Strongforrest9814

Recurrence and treatment resistance are major causes of cancer-associated death. There has been a growing interest in better understanding epithelial-mesenchymal transition (EMT), stemness of cancer cells, and exhaustion and dysfunction of the immune system for which numerous genomic, proteomic, microenvironmental, and immunological mechanisms have been demonstrated. However, practical treatments for such patients have not yet been established. Here we identified interleukin-33 (IL33) as a key driver of polyploidy followed by rapid proliferation after treatment. IL33 induction transformed tumor cells into polyploid giant cells, showing abnormal cell cycle without cell division accompanied by Snail deregulation and p53 inactivation; small progeny cells were generated in response to treatment stress. Simultaneously, soluble IL33 was released from tumor cells, leading to expansion of receptor ST2-expressing cells including IL17RB+GATA3+ cells, which promoted tumor progression and metastasis directly and indirectly via induction of immune exhaustion and dysfunction. Blocking IL33 with a specific mAb in murine IL33+ metastatic tumor models abrogated negative consequences and successfully elicited anti-tumor efficacy induced by other combined treatments. Ex vivo assays using tumor tissues and PBMCs of cancer patients validated the clinical relevancy of these findings. Together, these data suggest that targeting the IL33-ST2 axis is a promising strategy for diagnosis and treatment of patients likely to be resistant to treatments in the clinical setting. Copyright ©2020, American Association for Cancer Research.TAp63 is a p53 family member and potent tumor and metastasis suppressor. Here, we show that TAp63-/- mice exhibit an increased susceptibility to UVR-induced cutaneous squamous cell carcinoma (cuSCC). A human-to-mouse comparison of cuSCC tumors identified miR-30c-2* and miR-497 as underexpressed in TAp63-deficient cuSCC. Reintroduction of these microRNAs significantly inhibited the growth of cuSCC cell lines and tumors. Proteomic profiling of cells expressing either microRNA showed downregulation of cell cycle progression and mitosis associated proteins. check details A mouse to human and cross-platform comparison of RNA-Seq and proteomics data identified a 7-gene signature, including AURKA, KIF18B, PKMYT1, and ORC1, which were overexpressed in cuSCC. Knockdown of these factors in cuSCC cell lines suppressed tumor cell proliferation and induced apoptosis. Additionally, selective inhibition of AURKA suppressed cuSCC cell proliferation, induced apoptosis, and showed anti-tumor effects in vivo. Finally, treatment with miR-30c-2* or miR-497 microRNA mimics was highly effective in suppressing cuSCC growth in vivo. Our data establishes TAp63 as an essential regulator of novel microRNAs that can be therapeutically targeted for potent suppression of cuSCC. Copyright ©2020, American Association for Cancer Research.CONTEXT Pneumococcal conjugate vaccines (PCVs) (pneumococcal 13-valent conjugate vaccine [PCV-13] and pneumococcal 10-valent conjugate vaccine [PCV-10]) are available for prevention of pneumococcal infections in children. OBJECTIVE To determine the vaccine effectiveness (VE) of PCV-13 and PCV-10 in preventing invasive pneumococcal disease (IPD) and acute otitis media (AOM) in children less then 5 years. DATA SOURCES Systematic searches of Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, Web of Science, and Cochrane. STUDY SELECTION Eligible studies examined the direct effectiveness and/or efficacy of PCV-10 and PCV-13 in reducing the incidence of disease in healthy children less then 5 years. DATA EXTRACTION Two reviewers independently conducted data extraction and methodologic quality assessment. RESULTS Significant effectiveness against vaccine-type IPD in children ≤5 years was reported for ≥1 dose of PCV-13 in the 3 + 1 (86%-96%) and 2 + 1 schedule (67.2%-86%) and for PCV-10 for the 3 + 1 (72.8%-100%) and 2 + 1 schedules (92%-97%). In children less then 12 months of age, PCV-13 VE against serotype 19A post-primary series was significant for the 3 + 1 but not the 2 + 1 schedule. PCV-10 crossprotection against 19A was significant in children ≤5 years with ≥1 dose (82.2% and 71%). Neither PCVs were found effective against serotype 3. PCV-13 was effective against AOM (86%; 95% confidence interval [CI] 61 to 94). PCV-10 was effective against clinically defined (26.9%; 95% CI 5.9 to 43.3) and bacteriologically confirmed AOM (43.3%; 95% CI 1.7 to 67.3). LIMITATIONS Because of the large heterogeneity in studies, a meta-analysis for pooled estimates was not done. CONCLUSIONS Both PCVs afford protection against pneumococcal infections, with PCV-10 protecting against 19A IPD, but this VE has not been verified in the youngest age groups. Copyright © 2020 by the American Academy of Pediatrics.Photorespiration is an essential process in oxygenic photosynthetic organisms triggered by the oxygenase activity of ribulose-1,5-bisphosphate carboxylase/oxygenase. In peroxisomes, photorespiratory HYDROXYPYRUVATE REDUCTASE 1 (HPR1) catalyzes the conversion of hydroxypyruvate to glycerate together with the oxidation of a pyridine nucleotide cofactor. HPR1 regulation remains poorly understood; however, HPR1 phosphorylation at T335 has been reported. By comparing the kinetic properties of phospho-mimetic (T335D), non-phosphorylatable (T335A), and wild-type recombinant Arabidopsis thaliana HPR1, it was found that HPR1-T335D exhibits reduced NADH-dependent hydroxypyruvate reductase activity while showing improved NADPH-dependent activities. Complementation of the Arabidopsis hpr1-1 mutant by either wild-type HPR1 or HPR1-T335A fully complemented the photorespiratory growth phenotype of hpr1-1 in ambient air whereas HPR1-T335D containing hpr1-1 plants remained smaller and had lower photosynthetic CO2 assimilation rates. Metabolite analyses indicated that these phenotypes were associated with subtle perturbations in the photorespiratory cycle of HPR1-T335D-complemented hpr1-1 rosettes compared to all other HPR1-containing lines. Therefore, T335 phosphorylation may play a role in the regulation of HPR1 activity in planta although it was not required for growth under ambient air controlled conditions. Furthermore, improved NADP-dependent HPR1 activities in peroxisomes could not compensate for the reduced NADH-dependent HPR1 activity. copyright, serif 2020 American Society of Plant Biologists. All rights reserved.