77 results on '"Mitra SS"'
Search Results
2. Optical Properties of Infrared Transmitting Glasses
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Mitra, SS, primary
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3. Two-Photon Absorption in Direct-Gap Crystals—An Addendum
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Vaidyanathan, A, primary, Guenther, AH, additional, and Mitra, SS, additional
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4. Band Structure Calculations of the Two-Photon Absorption Coefficients of GaAs, InP, CdTe, and ZnSe
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Vaidyanathan, A, primary, Guenther, AH, additional, and Mitra, SS, additional
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5. Three-Photon Absorption in Direct-Gap Crystals
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Judell, N, primary, Mitra, SS, additional, Vaidyanathan, A, additional, and Guenther, AH, additional
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6. Coregulation of multiple signaling mechanisms in pp60v-Src-induced closure of Cx43 gap junction channels.
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Mitra SS, Xu J, Nicholson BJ, Mitra, Siddhartha S, Xu, Ji, and Nicholson, Bruce J
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Attenuation in gap junctional coupling has consistently been associated with induction of rapid or synchronous cell division in normal and pathological conditions. In the case of the v-src oncogene, gating of Cx43 gap junction channels has been linked to both direct phosphorylation of tyrosines (Y247 and 265) and phosphorylation of the serine targets of Erk1/2 (S255, 279 and 282) on the cytoplasmic C-terminal domain of Cx43. However, only the latter has been associated with acute, rather than chronic, gating of the channels immediately after v-src expression, a process that is mediated through a "ball-and-chain" mechanism. In this study we show that, while ERK1/2 is necessary for acute closure of gap junction channels, it is not sufficient. Rather, multiple pathways converge to regulate Cx43 coupling in response to expression of v-src, including parallel signaling through PKC and MEK1/2, with additional positive and negative regulatory effects mediated by PI3 kinase, distinguished by the involvement of Akt. [ABSTRACT FROM AUTHOR]
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- 2012
7. Tumor-Intrinsic Activity of Chromobox 2 Remodels the Tumor Microenvironment in High-grade Serous Carcinoma.
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Iwanaga R, Yamamoto TM, Gomez K, Nguyen LL, Woodruff ER, Post MD, Mikeska RG, Danis E, Danhorn T, Boorgula MP, Mitra SS, Marjon NA, Bitler BG, and Brubaker LW
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- Animals, Mice, Humans, Female, Cystadenocarcinoma, Serous pathology, Cystadenocarcinoma, Serous metabolism, Cystadenocarcinoma, Serous genetics, Cystadenocarcinoma, Serous immunology, Polycomb Repressive Complex 1 genetics, Polycomb Repressive Complex 1 metabolism, Ovarian Neoplasms pathology, Ovarian Neoplasms metabolism, Ovarian Neoplasms genetics, Ovarian Neoplasms immunology, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Macrophages metabolism, Macrophages immunology, BRCA2 Protein genetics, BRCA2 Protein metabolism, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Tumor Microenvironment
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Chromobox 2 (CBX2), an epigenetic reader and component of polycomb repressor complex 1, is highly expressed in >75% of high-grade serous carcinoma. Increased CBX2 expression is associated with poorer survival, whereas CBX2 knockdown leads to improved chemotherapy sensitivity. In a high-grade serous carcinoma immune-competent murine model, knockdown of CBX2 decreased tumor progression. We sought to explore the impact of modulation of CBX2 on the tumor immune microenvironment (TIME), understanding that the TIME plays a critical role in disease progression and development of therapy resistance. Exploration of existing datasets demonstrated that elevated CBX2 expression significantly correlated with specific immune cell types in the TIME. RNA sequencing and pathway analysis of differentially expressed genes demonstrated immune signature enrichment. Confocal microscopy and co-culture experiments found that modulation of CBX2 leads to increased recruitment and infiltration of macrophages. Flow cytometry of macrophages cultured with CBX2-overexpressing cells showed increased M2-like macrophages and decreased phagocytosis activity. Cbx2 knockdown in the Trp53-null, Brca2-null ID8 syngeneic murine model (ID8 Trp53-/-Brca2-/-) led to decreased tumor progression compared with the control. NanoString immuno-oncology panel analysis suggested that knockdown in Cbx2 shifts immune cell composition, with an increase in macrophages. Multispectral immunohistochemistry (mIHC) further confirmed an increase in macrophage infiltration. Increased CBX2 expression leads to recruitment and polarization of protumor macrophages, and targeting CBX2 may serve to modulate the TIME to enhance the efficacy of immune therapies., Significance: CBX2 expression correlates with the TIME. CBX2 modulation shifts the macrophage population, potentially leading to an immunosuppressive microenvironment, highlighting CBX2 as a target to improve efficacy of immunotherapy., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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8. Unraveling the complexity of the senescence-associated secretory phenotype in adamantinomatous craniopharyngioma using multimodal machine learning analysis.
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Prince EW, Apps JR, Jeang J, Chee K, Medlin S, Jackson EM, Dudley R, Limbrick D, Naftel R, Johnston J, Feldstein N, Prolo LM, Ginn K, Niazi T, Smith A, Kilburn L, Chern J, Leonard J, Lam S, Hersh DS, Gonzalez-Meljem JM, Amani V, Donson AM, Mitra SS, Bandopadhayay P, Martinez-Barbera JP, and Hankinson TC
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- Humans, Biomarkers, Tumor metabolism, Biomarkers, Tumor genetics, Phenotype, Gene Expression Regulation, Neoplastic, Child, Male, Female, Craniopharyngioma metabolism, Craniopharyngioma pathology, Craniopharyngioma genetics, Pituitary Neoplasms pathology, Pituitary Neoplasms metabolism, Pituitary Neoplasms genetics, Cellular Senescence, Machine Learning
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Background: Cellular senescence can have positive and negative effects on the body, including aiding in damage repair and facilitating tumor growth. Adamantinomatous craniopharyngioma (ACP), the most common pediatric sellar/suprasellar brain tumor, poses significant treatment challenges. Recent studies suggest that senescent cells in ACP tumors may contribute to tumor growth and invasion by releasing a senesecence-associated secretory phenotype. However, a detailed analysis of these characteristics has yet to be completed., Methods: We analyzed primary tissue samples from ACP patients using single-cell, single-nuclei, and spatial RNA sequencing. We performed various analyses, including gene expression clustering, inferred senescence cells from gene expression, and conducted cytokine signaling inference. We utilized LASSO to select essential gene expression pathways associated with senescence. Finally, we validated our findings through immunostaining., Results: We observed significant diversity in gene expression and tissue structure. Key factors such as NFKB, RELA, and SP1 are essential in regulating gene expression, while senescence markers are present throughout the tissue. SPP1 is the most significant cytokine signaling network among ACP cells, while the Wnt signaling pathway predominantly occurs between epithelial and glial cells. Our research has identified links between senescence-associated features and pathways, such as PI3K/Akt/mTOR, MYC, FZD, and Hedgehog, with increased P53 expression associated with senescence in these cells., Conclusions: A complex interplay between cellular senescence, cytokine signaling, and gene expression pathways underlies ACP development. Further research is crucial to understand how these elements interact to create novel therapeutic approaches for patients with ACP., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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9. Retraction Note: Barbaloin: an amazing chemical from the 'wonder plant' with multidimensional pharmacological attributes.
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Mitra SS, Ghorai M, Nandy S, Mukherjee N, Kumar M, Radha, Ghosh A, Jha NK, Proćków J, and Dey A
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- 2024
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10. Corrigendum: Phytotherapy for attention deficit hyperactivity disorder (ADHD): a systematic review and meta-analysis.
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Dutta T, Anand U, Mitra SS, Ghorai M, Jha NK, Shaikh NK, Shekhawat MS, Pandey DK, Proćków J, and Dey A
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[This corrects the article DOI: 10.3389/fphar.2022.827411.]., Competing Interests: Author UA was employed by the company CytoGene Research & Development LLP. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated., (Copyright © 2024 Dutta, Anand, Mitra, Ghorai, Jha, Shaikh, Shekhawat, Pandey, Proćków and Dey.)
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- 2024
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11. Surveillance of bacterial carriage in the nose and hands of healthcare workers and patients attending maternity and children's hospital.
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Mitra SS and Pachpute SR
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Introduction: Nosocomial infections have been acknowledged as a significant pathogen responsible for human illness due to the rise in the incidence of these infections that are mainly caused by resistant strains. As a result, it is important to prevent nosocomial infections. Therefore, in the epidemiology and pathogenesis of infection bacterial carriage appears to be of great importance and in healthy persons, three patterns of carriage are observed over time. The common ecological niches of microorganisms are the anterior nares and hands; hence, the present study aims to evaluate the surveillance of bacterial carriage from the hands and noses of healthcare workers that involve doctors, nurses, and housekeeping staffs and patients involving pregnant women or mothers., Materials and Methods: An observational prospective study was conducted for 1.5 years in which collection of swabs from both the hands and nose were taken and inoculated on mannitol salt agar, blood agar, and MacConkey agar and incubated at 37°C for 24 h following which biochemical reactions were performed from isolates and 160 nasal swabs and hand swabs were studied for bacterial growth., Results: The percentages of bacterial growth in the hands of mothers, doctors, housekeeping staff, and nurses were 17.5, 12.5, 52.5, and 25%, respectively, and in the nose were 7.5, 5, 32.5, and 12.5%, respectively. Total bacterial carriage in hand and nose swabs were 26.87 and 14.37%, respectively., Conclusion: Methicillin-resistant Staphylococcus aureus was the most common microorganism isolated and as a result to prevent its spread along with other nosocomial microorganisms, appropriate precautions should be taken as the spreading of these organisms can lead to drug resistance strains., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Family Medicine and Primary Care.)
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- 2023
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12. Investigating impact of CORDEX-based predicted climatic and LCM-based LULC scenarios on hydrologic response of a semi-gauged Indian catchment.
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Mitra SS, Kumar A, Santra A, and Routh S
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- Hydrology, Forecasting, Climate Change, Environmental Monitoring, Soil
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The present study aims at documenting the impact of different climate and land use change scenarios on runoff in the Kangsabati River basin. While the study relies on India Meteorological Department (IMD), National Oceanic and Atmospheric Administration's Physical Sciences Laboratory (NOAA-PSL), and a multi-model ensemble of six driving models from Coordinated Regional Downscaling Experiment-Regional Climate Models (CORDEX RCM) for climate data input, it depends on IDRISI Selva's Land Change Modeller (LCM) and Soil and Water Assessment Tool (SWAT) model to generate projected land use land change maps and simulate its streamflow response, respectively. A total of four land use and land cover (LULC) scenarios, representing four projected land use change, were modelled across three climatic scenarios, called Representative Concentration Pathways (RCPs). With runoff being predominantly impacted more by climate change than LULC, volumetric runoff is expected to be 12-46% higher than the baseline period of 1982-2017. Conversely, while surface runoff is expected to decrease by 4-28% in lower parts of the basin, it will increase by 2-39% in the rest of it, depending on the subtle alterations in land use and climatic variability., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
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- 2023
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13. Barbaloin: an amazing chemical from the 'wonder plant' with multidimensional pharmacological attributes.
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Mitra SS, Ghorai M, Nandy S, Mukherjee N, Kumar M, Radha, Ghosh A, Jha NK, Proćków J, and Dey A
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- Humans, Anthracenes pharmacology, Phytochemicals pharmacology, Plant Extracts pharmacology, Plant Extracts chemistry, COVID-19, Aloe chemistry
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Aloe vera (L.) Burm.f. is nicknamed the 'Miracle plant' or sometimes as the 'Wonder plant'. It is a plant that has been used since ancient times for the innumerable health benefits associated with it. It is one of the important plants that has its use in conventional medicinal treatments. It is a perennial succulent, drought-tolerant member of the family Asphodelaceae. There are scores of properties associated with the plant that help in curing various forms of human ailments. Extracts and gels obtained from plants have been shown to be wonderful healers of different conditions, mainly various skin problems. Also, this plant is popular in the cosmetics industry. The underlying properties of the plant are now mainly associated with the natural phytochemicals present in the plant. Diverse groups of phytoingredients are found in the plant, including various phenolics, amino acids, sugars, vitamins, and different other organic compounds, too. One of the primary ingredients found in the plant is the aloin molecule. It is an anthraquinone derivative and exists as an isomer of Aloin A and Aloin B. Barbaloin belonging to the first group is a glucoside of the aloe-emodin anthrone molecule. Various types of pharmacological properties exhibited by the plant can be attributed to this chemical. Few significant ones are antioxidant, anti-inflammatory, anti-diabetic, anti-cancer, anti-microbial, and anti-viral, along with their different immunity-boosting actions. Recently, molecular coupling studies have also found the role of these molecules as a potential cure against the ongoing COVID-19 disease. This study comprehensively focuses on the numerous pharmacological actions of the primary compound barbaloin obtained from the Aloe vera plant along with the mechanism of action and the potent application of these natural molecules under various conditions., (© 2022. The Author(s).)
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- 2022
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14. Mapping the tumor-infiltrating immune cells during glioblastoma progression.
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Lakshmanachetty S and Mitra SS
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- Humans, Lymphocytes, Tumor-Infiltrating, Brain Neoplasms, Glioblastoma
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- 2022
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15. Venetoclax Cooperates with Ionizing Radiation to Attenuate Diffuse Midline Glioma Tumor Growth.
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Madhavan K, Balakrishnan I, Lakshmanachetty S, Pierce A, Sanford B, Fosmire S, Elajaili HB, Walker F, Wang D, Nozik ES, Mitra SS, Dahl NA, Vibhakar R, and Venkataraman S
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- Animals, Apoptosis, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Cell Line, Tumor, Humans, Mice, Neoplasm Recurrence, Local drug therapy, Proto-Oncogene Proteins c-bcl-2, Radiation, Ionizing, Reactive Oxygen Species, Sulfonamides, Antineoplastic Agents pharmacology, Glioma drug therapy, Glioma genetics, Glioma radiotherapy
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Purpose: Tumor relapse after radiotherapy is a major hurdle in treating pediatric H3K27M-mutant diffuse midline gliomas (DMG). Radiotherapy-induced stress increases association of BCL2 family of proteins with BH3 pro-apoptotic activators preventing apoptosis. We hypothesized that inhibition of radiotherapy-induced BCL2 with a clinically relevant inhibitor, venetoclax, will block BCL2 activity leading to increased apoptosis. BCL2 has never been implicated in DMG as a radiotherapy-induced resistant mechanism., Experimental Design: We performed an integrated genomic analysis to determine genes responsible for radioresistance and a targeted drug screen to identify drugs that synergize with radiation in DMG. Effect of venetoclax on radiation-naïve and 6 Gy radiation on cells was evaluated by studying cell death, changes in BCL2 phosphorylation, reactive oxygen species (ROS), and apoptosis, as well as BCL2 association with BH3 apoptosis initiators. The efficacy of combining venetoclax with radiation was evaluated in vivo using orthotopic xenograft models., Results: BCL2 was identified as a key regulator of tumor growth after radiation in DMGs. Radiation sensitizes DMGs to venetoclax treatment independent of p53 status. Venetoclax as a monotherapy was not cytotoxic to DMG cells. Postradiation venetoclax treatment significantly increased cell death, reduced BCL2-BIM association, and augmented mitochondrial ROS leading to increased apoptosis. Combining venetoclax with radiotherapy significantly enhanced the survival of mice with DMG tumors., Conclusions: This study shows that venetoclax impedes the antiapoptotic function of radiation-induced BCL2 in DMG, leading to increased apoptosis. Results from these preclinical studies demonstrate the potential use of the BCL2 inhibitor venetoclax combined with radiotherapy for pediatric DMG., (©2022 American Association for Cancer Research.)
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- 2022
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16. Phytotherapy for Attention Deficit Hyperactivity Disorder (ADHD): A Systematic Review and Meta-analysis.
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Dutta T, Anand U, Mitra SS, Ghorai M, Jha NK, Shaikh NK, Shekhawat MS, Pandey DK, Proćków J, and Dey A
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Attention deficit hyperactivity disorder (ADHD) is commonly a neurodevelopmental behavioural disorder in children and adolescents. Mainly characterized by symptoms like lack of attention, hyperactivity, and impulsiveness, it can impact the overall mental development of the one affected. Several factors, both genetic and non-genetic, can be responsible for this disorder. Although several traditional treatment methods involve medication and other counselling techniques, they also come with different side effects. Hence, the choice is now shifting to alternative treatment techniques. Herbal treatments are considered one of the most popular complementary and alternative medicine (CAM) administered. However, issues related to the safety and efficacy of herbal remedies for the treatment of ADHD need to be investigated further. This study aims to find out the recent advancement in evidence-based use of herbal remedies for ADHD by a comprehensive and systematic review that depicts the results of the published works on herbal therapy for the disorder. The electronic databases and the references retrieved from the included studies present related randomized controlled trials (RCTs) and open-label studies. Seven RCTs involving children and adolescents diagnosed with ADHD met the inclusion criteria. There is a fair indication of the efficacy and safety of Melissa officinalis L., Bacopa monnieri (L.) Wettst., Matricaria chamomilla L., and Valeriana officinalis L. from the studies evaluated in this systematic review for the treatment of various symptoms of ADHD. Limited evidence was found for Ginkgo biloba L. and pine bark extract. However, various other preparations from other plants did not show significant efficacy. There is inadequate proof to strongly support and recommend the administration of herbal medicines for ADHD, but more research is needed in the relevant field to popularize the alternative treatment approach., Competing Interests: Author UA was employed by the company CytoGene Research & Development LLP.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated., (Copyright © 2022 Dutta, Anand, Mitra, Ghorai, Jha, Shaikh, Shekhawat, Pandey, Proćków and Dey.)
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- 2022
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17. Assessment of global health programs at accredited dental schools in the United States.
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Beck NA, Roudnitsky E, Ritchie CA, Mitra SS, and Afshar S
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- Cohort Studies, Cross-Sectional Studies, Curriculum, Humans, Surveys and Questionnaires, United States, Global Health, Schools, Dental
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Purpose: Oral diseases pose a serious global health challenge. As such, dental education must integrate global health with emphasis on scalable and sustainable solutions. The aim of our study was to capture the scope of global health programs offered to dental students in the United States and identify ways in which dental schools may modify their curricula to improve global health knowledge and accessibility for students., Materials and Methods: For this cross-sectional, cohort study, the investigators sent a confidential and electronic survey to 213 faculty members at the 67 accredited dental schools in the United States. This voluntary survey was distributed in September and October of 2020 with answers being self-reported., Results: A total of 40 different schools are represented in this study, representing 59.7% of accredited dental schools in the United States. Using descriptive statistics, the results present existing global health opportunities, barriers preventing schools from expanding global health education, and necessary resources that schools without a program need to establish one., Conclusion: Our results demonstrate promising findings, in relation to global health being a vital part of dental education. However, there is an urgent need for enhanced and more structured education in this space. As the global burden of oral disease contributes to the degree and severity of noncommunicable diseases worldwide, the development of a sustainable, preventive primary care approach must integrate oral health, making future dental professionals a crucial component of global health., (© 2021 American Dental Education Association.)
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- 2022
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18. Innate Immune Checkpoint Inhibitors: The Next Breakthrough in Medical Oncology?
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Lentz RW, Colton MD, Mitra SS, and Messersmith WA
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- Humans, Immune Checkpoint Inhibitors pharmacology, Medical Oncology, Immune Checkpoint Inhibitors therapeutic use, Immunotherapy methods, Neoplasms drug therapy
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While immunotherapy has revolutionized the treatment of many types of advanced cancer, most patients still do not derive benefit. The currently available immune checkpoint inhibitors target the adaptive immune system, generating a T-cell antitumor response. However, an antitumor immune response depends on a complex interplay of both innate and adaptive immune cells. The innate immune system is a promising new target, and innate immune checkpoint inhibitors can disrupt inhibitory interactions ("don't eat me" signals) between tumor and both phagocytes and natural killer cells. The checkpoint inhibitor may also provide a stimulatory interaction ("eat me" signal), or this can be achieved through use of combination therapy. This generates antitumor effector functions including phagocytosis, natural cytotoxicity, antibody-dependent effects, and synergistic activation of the adaptive immune system via antigen presentation. This is a rapidly expanding area of drug development, either alone or in combination (with anticancer antibodies or adaptive immune checkpoint inhibitors). Here, we comprehensively review the mechanism of action and up-to-date solid tumor clinical trial data of the drugs targeting phagocytosis checkpoints (SIRPα/CD47, LILRB1/MHC-I, and LILRB2/MHC-I) and natural killer-cell checkpoints (TIGIT/CD112 + CD155, PVRIG/CD112, KIRs/MHC-I, and NKG2A-CD94/HLA-E). Innate immune checkpoint inhibitors could once again revolutionize immune-based cancer therapies., (©2021 American Association for Cancer Research.)
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- 2021
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19. New Insights into the Multifaceted Role of Myeloid-Derived Suppressor Cells (MDSCs) in High-Grade Gliomas: From Metabolic Reprograming, Immunosuppression, and Therapeutic Resistance to Current Strategies for Targeting MDSCs.
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Lakshmanachetty S, Cruz-Cruz J, Hoffmeyer E, Cole AP, and Mitra SS
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- Brain Neoplasms pathology, Glioma pathology, Humans, Myeloid-Derived Suppressor Cells pathology, Neoplasm Grading, Brain Neoplasms immunology, Brain Neoplasms metabolism, Drug Resistance, Neoplasm, Glioma immunology, Glioma metabolism, Immunosuppression Therapy, Myeloid-Derived Suppressor Cells immunology, Myeloid-Derived Suppressor Cells metabolism
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Cancer cells "hijack" host immune cells to promote growth, survival, and metastasis. The immune microenvironment of high-grade gliomas (HGG) is a complex and heterogeneous system, consisting of diverse cell types such as microglia, bone marrow-derived macrophages (BMDMs), myeloid-derived suppressor cells (MDSCs), dendritic cells, natural killer (NK) cells, and T-cells. Of these, MDSCs are one of the major tumor-infiltrating immune cells and are correlated not only with overall worse prognosis but also poor clinical outcomes. Upon entry from the bone marrow into the peripheral blood, spleen, as well as in tumor microenvironment (TME) in HGG patients, MDSCs deploy an array of mechanisms to perform their immune and non-immune suppressive functions. Here, we highlight the origin, function, and characterization of MDSCs and how they are recruited and metabolically reprogrammed in HGG. Furthermore, we discuss the mechanisms by which MDSCs contribute to immunosuppression and resistance to current therapies. Finally, we conclude by summarizing the emerging approaches for targeting MDSCs alone as a monotherapy or in combination with other standard-of-care therapies to improve the current treatment of high-grade glioma patients.
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- 2021
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20. "Thanks for hearing me out": Voices of social work students during COVID-19.
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Cole SJ, Mitra SS, Robinson JA, Jen S, Paceley MS, Carr KA, Riquino M, and Wright K
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As social work educators and students, the COVID-19 pandemic impacted our teaching and learning in challenging ways. We embarked on a qualitative research study to better understand the ways in which the pandemic was affecting the social work students in our program. Three faculty mentors worked collaboratively with five social work students across BSW, MSW, and PhD programs to interview 66 BSW and MSW students about their experiences, challenges, and hopes during the early months of the pandemic. BSW and MSW students led the analysis and early dissemination for the project. This essay describes the unique experiences of social work students by using a research poem to capture the emotional and experiential aspects of the students we interviewed., (© The Author(s) 2020.)
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- 2021
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21. Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia.
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Danilov AV, Herbaux C, Walter HS, Hillmen P, Rule SA, Kio EA, Karlin L, Dyer MJS, Mitra SS, Yi PC, Humeniuk R, Huang X, Zhou Z, Bhargava P, Jürgensmeier JM, and Fegan CD
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- Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Female, Follow-Up Studies, Humans, Imidazoles administration & dosage, Indazoles administration & dosage, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Recurrence, Local pathology, Prognosis, Purines administration & dosage, Pyrazines administration & dosage, Pyrimidines administration & dosage, Quinazolinones administration & dosage, Tissue Distribution, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Drug Resistance, Neoplasm drug effects, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Neoplasm Recurrence, Local drug therapy, Salvage Therapy
- Abstract
Purpose: Bruton tyrosine kinase (BTK) inhibition alone leads to incomplete responses in chronic lymphocytic leukemia (CLL). Combination therapy may reduce activation of escape pathways and deepen responses. This open-label, phase Ib, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib alone, in combination with the PI3K delta (PI3Kδ) inhibitor idelalisib, or with the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with relapsed/refractory CLL., Patients and Methods: Patients received either tirabrutinib monotherapy (80 mg every day) or tirabrutinib 20-150 mg every day in combination with either idelalisib (50 mg twice a day or 100 mg every day) or entospletinib (200 mg or 400 mg every day)., Results: Fifty-three patients were included. Systemic tirabrutinib exposure was comparable between monotherapy and combination therapy. No MTD was identified. Across all treatment groups, the most common adverse event was diarrhea (43%, 1 patient grade ≥3); discontinuation due to adverse events was uncommon (13%). Objective response rates were 83%, 93%, and 100%, and complete responses were 7%, 7%, and 10% in patients receiving tirabrutinib, tirabrutinib/idelalisib, and tirabrutinib/entospletinib, respectively. As of February 21, 2019, 46 of 53 patients continue to receive treatment on study., Conclusions: Tirabrutinib in combination with idelalisib or entospletinib was well tolerated in patients with CLL, establishing an acceptable safety profile for concurrent selective inhibition of BTK with either PI3Kδ or SYK. This small study did not establish a superior efficacy of the combinations over tirabrutinib alone. This trial is registered at www.clinicaltrials.gov (NCT02457598)., (©2020 American Association for Cancer Research.)
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- 2020
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22. Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors.
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Theruvath J, Sotillo E, Mount CW, Graef CM, Delaidelli A, Heitzeneder S, Labanieh L, Dhingra S, Leruste A, Majzner RG, Xu P, Mueller S, Yecies DW, Finetti MA, Williamson D, Johann PD, Kool M, Pfister S, Hasselblatt M, Frühwald MC, Delattre O, Surdez D, Bourdeaut F, Puget S, Zaidi S, Mitra SS, Cheshier S, Sorensen PH, Monje M, and Mackall CL
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- Adult, Animals, Brain drug effects, Brain immunology, Brain pathology, Brain Neoplasms immunology, Brain Neoplasms pathology, Cells, Cultured, Child, Preschool, Female, Fetus pathology, Humans, Infant, Injections, Intraventricular, Mice, Mice, Inbred NOD, Mice, SCID, Receptors, Chimeric Antigen administration & dosage, Receptors, Chimeric Antigen genetics, Receptors, Chimeric Antigen immunology, Rhabdoid Tumor immunology, Rhabdoid Tumor pathology, T-Lymphocytes immunology, T-Lymphocytes metabolism, T-Lymphocytes transplantation, Teratoma immunology, Teratoma pathology, Xenograft Model Antitumor Assays, B7 Antigens immunology, Brain Neoplasms therapy, Cancer Vaccines administration & dosage, Immunotherapy, Adoptive methods, Rhabdoid Tumor therapy, Teratoma therapy
- Abstract
Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months
1,2 . We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs.3,4 ), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT5,6 , B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.- Published
- 2020
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23. Microglia in the Brain Tumor Microenvironment.
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Cole AP, Hoffmeyer E, Chetty SL, Cruz-Cruz J, Hamrick F, Youssef O, Cheshier S, and Mitra SS
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- Brain immunology, Brain Neoplasms therapy, Glioma therapy, Humans, Microglia immunology, Brain Neoplasms immunology, Glioma immunology, Microglia cytology, Tumor Microenvironment immunology
- Abstract
Microglia are the brain resident phagocytes that act as the primary form of the immune defense in the central nervous system. These cells originate from primitive macrophages that arise from the yolk sac. Advances in imaging and single-cell RNA-seq technologies provided new insights into the complexity of microglia biology.Microglia play an essential role in the brain development and maintenance of brain homeostasis. They are also crucial in injury repair in the central nervous system. The tumor microenvironment is complex and includes neoplastic cells as well as varieties of host and infiltrating immune cells. Microglia are part of the glioma microenvironment and play a critical part in initiating and maintaining tumor growth and spread. Microglia can also act as effector cells in treatments against gliomas. In this chapter, we summarize the current knowledge of how and where microglia are generated. We also discuss their functions during brain development, injury repair, and homeostasis. Moreover, we discuss the role of microglia in the tumor microenvironment of gliomas and highlight their therapeutic implications.
- Published
- 2020
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24. CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors.
- Author
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Majzner RG, Theruvath JL, Nellan A, Heitzeneder S, Cui Y, Mount CW, Rietberg SP, Linde MH, Xu P, Rota C, Sotillo E, Labanieh L, Lee DW, Orentas RJ, Dimitrov DS, Zhu Z, Croix BS, Delaidelli A, Sekunova A, Bonvini E, Mitra SS, Quezado MM, Majeti R, Monje M, Sorensen PHB, Maris JM, and Mackall CL
- Subjects
- Animals, B7 Antigens antagonists & inhibitors, Brain Neoplasms pathology, Brain Neoplasms therapy, Cell Line, Tumor, Disease Models, Animal, Humans, Immunohistochemistry, Mice, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell metabolism, Treatment Outcome, Xenograft Model Antitumor Assays, Antigens, Neoplasm immunology, B7 Antigens immunology, Brain Neoplasms etiology, Brain Neoplasms metabolism, Immunotherapy, Adoptive methods, Receptors, Chimeric Antigen metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
Purpose: Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system., Experimental Design: We developed a novel B7-H3 CAR whose binder is derived from a mAb that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models., Results: B7-H3 CAR T cells mediate significant antitumor activity in vivo , causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T-cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3., Conclusions: B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies, and should be tested in carefully designed clinical trials., (©2019 American Association for Cancer Research.)
- Published
- 2019
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25. Microglia are effector cells of CD47-SIRPα antiphagocytic axis disruption against glioblastoma.
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Hutter G, Theruvath J, Graef CM, Zhang M, Schoen MK, Manz EM, Bennett ML, Olson A, Azad TD, Sinha R, Chan C, Assad Kahn S, Gholamin S, Wilson C, Grant G, He J, Weissman IL, Mitra SS, and Cheshier SH
- Subjects
- Animals, Brain Neoplasms pathology, CD47 Antigen genetics, Glioblastoma genetics, Glioblastoma pathology, Macrophages immunology, Macrophages pathology, Mice, Mice, Inbred NOD, Mice, Transgenic, Microglia pathology, Monocytes immunology, Monocytes pathology, Neoplasm Proteins genetics, Neoplasms, Experimental genetics, Neoplasms, Experimental pathology, Receptors, Immunologic genetics, Signal Transduction genetics, Brain Neoplasms immunology, CD47 Antigen immunology, Glioblastoma immunology, Microglia immunology, Neoplasm Proteins immunology, Neoplasms, Experimental immunology, Phagocytosis, Receptors, Immunologic immunology, Signal Transduction immunology
- Abstract
Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor with fatal outcome. Tumor-associated macrophages and microglia (TAMs) have been found to be major tumor-promoting immune cells in the tumor microenvironment. Hence, modulation and reeducation of tumor-associated macrophages and microglia in GBM is considered a promising antitumor strategy. Resident microglia and invading macrophages have been shown to have distinct origin and function. Whereas yolk sac-derived microglia reside in the brain, blood-derived monocytes invade the central nervous system only under pathological conditions like tumor formation. We recently showed that disruption of the SIRPα-CD47 signaling axis is efficacious against various brain tumors including GBM primarily by inducing tumor phagocytosis. However, most effects are attributed to macrophages recruited from the periphery but the role of the brain resident microglia is unknown. Here, we sought to utilize a model to distinguish resident microglia and peripheral macrophages within the GBM-TAM pool, using orthotopically xenografted, immunodeficient, and syngeneic mouse models with genetically color-coded macrophages ( Ccr2
RFP ) and microglia ( Cx3cr1GFP ). We show that even in the absence of phagocytizing macrophages ( Ccr2RFP/RFP ), microglia are effector cells of tumor cell phagocytosis in response to anti-CD47 blockade. Additionally, macrophages and microglia show distinct morphological and transcriptional changes. Importantly, the transcriptional profile of microglia shows less of an inflammatory response which makes them a promising target for clinical applications., Competing Interests: Conflict of interest statement: S.G., S.S.M., S.H.C., and I.L.W. are coinventors on patents regarding the use of CD47 antibody targeting brain tumors. I.L.W. is the inventor of multiple patents regarding CD47 antibody targeting non-CNS tumors that have been licensed to Forty Seven, Inc. He serves on the board of directors and as a consultant. He has equity ownership in Forty Seven, Inc., (Copyright © 2019 the Author(s). Published by PNAS.)- Published
- 2019
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26. Publisher Correction: Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma.
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Kahn SA, Wang X, Nitta RT, Gholamin S, Theruvath J, Hutter G, Azad TD, Wadi L, Bolin S, Ramaswamy V, Esparza R, Liu KW, Edwards M, Swartling FJ, Sahoo D, Li G, Wechsler-Reya RJ, Reimand J, Cho YJ, Taylor MD, Weissman IL, Mitra SS, and Cheshier SH
- Abstract
The original version of this Article omitted Suzana A. Kahn, Siddhartha S. Mitra & Samuel H. Cheshier as jointly supervising authors. This has now been corrected in both the PDF and HTML versions of the Article.
- Published
- 2018
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27. Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma.
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Kahn SA, Wang X, Nitta RT, Gholamin S, Theruvath J, Hutter G, Azad TD, Wadi L, Bolin S, Ramaswamy V, Esparza R, Liu KW, Edwards M, Swartling FJ, Sahoo D, Li G, Wechsler-Reya RJ, Reimand J, Cho YJ, Taylor MD, Weissman IL, Mitra SS, and Cheshier SH
- Subjects
- Animals, Antibodies, Blocking immunology, Antibodies, Blocking pharmacology, Cell Line, Tumor, Cerebellar Neoplasms drug therapy, Cerebellar Neoplasms metabolism, Humans, Medulloblastoma drug therapy, Medulloblastoma metabolism, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Neoplasm Metastasis, Nuclear Proteins genetics, Nuclear Proteins metabolism, Polycomb Repressive Complex 1 genetics, Polycomb Repressive Complex 1 metabolism, Receptor, Notch1 immunology, Receptor, Notch1 metabolism, Signal Transduction drug effects, Signal Transduction genetics, Twist-Related Protein 1 genetics, Twist-Related Protein 1 metabolism, Xenograft Model Antitumor Assays methods, Cell Proliferation genetics, Cerebellar Neoplasms genetics, Gene Expression Regulation, Neoplastic, Medulloblastoma genetics, Receptor, Notch1 genetics
- Abstract
Medulloblastoma is the most common malignant brain tumor of childhood. Group 3 medulloblastoma, the most aggressive molecular subtype, frequently disseminates through the leptomeningeal cerebral spinal fluid (CSF) spaces in the brain and spinal cord. The mechanism of dissemination through the CSF remains poorly understood, and the molecular pathways involved in medulloblastoma metastasis and self-renewal are largely unknown. Here we show that NOTCH1 signaling pathway regulates both the initiation of metastasis and the self-renewal of medulloblastoma. We identify a mechanism in which NOTCH1 activates BMI1 through the activation of TWIST1. NOTCH1 expression and activity are directly related to medulloblastoma metastasis and decreased survival rate of tumor-bearing mice. Finally, medulloblastoma-bearing mice intrathecally treated with anti-NRR1, a NOTCH1 blocking antibody, present lower frequency of spinal metastasis and higher survival rate. These findings identify NOTCH1 as a pivotal driver of Group 3 medulloblastoma metastasis and self-renewal, supporting the development of therapies targeting this pathway.
- Published
- 2018
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28. Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors.
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Gholamin S, Mitra SS, Feroze AH, Liu J, Kahn SA, Zhang M, Esparza R, Richard C, Ramaswamy V, Remke M, Volkmer AK, Willingham S, Ponnuswami A, McCarty A, Lovelace P, Storm TA, Schubert S, Hutter G, Narayanan C, Chu P, Raabe EH, Harsh G 4th, Taylor MD, Monje M, Cho YJ, Majeti R, Volkmer JP, Fisher PG, Grant G, Steinberg GK, Vogel H, Edwards M, Weissman IL, and Cheshier SH
- Subjects
- Animals, Antibodies pharmacology, Brain Neoplasms pathology, Cell Proliferation drug effects, Child, Disease Models, Animal, Humans, Immunocompetence, Injections, Intraventricular, Medulloblastoma drug therapy, Medulloblastoma pathology, Meningeal Neoplasms pathology, Meningeal Neoplasms secondary, Mice, Inbred C57BL, Models, Biological, Neoplasm Metastasis, Survival Analysis, Xenograft Model Antitumor Assays, Antibodies therapeutic use, Antigens, Differentiation metabolism, Brain Neoplasms drug therapy, CD47 Antigen immunology, Phagocytosis drug effects, Receptors, Immunologic metabolism
- Abstract
Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies., (Copyright © 2017, American Association for the Advancement of Science.)
- Published
- 2017
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29. Surgical debulking promotes recruitment of macrophages and triggers glioblastoma phagocytosis in combination with CD47 blocking immunotherapy.
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Zhu H, Leiss L, Yang N, Rygh CB, Mitra SS, Cheshier SH, Weissman IL, Huang B, Miletic H, Bjerkvig R, Enger PØ, Li X, and Wang J
- Subjects
- Animals, Antibodies, Blocking immunology, Antibodies, Blocking pharmacology, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacology, CD47 Antigen immunology, Combined Modality Therapy, Cytokines metabolism, Glioblastoma metabolism, Glioblastoma pathology, Humans, Immunohistochemistry, Inflammation Mediators metabolism, Rats, Nude, Survival Analysis, Time Factors, Xenograft Model Antitumor Assays, CD47 Antigen metabolism, Cytoreduction Surgical Procedures methods, Glioblastoma therapy, Immunotherapy methods, Macrophages metabolism, Phagocytosis
- Abstract
Surgical resection is a standard component of treatment in the clinical management of patients with glioblastoma multiforme (GBM). However, experimental therapies are rarely investigated in the context of tumor debulking in preclinical models. Here, a surgical debulking GBM xenograft model was developed in nude rats, and was used in combination with CD47 blocking immunotherapy, a novel treatment strategy that triggers phagocytosis of tumor cells by macrophages in diverse cancer types including GBM. Orthotopic patient-derived xenograft tumors expressing CD47 were resected at 4 weeks after implantation and immediately thereafter treated with anti-CD47 or control antibodies injected into the cavity. Debulking prolonged survival (median survival, 68.5 vs 42.5 days, debulking and non-debulking survival times, respectively; n = 6 animals/group; P = 0.0005). Survival was further improved in animals that underwent combination treatment with anti-CD47 mAbs (median survival, 81.5 days vs 69 days, debulking + anti-CD47 vs debulking + control IgG, respectively; P = 0.0007). Immunohistochemistical staining of tumor sections revealed an increase in recruitment of cells positive for CD68, a marker for macrophages/immune cell types, to the surgical site (50% vs 10%, debulking vs non-debulking, respectively). Finally, analysis of tumor protein lysates on antibody microarrays demonstrated an increase in pro-inflammatory cytokines, such as CXCL10, and a decrease in angiogenic proteins in debulking + anti-CD47 vs non-debulking + IgG tumors. The results indicated that surgical resection combined with anti-CD47 blocking immunotherapy promoted an inflammatory response and prolonged survival in animals, and is therefore an attractive strategy for clinical translation.
- Published
- 2017
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30. Tumour-associated glial host cells display a stem-like phenotype with a distinct gene expression profile and promote growth of GBM xenografts.
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Leiss L, Mutlu E, Øyan A, Yan T, Tsinkalovsky O, Sleire L, Petersen K, Rahman MA, Johannessen M, Mitra SS, Jacobsen HK, Talasila KM, Miletic H, Jonassen I, Li X, Brons NH, Kalland KH, Wang J, and Enger PØ
- Subjects
- Animals, Biomarkers, Tumor, Brain Neoplasms genetics, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Glioblastoma genetics, Humans, Immunohistochemistry, Mice, Mice, Inbred NOD, Mice, SCID, Microarray Analysis, Xenograft Model Antitumor Assays, Brain metabolism, Brain Neoplasms metabolism, Glioblastoma metabolism, Transcriptome
- Abstract
Background: Little is known about the role of glial host cells in brain tumours. However, supporting stromal cells have been shown to foster tumour growth in other cancers., Methods: We isolated stromal cells from patient-derived glioblastoma (GBM) xenografts established in GFP-NOD/scid mice. With simultaneous removal of CD11b
+ immune and CD31+ endothelial cells by fluorescence activated cell sorting (FACS), we obtained a population of tumour-associated glial cells, TAGs, expressing markers of terminally differentiaed glial cell types or glial progenitors. This cell population was subsequently characterised using gene expression analyses and immunocytochemistry. Furthermore, sphere formation was assessed in vitro and their glioma growth-promoting ability was examined in vivo. Finally, the expression of TAG related markers was validated in human GBMs., Results: TAGs were highly enriched for the expression of glial cell proteins including GFAP and myelin basic protein (MBP), and immature markers such as Nestin and O4. A fraction of TAGs displayed sphere formation in stem cell medium. Moreover, TAGs promoted brain tumour growth in vivo when co-implanted with glioma cells, compared to implanting only glioma cells, or glioma cells and unconditioned glial cells from mice without tumours. Genome-wide microarray analysis of TAGs showed an expression profile distinct from glial cells from healthy mice brains. Notably, TAGs upregulated genes associated with immature cell types and self-renewal, including Pou3f2 and Sox2. In addition, TAGs from highly angiogenic tumours showed upregulation of angiogenic factors, including Vegf and Angiopoietin 2. Immunohistochemistry of three GBMs, two patient biopsies and one GBM xenograft, confirmed that the expression of these genes was mainly confined to TAGs in the tumour bed. Furthermore, their expression profiles displayed a significant overlap with gene clusters defining prognostic subclasses of human GBMs., Conclusions: Our data demonstrate that glial host cells in brain tumours are functionally distinct from glial cells of healthy mice brains. Furthermore, TAGs display a gene expression profile with enrichment for genes related to stem cells, immature cell types and developmental processes. Future studies are needed to delineate the biological mechanisms regulating the brain tumour-host interplay.- Published
- 2017
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31. The anti-hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ-dependent inhibition of the AKT pathway.
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Assad Kahn S, Costa SL, Gholamin S, Nitta RT, Dubois LG, Fève M, Zeniou M, Coelho PL, El-Habr E, Cadusseau J, Varlet P, Mitra SS, Devaux B, Kilhoffer MC, Cheshier SH, Moura-Neto V, Haiech J, Junier MP, and Chneiweiss H
- Subjects
- Animals, Antihypertensive Agents pharmacology, Apoptosis, Cell Survival drug effects, Disease Models, Animal, Heterografts, Humans, Mice, Survival Analysis, Antineoplastic Agents pharmacology, Drug Repositioning, Glioblastoma drug therapy, Oncogene Protein v-akt metabolism, Prazosin pharmacology, Protein Kinase C-delta metabolism, Signal Transduction
- Abstract
A variety of drugs targeting monoamine receptors are routinely used in human pharmacology. We assessed the effect of these drugs on the viability of tumor-initiating cells isolated from patients with glioblastoma. Among the drugs targeting monoamine receptors, we identified prazosin, an α1- and α2B-adrenergic receptor antagonist, as the most potent inducer of patient-derived glioblastoma-initiating cell death. Prazosin triggered apoptosis of glioblastoma-initiating cells and of their differentiated progeny, inhibited glioblastoma growth in orthotopic xenografts of patient-derived glioblastoma-initiating cells, and increased survival of glioblastoma-bearing mice. We found that prazosin acted in glioblastoma-initiating cells independently from adrenergic receptors. Its off-target activity occurred via a PKCδ-dependent inhibition of the AKT pathway, which resulted in caspase-3 activation. Blockade of PKCδ activation prevented all molecular changes observed in prazosin-treated glioblastoma-initiating cells, as well as prazosin-induced apoptosis. Based on these data, we conclude that prazosin, an FDA-approved drug for the control of hypertension, inhibits glioblastoma growth through a PKCδ-dependent mechanism. These findings open up promising prospects for the use of prazosin as an adjuvant therapy for glioblastoma patients., (© 2016 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2016
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32. Anti-CD47 Treatment Stimulates Phagocytosis of Glioblastoma by M1 and M2 Polarized Macrophages and Promotes M1 Polarized Macrophages In Vivo.
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Zhang M, Hutter G, Kahn SA, Azad TD, Gholamin S, Xu CY, Liu J, Achrol AS, Richard C, Sommerkamp P, Schoen MK, McCracken MN, Majeti R, Weissman I, Mitra SS, and Cheshier SH
- Subjects
- Animals, Cell Differentiation drug effects, Cell Line, Tumor, Glioblastoma metabolism, Humans, Macrophages metabolism, Mice, Mice, Inbred NOD, Phenotype, Antibodies pharmacology, CD47 Antigen metabolism, Glioblastoma drug therapy, Glioblastoma pathology, Macrophages drug effects, Macrophages pathology, Phagocytosis drug effects
- Abstract
Tumor-associated macrophages (TAMs) represent an important cellular subset within the glioblastoma (WHO grade IV) microenvironment and are a potential therapeutic target. TAMs display a continuum of different polarization states between antitumorigenic M1 and protumorigenic M2 phenotypes, with a lower M1/M2 ratio correlating with worse prognosis. Here, we investigated the effect of macrophage polarization on anti-CD47 antibody-mediated phagocytosis of human glioblastoma cells in vitro, as well as the effect of anti-CD47 on the distribution of M1 versus M2 macrophages within human glioblastoma cells grown in mouse xenografts. Bone marrow-derived mouse macrophages and peripheral blood-derived human macrophages were polarized in vitro toward M1 or M2 phenotypes and verified by flow cytometry. Primary human glioblastoma cell lines were offered as targets to mouse and human M1 or M2 polarized macrophages in vitro. The addition of an anti-CD47 monoclonal antibody led to enhanced tumor-cell phagocytosis by mouse and human M1 and M2 macrophages. In both cases, the anti-CD47-induced phagocytosis by M1 was more prominent than that for M2. Dissected tumors from human glioblastoma xenografted within NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice and treated with anti-CD47 showed a significant increase of M1 macrophages within the tumor. These data show that anti-CD47 treatment leads to enhanced tumor cell phagocytosis by both M1 and M2 macrophage subtypes with a higher phagocytosis rate by M1 macrophages. Furthermore, these data demonstrate that anti-CD47 treatment alone can shift the phenotype of macrophages toward the M1 subtype in vivo.
- Published
- 2016
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33. Neural Placode Tissue Derived From Myelomeningocele Repair Serves as a Viable Source of Oligodendrocyte Progenitor Cells.
- Author
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Mitra SS, Feroze AH, Gholamin S, Richard C, Esparza R, Zhang M, Azad TD, Alrfaei B, Kahn SA, Hutter G, Guzman R, Creasey GH, Plant GW, Weissman IL, Edwards MS, and Cheshier S
- Subjects
- Cell Differentiation physiology, Cells, Cultured, Female, Humans, Infant, Newborn, Male, Neural Stem Cells physiology, Neurons physiology, Oligodendroglia physiology, Meningomyelocele pathology, Neural Stem Cells cytology, Neurons cytology, Neurons pathology, Oligodendroglia cytology
- Abstract
Background: The presence, characteristics, and potential clinical relevance of neural progenitor populations within the neural placodes of myelomeningocele patients remain to be studied. Neural stem cells are known to reside adjacent to ependyma-lined surfaces along the central nervous system axis., Objective: Given such neuroanatomic correlation and regenerative capacity in fetal development, we assessed myelomeningocele-derived neural placode tissue as a potentially novel source of neural stem and progenitor cells., Methods: Nonfunctional neural placode tissue was harvested from infants during the surgical repair of myelomeningocele and subsequently further analyzed by in vitro studies, flow cytometry, and immunofluorescence. To assess lineage potential, neural placode-derived neurospheres were subjected to differential media conditions. Through assessment of platelet-derived growth factor receptor α (PDGFRα) and CD15 cell marker expression, Sox2+Olig2+ putative oligodendrocyte progenitor cells were successfully isolated., Results: PDGFRαCD15 cell populations demonstrated the highest rate of self-renewal capacity and multipotency of cell progeny. Immunofluorescence of neural placode-derived neurospheres demonstrated preferential expression of the oligodendrocyte progenitor marker, CNPase, whereas differentiation to neurons and astrocytes was also noted, albeit to a limited degree., Conclusion: Neural placode tissue contains multipotent progenitors that are preferentially biased toward oligodendrocyte progenitor cell differentiation and presents a novel source of such cells for use in the treatment of a variety of pediatric and adult neurological disease, including spinal cord injury, multiple sclerosis, and metabolic leukoencephalopathies.
- Published
- 2015
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34. Casein kinase 2α regulates glioblastoma brain tumor-initiating cell growth through the β-catenin pathway.
- Author
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Nitta RT, Gholamin S, Feroze AH, Agarwal M, Cheshier SH, Mitra SS, and Li G
- Subjects
- Animals, Benzimidazoles pharmacology, Brain Neoplasms genetics, Casein Kinase II antagonists & inhibitors, Casein Kinase II genetics, Cell Line, Tumor, Cell Proliferation, Glioblastoma genetics, Humans, Mice, Naphthyridines pharmacology, Neoplasm Transplantation, Neoplastic Stem Cells metabolism, Phenazines, Prognosis, Survival Analysis, beta Catenin genetics, beta Catenin metabolism, Brain Neoplasms metabolism, Brain Neoplasms pathology, Casein Kinase II metabolism, Glioblastoma metabolism, Glioblastoma pathology, Neoplastic Stem Cells pathology, Signal Transduction
- Abstract
Glioblastoma (GBM) is the most common and fatal primary brain tumor in humans, and it is essential that new and better therapies are developed to treat this disease. Previous research suggests that casein kinase 2 (CK2) may be a promising therapeutic target for GBMs. CK2 has enhanced expression or activity in numerous cancers, including GBM, and it has been demonstrated that inhibitors of CK2 regressed tumor growth in GBM xenograft mouse models. Our studies demonstrate that the CK2 subunit, CK2α, is overexpressed in and has an important role in regulating brain tumor-initiating cells (BTIC) in GBM. Initial studies showed that two GBM cell lines (U87-MG and U138) transduced with CK2α had enhanced proliferation and anchorage-independent growth. Inhibition of CKα using siRNA or small-molecule inhibitors (TBBz, CX-4945) reduced cell growth, decreased tumor size, and increased survival rates in GBM xenograft mouse models. We also verified that inhibition of CK2α decreased the activity of a well-known GBM-initiating cell regulator, β-catenin. Loss of CK2α decreased two β-catenin-regulated genes that are involved in GBM-initiating cell growth, OCT4 and NANOG. To determine the importance of CK2α in GBM stem cell maintenance, we reduced CK2α activity in primary GBM samples and tumor spheres derived from GBM patients. We discovered that loss of CK2α activity reduced the sphere-forming capacity of BTIC and decreased numerous GBM stem cell markers, including CD133, CD90, CD49f and A2B5. Our study suggests that CK2α is involved in GBM tumorigenesis by maintaining BTIC through the regulation of β-catenin.
- Published
- 2015
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35. Glioblastoma stem cells and stem cell-targeting immunotherapies.
- Author
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Esparza R, Azad TD, Feroze AH, Mitra SS, and Cheshier SH
- Subjects
- Animals, Humans, Immunosuppression Therapy, Brain Neoplasms immunology, Brain Neoplasms pathology, Brain Neoplasms therapy, Glioblastoma immunology, Glioblastoma pathology, Glioblastoma therapy, Immunotherapy methods, Neoplastic Stem Cells physiology
- Abstract
Advancements in immunotherapeutics promise new possibilities for the creation of glioblastoma (GBM) treatment options. Ongoing work in cancer stem cell biology has progressively elucidated the role of this tumor sub-population in oncogenesis and has distinguished them as prime therapeutic targets. Current clinical trials take a multifaceted approach with the intention of harnessing the intrinsic cytotoxic capabilities of the immune system to directly target glioblastoma cancer stem cells (gCSC) or indirectly disrupt their stromal microenvironment. Monoclonal antibodies (mAbs), dendritic cell (DC) vaccines, and chimeric antigen receptor (CAR) T cell therapies have emerged as the most common approaches, with particular iterations incorporating cancer stem cell antigenic markers in their treatment designs. Ongoing work to determine the comprehensive antigenic profile of the gCSC in conjunction with efforts to counter the immunosuppressive tumor microenvironment holds much promise in future immunotherapeutic strategies against GBM. Given recent advancements in these fields, we believe there is tremendous potential to improve outcomes of GBM patients in the continuing evolution of immunotherapies targeted to cancer stem cell populations in GBM.
- Published
- 2015
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36. Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion.
- Author
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Venkatesh HS, Johung TB, Caretti V, Noll A, Tang Y, Nagaraja S, Gibson EM, Mount CW, Polepalli J, Mitra SS, Woo PJ, Malenka RC, Vogel H, Bredel M, Mallick P, and Monje M
- Subjects
- Adolescent, Amino Acid Sequence, Animals, Brain Neoplasms metabolism, Glioma metabolism, Heterografts, Humans, Male, Mice, Molecular Sequence Data, Neoplasm Transplantation, Neurons metabolism, Brain Neoplasms pathology, Cell Adhesion Molecules, Neuronal metabolism, Cell Proliferation, Glioma pathology, Membrane Proteins metabolism, Nerve Tissue Proteins metabolism
- Abstract
Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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37. Macrophages eat cancer cells using their own calreticulin as a guide: roles of TLR and Btk.
- Author
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Feng M, Chen JY, Weissman-Tsukamoto R, Volkmer JP, Ho PY, McKenna KM, Cheshier S, Zhang M, Guo N, Gip P, Mitra SS, and Weissman IL
- Subjects
- Agammaglobulinaemia Tyrosine Kinase, Humans, Neoplasms enzymology, Neoplasms metabolism, Calreticulin physiology, Macrophages immunology, Neoplasms pathology, Protein-Tyrosine Kinases metabolism, Toll-Like Receptors physiology
- Abstract
Macrophage-mediated programmed cell removal (PrCR) is an important mechanism of eliminating diseased and damaged cells before programmed cell death. The induction of PrCR by eat-me signals on tumor cells is countered by don't-eat-me signals such as CD47, which binds macrophage signal-regulatory protein α to inhibit phagocytosis. Blockade of CD47 on tumor cells leads to phagocytosis by macrophages. Here we demonstrate that the activation of Toll-like receptor (TLR) signaling pathways in macrophages synergizes with blocking CD47 on tumor cells to enhance PrCR. Bruton's tyrosine kinase (Btk) mediates TLR signaling in macrophages. Calreticulin, previously shown to be an eat-me signal on cancer cells, is activated in macrophages for secretion and cell-surface exposure by TLR and Btk to target cancer cells for phagocytosis, even if the cancer cells themselves do not express calreticulin.
- Published
- 2015
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38. Targeting a glioblastoma cancer stem-cell population defined by EGF receptor variant III.
- Author
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Emlet DR, Gupta P, Holgado-Madruga M, Del Vecchio CA, Mitra SS, Han SY, Li G, Jensen KC, Vogel H, Xu LW, Skirboll SS, and Wong AJ
- Subjects
- AC133 Antigen, Animals, Antibodies, Bispecific therapeutic use, Antigens, CD immunology, Antineoplastic Agents, Biomarkers, Tumor metabolism, Brain Neoplasms metabolism, Brain Neoplasms pathology, Brain Neoplasms therapy, Cell Separation, ErbB Receptors immunology, Glioblastoma metabolism, Glioblastoma pathology, Glycoproteins immunology, Humans, Immunoconjugates therapeutic use, Mice, Mice, Inbred NOD, Mice, SCID, Neoplastic Stem Cells pathology, Peptides immunology, Spheroids, Cellular metabolism, Spheroids, Cellular pathology, Tumor Cells, Cultured, ErbB Receptors metabolism, Glioblastoma therapy, Molecular Targeted Therapy methods, Neoplastic Stem Cells metabolism
- Abstract
The relationship between mutated proteins and the cancer stem-cell population is unclear. Glioblastoma tumors frequently express EGFRvIII, an EGF receptor (EGFR) variant that arises via gene rearrangement and amplification. However, expression of EGFRvIII is restricted despite the prevalence of the alteration. Here, we show that EGFRvIII is highly coexpressed with CD133 and that EGFRvIII(+)/CD133(+) defines the population of cancer stem cells (CSC) with the highest degree of self-renewal and tumor-initiating ability. EGFRvIII(+) cells are associated with other stem/progenitor markers, whereas markers of differentiation are found in EGFRvIII(-) cells. EGFRvIII expression is lost in standard cell culture, but its expression is maintained in tumor sphere culture, and cultured cells also retain the EGFRvIII(+)/CD133(+) coexpression, self-renewal, and tumor initiating abilities. Elimination of the EGFRvIII(+)/CD133(+) population using a bispecific antibody reduced tumorigenicity of implanted tumor cells better than any reagent directed against a single epitope. This work demonstrates that a mutated oncogene can have CSC-specific expression and be used to specifically target this population., (©2013 AACR.)
- Published
- 2014
- Full Text
- View/download PDF
39. BET bromodomain inhibition of MYC-amplified medulloblastoma.
- Author
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Bandopadhayay P, Bergthold G, Nguyen B, Schubert S, Gholamin S, Tang Y, Bolin S, Schumacher SE, Zeid R, Masoud S, Yu F, Vue N, Gibson WJ, Paolella BR, Mitra SS, Cheshier SH, Qi J, Liu KW, Wechsler-Reya R, Weiss WA, Swartling FJ, Kieran MW, Bradner JE, Beroukhim R, and Cho YJ
- Subjects
- Animals, Cell Cycle Proteins, Cell Line, Tumor, Cell Survival, G1 Phase Cell Cycle Checkpoints, Gene Amplification, Gene Dosage, Humans, Medulloblastoma metabolism, Mice, Mice, Inbred NOD, Mice, SCID, Nuclear Proteins metabolism, Signal Transduction, Transcription Factors metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Azepines pharmacology, Medulloblastoma drug therapy, Nuclear Proteins antagonists & inhibitors, Proto-Oncogene Proteins c-myc genetics, Transcription Factors antagonists & inhibitors, Triazoles pharmacology
- Abstract
Purpose: MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma., Experimental Design: We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice., Results: Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index., Conclusion: JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma., (©2013 AACR)
- Published
- 2014
- Full Text
- View/download PDF
40. Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway.
- Author
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Lee KS, Wu Z, Song Y, Mitra SS, Feroze AH, Cheshier SH, and Lu B
- Subjects
- Animals, Brain Neoplasms physiopathology, Cell Line, Tumor, Cell Proliferation, Drosophila melanogaster genetics, Drosophila melanogaster metabolism, Gene Expression Regulation, Humans, Mechanistic Target of Rapamycin Complex 2, Microscopy, Electron, Transmission, Mitochondria enzymology, Mitochondria ultrastructure, Multiprotein Complexes genetics, Mutation, Protein Kinases genetics, RNA Interference, TOR Serine-Threonine Kinases genetics, Mitochondria metabolism, Multiprotein Complexes metabolism, Neoplastic Stem Cells metabolism, Protein Kinases metabolism, Receptors, Notch metabolism, Signal Transduction, TOR Serine-Threonine Kinases metabolism
- Abstract
The self-renewal versus differentiation choice of Drosophila and mammalian neural stem cells (NSCs) requires Notch (N) signaling. How N regulates NSC behavior is not well understood. Here we show that canonical N signaling cooperates with a noncanonical N signaling pathway to mediate N-directed NSC regulation. In the noncanonical pathway, N interacts with PTEN-induced kinase 1 (PINK1) to influence mitochondrial function, activating mechanistic target of rapamycin complex 2 (mTORC2)/AKT signaling. Importantly, attenuating noncanonical N signaling preferentially impaired the maintenance of Drosophila and human cancer stem cell-like tumor-forming cells. Our results emphasize the importance of mitochondria to N and NSC biology, with important implications for diseases associated with aberrant N signaling.
- Published
- 2013
- Full Text
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41. Usp16 contributes to somatic stem-cell defects in Down's syndrome.
- Author
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Adorno M, Sikandar S, Mitra SS, Kuo A, Nicolis Di Robilant B, Haro-Acosta V, Ouadah Y, Quarta M, Rodriguez J, Qian D, Reddy VM, Cheshier S, Garner CC, and Clarke MF
- Subjects
- Adult Stem Cells metabolism, Adult Stem Cells pathology, Animals, Cell Proliferation, Cellular Senescence, Chromosomes, Human, Pair 21 genetics, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Disease Models, Animal, Down Syndrome genetics, Epithelium metabolism, Female, Fibroblasts cytology, Fibroblasts metabolism, Fibroblasts pathology, Gene Dosage, Gene Expression Regulation, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells pathology, Humans, Mammary Glands, Animal cytology, Mammary Glands, Animal metabolism, Mice, Molecular Targeted Therapy, Trisomy genetics, Ubiquitin Thiolesterase genetics, Ubiquitination, Down Syndrome metabolism, Down Syndrome pathology, Neural Stem Cells metabolism, Neural Stem Cells pathology, Ubiquitin Thiolesterase metabolism
- Abstract
Down's syndrome results from full or partial trisomy of chromosome 21. However, the consequences of the underlying gene-dosage imbalance on adult tissues remain poorly understood. Here we show that in Ts65Dn mice, which are trisomic for 132 genes homologous to genes on human chromosome 21, triplication of Usp16 reduces the self-renewal of haematopoietic stem cells and the expansion of mammary epithelial cells, neural progenitors and fibroblasts. In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn fibroblasts. Usp16 can remove ubiquitin from histone H2A on lysine 119, a critical mark for the maintenance of multiple somatic tissues. Downregulation of Usp16, either by mutation of a single normal Usp16 allele or by short interfering RNAs, largely rescues all of these defects. Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and postnatal neural progenitors, whereas downregulation of USP16 partially rescues the proliferation defects of Down's syndrome fibroblasts. Taken together, these results suggest that USP16 has an important role in antagonizing the self-renewal and/or senescence pathways in Down's syndrome and could serve as an attractive target to ameliorate some of the associated pathologies.
- Published
- 2013
- Full Text
- View/download PDF
42. Expression of epidermal growth factor variant III (EGFRvIII) in pediatric diffuse intrinsic pontine gliomas.
- Author
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Li G, Mitra SS, Monje M, Henrich KN, Bangs CD, Nitta RT, and Wong AJ
- Subjects
- Adult, Blotting, Western, Brain Stem Neoplasms metabolism, Child, Preschool, ErbB Receptors metabolism, Flow Cytometry, Humans, Immunoenzyme Techniques, In Situ Hybridization, Fluorescence, Peptide Fragments immunology, Prognosis, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Brain Stem Neoplasms genetics, ErbB Receptors genetics
- Abstract
Despite numerous clinical trials over the past 2 decades, the overall survival for children diagnosed with diffuse intrinsic pontine glioma (DIPG) remains 9-10 months. Radiation therapy is the only treatment with proven effect and novel therapies are needed. Epidermal growth factor receptor variant III (EGFRvIII) is the most common variant of the epidermal growth factor receptor and is expressed in many tumor types but is rarely found in normal tissue. A peptide vaccine targeting EGFRvIII is currently undergoing investigation in phase 3 clinical trials for the treatment of newly diagnosed glioblastoma (GBM), the tumor in which this variant receptor was first discovered. In this study, we evaluated EGFRvIII expression in pediatric DIPG samples using immunohistochemistry with a double affinity purified antibody raised against the EGFRvIII peptide. Staining of pediatric DIPG histological samples revealed expression in 4 of 9 cases and the pattern of staining was consistent with what has been seen in EGFRvIII transfected cells as well as GBMs from adult trials. In addition, analysis of tumor samples collected immediately post mortem and of DIPG cells in culture by RT-PCR, western blot analysis, and flow cytometry confirmed EGFRvIII expression. We were therefore able to detect EGFRvIII expression in 6 of 11 DIPG cases. These data suggest that EGFRvIII warrants investigation as a target for these deadly pediatric tumors.
- Published
- 2012
- Full Text
- View/download PDF
43. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors.
- Author
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Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PØ, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, and Weissman IL
- Subjects
- Antibodies immunology, CD47 Antigen genetics, Cell Division immunology, Flow Cytometry, Humans, Neoplasms pathology, Neoplasms therapy, Phagocytosis immunology, Prognosis, Survival Analysis, Antigens, Differentiation metabolism, CD47 Antigen immunology, Neoplasms immunology, RNA, Messenger genetics, Receptors, Immunologic metabolism
- Abstract
CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.
- Published
- 2012
- Full Text
- View/download PDF
44. Heterogeneous reallocation of presynaptic efficacy in recurrent excitatory circuits adapting to inactivity.
- Author
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Mitra A, Mitra SS, and Tsien RW
- Subjects
- Anesthetics, Local pharmacology, Animals, Animals, Newborn, Biophysical Phenomena, Colforsin pharmacology, Cyclin-Dependent Kinase 5 metabolism, Electric Stimulation, Excitatory Postsynaptic Potentials drug effects, Feedback, Physiological, Gene Expression Regulation drug effects, Hippocampus cytology, Nerve Fibers physiology, Nerve Net drug effects, Nerve Net physiology, Nerve Tissue Proteins metabolism, Organ Culture Techniques, Patch-Clamp Techniques, Presynaptic Terminals drug effects, Protein Kinase Inhibitors pharmacology, Purines pharmacology, Rats, Rats, Sprague-Dawley, Roscovitine, Synapses drug effects, Tetrodotoxin pharmacology, Adaptation, Physiological physiology, Excitatory Postsynaptic Potentials physiology, Neurons cytology, Presynaptic Terminals physiology, Synapses physiology
- Abstract
Recurrent excitatory circuits face extreme challenges in balancing efficacy and stability. We recorded from CA3 pyramidal neuron pairs in rat hippocampal slice cultures to characterize synaptic and circuit-level changes in recurrent synapses resulting from long-term inactivity. Chronic tetrodotoxin treatment greatly reduced the percentage of connected CA3-CA3 neurons, but enhanced the strength of the remaining connections; presynaptic release probability sharply increased, whereas quantal size was unaltered. Connectivity was decreased in activity-deprived circuits by functional silencing of synapses, whereas three-dimensional anatomical analysis revealed no change in spine or bouton density or aggregate dendrite length. The silencing arose from enhanced Cdk5 activity and could be reverted by acute Cdk5 inhibition with roscovitine. Our results suggest that recurrent circuits adapt to chronic inactivity by reallocating presynaptic weights heterogeneously, strengthening certain connections while silencing others. This restricts synaptic output and input, preserving signaling efficacy among a subset of neuronal ensembles while protecting network stability.
- Published
- 2011
- Full Text
- View/download PDF
45. Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma.
- Author
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Monje M, Mitra SS, Freret ME, Raveh TB, Kim J, Masek M, Attema JL, Li G, Haddix T, Edwards MS, Fisher PG, Weissman IL, Rowitch DH, Vogel H, Wong AJ, and Beachy PA
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors metabolism, Cell Aggregation, Cell Proliferation, Humans, Intermediate Filament Proteins metabolism, Mice, Nerve Tissue Proteins metabolism, Nestin, Oligodendrocyte Transcription Factor 2, Pons growth & development, Pons pathology, Signal Transduction, Time Factors, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Brain Stem Neoplasms metabolism, Brain Stem Neoplasms pathology, Cell Lineage, Hedgehog Proteins metabolism
- Abstract
Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG self-renewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor.
- Published
- 2011
- Full Text
- View/download PDF
46. The role of the c-Jun N-terminal kinase 2-α-isoform in non-small cell lung carcinoma tumorigenesis.
- Author
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Nitta RT, Del Vecchio CA, Chu AH, Mitra SS, Godwin AK, and Wong AJ
- Subjects
- Aged, Aged, 80 and over, Animals, Cell Line, Tumor, Female, Humans, Isoenzymes metabolism, Lung enzymology, Male, Mice, Mice, SCID, Middle Aged, Mitogen-Activated Protein Kinase 9 analysis, RNA, Small Interfering pharmacology, STAT3 Transcription Factor metabolism, Adenocarcinoma, Bronchiolo-Alveolar enzymology, Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Squamous Cell enzymology, Cell Transformation, Neoplastic metabolism, Lung Neoplasms enzymology, Mitogen-Activated Protein Kinase 9 metabolism
- Abstract
The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase family and have been implicated in tumorigenesis. One isoform in particular, JNK2α, has been shown to be frequently activated in primary brain tumors, to enhance several tumorigenic phenotypes and to increase tumor formation in mice. As JNK is frequently activated in non-small cell lung carcinoma (NSCLC), we investigated the role of the JNK2α isoform in NSCLC formation by examining its expression in primary tumors and by modulating its expression in cultured cell lines. We discovered that 60% of the tested primary NSCLC tumors had three-fold higher JNK2 protein and two- to three-fold higher JNK2α mRNA expression than normal lung control tissue. To determine the importance of JNK2α in NSCLC progression, we reduced JNK2α expression in multiple NSCLC cell lines using short hairpin RNA. Cell lines deficient in JNK2α had decreased cellular growth and anchorage-independent growth, and the tumors were four-fold smaller in mass. To elucidate the mechanism by which JNK2α induces NSCLC growth, we analyzed the JNK substrate, signal transducer and activator of transcription 3 (STAT3). Our data demonstrates for the first time that JNK2α can regulate the transcriptional activity of STAT3 by phosphorylating the Ser727 residue, thereby regulating the expression of oncogenic genes, such as c-Myc. Furthermore, reintroduction of JNK2α2 or STAT3 restored the tumorigenicity of the NSCLC cells, demonstrating that JNK2α is important for NSCLC progression. Our studies reveal a novel mechanism in which phosphorylation of STAT3 is mediated by a constitutively active JNK2 isoform, JNK2α.
- Published
- 2011
- Full Text
- View/download PDF
47. Highly variable acquisition rates of Ixodes scapularis (Acari: Ixodidae) by birds on an Atlantic barrier island.
- Author
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Mitra SS, Buckley PA, Buckley FG, and Ginsberg HS
- Subjects
- Animals, Atlantic Ocean, Bird Diseases epidemiology, Birds, Geography, Seasons, Tick Infestations epidemiology, Tick Infestations parasitology, Time Factors, Bird Diseases parasitology, Ixodes physiology, Tick Infestations veterinary
- Abstract
Acquisition of ticks by bird hosts is a central process in the transmission cycles of many tick-borne zoonoses, but tick recruitment by birds has received little direct study. We documented acquisition of Ixodes scapularis Say on birds at Fire Island, NY, by removing ticks from mist-netted birds, and recording the number of ticks on birds recaptured within 4 d of release. Eight bird species acquired at least 0.8 ticks bird(-1) day(-1) during the seasonal peak for at least one age class of I. scapularis. Gray Catbirds, Eastern Towhees, Common Yellowthroats, and Northern Waterthrushes collectively accounted for 83% of all tick acquisitions; and six individuals apportioned among Black-billed Cuckoo, Gray Catbird, Eastern Towhee, and Common Yellowthroat were simultaneously infested with both larvae and nymphs. Bird species with the highest acquisition rates were generally ground foragers, whereas birds that did not acquire ticks in our samples generally foraged above the ground. Tick acquisition by birds did not differ between deciduous and coniferous forests. Among the 15 bird species with the highest recruitment rates, acquisition of nymphs was not correlated with acquisition of larvae. Tick acquisition rates by individual bird species were not correlated with the reservoir competence of those species for Lyme borreliae. However, birds with high tick acquisition rates can contribute large numbers of infected ticks, and thus help maintain the enzootic cycle, even if their levels of reservoir competence are relatively low.
- Published
- 2010
- Full Text
- View/download PDF
48. Development of an EGFRvIII specific recombinant antibody.
- Author
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Gupta P, Han SY, Holgado-Madruga M, Mitra SS, Li G, Nitta RT, and Wong AJ
- Subjects
- Animals, Antibody Affinity, Cell Line, Tumor, Cross Reactions, Epitopes immunology, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Mutagenesis, Site-Directed, Neoplasms, Experimental immunology, Recombinant Proteins genetics, Single-Chain Antibodies genetics, Antibody Specificity, ErbB Receptors immunology, Recombinant Proteins biosynthesis, Single-Chain Antibodies biosynthesis
- Abstract
Background: EGF receptor variant III (EGFRvIII) is the most common variant of the EGF receptor observed in human tumors. It results from the in frame deletion of exons 2-7 and the generation of a novel glycine residue at the junction of exons 1 and 8. This novel juxtaposition of amino acids within the extra-cellular domain of the EGF receptor creates a tumor specific and immunogenic epitope. EGFRvIII expression has been seen in many tumor types including glioblastoma multiforme (GBM), breast adenocarcinoma, non-small cell lung carcinoma, ovarian adenocarcinoma and prostate cancer, but has been rarely observed in normal tissue. Because this variant is tumor specific and highly immunogenic, it can be used for both a diagnostic marker as well as a target for immunotherapy. Unfortunately many of the monoclonal and polyclonal antibodies directed against EGFRvIII have cross reactivity to wild type EGFR or other non-specific proteins. Furthermore, a monoclonal antibody to EGFRvIII is not readily available to the scientific community., Results: In this study, we have developed a recombinant antibody that is specific for EGFRvIII, has little cross reactivity for the wild type receptor, and which can be easily produced. We initially designed a recombinant antibody with two anti-EGFRvIII single chain Fv's linked together and a human IgG1 Fc component. To enhance the specificity of this antibody for EGFRvIII, we mutated tyrosine H59 of the CDRH2 domain and tyrosine H105 of the CDRH3 domain to phenylalanine for both the anti-EGFRvIII sequence inserts. This mutated recombinant antibody, called RAb(DMvIII), specifically detects EGFRvIII expression in EGFRvIII expressing cell lines as well as in EGFRvIII expressing GBM primary tissue by western blot, immunohistochemistry (IHC) and immunofluorescence (IF) and FACS analysis. It does not recognize wild type EGFR in any of these assays. The affinity of this antibody for EGFRvIII peptide is 1.7 × 10⁷ M⁻¹ as determined by enzyme-linked immunosorbent assay (ELISA)., Conclusion: This recombinant antibody thus holds great potential to be used as a research reagent and diagnostic tool in research laboratories and clinics because of its high quality, easy viability and unique versatility. This antibody is also a strong candidate to be investigated for further in vivo therapeutic studies.
- Published
- 2010
- Full Text
- View/download PDF
49. Erlotinib induced skin rash spares skin in previous radiotherapy field.
- Author
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Mitra SS and Simcock R
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma secondary, Adenocarcinoma surgery, Back, Brain Neoplasms radiotherapy, Brain Neoplasms secondary, Chemotherapy, Adjuvant, Drug Eruptions etiology, Erlotinib Hydrochloride, Humans, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Lung Neoplasms surgery, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Recurrence, Local therapy, Pneumonectomy, Protein Kinase Inhibitors adverse effects, Quinazolines administration & dosage, Radiotherapy, Adjuvant, Reoperation, Skin drug effects, Thoracic Wall, Adenocarcinoma radiotherapy, Brain Neoplasms drug therapy, Drug Eruptions prevention & control, Lung Neoplasms radiotherapy, Quinazolines adverse effects, Skin radiation effects
- Published
- 2006
- Full Text
- View/download PDF
50. Preparation, physicochemical characterization and drug release studies of albendazole solid dispersions.
- Author
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Mallick S, Sahoo A, and Mitra SS
- Subjects
- Albendazole chemistry, Chemical Phenomena, Chemistry, Physical, Delayed-Action Preparations, Kinetics, Microscopy, Electron, Scanning, Solubility, Spectroscopy, Fourier Transform Infrared, X-Ray Diffraction, Albendazole administration & dosage
- Abstract
Albendazole (ALB) solid dispersions were prepared by codissolvation and solvent evaporation technique using water soluble carrier such as polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP) to improve the aqueous solubility of the drug and thus enhancing its bioavailability. The physicochemical characteristics of these solid dispersions were performed by scanning electron microscopy (SEM), X-ray diffraction (XRD), fourier-transform infrared (FT-IR) spectroscopy and dissolution rate analyses. SEM was used to clarify the surface and shape characteristics of the different samples. All characteristic bands of albendazole are seen in the FT-IR spectra of solid dispersions. Basically no significant changes in the frequency and shape of albendazole were noticed which leads to the conclusion that no strong interaction between the drug and the polymer exists in the solid dispersion (SD) particles. The degree of crystallinity of ALB decreased and also differed with the SD of different polymers. Dissolution rate and percent dissolution efficiency were significantly increased in the solid dispersions in comparison with drug alone. The drug release kinetics was ascertained by using F-test statistics using kinetic models of zero order, first order, Higuchi and Hixson-Crowell. Albendazole formed solid dispersions with water soluble polymers like PVP and PEG and the dissolution rate of the drug in the SD system was faster when the ratio of polymer to drug was greater. First order model may be used for explaining the kinetics of drug release from all the SD formulations as suggested by F-test.
- Published
- 2003
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