Mccoybork4342

Our previous study demonstrates that a juxtamembrane 2 (JM2) mimic peptide can inhibit proliferation and induce apoptosis of tumor cells. However, the mechanism remains unclear. In this study, JM2 is found to suppress the growth of 4T1 breast tumors by inducing apoptosis and inhibiting the proliferation of 4T1 tumor cells. Further study indicates that JM2 can stimulate the mitochondria to gather near the microtubule-organizing center of tumor cells and subsequently induce ROS-induced ROS release responses, which results in mitochondrial dysfunction and mitochondria-mediated apoptosis. In addition, JM2 can arrest cell cycle in S phase by regulating the expression of cell cycle-related proteins and consequently inhibit proliferation of tumor cells. Then, a previously designed JM2 grafted hyaluronic acid (HA) injectable hydrogel system (HA-JM2) is injected in a breast tumor-resected model and the HA-JM2 hydrogel can inhibit the malignant proliferation of residual tumor cells and suppress the breast tumor recurrence. These findings not only confirm the application potentials of JM2 in anti-tumor therapy and tumor post-surgery treatments but also provide greater understanding on the mechanisms by which JM2 inhibits tumor growth.Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related mortality with a dismal prognosis that has changed little over the past few decades. Further understanding of the molecular pathology of PDAC progression is urgently required in order to improve the prognosis of patients with PDAC. Herein, it was observed that trefoil factor 3 (TFF3) expression was elevated in PDAC, and was positively correlated with a worse overall patient survival outcome. Forced expression of TFF3 promoted oncogenic functions of PDAC cells in vitro including cell proliferation, survival, foci formation, cancer stem cell-like behavior and invasion, ex vivo colony growth in 3D-Matrigel, and xenograft growth in vivo. Depletion or pharmacological inhibition of TFF3 inhibited these same processes. RNA-Seq analysis and subsequent mechanistic analyses demonstrated that TFF3 increased the expression of various WNT ligands to mediate WNT pathway activation required for TFF3-stimulated PDAC progression. Combined pharmacological inhibition of TFF3 and WNT signaling significantly attenuated PDAC xenograft growth and potentiated the therapeutic efficacy of gemcitabine in both ex vivo and in vivo models. Hence, a mechanistic basis for combined inhibition of pathways enhancing PDAC progression is provided and suggests that inhibition of TFF3 may assist to ameliorate outcomes in PDAC.Hematopoietic stem cells (HSCs) develop from hemogenic endothelium within embryonic arterial vessels such as the aorta of the aorta-gonad-mesonephros region (AGM). To identify the signals responsible for HSC formation, here we use single cell RNA-sequencing to simultaneously analyze the transcriptional profiles of AGM-derived cells transitioning from hemogenic endothelium to HSCs, and AGM-derived endothelial cells which provide signals sufficient to support HSC maturation and self-renewal. Pseudotemporal ordering reveals dynamics of gene expression during the hemogenic endothelium to HSC transition, identifying surface receptors specifically expressed on developing HSCs. Transcriptional profiling of niche endothelial cells identifies corresponding ligands, including those signaling to Notch receptors, VLA-4 integrin, and CXCR4, which, when integrated in an engineered platform, are sufficient to support the generation of engrafting HSCs. These studies provide a transcriptional map of the signaling interactions necessary for the development of HSCs and advance the goal of engineering HSCs for therapeutic applications.Rapid advances in synthetic biology are driving the development of genetically engineered microbes as therapeutic agents for a multitude of human diseases, including cancer. The immunosuppressive microenvironment of solid tumors, in particular, creates a favorable niche for systemically administered bacteria to engraft and release therapeutic payloads. However, such payloads can be harmful if released outside the tumor in healthy tissues where the bacteria also engraft in smaller numbers. To address this limitation, we engineer therapeutic bacteria to be controlled by focused ultrasound, a form of energy that can be applied noninvasively to specific anatomical sites such as solid tumors. SP600125negativecontrol This control is provided by a temperature-actuated genetic state switch that produces lasting therapeutic output in response to briefly applied focused ultrasound hyperthermia. Using a combination of rational design and high-throughput screening we optimize the switching circuits of engineered cells and connect their activity to the release of immune checkpoint inhibitors. In a clinically relevant cancer model, ultrasound-activated therapeutic microbes successfully turn on in situ and induce a marked suppression of tumor growth. This technology provides a critical tool for the spatiotemporal targeting of potent bacterial therapeutics in a variety of biological and clinical scenarios.Using sequential excitation with a minimum of light to localize single fluorescent molecules represented a breakthrough because it delivers 1-2 nm precision with moderate photon counts, enabling tracking and super-resolution imaging with true molecular resolution. Expanding this concept to multi-photon regimes may be a useful complement to reach even higher localization precision and get deeper into biological specimens.Colorectal cancer is a major contributor to the worldwide prevalence of cancer-related deaths. Metastasis and chemoresistance are the two main causes for colorectal cancer treatment failure, and thus, high mortality. Calmodulin-binding transcription activator 1 (CAMTA1) is involved in tumor growth and development, but its mechanisms of action in the development of colorectal cancer and chemoresistance are poorly understood. Here, we report that Camta1 is a tumor suppressor. Immunohistochemical staining and western blotting analyses of normal and colorectal cancer tissues showed a significantly low expression of Camta1 expression in colorectal cancer tissues, when compared to adjacent normal tissues. In functional in vitro experiments, we observed that Camta1 overexpression significantly decreased the proliferation and invasion capacity of SW620 and SW480 cells, whereas Camta1 knockdown displayed a significant increase in the proliferative and invasive ability of these cells. Subsequently, we examined the effe and suppresses the phosphorylation of NFATc4. To verify the role of CAMTA1 in oxaliplatin resistance in colorectal cancer, we established a xenograft mouse model and show agreement between in vitro and in vivo results.The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.The hippocampus interacts with the neocortical network for memory retrieval and consolidation. Here, we found the lateral entorhinal cortex (LEC) modulates learning-induced cortical long-range gamma synchrony (20-40 Hz) in a hippocampal-dependent manner. The long-range gamma synchrony, which was coupled to the theta (7-10 Hz) rhythm and enhanced upon learning and recall, was mediated by inter-cortical projections from layer 5 neurons of the LEC to layer 2 neurons of the sensory and association cortices. Artificially induced cortical gamma synchrony across cortical areas improved memory encoding in hippocampal lesioned mice for originally hippocampal-dependent tasks. Mechanistically, we found that activities of cortical c-Fos labeled neurons, which showed egocentric map properties, were modulated by LEC-mediated gamma synchrony during memory recall, implicating a role of cortical synchrony to generate an integrative memory representation from disperse features. Our findings reveal the hippocampal mediated organization of cortical memories and suggest brain-machine interface approaches to improve cognitive function.MAPK signaling inhibitor (MAPKi) therapies show limited efficacy for advanced thyroid cancers despite constitutive activation of the signaling correlates with disease recurrence and persistence. Understanding how BRAF pathway stimulates tumorigenesis could lead to new therapeutic targets. Here, through genetic and pathological approaches, we demonstrate that BRAFV600E promotes thyroid cancer development by increasing myeloid-derived suppressor cells (MDSCs) penetrance. This BRAFV600E-induced immune suppression involves re-activation of the developmental factor TBX3, which in turn up-regulates CXCR2 ligands in a TLR2-NFκB dependent manner, leading to MDSCs recruitment into the tumor microenvironment. CXCR2 inhibition or MDSCs repression improves MAPKi therapy effect. Clinically, high TBX3 expression correlates with BRAFV600E mutation and increased CXCR2 ligands, along with abundant MDSCs infiltration. Thus, our study uncovers a BRAFV600E-TBX3-CXCLs-MDSCs axis that guides patient stratification and could be targeted to improve the efficacy of MAPKi therapy in advanced thyroid cancer patients.Post-translational modifications diversify protein functions and dynamically coordinate their signalling networks, influencing most aspects of cell physiology. Nevertheless, their genetic regulation or influence on complex traits is not fully understood. Here, we compare the genetic regulation of the same PTM of two proteins - glycosylation of transferrin and immunoglobulin G (IgG). By performing genome-wide association analysis of transferrin glycosylation, we identify 10 significantly associated loci, 9 of which were not reported previously. Comparing these with IgG glycosylation-associated genes, we note protein-specific associations with genes encoding glycosylation enzymes (transferrin - MGAT5, ST3GAL4, B3GAT1; IgG - MGAT3, ST6GAL1), as well as shared associations (FUT6, FUT8). Colocalisation analyses of the latter suggest that different causal variants in the FUT genes regulate fucosylation of the two proteins. Glycosylation of these proteins is thus genetically regulated by both shared and protein-specific mechanisms.