Stallingsabrahamsen7235

Gliomas are characterized by diffuse infiltration of tumor cells into surrounding brain tissue, and this highly invasive nature contributes to disease recurrence and poor patient outcomes. The molecular mechanisms underlying glioma cell invasion remain incompletely understood, limiting development of new targeted therapies. Here, we have identified phosphotyrosine adaptor protein ShcD as upregulated in malignant glioma and shown that it associates with receptor tyrosine kinase Tie2 to facilitate invasion. In human glioma cells, we find that expression of ShcD and Tie2 increases invasion, and this significant synergistic effect is disrupted with a ShcD mutant that cannot bind Tie2 or hyperphosphorylate the receptor. Expression of ShcD and/or Tie2 further increases invadopodia formation and matrix degradation in U87 glioma cells. In a coculture model, we show that U87-derived tumor spheroids expressing both ShcD and Tie2 display enhanced infiltration into cerebral organoids. Mechanistically, we identify changes in focal adhesion kinase phosphorylation in the presence of ShcD and/or Tie2 in U87 cells upon Tie2 activation. Finally, we identify a strong correlation between transcript levels of ShcD and Tie2 signaling components as well as N-cadherin in advanced gliomas and those with classical or mesenchymal subtypes, and we show that elevated expression of ShcD correlates with a significant reduction in patient survival in higher grade gliomas with mesenchymal signature. Altogether, our data highlight a novel Tie2-ShcD signaling axis in glioma cell invasion, which may be of clinical significance. IMPLICATIONS ShcD cooperates with Tie2 to promote glioma cell invasion and its elevated expression correlates with poor patient outcome in advanced gliomas.We demonstrate that inhibition of cyclin-dependent kinases 4/6 (CDK4/6) leads to senescence in human papillomavirus (HPV)-negative (-) head and neck squamous cell carcinoma (HNSCC), but not in HPV-positive (+) HNSCC. The BCL-2 family inhibitor, navitoclax, has been shown to eliminate senescent cells effectively. We evaluated the efficacy of combining palbociclib and navitoclax in HPV- HNSCC. Three HPV- HNSCC cell lines (CAL27, HN31, and PCI15B) and three HPV+ HNSCC cell lines (UPCI-SCC-090, UPCI-SCC-154, and UM-SCC-47) were treated with palbociclib. Treatment drove reduced expression of phosphorylated Rb (p-Rb) and phenotypic evidence of senescence in all HPV- cell lines, whereas HPV+ cell lines did not display a consistent response by Rb or p-Rb and did not exhibit morphologic changes of senescence in response to palbociclib. In addition, treatment of HPV- cells with palbociclib increased both β-galactosidase protein expression and BCL-xL protein expression compared with untreated controls in HPV- cells. Co-expression of β-galactosidase and BCL-xL occurred consistently, indicating elevated BCL-xL expression in senescent cells. Combining palbociclib with navitoclax led to decreased HPV- HNSCC cell survival and led to increased apoptosis levels in HPV- cell lines compared with each agent given alone. IMPLICATIONS This work exploits a key genomic hallmark of HPV- HNSCC (CDKN2A disruption) using palbociclib to induce BCL-xL-dependent senescence, which subsequently causes the cancer cells to be vulnerable to the senolytic agent, navitoclax.The mutational genetic landscape of colorectal cancer has been extensively characterized; however, the ability of "cooperation response genes" to modulate the function of cancer "driver" genes remains largely unknown. In this study, we investigate the role of aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, in modulating oncogenic cues in the colon. We show that intestinal epithelial cell-targeted AhR knockout (KO) promotes the expansion and clonogenic capacity of colonic stem/progenitor cells harboring ApcS580/+; KrasG12D/+ mutations by upregulating Wnt signaling. The loss of AhR in the gut epithelium increased cell proliferation, reduced mouse survival rate, and promoted cecum and colon tumorigenesis in mice. Mechanistically, the antagonism of Wnt signaling induced by Lgr5 haploinsufficiency attenuated the effects of AhR KO on cecum and colon tumorigenesis. IMPLICATIONS Our findings reveal that AhR signaling plays a protective role in genetically induced colon tumorigenesis at least by suppressing Wnt signaling and provides rationale for the AhR as a therapeutic target for cancer prevention and treatment.

To evaluate an intervention to reduce the nocebo effect (NE) when switching from the originator infliximab (OI) to the infliximab biosimilar SB2 in chronic inflammatory rheumatic disease (CIRD).

An intervention was built with healthcare professionals (HPs) and a patient representative, based on a systematic review of interventions reducing the NE in musculoskeletal diseases and semi-directed questioning of five patients. Our strategy consisted of training HPs, switch information given by the nurses, a consistent vocabulary. All CIRD patients switched from OI to SB2 were included for the intervention. The primary outcome was the SB2 retention rate (RR) at 34weeks. Secondary outcomes were the SB2 RR at 12months, discontinuation rates due to a possible NE and comparison with a historical cohort of CIRD patients receiving the OI and 6 published European cohorts.

45 patients were included from March 2018 (rheumatoid arthritis, n=17, spondylarthritis, n=28). After 34weeks, the SB2 RR was 91.2%, similar to the historical cohort RR (p=0.41) but higher than the 3 European cohort RRs (p<0.05). At 12months, the SB2 RR was 84.5% vs 88.4% for the historical cohort (p=0.52). SB2 discontinuation due to a possible NE was 6.6% after 12months.

A tailored communication with a prominent role of nurses reduced the NE in non-medical switches from the OI to SB2 as compared to published results. The RR was similar to the historical cohort RR. The methodology used to construct this intervention may help improve the outcomes of switches with upcoming biosimilars.

A tailored communication with a prominent role of nurses reduced the NE in non-medical switches from the OI to SB2 as compared to published results. JG98 ic50 The RR was similar to the historical cohort RR. The methodology used to construct this intervention may help improve the outcomes of switches with upcoming biosimilars.