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Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer’s cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets. Glioblastoma is thought to arise from neural stem cells. Here, to investigate this, the authors use single-cell RNA-sequencing to compare glioblastoma to the fetal human brain, and find a similarity between glial progenitor cells and a subpopulation of glioblastoma cells.

Viruses, as opportunistic intracellular parasites, hijack the cellular machinery of host cells to support their survival and propagation. Numerous viral proteins are subjected to host-mediated post-translational modifications. Here, we demonstrate that the SARS-CoV-2 nucleocapsid protein (SARS2-NP) is SUMOylated on the lysine 65 residue, which efficiently mediates SARS2-NP’s ability in homo-oligomerization, RNA association, liquid-liquid phase separation (LLPS). Thereby the innate antiviral immune response is suppressed robustly. These roles can be achieved through intermolecular association between SUMO conjugation and a newly identified SUMO-interacting motif in SARS2-NP. Importantly, the widespread SARS2-NP R203K mutation gains a novel site of SUMOylation which further increases SARS2-NP’s LLPS and immunosuppression. Notably, the SUMO E3 ligase TRIM28 is responsible for catalyzing SARS2-NP SUMOylation. An interfering peptide targeting the TRIM28 and SARS2-NP interaction was screened out to block SARS2-NP SUMOylation and LLPS, and consequently inhibit SARS-CoV-2 replication and rescue innate antiviral immunity. Collectively, these data support SARS2-NP SUMOylation is critical for SARS-CoV-2 virulence, and therefore provide a strategy to antagonize SARS-CoV-2. Here, the authors show that TRIM28-mediated SUMOylation of SARS-CoV-2 NP is critical for its liquid-liquid phase separation (LLPS) property and subsequent inhibition of innate antiviral immunity. The peptide NSIP-III is applied to unleash such connection by interfering TRIM28 and NP interaction.

Granulocyte-colony-stimulating factor (G-CSF) is a member of the hematopoietic growth factor family that primarily affects the neutrophil lineage. G-CSF serves as a powerful mobilizer of peripheral blood stem cells and recombinant human G-CSF (rhG-CSF) has been used to treat granulocytopenia and neutropenia after chemotherapy for cancer patients. However, recent studies have found that G-CSF plays an important role in cancer progression. G-CSF expression is increased in different types of cancer cells, such as lung cancer, gastric cancer, colorectal cancer, invasive bladder carcinoma, glioma and breast cancer. However, it is unclear whether treatment with G-CSF has an adverse effect. The current review provides an overview of G-CSF in malignant breast cancer development and the data presented in this review are expected to provide new ideas for cancer therapy.

The association between constipation and suicidal ideation remains inadequately explored. This study aims to investigate the potential correlation between constipation and suicidal ideation in US adults, while assessing the mediating role of depression.For this cross-sectional study, a total of 13,493 adults aged 20 years and older were included from the National Health and Nutrition Examination Survey 2005–2010. The definition of constipation was defined by considering the consistency or frequency of stool. The ninth item on the Patient Health Questionnaire-9 (PHQ-9) evaluated suicidal ideation, and depression was evaluated using the PHQ-8 score. Adjusted odds ratios (ORs) were calculated using multivariate logistic regression models. Sensitivity analysis was performed to ensure stable results. Furthermore, study employed mediation analysis to examine the effect of constipation on suicidal ideation through depression. The bootstrapping method was used to assess the significance of the mediation effect. After controlling for demographic factors, risk behaviors, comorbidities, dietary intake, and relevant medications, constipation was associated with an increased risk of suicidal ideation (OR 1.41, 95%CI 1.08–1.83, P  = 0.011). Sensitivity analyses showed the stability of the results. Moreover, mediation analysis demonstrated a significant direct effect of constipation on suicidal ideation ( P  = 0.016), with depression playing a partial mediating role in this interaction (40.81%, P  < 0.0001). In conclusion, this study demonstrated a significant association between constipation and suicidal ideation, with depression serving as a partial mediator in this relationship. Further prospective longitudinal studies are essential to establish a definitive causal relationship between these factors so as to guide the development and implementation of targeted intervention strategies.

Primary liver cancer is one of the leading causes for cancer-related death worldwide. Transforming growth factor beta (TGF-β) is a pleiotropic cytokine that signals through membrane receptors and intracellular Smad proteins, which enter the nucleus upon receptor activation and act as transcription factors. TGF-β inhibits liver tumorigenesis in the early stage by inducing cytostasis and apoptosis, but promotes malignant progression in more advanced stages by enhancing cancer cell survival, EMT, migration, invasion and finally metastasis. Understanding the molecular mechanisms underpinning the multi-faceted roles of TGF-β in liver cancer has become a persistent pursuit during the last two decades. Contextual regulation fine-tunes the robustness, duration and plasticity of TGF-β signaling, yielding versatile albeit specific responses. This involves multiple feedback and feed-forward regulatory loops and also the interplay between Smad signaling and non-Smad pathways. This review summarizes the known regulatory mechanisms of TGF-β signaling in liver cancer, and how they channel, skew and even switch the actions of TGF-β during cancer progression.

Metastasis is the main cause of death in cancer patients. TGF-β is pro-metastatic for malignant cancer cells. Here we report a loss-of-function screen in mice with metastasis as readout and identify OTUD1 as a metastasis-repressing factor. OTUD1-silenced cancer cells show mesenchymal and stem-cell-like characteristics. Further investigation reveals that OTUD1 directly deubiquitinates the TGF-β pathway inhibitor SMAD7 and prevents its degradation. Moreover, OTUD1 cleaves Lysine 33-linked poly-ubiquitin chains of SMAD7 Lysine 220, which exposes the SMAD7 PY motif, enabling SMURF2 binding and subsequent TβRI turnover at the cell surface. Importantly, OTUD1 is lost in multiple types of human cancers and loss of OTUD1 increases metastasis in intracardial xenograft and orthotopic transplantation models, and correlates with poor prognosis among breast cancer patients. High levels of OTUD1 inhibit cancer stemness and shut off metastasis. Thus, OTUD1 represses breast cancer metastasis by mitigating TGF-β-induced pro-oncogenic responses via deubiquitination of SMAD7. The activation of TGF-β signaling has been implicated in cancer metastasis. Here, the authors show that OTUD1 suppresses metastasis by antagonizing the TGF-β pathway via the deubiquitination of SMAD7, and its loss correlates with poor prognosis in breast cancer.

Lung morphogenesis is a well orchestrated, tightly regulated process through several molecular pathways, including TGF-β/bone morphogenetic protein (BMP) signaling. Alteration of these signaling pathways leads to lung malformation. We investigated the role of Follistatin-like 1 (Fstl1), a secreted follistatin-module-containing glycoprotein, in lung development. Deletion of Fstl1 in mice led to postnatal lethality as a result of respiratory failure. Analysis of the mutant phenotype showed that Fstl1 is essential for tracheal cartilage formation and alveolar maturation. Deletion of the Fstl1 gene resulted in malformed tracheal rings manifested as discontinued rings and reduced ring number. Fstl1-deficient mice displayed septal hypercellularity and end-expiratory atelectasis, which were associated with impaired differentiation of distal alveolar epithelial cells and insufficient production of mature surfactant proteins. Mechanistically, Fstl1 interacted directly with BMP4, negatively regulated BMP4/Smad1/5/8 signaling, and inhibited BMP4-induced surfactant gene expression. Reducing BMP signaling activity by Noggin rescued pulmonary atelectasis of Fstl1-deficient mice. Therefore, we provide in vivo and in vitro evidence to demonstrate that Fstl1 modulates lung development and alveolar maturation, in part, through BMP4 signaling.

This study conducts a case study on the characteristics of fixed deposit businesses in a Portuguese bank, analyzing the current customer data features and the limitations of marketing strategies. It also highlights the limitations of the traditional DBSCAN algorithm, including issues with parameter selection and a lack of diverse clustering metrics. Using machine learning techniques, the study explores the relationship between customer attribute features and fixed deposits. The proposed KM-DBSCAN algorithm, which combines K-means and DBSCAN, is used for customer segmentation. This method integrates both implicit and explicit customer indicators, incorporates weight factors, constructs a distance distribution matrix, and optimizes the process of selecting the neighborhood radius and density threshold parameters. As a result, the clustering accuracy of customer segmentation is improved by 15%. Based on the clustering results, customers are divided into four distinct groups, and personalized marketing strategies for customer deposits are proposed. Differentiated marketing plans are implemented, with a focus on customer relationship management and feedback. The model’s performance is evaluated using silhouette coefficients, accuracy, and F1 score. The model is then applied in a real-world scenario, leading to an average business revenue growth rate of 16.08% and a 4.5% increase in customer engagement.

[...]ubiquitination and ubiquitin-like protein modifications have also been widely involved in pathological processes including metabolic disorders, inflammation, tumorigenesis, amongst others. [...]in recent years, it has received increasing interest to identify novel molecular targets that could lead to the development of new drugs. In their study, they validated the ubiquitination of TRA2A and PYCR2 by E4B in vitro and in mammalian cells. [...]they concluded that other factors may exist to control the degradation of TRA2A and PYCR2 in HCC. [...]they reminded us that the neddylation inhibitor MLN4924, as an anti-tumor medicine, has negative effects in immunity and need to take careful consideration when it is clinically used.

Due to the therapeutic resistance of endocrine therapy and the limited efficacy of immune checkpoint inhibitors in estrogen receptor (ER)-positive breast cancer (BRCA), there is an urgent need to develop novel prognostic markers and understand the regulation of the tumor immune microenvironment (TIME). As a matricellular protein, CYR61 has been shown to either promote or suppress cancer progression depending on cancer types. However, how CYR61 functions in ER-positive BRCA remains elusive. In this study, we comprehensively analyzed the expression of CYR61 in BRCA based on the TCGA and METABRIC databases. Our findings showed that the expression of CYR61 is downregulated in different subtypes of BRCA, which is associated with elevated promoter methylation levels and predicts bad clinical outcomes. By comparing the high or low CYR61 expression groups of ER-positive BRCA patients, we found that CYR61 is intimately linked to the expression of genes involved in tumor-suppressive pathways, such as the TGF-β and TNF signaling pathways, and genes related to cytokine-receptor interaction that may regulate cancer immunity. Moreover, reduced CYR61 expression is associated with an altered TIME that favors cancer progression. Finally, experimental analyses ascertained that CYR61 is downregulated in clinical BRCA tissues compared to matched normal breast tissues. Furthermore, CYR61 is able to impede the proliferation and colony formation of ER-positive BRCA cells. In summary, our study reveals that CYR61 could serve as a novel prognostic marker for ER-positive BRCA, and function as an inhibitor of cancer progression by both acting on cancer cells and remodeling the TIME.