Tysondickey2017

© 2020. Published by The Company of Biologists Ltd.Basal bodies (BBs) are microtubule-based organelles that template and stabilize cilia at the cell surface. Centrins ubiquitously associate with BBs and function in BB assembly, maturation, and stability. Human POC5 (hPOC5) is a highly conserved centrin-binding protein that binds centrins through Sfi1p-like repeats and is required for building full-length, mature centrioles. Here, we use the BB-rich cytoskeleton of Tetrahymena thermophila to characterize Poc5 BB functions. Tetrahymena Poc5 (TtPoc5) uniquely incorporates into assembling BBs and is then removed from mature BBs prior to ciliogenesis. Complete genomic knockout of TtPOC5 leads to a significantly increased production of BBs yet a markedly reduced ciliary density, both of which are rescued by reintroduction of TtPoc5. A second Tetrahymena POC5-like gene, SFR1, is similarly implicated in modulating BB production. When TtPOC5 and SFR1 are co-deleted, cell viability is compromised, and levels of BB overproduction are exacerbated. Overproduced BBs display defective transition zone formation and a diminished capacity for ciliogenesis. This study uncovers a requirement for Poc5 in building mature BBs, providing a possible functional link between hPOC5 mutations and impaired cilia. © 2020. Published by The Company of Biologists Ltd.The protein-tyrosine phosphatase SHP2 binds to phosphorylated signaling motifs on regulatory immunoreceptors including PD-1, but its functional role in tumor immunity is unclear. Using preclinical models, we show that RMC-4550, an allosteric inhibitor of SHP2, induces anti-tumor immunity with effects equivalent to or greater than those resulting from checkpoint blockade. In the tumor microenvironment, inhibition of SHP2 modulated T cell infiltrates similar to checkpoint blockade. Additionally, RMC-4550 drove direct, selective depletion of pro-tumorigenic M2 macrophages via attenuation of CSF-1 receptor signaling and increased M1 macrophages via a mechanism independent of CD8+T-cells or IFN-γ. These dramatic shifts in polarized macrophage populations in favor of anti-tumor immunity were not seen with checkpoint blockade. Consistent with a pleiotropic mechanism of action, RMC-4550 in combination with either checkpoint or CSF-1R blockade caused additive anti-tumor activity with complete tumor regressions in some mice; tumors intrinsically sensitive to SHP2 inhibition or checkpoint blockade were particularly susceptible. Our preclinical findings demonstrate that SHP2 thus plays a multifaceted role in inducing immune suppression in the tumor microenvironment, through both targeted inhibition of RAS pathway-dependent tumor growth and liberation of anti-tumor immune responses. Furthermore, these data suggest that inhibition of SHP2 is a promising investigational therapeutic approach. Copyright ©2020, American Association for Cancer Research.Mature B-cell neoplasms are the fifth most common neoplasm. Due to significant heterogeneity at the clinical and genetic levels, current therapies for these cancers fail to provide long-term cures. The clinical success of proteasome inhibition for the treatment of multiple myeloma and B-cell lymphomas has made the ubiquitin pathway an important emerging therapeutic target. In this study, we assessed the role of the E3 ligase FBXW7 in mature B-cell neoplasms. FBXW7 targeted the frequently inactivated tumor suppressor KMT2D for protein degradation, subsequently regulating gene expression signatures related to oxidative phosphorylation (OxPhos). Loss of FBXW7 inhibited diffuse large B-cell lymphoma cell growth and further sensitized cells to OxPhos inhibition. These data elucidate a novel mechanism of regulation of KMT2D levels by the ubiquitin pathway and uncover a role of FBXW7 in regulating oxidative phosphorylation in B-cell malignancies. Copyright ©2020, American Association for Cancer Research.AIM To increase the documented use of the Lifestart trolley to allow premature infants' ( less then 32 weeks' gestation) resuscitation and stabilisation with an intact umbilical cord at delivery. DESIGN A 13-month quality improvement programme from April 2018 to April 2019 was undertaken using Plan, Do, Study and Act (PDSA) cycles. Data were reviewed from 113 consecutive preterm ( less then 32 weeks) deliveries to identify whether Lifestart was used and whether 2 min deferred cord clamping (DCC) occurred in eligible infants as per hospital policy. Episodes of non-compliance were analysed, causes established and interventions implemented to reduce similar future non-compliance. Data collected were presented graphically and included in alternate monthly newsletters to staff, which also included lessons learnt from the reviews of non-compliance. RESULTS Documented use of the Lifestart rose from 10% at the start of the project to 79% in the final month. Not all babies are eligible for DCC. learn more Within this project, 40 (35%) of preterm infants were not eligible to receive DCC. Of those that were eligible, the rate of DCC increased from 17% in the first 3 months to 92% in the last 3 months of the project (p less then 0.0001). IMPLICATIONS AND RELEVANCE By undertaking regular PDSA cycles and improving education surrounding importance of DCC, we have noted a significant improvement in the use of Lifestart, which in turn facilitates DCC.The learning from this project has been used to create an instructional video to help maintain the improved compliance rates. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Some neural circuits within infants are not fully developed at birth, especially in preterm infants. Therefore, it is unclear whether reflexes that affect breathing may or may not be activated during the neonatal stabilisation at birth. Both sensory reflexes (eg, tactile stimulation) and non-invasive ventilation (NIV) can promote spontaneous breathing at birth, but the application of NIV can also compromise breathing by inducing facial reflexes that inhibit spontaneous breathing. Applying an interface could provoke the trigeminocardiac reflex (TCR) by stimulating the trigeminal nerve resulting in apnoea and a reduction in heart rate. Similarly, airflow within the nasopharynx can elicit the TCR and/or laryngeal chemoreflex (LCR), resulting in glottal closure and ineffective ventilation, whereas providing pressure via inflations could stimulate multiple receptors that affect breathing. Stimulating the fast adapting pulmonary receptors may activate Head's paradoxical reflex to stimulate spontaneous breathing. In contrast, stimulating the slow adapting pulmonary receptors or laryngeal receptors could induce the Hering-Breuer inflation reflex or LCR, respectively, and thereby inhibit spontaneous breathing.