Oncogenic KRAS mutations are nearly ubiquitous in pancreatic ductal adenocarcinoma (PDAC), yet therapeutic attempts to target KRAS as well as its target MAPK pathway effectors have shown limited success due to the difficulty to pharmacologically target KRAS, inherent drug resistance in PDAC cells, and acquired resistance through activation of alternative mitogenic pathways such JAK-STAT and PI3K-AKT. While KRAS canonically drives the MAPK signaling pathway via RAF-MEK-ERK, it is also known to play a role in PI3K-AKT signaling. Our therapeutic study targeted the PI3K-AKT pathway with the drug Omipalisib (p110α/β/δ/γ and mTORC1/2 inhibitor) in combination with MAPK pathway targeting drug Trametinib (MEK1/2 inhibitor) or SHP099-HCL (SHP099), which is an inhibitor of the KRAS effector SHP2. Western blot analysis demonstrated that application of Trametinib or SHP099 alone selectively blocked ERK phosphorylation (pERK) but failed to suppress phosphorylated AKT (pAKT) and in some instances increased pAKT levels. Conversely, Omipalisib alone successfully inhibited pAKT but failed to suppress pERK. Therefore, we hypothesized that a combination therapeutic comprised of Omipalisib with either Trametinib or SHP099 would inhibit two prominent mitogenic pathways, MEK and PI3K-AKT, to more effectively suppress pancreatic cancer. studies demonstrated that both Omipalisib/Trametinib and Omipalisib/SHP099 combination therapeutic strategies were generally more effective than treatment with each drug individually at reducing proliferation, colony formation, and cell migration compared to vehicle controls. Additionally, we found that while combination Omipalisib/SHP099 treatment reduced implanted tumor growth , the Omipalisib/Trametinib treatment was significantly more effective. Therefore, we additionally tested the Omipalisib/Trametinib combination therapeutic in the highly aggressive PKT (Ptf1a , LSL-Kras , TGFbR2 ) spontaneous mouse model of PDAC. We subsequently found that PKT mice treated with the Omipalisib/Trametinib combination therapeutic survived significantly longer than mice treated with either drug alone, and more than doubled the mean survival time of vehicle control mice. Altogether, our data support the importance of a dual treatment strategy targeting both MAPK and PI3K-AKT pathways.
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http://dx.doi.org/10.1101/2023.08.15.553438 | DOI Listing |
Nutr Res
January 2025
Department of Molecular Medicine, University of Padova, Padova, Italy; IMDEA-Food, Madrid, Spain. Electronic address:
l-Theanine is a unique non-protein amino acid found abundantly in tea leaves. Interest in its potential use as a dietary supplement has surged recently, especially claims related to promoting relaxation and cognitive enhancement. This review surveys the chemistry, metabolism, and purported biological activities of l-theanine.
View Article and Find Full Text PDFJ Med Food
January 2025
Department of Infectious Diseases and Liver Diseases, Ningbo Medical Centre Lihuili Hospital, Affiliated Lihuili Hospital of Ningbo University, Ningbo, China.
Disturbances of the intestinal barrier enabling bacterial translocation exacerbate alcoholic liver disease (ALD). GG (LGG) has been shown to exert beneficial effects in gut dysbiosis and chronic liver disease. The current study assessed the combined effects of LGG and metformin, which play roles in anti-inflammatory and immunoregulatory processes, in alcohol-induced liver disease mice.
View Article and Find Full Text PDFMedicine (Baltimore)
January 2025
Department of Gastroenterology, The Affiliated People's Hospital of Ningbo University, Ningbo, China.
Rationale: Gastric antral vascular ectasia (GAVE) is a rare acquired lesion characterized by vascular dilation in the gastric antrum, frequently results in occult or overt gastrointestinal bleeding. Endoscopic intervention remains the cornerstone of therapy. Argon plasma coagulation was previously considered a first treatment option.
View Article and Find Full Text PDFMedicine (Baltimore)
January 2025
Second Hospital of the Air Force Medical University, Xi 'an, China.
Background: This study investigates the therapeutic efficacy of dynamic neuromuscular stabilization (DNS) technology paired with Kinesio Taping in patients with persistent nonspecific low back pain, as well as the effect on neuromuscular function and pain self-efficacy.
Methods: A randomized controlled clinical study was conducted to collect clinical data on DNS combined with KT for the treatment of chronic nonspecific low back pain from November 2023 to April 2024. The inclusion criteria were patients with chronic nonspecific lower back pain, aged between 18 and 30 years old, and without serious underlying medical conditions, such as cardiac disease, hypertension, and diabetes.
Medicine (Baltimore)
January 2025
Department of Medical Imaging, Jincheng People's Hospital, Shanxi, China.
Rationale: Thrombus is the most common occupying lesion in the cardiac chambers, it is often distinguished from cardiac neoplastic occupations. Among them, the most common is cardiac myxoma, whose imaging manifestations are often confused with thrombus. However, the 2 types of lesions have different therapeutic strategies and are both potentially high-risk sources of embolism, so early differentiation between intracardiac thrombus and cardiac tumor is essential.
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