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13. Tipifarnib potentiates the antitumor effects of PI3Kα inhibition in PIK3CA- and HRAS-dysregulated HNSCC via convergent inhibition of mTOR activity

Author

Smith, Alison E, Chan, Stacia, Wang, Zhiyong, McCloskey, Asako, Reilly, Quinn, Wang, Jayden Z, Patel, Hetika Vora, Koshizuka, Keiichi, Soifer, Harris S, Kessler, Linda, Dayoub, Ashley, Villaflor, Victoria, Adkins, Douglas R, Bruce, Justine Y, Ho, Alan L, Perez, Cesar A, Hanna, Glenn J, Hernandez, Amaya Gasco, Saunders, Andrew, Dale, Stephen, Gutkind, J Silvio, Burrows, Francis, and Malik, Shivani

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Clinical Research, Dental/Oral and Craniofacial Disease, Cancer, Orphan Drug, Rare Diseases, Humans, Squamous Cell Carcinoma of Head and Neck, Carcinoma, Squamous Cell, Neoplasm Recurrence, Local, TOR Serine-Threonine Kinases, Head and Neck Neoplasms, Class I Phosphatidylinositol 3-Kinases, Biomarkers, Proto-Oncogene Proteins p21(ras), Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18 months. For those who progress on standard-of-care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Kα- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility.SignificanceThe mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease. See related commentary by Lee et al., p. 3162.

Published
2023

17. Losing it

Author

Smith, Alison

Published
2018

25. The importance of vitamin B12 for individuals choosing plant-based diets

Author

Niklewicz, Ali, Smith, A David, Smith, Alison, Holzer, Andre, Klein, Andrew, McCaddon, Andrew, Molloy, Anne M, Wolffenbuttel, Bruce HR, Nexo, Ebba, McNulty, Helene, Refsum, Helga, Gueant, Jean-Louis, Dib, Marie-Joe, Ward, Mary, Murphy, Michelle, Green, Ralph, Ahmadi, Kourosh R, Hannibal, Luciana, Warren, Martin J, and Owen, P Julian

Subjects
Complementary and Integrative Health, Prevention, Nutrition, Prevention of disease and conditions, and promotion of well-being, 3.3 Nutrition and chemoprevention, Reproductive health and childbirth, Metabolic and endocrine, Zero Hunger, Humans, Female, Pregnancy, Vitamin B 12, Diet, Diet, Vegetarian, Diet, Vegan, Vitamins, Vitamin B12, Plant-based diets, Public health, Planetary health, Dietary recommendations, Vegetarian and vegan populations, Women of child-bearing age, CluB-12, Nutrition and Dietetics, Nutrition & Dietetics
Abstract

Vitamin B12 is an essential nutrient that is not made by plants; consequently, unfortified plant-based foods are not a reliable supply. Recent estimates suggest high rates of vitamin B12 deficiency among the vegetarian and vegan populations, particularly in pregnant women or women of child-bearing age who, for ethical and health reasons, are shifting towards higher consumption of plant-based foods in ever-increasing numbers. Vitamin B12 plays crucial metabolic roles across the life-course and in particular during pregnancy and in early development (first 1000 days of life). Evidence now implicates vitamin B12 deficiency with increased risk to a range of neuro, vascular, immune, and inflammatory disorders. However, the current UK recommended nutrient intake for vitamin B12 does not adequately consider the vitamin B12 deficit for those choosing a plant-based diet, including vegetarianism and in particular veganism, representing a hidden hunger. We provide a cautionary note on the importance of preventing vitamin B12 deficits for those individuals choosing a plant-based diet and the health professionals advising them.

Published
2023

29. How can diverse national food and land-use priorities be reconciled with global sustainability targets? Lessons from the FABLE initiative

Author

Mosnier, Aline, Schmidt-Traub, Guido, Obersteiner, Michael, Jones, Sarah, Javalera-Rincon, Valeria, DeClerck, Fabrice, Thomson, Marcus, Sperling, Frank, Harrison, Paula, Pérez-Guzmán, Katya, McCord, Gordon Carlos, Navarro-Garcia, Javier, Marcos-Martinez, Raymundo, Wu, Grace C, Poncet, Jordan, Douzal, Clara, Steinhauser, Jan, Monjeau, Adrian, Frank, Federico, Lehtonen, Heikki, Rämö, Janne, Leach, Nicholas, Gonzalez-Abraham, Charlotte E, Ghosh, Ranjan Kumar, Jha, Chandan, Singh, Vartika, Bai, Zhaohai, Jin, Xinpeng, Ma, Lin, Strokov, Anton, Potashnikov, Vladimir, Orduña-Cabrera, Fernando, Neubauer, Rudolf, Diaz, Maria, Penescu, Liviu, Domínguez, Efraín Antonio, Chavarro, John, Pena, Andres, Basnet, Shyam, Fetzer, Ingo, Baker, Justin, Zerriffi, Hisham, Reyes Gallardo, René, Bryan, Brett Anthony, Hadjikakou, Michalis, Lotze-Campen, Hermann, Stevanovic, Miodrag, Smith, Alison, Costa, Wanderson, Habiburrachman, AHF, Immanuel, Gito, Selomane, Odirilwe, Daloz, Anne-Sophie, Andrew, Robbie, van Oort, Bob, Imanirareba, Dative, Molla, Kiflu Gedefe, Woldeyes, Firew Bekele, Soterroni, Aline C, Scarabello, Marluce, Ramos, Fernando M, Boer, Rizaldi, Winarni, Nurul Laksmi, Supriatna, Jatna, Low, Wai Sern, Fan, Andrew Chiah Howe, Naramabuye, François Xavier, Niyitanga, Fidèle, Olguín, Marcela, Popp, Alexander, Rasche, Livia, Godfray, Charles, Hall, Jim W, Grundy, Mike J, and Wang, Xiaoxi

Subjects
Life on Land, Zero Hunger, Food system, Land use, Sustainability, Integrated models, Trade, Climate change, Environmental Sciences
Abstract

There is an urgent need for countries to transition their national food and land-use systems toward food and nutritional security, climate stability, and environmental integrity. How can countries satisfy their demands while jointly delivering the required transformative change to achieve global sustainability targets? Here, we present a collaborative approach developed with the FABLE—Food, Agriculture, Biodiversity, Land, and Energy—Consortium to reconcile both global and national elements for developing national food and land-use system pathways. This approach includes three key features: (1) global targets, (2) country-driven multi-objective pathways, and (3) multiple iterations of pathway refinement informed by both national and international impacts. This approach strengthens policy coherence and highlights where greater national and international ambition is needed to achieve global goals (e.g., the SDGs). We discuss how this could be used to support future climate and biodiversity negotiations and what further developments would be needed.

Published
2023

38. The impact of post-operative enteral nutrition on duodenal injury outcomes: A post hoc analysis of an EAST multicenter trial

Author

Choron, Rachel L., Rallo, Michael, Piplani, Charoo, Youssef, Sara, Teichman, Amanda L., Bargoud, Christopher G., Sciarretta, Jason D., Smith, Randi N., Hanos, Dustin S., Afif, Iman N., Beard, Jessica H., Dhillon, Navpreet K., Zhang, Ashling, Ghneim, Mira, Devasahayam, Rebekah J., Gunter, Oliver L., Smith, Alison A., Sun, Brandi L., Cao, Chloe, Reynolds, Jessica K., Hilt, Lauren A., Holena, Daniel, Chang, Grace, Jonikas, Meghan, Echeverria, Karla, Fung, Nathaniel, Anderson, Aaron, Dumas, Ryan P., Fitzgerald, Caitlin A., Levin, Jeremy, Trankiem, Christine, Yoon, JaeHee Jane, Blank, Jacqueline, Hazelton, Joshua, McLaughlin, Christopher J., Al-Aref, Rami, Kirsch, Jordan M., Howard, Daniel S., Scantling, Dane R., Dellonte, Kate, Vella, Michael, Hopkins, Brent, Shell, Chloe, Udekwu, Pascal O., Wong, Evan G., Joseph, Bellal A., Lieberman, Howard, Ramsey, Walter, Stewart, Collin, Alvarez, Claudia, Berne, John D., Nahmias, Jeffry, Puente, Ivan, Patton, J. Pat, Rakitin, Ilya, Perea, Lindsey L., Pulido, Odessa R., Ahmed, Hashim, Keating, Jane, Kodadek, Lisa, Wade, Jason, Henry, Reynold, Schreiber, Martin, Benjamin, Andrew, Khan, Abid, Mann, Laura K., Mentzer, Caleb, Mousafeiris, Vasileios, Mulita, Francesk, Reid-Gruner, Shari, Sais, Erica, Foote, Christopher, Palacio-Lascano, Carlos, Argandykov, Dias, Kaafarani, Haytham, Bover Manderski, Michelle, Narayan, Mayur, and Seamon, Mark J.

Published
2024
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43. MultiCenter Study of Intra-Abdominal Abscess Formation After Major Operative Hepatic Trauma

Author

Zorrilla, Alexander, Hoefer, Lea, Fraser, Douglas R., Inaba, Kenji, Mooney, Jennifer, Bjordahl, Paul, Dammann, Kyle, Samra, Navdeep, Smith, Alison A., Cone, Jennifer T., McNickle, Allison G., Mitchao, Delbrynth P., Kostka, Ryan, Martinez, Benjamin, Schroeppel, Thomas, Cavalea, Alexander, Shahan, Charles Patrick, Axtman, Benjamin, and Braverman, Maxwell A.

Published
2024
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44. Faster refill in an urban emergency medical services system saves lives: A prospective preliminary evaluation of a prehospital advanced resuscitative care bundle

Author

Broome, Jacob M., Nordham, Kristen D., Piehl, Mark, Tatum, Danielle, Caputo, Sydney, Belding, Cameron, De Maio, Valerie J., Taghavi, Sharven, Jackson-Weaver, Olan, Harris, Charlie, McGrew, Patrick, Smith, Alison, Nichols, Emily, Dransfield, Thomas, Rayburn, David, Marino, Megan, Avegno, Jennifer, and Duchesne, Juan

Published
2024
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45. Introducing Transformative Plant Biotechnology: Using microalgae to produce high value compounds

Author

Smith, Alison, speaker

Abstract

There is enormous potential to use microalgae as feedstocks for everything from biofuels to recombinant proteins and high value chemicals, but to implement this technology in a sustainable and economic manner, it will be necessary to optimize many parameters. We have taken a synthetic biology approach to develop two microalgal strains as production platforms for plant diterpenoids. We have established ways to regulate transgene expression, which will be essential for sophisticated metabolic engineering. To demonstrate the potential for commercial exploitation of these platforms we have grown the engineered strains outdoors under natural conditions in the Algal Innovation Centre in Cambridge, which has allowed us to identify bottlenecks and challenges that will need to be overcome to make such systems economically and sustainably viable. **Co-Authors**: Payam Mehrshahi, Katrin Geisler, Nhan-An Tran

Published
2023
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47. Synthetic algal-bacteria consortia for space-efficient microalgal growth in a simple hydrogel system

Author

Martin, Noah, Bernat, Tatum, Dinasquet, Julie, Stofko, Andrea, Damon, April, Deheyn, Dimitri D, Azam, Farooq, Smith, Jennifer E, Davey, Matthew P, Smith, Alison G, Vignolini, Silvia, and Wangpraseurt, Daniel

Subjects
Bioengineering, Co-culture, Algae-bacteria, Hydrogel, Photosynthesis, Biopolymer, Erythrobacter, Marinichlorella, Synthetic consortia, Plant Biology, Fisheries Sciences, Environmental Biotechnology, Marine Biology & Hydrobiology
Abstract

AbstractPhotosynthetic microalgae are an attractive source of food, fuel, or nutraceuticals, but commercial production of microalgae is limited by low spatial efficiency. In the present study we developed a simple photosynthetic hydrogel system that cultivates the green microalga, Marinichlorella kaistiae KAS603, together with a novel strain of the bacteria, Erythrobacter sp. We tested the performance of the co-culture in the hydrogel using a combination of chlorophyll-a fluorimetry, microsensing, and bio-optical measurements. Our results showed that growth rates in algal–bacterial hydrogels were about threefold enhanced compared to hydrogels with algae alone. Chlorophyll-a fluorimetry–based light curves found that electron transport rates were enhanced about 20% for algal–bacterial hydrogels compared to algal hydrogels for intermediate irradiance levels. We also show that the living hydrogel is stable under different environmental conditions and when exposed to natural seawater. Our study provides a potential bio-inspired solution for problems that limit the space-efficient cultivation of microalgae for biotechnological applications.

Published
2021

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