Stormvistisen8804

High Grade Serous Ovarian cancer (HGSOC) is a major unmet need in oncology, due to its precocious dissemination and the lack of meaningful human models for the investigation of disease pathogenesis in a patient-specific manner. To overcome this roadblock, we present a new method to isolate and grow single cells directly from patients' metastatic ascites, establishing the conditions for propagating them as 3D cultures that we refer to as single cell-derived metastatic ovarian cancer spheroids (sMOCS). By single cell RNA sequencing (scRNAseq) we define the cellular composition of metastatic ascites and trace its propagation in 2D and 3D culture paradigms, finding that sMOCS retain and amplify key subpopulations from the original patients' samples and recapitulate features of the original metastasis that do not emerge from classical 2D culture, including retention of individual patients' specificities. By enabling the enrichment of uniquely informative cell subpopulations from HGSOC metastasis and the clonal interrogation of their diversity at the functional and molecular level, this method provides a powerful instrument for precision oncology in ovarian cancer.The global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused severe morbidity and mortality in humans. It is urgent to understand the function of viral genes. However, the function of open reading frame 10 (ORF10), which is uniquely expressed by SARS-CoV-2, remains unclear. In this study, we showed that overexpression of ORF10 markedly suppressed the expression of type I interferon (IFN-I) genes and IFN-stimulated genes. Then, mitochondrial antiviral signaling protein (MAVS) was identified as the target via which ORF10 suppresses the IFN-I signaling pathway, and MAVS was found to be degraded through the ORF10-induced autophagy pathway. Furthermore, overexpression of ORF10 promoted the accumulation of LC3 in mitochondria and induced mitophagy. Mechanistically, ORF10 was translocated to mitochondria by interacting with the mitophagy receptor Nip3-like protein X (NIX) and induced mitophagy through its interaction with both NIX and LC3B. Moreover, knockdown of NIX expression blocked mitophagy activation, MAVS degradation, and IFN-I signaling pathway inhibition by ORF10. Consistent with our observations, in the context of SARS-CoV-2 infection, ORF10 inhibited MAVS expression and facilitated viral replication. In brief, our results reveal a novel mechanism by which SARS-CoV-2 inhibits the innate immune response; that is, ORF10 induces mitophagy-mediated MAVS degradation by binding to NIX.Ras has long been viewed as a promising target for cancer therapy. Farnesylthiosalicylic acid (FTS), as the only Ras inhibitor has ever entered phase II clinical trials, has yielded disappointing results due to its strong hydrophobicity, poor tumor-targeting capacity, and low therapeutic efficiency. Thus, enhancing hydrophilicity and tumor-targeting capacity of FTS for improving its therapeutic efficacy is of great significance. In this study we conjugated FTS with a cancer-targeting small molecule dye IR783 and characterized the anticancer properties of the conjugate FTS-IR783. We showed that IR783 conjugation greatly improved the hydrophilicity, tumor-targeting and therapeutic potential of FTS. After a single oral administration in Balb/c mice, the relative bioavailability of FTS-IR783 was increased by 90.7% compared with FTS. We demonstrated that organic anion transporting polypeptide (OATP) and endocytosis synergistically drove the uptake of the FTS-IR783 conjugate in breast cancer MDA-MB-231 cells, resulting in superior tumor-targeting ability of the conjugate both in vitro and in vivo. selleck kinase inhibitor We further revealed that FTS-IR783 conjugate could bind with and directly activate AMPK rather than affecting Ras, and subsequently regulate the TSC2/mTOR signaling pathway, thus achieving 2-10-fold increased anti-cancer therapeutic efficacy against 6 human breast cancer cell lines compared to FTS both in vivo and in vitro. Overall, our data highlights a promising approach for the modification of the anti-tumor drug FTS using IR783 and makes it possible to return FTS back to the clinic with a better efficacy.Despite novel drugs and autologous HCT, MM remains incurable, with short survival in patients with poor biological characteristics. Allo HCT may be curative in some patients but is hampered by high rates of toxicity and relapse. We hypothesized that bortezomib (BTZ), with its anti-myeloma and immunologic properties, could improve PFS and cGVHD after allo HCT in newly diagnosed MM patients. In this prospective phase II study, we included 39 young (≤50 years) and high-risk patients who received a tandem auto-allo HCT followed by BTZ. Patients had prospective minimal residual disease (MRD) evaluations using Next-Generation Flow cytometry prior to allo HCT, prior BTZ and every 3 months for 2 years. With a median follow-up of 48 months, we report PFS and OS at 5 years of 41% and 80%, with a non-relapse mortality of 12%. Incidences of grade II-IV aGVHD at 12 months and moderate/severe cGVHD at 2 years were 26% and 57%. In a multivariate analysis model including cytogenetics, ISS and MRD status, MRD positivity prior to allo HCT (HR 3.75, p = 0.037), prior BTZ (HR 11.3, p = 0.018) and 3 months post-BTZ initiation (HR 9.7, p = 0.001) was highly predictive of progression. Peritransplant MRD assessment thus strongly predicts disease progression.Progress in understanding crystallization pathways depends on the ability to unravel relationships between intermediates and final crystalline products at the nanoscale, which is a particular challenge at elevated pressure and temperature. Here we exploit a high-pressure atomic force microscope to directly visualize brucite carbonation in water-bearing supercritical carbon dioxide (scCO2) at 90 bar and 50 °C. On introduction of water-saturated scCO2, in situ visualization revealed initial dissolution followed by nanoparticle nucleation consistent with amorphous magnesium carbonate (AMC) on the surface. This is followed by growth of nesquehonite (MgCO3·3H2O) crystallites. In situ imaging provided direct evidence that the AMC intermediate acts as a seed for crystallization of nesquehonite. In situ infrared and thermogravimetric-mass spectrometry indicate that the stoichiometry of AMC is MgCO3·xH2O (x = 0.5-1.0), while its structure is indicated to be hydromagnesite-like according to density functional theory and X-ray pair distribution function analysis. Our findings thus provide insight for understanding the stability, lifetime and role of amorphous intermediates in natural and synthetic systems.Synchronization of large spin Hall nano-oscillator (SHNO) arrays is an appealing approach toward ultrafast non-conventional computing. However, interfacing to the array, tuning its individual oscillators and providing built-in memory units remain substantial challenges. Here, we address these challenges using memristive gating of W/CoFeB/MgO/AlOx-based SHNOs. In its high resistance state, the memristor modulates the perpendicular magnetic anisotropy at the CoFeB/MgO interface by the applied electric field. In its low resistance state the memristor adds or subtracts current to the SHNO drive. Both electric field and current control affect the SHNO auto-oscillation mode and frequency, allowing us to reversibly turn on/off mutual synchronization in chains of four SHNOs. We also demonstrate that two individually controlled memristors can be used to tune a four-SHNO chain into differently synchronized states. link2 Memristor gating is therefore an efficient approach to input, tune and store the state of SHNO arrays for non-conventional computing models.Organic long-persistent-luminescent (OLPL) materials demonstrating hour-long photoluminescence have practical advantages in applications owing to their flexible design and easy processability. However, the energy absorbed in these materials is typically stored in an intermediate charge-separated state that is unstable when exposed to oxygen, thus preventing persistent luminescence in air unless oxygen penetration is suppressed through crystallization. Moreover, OLPL materials usually require ultraviolet excitation. Here we overcome such limitations and demonstrate amorphous OLPL systems that can be excited by radiation up to 600 nm and exhibit persistent luminescence in air. By adding cationic photoredox catalysts as electron-accepting dopants in a neutral electron-donor host, stable charge-separated states are generated by hole diffusion in these blends. Furthermore, the addition of hole-trapping molecules extends the photoluminescence lifetime. link3 By using a p-type host less reactive to oxygen and tuning the donor-acceptor energy gap, our amorphous blends exhibit persistent luminescence stimulated by visible light even in air, expanding the applicability of OLPL materials.Electrophilic and oxidative stress is caused when homeostatic mechanisms are disrupted. A major defense mechanism involves the activation of the nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor encoded by the NFE2L2 gene, which can accelerate the detoxification of electrophilic carcinogens and prevent cancer and on the other hand in certain exposure contexts may exacerbate the carcinogenic process. NRF2-target genes activated under these conditions can be used as biomarkers of stress signalling, while activation of NRF2 can also reveal the epigenetic mechanisms that modulate NFE2L2 expression. Epigenetic mechanisms that regulate NFE2L2 and the gene for its adaptor protein KEAP1 include DNA methylation, histone modifications and microRNA. Understanding the activation of the NRF2-KEAP1 signalling pathway in human lung cancer, its epigenetic regulation and its role in oncogenesis is the subject of this review.Intervertebral disc (IVD) degeneration is a common finding on spine imaging that increases in prevalence with age. IVD degeneration is a frequent cause of low back pain, which is a leading cause of disability. The process of IVD degeneration consists of gradual structural change accompanied by severe alterations in metabolic homeostasis. IVD degeneration, like osteoarthritis, is a common comorbidity in patients with obesity and type 2 diabetes mellitus, two metabolic syndrome pathological conditions in which adipokines are important promoters of low-grade inflammation, extracellular matrix degradation and fibrosis. Impairment in white adipose tissue function, due to the abnormal fat accumulation in obesity, is characterized by increased production of specific pro-inflammatory proteins such as adipokines by white adipose tissue and of cytokines such as TNF by immune cells of the stromal compartment. Investigations into the immunometabolic alterations in obesity and type 2 diabetes mellitus and their interconnections with IVD degeneration provide insights into how adipokines might affect the pathogenesis of IVD degeneration and impair IVD function and repair. Toll-like receptor-mediated signalling has also been implicated as a promoter of the inflammatory response in the metabolic alterations associated with IVD and is thus thought to have a role in IVD degeneration. Pathological starvation, obesity and adipokine dysregulation can result in immunometabolic alterations, which could be targeted for the development of new therapeutics.