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Nutrition and Metabolic Factors
Published in Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan, Strength and Conditioning in Sports, 2023
Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan
Fat is present in all human cells and the physiological functions are quite diverse, ranging from their use as energy substrates, physiological structures (e.g., cell membranes and myelin sheath of nerve cells), vitamin transporters, and their role in the production of cholesterol and associated steroids. Fat (lipid) serves as the largest energy store that is readily available for biological work and may consist of approximately 35–45% of the total daily caloric intake within the Western diet (101). While fat is involved in a variety of metabolic processes within the human body, it has been associated with disease states including cardiovascular disease and some types of cancer.
Lipids and Lipid Metabolism in Postnatal Gut Development and Risk of Intestinal Injury
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
To address this latter concept, Singh et al. investigated the impact of ileal tissue LCPUFA profiles on intestinal development in WT versus fat-1 mouse pups (20). Fat-1 mice are unique in their ability to metabolize n-6 precursors to the n-3 pathway, inducing an n-3 dominant fatty acid profile. Thus, relative to WT mice, fat-1 mice have higher EPA and DHA tissue levels and lower ARA levels. Morphological metrics and gene expression were compared between the two groups at three postnatal time points: day 3, 14, and 28. During the preweaning period (days 3 and 14), fat-1 relative to WT mice had an increase in gene expression of Wnt signaling and cell proliferation markers Ephb2 and Fzd5, decreased expression of the tight junction genes Cldn3 and Cldn7, decreased expression of inflammatory regulators Camp and TLR9, and decreased expression of innate host defenses muc2 and Tff3. Alcian blue staining confirmed a decreased number of goblet cells in fat-1 versus WT mice at all time points. These findings are relevant to the current clinical strategies to optimize n-3 delivery for the preterm infant. These data by Singh et al. suggest that there may be an undesirable impact on tight junction and innate immune defenses early in postnatal development in response to increased levels of n-3 fatty acids. The clinical ramifications of these changes and whether they can be modified by increasing ARA delivery remain to be determined.
Comparative Anatomy, Physiology, and Biochemistry of Mammalian Skin
Published in David W. Hobson, Dermal and Ocular Toxicology, 2020
Adipose cells (Figure 13) may accumulate along small vessels but are primarily located in the deeper dermis where they merge with the subcutaneous fatty tissue. Adipose or fat is defined as an area with a large number of fat cells. At the light microscopic level, they appear polygonal and range in size from 25 to 200 μm. The dehydration process usually extracts their lipid content and thus in light microscopic sections, they appear as empty spaces or holes. Ultrastructurally, the cytoplasm is only a thin layer surrounding the large central lipid inclusion. The presence of this inclusion displaces the nucleus to one side. Few organelles are present in the area of the nucleus, with mitochondria being the most obvious. Collagen or reticular fibers may be found along the cytoplasmic rim of the fat cell. Several fat cells may coalesce to give rise to a single large cell. Fat cells may also aggregate into lobules and be divided by septa within which blood vessels and nerves can travel. Mitotic activity in predetermined fat cells is complete by 2 to 3 weeks after birth. In the adult fat cells do not divide. It has been postulated that undifferentiated, spindle-shaped, mesenchymal cells resembling fibroblasts give rise to fat cells.38,202
Genome-Wide Association Study of Metachronous Colorectal Adenoma Risk among Participants in the Selenium Trial
Published in Nutrition and Cancer, 2022
Mario Jesus Trejo, Ken Batai, Yuliang Chen, Stefanie Brezina, H-H Sherry Chow, Nathan Ellis, Peter Lance, Chiu-Hsieh Hsu, Kristen Pogreba-Brown, Maria Bishop, Andrea Gsur, Elizabeth T. Jacobs
Pathways leading to the development of colorectal adenomaand cancer are complex. The Wnt/β-catenin pathway has been extensively studied and has been causally linked to colorectal cancer development (38, 39). While the FAT gene family (FAT1-4), which encodes transmembrane proteins, are mutated in various types of cancers, to date FAT3 has not been extensively studied (40–42). FAT3 is most closely related to FAT1, which is believed to be a tumor suppressor and to play opposing roles in development and cell growth through the binding of β-catenin (40–43). When FAT1 is inactivated, there is an excess of cytoplasmic β-catenin, which can then enter the nucleus, increasing TCF transcription factors which in turn activate expression of Wnt target genes (40). FAT3 may have a role in the Wnt signaling pathway in a similar way that FAT1 does, as FAT3 has its expression downregulated in non-small cell lung cancer, while β-catenin and downstream genes of the Wnt signaling pathway are upregulated (42, 44). Further investigation is required to better understand the role of FAT3 variants in metachronous adenoma development.
Atezolizumab prolongs overall survival over docetaxel in advanced non-small-cell lung cancer patients harboring STK11 or KEAP1 mutation
Published in OncoImmunology, 2021
Wei Nie, Lu Gan, Xin Wang, Kai Gu, Fang-Fei Qian, Min-Juan Hu, Ding Zhang, Shi-Qing Chen, Jun Lu, Shu-Hui Cao, Jing-Wen Li, Yue Wang, Bo Zhang, Shu-Yuan Wang, Chang-Hui Li, Ping Yang, Mi–Die Xu, Xue-Yan Zhang, Hua Zhong, Bao-Hui Han
Fortunately, FAT3 mutation was found to predict the response of ICIs treatment, which was also validated as a favorable surrogate biomarker in an independently published dataset. Fang and colleagues suggested that, compared with wild-type, cancer patients treated with ICIs with FAT1 mutation had higher DCB and ORR.53FAT1 is regarded as a tumor-suppressive gene and loss of FAT1 in cells activates the Wnt signaling pathway.54FAT3 is similar to FAT1, but it has not been well characterized to date. We observed a significant association between FAT3 mutation and DDR pathways mutations and high TMB, which might be part of the reason in predicting superior outcomes in SKmut patients receiving atezolizumab. Interestingly, FAT3 mutation could not predict clinical benefit in non-SKmut patients, suggesting that there might be an unknown mechanism between FAT3 mutation and STK11 or KEAP1 mutation in predicting immunotherapeutic outcomes. Overall, the role of FAT3 mutation as a predictive biomarker for ICIs treatment in this setting warrants further evaluation.
Genomic-based treatment of patients with head and neck cancer
Published in Expert Review of Precision Medicine and Drug Development, 2020
Arpan Patel, Seyed Mohammad Abedi, Manidhar Lekkala, Megan Baumgart
Mutations in FAT1, a tumor suppressor gene, have been identified in approximately 29% of HNSCC tumors and are associated with poor disease-free survival [24]. While identification of FAT1 mutations may have prognostic implications, there are currently no therapeutic strategies to target this mutation. It is recognized that NOTCH1 is frequently mutated in HNSCC, with primarily inactivating mutations; however, activating mutations and upregulation of NOTCH1 are also found, consistent with an oncogenic role as well [25]. The NOTCH signaling induces epithelial-mesenchymal transitions and promotes chemo resistance [26]. The frequency with which mutations in FAT1 and NOTCH1 are found in HNSCC suggests great potential for therapeutic benefit though no targeted agent currently exists.