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Burdet, E. „Un Modele Connectionniste du Regulateur Adaptatif du Bras Humain“. Archives of Physiology and Biochemistry 103, Nr. 3 (01.01.1995): C110. http://dx.doi.org/10.3109/13813459509037324.
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Lee, Seong-Ho, Jihye Lee, Darshika Amarakoon, Zhiyuan Lou, Thomas Herald, Sarah Cox, Leela Noronha, Ramasamy Perumal und Dmitriy Smolensky. „Tumor Suppressive Activity of High Phenolic Sorghum Brans in Colon Cancer Mouse Model and Proposed Mechanisms“. Current Developments in Nutrition 4, Supplement_2 (29.05.2020): 329. http://dx.doi.org/10.1093/cdn/nzaa044_028.
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Abstract Objectives Colon cancer occupy third rank in the United States and its incidence is inversely associated with high consumption of plant-based diet including whole grains. Sorghum is one of broadly cultivated crops and the bran of sorghum contains high content of bioactive compounds including polyphenols. The current study was designed to examine if different type of high phenolic sorghum brans (PI570481, SC84 and Sumac) suppress tumor formation in genetic colon cancer mouse model and elucidate related biochemical and molecular mechanisms using human colon cancer cells. Methods Fifty-three ApcMin/+ mice (4-week old male and female) were assigned and provided with one of following diets; 1) control (n = 11), 2) low dose of PI570481 (7.5% w/w) (n = 11), 3) high dose of PI570481 (15% w/w) (n = 11), 4) SC84 (15% w/w) (n = 10) and 5) Sumac (15% w/w) (n = 10) for 6 weeks. All mice were treated with 2% dextran sodium sulfate for one week in drinking water at 5 weeks of age. The number and size of tumor were measured from the large intestine. For in vitro study, human colon cancer cell lines were treated with different doses (0, 1.25 and 2.5 mg/mL) of high phenolic sorghum bran extracts (PI570481, SC84 and Sumac). Transcriptional activity of β-catenin was analyzed by measuring luciferase activity of reporter gene (Top and Fop flash). Gene expression was analyzed by Western blot using specific antibodies. Results Feeding three different types of high phenolic sorghum brans (PI570481, SC84 and Sumac) to ApcMin/+ mice for 6 weeks did not change body weight and cause any toxicity. The tumor number and tumor load in the large intestine were significantly decreased in the mice treated with three types of high phenolic sorghum brans. Regarding mechanisms, treatment of high phenolic sorghum bran extracts repressed transcriptional activity of β-catenin and IGF-1-stimulated phosphorylation of Akt in human colon cancer cells. Conclusions Our data propose a potential use of high phenolic sorghum brans as diets for the prevention of human colon cancer. Funding Sources Cooperative Agreement from USDA-ARS to University of Maryland (S-HL).
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Meziani, Samira, Souad Saidani, Lahouaria Labga, Rawda Benguella und Imene Bekhaled. „Bioactive compounds and antioxidant potential of soft wheat and oat bran on the Algerian market“. North African Journal of Food and Nutrition Research 4, Nr. 7 (17.04.2020): 245–51. http://dx.doi.org/10.51745/najfnr.4.7.245-251.
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Background: Rich in dietary fibers and beneficial to health, wheat and oats have been a popular part of the human diet. The whole grain is rich in protein, lipid, starch and phenolic compounds concentrated at the level of the peripheral layer of the bran. Aims: The natural compounds and the antioxidant potential of two different species of soft wheat and oat bran on the Algerian market have been studied in this work. Wheat bran was furnished by Azzouz’s Cereal and Dried Vegetable Cooperative (CCLS) being the most commercialized oat bran in Algeria. Material and Methods: Some parameters and bran biochemical compounds such as proteins, cellulose, ash content, phenolics, and antioxidant potential (DPPH) were determined using different techniques and methods (infra-red approach spectrophotometer, and flame spectrophotometer). Results: The results obtained showed that studied soft wheat bran was rich in protein (17.36%). Concerning cellulose, a high value was recorded for this bran variety 11.3%, which was lower for oat bran (2.7%). The maximum concentration of potassium and sodium was observed in the soft wheat bran variety; 3.16 mg/L, 30.36 mg/L respectively. The levels of the phenolic compounds were 0.720 ± 0.050 mg EAG / g and 1.101 ± 0.01mg EAG / g for the oat bran and the soft wheat bran respectively. These results underline that both studied brans contain significant levels of compounds essential for consumer needs. Conclusions: The studied soft wheat bran variety is considered to be an important source of phytonutrients. Keywords: Wheat, oat, antioxidants, radical scavenging, phenolic contents.
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Bras, Pierre-Louis, und Isabelle Bridenne. „Entretien avec Pierre-Louis Bras“. Retraite et société N°83, Nr. 3 (2019): 165. http://dx.doi.org/10.3917/rs1.083.0166.
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Maksymowicz, Agata, und �ucja Kapralska. „AKTYWNO�� JAKO STRATEGIA POMY�LNEGO STARZENIA SI� W �WIETLE INTERNETOWYCH RAD I WSKAZ�WEK DLA SENIOR�W“. Studia Humanistyczne AGH 22, Nr. 2 (2023): 29–46. http://dx.doi.org/10.7494/human.2023.22.2.29.
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Niniejsza praca dotyczy zagadnienia organizacji czasu wolnego os�b przebywaj�cych na emeryturze. Kolejny etap �ycia po zako�czeniu pracy niesie za sob� brak obowi�zk�w zawodowych i powolne wycofywanie si� z pe�nionych dot�d r�l spo�ecznych. Stan ten z jednej strony mo�e by� b�ogos�awie�stwem, z drugiej powodowa� uczucie pustki i stres z powodu tak nadmiaru czasu wolnego, jak i konieczno�ci przystosowania si� do nowej sytuacji. St�d pytanie: co robi� na emeryturze, by przeciwdzia�a� wspomnianym powy�ej stanom i zjawiskom i odnale�� si� w nowej spo�ecznej roli? Analiza zasob�w internetu oraz rynku wydawniczego pozwala znale�� r�ne �r�d�a porad, z kt�rych seniorzy przechodz�cy na emerytur� mog� skorzysta�. W pracy poddano analizie kilka z nich. S� to rady starszych senior�w, poradniki ksi��kowe, portale przeznaczone dla senior�w, strony www i publikacje instytucji aktywizuj�cych osoby starsze, w ko�cu � portale firm komercyjnych zainteresowanych seniorami jako konsumentami. Wi�kszo�� rad wpisuje si� w model staro�ci aktywnej, emerytury zaplanowanej i zorganizowanej pod wzgl�dem zagospodarowania czasu wolnego, przygotowania mentalnego, zdrowotnego oraz administracyjnego. Jest to model po��dany, gdy� pozwala zwi�kszy� szanse na fizyczny i psychiczny dobrostan senior�w, st�d rady takie wydaj� si� wspiera� samodzielne uczestnictwo os�b starszych w �yciu spo�ecznym.
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Lankenau, Malori A., Ravi Patel, Sandya Liyanarachchi, Sophia E. Maharry, Kevin W. Hoag, Megan Duggan, Christopher J. Walker et al. „MicroRNA-3151 inactivates TP53 in BRAF-mutated human malignancies“. Proceedings of the National Academy of Sciences 112, Nr. 49 (18.11.2015): E6744—E6751. http://dx.doi.org/10.1073/pnas.1520390112.
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The B-Raf proto-oncogene serine/threonine kinase (BRAF) gene is the most frequently mutated gene in malignant melanoma (MM) and papillary thyroid cancer (PTC) and is causally involved in malignant cell transformation. Mutated BRAF is associated with an aggressive disease phenotype, thus making it a top candidate for targeted treatment strategies in MM and PTC. We show that BRAF mutations in both MM and PTC drive increased expression of oncomiR-3151, which is coactivated by the SP1/NF-κB complex. Knockdown of microRNA-3151 (miR-3151) with short hairpin RNAs reduces cell proliferation and increases apoptosis of MM and PTC cells. Using a targeted RNA sequencing approach, we mechanistically determined that miR-3151 directly targets TP53 and other members of the TP53 pathway. Reducing miR-3151’s abundance increases TP53’s mRNA and protein expression and favors its nuclear localization. Consequently, knockdown of miR-3151 also leads to caspase-3–dependent apoptosis. Simultaneous inhibition of aberrantly activated BRAF and knockdown of miR-3151 potentiates the effects of sole BRAF inhibition with the BRAF inhibitor vemurafenib and may provide a novel targeted therapeutic approach in BRAF-mutated MM and PTC patients. In conclusion, we identify miR-3151 as a previously unidentified player in MM and PTC pathogenesis, which is driven by BRAF-dependent and BRAF-independent mechanisms. Characterization of TP53 as a downstream effector of miR-3151 provides evidence for a causal link between BRAF mutations and TP53 inactivation.
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Lima, André Luiz de Araújo, Ana Lúcia Gomes da Silva und Antenor Rita Gomes. „SO[M]BRAS, PÉROLAS E PORCOS“. Revista Espaço do Currículo 16, Nr. 3 (19.12.2023): 1–12. http://dx.doi.org/10.15687/rec.v16i3.68491.
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Este artigo é resultado da pesquisa de mestrado intitulada O fotográfico e a professoralidade: uma cartografia de aproximações e distanciamentos. Nele rastrea-se processos de criação na perspectiva de uma esquizoanálise de memórias, tensionando, entretanto, sem negar frontalmente a ideia de santidade impressa na laicidade da escola, num modo de estetização do espaço escolar e, alhures, produzir linhas de fuga singularizantes a partir do fotográfico, cartografando algumas passagens dessa trilha, embate entre santidade, pérolas e porcos em meio ao lamaçal sombrio e fecundo do processo de vir a ser professor, para alcançar um certo modo de ser metaestável. Adota como método a cartografia e toma a esquizoanálise como inspiração processual da análise. Aponta como resultados centrais emergentes: percurso cartográfico desse jogo de sombras permite experimentar ser encharcado pelos acasos, pelas pequenas formas dos acontecimento microfísicos, na educação básica como docente de arte, pela luz que chega, pelo peso do ferro que morre, pela leveza do ar, tudo isso retorna como uma energia potencial pelo fotográfico, que rearranja esses vetores de força e produz uma existência outra, uma existência artística, encarnada por inteiro no presente.
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Mansor, Mohd Rizuan, Mohd Sharizan Md Sarip, Nik Muhammad Azhar Nik Daud, Syahrul Affandi Saidi, Mohd Al Hafiz Mohd Nawi und Mohd Aminudin Jamlos. „Preparation of Rice Bran Protein (RBP) Powder Using Spray Drying Method at the Optimal Condition and Its Protein Quality“. Processes 10, Nr. 10 (07.10.2022): 2026. http://dx.doi.org/10.3390/pr10102026.
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Rice bran is a by-product of the rice milling process. It contains a high concentration of protein. Rice brans are frequently utilized as feed cattle, fertilizer, and fuel. However, their application as human nutrition supplements is uncommon, and the necessary process for this purpose is yet to be established, including the drying process. This study aims to evaluate the effect of the spray-drying parameters, the inlet temperature, inlet flowrate, and inlet air flowrate, on rice bran protein (RBP) powder and optimize it using response surface methodology (RSM). A thermal water-based extraction method was utilized prior to the drying process. The correlation between the spray-drying parameters, i.e., the inlet temperature (120 to 210 °C), feed flowrate (5 to 55%), and air flowrate (246 to 670 L/h), and the RBP yield were investigated. The quality of the RBP powder was evaluated based on acid amino profiling in the mixture through de novo peptide sequencing. The optimized operating conditions for the maximum yield of RBP powder (25.7 g RBP/100 g RRB) are 178 °C, feed flowrate of 25%, and air flowrate of 450 L/h. The main peptides that contribute to RBP powder protein are globulin and glutelin; meanwhile, prolamin is believed to degrade during the drying process. The process also produced protein sugar, helping to produce fine particles powder without the drying agent.
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Migalska, Aleksandra. „Jak po dwustu latach zrobić miejsce dla prababki, czyli kogo brak w historii myśli socjologicznej recenzja z: Mary Wollstonecraft, Wołanie o prawa kobiety, red. K. Michalczak, Wydawnictwo Ma-mania. Warszawa 2011“. Studia Humanistyczne AGH 11, Nr. 2 (2012): 161. http://dx.doi.org/10.7494/human.2012.11.2.161.
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Bolaji, Josephine Taiye, und Patricia I. Dolez. „Supportive, Fitted, and Comfortable Bras for Individuals with Atypical Breast Shape/Size: Review of the Challenges and Proposed Roadmap“. Textiles 2, Nr. 4 (24.10.2022): 560–78. http://dx.doi.org/10.3390/textiles2040032.
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Individuals with atypical breast shape/size often find it quite challenging to obtain a comfortable, supportive, and fitted bra off-the-shelf. They include people with very large breasts, who have significant breast asymmetry, and/or have undergone mastectomy or mammoplasty. This paper provides insights in their challenges and attempts to fill the gap in terms of critical review of the current state of knowledge around the topic of bras. Poor and ill fitted bras are associated with breast, chest and shoulder pain, embarrassment, and an overall reduction in quality of life among others. Building upon the advantages and limitations of solutions to improve the fit, support and comfort of bras found in the literature, this paper proposes strategies to solve these challenges. As the problem is multidisciplinary, a human-centered interdisciplinary approach is key to ensure that all aspects are considered at all stages of the process. A modular design allows selecting the fabric characteristics based on the requirements of each bra part. In terms of materials, stretch woven fabrics offer a large potential in the production of bras to enhance the support provided by areas such as the under band and back panels. Bespoke manufacturing takes into account the specificities of each individual. The road map proposed here will contribute to enhance the quality of life of individuals with atypical breast shape/size.
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Pricl, Sabrina, Erik Laurini, Domenico Marson und Gabriele Cavalieri. „Abstract C153: Rare BRAF mutations in menlanoma and beyond: Rationalizing the afficacy of B-raf inhibitors via HPC-based in silico/in vitro investigations“. Molecular Cancer Therapeutics 22, Nr. 12_Supplement (01.12.2023): C153. http://dx.doi.org/10.1158/1535-7163.targ-23-c153.
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Abstract Melanoma is a highly aggressive type of cancer that affects the integumentary system and for which a family history of the disease, a fair complexion, the presence of a large number of moles, and skin exposure to natural/artificial ultraviolet (UV) radiation constitute established risk factors for malignancy development. The v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a serine/threonine protein kinase that plays a critical role in the RAS-RAF-MEK-ERK mitogen–activated protein kinase (MAPK) cell signaling pathway. Despite over 20 years of research into the regulation and function of the RAF proteins, it was only relatively recently that the BRAF isoform is mutated at a high frequency in different human cancers, identifying this kinase as another important oncogene along this pathway. FFocusing on melanoma, activating BRAF mutations were identified in 37%−53% of patients with the malignant form of this pathology, the most prevalent, missense kinase alteration being the replacement of the small, apolar residue valine (V) with the negatively-charged, phosphorylation mimicking glutamic acid (E) at position 600 (BRAFV600E) within the protein catalytic (i.e., ATP binding) site. It is interesting to note that BRAFV600E is not a UV-driven mutation; in fact, it may also be found in the molecular profile of atypical benign nevi; moreover, although BRAFV600E is the most frequent mutation (accounting for nearly 40% of all melanomas and in approximately 90% of BRAF-mutant melanomas), other more or less frequent activating variants in BRAF have also been reported, which include other aminoacidic substitutions at the same position (e.g., V600K/D/R), G469A/V/S, L597Q/R/S/V, A598V, and K601E/N/T, among others. Importantly, these mutations are also found in other cancers, e.g., thyroid cancer, colorectal cancer, and some brain malignancies including glioblastoma, pilocytic astrocytoma, and pediatric low-grade glioma. In this multidisciplinary work, we focused on some of these rare BRAF variants and studied their ability to interact with several, first-line FDA approved BRAF initbitors (BRAFis) from a structural, chemico-phisical and in vitro perspectives. To the purpose, we employed a combitation of in silico techniques, based on the use of high-performance computing (HPC), chemico-physical and spectroscopical techniques, and in vitro tests to verify the interactions between these mutated BRAF isoforms with the inhibitors. As a main point, we were able to determine the binding thermodinamics and kinetics of the selected BRAFis to the mutant BRAF proteins, and each BRAF/drug complex was characterized from a structural standpoint. All these information ultimately revelaed that some of the BRAF isoforms are able to effectively bind the corresponding BRAi, with consequent switch-off of the signaling patwhay, at least in vitro. The presented mutlidisciplinary protocol could be adoped in the future to predict the response of newly discovered BARF variants and/or variants of unknown significance towards current or newly-designed BRAFis. Citation Format: Sabrina Pricl, Erik Laurini, Domenico Marson, Gabriele Cavalieri. Rare BRAF mutations in menlanoma and beyond: Rationalizing the afficacy of B-raf inhibitors via HPC-based in silico/in vitro investigations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C153.
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Jung, Hyojik, Kieun Bae, Ja Young Lee, Jung-Hyun Kim, Hyun-Jung Han, Hun-Young Yoon und Kyong-Ah Yoon. „Establishment of Canine Transitional Cell Carcinoma Cell Lines Harboring BRAF V595E Mutation as a Therapeutic Target“. International Journal of Molecular Sciences 22, Nr. 17 (25.08.2021): 9151. http://dx.doi.org/10.3390/ijms22179151.
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Transitional cell carcinoma (TCC) is the most common malignant tumor of the canine urinary tract and tends to have a poor prognosis due to its invasive potential. Recent studies have reported that up to 80% of canine urothelial carcinoma has the BRAF V595E mutation, which is homologous to the human V600E mutation. Activating the BRAF mutation is an actionable target for developing effective therapeutic agents inhibiting the BRAF/mitogen-activated protein kinase (MAPK) pathway in canine cancer as well as human cancer. We established novel canine TCC cell lines from two tumor tissues and one metastatic lymph node of canine TCC patients harboring the BRAF V595E mutation. Tumor tissues highly expressed the BRAF mutant and phosphorylated extracellular signal-related kinases (ERK)1/2 proteins. The derived cell lines demonstrated activated MAPK pathways. We also evaluated the cell lines for sensitivity to BRAF inhibitors. Sorafenib, a multiple kinase inhibitor targeting RAF/vascular endothelial growth factor receptor (VEGFR), successfully inhibited the BRAF/MAPK pathway and induced apoptosis. The established canine TCC cell lines responded with greater sensitivity to sorafenib than to vemurafenib, which is known as a specific BRAF inhibitor in human cancer. Our results demonstrated that canine TCC cells showed different responses compared to human cancer with the BRAF V600E mutation. These cell lines would be valuable research materials to develop therapeutic strategies for canine TCC patients.
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Tamura, Shuta, Hiroshi Tazawa, Naoto Hori, Yuncheng Li, Motohiko Yamada, Satoru Kikuchi, Shinji Kuroda, Yasuo Urata, Shunsuke Kagawa und Toshiyoshi Fujiwara. „p53-armed oncolytic adenovirus induces autophagy and apoptosis in KRAS and BRAF-mutant colorectal cancer cells“. PLOS ONE 18, Nr. 11 (16.11.2023): e0294491. http://dx.doi.org/10.1371/journal.pone.0294491.
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Colorectal cancer (CRC) cells harboring KRAS or BRAF mutations show a more-malignant phenotype than cells with wild-type KRAS and BRAF. KRAS/BRAF–wild-type CRCs are sensitive to epidermal growth factor receptor (EGFR)-targeting agents, whereas KRAS/BRAF–mutant CRCs are resistant due to constitutive activation of the EGFR-downstream KRAS/BRAF signaling pathway. Novel therapeutic strategies to treat KRAS/BRAF mutant CRC cells are thus needed. We recently demonstrated that the telomerase-specific replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 exhibit therapeutic potential against KRAS-mutant human pancreatic cancer cells. In this study, we evaluated the therapeutic potential of OBP-301 and OBP-702 against human CRC cells with differing KRAS/BRAF status. Human CRC cells with wild-type KRAS/BRAF (SW48, Colo320DM, CACO-2), mutant KRAS (DLD-1, SW620, HCT116), and mutant BRAF (RKO, HT29, COLO205) were used in this study. The antitumor effect of OBP-301 and OBP-702 against CRC cells was analyzed using the XTT assay. Virus-mediated modulation of apoptosis, autophagy, and the EGFR-MEK-ERK and AKT-mTOR signaling pathways was analyzed by Western blotting. Wild-type and KRAS-mutant CRC cells were sensitive to OBP-301 and OBP-702, whereas BRAF-mutant CRC cells were sensitive to OBP-702 but resistant to OBP-301. Western blot analysis demonstrated that OBP-301 induced autophagy and that OBP-702 induced autophagy and apoptosis in human CRC cells. In BRAF-mutant CRC cells, OBP-301 and OBP-702 suppressed the expression of EGFR, MEK, ERK, and AKT proteins, whereas mTOR expression was suppressed only by OBP-702. Our results suggest that p53-armed oncolytic virotherapy is a viable therapeutic option for treating KRAS/BRAF-mutant CRC cells via induction of autophagy and apoptosis.
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Hernández, Ernesto Almora, Nabila Figueredo Moreno, Susana Matos Oliveros, Vivian Lago Abascal und Efraín Rodríguez Jiménez. „Benefits of the Moringa oleifera seed husk as bran for human consumption“. International Journal of Complementary & Alternative Medicine 17, Nr. 1 (09.01.2024): 1–5. http://dx.doi.org/10.15406/ijcam.2024.17.00675.
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Bran is the husk of cereals, crushed by grinding. It is a food that helps improving different symptoms, mainly for the digestive system. Moringa oleifera Lam. It is a plant with a high nutritional value, so the use of Moringa seed husk was evaluated for human consumption and for strengthening foods by producing bran. To characterize the Moringa seed husk for human consumption as bran and emphasize its benefits to health. The bran was produced by grinding Moringa oleifera Lam. seed husks with a sieve of 2.0mm. The proximal composition was made by infrared near spectrocospy. The determination of minerals and metals was done by the method PT-AQ-23 and moisture by the gravimetric method. The bran from Moringa seed husks, allowed to have a product with soft powder characteristics and a slightly sandy feel, of beige color with brown tips, discreetly bitter and fresh wood odor. From the nutritional point of view, it contributed the following compounds: fiber protein, starch and fat; everything comparable or superior to the contents in other bran of wheat, rice, oat and barley, among others. The bran from Moringa seed husk is a highly beneficial product for digestive health due to the quantity of fiber it provides, the high nutritional value of its other properties.
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De Paepe, Kim, Joran Verspreet, Mohammad Naser Rezaei, Silvia Hidalgo Martinez, Filip Meysman, Davy Van de Walle, Koen Dewettinck, Jeroen Raes, Christophe Courtin und Tom Van de Wiele. „Isolation of wheat bran-colonizing and metabolizing species from the human fecal microbiota“. PeerJ 7 (25.01.2019): e6293. http://dx.doi.org/10.7717/peerj.6293.
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Undigestible, insoluble food particles, such as wheat bran, are important dietary constituents that serve as a fermentation substrate for the human gut microbiota. The first step in wheat bran fermentation involves the poorly studied solubilization of fibers from the complex insoluble wheat bran structure. Attachment of bacteria has been suggested to promote the efficient hydrolysis of insoluble substrates, but the mechanisms and drivers of this microbial attachment and colonization, as well as subsequent fermentation remain to be elucidated. We have previously shown that an individually dependent subset of gut bacteria is able to colonize the wheat bran residue. Here, we isolated these bran-attached microorganisms, which can then be used to gain mechanistic insights in future pure culture experiments. Four healthy fecal donors were screened to account for inter-individual differences in gut microbiota composition. A combination of a direct plating and enrichment method resulted in the isolation of a phylogenetically diverse set of species, belonging to theBacteroidetes,Firmicutes,ProteobacteriaandActinobacteriaphyla. A comparison with 16S rRNA gene sequences that were found enriched on wheat bran particles in previous studies, however, showed that the isolates do not yet cover the entire diversity of wheat-bran colonizing species, comprising among others a broad range ofPrevotella,BacteroidesandClostridiumcluster XIVa species. We, therefore, suggest several modifications to the experiment set-up to further expand the array of isolated species.
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Crispo, Fabiana, Tiziana Notarangelo, Michele Pietrafesa, Giacomo Lettini, Giovanni Storto, Alessandro Sgambato, Francesca Maddalena und Matteo Landriscina. „BRAF Inhibitors in Thyroid Cancer: Clinical Impact, Mechanisms of Resistance and Future Perspectives“. Cancers 11, Nr. 9 (18.09.2019): 1388. http://dx.doi.org/10.3390/cancers11091388.
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The Kirsten rat sarcoma viral oncogene homolog (RAS)/v-raf-1 murine leukemia viral oncogene homolog 1 (RAF)/mitogen-activated protein kinase 1 (MAPK) signaling cascade is the most important oncogenic pathway in human cancers. Tumors leading mutations in the gene encoding for v-raf murine sarcoma viral oncogene homolog B (BRAF) serine-threonine kinase are reliant on the MAPK signaling pathway for their growth and survival. Indeed, the constitutive activation of MAPK pathway results in continuous stimulation of cell proliferation, enhancement of the apoptotic threshold and induction of a migratory and metastatic phenotype. In a clinical perspective, this scenario opens to the possibility of targeting BRAF pathway for therapy. Thyroid carcinomas (TCs) bearing BRAF mutations represent approximately 29–83% of human thyroid malignancies and, differently from melanomas, are less sensitive to BRAF inhibitors and develop primary or acquired resistance due to mutational events or activation of alternative signaling pathways able to reactivate ERK signaling. In this review, we provide an overview on the current knowledge concerning the mechanisms leading to resistance to BRAF inhibitors in human thyroid carcinomas and discuss the potential therapeutic strategies, including combinations of BRAF inhibitors with other targeted agents, which might be employed to overcome drug resistance and potentiate the activity of single agent BRAF inhibitors.
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Franovic, Aleksandra, Nichol Miller, Paul Severson, Toufike Kanouni, Noelito Timple, Ping Jiang, Eric Murphy und Eric Martin. „The next-generation pan-RAF inhibitor, KIN-2787, is active in class II and class III BRAF mutant models.“ Journal of Clinical Oncology 39, Nr. 15_suppl (20.05.2021): 3116. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3116.
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3116 Background: Oncogenic BRAF gene alterations, leading to aberrantly activated BRAF monomers (Class I mutations) or dimers (Class II and Class III mutations), are observed in approximately 6% of all human cancers. First-generation BRAF inhibitors targeting Class I BRAF mutants, including dabrafenib, encorafenib, and vemurafenib, provide significant clinical benefit to patients with BRAF V600 mutation-driven melanoma and select solid tumors as monotherapies or in combination with other targeted therapies. The currently approved BRAF inhibitors have not, however, proven to be effective in patients with Class II or III BRAF alterations which account for a large proportion (34%) of BRAF mutations. KIN-2787 is an orally available, potent and selective small molecule pan-RAF inhibitor specifically designed to inhibit Class II and III BRAF dimers, in addition to Class I mutants. Methods: The efficacy and tolerability of the pan-RAF inhibitor, KIN-2787, was evaluated in vitro and in vivo in Class I, II, and III BRAF mutation-driven human cancer models. Results: In biochemical assays, KIN-2787 showed low nanomolar to picomolar potency against RAF1, BRAF, and ARAF (IC50 0.06-3.46 nM) with minimal activity towards non-RAF kinases. In cell-based assays, KIN-2787 inhibited RAF activity, as measured by inhibition of downstream ERK phosphorylation (pERK), across multiple BRAF mutant cancer cell lines. Class II and III BRAF mutant cell lines were the most responsive when treated with KIN-2787 (IC50 < 50 nM); 19- and 7-fold more sensitive compared to cells harboring wild-type BRAF, respectively. Dose-dependent inhibition of A-375 (Class I), BxPC-3 (Class II), and WM3629 (Class III) BRAF mutant human xenograft tumor growth was attained with daily KIN-2787 treatment and was well-tolerated. A trend towards greater tumor responses was observed with twice daily (BID) compared to once daily (QD) dosing of KIN-2787; however, the two dosing regimens led to similar tumor growth inhibition (TGI) and regressions (mean TGI up to 101-118%; p ≤0.0001) at equivalent total daily doses. Furthermore, KIN-2787 led to a significant in vivo pharmacodynamic response using either regimen, however, prolonged target coverage, as measured by pERK, was achieved with BID dosing. The impact of KIN-2787 treatment on additional biomarkers, including transcriptional changes and MAPK pathway modulation in cell-based models and patient-derived samples, will be presented at the meeting. Conclusions: KIN-2787 is a next-generation pan-RAF inhibitor with pronounced in vitro and in vivo activity against human cancers driven by Class II and III BRAF mutations. A phase 1 dose escalation and expansion clinical trial evaluating the safety and efficacy of KIN-2787 monotherapy in patients with advanced or metastatic solid tumors harboring BRAF gene alterations, including Class II and III mutations, is expected to initiate in 2021.
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Zarei, Iman, Emily Luna, Jan Leach, Anna McClung, Samuel Vilchez, Ousmane Koita und Elizabeth Ryan. „Comparative Rice Bran Metabolomics across Diverse Cultivars and Functional Rice Gene–Bran Metabolite Relationships“. Metabolites 8, Nr. 4 (09.10.2018): 63. http://dx.doi.org/10.3390/metabo8040063.
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Rice (Oryza sativa L.) processing yields ~60 million metric tons of bran annually. Rice genes producing bran metabolites of nutritional and human health importance were assessed across 17 diverse cultivars from seven countries using non-targeted metabolomics, and resulted in 378–430 metabolites. Gambiaka cultivar had the highest number and Njavara had the lowest number of metabolites. The 71 rice bran compounds of significant variation by cultivar included 21 amino acids, seven carbohydrates, two metabolites from cofactors and vitamins, 33 lipids, six nucleotides, and two secondary metabolites. Tryptophan, α-ketoglutarate, γ-tocopherol/β-tocopherol, and γ-tocotrienol are examples of bran metabolites with extensive cultivar variation and genetic information. Thirty-four rice bran components that varied between cultivars linked to 535 putative biosynthetic genes using to the OryzaCyc 4.0, Plant Metabolic Network database. Rice genes responsible for bran composition with animal and human health importance is available for rice breeding programs to utilize in crop improvement.
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Stämpfli, Rolf, Martin Camenzind, Simon Annaheim, Ivona Jerkovic, Rene M. Rossi und Claudia Glass. „Female manikin for the evaluation of breast support provided by sports bras“. Current Issues in Sport Science (CISS) 9, Nr. 2 (06.02.2024): 074. http://dx.doi.org/10.36950/2024.2ciss074.
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Introduction
The effect of breast support on running biomechanics (Milligan, 2013) and breast pain on upper-extremity kinematics during running (White et al., 2015) is investigated by different research groups. They mostly found a higher implication for females with large breasts and showed that the use of sports bras is generally beneficial compared to regular bras. A well-fitted supportive sports bra can increase an athlete's performance (Fong & Powell, 2022) and reduce the risk of injuries.
The support properties of bras are conventionally evaluated by human trials. This is expensive and challenging when comparing the results of different studies.
Methods
Empa developed a manikin to investigate the load impact on the body (Wettenschwiler et al., 2017). This manikin was reshaped to a female upper body model equipped with breast prostheses for the realistic simulation of defined running conditions. A Polhemus motion tracking system was used to assess the relative movement of the manikin shell and the nipples during two simulated running conditions (8 km/h). A set of 16 sports bras was tested on the manikin regarding the reduction of relative movement of the nipples during running. In a first validation study, 6 of them were tested by human subjects during jogging (8 km/h) in 3 participants. The subjective support assessment was compared to the manikin data.
Results
A comparison of manikin measurement data (reduction in relative movement at 8 km/h) and subject data showed an excellent correlation (R2 > 0.95) for the subjective support assessment.
The sports bra developed in this project reached high marks regarding support, thermal comfort, and fit.
Discussion/Conclusion
Preliminary data indicates that the female manikin is able to provide objective data about breast movement in line with the perceived support of sports bras. In combination with additional methods such as sensory and thermal comfort assessment, this new methodology provides a scientific basis for developing improved sports bras meeting specific requirements for various sports.
References
Fong, H. B., & Powell, D. W. (2022). Greater breast support is associated with reduced oxygen consumption and greater running economy during a rreadmill running task. Frontiers in Sports and Active Living, 4, Article 902276. https://doi.org/10.3389/fspor.2022.902276
Milligan, A. K. (2013). The effect of breast support on running biomechanics [Doctoral Dissertation, University of Portsmouth].
Wettenschwiler, P. D., Annaheim, S., Lorenzetti, S., Ferguson, S. J., Stämpfli, R., Psikuta, A., & Rossi, R. M. (2017). Validation of an instrumented dummy to assess mechanical aspects of discomfort during load carriage. PLOS ONE, 12(6), Article e0180069. https://doi.org/10.1371/journal.pone.0180069
White, J., Mills, C., Ball, N., & Scurr, J. (2015). The effect of breast support and breast pain on upper-extremity kinematics during running: Implications for females with large breasts. Journal of Sports Sciences, 33(19), 2043-2050. https://doi.org/10.1080/02640414.2015.1026378
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Trianto, Agus, Sri Sedjati, Ocky Karna Radjasa, Rachmat Afriyanto, Sakti Imam Muchlisin, Septhy Kusuma Radjasa und Muhammad Syaifudien Bahry. „Pemanfaatan Jamur Simbion Sponge dalam Bioisomerasi Asam Lemak pada Dedak untuk Menghasilkan Asam Lemak Cis“. Jurnal Kelautan Tropis 21, Nr. 2 (07.12.2018): 121. http://dx.doi.org/10.14710/jkt.v21i2.3559.
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Utilization of Sponges Symbiotic Fungus in the Bioisomeration of Fatty Acids in Brans to Produce Cis Fatty Acid Trans fatty acids are known to have a negative impact on human health such as triggering the coronary heart and blood vessel related diseases. However, many food and animal feed contain trans fatty acids. Bran, which is widely used as animal feed has high fatty acid content and the majority are trans fatty acids. This study aims to determine the potential of Trichoderma harzanum, a sponge symbiont fungus, in the process of fatty acid bioconversion in bran. Bran was fermented in saline and non-salin condition for 15 days in the room temperature. Both fermented and not bran was extracted with methanol, and the extracts were concentrated with rotary evaporator. Fatty acid extracts were analyzed on the GC with hydrolysis and methylation as pre-treatments. The test results showed the fatty acid composition changed, and the was formation of new fatty acids. The bioisomeration process occurs in the Trans-9-Elaidic acid Methyl esther into Cis-9-Oleic Methyl ester. Cis-9-oleic acid is known as oleic acid which is widely found in olive and sunflowers oil. The fungus has potential as biocatalys for production of cis fatty acid. Asam lemak trans dikenal mempunyai dampak negatif terhadap kesehatan manusia seperti memicu terjadinya penyakit jantung koroner dan penyakit terkait pembuluh darah. Namun asam lemak trans banyak terkandung dalam berbagai jenis bahan makanan maupun pakan ternak diantaranya adalah dedak. Dedak banyak digunakan sebagai pakan ternak mempunyai kandungan asam lemak yang tinggi dan mayoritas adalah asam lemak trans. Penelitian ini bertujuan untuk mengetahui potensi jamur simbion spons Trichoderma harzanum dalam proses biokonversi asam lemak pada dedak. Fermentasi dedak dilakukan dalam kondisi salin dan unsalin selama 15 hari pada suhu ruang. Dedak yang difermentasi maupun tidak kemudian diekstrak dengan metanol kemudian dipekatkan dengan rotari eveporator. Ekstrak asam lemak degan GC dengan pre-treatment meliputi hidrolisis dan metilasi. Hasil uji menunjukan adanya perubahan komposisi dan terbentuknya asam lemak baru. Proses bioisomerasi terjadi pada Trans-9-Elaidic acid Methyl estermenjadi Cis-9-Oleic Methyl ester. Cis-9-oleic acid yang dikenal dengan asam oleat yang banyak terdapat dalam minyak zaitun dan bunga matahari. Jamur T. Harzianum mempunyai potensi sebagai biokatalis untuk memproduksi asam lemak cis.
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Smith, Andrew Paul, Eddie Deaville und Glenn Gibson. „Wheat Bran Cereal, Human Gut Bacteria and Subjective Wellbeing“. Journal of Food Research 7, Nr. 3 (16.03.2018): 8. http://dx.doi.org/10.5539/jfr.v7n3p8.
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Research has shown that consumption of high fiber breakfast cereal is associated with improved subjective well-being, especially increased energy. One possible explanation of these results is through metabolism by gut bacteria and concomitant production of metabolites that influence psychological and gastrointestinal (GI) welfare. This was examined in the present study to determine whether consumption of wheat bran could modulate the composition of the GI microbiota. This human volunteer study (20 volunteers) involved the comparison of three breakfast cereals, All-Bran, Bran Flakes and Cornflakes (60 g/d). The study involved a 14-day baseline phase (no breakfast cereals) and an eight-week experimental phase. Each cereal was consumed for 14 days. A seven-day washout period (no cereals) was carried out between each successive cereal condition. Faecal samples were collected every seven days. Enumeration of predominant faecal bacterial populations (bacteroides, bifidobacteria, clostridia, lactobacilli and eubacteria) was carried out using the culture independent fluorescent in situ hybridisation (FISH) technique. Faecal short chain fatty acid content was also determined. The volunteers completed a battery of questionnaires to assess fatigue/energy, subjective mood, physical and mental health, bowel function and fiber intake. The results showed that in general there was no overall significant effect of breakfast cereal type on the faecal bacterial populations studied. There was also no major effect of breakfast type on short chain fatty acid content. The high-fiber conditions (All-Bran and Bran Flakes) were associated with less fatigue, a significant reduction in cognitive difficulties, looser stools, more motions and feeling more energised.
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Hersey, Peter, David Wroblewski, Branka Mijatov, Xu Dong Zhang und Nikolas Haass. „Effect of the BH3 mimetic ABT-737 on human melanoma cells to apoptosis induced by selective BRAF inhibitors.“ Journal of Clinical Oncology 30, Nr. 15_suppl (20.05.2012): 8553. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8553.
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8553 Background: Although the introduction of selective BRAF inhibitors has been a major advance in treatment of metastatic melanoma, approximately 50% of patients have limited responses including stabilisation of disease or no response at all. The present study aims to identify a novel means of overcoming resistance of melanoma to killing by BRAF inhibitors. Methods: We examined the influence of the BH3 mimetic ABT-737 on induction of apoptosis by the selective BRAF inhibitor PLX4720 on a panel of melanoma cells with BRAF V600E mutations with or without mutations of CDK4 and BRAF wildtype cells with or without NRAS mutations. Included in the studies were cell lines established from 4 patients before and during treatment with selective BRAF inhibitors. Results: Cell lines with no or low sensitivity to PLX 4720 underwent synergistic increases and increased rates of apoptosis when combined with ABT-737. This degree of synergism was not seen in cell lines without BRAF V600E mutations. Apoptosis was mediated through the mitochondrial pathway and was due in part to upregulation of Bim as shown by inhibition of apoptosis following siRNA knockdown of Bim. Similar effects were seen in cell lines established from patients prior to treatment but not in lines from patients clinically resistant to the selective BRAF inhibitors. Conclusions: These results suggest that combination of selective BRAF inhibitors with ABT-737 or the oral form ABT-263 may increase the degree and rate of responses in previously untreated patients with V600E melanoma but not in those with acquired resistance to these agents.
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Marais, R. „BRAF and RAS signalling in human melanoma“. European Journal of Cancer Supplements 6, Nr. 9 (Juli 2008): 120. http://dx.doi.org/10.1016/s1359-6349(08)71632-x.
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Parker, Kristopher D., Akhilendra K. Maurya, Hend Ibrahim, Sangeeta Rao, Petronella R. Hove, Dileep Kumar, Rama Kant et al. „Dietary Rice Bran-Modified Human Gut Microbial Consortia Confers Protection against Colon Carcinogenesis Following Fecal Transfaunation“. Biomedicines 9, Nr. 2 (03.02.2021): 144. http://dx.doi.org/10.3390/biomedicines9020144.
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Rice bran, removed from whole grain rice for white rice milling, has demonstrated efficacy for the control and suppression of colitis and colon cancer in multiple animal models. Dietary rice bran intake was shown to modify human stool metabolites as a result of modifications to metabolism by gut microbiota. In this study, human stool microbiota from colorectal cancer (CRC) survivors that consumed rice bran daily was examined by fecal microbiota transplantation (FMT) for protection from azoxymethane and dextran sodium sulfate (AOM/DSS) induced colon carcinogenesis in germ-free mice. Mice transfaunated with rice bran-modified microbiota communities (RMC) harbored fewer neoplastic lesions in the colon and displayed distinct enrichment of Flavonifractor and Oscillibacter associated with colon health, and the depletion of Parabacteroides distasonis correlated with increased tumor burden. Two anti-cancer metabolites, myristoylcarnitine and palmitoylcarnitine were increased in the colon of RMC transplanted mice. Trimethylamine-N-oxide (TMAO) and tartarate that are implicated in CRC development were reduced in murine colon tissue after FMT with rice bran-modified human microbiota. Findings from this study show that rice bran modified gut microbiota from humans confers protection from colon carcinogenesis in mice and suggests integrated dietary-FMT intervention strategies should be tested for colorectal cancer control, treatment, and prevention.
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Miller, Nichol L. G., Tim S. Wang, Paul Severson, Ping Jiang, Michelle Perez, Noel Timple, Toufike Kanouni, Aleksandra Franovic, Eric S. Martin und Eric Murphy. „Abstract 2674: Antitumor activity of KIN-2787, a next-generation pan-RAF inhibitor, in preclinical models of human RAF/RAS mutant melanoma“. Cancer Research 82, Nr. 12_Supplement (15.06.2022): 2674. http://dx.doi.org/10.1158/1538-7445.am2022-2674.
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Abstract Background: In the US in 2021, invasive melanoma will account for an estimated 106,000 new cases and > 7,000 deaths. Somatic mutations that activate the MAPK signaling pathway are a leading cause of melanoma with 50% harboring oncogenic BRAF alterations and another 20% with activating NRAS mutations. Of note, NRAS mutant melanoma has been shown to be dependent upon RAF signaling via CRAF dimers for downstream activation of MEK/ERK. While targeted therapies are approved for V600 (Class I, monomer-driven) BRAF mutant melanoma, no approved targeted therapy exists for patients with melanoma driven by Class II or Class III dimer-dependent BRAF alterations or NRAS mutations. KIN-2787 is a novel, orally available, potent, and selective pan-RAF inhibitor designed to be effective in RAF-dependent cancers, including all classes of BRAF alterations, by targeting mutant BRAF monomers and RAF dimers, regardless of isoform. Methods: KIN-2787 activity was assessed by suppression of downstream MAPK pathway signaling and subsequent cell growth inhibition in a panel of human melanoma cell lines. In vivo KIN-2787 efficacy was evaluated in BRAF and NRAS mutant melanoma cell- and patient-derived xenograft models. Results: KIN-2787 cellular activity was measured by inhibition of ERK phosphorylation across a panel of melanoma cell lines, including those harboring Class I BRAF alterations, Class II and III BRAF alterations, NRAS mutations, KRAS mutations, and wild type RAF/RAS. In contrast to vemurafenib, an approved BRAF inhibitor with activity limited to Class I BRAF alterations, KIN-2787 was active across all classes of BRAF mutant melanoma cells (EC50 values < 100 nM). NRAS and KRAS mutant cell lines were moderately responsive to KIN-2787 inhibition. Melanoma cells expressing wild type RAS/RAF were the least sensitive to MAPK pathway inhibition by KIN-2787. KIN-2787 also inhibited cell proliferation in BRAF and NRAS mutant melanoma in 2D and 3D cell cultures. Daily KIN-2787 treatment resulted in significant tumor growth inhibition in human melanoma xenograft models bearing Class I, II and III BRAF alterations as well as NRAS mutations and was associated with MAPK pathway suppression. Additionally, KIN-2787 was efficacious in a pre-/post-treatment melanoma PDX pair in which the original tumor was Class I BRAF V600E but acquired a Class II BRAF kinase domain duplication upon progression on dabrafenib + trametinib. Details from the above findings will be presented at the meeting. Conclusions: KIN-2787 is a next-generation, pan-RAF inhibitor with in vitro and in vivo activity against human melanoma driven by BRAF and/or NRAS mutations. Data supports KIN-2787 use in acquired BRAF dimer-dependent resistance to BRAF+MEK inhibitor therapy. A Phase I dose escalation and expansion clinical trial evaluating the safety and efficacy of KIN-2787 is ongoing (NCT04913285). Citation Format: Nichol L. G. Miller, Tim S. Wang, Paul Severson, Ping Jiang, Michelle Perez, Noel Timple, Toufike Kanouni, Aleksandra Franovic, Eric S. Martin, Eric Murphy. Antitumor activity of KIN-2787, a next-generation pan-RAF inhibitor, in preclinical models of human RAF/RAS mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2674.
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Kuan, Feng-Che, Chung-Sheng Shi und Meng-Hung Lin. „Correlation of BRAF genomic alterations with higher mutation burden and predictive response to immune checkpoint inhibitors among human malignancies.“ Journal of Clinical Oncology 40, Nr. 16_suppl (01.06.2022): e14589-e14589. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e14589.
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e14589 Background: The treatment of BRAF-mutated melanoma leads the evolution of management in BRAF-mutated human malignancies from targeted agents to immune checkpoint inhibition. The correlation between BRAF genomic alterations and mutation burden is not well-studied as well as its prognostic role and predictive role to immune checkpoint inhibitors. Methods: Three Public genomic database (AACR GENIE v.11 [N = 119,058], MSKCC pan-cancer [10,080], MSKCC ICI [1,608]) were retrieved from cBioPortal ( https://www.cbioportal.org ). Raw data of cancer types, BRAF status, mutation counts (MC), exposure to immune checkpoints inhibitors (ICIs), and survival were analyzed. Violin plots were used to compare the distribution of MC among BRAF-altered and -wild tumors, and the Kaplan-Meier method was used to estimate survival rates. Statistical significance was set at a two-sided P < 0.05. Results: BRAF genomic alterations exist in 7,361 (6.2%, AACR GENIE v.11), 560 (5.6%, MSKCC pan-cancer) and 165 patients (10.3%, MSKCC ICI). There are 4,851 (4.1%), 357 (3.6%), and 312 (19.4%) patients with melanoma in these database, respectively. AACR GENIE v.11 includes the other two MSKCC databases, and 10.7% (N = 1,074) patients in MSKCC pan-cancer databases are also cases in MSKCC ICI. The median MCs were 7/Mb and 4/Mb, with interquartile ranges of 1 to 1,467 and 1 to 821 in the BRAF-altered and -wild tumors in AACR GENIE v.11. In this three databases, the distribution of MC was different between the BRAF-altered and -wild tumors (p < 0.001). In MSKCC pan-cancer cohort, the median overall survival in BRAF-altered and -wild tumors are 22.8 vs. 26.3 months (logrank p = 0.005). In MSKCC ICI cohort, the median overall survival of BRAF-altered and -wild tumors are 47.0 vs. 17.0 months (logrank p < 0.001). Conclusions: BRAF genomic alterations are associated with higher mutation counts, represent a poor prognostic factor and positively predictive to immune checkpoint inhibition among human malignancies.
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Kuan, Feng-Che, Chung-Sheng Shi und Meng-Hung Lin. „Correlation of BRAF genomic alterations with higher mutation burden and predictive response to immune checkpoint inhibitors among human malignancies.“ Journal of Clinical Oncology 40, Nr. 16_suppl (01.06.2022): e14589-e14589. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e14589.
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e14589 Background: The treatment of BRAF-mutated melanoma leads the evolution of management in BRAF-mutated human malignancies from targeted agents to immune checkpoint inhibition. The correlation between BRAF genomic alterations and mutation burden is not well-studied as well as its prognostic role and predictive role to immune checkpoint inhibitors. Methods: Three Public genomic database (AACR GENIE v.11 [N = 119,058], MSKCC pan-cancer [10,080], MSKCC ICI [1,608]) were retrieved from cBioPortal ( https://www.cbioportal.org ). Raw data of cancer types, BRAF status, mutation counts (MC), exposure to immune checkpoints inhibitors (ICIs), and survival were analyzed. Violin plots were used to compare the distribution of MC among BRAF-altered and -wild tumors, and the Kaplan-Meier method was used to estimate survival rates. Statistical significance was set at a two-sided P < 0.05. Results: BRAF genomic alterations exist in 7,361 (6.2%, AACR GENIE v.11), 560 (5.6%, MSKCC pan-cancer) and 165 patients (10.3%, MSKCC ICI). There are 4,851 (4.1%), 357 (3.6%), and 312 (19.4%) patients with melanoma in these database, respectively. AACR GENIE v.11 includes the other two MSKCC databases, and 10.7% (N = 1,074) patients in MSKCC pan-cancer databases are also cases in MSKCC ICI. The median MCs were 7/Mb and 4/Mb, with interquartile ranges of 1 to 1,467 and 1 to 821 in the BRAF-altered and -wild tumors in AACR GENIE v.11. In this three databases, the distribution of MC was different between the BRAF-altered and -wild tumors (p < 0.001). In MSKCC pan-cancer cohort, the median overall survival in BRAF-altered and -wild tumors are 22.8 vs. 26.3 months (logrank p = 0.005). In MSKCC ICI cohort, the median overall survival of BRAF-altered and -wild tumors are 47.0 vs. 17.0 months (logrank p < 0.001). Conclusions: BRAF genomic alterations are associated with higher mutation counts, represent a poor prognostic factor and positively predictive to immune checkpoint inhibition among human malignancies.
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Wang, Hui, Wenrui Zhang, Rujiao Liu, Jiaoyun Zheng, Xueping Yao, Hui Chen, Jie Wang et al. „Lack of bombesin receptor–activated protein attenuates bleomycin-induced pulmonary fibrosis in mice“. Life Science Alliance 5, Nr. 11 (12.07.2022): e202201368. http://dx.doi.org/10.26508/lsa.202201368.
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Bombesin receptor–activated protein (BRAP) was found to express in the interstitial cells of human fibrotic lungs with unknown function. Its homologous protein, encoded by BC004004 gene, was also present in mouse lung tissues. We used BC004004−/− mice which lack BRAP homologous protein expression to establish a bleomycin-induced lung fibrotic model. After bleomycin treatment, BC004004−/− mice exhibited attenuation of pulmonary injury and less pulmonary fibrosis. Fibroblasts from BC004004−/− mice proliferated at a lower rate and produced less collagen. Autophagy-related gene 5 (ATG5) was identified as a partner interacting with human BRAP. Lacking BRAP homologous protein led to enhanced autophagy activity in mouse lung tissues as well as in isolated lung fibroblasts, indicating a negative regulatory role of this protein in autophagy via interaction with ATG5. Enhanced autophagy process in fibroblasts due to lack of BRAP homologous protein might contribute to the resistance of BC004004−/− mice to pulmonary fibrosis.
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Cesta Incani, Ursula, Anais Del Curatolo, Cristina Di Sanza, Italia Falcone, Francesco Cognetti, Ludovica Ciuffreda und Michele Milella. „Synergistic activity of vertical combinations of agents targeting multiple steps along the RAF/MEK/ERK cascade as a therapeutic strategy in human tumors.“ Journal of Clinical Oncology 30, Nr. 15_suppl (20.05.2012): e13572-e13572. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13572.
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e13572 Background: BRAF-selective kinase inhibitors have potent antitumor effects in mutant BRAF(V600E) tumors; however, in BRAF-wt cells, they paradoxically activate MEK/ERK. In addition, MEK blockade may induce compensatory signaling through both upstream pathway elements (RAF) and parallel pathways (PI3K/AKT/mTOR). Methods: We set out to define molecular and functional effects of single and combined BRAF (GSK2118436A, BRAF-I) and MEK (GSK1120212B, MEK-I) inhibition, using WB analysis to dissect signaling and a fixed dose-ratio experimental design to assess functional synergism by conservative isobologram analysis. Results: In A549 lung adenocarcinoma (KRAS G12S), BRAF-I (10 μM) induces hyperphosphorylation of CRAF, MEK, ERK, and p90RSK, while MEK-I (10 nM), alone or in combination with BRAF-I, potently offsets MAPK activation. Combined BRAF-I and MEK-I suppress malignant growth and survival at 72 h with highly synergistic effects in the A549 (lung, KRAS G12S), H1299 (lung, NRAS), HCT116 (colon, KRAS G13D), and MIAPACA (pancreatic, KRAS G12V) models, with combination indexes (CI), ranging from 1.37 to 0.12. Conversely, in other lung cancer models (H460, Calu-1, Calu-3) the combination of BRAF-I and MEK-I produced modestly additive to highly antagonistic antitumor effects. In BRAF-mutant melanoma and colon carcinoma models (M14 and HT29), there was no paradoxical activation of the MEK/ERK module in response to BRAF-I and both BRAF-I and MEK-I had pronounced growth inhibitory effects as single agents, but were frankly antagonistic in combination. Similarly, the pan-RAF inhibitor RAF265 did not cause MAPK activation and did not result in synergistic growth inhibition when combined with the MEK-I in the A549 and MIAPACA cell lines. Conclusions: Overall, our data indicate that combined inhibition of multiple signaling elements along the RAF/MEK/ERK pathway results in strongly synergistic growth inhibition, particularly in tumors with RAS mutations. Additional studies to better define genetic determinants of sensitivity/resistance and molecular mechanisms of therapeutic synergism of combined BRAF-I and MEK-I are currently ongoing.
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Santoso, V., T. Estiasih und W. D. R. Putri. „Utilization of rice bran for wheat flour substitution in noodle product development: a review“. IOP Conference Series: Earth and Environmental Science 924, Nr. 1 (01.11.2021): 012023. http://dx.doi.org/10.1088/1755-1315/924/1/012023.
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Abstract Rice bran is a by-product of polishing in the rice milling process. Rice bran contains numerous bioactive compounds with a beneficial effect on human health, namely dietary fiber, flavonoid, tocopherol, tocotrienol, and gamma-oryzanol. Since the trend of healthy food has been rising, rice bran has been taken an interest to use in functional food development. Noodle products are often developed as a functional food due to widely consumed foods and as a great carrier to deliver bioactive compounds. The utilization of rice bran could change noodle quality attributes which influences market acceptance. Dietary fiber in rice bran could affect noodles cooking quality and texture profile. Stabilization of rice bran before use could reduce adverse effects of rice bran on noodles’ quality. Noodle processing such as kneading and cooking could affect antioxidant compounds. The aim of this paper is to review rice bran substituted noodle quality, including nutritional product value, factors affecting noodle characteristics, and methods to improve rice bran noodle quality. This paper discussed not only noodles enriched with white rice bran but also with red and black rice bran. Thus, it could provide broad information to support further rice bran utilization in noodle development.
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McCallum, Margaret E., und Deborah L. Rhode. „"Now That We've Burned Our Bras...": Review of "Justice and Gender"“. Labour / Le Travail 27 (1991): 257. http://dx.doi.org/10.2307/25130254.
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Schreck, Karisa, Andrew Morin, Guisheng Zhao, Bridget Sanford, Adam Green, Kenneth Jones, Anurhada Banerjee et al. „DDRE-13. DECONVOLUTING MECHANISMS OF RESISTANCE TO BRAF INHIBITORS IN BRAF V600E HUMAN GLIOMA“. Neuro-Oncology 22, Supplement_2 (November 2020): ii64. http://dx.doi.org/10.1093/neuonc/noaa215.258.
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Abstract BACKGROUND While BRAF-targeted therapy can be effective in a subset of patients with glioma, resistance to treatment can emerge over time. The description and validation of mechanisms of resistance in BRAF-mutant glioma are not previously described. METHODS Pre- and post- BRAF inhibitor (BRAFi) or BRAFi/MEK inhibitor (MEKi) treated patient samples were obtained under IRB-approved protocols at University of Colorado Denver, UCSF, and Johns Hopkins. Targeted DNA sequencing or whole exome sequencing (WES), and RNA-seq were conducted on paired samples. Functional validation of putative resistance mechanisms was performed using established glioma cell lines with BRAF V600E mutation (DBTRG-5MG, AM38, B76). RESULTS Analysis of 15 tissue sample pairs identified point mutations in 15 genes (including CBL, NF1, PTEN, and MAP2K1) and expression changes in RAF1 leading to putative mechanisms of resistance. We performed functional validation of loss of NF1 and CBL as resistance mechanisms and demonstrated growth inhibition and cell death in response to BRAFi with siRNA/sgRNA-mediated knockdown of each gene. Knockdown of CBL resulted in increased EGFR expression and phosphorylation, a possible mechanism for maintaining ERK signaling within the cell. Combination therapy with a MEKi or EGFR inhibitor was able to overcome resistance to BRAFi, in NF1 knockdown and CBL knockdown, respectively. Restoration of wild-type PTEN in B76 cells (PTEN-/-) restored sensitivity to BRAFi. Ingenuity pathway analysis suggested that a switch from BRAF to CRAF dependence mediated resistance in some tumors. Indeed, inhibition of CRAF expression using siRNA in a patient-derived glioma cell line re-sensitized cells to BRAFi. CONCLUSIONS Analysis of pre-/post-treatment BRAF mutant glioma sample pairs, primarily from pediatric patients, identified a variety of putative resistance mechanisms, some of which have been validated in vitro. Resistance mechanisms to BRAFi in glioma are varied and may be susceptible to different combinations of targeted therapy, highlighting the importance of a personalized approach.
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Sheldon, William. „Rafting the Martha Brae“. Organization & Environment 11, Nr. 4 (Dezember 1998): 478. http://dx.doi.org/10.1177/0921810698114018.
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Stewart, Maria L., und Joanne L. Slavin. „Particle size and fraction of wheat bran influence short-chain fatty acid productionin vitro“. British Journal of Nutrition 102, Nr. 10 (07.08.2009): 1404–7. http://dx.doi.org/10.1017/s0007114509990663.
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Whole grains are associated with decreased risk of chronic disease and decreased risk of obesity. Several mechanisms may be involved including SCFA production via fibre fermentation in the colon. The aim of the present study was to evaluate the role of wheat bran particle size (large/coarsev.small/fine) and wheat bran fraction (whole branv.aleuronev.aleurone by-product) in SCFA production using a batchin vitrofermentation system with human faecal inoculum. Five samples were compared: large-particle bran, small-particle bran, aleurone, coarse by-product, fine by-product. Fine by-product produced the greatest SCFA concentrations. By-product (both coarse and fine) produced greater SCFA concentrations than bran (both large and small particle sizes). Aleurone produced SCFA concentrations similar to small-particle bran. The molar percentage of butyrate at 24 h was significantly greater for large-particle bran than the other samples. Small/fine particle size and by-product fraction of bran increased SCFA production compared with large/coarse particle size, and aleurone and whole bran. Bran characteristics and composition should be considered when manufacturing foods due to the diversity of physiological effects.
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Zhang, Zongjing, Dingxie Liu, Avaniyapuram Kannan Murugan, Zhimin Liu und Mingzhao Xing. „Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer“. Endocrine-Related Cancer 21, Nr. 2 (15.11.2013): 161–73. http://dx.doi.org/10.1530/erc-13-0399.
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The BRAF V600E mutation causes impaired expression of sodium iodide symporter (NIS) and radioiodine refractoriness of thyroid cancer, but the underlying mechanism remains undefined. In this study, we hypothesized that histone deacetylation at the NIS (SLC5A5) promoter was the mechanism. Using the chromatin immunoprecipitation approach, we examined histone acetylation status on the lysine residues H3K9/14, H3K18, total H4, and H4K16 at the NIS promoter under the influence of BRAF V600E. We found that expression of stably or transiently transfected BRAF V600E inhibited NIS expression while the deacetylase inhibitor SAHA stimulated NIS expression in PCCL3 rat thyroid cells. Although BRAF V600E enhanced global histone acetylation, it caused histone deacetylation at the NIS promoter while SAHA caused acetylation in the cells. In human thyroid cancer BCPAP cells harboring homozygous BRAF V600E mutation, BRAF V600E inhibitor, PLX4032, and MEK inhibitor, AZD6244, increased histone acetylation of the NIS promoter, suggesting that BRAF V600E normally maintained histone in a deacetylated state at the NIS promoter. The regions most commonly affected with deacetylation by BRAF V600E were the transcriptionally active areas upstream of the translation start that contained important transcription factor binding sites, including nucleotides −297/−107 in the rat NIS promoter and −692/−370 in the human NIS promoter. Our findings not only reveal an epigenetic mechanism for BRAF V600E-promoted NIS silencing involving histone deacetylation at critical regulatory regions of the NIS promoter but also provide further support for our previously proposed combination therapy targeting major signaling pathways and histone deacetylase to restore thyroid gene expression for radioiodine treatment of thyroid cancer.
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Jansen, Philipp, Ioana Cosgarea, Rajmohan Murali, Inga Möller, Antje Sucker, Cindy Franklin, Annette Paschen et al. „Frequent Occurrence of NRAS and BRAF Mutations in Human Acral Naevi“. Cancers 11, Nr. 4 (16.04.2019): 546. http://dx.doi.org/10.3390/cancers11040546.
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Acral naevi are benign melanocytic tumors occurring at acral sites. Occasionally they can progress to become malignant tumors (melanomas). The genetics of acral naevi have not been assessed in larger studies. In our study, a large cohort of 130 acral naevi was screened for gene mutations known to be important in other naevi and melanoma subtypes by targeted next-generation sequencing. Mutation status was correlated with clinicopathological parameters. Frequent mutations in genes activating the MAP kinase pathway were identified, including n = 87 (67%) BRAF, n = 24 (18%) NRAS, and one (1%) MAP2K1 mutations. BRAF mutations were almost exclusively V600E (n = 86, 99%) and primarily found in junctional and compound naevi. NRAS mutations were either Q61K or Q61R and frequently identified in dermal naevi. Recurrent non-V600E BRAF, KIT, NF1, and TERT promoter mutations, present in acral melanoma, were not identified. Our study identifies BRAF and NRAS mutations as the primary pathogenic event in acral naevi, however, distributed differently to those in non-acral naevi. The mutational profile of acral naevi is distinct from acral melanoma, which may be of diagnostic value in distinguishing these entities.
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Yu, Shihui, und William D. Graf. „BRAF Gene Deletion Broadens the Clinical Spectrum Neuro-Cardio-Facial-Cutaneous Syndromes“. Journal of Child Neurology 26, Nr. 12 (23.08.2011): 1593–96. http://dx.doi.org/10.1177/0883073811413830.
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Point mutations in the human BRAF gene are associated with a group of heterogeneous autosomal dominant neuro-cardio-facial-cutaneous syndromes. We identified a novel 93 kb intragenic deletion of the BRAF gene in a boy with severe developmental encephalopathy using microarray-based comparative genomic hybridization. The unique genotype and phenotype in this patient expands the spectrum of BRAF-related neurodevelopmental disorders. We propose a BRAF gene loss-of-function mechanism to best explain the biological basis of this severe developmental encephalopathy with postnatal growth deficiency.
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Karreth, Florian, Markus Reschke, Bjoern Chapuy, Margaret A. Shipp, Roberto Chiarle und Pier Paolo Pandolfi. „The BRAF Pseudogene Is a Proto-Oncogenic Competitive Endogenous RNA“. Blood 124, Nr. 21 (06.12.2014): 263. http://dx.doi.org/10.1182/blood.v124.21.263.263.
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Abstract Non-coding RNAs have long been viewed as non-functional genomic relicts of evolution, but recetn findings have implicated their importance in physiology and disease. Recently, in vitro experiments demonstrated that the pseudogenes of PTEN and KRAS operate as natural miRNA decoys (competitive endogenous RNAs or ceRNAs) that regulate the expression of their parental genes. However, in vivo evidence for a causal role of pseudogenes in cancer development is lacking. To investigate whether the BRAF pseudogene (BRAFps) possesses oncogenic properties we generated transgenic mice carrying a Tet-inducible BRAF pseudogene allele. Global BRAFps overexpression resulted in the development of aggressive B-cell lymphoma after 6-12 months. These tumors were characterized by a profound expansion of B-lymphocytes in the spleen, as well as splenomegaly, lymphadenopathy and infiltration of the kidneys, lungs, and liver by neoplastic cells. The BRAFps-induced lymphoma was polyclonal, transplantable, dependent on continuous BRAFps expression, and cooperated with heterozygous loss of PTEN to accelerate disease onset. Mechanistically, we propose that BRAFps functions as a ceRNA that sequesters miRNAs from BRAF and possibly other targets. Indeed, overexpression of BRAFps results in elevated levels of BRAF in a Dicer-dependent manner. This, in turn, increased BRAF-dependent MAPK signaling and proliferation. To further validate the ceRNA activity of BRAFps, we engineered mice to express only the 3’UTR or CDS of BRAFps as each portion of the pseudogene may individually engage in miRNA-mediated crosstalk with BRAF. Notably, both BRAFps-CDS and BRAFps-3’UTR increased spleen and lymph node weights 6 months after induction. Interestingly, BRAFps-3’UTR elicited a lymphoma phenotype similar to full length BRAFps, while mice expressing BRAFps-CDS developed a more indolent form of this phenotype, suggesting that lymphomagenesis is primarily mediated by the BRAFps 3’UTR. BRAFps transcript was undetectable in primary human B-cells, but was aberrantly expressed in primary human DLBCL and human DLBCL cell lines. Expression of BRAF and BRAFps was positively correlated in human primary DLBCL and human DLBCL cell lines. In addition, gains or amplifications of the genomic locus containing BRAFps were found in various human cancer types. Overexpression of BRAFps in human lymphoma cells elevated BRAF levels, MAPK activation, proliferation and growth in xenografts. Our results demonstrate for the first time the oncogenic potential of a pseudogene in an engineered mouse model and indicate that ceRNA- mediated regulation is an important regulatory mechanism of gene expression in vivo. Disclosures No relevant conflicts of interest to declare.
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Vera, Olga, Ilah Bok, Neel Jasani, Oluwashanu Balogun, Koji Nakamura und Florian Karreth. „Abstract PR12: Regulation of the tumor-suppressive miR-29 family by oncogenic MAPK signaling in melanoma“. Cancer Research 80, Nr. 19_Supplement (01.10.2020): PR12. http://dx.doi.org/10.1158/1538-7445.mel2019-pr12.
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Abstract MicroRNAs are a group of noncoding RNAs that can regulate gene expression by targeting the mRNA of a gene. Many microRNAs respond to different stimuli such as growth signals or cellular stress. The tumor-suppressive miR-29 family (miR-29a, b and c), for example, is induced during aging and senescence as a p53-dependent response to DNA damage. Given the tumor-suppressive potential of miR-29, we sought to examine if its expression is induced by oncogenic stress in a p53-dependent manner. Ectopic overexpression of oncogenic Braf-V600E and Kras-G12D in mouse embryonic fibroblasts (MEFs) using retroviral transduction resulted in increased expression of pri-miR-29a-b1 and, to a lesser extent, pri-miR-29b2~c. While ectopic Kras-G12D overexpression stimulated p53 activity, Braf-V600E failed to elicit a p53 response, suggesting that this oncogene provokes miR-29 expression in a p53-independent manner. Moreover, expression of Braf-V600E at physiologic levels induced miR-29 in the absence of a p53 response. Accordingly, expression of endogenous Braf-V600E stimulated miR-29 in MEFs even when p53 was silenced by RNAi. When Braf-V600E MEFs were treated with a MEK inhibitor, miR-29 levels decreased in both the presence and absence of p53, suggesting that the MAPK pathway downstream of Braf-V600E directly regulates miR-29 transcription. Importantly, TPA-mediated stimulation of the MAPK pathway increased miR-29 levels in human melanocytes. Similarly, expression of Braf-V600E induced miR-29 in human melanocytes and MEK inhibition rescued this effect. These results strongly support the notion that miR-29 transcription is induced by MAPK signaling and suggest that oncogenic BRAF provokes a tumor-suppressive miR-29 checkpoint that needs to be inactivated for further tumor progression. Indeed, human melanoma cells lines express lower levels of miR-29 compared to human melanocytes, and inactivation of miR-29 by a lentiviral sponge in Braf-V600E mutant melanocytes and melanoma cells promotes cell transformation. We are now utilizing our ESC-GEMM platform to generate Braf-V600E; Pten-deficient mice expressing the miR-29 sponge and will assess if counteracting the induction of miR-29 by Braf-V600E promotes melanoma formation in vivo. Our results suggest a biphasic role of miR-29 during melanomagenesis where Braf-V600E-induced miR-29 upregulation prevents the progression of early lesions until miR-29 is downregulated, likely by inactivation of the ARF-p53 axis. This abstract is also being presented as Poster B24. Citation Format: Olga Vera, Ilah Bok, Neel Jasani, Oluwashanu Balogun, Koji Nakamura, Florian Karreth. Regulation of the tumor-suppressive miR-29 family by oncogenic MAPK signaling in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR12.
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Li, Yinghui, Hui Shan Cheng, Wee Joo Chng und Vinay Tergaonkar. „Activation of mutantTERTpromoter by RAS-ERK signaling is a key step in malignant progression of BRAF-mutant human melanomas“. Proceedings of the National Academy of Sciences 113, Nr. 50 (23.11.2016): 14402–7. http://dx.doi.org/10.1073/pnas.1611106113.
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Although activating BRAF/NRAS mutations are frequently seen in melanomas, they are not sufficient to drive malignant transformation and require additional events. Frequent co-occurrence of mutations in the promoter fortelomerase reverse transcriptase(TERT), along with BRAF alterations, has recently been noted and correlated with poorer prognosis, implicating a functional link between BRAF signaling and telomerase reactivation in melanomas. Here, we report that RAS-ERK signaling in BRAF mutant melanomas is critical for regulating active chromatin state and recruitment of RNA polymerase II at mutantTERTpromoters. Our study provides evidence that the mutantTERTpromoter is a key substrate downstream of the RAS-ERK pathway. ReactivatingTERTand hence reconstituting telomerase is an important step in melanoma progression from nonmalignant nevi with BRAF mutations. Hence, combined targeting of RAS-ERK andTERTpromoter remodeling is a promising avenue to limit long-term survival of a majority of melanomas that harbor these two mutations.
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Ross, Yasmeen B., Mahbubul Hoque, Jesse D. Blanton, Erin D. Kennedy, MD Sohel Rana, Sanya Tahmina, Sarah Bonaparte, Jennifer R. Head und Ryan M. Wallace. „Rabies healthcare-seeking behaviors of urban and peri-urban residents: Results from a rabies knowledge, attitudes, and practices survey, Bangladesh, 2018“. PLOS Neglected Tropical Diseases 16, Nr. 8 (09.08.2022): e0010634. http://dx.doi.org/10.1371/journal.pntd.0010634.
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Rabies is one of the most lethal infectious diseases, with those living in Asia and Africa having the highest risk of dying from rabies. We conducted a knowledge, attitudes and practices survey in urban and peri-urban areas of Bangladesh to describe canine bite rates, rabies knowledge, and healthcare seeking behaviors and barriers to human and dog vaccination. A bite risk assessment score (BRAS) and healthcare-seeking behavior score (HSBS) was calculated for each bite victim. Respondents were given two hypothetical situations to assess potential behaviors after a bite and willingness to pay for rabies vaccine and immunoglobulin. In total, 2,447 households participated in the survey and 85 bite victims were identified. The BRAS identified that 31% of bites posed no risk of rabies transmission. Multivariate analyses showed that living in Chittagong (β = 1.4; 95% CI: 0.1, 2.7) was associated with a higher HSBS. Findings presented here provide useful information regarding bite occurrences, healthcare-seeking behaviors, and a need for strategies to increase rabies awareness.
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Smythe, J., B. Gardner und DJ Anstee. „Quantitation of the number of molecules of glycophorins C and D on normal red blood cells using radioiodinated Fab fragments of monoclonal antibodies“. Blood 83, Nr. 6 (15.03.1994): 1668–72. http://dx.doi.org/10.1182/blood.v83.6.1668.1668.
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Abstract Two rat monoclonal antibodies (BRAC 1 and BRAC 11) have been produced. BRAC 1 recognizes an epitope common to the human erythrocyte membrane glycoproteins glycophorin C (GPC) and glycophorin D (GPD). BRAC 11 is specific for GPC. Fab fragments of these antibodies and BRIC 10, a murine monoclonal anti-GPC, were radioiodinated and used in quantitative binding assays to measure the number of GPC and GPD molecules on normal erythrocytes. Fab fragments of BRAC 11 and BRIC 10 gave values of 143,000 molecules GPC per red blood cell (RBC). Fab fragments of BRAC 1 gave 225,000 molecules of GPC and GPD per RBC. These results indicate that GPC and GPD together are sufficiently abundant to provide membrane attachment sites for all of the protein 4.1 in normal RBCs.
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Smythe, J., B. Gardner und DJ Anstee. „Quantitation of the number of molecules of glycophorins C and D on normal red blood cells using radioiodinated Fab fragments of monoclonal antibodies“. Blood 83, Nr. 6 (15.03.1994): 1668–72. http://dx.doi.org/10.1182/blood.v83.6.1668.bloodjournal8361668.
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Two rat monoclonal antibodies (BRAC 1 and BRAC 11) have been produced. BRAC 1 recognizes an epitope common to the human erythrocyte membrane glycoproteins glycophorin C (GPC) and glycophorin D (GPD). BRAC 11 is specific for GPC. Fab fragments of these antibodies and BRIC 10, a murine monoclonal anti-GPC, were radioiodinated and used in quantitative binding assays to measure the number of GPC and GPD molecules on normal erythrocytes. Fab fragments of BRAC 11 and BRIC 10 gave values of 143,000 molecules GPC per red blood cell (RBC). Fab fragments of BRAC 1 gave 225,000 molecules of GPC and GPD per RBC. These results indicate that GPC and GPD together are sufficiently abundant to provide membrane attachment sites for all of the protein 4.1 in normal RBCs.
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Wang, Tim S., Catherine Lee, Paul Severson, Robert J. Pelham, Richard Williams und Nichol L. G. Miller. „Abstract 4927: Exarafenib (KIN-2787) is a potent, selective pan-RAF inhibitor with activity in preclinical models of BRAF class II/III mutant and NRAS mutant melanoma“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 4927. http://dx.doi.org/10.1158/1538-7445.am2023-4927.
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Abstract Background: MAPK activating mutations are common in melanoma, with 40% of cases attributed to oncogenic BRAF mutations and 20-25% NRAS mutations. Secondary MAPK activation is a known resistance mechanism to approved BRAF inhibitors in BRAFV600 melanoma. While BRAF inhibitors are approved for Class I BRAFV600 melanomas, patients with dimer-driven BRAF Class II/III and RAF1-dependent NRAS activated melanomas lack approved targeted therapy. Development of next-gen pan-RAF inhibitors targeting all RAF proteins and mutant dimers remains a priority. Emerging clinical data from pan-RAF inhibitors combined with MEK inhibitors suggests increased benefit for MAPK-altered melanoma patients. Exarafenib (KIN-2787) is a clinical stage, novel, highly selective pan-RAF inhibitor designed to be effective in RAF-dependent cancers.Methods: KIN-2787 was evaluated using enzyme assays across the human kinome and activity against oncogenic RAF alterations were validated in BaF3 cells. MAPK pathway suppression and cell growth inhibition were assessed across a panel of human tumor cell lines. Combination dose matrices were performed with KIN-2787 and binimetinib (bini) to evaluate synergistic cell growth inhibition. Extended cell growth studies were performed by Incucyte. In vivo KIN-2787 efficacy was evaluated in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of human BRAF and NRAS mutant cancer.Results: Exarafenib demonstrated exceptional kinome selectivity with minimal off-target kinases significantly inhibited relative to BRAF. Exarafenib potently inhibited a broad panel of oncogenic BRAF mutations in biochemical and BaF3 cell assays. Functional MAPK signaling and viability studies in human tumor cell lines highlighted exarafenib activity in BRAF and NRAS mutant melanoma with minimal activity in normal (BRAF WT) cells. Synergy with the MEK inhibitor bini was determined and the exarafenib + bini combination durably inhibited growth in NRAS mutant melanoma cell lines. In line with cellular studies, treatment with exarafenib demonstrated significant tumor growth inhibition at 30 mg/kg BID in CDX and PDX models of human NRAS mutant melanoma. 10 mg/kg BID exarafenib combined with a clinically relevant dose of bini resulted in combination benefit and durable suppression of the MAPK pathway, relative to either agent alone.Conclusions: The superior kinome selectivity of exarafenib and its activity across multiple RAF-dependent melanoma models position it as a potentially class-leading pan-RAF inhibitor. In addition to efficacy in BRAF mutant tumors, these data support use of exarafenib in combination therapy with MEK inhibitors in NRAS mutant melanoma. A Ph I dose escalation clinical trial evaluating the safety and efficacy of exarafenib in monotherapy and in combination with binimetinib is ongoing (NCT04913285). Citation Format: Tim S. Wang, Catherine Lee, Paul Severson, Robert J. Pelham, Richard Williams, Nichol L. G. Miller. Exarafenib (KIN-2787) is a potent, selective pan-RAF inhibitor with activity in preclinical models of BRAF class II/III mutant and NRAS mutant melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4927.
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Wakuda, Yuki, Akiko Noda, Yasuhisa Hasegawa, Fumihito Arai, Toshio Fukuda und Mitsuo Kawaguchi. „Biological Rhythm Based Wearable Sleep State Observer“. Journal of Advanced Computational Intelligence and Intelligent Informatics 11, Nr. 2 (20.02.2007): 232–41. http://dx.doi.org/10.20965/jaciii.2007.p0232.
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This research aimed to observe human biological rhythm and adjust the human sleep wake pattern based on controlling wakeup timing using low stress system. An ordinary alarm clock operates according to preset time. Biological rhythm determines the human sleep cycle, which affects sleep depth and wakeup timing, which in turn resets the daily rhythm that affects human’s behavior, life-cycle pattern, life-style related disease. We developed a wearable biological rhythm based awakening controller (BRAC) that determines the biological rhythm in the sleep state (sleep cycle) and stimulates the user at a suitable time to enable the person to wakeup refreshed. The proposed system BRAC gauges human’s sleep quality and rhythms from peak to peak interval time of fingertip-pulse waves, that are measured more easily than polysomnography (PSG). In this paper, we detail the method of sleep cycle estimation using a wearable sensor device as the first feature of BRAC, then, in experiments, evaluate the performance of sleep cycle estimation based on a comparison of the BRAC-sleep cycle and the PSG-determined sleep stage.
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Yick, Kit-Lun, Yin-Ching Keung, Annie Yu, Kam-Ho Wong, Kwok-Tung Hui und Joanne Yip. „Sports Bra Pressure: Effect on Body Skin Temperature and Wear Comfort“. International Journal of Environmental Research and Public Health 19, Nr. 23 (26.11.2022): 15765. http://dx.doi.org/10.3390/ijerph192315765.
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Sports bras are an essential apparel for active women, but may exert excessive pressure that negatively affects thermoregulation, thermal comfort and wear sensation. This study measures skin temperature changes during short durations of exercise on a treadmill with different bra pressures. The results based on 21 female subjects (age: 27.2 ± 4.5 years old) show that bras with more pressure at the underband or shoulder straps do not cause statistically significant skin temperature changes during exercise (p > 0.05). Nevertheless, compared to the optimal bra fit, significant differences in bra-breast skin temperature are found during running, cooling down and sitting when the bra pressure is increased (p < 0.05), particularly under bra cup (T1) in this study. The FLIR thermal images can visualize the skin temperature changes at abdomen throughout the four activity stages. Subjective sensations of bra thermal comfort, pressure and breast support are assessed. Despite the increased pressure on the shoulders and chest wall, perceptions towards thermal comfort remain unchanged. The perceived pressure comfort and support sensation amongst the 4 bra conditions are comparable. Interestingly, positive sensations of pressure comfort and breast support are perceived with a tight-fitting sports bra during treadmill exercise. High pressures induced by sports bras (>4 kPa) that habitually considered harmful to the human body may not lead to wear discomfort but enhance bra support sensation and a sense of security to the wearers.
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Dolinsek, Tanja, Lara Prosen, Maja Cemazar, Tjasa Potocnik und Gregor Sersa. „Electrochemotherapy with bleomycin is effective in BRAF mutated melanoma cells and interacts with BRAF inhibitors“. Radiology and Oncology 50, Nr. 3 (01.09.2016): 274–79. http://dx.doi.org/10.1515/raon-2016-0042.
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Abstract Background The aim of the study was to explore the effectiveness of electrochemotherapy (ECT) during the treatment of melanoma patients with BRAF inhibitors. Its effectiveness was tested on BRAF mutated and non-mutated melanoma cells in vitro and in combination with BRAF inhibitors. Materials and methods ECT with bleomycin was performed on two human melanoma cell lines, with (SK-MEL-28) or without (CHL-1) BRAF V600E mutation. Cell survival was determined using clonogenic assay to determine the effectiveness of ECT in melanoma cells of different mutation status. Furthermore, the effectiveness of ECT in concomitant treatment with BRAF inhibitor vemurafenib was also determined in BRAF mutated cells SK-MEL-28 with clonogenic assay. Results The survival of BRAF V600E mutated melanoma cells was even lower than non-mutated cells, indicating that ECT is effective regardless of the mutational status of melanoma cells. Furthermore, the synergistic interaction between vemurafenib and ECT with bleomycin was demonstrated in the BRAF V600E mutated melanoma cells. Conclusions The effectiveness of ECT in BRAF mutated melanoma cells as well as potentiation of its effectiveness during the treatment with vemurafenib in vitro implies on clinical applicability of ECT in melanoma patients with BRAF mutation and/or during the treatment with BRAF inhibitors.
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Robbins, Richard J., Jessica S. Thomas, Patricia Mejia Osuna und Jawairia Shakil. „A BRAF V600E Mutation in RET-Negative Medullary Thyroid Cancer“. Case Reports in Endocrinology 2020 (10.03.2020): 1–4. http://dx.doi.org/10.1155/2020/7641940.
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We report the case of a woman with a sporadic medullary thyroid carcinoma. Genomic analysis found that her tumor did not contain any common RET mutations but did harbor a BRAF V600E mutation. Only one other well-confirmed example of the BRAF V600E mutation has been reported in an MTC patient. We conclude that this common BRAF mutation may independently drive neoplastic transformation of human parafollicular C cells.
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Perna, Daniele, Florian A. Karreth, Alistair G. Rust, Pedro A. Perez-Mancera, Mamunur Rashid, Francesco Iorio, Constantine Alifrangis et al. „BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model“. Proceedings of the National Academy of Sciences 112, Nr. 6 (26.01.2015): E536—E545. http://dx.doi.org/10.1073/pnas.1418163112.
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BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors elicit a transient anti-tumor response in ∼80% of BRAFV600-mutant melanoma patients that almost uniformly precedes the emergence of resistance. Here we used a mouse model of melanoma in which melanocyte-specific expression of BrafV618E (analogous to the human BRAFV600E mutation) led to the development of skin hyperpigmentation and nevi, as well as melanoma formation with incomplete penetrance. Sleeping Beauty insertional mutagenesis in this model led to accelerated and fully penetrant melanomagenesis and synchronous tumor formation. Treatment of BrafV618E transposon mice with the BRAF inhibitor PLX4720 resulted in tumor regression followed by relapse. Analysis of transposon insertions identified eight genes including Braf, Mitf, and ERas (ES-cell expressed Ras) as candidate resistance genes. Expression of ERAS in human melanoma cell lines conferred resistance to PLX4720 and induced hyperphosphorylation of AKT (v-akt murine thymoma viral oncogene homolog 1), a phenotype reverted by combinatorial treatment with PLX4720 and the AKT inhibitor MK2206. We show that ERAS expression elicits a prosurvival signal associated with phosphorylation/inactivation of BAD, and that the resistance of hepatocyte growth factor-treated human melanoma cells to PLX4720 can be reverted by treatment with the BAD-like BH3 mimetic ABT-737. Thus, we define a role for the AKT/BAD pathway in resistance to BRAF inhibition and illustrate an in vivo approach for finding drug resistance genes.
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Pritchard, C., L. Carragher, V. Aldridge, S. Giblett, H. Jin, C. Foster, C. Andreadi und T. Kamata. „Mouse models for BRAF-induced cancers“. Biochemical Society Transactions 35, Nr. 5 (25.10.2007): 1329–33. http://dx.doi.org/10.1042/bst0351329.
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Oncogenic mutations in the BRAF gene are detected in ∼7% of human cancer samples with a particularly high frequency of mutation in malignant melanomas. Over 40 different missense BRAF mutations have been found, but the vast majority (>90%) represent a single nucleotide change resulting in a valine→glutamate mutation at residue 600 (V600EBRAF). In cells cultured in vitro, V600EBRAF is able to stimulate endogenous MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] and ERK phosphorylation leading to an increase in cell proliferation, cell survival, transformation, tumorigenicity, invasion and vascular development. Many of these hallmarks of cancer can be reversed by treatment of cells with siRNA (small interfering RNA) to BRAF or by inhibiting MEK, indicating that BRAF and MEK are attractive therapeutic targets in cancer samples with BRAF mutations. In order to fully understand the role of oncogenic BRAF in cancer development in vivo as well as to test the in vivo efficacy of anti-BRAF or anti-MEK therapies, GEMMs (genetically engineered mouse models) have been generated in which expression of oncogenic BRaf is conditionally dependent on the Cre recombinase. The delivery/activation of the Cre recombinase can be regulated in both a temporal and spatial manner and therefore these mouse models can be used to recapitulate the somatic mutation of BRAF that occurs in different tissues in the development of human cancer. The data so far obtained following Cre-mediated activation in haemopoietic tissue and the lung indicate that V600EBRAF mutation can drive tumour initiation and that its primary effect is to induce high levels of cyclin D1-mediated cell proliferation. However, hallmarks of OIS (oncogene-induced senescence) are evident that restrain further development of the tumour.