGFR) and the Nuclear Factor kB (NF-kB) Pathways in Metastatic Non-Small-Cell Lung Cancer (NSCLC) Patients (P)." European Journal of Cancer 47 (September 2011): S636. http://dx.doi.org/10.1016/s0959-8049(11)72454-6.
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Naveh-Many, Tally, and Oded Volovelsky. "Parathyroid Cell Proliferation in Secondary Hyperparathyroidism of Chronic Kidney Disease." International Journal of Molecular Sciences 21, no. 12 (June 18, 2020): 4332. http://dx.doi.org/10.3390/ijms21124332.
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Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that correlates with morbidity and mortality in uremic patients. It is characterized by high serum parathyroid hormone (PTH) levels and impaired bone and mineral metabolism. The main mechanisms underlying SHP are increased PTH biosynthesis and secretion as well as increased glandular mass. The mechanisms leading to parathyroid cell proliferation in SHP are not fully understood. Reduced expressions of the receptors for calcium and vitamin D contribute to the disinhibition of parathyroid cell proliferation. Activation of transforming growth factor-α-epidermal growth factor receptor (TGF-α-EGFR), nuclear factor kappa B (NF-kB), and cyclooxygenase 2- prostaglandin E2 (Cox2-PGE2) signaling all correlate with parathyroid cell proliferation, underlining their roles in the development of SHP. In addition, the mammalian target of rapamycin (mTOR) pathway is activated in parathyroid glands of experimental SHP rats. Inhibition of mTOR by rapamycin prevents and corrects the increased parathyroid cell proliferation of SHP. Mice with parathyroid-specific deletion of all miRNAs have a muted increase in serum PTH and fail to increase parathyroid cell proliferation when challenged by CKD, suggesting that miRNA is also necessary for the development of SHP. This review summarizes the current knowledge on the mechanisms of parathyroid cell proliferation in SHP.
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Nadile, Matteo, Maria Ilektra Retsidou, Katerina Gioti, Apostolos Beloukas, and Evangelia Tsiani. "Resveratrol against Cervical Cancer: Evidence from In Vitro and In Vivo Studies." Nutrients 14, no. 24 (December 10, 2022): 5273. http://dx.doi.org/10.3390/nu14245273.
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Cervical cancer affects many women worldwide, with more than 500,000 cases diagnosed and approximately 300,000 deaths each year. Resveratrol is a natural substance of the class of phytoalexins with a basic structure of stilbenes and has recently drawn scientific attention due to its anticancer properties. The purpose of this review is to examine the effectiveness of resveratrol against cervical cancer. All available in vitro and in vivo studies on cervical cancer were critically reviewed. Many studies utilizing cervical cancer cells in culture reported a reduction in proliferation, cell cycle arrest, and induction of apoptosis. Apart from apoptosis, induction of autophagy was seen in some studies. Importantly, many studies have shown a reduction in the HPV oncoproteins E6 and E7 and increased levels of the tumor suppressor p53 with resveratrol treatment. A few studies examined the effects of resveratrol administration in mice ectopic-xenografted with cervical cancer cells showing reduced tumor volume and weight. Overall, the scientific data show that resveratrol has the ability to target/inhibit certain signaling molecules (EGFR, VEGFR, PKC, JNK, ERK, NF-kB, and STAT3) involved in cervical cancer cell proliferation and survival. Further in vivo experiments and clinical studies are required to better understand the potential of resveratrol against cervical cancer.
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Bredel, Markus, Hyunsoo Kim, Nanda K. Thudi, Denise M. Scholtens, James A. Bonner, and Branimir I. Sikic. "NFKBIA deletion in triple-negative breast cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 1012. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.1012.
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1012 Background: While effective, target-directed therapies are available for ER-positive and HER2-amplified breast cancer, adjuvant therapeutic options for triple-negative breast cancer (TNBC) are limited in the absence of well-defined molecular targets. Constitutive activation of oncogenic nuclear factor kB (NFkB) has been associated with ER-negative or basal-like (BL) breast cancers, but the underlying mechanism of this activation remains undefined. We previously showed that deletion of the endogenous NFkB repressor gene NFKBIA associates with EGFR non-amplified glioblastoma multiforme and portends unfavorable clinical outcome (Bredel et al. NEJM 2011). Methods: We analyzed >5,000 human breast cancers for deletions, mutations and/or expression of NFKBIA. We studied tumor suppressor activity of NFKBIA and the effect of targeted NFkB inhibition in cell culture with various NFKBIA genotypes. We compared molecular results with outcomes of affected persons. Results: NFKBIA is often (10.8%) deleted but not mutated in breast cancer. NFKBIA deletions are significantly associated with TNBC (32.8%) and particularly frequent in the BL subtype (36.7%). Loss of NFKBIA exerts a haploinsufficient effect on NFKBIA expression and the transactivation of several NF-kB target genes with important roles in breast carcinogenesis. Restoration of NFKBIA expression or pharmacologic NFkB inhibition attenuates the malignant phenotype of cells cultured from TNBC with NFKBIA deletion. Deletion and low expression of NFKBIA are highly associated with unfavorable overall survival, independent of patient age, tumor stage, nodal status, and tumor subtype. Loss of NFKBIA expression portends significantly poorer disease-specific survival, recurrence-free survival, and distant metastasis-free survival. Moreover, NFKBIA expression is significantly associated with duration of metastasis-free survival in subgroups of patients with brain or lung metastases from breast cancer. Conclusions: NFKBIA is a new, prognostically relevant, molecular target in TNBC, which remains a clinically challenging subtype of breast cancer with limited treatment options.
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Haq, Md Mazedul, Md Arifur Rahman Chowdhury, Hilal Tayara, Ibrahim Abdelbaky, Md Shariful Islam, Kil To Chong, and Sangyun Jeong. "A Report on Multi-Target Anti-Inflammatory Properties of Phytoconstituents from Monochoria hastata (Family: Pontederiaceae)." Molecules 26, no. 23 (December 6, 2021): 7397. http://dx.doi.org/10.3390/molecules26237397.
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This study aims to investigate the potential analgesic properties of the crude extract of Monochoria hastata (MH) leaves using in vivo experiments and in silico analysis. The extract, in a dose-dependent manner, exhibited a moderate analgesic property (~54% pain inhibition in acetic acid-induced writhing test), which is significant (** p < 0.001) as compared to the control group. The complex inflammatory mechanism involves diverse pathways and they are inter-connected. Therefore, multiple inflammatory modulator proteins were selected as the target for in silico analysis. Computational analysis suggests that all the selected targets had different degrees of interaction with the phytochemicals from the extract. Rutin (RU), protocatechuic acid (PA), vanillic acid (VA), and ferulic acid (FA) could regulate multiple targets with a robust efficiency. None of the compounds showed selectivity to Cyclooxygenase-2 (COX-2). However, regulation of COX and lipoxygenase (LOX) cascade by PA can reduce non-steroidal analgesic drugs (NSAIDs)-related side effects, including asthma. RU showed robust regulation of cytokine-mediated pathways like RAS/MAPK and PI3K/NF-kB by inhibition of EGFR and IKBα (IKK), which may prevent multi-organ failure due to cytokine storm in several microbial infections, for example, SARS-CoV-2. Further investigation, using in vivo and in vitro experiments, can be conducted to develop multi-target anti-inflammatory drugs using the isolated compounds from the extract.
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El-Ghonaimy, Eslam A., Sherif A. Ibrahim, Amal Youns, Zeinab Hussein, Mohamed Akram Nouh, Tahani El-mamlouk, Mohamed El-Shinawi, and Mona Mostafa Mohamed. "Erratum to: Secretome of tumor-associated leukocytes augment epithelial-mesenchymal transition in positive lymph node breast cancer patients via activation of EGFR/Tyr845 and NF-kB/p65 signaling pathway." Tumor Biology 37, no. 10 (July 29, 2016): 14333. http://dx.doi.org/10.1007/s13277-016-5137-4.
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Georgescu, Maria-Magdalena. "TAMI-32. TEMPOROSPATIAL INVASION AND GENETIC EVOLUTION FROM INFRATENTORIAL TO SUPRATENTORIAL COMPARTMENT IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii220. http://dx.doi.org/10.1093/neuonc/noaa215.920.
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Abstract Diffuse midline gliomas (DMGs) are very aggressive pediatric brain tumors with dismal prognosis due to therapy-resistant tumor growth and invasion. We performed the first integrated histologic/genomic/proteomic analysis of 21 tumor foci from three pontine DMG cases with supratentorial dissemination. Histone H3.3 K27M was the driver mutation, usually at high variant allele fraction due to recurrent chromosome 1q copy number gain, in combination with germline variants in ATM, FANCM and MYCN genes. Both previously reported and novel recurrent copy number variations and somatic pathogenic mutations in chromatin remodeling, DNA damage response and PI3K/MAPK growth pathways were variably detected, either in multiple or isolated foci. Proteomic analysis showed global upregulation of histone H3, lack of K27 tri-methylation, and further impairment of polycomb repressive complex 2 by ASXL1 downregulation. Activation of oncogenic pathways resulted from combined upregulation of N-Myc, SOX2, p65/p50 NF-kB and STAT3 transcription factors, EGFR, FGFR2, PDGFRa/b and MET receptor tyrosine kinases, and downregulation of PHLPP1/2, PTEN and p16/INK4A tumor suppressors. Upregulation of SMAD4, PAI-1, CD44, and c-Src in multiple foci most likely contributed to invasiveness. This integrated comprehensive analysis allowed spatiotemporal modeling of tumor progression and identified two general pathways of supratentorial invasion, and a multitude of migratory subpopulations within the infratentorial compartment. It also delineated common signaling pathways and potential therapeutic targets, revealing an unsuspected activation of a multitude of oncogenic pathways that may explain the resistance of DMG to current therapies.
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Han, Guangchun, Ansam Sinjab, Warapen Treekitkarnmongkol, Dapeng Hao, Enyu Dai, Luisa M. Solis, Edwin R. Parra, et al. "Abstract 2126: Single-cell sequencing of early-stage lung adenocarcinomas reveals prominent intratumoral heterogeneity and epithelial plasticity programs." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2126. http://dx.doi.org/10.1158/1538-7445.am2022-2126.
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Abstract Decoding the complex molecular and cellular processes during lung adenocarcinoma (LUAD) development is needed to devise early intervention strategies. To comprehensively capture LUAD neoplastic heterogeneity and cellular plasticity, we performed single-cell RNA-sequencing (scRNA-seq) of 257,481 enriched epithelial cells (EPCAM+ sorting) from 16 early-stage LUADs, each with 3 matched normal lung (NL) samples at defined spatial proximities to the tumor (n=47). 29,076 LUAD-derived cells clustered by patient and harbored distinct gene expression features (e.g., oxidative stress response), signifying interpatient LUAD heterogeneity. We also identified, using whole exome sequencing (WES) of matching lung and germline control samples, recurrent oncogenic driver alterations (e.g., EGFR, TP53, KRAS). Transcriptomic features of malignant cells were shared between LUADs (e.g., loss of lineage-specific gene expression) or private such as those associated with driver mutation status (e.g., KRAS). Indeed, clusters of malignant cells were overall segregated based on driver mutations (e.g., KRAS, EGFR). Malignant cells from KRAS-mutant LUADs (KM-LUADs) had increased activation of NF-kB, estrogen and hypoxia signaling, comprising a unique gene module (GM) that correlated with a less differentiated state. We also found hallmark pathways (cholesterol metabolism, DNA replication, cell fate decision) specific to EGFR-mutant LUADs (EM-LUADs). Notably, cells from one EM-LUAD and its 3 multiregion NL tissues clustered closely and had activated pro-tumor lymphoid signatures (CD4 naïve, Treg). Mutation burden increased with tumor proximity and intriguingly, EGFR exon20 mutation was evident in the tumor (VAF = 0.29) and its most proximal NL (VAF = 0.05), signifying a mutational field effect. Copy number variations (CNVs) derived from WES of all samples were overall consistent with those inferred from scRNA-seq data. Relative to EM-LUADs, malignant cells from KM-LUADs displayed lower CNV burdens. Interpatient CNV heterogeneity was prominent even among LUADs harboring the same oncogenic drivers. Notably, intratumor heterogeneity (ITH) was high among epithelial cells within single regions from the same LUAD. Among LUADs, malignant cell clades with KRAS mutations and lower CNV scores displayed less differentiated states. To investigate biological pathways driving ITH, we derived 6 GMs with tumor-relevant functional features, including a transcription/translation regulation GM that consistently correlated with reduced differentiation. Our analysis of a large number of lung epithelial cells from LUAD patients reveals in-depth insights into LUAD taxonomy which can help identify epithelial heterotypes, unravel the continuum of early differentiation events and expand our understanding of early LUAD pathogenesis. Citation Format: Guangchun Han, Ansam Sinjab, Warapen Treekitkarnmongkol, Dapeng Hao, Enyu Dai, Luisa M. Solis, Edwin R. Parra, Stephen Swisher, Tina Cascone, Boris Sepesi, Jichao Chen, Steven Dubinett, Junya Fujimoto, Ignacio I. Wistuba, Christopher S. Stevenson, Avrum E. Spira, Linghua Wang, Humam Kadara. Single-cell sequencing of early-stage lung adenocarcinomas reveals prominent intratumoral heterogeneity and epithelial plasticity programs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2126.
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Koltai, Tomas. "Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity." F1000Research 4 (March 5, 2015): 9. http://dx.doi.org/10.12688/f1000research.5827.2.
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Objective:To review the mechanisms of anti-cancer activity of nelfinavir and other protease inhibitors (PIs) based on evidences reported in the published literature.Methods:We extensively reviewed the literature concerning nelfinavir (NFV) as an off target anti-cancer drug and other PIs. A classification of PIs based on anti-cancer mode of action was proposed. Controversies regarding nelfinavir mode of action were also addressed.Conclusions:The two main mechanisms involved in anti-cancer activity are endoplasmic reticulum stress-unfolded protein response pathway and Akt inhibition. However there are many other effects, partially dependent and independent of those mentioned, that may be useful in cancer treatment, including MMP-9 and MMP-2 inhibition, down-regulation of CDK-2, VEGF, bFGF, NF-kB, STAT-3, HIF-1 alfa, IGF, EGFR, survivin, BCRP, androgen receptor, proteasome, fatty acid synthase (FAS), decrease in cellular ATP concentration and upregulation of TRAIL receptor DR5, Bax, increased radiosensitivity, and autophagy. The end result of all these effects is slower growth, decreased angiogenesis, decreased invasion and increased apoptosis, which means reduced proliferation and increased cancer cells death.PIs may be classified according to their anticancer activity at clinically achievable doses, in AKT inhibitors, ER stressors and Akt inhibitors/ER stressors.Beyond the phase I trials that have been recently completed, adequately powered and well-designed clinical trials are needed in the various cancer type settings, and specific trials where NFV is tested in association with other known anti-cancer pharmaceuticals should be sought, in order to find an appropriate place for NFV in cancer treatment.The analysis of controversies on the molecular mechanisms of NFV hints to the possibility that NFV works in a different way in tumor cells and in hepatocytes and adipocytes.
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Karak, Prithviraj, and Anindya Modak. "Curcumin and its Anti-Cancer Properties: Kitchen to the Laboratory." INDIAN JOURNAL OF PHYSIOLOGY AND ALLIED SCIENCES 74, no. 02 (June 15, 2022): 13–18. http://dx.doi.org/10.55184/ijpas.v74i02.51.
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Curcumin is a naturally derived hydrophobic polyphenolic compound extracted from the rhizome (turmeric) of the herb Curcumalonga. It has been used as a common Indian spice in the form of turmeric since time immemorial. Curcumin is an active ingredient ofturmeric and has been found to have many health benefits.Our main aim is to highlight curcumin's biological activity and anti-cancer properties.Curcumin is a bright yellow-colored substance; curcumin plays a vital role in anti-cancer therapy by suppressing cell proliferationand metastasis. Curcumin has regulatory effects on secondary signaling molecules and the further downstream process leading toregulation of transcription factors like nuclear factor-kappa light chain enhancer of activated B cell or NF-kB. Cancer cells have enhancedtelomerase activity; therefore, their DNA never shortens due to the loss of telomeres. Curcumin initiates p53 protein-dependent andprotein-independent G2/M phase cell cycle arrest. Curcumin has plenty of targets like growth factor receptors (Epidermal GrowthFactor Receptor or EGFR), enzymes, and cytokines. Curcumin has poor bioavailability due to its low solubility in water (0.0004mg/mL atnormal pH 7) and hence produces poor effects when administered orally. Curcumin also produces toxicity in patients when consumedin high concentrations.The 21st century is the age of technology. We see that nanotechnology has enabled us to design curcumin-encapsulated, which reducesits bulk size and brings it within 100 nm. Particles like liposomes (phospholipid vesicles), polymer micelles, SLNs, and microspheresare some drug target delivery systems that can solve problems of transporting curcumin. Nanocurcumins can also be extracted frompure curcumin without any carriers. It is under clinical trial where curcumin has been used as an adjuvant with other chemical agentsto control the spread of cancer.
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Koh, Youngil, Kwang-Sung Ahn, Chansu Lee, Woo June Jung, Hyun Jung Lee, Dong Soon Lee, Hyo Jung Kim, Hwi-Joong Yoon, and Sung-Soo Yoon. "Genomic Characterization Of Newly Established Two Distinct Patient-Driven Multiple Myeloma Cell Lines (SNU_MM1393_BM and SNU_MM1393_SC) From a Single Patient." Blood 122, no. 21 (November 15, 2013): 5361. http://dx.doi.org/10.1182/blood.v122.21.5361.5361.
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Abstract To establish patient-derived multiple myeloma (MM) cell lines, mononuclear cells obtained from a MM patient’s bone marrow were directly injected via tail vein into a NRG/SCID mouse. Fourteen weeks after injection, tumor developed at subcutis and bone marrow (BM) in the same mouse. We separated and cultured cells from these two sites (subcutis and BM) and established two cell lines originating from a single patient (SNU_MM1393_BM and SNU_MM1393_SC). In cytogenetic analysis, karyotype of newly established two MM cell lines showed tetraploidy which is different from the karyotype of the patient (diploidy) indicating clonal evolution. In FACS analysis, the expression of CD138 and CD45 was detected in both cell lines. Response to IL-6 and soluble IL-6 receptor was different between the two cell lines. Moreover, SNU_MM1393_SC showed higher degree of resistance against proteasome inhibitor (bortezomib) compared to SNU_MM1393_BM. However, two cell lines were both sensitive to histone deacetylase inhibitor (panobinostat). When whole exome sequencing was performed using the DNA of these two cell lines, a set of somatic mutations involving Wnt signaling and NF-kB pathway were detected in both cell lines. Additional somatic mutations of JAK1, PLCG1, IRS2, and HGS which are known to interact with JAK/STAT pathway were detected in SNU_MM1393_BM. Whereas, additional somatic mutations of EGFR, HSP90AB1, CFDR, and CALML5, which are known to interact with growth factor cell signaling pathway were detected in SNU_MM1393_SC. These findings highlight the importance of interactions between tumor and tumor microenvironment as the myeloma progresses and will pave a way to more effective selection of targeted agents according to specific tumor characteristics obtained in the process of disease progression. Disclosures: No relevant conflicts of interest to declare.
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Cascinu, S., R. Berardi, S. Salvagni, G. D. Beretta, V. Catalano, F. Pucci, A. Sobrero, et al. "A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation." British Journal of Cancer 98, no. 1 (December 4, 2007): 71–76. http://dx.doi.org/10.1038/sj.bjc.6604121.
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Singh, Santosh Kumar, Manoj Kumar Mishra, and Rajesh Singh. "Abstract 301: Repurposing engineered thymoquinone nanoparticles to inhibit drug-resistant prostate cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 301. http://dx.doi.org/10.1158/1538-7445.am2022-301.
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Abstract Despite advanced treatment strategies and therapeutics for prostate cancer (PCa), the metastatic castration-resistant prostate cancer (mCRPC) mechanism remains obscure. Although docetaxel (DTX) and other anti-mitotic chemotherapeutic drug are considered the first line drugs for PCa patients; the resulting side effects and drug resistance increase the demand for an alternative such as natural compounds for effective treatment. However, the natural compounds that achieved remarkable height to overcome drug resistance, their bioavailability and targeted delivery during treatment has become a new challenge. As prostate-specific membrane antigen (PSMA) receptors are expressed on the surface of most PCa cells, we anticipated that these receptors may provide the potential target for effective therapy. Considering these, we employed the natural compound, thymoquinone (TQ)-encapsulated planetary ball-milled nanoparticles (PBM-NPs) formulated with starch (FDA approved, natural polysaccharides) inner core and biocompatible and biodegradable co-polymers poly (ε-caprolactone)/poly (ethylene glycol), functionalized with a PSMA aptamer (A10), which can selectively recognize and bind to PSMA membrane. The functionalities of this strategy were analyzed by targeting A10-TQ-PBM-NP in DTX-resistant cells (C4-2B-R and LNCaP-R), which overexpresses PSMA protein and multidrug resistance (MDR) gene ABCB1, and validated through flow cytometry, immunofluorescence, qRT-PCR, and western blot techniques. The results showed that the aptamer-based nano delivery of a TQ can modulate the cellular and molecular pathways responsible for DTX resistance in PCa cells through the EGFR and ZEB1 dependent mechanism. The A10-TQ-PBM-NPs counteract ATP-binding cassette (ABC)-transporter-mediated chemoresistance in PCa cells. In both cell lines, these NPs rapidly internalized and induced significant cell death at five times lower concentrations than non-conjugated PBM-TQ-NP. Further, A10-TQ-PBM-NPs have high selectivity to the PSMA receptor and downregulated the EGFR dependent pathway, Akt-1, ERK1/2, NF-kB, STAT3, and epithelial-mesenchymal transition (EMT) markers in both C4-2B-R and LNCaP-R cells, thus constraining cell survival, proliferation, and migration. The A10-TQ-PBM-NP bioconjugates also reveal remarkable efficacy and reduced toxicity as measured by body weight loss in the LNCaP-R cells xenograft mice. Altogether, our findings demonstrate that targeting PCa cells with PBM-NPs may reverse the MDR and could be used as potential therapeutic options for patients. Citation Format: Santosh Kumar Singh, Manoj Kumar Mishra, Rajesh Singh. Repurposing engineered thymoquinone nanoparticles to inhibit drug-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 301.
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Mousa, Shaker A., Thangirala Institute Sudha, Kavitha Godugu, Mehdi Rajabi, Nazeer Tipu, and Paul J. Davis. "Novel Thyrointegrin αvβ3 Antagonist for the Treatment of Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 4068. http://dx.doi.org/10.1182/blood-2018-99-119455.
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Abstract Acute myeloid leukemia accounts for up to one-third of the more than 60,000 leukemias diagnosed annually in the U.S. Primary AML cells express membrane αvβ3 integrin, which is associated with adverse prognosis and resistance to chemotherapies used in AML. A macromolecule Polyethylene glycol-conjugated bi-TriAzole Tetraiodothyroacetic acid (P-bi-TAT) acts with high affinity (Ki 3.1 nM) and specificity for the thyrointegrin αvβ3 receptors, without nuclear translocation and has demonstrated effective suppression of cancer cell proliferation, NF-kB expression and invasion in leukemic cells. We evaluated P-bi-TAT in two different AML models against two forms of acute leukemia (monocytic and myelocytic) that are largely resistant to existing therapy, by grafting human leukemia cells in immunocompromised male and female mice. IVIS imaging scans revealed that leukemic colonies were extensively established in bone marrow throughout the control (untreated) grafted animals, as well in liver, lung and kidney. Smears of bone marrow aspirates from untreated animals were found to contain multinucleate myeloblast and monoblast leukemic cells, and peripheral blood smears contained blast cells, multinucleated megakaryocytes, giant platelets and platelet aggregates, which are hallmarks of acute leukemia. IVIS imaging scans revealed 95% reduction in bone marrow colonies and resolution of liver, kidney and lung colonies in animals treated with P-bi-TAT at daily doses ranging from 1-10 mg/kg, subcutaneously for 2-3 weeks. Peripheral blood smears from treated animals were normal. Normal myeloblasts, which are the source of functional white blood cells, were found in the marrow smears, but leukemic cells were not detected in P-bi-TAT treated animals. Thus, against two forms of leukemia models, P-bi-TAT was extraordinarily effective, with the potential in treating most AML sub-types because αvβ3 receptors are expressed in the majority of AML. Among genes targeted by multiple laboratories for pharmacological downregulation of expression in AML are BCL2, VEGF, AKT1, KIT, IDH2, CDK4/6, TIMP1, VEGF, EGFR, and PD-L1. In that regard, P-bi-TAT has been shown in various tumor cell models to downregulate transcription of each of the genes listed, which are relevant to AML disease progression. Additionally, the pro-apoptotic P53 gene transcription is enhanced by P-bi-TAT. In conclusion, P-bi-TAT is a promising lead clinical candidate that warrants clinical trials in AML patients. Disclosures Mousa: NanoPharmaceuticals LLC: Equity Ownership, Patents & Royalties. Davis:NanoPharmaceuticals LLC: Employment, Equity Ownership.
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Shah, Urvi A., B. Hilda Ye, Jeff Hall, Yanhua Wang, Ronald Rice, Rizwan Naeem, Amara Gayathri Nandikolla, et al. "Genetic Sequencing of Adult T-Cell Leukemia/Lymphoma in the Caribbean Population Shows a Distinct Mutational Profile When Compared to the Japanese Cohort." Blood 128, no. 22 (December 2, 2016): 1758. http://dx.doi.org/10.1182/blood.v128.22.1758.1758.
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Abstract Introduction Adult T-cell leukemia/lymphoma (ATL) is a rare, aggressive disease caused by human T cell lymphotropic virus type 1 (HTLV1) that predominantly affects Japanese and Caribbean populations. (Goncalves, Proietti et al. 2010) Most studies have focused on Japanese cohorts. A recent whole genome/exome sequencing of 81 Japanese ATL cases identified alterations that overlap with the HTLV1 Tax interactome and are highly enriched for T cell receptor-NF-kB signaling, and T cell trafficking (Kataoka, Nagata et al. 2015). We recently showed that ATL in Caribbean patients has a poor prognosis and may have distinctive clinical features when compared to the Japanese cohort (Zell, Assal et al. 2016). In order to determine whether there are genomic differences between the two cohorts, we sequenced 15 ATL samples from the Caribbean cohort. Methods In this prospective study we perform comprehensive Next Generation Sequencing to assess the mutational spectrum of ATL in Caribbean patients. Samples were analyzed by complete genetic profiling with the Genoptix Nexcourse complete assay that contains 173 cancer related genes. Patient genomic DNA was utilized to identify relevant single nucleotide variants, insertion/deletions, copy number variations, and translocation fusion genomic alterations in a panel of up to 173 reportable genes at an average mean sequencing depth of 500X coverage. Results In the 15 patients, a total of 49 genes were found to be mutated ranging from 3 to 7 mutated genes in each patient. The percent of mutated genes amongst the total analyzed ranged from 1.7-4% for each patient and the percent of mutated genes known to be pathogenic ranged from 0-2.3% for each patient. There were 18 known pathogenic mutations in a total of 70 genetic mutations identified in this cohort (25.7%). The mean number of mutations in the acute and lymphomatous subtype was approximately 0.9%. Genes most commonly mutated in out cohort were TP53 (26.7%), FAT1 (26.7%), NOTCH1 (20%) and APC (20%). Novel mutations not reported by the Japanese cohort but present in our cohort are - NRAS, KRAS, EZH2, RICTOR, XPO1, VHL (known to be pathogenic), FAT1, APC, DDX3X, KIT, NOTCH2, MYC, TSC1, PLCG2, FGFR2, FGFR4, PDGFRA, EGFR, KEAP1, MCL1, ALK, BCL6, RIPK1, IGF1R, DDR2, KDR, AKT1, ERBB2, NKX2-1, BRCA2, PBRM1, CD79A, STAG2, PTCH1, KMT2A, HIST1HE, SPEN, ASXL1 (not known to be pathogenic). Mutations common to both the Japanese and our Caribbean cohort are - CARD11, TNFAIP3, TRAF3 (TCR signaling/NFkB pathway), NOTCH1 (signaling pathway), GATA3, CEBPA, TBL1XR1 (transcriptional regulation), EP300 (epigenetic regulation), TP53, POT1 (Telomere regulation and DNA repair). Serial analysis of a patient revealed increase in the size of the pathogenic clone with XPO1 mutation. XPO1 has been involved in nuclear transport of p53 and the increase in its clone size occurred with relapse after cytotoxic chemotherapy. The overall survival (OS) was shorter for TP53 mutated patients (99.3 days) versus non TP53 mutated patients (307.8 days). Discussion We report on mutational profiling in the largest cohort of Caribbean ATL and an additional 8 patients will be included in the analysis to be presented at ASH. A significant number of genes found to be mutated affected known pathways in the pathogenesis of ATL. There are known genes which are common between the Japanese and Caribbean cohorts but there are some notable differences. Previously we showed that the Caribbean cohort has a poorer OS than the Japanese cohort. TP53 mutations are more frequent and associated with decreased OS in this cohort. Genes involved in Wnt pathway - FAT1, APC, NOTCH1 were more frequently mutated in our cohort. FAT1 mutations have not been described in ATL. However, they have been implicated in oncogenesis in solid tumors, chronic lymphocytic leukemia and T-cell acute lymphoblastic leukemia. FAT1 acts as a tumor suppressor gene and encodes a cadherin-like protein, which potently suppresses cancer cell growth. Inactivation of FAT1 via mutation therefore promotes Wnt signaling and tumorigenesis and affects patient survival (Morris, Kaufman et al. 2013). In in-vitro models of ATL, Wnt pathway dysregulation has been shown to promote ATL tumorigenesis (Bellon, Ko et al. 2013, Ma, Yasunaga et al. 2013). Based on this study the driver mutations of the Caribbean cohort appear to be the Wnt signaling pathway which is different from the TCR- NF-kB signaling pathway seen in the Japanese cohort. Figure Figure. Disclosures Hall: Genoptix, a Novartis Company: Employment.
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Scartozzi, M., R. Giampieri, E. Maccaroni, A. Mandolesi, L. Giustini, R. R. Silva, E. Galizia, A. Falcone, I. Bearzi, and S. Cascinu. "PP 22 Analysis of HER-3, insulin-growth factor-1 (IGF-1), nuclear factor k-B (NF-kB) and epidermal growth factor receptor (EGFR) gene copy number (GCN) in the prediction of clinical outcome for K-RAS wild type colorectal cancer patients receiving irinotecan–cetuximab." European Journal of Cancer 47 (October 2011): S29. http://dx.doi.org/10.1016/s0959-8049(11)72700-9.
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Magness, Scott T., Antonio Tugores, and David A. Brenner. "Analysis of ferrochelatase expression during hematopoietic development of embryonic stem cells." Blood 95, no. 11 (June 1, 2000): 3568–77. http://dx.doi.org/10.1182/blood.v95.11.3568.
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Abstract Ferrochelatase, the last enzyme in the heme pathway, chelates protoporphyrin IX and iron to form heme and is mutated in protoporphyria. The ferrochelatase gene is expressed in all tissues at low levels to provide heme for essential heme-containing proteins and is up-regulated during erythropoiesis for the synthesis of hemoglobin. The human ferrochelatase promoter contains 2 Sp1 cis-elements and GATA and NF–E2 sites, all of which bind their cognatetrans-acting factors in vitro. To investigate the role of these elements during erythropoiesis, we introduced expression of the green fluorescent protein (EGFP) transgenes driven by various ferrochelatase promoter fragments into a single locus in mouse embryonic stem cells. EGFP expression was monitored during hematopoietic differentiation in vitro using flow cytometry. We show that a promoter fragment containing the Sp1 sites, the NF–E2 and GATA elements, was sufficient to confer developmental-specific expression of the EGFP transgene, with an expression profile identical to that of the endogenous gene. In this system the −0.275 kb NF–E2 cis-element is required for erythroid-enhanced expression, the GATA cis-element functions as a stage-specific repressor and enhancer, and elements located between −0.375kb and −1.1kb are necessary for optimal levels of expression. Ferrochelatase mRNA increased before the primitive erythroid-cell stage without a concomitant increase in ferrochelatase protein, suggesting the presence of a translational control mechanism. Because of the sensitivity of this system, we were able to assess the effect of an A-to-G polymorphism identified in the promoters of patients with protoporphyria. There was no effect of the G haplotype on transcriptional activity of the −1.1 kb transgene.
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Magness, Scott T., Antonio Tugores, and David A. Brenner. "Analysis of ferrochelatase expression during hematopoietic development of embryonic stem cells." Blood 95, no. 11 (June 1, 2000): 3568–77. http://dx.doi.org/10.1182/blood.v95.11.3568.011k40_3568_3577.
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Ferrochelatase, the last enzyme in the heme pathway, chelates protoporphyrin IX and iron to form heme and is mutated in protoporphyria. The ferrochelatase gene is expressed in all tissues at low levels to provide heme for essential heme-containing proteins and is up-regulated during erythropoiesis for the synthesis of hemoglobin. The human ferrochelatase promoter contains 2 Sp1 cis-elements and GATA and NF–E2 sites, all of which bind their cognatetrans-acting factors in vitro. To investigate the role of these elements during erythropoiesis, we introduced expression of the green fluorescent protein (EGFP) transgenes driven by various ferrochelatase promoter fragments into a single locus in mouse embryonic stem cells. EGFP expression was monitored during hematopoietic differentiation in vitro using flow cytometry. We show that a promoter fragment containing the Sp1 sites, the NF–E2 and GATA elements, was sufficient to confer developmental-specific expression of the EGFP transgene, with an expression profile identical to that of the endogenous gene. In this system the −0.275 kb NF–E2 cis-element is required for erythroid-enhanced expression, the GATA cis-element functions as a stage-specific repressor and enhancer, and elements located between −0.375kb and −1.1kb are necessary for optimal levels of expression. Ferrochelatase mRNA increased before the primitive erythroid-cell stage without a concomitant increase in ferrochelatase protein, suggesting the presence of a translational control mechanism. Because of the sensitivity of this system, we were able to assess the effect of an A-to-G polymorphism identified in the promoters of patients with protoporphyria. There was no effect of the G haplotype on transcriptional activity of the −1.1 kb transgene.
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Ikeda, Hiroshi, Yasushi Sasaki, Soushi Ibata, Masahiro Yoshida, Ayumi Tatekoshi, Satoshi Iyama, Kazuyuki Murase, et al. "Next Generation Sequencing of CD138+ Myeloma Cells Could Predict Response Rate and Appropriate Therapy at Diagnosis." Blood 128, no. 22 (December 2, 2016): 5609. http://dx.doi.org/10.1182/blood.v128.22.5609.5609.
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Abstract Introduction 2016 NCCN guideline recommended that induction therapy used conventional chemotherapy such as proteasome inhibitors and immunomodulatory drugs for newly diagnosis Multiple Myeloma (MM) patients. Now, HDAC inhibitor, CS-1 Antibody agents, and novel proteasome inhibitor were available for the treatment of MM. Thereby, the outcome of MM was significantly improved regarding response rates and overall survival. However, relapse is inevitable in almost all patients and the cure of myeloma is difficult even now. Recurrence of myeloma is typically more aggressive with each relapse, leading to the development of treatment-refractory disease. For each treatment, we have to choose appropriate new agents. However, we do not know how to choose these new agents Therefore, we try to use next generation sequencer as a tool of drug choosing system. The aim of this study is to identify genetic alterations in MM cells by next generation sequencer for determining the optimal drug and predicting drug resistance in the future. Patients and Methods: At first, we reviewed newly diagnosed 11 patients with MM (Male: Female 6:5) The median age was 62.27 years (range, 37-78 ). Patients received novel agents including bortezomib in Sapporo Medical University Hospital. Patient plasma cell DNA was extracted from magnetic bead-enriched bone marrow CD138-positive fraction.CD138-negative cells and peripheral lymphocyte were used as matched non-tumor cells. Next, forty nanograms of DNA were used for multiplex PCR amplification with an Ion Ampliseq Comprehensive Cancer Panel. This cancer panel offers targeted coverage of all exons in 409 tumor suppressor genes and oncogenes frequently cited and frequently mutated in human cancers. (covered regions: 95.4% of total). We sequenced 15,992 regions which obtained more than 1.5 megabases of target sequence. Result: Each sample underwent on average 8.3 million sequencing reads after quality filtering. The mean read depths were 539x, and >95% of targeted bases were represented by at least 20 reads. The average number of synonymous mutations detected per patient was 5.8 (range 0-11). We also detected copy number variations which segments of genome can be deleted from sequencing data. We found genetic alterations that associated with poor prognosis and refractory to chemotherapy of MM patients. We detected mutationin several patients such as EGFR,IKBKB,ERBB3,MYH11,CYLD,TP53,CDH2. These genomes are mainly involved in several important pathways, including cell cycle regulation, RTK-MAPK-PI3K and NF-kB. And then, we can detect main mutation pathway of cancer cells and choose the pathway blockable agents. Conclusion: We performed targeted next-generation sequencing gene analysis of malignant plasma cells from patients with MM. Next generation sequencing analysis of Myeloma cells can detect mutation and copy number variations. These data predict of drug resistance and facilitate improvements in the treatment of MM patients. We can use targeted next-generation sequencing as tool of drug choosing system. This method is useful for determining the optimal drug for patients with MM in the future. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Shaughnessy, John D., Samir Parekh, Hearn Jay Cho, Alessandro Lagana, Ajai Chari, Ryan van Laar, Sundar Jagannath, and Bart Barlogie. "Mutation Burden in Multiple Myeloma Is Captured By Gene Expression Profiles." Blood 128, no. 22 (December 2, 2016): 4450. http://dx.doi.org/10.1182/blood.v128.22.4450.4450.
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Abstract In the current study we sought to determine whether mutation burden (MB) is reflected in gene expression patterns. We generated 389 gene expression profiles and 311 mutation profiles from 182 cases, split into a training set of 97 and test set of 84. Copy number variants (CNV), rearrangements (TX) and short variant mutations (SV) were identified with FoundationOne Heme (F1) and U133Plus2.0 (u133) gene expression data, GEP70 and GEP80 risk scores, subgroup and CNV calls provided by Signal Genetics. 145 Kegg pathways, transcription factor binding sites (TFbs) for 195 TF mapped to u133 genes and 1161 F1 features and u133 GEP signatures/scores were evaluated for enrichment of defined genes. u133 data for normal plasma cells (n=22), MGUS (n=44), smoldering MM (n=12), relapsed MM (n=76), and MM cell lines (n=42) were derived from GSE31162. Newly diagnosed MM samples came from GSE31162 (n=584), GSE19784 (n=321), GSE15695 (n=247) and E-MTAB-317 (n=233). Of 593 genes assayed by F1, 293 were mutated at least twice. There were a total of 3454 mutations (average = 11, minimum = 3, and maximum = 37). KRAS was mutated in 40 tumors, while TP53 was mutated 45 times in 31 tumors. TP53 and 62 other genes had 2 or more unique mutations in a single tumor. A linear curve of MB exhibited a sharp upward inflection at 19 mutations. We sought to determine if GEP could identify characteristic features of MM flanking the inflection point. A training set of 97 (86 <= 15 MB and 11 >= 21 MB) and a test set of 84 (49 <= 15 MB, 28 >15 but < 21 MB and 7 >= 21MB) was produced. A mean ratio identified 576 genes exhibiting 2-fold higher expression in MM with high MB (hiMB) and 1617 genes from low MB (loMB). Notably, forty-four of the 293 mutated genes were in this list of genes. A geometric mean ratio of the two gene sets was then calculated for all samples. The mean of the resulting score (MB.2) was higher in MM with hiMB (1.66) than MM with loMB (-0.235) in the training set. MM with hiMB (0.329) had a higher MB.2 score than the group with intermediate MB.2 (0.158) and both higher than MM with loMB (-0.122). MB.2 was lowest in normal PC (-0.518) and progressively increased with disease progression: MGUS (-0.341), SMM (-0.308), MM (0.199), relapsed MM (0.334), MM cell lines (1.168).[SP1] 57% of the 182 cases harbored only SV mutations, 32% had SV and CNV, 32% SV and TX and 7% had SV, CNV and TX mutations. SV only mutations were present in 76% of MB.2 quartile 1 (MBq1) and 30% of MBq4. SV, CNV and TX mutations were present in 4% of MBq1 and 17% of MBq4. MB.2 was positively correlated with GEP70, GEP80, proliferation index, and TP53 target genes in MM and genes modulated by thalidomide and dexamethasone in PGx studies, in at least 6 of the 7 cohorts studied. The CD2 subtype, a myeloid classification and GEP70 low risk were significantly overrepresented in both MBq1 and GEP70q1 in all 7 cohorts. Conversely, the MF, MS, and PR subtypes, GEP70 and GEP80 high risk, as well as +1q, amp1q21, and del13q were significantly overrepresented in MBq4 and GEP70q4 in all 7 cohorts. MB.2 [SP2] genes derived from MM with loMB where enriched in 45 of 148 Kegg pathways. Notable were Hedgehog, Prostaglandin, Tx factors in cancer, HOX, MYB signaling, ephrin-B reverse signaling and embryonic stem cells. Five pathways related to B-cell biology were enriched. Mitotic cell cycle, integrin signaling, chromatin acetylation, ubiquitin ligation, and G1 to G1/S were underrepresented. MB.2 genes from MM with hiMB were enriched in TP53, lipid lysis, complement cascade, adherens junctions, Wnt regulation of CYR61, cyclins, prostaglandins, cell cycle, and MYC target pathways. Interferon signaling, TNF-NF-kB, EGFR, NOD, endoplasmic reticulum, ubiquitin ligation, Wnt-Hedgehog-NOTCH and BMP-SMAD modules were underrepresented. An enrichment of Rel and NF-kB TFbs was observed for genes negatively correlated with MB.2. and genes positively correlated with MB.2 and GEP70 were enriched for E2F and TP53 binding site. In conclusion, we show that MB can be captured by GEP in MM, that MB increases with disease progression, and pathways enriched by hiMB and loMB are different and may imply differences in pathogenesis as well as treatment. [SP1]This is an important finding - suggest emphasizing more [SP2]Starting with this para suggest referring to groups are low vs high mutation burden for improved readability. Disclosures Shaughnessy: Signal Genetics: Consultancy, Patents & Royalties. Cho:Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agenus, Inc.: Research Funding; Janssen: Consultancy, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees. Chari:Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Pharmacyclics: Research Funding. van Laar:Signal Genetics, Inc.: Employment. Jagannath:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Barlogie:Signal Genetics: Patents & Royalties.
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Du, Wei, Jared Sipple, Jonathan Schick, and Qishen Pang. "Enhanced Notch Signaling Skews Hematopoietic Stem Cell Differentiation in Fanconi Anemia Murine Models." Blood 120, no. 21 (November 16, 2012): 1191. http://dx.doi.org/10.1182/blood.v120.21.1191.1191.
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Abstract Abstract 1191 Objective: Hematopoietic stem cells (HSCs) can either self-renew or differentiate into various types of cells of the blood lineage. Little is known about the signaling pathways that regulate this choice of self-renewal versus differentiation. We studied the effect of altered Notch signaling on HSC differentiation in mouse models of Fanconi anemia (FA), a genetic disorder associated with bone marrow failure and progression to leukemia and other cancers. Methods: The study used a Notch reporter mouse, in which Notch-driven GFP expression acts as a sensor for HSC differentiation. Long-term hematopoietic stem cell (LT-HSC) and multipotential progenitor (MPP) cell compartments, as well as GFP expression in different cell populations were detected by Flow Cytometry analysis using primary bone marrow cells from Notch-eGFP-WT, Notch-eGFP-Fanca−/− or Notch-eGFP-Fancc−/− mice. Cell Cycle analysis was performed to distinguish the difference of quiescent state in GFP-gated LSK cells from these Notch-eGFP reporter mice. Colony forming units (CFU) assay and bone marrow transplantation (BMT) were utilized to determine HSC self-renew capacity. Gene arrays for pathways involved in DNA repair, cell cycle control, anti-oxidant defense, inflammatory response and apoptotic signaling were employed to define the gene expression signatures of the MPP population. Results and conclusions: In mice expressing a transgenic Notch reporter, deletion of the Fanca or Fancc gene enhanced Notch signaling in MPPs, which was correlated with decreased phenotypic long-term HSCs and increased formation of MPP1 progenitors. Furthermore, we found a functional correlation between Notch signaling and self-renewal capacity in FA hematopoietic stem and progenitor cells (HSPCs). Significantly, we show that FA deficiency in MPPs deregulates a complex network of genes in the Notch and canonical NF-kB pathways. Specifically, enhanced Notch signaling in FA MPPs was associated with the unregulation of genes involved in inflammatory and stress responses (including Rela, Tnfrsf1b, Gadd45b, Sod2, Stat1, Irf1 and Xiap), cell-cycle regulation (including Ccnd1, Cdc16, Cdkn1a, Gsk3b, Notch2 and Nr4a2), and transcription regulation (including Rela, Stat1, Hes1, Hey1, Hoxb4, Notch1 and Notch2). Consequently, TNF-a stimulation enhanced Notch signaling of FA LSK cells, leading to decreased HSC quiescence and compromised HSC self-renewal. Finally, genetic ablation of NF-kB reduced Notch signaling in FA MPPs to nearly wide-type level, and blocking either NF-kB or Notch signaling partially restored FA HSC quiescence and self-renewal capacity. Translational Applicability: The study identifies a functional interaction between the FA pathway and Notch signaling in HSC differentiation and establishes a role of FA proteins in the control of balance between renewal and lineage commitment, hence contributing to hematopoiesis. These findings indicate that the Notch signaling pathway may represent a novel and therapeutically accessible pathway in FA. Disclosures: No relevant conflicts of interest to declare.
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Li, Yingru, Zhaoyu Lin, Bin Chen, Shuang Chen, Zhipeng Jiang, Taicheng Zhou, Zehui Hou, and Youyuan Wang. "Ezrin/NF-kB activation regulates epithelial- mesenchymal transition induced by EGF and promotes metastasis of colorectal cancer." Biomedicine & Pharmacotherapy 92 (August 2017): 140–48. http://dx.doi.org/10.1016/j.biopha.2017.05.058.
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Song, Jeong-Sup, Kyung-Sook Cho, Hyung-Kyu Yoon, Hwa-Sik Moon, and Sung-Hak Park. "Neutrophil Elastase Causes MUC5AC Mucin Synthesis Via EGF Receptor, ERK and NF-kB Pathways in A549 Cells." Korean Journal of Internal Medicine 20, no. 4 (2005): 275. http://dx.doi.org/10.3904/kjim.2005.20.4.275.
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Coughlin, Caroline A., Preet Kumar, Evan R. Roberts, Horacio Gonzalez Lopez, Marianna Lekakis, Lingxio Li, Daniel Bilbao, and Jonathan H. Schatz. "Abstract 3976: Recurrent BCL10 mutations drive BTK inhibitor resistance in BN2-subtype diffuse large B-cell lymphomas by constitutively activating NF-kB and the MALT1 protease." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3976. http://dx.doi.org/10.1158/1538-7445.am2022-3976.
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Abstract Diffuse large B cell lymphoma (DLBCL), the most common lymphoma diagnosis, is a heterogeneous group of sub-entities with differing biology and prognosis. Frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), used regardless of subtype, cures 60-70%. Patients failed by this combination have poor prognosis. Extensive efforts to improve on R-CHOP in the frontline have failed, but recent post-hoc analysis of one negative trial suggested younger patients with specific DLBCL biologic subtypes may benefit from addition of a Bruton’s Tyrosine Kinase inhibitor (BTKi). These results could inform prospective studies in a small subset of DLBCL cases, but the rest lack biomarker-driven frontline optimizations. Newer classification systems define the BN2 (LymphGen) or Cluster 1 (Chapuy consensus clusters) subtype, characterized by BCL6 translocations and/or NOTCH2 truncations. BN2 cases specifically saw no benefit from adding BTKi to R-CHOP regardless of patient age. BCL10, encoding a key protein promoting NF-kB activation through formation of a signaling complex with CARD11 and MALT1, is recurrently mutated in DLBCL (~5%), clustering strongly in BN2 (30-40%). We hypothesize that activation of NF-kB downstream of BTK due to BCL10 gain of function promotes BTKi resistant lymphomagenesis. Recurrent BCL10 mutations include the R58Q missense mutation in the oncogenic N-terminal CARD domain and frequent truncations of the regulatory C-terminal S/T-rich domain. Overexpression of BCL10 with either mutation type in DLBCL cells promoted strong activation of NF-kB assessed by immunoblotting and EGFP NF-kB reporters. Truncated BCL10 also increased MALT1 protease activity, measured by increased substrate cleavage. BCL10 mutations drove resistance to BTKis as hypothesized, but there was no difference in sensitivity to MALT1 inhibition, revealing that downstream targets overcome drug resistance by BCL10 mutant-mediated activation. Combining MALT1i with BTKi synergistically killed cells, identifying a promising therapeutic strategy for BN2 cases. Delving into the mechanism of BCL10-mutant lymphomagenesis, gene ontology analysis of transcriptome data showed cross-activation of ERK1/2 signaling, confirmed by immunoblotting, and strong induction of cytokine production and related signaling. To fuel future studies, we have established a cre-inducible conditional BCL10-truncation mouse model at the ROSA26 locus in C57BL/6J mice. After crossing into the Mb1-Cre background, these animals showed expansion of the B-cell compartment by three months of age and remain under observation for onset of lymphoma. We therefore define mechanisms and therapeutic consequences of recurrent BCL10 mutations in DLBCL and provide new drug combinations aimed at overcoming them. Citation Format: Caroline A. Coughlin, Preet Kumar, Evan R. Roberts, Horacio Gonzalez Lopez, Marianna Lekakis, Lingxio Li, Daniel Bilbao, Jonathan H. Schatz. Recurrent BCL10 mutations drive BTK inhibitor resistance in BN2-subtype diffuse large B-cell lymphomas by constitutively activating NF-kB and the MALT1 protease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3976.
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Pahlavan, Payam S. "Pre- and Post- Morris Water Maze Learning Comparison Expression of Transcription Factors NF-kB, CREB, and Egr-2." American Journal of Clinical Pathology 138, suppl 2 (November 1, 2012): A356. http://dx.doi.org/10.1093/ajcp/138.suppl2.166.
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Song, M. K., S. C. Jeong, Y. Cho, E. Lee, and J. C. Ryu. "EGF-MAPK-NF-kB cascade signaling pathway: Possible mechanism of particulate matter (PM) 2.5 -induced lung inflammatory responses." Toxicology Letters 238, no. 2 (October 2015): S313. http://dx.doi.org/10.1016/j.toxlet.2015.08.894.
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Kurita, Daisuke, Jun-ichirou Yasunaga, Azusa Tanaka, Mahgoub Mohamed, and Masao Matsuoka. "Dynamic Changes of Chromatin Structure and Transcriptome By Transient Expression of HTLV-1 Tax in ATL Cells." Blood 132, Supplement 1 (November 29, 2018): 4094. http://dx.doi.org/10.1182/blood-2018-99-111125.
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Abstract Adult T-cell leukemia-lymphoma (ATL) is a fatal malignancy of CD4+ T cells, which is caused by human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 encodes two oncogenic viral factors, Tax and HTLV-1 bZIP factor (HBZ) in the sense and antisense of the provirus respectively. HBZ is constitutively expressed in infected cells and plays critical roles for cell proliferation. Tax potently promotes viral replication and activates various oncogenic signaling pathways in HTLV-1 infected cells; however, Tax expression is generally suppressed in infected cells owing to its high immunogenicity. Therefore, the dynamics of Tax expression and contribution of oncogenic transformation by Tax in HTLV-1 infected cells have not been well elucidated. Recently, we have reported that Tax is transiently expressed in a small subpopulation of ATL cells, which induces drastic changes in the host transcriptional profile (Mahgoub M., et al. Proc Natl Acad Sci USA. 2018). Moreover, the single cell analysis showed that expression of anti-apoptotic and NF-kB related genes were upregulated in Tax-expressing cells compared to Tax-non-expressing cells. HBZ expression was increased in Tax-non-expressing cells than Tax-expressing cells, suggesting that HBZ may regulate cell proliferation in a different time phase from Tax. On the other hand, precise mechanisms for regulation of host gene expression by transient Tax expression are not well known. In this study, we analyzed structural change of host chromatin accompanied by transient Tax expression to clarify the transcriptional dynamics of host genes in ATL cells. ATL cell lines (MT-1 and KK-1), which express EGFP under the control of Tax, were used to sort Tax-expressing and -non-expressing cells by a cell sorter, and each population was subjected to H3K27ac ChIP-seq and ATAC-seq analyses. DNA libraries were quantified and sequenced on Illumina NextSeq 500 (single-end) for ChIP-seq, and on Illumina Hiseq 4000 (paired-end) for ATAC-seq, respectively. H3K27ac ChIP-seq data showed that the peaks correlated with Tax expression were observed in many genetic loci including NF-kB related genes. Among Tax-expressing MT-1 cells, H3K27ac were highly enriched super-enhancers, such as IL2RA, TRAF3, TNFRSF8, PHF13 loci, compared to Tax-non-expressing cells. There were more H3K27ac-marked active enhancers in Tax-expressing cells than Tax-non-expressing cells across the entire region, suggesting that global structural change may occur in Tax-expressing cells. Using the data of ATAC-seq, pathway analyses were performed by GREAT. This analysis revealed that the pathways associated with immune activation, such as Toll-like receptor signaling, TNFR2 signaling, IL-2 signaling, and Th1/Th2 differentiation pathways were significantly enriched in Tax-expressing cells. Analysis of genome-wide distribution of motifs in open chromatin region, were carried out with HOMER, and result showed that motifs of NF-kB, and AP-1 family (e.g., JunB, Fra1, Fra2) were significantly enriched in Tax-expressing cells compared to Tax-non-expressing cells, which is consistent with the results of pathway analyses of RNA-seq. The genome-wide motif footprinting analysis was performed using Protein interaction quantitation (PIQ) methods. It was found that motifs of NF-kB, and AP-1 family (e.g., JunB, Fra1, Fra2) were occupied in large number of regions and showed higher DNA accessibility in Tax-expressing cells. In contrast, motif of CTCF was likely occupied in large number of regions and exhibit higher DNA accessibility in Tax-non-expressing cells. Importantly, mRNA levels of NF-kB and AP-1 transcription factors were significantly higher in Tax-expressing than Tax-non-expressing cells. These findings suggest that structural changes of NF-kB and AP-1 family recognition sites, and activation of pathways related to these factors could trigger global transcriptional changes in host genome by transient Tax expression, which is the critical event for persistent infection of HTLV-1 and leukemogenesis of ATL. Disclosures Matsuoka: Bristol Myers Squibb: Research Funding.
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Chung, Hung Hui, and Azham Zulkharnain. "Molecular cloning of a functional Fads2 promoter from Zebrafish." Journal of Biochemistry, Microbiology and Biotechnology 4, no. 1 (July 31, 2016): 1–6. http://dx.doi.org/10.54987/jobimb.v4i1.280.
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The FADS2 catalyzes the first rate-limiting step in the long chain-polyunsaturated fatty acids (LC-PUFAs) biosynthesis pathway by converting α-linolenic acid and linoleic acid into stearidonic acid and γ-linolenic acid via the ω-3 and ω-6 pathways respectively. In mammals, PPARα and SREBP-1c have been implicated in the polyunsaturated fatty acids (PUFAs) mediated transcriptional activation of FADS2 promoter. However, in zebrafish, not much is known regarding the regulation of fads2 transcriptional regulation. Here, in this study, five vectors containing different promoter regions were constructed in order to analyse putative promoter activities. Through truncation analysis, it was found that the 1.2 kb promoter was able to drive luciferase activity to an approximate 40-fold in HepG2 cells. Upon mutagenesis analysis, three sites which are the putative NF-Y, SREBP and PPAR binding sites were found to be essential in driving the promoter activity. Lastly, the 1.2 kb fads2 promoter was able to direct EGFP expression specifically to the yolk syncytial layer (YSL) when transiently expressed in microinjected zebrafish embryos.
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Zhang, Xiaofan, Wenci Gong, Chaohui Duan, Huixia Cai, Yujuan Shen, and Jianping Cao. "Echinococcus granulosus Protoscoleces-Derived Exosome-like Vesicles and Egr-miR-277a-3p Promote Dendritic Cell Maturation and Differentiation." Cells 11, no. 20 (October 14, 2022): 3220. http://dx.doi.org/10.3390/cells11203220.
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Cystic echinococcosis, a major parasitic disease caused by Echinococcus granulosus, seriously threatens human health. The excretory–secretory (ES) products of E. granulosus can induce immune tolerance in dendritic cells (DCs) to downregulate the host’s immune response; however, the effect of exosomes in the ES products on the DCs has remained unclear. This study showed that E. granulosus protoscoleces-derived exosome-like vesicles (PSC-ELVs) could be internalized by bone marrow-derived dendritic cells (BMDCs), allowing for the delivery of the parasite microRNAs to the BMDCs. Moreover, PSC-ELVs induced BMDCs to produce the proinflammatory cytokinesinterleukin (IL)-6, IL-12, IL-β, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ). PSC-ELVs also upregulated the BMDCs surface marker major histocompatibility complex class II (MHC II), as well as costimulatory molecules CD40, CD80, and CD86. PSC-ELV-derived egr-miR-277a-3p upregulated the IL-6, IL-12, and TNF-α mRNA levels in BMDCs. Moreover, egr-miR-277a-3p directly targeted Nfkb1 (encoding nuclear factor kappa B 1) to significantly suppress the mRNA and protein levels of NF-κB1 in BMDCs, while the expression of NF-κB p65 significantly increased, suggesting that egr-miR-277a-3p induces the production of proinflammatory cytokines by the modification of the NF-kB p65/p50 ratio in BMDCs. These results demonstrated that PSC-ELVs and egr-miR-277a-3p might enhance DCs maturation and differentiation in a cross-species manner, which in turn may modulate the host immune responses and offer a new approach to echinococcosis prevention and treatment.
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Yang, Xue-Song, Shui-Ai Liu, Ji-Wei Liu, and Qiu Yan. "Fucosyltransferase IV Enhances Expression of MMP-12 Stimulated by EGF via the ERK1/2, p38 and NF-kB Pathways in A431Cells." Asian Pacific Journal of Cancer Prevention 13, no. 4 (April 30, 2012): 1657–62. http://dx.doi.org/10.7314/apjcp.2012.13.4.1657.
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Lee, S. J., C. E. Kim, K. W. Seo, and C. D. Kim. "MS34 HNE-INDUCED 5-LOX EXPRESSION IS TRANSCRIPTIONAL REGULATED BY NF-kB/ERK AND SP1/P38 MAPK PATHWAYS VIA EGF RECEPTOR IN MURINE MACROPHAGES." Atherosclerosis Supplements 11, no. 2 (June 2010): 116. http://dx.doi.org/10.1016/s1567-5688(10)70535-3.
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Ballon, Gianna, Amy Chadburn, Rocio Perez, Yi-Fang Liu, Yoshiteru Sasaki, and Ethel Cesarman. "Generation of vFLIP Transgenic Mice: A Model to Study KSHV-Associated Lymphomagenesis." Blood 112, no. 11 (November 16, 2008): 81. http://dx.doi.org/10.1182/blood.v112.11.81.81.
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Abstract Primary effusion lymphoma (PEL) is a distinct subtype of aggressive non-Hodgkin’s lymphoma (NHL), specifically associated with infection by Kaposi’s sarcoma-associated herpesvirus (KSHV) and occurring more frequently in HIV-infected individuals. Several in vitro observations suggest that vFLIP, a viral protein expressed during latency, is an important viral oncogene. It is essential for the survival of KSHV-infected PEL cells, mainly by constitutively activating the NF-kB pathway. In order to assess the role of vFLIP in the pathogenesis of PEL, we knocked a cDNA encoding vFLIP, preceded by a loxP-flanked neoR-Stop cassette and followed by Frt-flanked IRES-eGFP sequences, into the ubiquitously expressed ROSA26 locus. A specifically restricted expression of the transgene in CD19+ B-cells has been achieved by crossing the ROSA26. vFLIP knock-in mice with mice expressing cre recombinase under the control of the CD19 promoter. These mice have also been crossed with transgenic mice expressing KSHV LANA, which is considered to also be a viral oncogene, to assess a potential synergistic effect of these two KSHV latent proteins in the lymphomagenic process of PEL. vFLIP expression in the CD19+ B-cells results in splenomegaly, with an increase in both T and B-cells, and with a relative increase of the T versus B-cell ratio. Although primary follicles were enlarged, the expression of vFLIP in the CD19+ B-cells results in lack of germinal center formation in the spleen, lymph nodes and intestine, and in partially impaired class-switching recombination. vFLIP transgenic mice had an increased number of plasmablast-like cells expressing lambda light chain, reminiscent of a phenomenon seen in KSHV-associated multicentric Castleman’s disease (MCD). These results indicate that by constitutively activating the NF-κB pathway in pre-germinal center B-cells expressing CD19, the normal B-cell differentiation is impaired, and provide clues about possible aberrant differentiation in PEL and MCD.
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Banan, Ali, Ashkan Farhadi, Jeremy Fields, Lijuan Zhang, Maliha Shaikh, and Ali Keshavarzian. "Evidence that NF-kB activation is critical to oxidant disruption of cytoskeleton & barrier integrity (BI) and that its inactivation is key to EGF protection of monolayers of intestinal epithelia." Gastroenterology 124, no. 4 (April 2003): A119. http://dx.doi.org/10.1016/s0016-5085(03)80586-3.
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Islam, Md Tariqul, Fang-Zhi Chen, Han-Chun Chen, and Abdul Wahid. "Knockdown of USP8 inhibits prostate cancer cell growth, proliferation, and metastasis and promotes docetaxel’s activity by suppressing the NF-kB signaling pathway." Frontiers in Oncology 12 (October 20, 2022). http://dx.doi.org/10.3389/fonc.2022.923270.
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Ubiquitin-specific protease 8 (USP8) has been recently reported to be involved in tumorigenesis. Prostate cancer (PCa) is the most diagnosed malignancy among men, but USP8’s role in PCa is not yet investigated comprehensively. Therefore, the PCa cell lines DU145 and PC3 were transfected with USP8 siRNA or overexpressing vector together with or without docetaxel. The silencing USP8 and docetaxel treatment reduced cell viability and migration and promoted apoptosis. In contrast, USP8 knockdown was found to enhance docetaxel antitumor activity. In contrast, increased cell viability and migration were noticed upon USP8 overexpression, thereby decreasing apoptosis and suppressing docetaxel antitumor activity. Notably, although EGFR, PI3K, and NF-kB were found to be increased in both USP8 overexpression and docetaxel treatment, it significantly attenuated the effects in USP8 silencing followed by with or without docetaxel. Although EGFR silencing decreased PI3K and NF-kB activation, overexpression of USP8 was shown to counteract SiEGFR’s effects on NF-kB signaling by increasing PI3K expression. Our findings revealed that USP8 plays an oncogenic role in PCa and can suppress docetaxel activity. Additionally, as EGFR/PI3K/NF-kB was previously reported to develop docetaxel resistance, the combination treatment of USP8 knockdown with docetaxel might be a potential PCa therapeutic.
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Garcia, Victor, Laura Milhau, John R. Falck, and Michal L. Schwartzman. "Abstract 024: 20-HETE Activates the Transcription of Endothelial Angiotensin Converting Enzyme (ACE) via NF-kB Translocation and Promoter Binding." Hypertension 64, suppl_1 (September 2014). http://dx.doi.org/10.1161/hyp.64.suppl_1.024.
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Increased vascular 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P450-arachidonic acid metabolite, promotes vascular dysfunction, injury and hypertension that is dependent, in part, on the renin angiotensin system (RAS). We showed that in cultured human microvascular endothelial cells (HMVEC), 20-HETE (5 nM) increases angiotensin converting enzyme (ACE) mRNA, protein, and cellular and extracellular ACE activity via EGFR-tyrosine kinase-MAPK-IKKβ- signaling pathway. Here we show that treatment of HMVEC with EGF (100 ng/ml) alone or with 20-HETE (10 nM) did not induce or further increase ACE mRNA levels. Pretreatment of cells with a neutralizing antibody against EGF did not prevent the 20-HETE- or 20-HETE+EGF-mediated ACE induction, indicating that the induction of ACE by 20-HETE is EGF-independent. The NF-kB inhibitor JSH-23 prevented the 4.58-fold (±0.78; p<0.05) 20-HETE (10nM)-mediated induction of ACE. EMSA of 20-HETE-treated cells showed increased NF-kB binding activity in nuclear extracts. In cells transfected with luciferase promoter-reporter constructs for the somatic or germinal ACE promoter regions, 20-HETE (10 nM) increased promoter activity by 4.37-fold (±0.18; p<0.05) and 2.53-fold (± 0.24; p<0.05), respectively. 20-HETE-stimulated ACE promoter activity was abrogated by the 20-HETE antagonist 20-HEDE and by inhibitors of EGFR, MAPK, IKKβ and NF-kB activation. Sequence analysis demonstrated the presence of two (Chr 17: S1: 61554061-61554075 , S2: 61554157-61554171) and one (Chr 17: S3: 61562250-61562264) putative NF-kB binding sites on the human somatic and germinal ACE promoters, respectively. CHIP assay indicated that 20-HETE stimulates the translocation and subsequent binding of NF-kB to each of the putative binding sites (S1: 3.43±0.3, S2: 3.72±0.68, S3: 3.20±0.18-fold enrichment vs vehicle; p<0.05). In vivo, increased vascular 20-HETE levels are associated with increased phospho-IKK and ACE levels that are prevented by treatment with 20-HETE antagonists. This is the first study to identify NF-kB as a transcriptional factor for ACE and to implicate a distinct EGFR/MAPK/IKK/NF-kB signaling cascade underlying 20-HETE-mediated transcriptional activation of ACE mRNA and stimulation of ACE activity.
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Ament, Cindy E., Sara Steinmann, Katja Evert, Giovanni M. Pes, Silvia Ribback, Isabella Gigante, Elena Pizzuto, et al. "Aberrant fucosylation sustains the NOTCH and EGFR/NF-kB pathways and has a prognostic value in human intrahepatic cholangiocarcinoma." Hepatology Publish Ahead of Print (February 16, 2023). http://dx.doi.org/10.1097/hep.0000000000000322.
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Kim, Jieun, Su-Jin Kim, Ha-Ram Jeong, Jin-Hee Park, Minho Moon, and Hyang-Sook Hoe. "Inhibiting EGFR/HER-2 ameliorates neuroinflammatory responses and the early stage of tau pathology through DYRK1A." Frontiers in Immunology 13 (October 20, 2022). http://dx.doi.org/10.3389/fimmu.2022.903309.
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The FDA-approved EGFR/HER2 inhibitor varlitinib inhibits tumor growth and is used in cancer treatment. However, the neuroinflammatory response associated with EGFR/HER2 and its underlying mechanism have not been elucidated. This study evaluates the impact of varlitinib on LPS- and tau-mediated neuroinflammatory responses for the first time. In BV2 microglial cells, varlitinib reduced LPS-stimulated il-1β and/or inos mRNA levels and downstream AKT/FAK/NF-kB signaling. Importantly, varlitinib significantly diminished LPS-mediated microglial nlrp3 inflammasome activation in BV2 microglial cells. In primary astrocytes, varlitinib downregulated LPS-evoked astroglial il-1β mRNA levels, AKT signaling, and nlrp3 inflammasome activation. In LPS-treated wild-type mice, varlitinib significantly reduced LPS-stimulated glial activation and IL-1β/NLRP3 inflammasome formation. Moreover, varlitinib significantly reduced micro- and astroglial activation and tau hyperphosphorylation in 3-month-old tau-overexpressing PS19 mice by downregulating tau kinase DYRK1A levels. However, in 6-month-old tau-overexpressing PS19 mice, varlitinib only significantly diminished astroglial activation and tau phosphorylation at Thr212/Ser214. Taken together, our findings suggest that varlitinib has therapeutic potential for LPS- and tau-induced neuroinflammatory responses and the early stages of tau pathology.
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Huang, Yin-Cheng, Joseph Chieh-Yu Lai, Pei-Hua Peng, Kuo-Chen Wei, and Kou-Juey Wu. "Chromatin accessibility analysis identifies GSTM1 as a prognostic marker in human glioblastoma patients." Clinical Epigenetics 13, no. 1 (November 3, 2021). http://dx.doi.org/10.1186/s13148-021-01181-8.
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Abstract Background Glioblastoma (GBM) is a malignant human brain tumor that has an extremely poor prognosis. Classic mutations such as IDH (isocitrate dehydrogenase) mutations, EGFR (epidermal growth factor receptor) alternations, and MGMT (O6-methylguanine-methyltransferase) promoter hypermethylation have been used to stratify patients and provide prognostic significance. Epigenetic perturbations have been demonstrated in glioblastoma tumorigenesis. Despite the genetic markers used in the management of glioblastoma patients, new biomarkers that could predict patient survival independent of known biomarkers remain to be identified. Methods ATAC-seq (assay for transposase accessible chromatin followed by sequencing) and RNA-seq have been used to profile chromatin accessible regions using glioblastoma patient samples with short-survival versus long-survival. Cell viability, cell cycle, and Western blot analysis were used to characterize the cellular phenotypes and identify signaling pathways. Results Analysis of chromatin accessibility by ATAC-seq coupled with RNA-seq methods identified the GSTM1 (glutathione S-transferase mu-1) gene, which featured higher chromatin accessibility in GBM tumors with short survival. GSTM1 was confirmed to be a significant prognostic marker to predict survival using a different GBM patient cohort. Knockdown of GSTM1 decreased cell viability, caused cell cycle arrest, and decreased the phosphorylation levels of the NF-kB (nuclear factor kappa B) p65 subunit and STAT3 (signal transducer and activator of transcription 3) (pSer727). Conclusions This report demonstrates the use of ATAC-seq coupled with RNA-seq to identify GSTM1 as a prognostic marker of GBM patient survival. Activation of phosphorylation levels of NF-kB p65 and STAT3 (pSer727) by GSTM1 is shown. Analysis of chromatin accessibility in patient samples could generate an independent biomarker that can be used to predict patient survival.
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Zhao, Y., H.-Y. Lin, J.-N. Yu, W.-W. Jiang, and X.-L. Sun. "Effects of Traditional Chinese Medicine Wei-Wei-Kang-Granule on the Expression of Egfr and Nf-Kb in Chronic Atrophic Gastritis Rats." African Journal of Traditional, Complementary and Alternative Medicines 9, no. 1 (October 5, 2011). http://dx.doi.org/10.4314/ajtcam.v9i1.1.
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