NICD (NOTCH1 intracellular domain)

MIR31 deletion upregulates LYN, enhancing stiffness perception and tipping the balance toward O-GlcNAc addition to NICD1, finally resulting in mechanoadaptation- and tumor stemness-driven recurrence. Consequently, MIR31 deletion is a potential biomarker for recurrence and patient stratification in Notch- or OGT-targeted therapies.

Using NSCLC patient-derived xenografts displaying intrinsic carboplatin resistance, we demonstrated that combining carboplatin with a γ-secretase inhibitor, which hinders NICD generation, significantly improves survival and reduces tumour growth compared with carboplatin monotherapy. Furthermore, in patients with NSCLC who received platinum-based chemotherapy, the level of MDM2 expression in the tumour correlated with poor progression-free survival, which further validates the key role of MDM2 in response to platinum compounds. Our findings present a new therapeutic opportunity for patients with NSCLC, the most common form of lung cancer.

These cells were then exposed to norepinephrine (NE), epinephrine (EPI), or corticosterone (CC)...Moreover, tumors from mice subjected to restraint stress had elevated expression of Notch1, Jagged 2, NICD, HES1, GR, ADRB2, and pS9-GSK3β. These data indicate that chronic stress leads to MDSCs infiltration and suppressive activity, which contributes to an immunosuppressive TME and OC progression.

Conversely, stiff, elastic matrices inhibit HSC commitment to the T-lineage, and rather promotes Myeloid-cell differentiation. Our observations indicate mechanical reciprocity in signaling pathways indispensable to thymopoiesis and highlight extracellular matrix mechanics as a variable in controlling hematopoietic stem cell fate decisions.

Histopathological examination corroborated biochemical findings. Lacosamide demonstrates significant uro-protective efficacy through coordinated anti-inflammatory, antioxidant, and anti-apoptotic mechanisms through modulation of Notch-1/NICD/NF-κB pathway.

In vivo, RIN1 promoted the expression of IL-17 and IFN-γ in CD4+ TILs while suppressing PD-1 expression and reducing the frequency of Treg cells, exhibiting tumor growth inhibition. These findings suggested that RIN1 enhances CD4+ T cell-mediated antitumor immunity in HCC by modulating gene transcription and cell subset differentiation, highlighting its potential as an immunostimulatory agent (Graphical abstract).

CPT-01 demonstrates enhanced anti-tumor efficacy and reduced toxicity compared to TPT, offering promising clinical potential for liver cancer treatment.

Consistently, Top I inhibitor YCJ-02 blocked the proliferation of ICC cells and showed superior cytotoxic activity compared to reference drugs ARC-111, topotecan, and SN-38...Interestingly, DNA relaxation assay and Western blotting showed that YCJ-02 not only functions as a Top I poison but also promotes its degradation via a ubiquitin/26S proteasome pathway. Critically, YCJ-02 dramatically suppressed AKT/NICD-induced ICC growth in mice and decreased the expression of Top I. Together, this study demonstrates that YCJ-02 is an effective Top I inhibitor with high potency in inhibiting ICC growth and merits further preclinical evaluation.

Strikingly, activating KDM6B expression with paricalcitol or inhibiting the Notch pathway with DAPT effectively counteracted NSUN2-induced osteolytic bone metastasis in vivo. Collectively, our findings underscore the pivotal role of the NSUN2-KDM6B-Notch axis in promoting osteoclast differentiation and bone metastasis in BCa, providing potential therapeutic targets for BCa patients with bone metastasis.

We showed that chemotherapy combined with the USP5 inhibitor can additionally repress tumor growth and angiogenesis in mice. These findings explain why ESCC cells have much fewer NOTCH1 mutations than normal and precancerous epithelium, reveal a novel mechanism for Notch-signaling to drive tumor angiogenesis via the NOTCH1-USP5-STAT3 axis, and open a potential new avenue for anti-tumor angiogenesis therapy.

Thus, the NOTCH1 152 variant acts as a "sponge" protein in a novel mechanism of oncogenic NOTCH signaling activation, explaining the detrimental disease outcome of CLL patients with non-coding NOTCH1 mutations. We propose that the detection of NOTCH1 152 protein by specific antibodies is a useful prognostic marker for CLL patients.