272 results on '"Edwards CM"'
Search Results
2. Adipocyte autophagy limits gut inflammation by controlling oxylipin and <scp>IL‐10</scp>
- Author
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Richter, FC, Friedrich, M, Kampschulte, N, Piletic, K, Alsaleh, G, Zummach, R, Hecker, J, Pohin, M, Ilott, N, Guschina, I, Wideman, SK, Johnson, E, Borsa, M, Hahn, P, Morriseau, C, Hammock, BD, Schipper, HS, Edwards, CM, Zechner, R, Siegmund, B, Weidinger, C, Schebb, NH, Powrie, F, and Simon, AK
- Subjects
autophagy ,1.1 Normal biological development and functioning ,adipocyte ,oxylipin ,Medical and Health Sciences ,Oral and gastrointestinal ,General Biochemistry, Genetics and Molecular Biology ,Cytochrome P-450 Enzyme System ,Underpinning research ,Information and Computing Sciences ,Adipocytes ,Humans ,2.1 Biological and endogenous factors ,Oxylipins ,Obesity ,Aetiology ,Molecular Biology ,Metabolic and endocrine ,Nutrition ,Inflammation ,General Immunology and Microbiology ,Inflammatory and immune system ,General Neuroscience ,Fatty Acids ,Biological Sciences ,Interleukin-10 ,Cardiovascular and Metabolic Diseases ,IL-10 ,Nonesterified ,Developmental Biology - Abstract
Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte-specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti-inflammatory energy substrates. Instead, Atg7-deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2-mediated upregulation of Ephx1. This shift reduced secretion of IL-10 from adipose tissues, which was dependent on the cytochrome P450-EPHX pathway, and lowered circulating levels of IL-10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat-gut crosstalk through an autophagy-dependent regulation of anti-inflammatory oxylipins via the cytochrome P450-EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation.
- Published
- 2023
3. Multiple myeloma metabolism – a treasure trove of therapeutic targets?
- Author
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Roman-Trufero, M, Auner, HW, Edwards, CM, and Cancer Research UK
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KINASE GCN2 ,plasma cell ,Immunology ,Bone Marrow ,1108 Medical Microbiology ,Tumor Microenvironment ,Humans ,Immunology and Allergy ,BONE-MARROW MICROENVIRONMENT ,cancer biology ,Science & Technology ,proteostasis ,bone marrow (BM) adipocytes ,UNFOLDED PROTEIN RESPONSE ,SECRETORY APPARATUS ,ADIPOCYTES ,multiple myeloma ,proteasome ,MAMMALIAN TARGET ,PROTEASOME INHIBITION ,PLASMA-CELLS ,1107 Immunology ,B-CELLS ,AUTOPHAGY ,Proteasome Inhibitors ,Life Sciences & Biomedicine ,metabolism - Abstract
Multiple myeloma is an incurable cancer of plasma cells that is predominantly located in the bone marrow. Multiple myeloma cells are characterized by distinctive biological features that are intricately linked to their core function, the assembly and secretion of large amounts of antibodies, and their diverse interactions with the bone marrow microenvironment. Here, we provide a concise and introductory discussion of major metabolic hallmarks of plasma cells and myeloma cells, their roles in myeloma development and progression, and how they could be exploited for therapeutic purposes. We review the role of glucose consumption and catabolism, assess the dependency on glutamine to support key metabolic processes, and consider metabolic adaptations in drug-resistant myeloma cells. Finally, we examine the complex metabolic effects of proteasome inhibitors on myeloma cells and the extracellular matrix, and we explore the complex relationship between myeloma cells and bone marrow adipocytes.
- Published
- 2022
4. The antidiabetic drug metformin acts on the bone microenvironment to promote myeloma cell adhesion to preosteoblasts and increase myeloma tumour burden in vivo
- Author
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Gamez, B, Morris, E, Olechnowicz, SWZ, Webb, S, Edwards, JR, Sowman, A, Turner, CJ, Edwards, CM, Gamez, B, Morris, E, Olechnowicz, SWZ, Webb, S, Edwards, JR, Sowman, A, Turner, CJ, and Edwards, CM
- Abstract
Multiple myeloma is a haematological malignancy that is dependent upon interactions within the bone microenvironment to drive tumour growth and osteolytic bone disease. Metformin is an anti-diabetic drug that has attracted attention due to its direct antitumor effects, including anti-myeloma properties. However, the impact of the bone microenvironment on the response to metformin in myeloma is unknown. We have employed in vitro and in vivo models to dissect out the direct effects of metformin in bone and the subsequent indirect myeloma response. We demonstrate how metformin treatment of preosteoblasts increases myeloma cell attachment. Metformin-treated preosteoblasts increased osteopontin (OPN) expression that upon silencing, reduced subsequent myeloma cell adherence. Proliferation markers were reduced in myeloma cells cocultured with metformin-treated preosteoblasts. In vivo, mice were treated with metformin for 4 weeks prior to inoculation of 5TGM1 myeloma cells. Metformin-pretreated mice had an increase in tumour burden, associated with an increase in osteolytic bone lesions and elevated OPN expression in the bone marrow. Collectively, we show that metformin increases OPN expression in preosteoblasts, increasing myeloma cell adherence. In vivo, this translates to an unexpected indirect pro-tumourigenic effect of metformin, highlighting the importance of the interdependence between myeloma cells and cells of the bone microenvironment.
- Published
- 2022
5. Cell-extrinsic autophagy in mature adipocytes regulates anti-inflammatory response to intestinal tissue injury through lipid mobilization
- Author
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Richter, FC, Friedrich, M, Pohin, M, Alsaleh, G, Guschina, I, Wideman, SK, Johnson, E, Borsa, M, Piletic, K, Hahn, P, Schipper, HS, Edwards, CM, Powrie, F, and Simon, AK
- Abstract
Autophagy is a critical cellular recycling pathway which is genetically linked to the development of intestinal inflammation in humans. Inflammation drives adipose tissue breakdown and provision of major nutrients such as free fatty acids (FFA). However, the effect of autophagy-mediated FFA release by adipocytes in immune-mediated inflammatory diseases remains unexplored. In a mouse model of intestinal inflammation, we found that visceral adipocytes upregulate autophagy at peak inflammation. Adipocyte-specific loss of the key autophagy gene Atg7 (Atg7Ad) resulted in the exacerbation of intestinal inflammation. TNFα-induced lipolysis was impaired in Atg7-deficient adipocytes leading to the reduced availability of several FFA species, and decreased expression of the FFA transporter CD36 on adipose tissue macrophages (ATMs). Visceral adipose tissues from Atg7Ad mice released less IL-10 resulting in lower levels of circulating IL-10 in colitis. ATMs present the main source of adipose tissue-derived IL-10 during colitis. In vitro assays confirmed that FFA restriction from macrophages reduced CD36 expression and diminished IL-10 production. Taken together, our study demonstrates that autophagy-mediated FFA release from adipocytes directs anti-inflammatory responses in ATMs, which in turn conveys protective effects for distant intestinal inflammation.
- Published
- 2021
6. Myeloma and marrow adiposity: Unanswered questions and future directions
- Author
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Morris, EV and Edwards, CM
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0301 basic medicine ,Cell type ,Bone disease ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,03 medical and health sciences ,Paracrine signalling ,0302 clinical medicine ,Endocrinology ,Bone Marrow ,Bone cell ,medicine ,Tumor Microenvironment ,Humans ,Obesity ,Bone pain ,Multiple myeloma ,Adiposity ,business.industry ,Osteoblast ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,Bone marrow ,medicine.symptom ,Neoplasm Recurrence, Local ,business ,Multiple Myeloma - Abstract
Multiple myeloma (MM) is a haematological malignancy characterised by the proliferation and accumulation of terminally differentiated abnormal plasma cells in the bone marrow. Patients suffer from bone pain, factures, anaemia, osteolytic lesions and renal failure. Despite recent advancement in therapy MM remains an incurable disease due to the emergences of drug resistance and frequent relapse. For many decades, research has been heavily focused on understanding the relationship between bone cells such as osteoblast, osteocytes and osteoclasts and the infiltrating tumour cells. However, it is now clear that the tumour-supportive bone microenvironment including cellular and non-cellular components play an important role in driving MM progression and bone disease. One of the most abundant cell types in the bone microenvironment is the bone marrow adipocyte (BMAd). Once thought of as inert space filling cells, they have now been recognised as having specialised functions, signalling in an autocrine, paracrine and endocrine manner to support normal systemic homeostasis. BMAds are both an energy store and a source of secreted adipokines and bioactive substances, MM cells are able to hijack this metabolic machinery to fuel migration, growth and survival. With global obesity on the rise, it has never been more important to further understand the contribution these cells have in both normal and disease settings. The aim of this review is to summarise the large body of emerging evidence supporting the interplay between BMAds and MM cells and to delineate how they fit into the vicious cycle of disease.
- Published
- 2021
7. Ten new insights in climate science 2020-a horizon scan
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Pihl, E, Alfredsson, E, Bengtsson, M, Bowen, KJ, Broto, VC, Chou, KT, Cleugh, H, Ebi, K, Edwards, CM, Fisher, E, Friedlingstein, P, Godoy-Faundez, A, Gupta, M, Harrington, AR, Hayes, K, Hayward, BM, Hebden, SR, Hickmann, T, Hugelius, G, Ilyina, T, Jackson, RB, Keenan, TF, Lambino, RA, Leuzinger, S, Malmaeus, M, McDonald, R, McMichael, C, Miller, CA, Muratori, M, Nagabhatla, N, Nagendra, H, Passarello, C, Penuelas, J, Pongratz, J, Rockstrom, J, Romero-Lankao, P, Roy, J, Scaife, AA, Schlosser, P, Schuur, E, Scobie, M, Sherwood, SC, Sioen, GB, Skovgaard, J, Obregon, EAS, Sonntag, S, Spangenberg, JH, Spijkers, O, Srivastava, L, Stammer, DB, Torres, PHC, Turetsky, MR, Ukkola, AM, van Vuuren, DP, Voigt, C, Wannous, C, Zelinka, MD, Pihl, E, Alfredsson, E, Bengtsson, M, Bowen, KJ, Broto, VC, Chou, KT, Cleugh, H, Ebi, K, Edwards, CM, Fisher, E, Friedlingstein, P, Godoy-Faundez, A, Gupta, M, Harrington, AR, Hayes, K, Hayward, BM, Hebden, SR, Hickmann, T, Hugelius, G, Ilyina, T, Jackson, RB, Keenan, TF, Lambino, RA, Leuzinger, S, Malmaeus, M, McDonald, R, McMichael, C, Miller, CA, Muratori, M, Nagabhatla, N, Nagendra, H, Passarello, C, Penuelas, J, Pongratz, J, Rockstrom, J, Romero-Lankao, P, Roy, J, Scaife, AA, Schlosser, P, Schuur, E, Scobie, M, Sherwood, SC, Sioen, GB, Skovgaard, J, Obregon, EAS, Sonntag, S, Spangenberg, JH, Spijkers, O, Srivastava, L, Stammer, DB, Torres, PHC, Turetsky, MR, Ukkola, AM, van Vuuren, DP, Voigt, C, Wannous, C, and Zelinka, MD
- Abstract
Non-technical summary We summarize some of the past year's most important findings within climate change-related research. New research has improved our understanding of Earth's sensitivity to carbon dioxide, finds that permafrost thaw could release more carbon emissions than expected and that the uptake of carbon in tropical ecosystems is weakening. Adverse impacts on human society include increasing water shortages and impacts on mental health. Options for solutions emerge from rethinking economic models, rights-based litigation, strengthened governance systems and a new social contract. The disruption caused by COVID-19 could be seized as an opportunity for positive change, directing economic stimulus towards sustainable investments. Technical summary A synthesis is made of ten fields within climate science where there have been significant advances since mid-2019, through an expert elicitation process with broad disciplinary scope. Findings include: (1) a better understanding of equilibrium climate sensitivity; (2) abrupt thaw as an accelerator of carbon release from permafrost; (3) changes to global and regional land carbon sinks; (4) impacts of climate change on water crises, including equity perspectives; (5) adverse effects on mental health from climate change; (6) immediate effects on climate of the COVID-19 pandemic and requirements for recovery packages to deliver on the Paris Agreement; (7) suggested long-term changes to governance and a social contract to address climate change, learning from the current pandemic, (8) updated positive cost–benefit ratio and new perspectives on the potential for green growth in the short- and long-term perspective; (9) urban electrification as a strategy to move towards low-carbon energy systems and (10) rights-based litigation as an increasingly important method to address climate change, with recent clarifications on the legal standing and representation of future generations. Social media summary Stronger permafrost t
- Published
- 2021
8. Ten new insights in climate science 2021: a horizon scan
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Martin, MA, Alcaraz Sendra, O, Bastos, A, Bauer, N, Bertram, C, Blenckner, T, Bowen, K, Brando, PM, Rudolph, TB, Buchs, M, Bustamante, M, Chen, D, Cleugh, H, Dasgupta, P, Denton, F, Donges, JF, Donkor, FK, Duan, H, Duarte, CM, Ebi, KL, Edwards, CM, Engel, A, Fisher, E, Fuss, S, Gaertner, J, Gettelman, A, Girardin, CAJ, Golledge, NR, Green, JF, Grose, MR, Hashizume, M, Hebden, S, Hepach, H, Hirota, M, Hsu, H-H, Kojima, S, Lele, S, Lorek, S, Lotze, HK, Matthews, HD, McCauley, D, Mebratu, D, Mengis, N, Nolan, RH, Pihl, E, Rahmstorf, S, Redman, A, Reid, CE, Rockstrom, J, Rogelj, J, Saunois, M, Sayer, L, Schlosser, P, Sioen, GB, Spangenberg, JH, Stammer, D, Sterner, TNS, Stevens, N, Thonicke, K, Tian, H, Winkelmann, R, Woodcock, J, Martin, MA, Alcaraz Sendra, O, Bastos, A, Bauer, N, Bertram, C, Blenckner, T, Bowen, K, Brando, PM, Rudolph, TB, Buchs, M, Bustamante, M, Chen, D, Cleugh, H, Dasgupta, P, Denton, F, Donges, JF, Donkor, FK, Duan, H, Duarte, CM, Ebi, KL, Edwards, CM, Engel, A, Fisher, E, Fuss, S, Gaertner, J, Gettelman, A, Girardin, CAJ, Golledge, NR, Green, JF, Grose, MR, Hashizume, M, Hebden, S, Hepach, H, Hirota, M, Hsu, H-H, Kojima, S, Lele, S, Lorek, S, Lotze, HK, Matthews, HD, McCauley, D, Mebratu, D, Mengis, N, Nolan, RH, Pihl, E, Rahmstorf, S, Redman, A, Reid, CE, Rockstrom, J, Rogelj, J, Saunois, M, Sayer, L, Schlosser, P, Sioen, GB, Spangenberg, JH, Stammer, D, Sterner, TNS, Stevens, N, Thonicke, K, Tian, H, Winkelmann, R, and Woodcock, J
- Abstract
Non-technical summary We summarize some of the past year's most important findings within climate change-related research. New research has improved our understanding about the remaining options to achieve the Paris Agreement goals, through overcoming political barriers to carbon pricing, taking into account non-CO2factors, a well-designed implementation of demand-side and nature-based solutions, resilience building of ecosystems and the recognition that climate change mitigation costs can be justified by benefits to the health of humans and nature alone. We consider new insights about what to expect if we fail to include a new dimension of fire extremes and the prospect of cascading climate tipping elements. Technical summary A synthesis is made of 10 topics within climate research, where there have been significant advances since January 2020. The insights are based on input from an international open call with broad disciplinary scope. Findings include: (1) the options to still keep global warming below 1.5 °C; (2) the impact of non-CO2factors in global warming; (3) a new dimension of fire extremes forced by climate change; (4) the increasing pressure on interconnected climate tipping elements; (5) the dimensions of climate justice; (6) political challenges impeding the effectiveness of carbon pricing; (7) demand-side solutions as vehicles of climate mitigation; (8) the potentials and caveats of nature-based solutions; (9) how building resilience of marine ecosystems is possible; and (10) that the costs of climate change mitigation policies can be more than justified by the benefits to the health of humans and nature. Social media summary How do we limit global warming to 1.5 °C and why is it crucial? See highlights of latest climate science.
- Published
- 2021
9. Editorial – Cancer and Bone special issue
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Edwards, CM and Drake, MT
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Histology ,Physiology ,Neoplasms ,Endocrinology, Diabetes and Metabolism ,Humans ,Bone and Bones - Published
- 2022
10. The Easter and Passover Blip in New York City: How exceptions can cause detrimental effects in pandemic times
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Maximilian Vierlboeck, Roshanak Nilchiani, and Edwards Cm
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General observation ,History ,Coronavirus disease 2019 (COVID-19) ,Pandemic ,Demographic economics ,Infection rate - Abstract
and Executive SummaryWhen it comes to pandemics such as the currently present COVID-19 [1], various issues and problems arise for infrastructures and institutions. Due to possible extreme effects, such as hospitals potentially running out of beds or medical equipment, it is essential to lower the infection rate to create enough space to attend to the affected people and allow enough time for a vaccine to be developed. Unfortunately, this requires that measures put into place are upheld long enough to reduce the infection rate sufficiently.In this paper, we describe research simulating the influences of the contact rate on the spread of the pandemic using New York City as an example (Section IV) and especially already observed effects of contact rate increases during holidays [2-4] (Section V). In multiple simulations scenarios for Passover and Easter holidays, we evaluated 25%, 50%, 75%, and 100% temporary increases in contact rates using a scenario close to the currently reported numbers as reference and contact rates based on bioterrorism research as a “normal” baseline for NYC.The first general finding from the simulations is that singular events of increased visits/contacts amplify each other disproportionately if they are happening in close proximity (time intervals) together. The second general observation was that contact rate spikes leave a permanently increased and devastating infection rate behind, even after the contact rate returns to the reduced one. In case of a temporary sustained increase of contact rate for just three days in a row, the aftermath results in an increase of infection rate up to 40%, which causes double the fatalities in the long run.In numbers, given that increases of 25% and 50% seem to be most likely given the data seen in Germany for the Easter weekend for example [2, 3], our simulations show the following increases (compared to the realistic reference run): for a temporary 25% surge in contact rate, the total cases grew by 215,880, the maximum of required hospitalizations over time increased to 63,063, and the total fatalities climbed by 8,844 accumulated over 90 days. As for the 50% surge, we saw the total number of cases rise by 461,090, the maximum number of required hospitalizations increase to 79,733, and the total number of fatalities climb by 19,125 over 90 days in NYC.All in all, we conclude that even very short, temporary increases in contact rates can have disproportionate effects and result in unrecoverable phenomena that can hardly be reversed or managed later. The numbers show possible phenomena before they might develop effects in reality. This is important because phenomena such as the described blip can impact the hospitals in reality. Therefore, we warn that a wave of infections due to increased contact rates during Passover/Easter might come as a result!
- Published
- 2020
11. Modeling the Human Bone–Tumor Niche: Reducing and Replacing the Need for Animal Data
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Rao, SR, Edwards, CM, and Edwards, JR
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Bone disease ,Endocrinology, Diabetes and Metabolism ,Computational biology ,Review ,Diseases of the musculoskeletal system ,Biology ,Bone remodeling ,03 medical and health sciences ,Animal data ,0302 clinical medicine ,TUMOR‐INDUCED BONE DISEASE ,In vivo ,medicine ,Orthopedics and Sports Medicine ,Animal testing ,030304 developmental biology ,Bone mineral ,Orthopedic surgery ,0303 health sciences ,Cancer ,medicine.disease ,BONE MODELING ,CANCER ,BONE REMODELING ,RC925-935 ,030220 oncology & carcinogenesis ,ANIMAL MODELS ,Cancer cell ,RD701-811 - Abstract
Bone is the most common site for cancer metastasis. Understanding the interactions within the complex, heterogeneous bone–tumor microenvironment is essential for the development of new therapeutics. Various animal models of tumor‐induced bone disease are routinely used to provide valuable information on the relationship between cancer cells and the skeleton. However, new model systems exist that offer an alternative approach to the use of animals and might more accurately reveal the cellular interactions occurring within the human bone–tumor niche. This review highlights replacement models that mimic the bone microenvironment and where cancer metastases and tumor growth might be assessed alongside bone turnover. Such culture models include the use of calcified regions of animal tissue and scaffolds made from bone mineral hydroxyapatite, synthetic polymers that can be manipulated during manufacture to create structures resembling trabecular bone surfaces, gel composites that can be modified for stiffness and porosity to resemble conditions in the tumor–bone microenvironment. Possibly the most accurate model system involves the use of fresh human bone samples, which can be cultured ex vivo in the presence of human tumor cells and demonstrate similar cancer cell–bone cell interactions as described in vivo. In addition, the use of mathematical modeling and computational biology approaches provide an alternative to preliminary animal testing. The use of such models offers the capacity to mimic significant elements of the human bone–tumor environment, and complement, refine, or replace the use of preclinical models. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
- Published
- 2020
12. Interferon-Induced Sarcoidosis Presenting as Hypercalcemia without Apparent Organ Involvement.
- Author
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McCauley, MM, primary and Edwards, CM, additional
- Published
- 2010
- Full Text
- View/download PDF
13. Small Animal Video Tracking for Activity and Path Analysis Using a Novel Open-Source Multi-Platform Application (AnimApp)
- Author
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Rao, SR, Olechnowicz, SWZ, Kratschmer, P, Jepson, JEC, Edwards, CM, Edwards, JR, Rao, SR, Olechnowicz, SWZ, Kratschmer, P, Jepson, JEC, Edwards, CM, and Edwards, JR
- Abstract
Experimental biological model system outcomes such as altered animal movement capability or behaviour are difficult to quantify manually. Existing automatic movement tracking devices can be expensive and imposing upon the typical environment of the animal model. We have developed a novel multiplatform, free-to-use open-source application based on OpenCV, called AnimApp. Our results show that AnimApp can reliably and reproducibly track movement of small animals such as rodents or insects, and quantify parameters of action including distance and speed in order to detect activity changes arising from handling, environment enrichment, or temperature alteration. This system offers an accurate and reproducible experimental approach with potential for simple, fast and flexible analysis of movement and behaviour in a wide range of model systems.
- Published
- 2019
14. Transcriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease
- Author
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Gooding, S, Olechnowicz, SWZ, Morris, E, Armitage, AE, Arezes, J, Frost, J, Repapi, E, Edwards, JR, Ashley, N, Waugh, C, Gray, N, Martinez-Hackert, E, Lim, PJ, Pasricha, S-R, Knowles, H, Mead, AJ, Ramasamy, K, Drakesmith, H, Edwards, CM, Gooding, S, Olechnowicz, SWZ, Morris, E, Armitage, AE, Arezes, J, Frost, J, Repapi, E, Edwards, JR, Ashley, N, Waugh, C, Gray, N, Martinez-Hackert, E, Lim, PJ, Pasricha, S-R, Knowles, H, Mead, AJ, Ramasamy, K, Drakesmith, H, and Edwards, CM
- Abstract
Multiple myeloma is an incurable, bone marrow-dwelling malignancy that disrupts bone homeostasis causing skeletal damage and pain. Mechanisms underlying myeloma-induced bone destruction are poorly understood and current therapies do not restore lost bone mass. Using transcriptomic profiling of isolated bone lining cell subtypes from a murine myeloma model, we find that bone morphogenetic protein (BMP) signalling is upregulated in stromal progenitor cells. BMP signalling has not previously been reported to be dysregulated in myeloma bone disease. Inhibition of BMP signalling in vivo using either a small molecule BMP receptor antagonist or a solubilized BMPR1a-FC receptor ligand trap prevents trabecular and cortical bone volume loss caused by myeloma, without increasing tumour burden. BMP inhibition directly reduces osteoclastogenesis, increases osteoblasts and bone formation, and suppresses bone marrow sclerostin levels. In summary we describe a novel role for the BMP pathway in myeloma-induced bone disease that can be therapeutically targeted.
- Published
- 2019
15. Osteoblasts protect multiple myeloma cells from T-cell-induced apoptosis
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Locklin, RM, Russell, RGG, Croucher, PI, and Edwards, CM
- Published
- 2016
16. The ubiquitin-proteasome pathway is dysregulated in myeloma cells in the bone microenvironment in vivo
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Edwards, CM, Fowler, JA, Caldwell, RL, Bates, AL, Edwards, JR, Zhang, J, Foehr, DE, Parker, R, Roberts, A, and Mundy, GR
- Published
- 2016
17. Lithium inhibits the development of myeloma bone disease in vivo
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Edwards, CM, Edwards, JR, Esparza, J, Oyajobi, BO, McCluskey, B, Munoz, S, Grubbs, B, and Mundy, GR
- Published
- 2016
18. Blocking TGF beta Signaling Reduces Gammopathy and Improves Bone Volume and Strength In Vivo
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Hart, AJ, Fowler, JA, Lwin, ST, Munoz, SA, O'Quinn, EC, Nyman, JS, Edwards, CM, and Mundy, GR
- Published
- 2016
19. The role of microRNAs in functional osteomimicry in prostate cancer cells
- Author
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Rao, SR, Hamdy, FC, and Edwards, CM
- Published
- 2016
20. Decoherence in pre-symmetric spaces
- Author
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Edwards, CM and Hugli, RV
- Abstract
Pre-symmetric complex Banach spaces have been proposed as models for state spaces of physical systems. A structural projection on a pre-symmetric space At represents an operation on the corresponding system, and has as its range a further pre-symmetric space which represents the state space of the resulting system and symmetries of the system are represented by elements of the group Aut(A*) of linear isometries of A*. Two structural projections R and S on the pre-symmetric space A, represent decoherent operations when their ranges axe rigidly collinear. It is shown that, for decoherent elements x and y of A*, there exists an involutive element φ* in Aut(A*) which conjugates the structural projections corresponding to x and y, and conditions are found for φ*, to exchange x and y. The results are used to investigate when certain subspaces of A* are the ranges of contractive projections and, therefore, represent systems arising from filtering operations.
- Published
- 2016
21. Sulforaphane - A new therapy for mutliple myeloma?
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Locklin, RM, Hulley, PA, Russell, RGG, and Edwards, CM
- Published
- 2016
22. The Bone Marrow Microenvironment in Multiple Myeloma
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Edwards, CM
- Published
- 2016
23. Zoledronic Acid Inhibits the Capacity of Myeloid-Immune Suppressor Cells in Myeloma to Form Osteoclasts
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Zhuang, J, Edwards, CM, Zhang, J, Lwin, ST, and Mundy, GR
- Published
- 2016
24. Host Bone Marrow-Derived Stromal Cells Promote Myeloma Initiation and Development of Osteolysis
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Fowler, JA, Mundy, GR, Lwin, ST, and Edwards, CM
- Published
- 2016
25. Histone deacetylase 1 (HDAC1) regulates dickkopf 1 (DKK1) expression: Implications for myeloma bone disease
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Wideman, C, Gupta, A, Sterling, J, Edwards, CM, Zhao, M, Harris, SE, Mundy, GR, Garrett, IR, and Oyajobi, BO
- Published
- 2016
26. American Indians with HIV/AIDS: Health and Social Service Needs, Barriers to Care, and Staisfaction with Services Among A Western Tribe
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Iralu J, Graham Ahmed Edwards Cm, Bulterys M, Harrison M, Bonnie Duran, and Edwards A
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Adult ,Male ,Social Work ,History ,medicine.medical_specialty ,HIV Infections ,Education ,Limited access ,Nursing ,Acquired immunodeficiency syndrome (AIDS) ,Health care ,Tribe ,Humans ,Medicine ,General Psychology ,Acquired Immunodeficiency Syndrome ,Health Services Needs and Demand ,Social work ,business.industry ,medicine.disease ,Clothing ,Mental health ,Psychiatry and Mental health ,Anthropology ,Family medicine ,Indians, North American ,Rural area ,business ,Attitude to Health ,Delivery of Health Care - Abstract
This study investigated the health care and social service needs, barriers to care and satisfaction with services among American Indians with HIV/AIDS in a western tribe. Individual interviews were conducted with 28 respondents, which constituted nearly the entire population obtaining HIV/AIDS medical services from the IHS in the target area. The survey found that expressed need for services in this frontier rural area were lower than urban counterparts, but that access to needed services was lower. Common unmet medical needs include mental health services, eye and dental care, traditional Native medicine, and substance abuse treatment. Common unmet social service needs include housing assistance, help obtaining food and clothing, and transportation. Limited access to essential services impedes the ability of American Indians with HIV/AIDS to maintain effective medical regimens.
- Published
- 2000
27. Myeloma cells decrease EphB4 expression in osteoblasts; A novel mechanism for regulation of bone formation in multiple myeloma
- Author
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Bates, AL, Mundy, GR, and Edwards, CM
- Published
- 2007
28. The effect of the orexins on food intake: comparison with neuropeptide Y, melanin-concentrating hormone and galanin
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Edwards, CM, primary, Abusnana, S, additional, Sunter, D, additional, Murphy, KG, additional, Ghatei, MA, additional, and Bloom, SR, additional
- Published
- 1999
- Full Text
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29. Cardiovascular and pancreatic endocrine responses to glucagon-like peptide-1(7-36) amide in the conscious calf
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Edwards, CM, primary, Edwards, AV, additional, and Bloom, SR, additional
- Published
- 1997
- Full Text
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30. Clot formation and gelatin-based plasma substitutes
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Mardel, SN, primary, Saunders, FM, additional, Edwards, CM, additional, and Baddeley, DT, additional
- Published
- 1996
- Full Text
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31. Anti-thrombotic effects of novel fluoro-surfactants
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Edwards, CM., primary, Lowe, K. C., additional, Lucas, P., additional, Trabelsi, N., additional, and Cambon, A., additional
- Published
- 1996
- Full Text
- View/download PDF
32. Should azathioprine and 5-aminosalicylates be coprescribed in inflammatory bowel disease?: an audit of adverse events and outcome.
- Author
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Shah JA, Edwards CM, and Probert CS
- Published
- 2008
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33. Evaluation of a tool to benchmark hospital antibiotic prescribing in the United Kingdom.
- Author
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Fitzpatrick RW and Edwards CM
- Abstract
Abstract  Objective: To investigate whether Defined Daily Dose/Finished Consultant Episode (DDD/FCE) ratio is sensitive to changes in prescribing patterns and could be used as a prescribing indicator in hospitals. Method: The study comprised two phases. In phase 1 the weekly DDD/FCE ratios for two antibiotics were calculated and monitored in one acute NHS hospital before and after the implementation of prescribing guidelines, which impacted on the use of the antibiotics. In phase 2 data on the use of four antibiotics over one year was collected from fifty-eight medium to large acute hospitals in England, together with corresponding FCE data. DDD/FCE ratios for each antibiotic in each hospital were compared. Main Outcome measure: Whether the DDD/FCE ratio for two antibiotics changed in one hospital following the introduction of prescribing guidelines for these antibiotics. The variability in DDD/FCE ratio for two broad spectrum antibiotics compared to two narrow spectrum antibiotics across a number of acute hospitals in England. Results: In phase 1 the DDD/FCE ratios for the two antibiotics were lower post implementation of the guidelines indicating that the ratio was sensitive to changes in prescribing. In phase 2 the median DDD/FCE ratios of the two broad spectrum antibiotics from all fifty eight hospitals were much higher (0.126, and 0.265) than for the two narrow spectrum antibiotics (0.048, and 0.021), indicating higher use of the broad spectrum antibiotics. Furthermore, the variation in prescribing between the hospitals, as indicated by the inter-quartile range about the median, was greater for the two broad spectrum agents (0.201 and 0.193), than for the narrow spectrum agents (0.06, and 0.042), as was expected. Conclusion: The DDD/FCE ratio is sensitive to changes in prescribing and can reflect differences in the use of antibiotics between hospitals, after accounting for differences in activity. DDD/FCE ratio has the potential to be used to also account for differences in case mix between hospitals although further work is needed in this area. [ABSTRACT FROM AUTHOR]
- Published
- 2008
34. A randomised four-intervention crossover study investigating the effect of carbohydrates on daytime profiles of insulin, glucose, non-esterified fatty acids and triacylglycerols in middle-aged men.
- Author
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Brynes AE, Edwards CM, Ghatei MA, Dornhorst A, Morgan LM, Bloom SR, and Frost GS
- Published
- 2003
- Full Text
- View/download PDF
35. Arginine vasopressin--a mediator of chemotherapy induced emesis?
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Edwards, CM, Carmichael, J, Baylis, PH, Harris, AL, Edwards, C M, Baylis, P H, and Harris, A L
- Published
- 1989
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36. Quantum diffusion of vacancies and impurities in solid hydrogen
- Author
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Sullivan Ns, D. Zhou, and Edwards Cm
- Subjects
Nuclear relaxation ,Materials science ,Condensed matter physics ,Hydrogen ,chemistry ,Proton ,Impurity ,Solid hydrogen ,Diffusion ,Vacancy defect ,General Physics and Astronomy ,chemistry.chemical_element ,Quantum diffusion - Published
- 1989
37. Sexual hybrids of : biochemical, cytological and pharmacological characterization.
- Author
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Brown, AMG, Edwards, CM, Hartman, TPB, Marshall, JA, Smith, RM, Davey, MR, Power, JB, and Lowe, KC
- Subjects
- *
TANACETUM , *PLANT breeding , *FEVERFEW , *TANACETUM vulgare , *SPECIES hybridization - Abstract
Studies novel sexual hybrids produced between the species Tanacentum parthenium (L.) Schultz-Bip. (feverfew) and T. vulgare (L.) Schultz-Bip. (tansy). Alignment of the F[sub 1] hybrids to feverfew than to tansy; Similarity in the glandular trichome morphology and density between F[sub 1] hybrids and feverfew; Presence of bioactive germacronolide progenitors.
- Published
- 1999
38. Galactose stimulation of carbon import into roots is confined to the Poaceae.
- Author
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Thorpe, MR, Thorpe, M.R., MacRae, EA, MacRae, E.A., Minchin, MEH, Minchin, P.E.H., Edwards, CM, and Edwards, C.M.
- Subjects
EFFECT of galactose on plants ,BARLEY ,CARBON - Abstract
Investigates the effect of galactose in the promotion of carbon import into the barley roots. Transient increase in carbon import in roots; Effect of the D-galactono-1,4-lactone to barley roots; Mechanism of root elongation and carbon import in the cell.
- Published
- 1999
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39. The role of metabolism in prostate cancer progression and bone metastases
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Whitburn, J, Edwards, CM, Rao, SR, and Hamdy, FC
- Subjects
Prostate Cancer ,Bone Metastases ,Cancer Metabolism - Abstract
Prostate cancer (PCa) is the most common cancer in males in the Western world, and whilst treatment of localised disease is very effective, bone metastatic disease remains incurable and overall survival is only around 2-3 years. In view of this there is a need to identify novel therapeutics. Dysregulated cellular energetics is one of the new hallmarks of cancer, however the changes in cancer metabolism that occur when cancer metastasises remain relatively unexplored. The aim of this project was to identify the changes in PCa metabolism when it metastasises to the bone microenvironment, with the hope of identifying novel targets for advanced PCa therapeutics. Using a combination of in vitro metabolomic profiling of PCa/bone cell co-cultures, an in vivo mouse model of PCa bone disease and in silico analyses of patient data sets it was established that the bone metastatic site causes alterations in several metabolic pathways in PCa cells, including up-regulation of oxidative phosphorylation, the tricarboxylic acid cycle, and the pentose phosphate pathway (PPP). The PPP alterations were of interest as this pathway provides nucleotide precursors necessary for cellular proliferation, and is the main cellular source of NADPH, which is vital in cellular detoxification of potentially harmful free radicals. PPP enzymes were found to be more highly expressed in bone metastatic PCa cell lines compared to benign or non-bone metastatic cell lines, and expression of its rate limiting enzyme glucose-6-phosphate-dehydrogenase (G6PD) could be up-regulated by bone marrow stromal cells (BMSCs), suggesting that the bone microenvironment is driving this effect. In multiple patient data sets G6PD mRNA expression was elevated in metastatic samples, particularly bone metastatic samples, and expression was higher in castration resistant prostate cancer samples compared to hormone dependent. BMSCs were found to secrete high levels of interleukin-6 (IL-6), and blocking IL-6 was able to in part abrogate the up-regulation of G6PD, whilst recombinant IL-6 could induce G6PD up-regulation. BMSCs increased reactive oxygen species (ROS) in PCa cells and reduced the viability of non-bone metastatic cell lines. This was evident in vitro and in a xenograft mouse model. Pharmacological inhibition of G6PD further increased ROS levels, suggesting PCa up-regulates G6PD to counteract the high ROS induced by BMSCs. Pharmacological or genetic blockade of G6PD in PCa cells reduced their proliferation, inhibited cell migration, reduced expression of mesenchymal markers, decreased antioxidant levels, increased ROS levels, and increased sensitivity to chemotherapy. Overexpression of G6PD promoted PCa cell proliferation and increased antioxidant levels. In vivo, knockdown of G6PD expression in PCa cells could reduce tumour burden within bone. This work demonstrates for the first time that stromal cells of the metastatic environment drive changes in the metabolism of cancer cells that can promote their anti-oxidant abilities and increase their resistance to chemotherapy. Pharmacological targeting of the PPP pathway could be a novel approach to improve the efficacy of currently used treatments.
- Published
- 2020
40. Novel signalling pathways regulating epithelial-mesenchymal transition in bone metastatic prostate cancer
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Rao, SR, Edwards, CM, and Hamdy, FC
- Subjects
Tumours ,Oncology ,Biology (medical sciences) - Abstract
Prostate cancer (PCa) cells predominantly metastasize to bone and the complex crosstalk between PCa cells and osteoblasts (bone-forming cells) and osteoclasts (bone-destroying cells) leads to increased tumour growth and worsening of bone disease. Understanding the mechanisms of PCa bone metastasis can identify the aggressive fraction of PCa resulting in earlier intervention. The ability of PCa cells to express bone cell-specific features, termed osteomimicry, could potentially explain the osteotropic nature of PCa cells. The aim of this study was to determine the role of osteomimicry in the regulation of epithelial-mesenchymal transition (EMT) in bone metastatic prostate cancer cells. It was demonstrated that the osteoblast-specific marker alkaline phosphatase (bone/liver/kidney) (ALPL) was overexpressed in bone metastatic (ARCaPM), compared to non-metastatic (ARCaPE), human PCa cells. Knockdown of ALPL resulted in decreased cell viability, increased cell death and a change from mesenchymal to epithelial morphology in ARCaPM and PC3 cells, and increased CDH1 expression along with decreased migration in ARCaPM cells. Treatment with extracellular ATP also resulted in decreased viability, increased expression of epithelial markers (CDH1, KRT14) and decreased expression of mesenchymal markers (VIM, ZEB1), and reduced expression of ALPL in ARCaPM cells. Small RNA-sequencing identified microRNAs differentially expressed between ARCaPE and ARCaPM PCa cell lines: miR-373 expression was lower in ARCaPM compared to ARCaPE cells and its overexpression in ARCaPM cells resulted in a change to epithelial morphology, increased expression of the epithelial marker CDH1 and decreased expression of the mesenchymal markers VIM and ZEB1. Finally, the development of a high-throughput screening method to identify novel microRNA regulators of osteomimicry was described, which identified two microRNAs miR-199a-5p and miR-212 as positive regulators of ALP activity. Taken together, this thesis describes the identification of ALPL and ATP as novel regulators of epithelial-mesenchymal transition in PCa cells and high-throughput ALP-activity screening as a powerful tool to identify novel microRNA regulators of ALP expression.
- Published
- 2016
41. Patterns of Paging Activity Among Oral and Maxillofacial Surgery Residents: Implications for Patient Care.
- Author
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Burgois AJ, Edwards CM, Austin T, and Abramowicz S
- Abstract
Background: One-way alphanumeric pagers remain a primary communication method for health care providers, despite the rise of app-based communication systems. Frequent nonurgent pages can disrupt workflows and potentially impact patient care, particularly in high-demand specialties like Oral and Maxillofacial Surgery (OMS)., Purpose: The purpose of this study was to examine the association between paging patterns and time of day among OMS residents., Study Design, Setting, Sample: This retrospective cohort study analyzed paging data from the Emory Healthcare OMS service in 2021 and 2022. Pages included were those received by primary OMS residents responsible for inpatient care, consultations, and emergency department evaluations. Exclusions were pages related to outpatient matters and those sent to backup or senior-level residents., Predictor Variable: The primary predictor variable was paging rate, defined as the number of pages received per hour. This measure captures the intensity of paging activity during specific periods., Main Outcome Variable: The primary outcome variable was time of day, categorized into peak and off-peak hours. Peak hours were statistically determined through data analysis and were defined as 07:00-20:00 on weekdays and 09:00-14:00 on weekends. Off-peak hours included all other time periods. Secondary outcomes included the comparison of paging rates on weekdays versus weekends to identify potential variations in paging activity., Covariates: There are no covariates., Results: There were 7,224 pages. Of them, 4,626 pages met the inclusion criteria. In 2021, there was an average of 18.8 pages per day (range: 0 to 56; SD: 10.2). In 2022, there were 19.2 pages per day (range: 3 to 52; SD: 8.7). Weekdays had more pages (20.8 pages/day) than weekends (14.3 pages/day; P < .001). During weekday peak hours, there were 1.3 pages/hour compared to 0.4 pages/hour during off peak hours (P < .001). During weekend peak hours, there were 0.9 pages/hour compared to 0.5 pages/hour during off-peak hours (P value < .001). Weekdays between 0700 and 0800 had the highest average number of pages (1.53 pages/hour)., Conclusion and Relevance: This study identified patterns in paging rates, with significantly higher paging activity during peak hours and on weekdays. Awareness of these patterns may inform the development of protocols to minimize nonurgent interruptions during critical times, such as during patient handoffs., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
- Full Text
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42. Low physical fitness indicates future injury, mental health, menstrual cycle disruptions and burnout in female emergency service personnel and healthcare providers.
- Author
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Edwards CM, Puranda JL, Miller É, MacDonald ML, Aboudlal M, and Adamo KB
- Abstract
Musculoskeletal injury (MSKi), depression, anxiety and burnout place a considerable burden on emergency services personnel and healthcare providers (HCP). Physical fitness is related to both mental and physical health in these populations but females in these are hugely underrepresented in this literature. As female representation in first-responder and HCP roles increases, the need for female specific research is needed. This study examines physical fitness as a short-term indicator of future reproductive health, MSKi, and mental health for females employed as first-responders or HCP. Thirteen first-responders and 29 HCP completed an initial health and demographics questionnaire, a comprehensive physical assessment (e.g., bone mineral density, muscular strength, muscular endurance, muscular power, flexibility, and aerobic capacity), and a health questionnaire 6-7 months after the physical testing. We found that i) bone mineral density, relative upper body strength, and lowerbody power were related to sustaining future MSKi, ii) better lower body endurance and flexibility was related to future menstrual cycle disruptions, and iii) low bone mineral density was related future self-reported burnout and Patient Health Questionnaire score >10. Physical fitness characteristics can be helpful indicators of future MSKi risk, menstrual cycle disruptions, and mental health status in females employed in arduous occupations.
- Published
- 2024
- Full Text
- View/download PDF
43. A Novel Mouse Home Cage Lickometer System Reveals Sex- and Housing-Based Influences on Alcohol Drinking.
- Author
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Petersen N, Adank DN, Quan Y, Edwards CM, Hallal SD, Taylor A, Winder DG, and Doyle MA
- Subjects
- Animals, Female, Male, Sex Characteristics, Ethanol administration & dosage, Mice, Radio Frequency Identification Device, Sex Factors, Mice, Inbred C57BL, Alcohol Drinking psychology, Social Isolation psychology, Housing, Animal
- Abstract
Alcohol use disorder (AUD) is a significant global health issue. Despite historically higher rates among men, AUD prevalence and negative alcohol-related outcomes in women are rising. Loneliness in humans has been associated with increased alcohol use, and traditional rodent drinking models involve single housing, presenting challenges for studying social enrichment. We developed LIQ PARTI (Lick Instance Quantifier with Poly-Animal RFID Tracking Integration), an open-source tool to examine home cage continuous access two-bottle choice drinking behavior in a group-housed setting, investigating the influence of sex and social isolation on ethanol consumption and bout microstructure in C57Bl/6J mice. LIQ PARTI, based on our previously developed single-housed LIQ HD system, accurately tracks drinking behavior using capacitive-based sensors and RFID technology. Group-housed female mice exhibited higher ethanol preference than males, while males displayed a unique undulating pattern of ethanol preference linked to cage changes, suggesting a potential stress or novelty-related response. Chronic ethanol intake distinctly altered bout microstructure between male and female mice, highlighting sex and social environmental influences on drinking behavior. Social isolation with the LIQ HD system amplified fluid intake and ethanol preference in both sexes, accompanied by sex- and fluid-dependent changes in bout microstructure. However, these effects largely reversed upon resocialization, indicating the plasticity of these behaviors in response to social context. Utilizing a novel group-housed home cage lickometer device, our findings illustrate the critical interplay of sex and housing conditions in voluntary alcohol drinking behaviors in C57Bl/6J mice, facilitating nuanced insights into the potential contributions to AUD etiology., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Petersen et al.)
- Published
- 2024
- Full Text
- View/download PDF
44. Ascending Vagal Sensory and Central Noradrenergic Pathways Modulate Retrieval of Passive Avoidance Memory in Male Rats.
- Author
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Edwards CM, Guerrero IE, Thompson D, Dolezel T, and Rinaman L
- Subjects
- Animals, Male, Rats, Saporins, Adrenergic Neurons drug effects, Adrenergic Neurons physiology, Adrenergic Neurons metabolism, Neural Pathways drug effects, Neural Pathways physiology, Norepinephrine metabolism, Ribosome Inactivating Proteins, Type 1 pharmacology, Mental Recall physiology, Mental Recall drug effects, Memory physiology, Memory drug effects, Septal Nuclei drug effects, Septal Nuclei metabolism, Septal Nuclei physiology, Avoidance Learning physiology, Avoidance Learning drug effects, Vagus Nerve physiology, Vagus Nerve drug effects, Vagus Nerve metabolism, Rats, Sprague-Dawley
- Abstract
Visceral feedback from the body is often subconscious, but plays an important role in guiding motivated behaviors. Vagal sensory neurons relay "gut feelings" to noradrenergic (NA) neurons in the caudal nucleus of the solitary tract (cNTS), which in turn project to the anterior ventrolateral bed nucleus of the stria terminalis (vlBNST) and other hypothalamic-limbic forebrain regions. Prior work supports a role for these circuits in modulating memory consolidation and extinction, but a potential role in retrieval of conditioned avoidance remains untested. To examine this, adult male rats underwent passive avoidance conditioning. We then lesioned gut-sensing vagal afferents by injecting cholecystokinin-conjugated saporin toxin (CSAP) into the vagal nodose ganglia (Experiment 1), or lesioned NA inputs to the vlBNST by injecting saporin toxin conjugated to an antibody against dopamine-beta hydroxylase (DSAP) into the vlBNST (Experiment 2). When avoidance behavior was later assessed, rats with vagal CSAP lesions or NA DSAP lesions displayed significantly increased conditioned passive avoidance. These new findings support the view that gut vagal afferents and the cNTS
NA -to-vlBNST circuit play a role in modulating the expression/retrieval of learned passive avoidance. Overall, our data suggest a dynamic modulatory role of vagal sensory feedback to the limbic forebrain in integrating interoceptive signals with contextual cues that elicit conditioned avoidance behavior., (© 2024 Wiley Periodicals LLC.)- Published
- 2024
- Full Text
- View/download PDF
45. ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells.
- Author
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Carretero-Iglesia L, Hall OJ, Berret J, Pais D, Estoppey C, Chimen M, Monney T, Loyau J, Dreyfus C, Macoin J, Perez C, Menon V, Gruber I, Laurendon A, Caro LN, Gudi GS, Matsuura T, van der Graaf PH, Blein S, Mbow ML, Croasdale-Wood R, Srivastava A, Dyson MR, Matthes T, Kaya Z, Edwards CM, Edwards JR, Maiga S, Pellat-Deceunynck C, Touzeau C, Moreau P, Konto C, Drake A, Zhukovsky EA, Perro M, and Pihlgren M
- Subjects
- Animals, Humans, Mice, Antigens, Neoplasm immunology, B-Cell Maturation Antigen immunology, Cell Line, Tumor, Cytotoxicity, Immunologic drug effects, Immunotherapy methods, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, T-Lymphocytes immunology, T-Lymphocytes drug effects, Xenograft Model Antitumor Assays, Clinical Trials as Topic, ADP-ribosyl Cyclase 1 immunology, Multiple Myeloma immunology, Multiple Myeloma drug therapy, Tumor Escape drug effects, Tumor Escape immunology
- Abstract
Despite recent advances in immunotherapies targeting single tumor-associated antigens, patients with multiple myeloma eventually relapse. ISB 2001 is a CD3
+ T cell engager (TCE) co-targeting BCMA and CD38 designed to improve cytotoxicity against multiple myeloma. Targeting of two tumor-associated antigens by a single TCE resulted in superior cytotoxic potency across a variable range of BCMA and CD38 tumor expression profiles mimicking natural tumor heterogeneity, improved resistance to competing soluble factors and exhibited superior cytotoxic potency on patient-derived samples and in mouse models. Despite the broad expression of CD38 across human tissues, ISB 2001 demonstrated a reduced T cell activation profile in the absence of tumor cells when compared to TCEs targeting CD38 only. To determine an optimal first-in-human dose for the ongoing clinical trial ( NCT05862012 ), we developed an innovative quantitative systems pharmacology model leveraging preclinical data, using a minimum pharmacologically active dose approach, therefore reducing patient exposure to subefficacious doses of therapies., (© 2024. The Author(s).)- Published
- 2024
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- View/download PDF
46. Contrast-enhanced computed tomography for ex vivo assessment of human kidneys: A proof-of-concept study.
- Author
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Feizi A, DiRito JR, Richfield O, Stendahl JC, Harris M, Spindler S, Edwards CM, Lysyy T, Lee SR, Boutagy NE, Feher A, Yoo P, Hosgood SA, Mulligan DC, Nicholson ML, Sinusas AJ, Haakinson DJ, and Tietjen GT
- Subjects
- Humans, Organ Preservation methods, Female, Male, Kidney Transplantation methods, Middle Aged, Kidney diagnostic imaging, Kidney blood supply, Contrast Media, Tomography, X-Ray Computed methods, Proof of Concept Study, Perfusion methods
- Abstract
Background: Ex vivo perfusion of transplant-declined human organs has emerged as a promising platform to study the response of an organ to novel therapeutic strategies. However, to fully realize the capability of this platform for performing translational research in human organ pathophysiology, there is a need for robust assays to assess organ function and disease. State-of-the-art research methods rely on analyses of biopsies taken during perfusion, which both damages the organ and only provides localized information. Developing non-invasive, whole organ methods of assessment is critical to the further development of this research platform., Methods: We use ex vivo cold infusion scanning (EXCIS) with contrast-enhanced computed tomography (CT) to quantify perfusion in kidneys preserved ex vivo. EXCIS-CT computes three complementary metrics for whole organ assessment: a dynamic assessment of contrast filling, a measure of vascular network anatomical structure, and a static assessment of perfusion heterogeneity., Results: These metrics were applied to a series of six transplant-declined human kidneys, which demonstrated a range of anatomies and perfusion. Lastly, two transplant-declined human kidneys were imaged before and after a 1-h period of ex vivo normothermic perfusion (NMP). We found variable responses to NMP, with one kidney maintaining the vascular network and hemodynamics and the other showing significant changes in vessel size and spatial perfusion profile., Conclusions: EXCIS-CT provides metrics that can be used to characterize whole organ perfusion and vascular function., (© 2024 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)
- Published
- 2024
- Full Text
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47. A Rare Case of Retinal Vasculitis in a Patient With Autoimmune Lymphoproliferative Syndrome.
- Author
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Edwards CM and Nanda T
- Abstract
This report describes a case of retinal vasculitis in a patient with autoimmune lymphoproliferative syndrome (ALPS). A 13-year-old girl undergoing work-up for immune dysregulation was referred for retinal vasculitis. The patient was asymptomatic on presentation, but her retinal examination was remarkable for areas of outer retinal and choriocapillary loss and focal vascular inflammation. Subsequent bone marrow biopsy with genetic sequencing revealed a diagnosis of ALPS, and she was started on immunosuppression. Most cases of ocular ALPS have anterior involvement, but retinal changes may rarely occur in isolation. Patients with ALPS may benefit from routine eye examination and monitoring. [ Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.] .
- Published
- 2024
- Full Text
- View/download PDF
48. Validity of an ultrasound device to measure bone mineral density.
- Author
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Puranda JL, Edwards CM, Weber VMR, Aboudlal M, Semeniuk K, and Adamo KB
- Abstract
This study aims to examine the validity and reliability of the UltraScan650™, a portable ultrasound device, used to measure BMD at the 1/3rd radius position. Fifty-two female first responders and healthcare providers were assessed using DXA (forearm, femur, lumbar, and total body) and the UltraScan650™. Fat and lean mass were also assessed using the DXA. Pearson correlations, Bland-Altman plots, t-tests, and linear regressions were used to assess validity. Intra-class correlation (ICC) coefficients were used to assess reliability. Inter-rater reliability and repeatability were good (ICC = 0.896 [0.818; 0.942], p < 0.001) and excellent (ICC = 0.917 [0.785; 0.989], p < 0.001), respectively. BMD as measured by the UltraScan650™ was weakly correlated to the DXA (r = 0.382 [0.121; 0.593], p = 0.0052). Bland-Altman plots revealed that the UltraScan650™ underestimated BMD (-0.0569 g/cm
2 ), this was confirmed with a significant paired t-test (p < 0.001). A linear regression was performed (0.4744 × UltraScan650™ + 0.4170) to provide more information as to the issue of agreement. Bland-Altman plots revealed a negligible bias, supported by a paired t-test (p = 0.9978). Pearson's correlation revealed a significant relationship (r = -0.771 [-0.862; -0.631], p < 0.0001) between adjusted UltraScan650™-DXA and the average of the two scans (i.e., adjusted UltraScan650™ and DXA), suggesting a proportional constant error and proportional constant variability in measurements of BMD from the UltraScan650™. The UltraScan650™ is not a valid alternative to DXA for diagnostic purposes; however, the UltraScan650™ could be used as a screening tool in the clinical and research setting given the linear transformation is employed., (© 2024 American Association of Clinical Anatomists and British Association of Clinical Anatomists.)- Published
- 2024
- Full Text
- View/download PDF
49. Are physical fitness, a history of childbirth and injury history related to knee valgus in female Canadian Armed Forces members during a bodyweight overhead squat movement?
- Author
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Edwards CM, da Silva D, Puranda JL, Miller É, Semeniuk K, and Adamo KB
- Abstract
Objectives: A history of childbirth is associated with musculoskeletal injury (MSKi) in female members of the Canadian Armed Forces (CAF). While previous injury and pregnancy impact knee kinematics, it is unclear if a history of childbirth is associated with medial knee displacement (MKD) in an overhead squat movement screen. The aim of this study is to examine the relationship between MKD and (1) MSKi and (2) parity status in female CAF members., Methods: 24 nulliparous and 21 parous female participants employed by the CAF completed a comprehensive physical fitness assessment of muscular flexibility, power, strength, endurance, aerobic capacity and a bodyweight overhead squat movement screen (recorded using two-dimensional video, and hip-knee-ankle angle measured using Kinovea software). Interactions between MKD, parity status and MSKi history were assessed by one-way analysis of variance and two-way analysis of covariance (ANCOVA) (adjusted for age)., Results: An interaction between parity status and acute injury of the lower extremity was observed (F=4.379, p=0.043, η
2 = 0.099) in MKD of the right knee. The two-way ANCOVA examining acute injury of the lumbopelvic hip complex (lower back, pelvis, hip) yielded an interaction between acute injury to the lumbopelvic hip complex and parity status (F=4.601, p=0.038, η2 =0.103) in MKD asymmetry., Discussion: Parous participants with acute injury to the lower extremity had larger MKD than parous without this injury type. Parous participants without acute injury to the lumbopelvic hip complex had greater MKD asymmetry than nulliparous without this injury type. Our findings suggest that researchers and clinicians should consider parity status in conjunction with MSKi history when assessing knee kinematics in female military members., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2024
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- View/download PDF
50. Musculoskeletal Injuries, Exercise Behaviors, and Reproductive Health Are Related to Physical Fitness of Female First-Responders and Health Care Providers.
- Author
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Edwards CM, Puranda JL, Miller É, Aboudlal M, O'Rourke N, MacDonald ML, and Adamo KB
- Abstract
Introduction: Musculoskeletal injuries (MSKi) are the most common injury type experienced by first-responders and health care providers (HCPs), making them a significant threat to physical and mental well-being. Female reproductive health and injury history has been related to physical fitness in female members of the Canadian Armed Forces. This relationship has not been explored in Canadian protective services personnel (first-responders) or HCPs., Methods: Fifty-seven females employed as firefighters, paramedics, law enforcements, or HCPs completed a physical fitness protocol to assess the following: (1) muscular power (standing long jump and medicine ball throw), (2) muscular strength (4 repetition maximum (4RM) back squats and bench press), (3) muscular endurance (Biering-Sorenson test, single-leg wall sit, and push-ups), (4) flexibility (sit-and-reach), and (5) aerobic capacity (graded treadmill VO
2max test). Spearman rho correlation analyses were applied to descriptive analysis, independent-samples t -test, one-way ANCOVA (adjusted by age), and chi-square test. Spearman rho correlation analyses were used to compare physical fitness results for female reproductive health history ( e.g., parity status), previous MSKi, and physical activity behaviors ( e.g., sports participation). A p value of <0.05 is considered significant., Results: History of childbirth, body composition, and exercise behaviors were related to physical fitness ( i.e., standing long jump, Biering-Sorenson test, bench press, and back squat) in law enforcement, firefighting, paramedicine, and health care personnel., Conclusions: Physical training programs aimed at supporting parous first-responders or HCPs should emphasize lower body power, lower body strength, and upper body strength., (© C. M. Edwards et al., 2024; Published by Mary Ann Liebert, Inc.)- Published
- 2024
- Full Text
- View/download PDF
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