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KRASG12D , the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRASG12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRASG12D PROTACs. Mechanism studies with the representative compound 8o demonstrated that the potent, rapid, and selective degradation of KRASG12D induced by 8o was via a VHL- and proteasome-dependent manner...

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Cancer cells are exposed to major compressive and shearing forces during invasion and metastasis, leading to extensive plasma membrane damage. To survive this mechanical stress, they need to repair membrane injury efficiently. Targeting the membrane repair machinery is thus potentially a new way to prevent invasion and metastasis. We show here that annexin-A2 (ANXA2) is required for membrane repair in invasive breast and pancreatic cancer cells. Mechanistically, we show by fluorescence and electron microscopy that cells fail to reseal shear-stress damaged membrane when ANXA2 is silenced or the protein is inhibited with neutralizing antibody...

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In the coastal areas of China, the eutrophication of seawater leads to the continuous occurrence of red tide, which has caused great damage to Marine fisheries and aquatic resources. Therefore, the detection and prediction of red tide have important research significance. The rapid development of optical remote sensing technology and deep-learning technology provides technical means for realizing large-scale and high-precision red tide detection. However, the difficulty of the accurate detection of red tide edges with complex boundaries limits the further improvement of red tide detection accuracy...

Metformin (Met) is the first-line therapy in type 2 diabetes mellitus but, in last few years, it has also been evaluated as anti-cancer agent. Several pathways, such as AMPK or PI3K/Akt/mTOR, are likely to be involved in the anti-cancer Met activity. In addition, hydrogen sulfide (H2 S) and H2 S donors have been described as anti-cancer agents affecting cell-cycle and inducing apoptosis. Among H2 S donors, isothiocyanates are endowed with a further anti-cancer mechanism: the inhibition of the histone deacetylase enzymes...

Gemcitabine (GEM) is a non-selective chemotherapeutic agent used in the treatment of pancreatic cancer. Its antitumor efficacy is limited by a short plasma half-life and severe adverse reactions. To overcome these shortcomings, four novel lipid-like GEM diesters were synthesized and encapsulated into liposomes. Through optimization, dimyristoyl GEM (dmGEM)-loaded liposomes (LipodmGEM) were successfully obtained with an almost complete encapsulation efficiency. Compared to free GEM, LipodmGEM showed enhanced cellular uptake and cell apoptosis, improved inhibition of cell migration on AsPC-1 cells and a greatly extended half-life (7...

From lead 1, ( N -(4-((4-(3-(4-(3-methoxyphenyl)-1 H -1,2,3-triazol-1-yl)propyl)piperazin-1-yl)sulfonyl)-phenyl)acetamide), a S100A2-p53 protein-protein interaction inhibitor based on an in silico modelling driven hypothesis, four focused libraries were designed and synthesised. Growth inhibition screening was performed against 16 human cancer cell lines including the pancreatic cell lines MiaPaCa2, BxPC3, AsPC-1, Capan-2, HPAC, PANC-1 and the drug resistant CFPAC1. Modification of 1's phenylacetamide moiety, gave Library 1 with only modest pancreatic cancer activity...

Radiolabeled neurotensin analogs have been developed as candidates for theranostic use against neurotensin subtype 1 receptor (NTS1 R)-expressing cancer. However, their fast degradation by two major peptidases, neprilysin (NEP) and angiotensin-converting enzyme (ACE), has hitherto limited clinical success. We have recently shown that palmitoylation at the ε -amine of Lys7 in [99m Tc]Tc-[Lys7 ]DT1 (DT1, N4 -Gly-Arg-Arg-Pro-Tyr-Ile-Leu-OH, N4 = 6-(carboxy)-1,4,8,11-tetraazaundecane) led to the fully stabilized [99m Tc]Tc-DT9 analog, displaying high uptake in human pancreatic cancer AsPC-1 xenografts but unfavorable pharmacokinetics in mice...

The breakthrough in drug development of KRASG12C inhibitors provides inspiration for targeting alternative KRAS mutations, especially the most prevalent KRASG12D variant. Based on the structural analysis of MRTX1133 in complex with KRASG12D , a comprehensive structure-activity study was conducted, which led to the discovery of several compounds ( 22 , 28 , and 31 ) that showed higher potency in suppressing the clonogenic growth of KRASG12D -dependent cancer cells. These new compounds markedly and selectively inhibited the binding of RBD peptide to GTP-bound KRASG12D with IC50 values between 0...

Pancreatic cancer is a highly lethal solid malignancy with limited treatment options. Chimeric antigen receptor T (CAR-T) cell therapy has been successfully applied to treat hematological malignancies, but faces many challenges in solid tumors. One major challenge is the shortage of tumor-selective targets. Cell surface GRP78 (csGRP78) is highly expressed on various solid cancer cells including pancreatic cancer, but not normal cells, providing a potential target for CAR-T cell therapy in pancreatic cancer...

Inducing paraptosis, a nonapoptotic form of cell death, has great therapeutic potential in cancer therapy, especially for drug-resistant tumors. However, the specific molecular target(s) that trigger paraptosis have not yet been deciphered yet. Herein, by using activity-based protein profiling, we identified the GDP-dissociation inhibitor beta (GDI2) as a manipulable target for inducing paraptosis and uncovered benzo[ a ]quinolizidine BQZ-485 as a potent inhibitor of GDI2 through the interaction with Tyr245...

This report provides a descriptive summary of the ACC/AHA/ASE/ASNC/ASPC/HFSA/HRS/SCAI/SCCT/SCMR/STS 2023 Multimodality Appropriate Use Criteria for the Detection and Risk Assessment of Chronic Coronary Disease with an emphasis on the role of stress echocardiography.

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The American College of Cardiology (ACC) Foundation, along with key specialty and subspecialty societies, conducted an appropriate use review of stress testing and anatomic diagnostic procedures for risk assessment and evaluation of known or suspected chronic coronary disease (CCD), formerly referred to as stable ischemic heart disease (SIHD). This document reflects an updating of the prior Appropriate Use Criteria (AUC) published for radionuclide imaging, stress echocardiography (echo), calcium scoring, coronary computed tomography angiography (CCTA), stress cardiac magnetic resonance (CMR), and invasive coronary angiography for SIHD...

KRAS G12D mutation has been found in approximately 45% of pancreatic ductal adenocarcinoma (PDAC) cases, making it an attractive therapeutic target. Through structure-based drug design, a series of potent and selective KRAS G12D inhibitors were designed. The lead compound, ERAS-5024, inhibited ERK1/2 phosphorylation and cell proliferation in three-dimensional Cell-Titer Glo assays in AsPC-1 PDAC cells with single-digit nanomolar potency and caused tumor regression in the in vivo efficacy studies. We describe here the details of the design and synthesis program that led to the discovery of ERAS-5024...

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The presence of oncogene carrying eccDNAs is strongly associated with carcinogenesis and poor patient survival. Tumour biopsies and in vitro cancer cell lines are frequently utilized as models to investigate the role of eccDNA in cancer. However, eccDNAs are often lost during the in vitro growth of cancer cell lines, questioning the reproducibility of studies utilizing cancer cell line models. Here, we conducted a comprehensive analysis of eccDNA variability in seven cancer cell lines (MCA3D, PDV, HaCa4, CarC, MIA-PaCa-2, AsPC-1, and PC-3)...