Halseygreen2950

Finally, in vivo experiments showed that the inhibition of SNHG16 suppressed tumor progression, and that YAP1 rescued the effect of SNHG16 on tumor progression. Herein, we have clarified a hitherto unexplored SNHG16-YAP1/TEAD1 positive feedback loop, that may be a candidate target for CRC treatment.The incidence of cholangiocarcinoma (CCA) has been increasing over the past few years. Although there are surgery, chemotherapy and other conventional treatment methods, the effect is not as expected. At present, immunotherapy has become the research frontier of cancer treatment, and CCA tumor microenvironment (TME) is becoming a hot exploration direction of immunobiology. TME can affect tumor progression through changes in metabolism, secretion and immunity. Accordingly, understanding the role played by immune cells and stromal cells in TME is important for the study of CCA immunotherapy. This review will discuss the interactions between immune cells (including CD8+ T cells, CD4+ T cells, macrophages, natural killer cells, dendritic cells, myeloid suppressor cells, mast cells, and neutrophils) and stromal cells (including cancer-associated fibroblasts, endothelial cells) in the TME of CCA. In addition, we will also discuss current research results on TME of CCA and recent advances in immunotherapy.Colorectal cancer (CRC) is an aggressive malignancy with poor prognosis. It is imperative to elucidate the potential molecular mechanisms that regulate CRC cell aggressiveness. In present study, the transient receptor potential melastatin 4 (TRPM4), a calcium-activated nonselective cation channel, is downregulated in CRC as a novel methylated tumor suppressor gene (TSG). The reduced mRNA level of TRPM4 is due to the epigenetic methylation of its promoter CpG island (CGI). Moreover, ectopic expression of TRPM4 inhibited tumor growth and metastasis both in vitro and in vivo. Our experiments also demonstrate that TRPM4 restructures the CRC cytoskeleton and activates the Ca2+-mediated calpain pathway through enhancing calcium influx. The western blot analysis shows that the expression of focal adhesion kinase (FAK), a calpain-mediated proteolytic substrate, is markedly suppressed after ectopic overexpression of TRPM4, besides, Akt (also known as protein kinase B, PKB), phosphatidylinositol 3-kinase (PI3K) as well as its central target mTOR have significantly decreased expression accompanied by elevated E-cadherin and restrained matrix metalloproteinases (MMP2/MMP9) expression. The inhibition of protease calpain effectively relieves the retard of FAK/Akt signals and reverses the migration suppression of TRPM4. Taken together, TRPM4, identified as a novel methylated TSG, employs intracellular Ca2+ signals to activate calpain-mediated cleavage of FAK and impede CRC migration and invasion through modulating the PI3K/Akt/mTOR signaling cascade, providing the first evidence that TRPM4 is likely to be a significant biomarker and potential target for CRC therapy.Fibrosis is a detrimental outcome of most chronic inflammatory disorders and is defined by the buildup of excess extracellular matrix (ECM) components, which eventually leads to organ failure and death. Interleukin 6 (IL-6) is promptly produced by immune cells in response to tissue injuries and has a wide range of effects on cellular processes such as acute responses, hematopoiesis, and immune reactions. Furthermore, high levels of IL-6 have been found in a variety of chronic inflammatory disorders characterized by fibrosis, and this factor plays a significant role in fibrosis in various organs via Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) activation. Here, we review what is known about the role of IL-6 in fibrosis and why targeting IL-6 for fibrotic disease treatment makes sense.Overcoming energy stress is a critical step for cells in solid tumors. Under this stress microenvironment, cancer cells significantly alter their energy metabolism to maintain cell survival and even metastasis. Our previous studies have shown that thioredoxin-1 (Trx-1) expression is increased in colorectal cancer (CRC) and promotes cell proliferation. However, the exact role and mechanism of how Trx-1 is involved in energy stress are still unknown. Here, we observed that glucose deprivation of CRC cells led to cell death and promoted the migration and invasion, accompanied by upregulation of Trx-1. Increased Trx-1 supported CRC cell survival under glucose deprivation. Whereas knockdown of Trx-1 sensitized CRC cells to glucose deprivation-induced cell death and reversed glucose deprivation-induced migration, invasion, and epithelial-mesenchymal transition (EMT). Furthermore, we identified glucose-6-phosphate dehydrogenase (G6PD) interacting with Trx-1 by HuPortTM human protein chip, co-IP and co-localization. Trx-1 promoted G6PD protein expression and activity under glucose deprivation, thereby increasing nicotinamide adenine dinucleotide phosphate (NADPH) generation. Moreover, G6PD knockdown sensitized CRC cells to glucose deprivation-induced cell death and suppressed glucose deprivation-induced migration, invasion, and EMT. Inhibition of Trx-1 and G6PD, together with inhibition of glycolysis using 2-deoxy-D-glucose (2DG), resulted in significant anti-tumor effects in CRC xenografts in vivo. These findings demonstrate a novel mechanism and may represent a new effective therapeutic regimen for CRC.Warburg effect of aerobic glycolysis in hepatic M1 macrophages is a major cause for metabolic dysfunction and inflammatory stress in non-alcoholic fatty liver disease (NAFLD). Plant-derived triterpene celastrol markedly inhibited macrophage M1 polarization and adipocyte hypertrophy in obesity. JTZ-951 HIF inhibitor The present study was designed to identify the celastrol-bound proteins which reprogrammed metabolic and inflammatory pathways in M1 macrophages. Pyruvate kinase M2 (PKM2) was determined to be a major celastrol-bound protein. Peptide mapping revealed that celastrol bound to the residue Cys31 while covalent conjugation altered the spatial conformation and inhibited the enzyme activity of PKM2. Mechanistic studies showed that celastrol reduced the expression of glycolytic enzymes (e.g., GLUT1, HK2, LDHA, PKM2) and related signaling proteins (e.g., Akt, HIF-1α, mTOR), shifted aerobic glycolysis to mitochondrial oxidative phosphorylation and skewed macrophage polarization from inflammatory M1 type to anti-inflammatory M2 type. Animal experiments indicated that celastrol promoted weight loss, reduced serum cholesterol level, lipid accumulation and hepatic fibrosis in the mouse model of NAFLD. Collectively, the present study demonstrated that celastrol might alleviate lipid accumulation, inflammation and fibrosis in the liver via covalent modification of PKM2.

Despite medical advancements, pain is a major source of suffering at the end of life for patients with a solid metastatic cancer. We aimed to assess the trajectory of pain prevalence, severity, interference, and inadequacy of analgesia during the last year of life.

We analysed data from the last year of life of 345 decedents from a prospective cohort study of 600 patients with a solid metastatic cancer in Singapore. Patients were surveyed every 3 months and their pain outcomes (prevalence, severity, and interference) and inadequacy of analgesia were analysed. We used mixed-effects regressions to assess the association of pain outcomes with patients' time from death, demographics, and planned or unplanned hospitalisations.

Prevalence of pain was higher in the last 2 months (65%) compared to 11 to 12 months (41%) before death. Pain severity and interference scores (mean ± SD) were also higher in the last month (severity 2.5±2.6; interference 2.6±3.0) compared to 12 months before death (severity 1.4±2.0; iention in monitoring and treatment of pain even earlier in the disease trajectory, and increased attention to patients discharged from an unplanned hospitalisation.

Loneliness increased during the COVID-19 pandemic and social distancing guidelines, potentially exacerbating negative cognitions about pain. The present study investigated the longitudinal relationship between loneliness, assessed during the early weeks of the pandemic, and pain catastrophizing, assessed after living in the pandemic for approximately 1 year, among chronic pain patients. We also examined whether severity of depressive symptoms mediated this association.

This prospective longitudinal study recruited individuals with chronic pain (N=93) from Massachusetts using an online convenience sampling method via the platform Rally. Participants completed an initial survey early after the onset of social distancing (4/28/20-6/17/20; Time 1) and a follow-up survey 1 year later (5/21/21-6/7/21; Time 2). Participants completed validated assessments of loneliness (T1), pain catastrophizing (T2), and depression (T2). Spearman correlations and Mann-Whitney

-tests were used to explore associations among psyth behavioral interventions, understanding the temporal associations among these variables is important for the employment of future empirically supported treatments.

Findings suggest that greater loneliness during the pandemic was associated with higher pain catastrophizing 1 year later, and severity of depression after living in the pandemic mediated this association. As loneliness, depression, and catastrophizing can all be modified with behavioral interventions, understanding the temporal associations among these variables is important for the employment of future empirically supported treatments.

Readiness to change is a key component of substance use behavioral change; yet little is known about readiness to change among justice-involved young adults. This study 1) describes readiness to change alcohol and drug use and 2) examines predictors of readiness to change alcohol and drug use among justice-involved young adults.

Justice-involved young adults (18-24years; n=137) who were positive on a validated alcohol and/or drug screening tool completed an interview assessing substance use, readiness to change, and reasons to quit. A multivariable linear regression model examined whether reasons to change and substance use severity, and interactions between these, predicted readiness.

More than half of participants were contemplating or had decided to quit/cut down substance use. Personal reasons to quit were positively related to readiness to change; interpersonal reasons were negatively associated.

This study contributes information needed to design motivational interventions for substance use among justice-involved young adults. Personal reasons to quit using drugs are a potential intervention target.

This study contributes information needed to design motivational interventions for substance use among justice-involved young adults. Personal reasons to quit using drugs are a potential intervention target.Visual snow syndrome is characterized by a continuous visual disturbance resembling a badly tuned analogue television and additional visual and non-visual symptoms causing significant disability. The natural course of visual snow syndrome has not hitherto been studied. In this prospective longitudinal study, 78 patients with the diagnosis of visual snow syndrome made in 2011 were re-contacted in 2019 to assess symptom evolution using a semi-structured questionnaire. Forty patients (51% of 78) were interviewed after 84 ± 5 months (mean ± SD). In all patients, symptoms had persisted. Visual snow itself was less frequently rated as the most disturbing symptom (72 versus 42%, P = 0.007), whereas a higher proportion of patients suffered primarily from entopic phenomena (2 versus 17%, P = 0.024). New treatment was commenced in 14 (35%) patients, of whom in seven, visual snow syndrome was ameliorated somewhat. Three (7%) experienced new visual migraine aura without headache, and one (2%) had new migraine headache. There were no differences in the levels of anxiety and depression measured by the Patient Health Questionnaire 8 and the Generalized Anxiety Disorder Scale 7.