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Tumor microenvironment-activated ferritin nanovector enables enhanced tumor delivery of KRASG12C inhibitors and degraders – Research

Dr AF Saeed
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Tumor microenvironment-activated ferritin nanovector enables enhanced tumor delivery of KRASG12C inhibitors and degraders – Research



FIGURE 1

Molecular mechanisms of KRAS, PROTACs and The-05. (A) KRAS as a Molecular Switch and its Role in Cancer. KRAS functions as a guanosine diphosphate (GDP)/triphosphate (GTP) binary switch, which is mainly determined by regulatory guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). KRAS controls important signal transduction from activated membrane receptors to intracellular molecules to nucleus, and particularly the PI3K-PDK1-AKT pathway, the RAF-MEK-ERK pathway, the PLC-PKC pathway and the RALGDS-RAL pathway. These pathways control cellular proliferation, survival, differentiation and angiogenesis. Mutated KRAS (in particular, KRAS mutations G12C, G12D and G12V) is permanently activated, and leads to uncontrolled signal transduction, uncontrolled cellular proliferation, survival, differentiation and angiogenesis, that lead to tumor development and metastasis. (B) Mechanism of action of a PROTAC. PROTACs are heterobifunctional molecules designed to induce the ubiquitination and subsequent degradation of specific proteins of interest (POIs). A PROTAC consists of three key components: a moiety that binds to an E3 ubiquitin ligase, a linker and a moiety that binds to the POI (a) PROTACs hijack the ubiquitin-proteasome system (UPS). The UPS is a highly conserved cellular mechanism for degrading proteins. It involves three main enzymes: Ubiquitin-activating enzyme (E1), Ubiquitin-conjugating enzyme (E2), and Ubiquitin ligase (E3). E1 activates free ubiquitin (Ub), which is then transferred to E2. E3 ligases are responsible for specifically recognizing substrates and facilitating the transfer of Ub from E2 to a lysine residue (Lys) on the substrate. Repeated ubiquitination forms a poly-ubiquitin chain, targeting the substrate for degradation by the 26S proteasome. PROTACs work by bringing the POI into close proximity with the E2-E3 complex (b) This trimeric complex formation facilitates the transfer of ubiquitins to the POI (c) The resulting poly-ubiquitinated POIs (d) are then rapidly degraded by the proteasome (e) A key feature of PROTACs is their catalytic, event-driven mechanism of action: a single PROTAC molecule can induce the degradation of multiple POI molecules, as it is released to bind another POI after inducing degradation. (C) Mechanism of Action of The-05 Nanocarrier. The The-05 polypeptide is engineered with an N-terminal shielding PASE moiety (blue), a matrix metalloprotease (MMP)-cleavable linker (green), and a C-terminal human ferritin heavy chain (HFt, orange). These components fold into a The-05 monomer. In the presence of the drug (either Adagrasib or the LC-2 PROTAC), and using a simple pH-dependent association-dissociation protocol, these monomers self-assemble into a shielded The-05 24-mer. The drug is encapsulated within the internal cavity of this stimuli-sensitive protein, which is then ready for administration. In vivo, within the tumor microenvironment (TME), the abundant MMPs cleave the PASE shield, leading to its release. The de-shielded The-05 is subsequently internalized by tumor cells via the highly expressed Transferrin Receptor 1 (TfR1, CD71). Once inside the tumor cell, the encapsulated drug is rapidly released, where it can then exert its inhibitory effect on KRAS.



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University of Bonn Research Training PhD Scholarships 2026 Now Open – After School Africa – Open Positions

Dr AF Saeed
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University of Bonn Research Training PhD Scholarships 2026 Now Open – After School Africa – Open Positions



University of Bonn Research Training PhD Scholarships 2026 Now Open  After School Africa



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Cats May Hold the Key to Treating Human Cancer – Science News

Dr AF Saeed
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Cats May Hold the Key to Treating Human Cancer – Science News



Doctor Cat CostumeA large international study has mapped the genetic landscape of feline cancers for the first time, revealing striking similarities between tumor-driving mutations in cats, humans, and dogs. The genetics of cat tumors are no longer a “black box,” according to researchers behind a new study that represents one of the most significant advances in feline […]



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AITHYRA-CeMM Joint International PhD Call in Molecular Medicine and Artificial Intelligence (m/f/d) – Österreichische Akademie der Wissenschaften – Open Positions

Dr AF Saeed
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AITHYRA-CeMM Joint International PhD Call in Molecular Medicine and Artificial Intelligence (m/f/d) – Österreichische Akademie der Wissenschaften – Open Positions



AITHYRA-CeMM Joint International PhD Call in Molecular Medicine and Artificial Intelligence (m/f/d)  Österreichische Akademie der Wissenschaften



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Scientists Solve a Mystery Behind Your Sense of Touch – Science News

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Scientists Solve a Mystery Behind Your Sense of Touch – Science News



Fingertip Touches Fogged GlassA new study from Scripps Research reveals how a key touch-sensing protein detects mechanical forces with remarkable precision. Each time something lightly presses against your skin, specialized sensory neurons translate that mechanical force into electrical signals that the brain interprets as touch. Researchers have long known that a protein called PIEZO2 plays a central role […]



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HIV-1-encoded circular RNA enhances viral transcription through Tat binding – Microbiology Research

Dr AF Saeed
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HIV-1-encoded circular RNA enhances viral transcription through Tat binding – Microbiology Research


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    Astronomers Detect a Vast Hidden Web of Galaxies in the Early Universe – Science News

    Dr AF Saeed
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    Astronomers Detect a Vast Hidden Web of Galaxies in the Early Universe – Science News



    Line Intensity Map HETDEXAstronomers have uncovered a hidden cosmic web of galaxies and gas by mapping hydrogen light from the early universe. Astronomers working with the Hobby-Eberly Telescope Dark Energy Experiment (HETDEX) have produced the most detailed three-dimensional map yet of light emitted by energized hydrogen in the early universe. The map traces light from a period between […]



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    Faculty Development and Educational Support Specialist – Open Positions

    Dr AF Saeed
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    Faculty Development and Educational Support Specialist – Open Positions



    Des Moines University (Des Moines, IA)



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    Cuprotosis-related gene subtypes, prognostic modeling, and tumor microenvironment remodeling in breast cancer – Research

    Dr AF Saeed
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    Tumor microenvironment-activated ferritin nanovector enables enhanced tumor delivery of KRASG12C inhibitors and degraders – Research



    Background:

    A newly discovered mode of cell death is called cuprotosis. Current evidence confirms that cuprotosis is involved in the occurrence and development of malignant tumors. However, the prognostic significance and function of cuprotosis-related genes (CRGs) in breast cancer (BC) remain unclear. The aim of this study is to establish a model for predicting the prognosis of BC patients with cuprotosis-related pattern-related gene (CRPRG) score, and explore the functional role of CRGs in the tumor microenvironment (TME).


    Methods:

    In this study, transcriptome profiles, corresponding clinical information and tumor mutation data were collected from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database (GSE20685). The multigene prediction model was constructed using the least absolute shrinkage and selection operator (LASSO) and Cox regression analysis, and then validated by Kaplan-Meier and receiver operating characteristic (ROC) analysis.


    Results:

    Using LASSO analysis and Cox regression analysis, we screened out eight cuprotosis-related pattern genes (including PANX1, GPR107, MTFR1, FKBP5, CD24, CRISP3, NPY1R and ADIRF) that were associated with prognosis. According to the median risk score, the patients were divided into high- and low-risk groups. The results of survival analysis, ROC curve analysis and risk curve analysis of the prognostic model showed that the prognosis of the high-risk group was poor, and the predictive ability of the risk prognosis model was also verified. In multivariate Cox regression analysis, risk score was an independent prognostic factor (P<0.001). Functional analysis revealed differences in immune infiltration, tumor mutational burden (TMB), stem cell content, and drug sensitivity between the two groups.


    Conclusions:

    In conclusion, we identified two CRG subtypes and three cuprotosis-related differentially expressed gene (DEG) clusters in BC. CRPRG score has shown good performance in predicting the prognosis and efficacy of treatments for BC and is expected to provide potential biological therapeutic targets for BC.


    Keywords:

    Breast cancer (BC); cuprotosis; prognosis model; tumor microenvironment (TME).



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    Cuprotosis-related gene subtypes, prognostic modeling, and tumor microenvironment remodeling in breast cancer – Research

    Dr AF Saeed
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    0
    Tumor microenvironment-activated ferritin nanovector enables enhanced tumor delivery of KRASG12C inhibitors and degraders – Research



    Background:

    A newly discovered mode of cell death is called cuprotosis. Current evidence confirms that cuprotosis is involved in the occurrence and development of malignant tumors. However, the prognostic significance and function of cuprotosis-related genes (CRGs) in breast cancer (BC) remain unclear. The aim of this study is to establish a model for predicting the prognosis of BC patients with cuprotosis-related pattern-related gene (CRPRG) score, and explore the functional role of CRGs in the tumor microenvironment (TME).


    Methods:

    In this study, transcriptome profiles, corresponding clinical information and tumor mutation data were collected from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database (GSE20685). The multigene prediction model was constructed using the least absolute shrinkage and selection operator (LASSO) and Cox regression analysis, and then validated by Kaplan-Meier and receiver operating characteristic (ROC) analysis.


    Results:

    Using LASSO analysis and Cox regression analysis, we screened out eight cuprotosis-related pattern genes (including PANX1, GPR107, MTFR1, FKBP5, CD24, CRISP3, NPY1R and ADIRF) that were associated with prognosis. According to the median risk score, the patients were divided into high- and low-risk groups. The results of survival analysis, ROC curve analysis and risk curve analysis of the prognostic model showed that the prognosis of the high-risk group was poor, and the predictive ability of the risk prognosis model was also verified. In multivariate Cox regression analysis, risk score was an independent prognostic factor (P<0.001). Functional analysis revealed differences in immune infiltration, tumor mutational burden (TMB), stem cell content, and drug sensitivity between the two groups.


    Conclusions:

    In conclusion, we identified two CRG subtypes and three cuprotosis-related differentially expressed gene (DEG) clusters in BC. CRPRG score has shown good performance in predicting the prognosis and efficacy of treatments for BC and is expected to provide potential biological therapeutic targets for BC.


    Keywords:

    Breast cancer (BC); cuprotosis; prognosis model; tumor microenvironment (TME).



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