Real world outcomes of combination and timing of immunotherapy with radiotherapy for melanoma with brain metastases

xloma.fota13 shared this article with you from Inoreader Real world outcomes of combination and timing of immunotherapy with radiotherapy for melanoma with brain metastases Via Cancer Medicine In our study of the National Cancer Data Base (NCBD), addition of immunotherapy to radiation therapy improves survival in patients with melanoma with brain metastases when added to SBRT or WBRT, with the best survival observed for IT with SBRT. Concurrrent versus Noncurrent immunotherapy combined with radiation had no significantly different survival. Abstract Introduction Immunotherapy (IT) and radiotherapy (RT) have improved overall survival in patients with melanoma with brain metastasis (MBM). We examined the real‐world survival impact of IT and RT combination and timing strategies. Materials and Methods From the facility‐based National Cancer Database (NCDB) data set, 3008 cases of MBM were identified between 2011 and 2015. Six treatment cohorts were identified: stereotactic radiosurgery (SRS) + IT, SRS alone, whole brain radiotherapy (WBRT) + IT, WBRT alone, IT alone, and none. Concurrent therapy was defined as IT given within 28 days before or after RT; nonconcurrent defined as IT administered within 28–90 days of RT. The co‐primary outcomes were propensity score‐adjusted overall survival by treatment regimen and overall survival by RT and IT timing. Results Median overall survival (mOS) was performed for each treatment category; SRS +IT 15.77 m; (95%CI 12.13–21.29), SRS alone (9.33 m; 95%CI: 8.0–11.3), IT alone (7.29 m; 95%CI: 5.35–12.91), WBRT +IT (4.89 m; 95%CI: 3.65–5.92), No RT or IT (3.29 m; 95%CI: 2.96–3.75), and WBRT alone (3.12 m; 95%CI 2.79–3.52). By propensity score matching, mOS for SRS +IT (15.5 m; 95%CI: 11.5–20.2) was greater than SRS alone (10.1 m; 95%CI: 8.4–11.8) (p = 0.010), and median survival for WBRT +IT (4.6 m; 95%CI: 3.4–5.6) was greater than WBRT alone (2.9 m; 95%CI: 2.5–3.5) (p < 0.001). In the SRS +IT group, 24‐month landmark survival was 47% (95%CI; 42–52) for concurrent versus 37% (95%CI; 30–44) for nonconcurrent (p = 0.40). Conclusion Those who received IT in addition to WBRT and SRS experienced longer survival compared to RT modalities alone, while those receiving concurrent SRS and IT trended toward improved survival versus nonconcurrent therapy. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Targeting YAP‐p62 signaling axis suppresses the EGFR‐TKI‐resistant lung adenocarcinoma

xloma.fota13 shared this article with you from Inoreader Targeting YAP‐p62 signaling axis suppresses the EGFR‐TKI‐resistant lung adenocarcinoma Via Cancer Medicine The accumulated p62 by autophagy inhibitor, chloroquine has oncogenic functions in EGFR‐TKI resistant lung adenocarcinoma. Hippo effector YAP regulates p62 transcription through ERK, and YAP inhibition significantly suppresses the expression of p62. We suggest that targeting YAP‐p62 signaling axis can be useful to overcome the EGFR‐TKI resistance in lung adenocarcinoma. Abstract Background Despite the progress of advanced target therapeutic agents and immune checkpoint inhibitors, EGFR‐TKI resistance is still one of the biggest obstacles in treating lung cancer. Clinical studies with autophagy inhibitors are actively underway to overcome drug resistance. Methods We used PC9, PC9/GR, and HCC827/GR cell lines to evaluate the activation of autophagy and EGFR‐TKI resistance. Chloroquine was applied as an autophagic blocker and verteporfin was utilized as a YAP inhibitor. Results In this study, we tried to reveal the effect of autophagy adaptor p62 which is accumulated by autophagy inhibitor in EGFR‐TKI‐resistant lung adenocarcinoma. We identified that p62 has oncogenic functions that induce cell proliferation and invasion of EGFR‐TKI‐resistant lung adenocarcinoma. Interestingly, we found for the first time that YAP regulates p62 transcription through ERK, and YAP inhibition can suppress the expression of oncogenic p62. We also confirmed that the expressions of p62 and YAP have a positive correlation in EGFR‐mutant lung adenocarcinoma patients. To block cell survival via perturbing YAP‐p62 axis, we treated EGFR‐TKI‐resistant lung cancer cells with YAP inhibitor verteporfin. Remarkably, verteporfin effectively caused the death of EGFR‐TKI‐resistant lung cancer cells by decreasing the expressions of p62 with oncogenic function, YAP, and its target PD‐L1. So, the cumulative effect of oncogenic p62 should be considered when using autophag y inhibitors, especially drugs that act at the last stage of autophagy such as chloroquine and bafilomycin A1. Conclusion Finally, we suggest that targeting YAP‐p62 signaling axis can be useful to suppress the EGFR‐TKI‐resistant lung cancer. Therefore, drug repurposing of verteporfin for lung cancer treatment may be valuable to consider because it can inhibit critical targets: p62, YAP, and PD‐L1 at the same time. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Plasmodium falciparum FIKK9.1 is a monomeric serine–threonine protein kinase with features to exploit as a drug target

xloma.fota13 shared this article with you from Inoreader Plasmodium falciparum FIKK9.1 is a monomeric serine–threonine protein kinase with features to exploit as a drug target Via Chemical Biology & Drug Design FIKK‐9.1 kinase is monomeric with a native molecular weight of 60 ± 1.6 kDa. The C‐terminal domain of protein has a well‐defined pocket to bind ATP. FIKK protein binds ATP with a K d of 45.6 ± 2.4 µM. FIKK‐9.1 has 23 pockets to serve potential docking sites for substrates. Peptide P277 is fitting nicely into the binding pocket. FIKK‐9.1 is phosphorylating spectrin, ankyrin, band 3 in the IRBC. FIKK 9.1 can be exploited in drug discovery and diagnostics. Abstract FIKK‐9.1 is essential for parasite survival, but its structural and biochemical characterization will enable us to understand its role in the parasite life cycle. The recombinant FIKK9.1 kinase is monomeric with a native molecular weight of 60 ± 1.6 kDa. Structural characterization of FIKK9.1 kinase reveals that it consists of two domains: N‐terminal FHA like domain and C‐terminal kinase domain. The C‐terminal domain has a well‐defined pocket, but it displayed RMSD deviation of 1.38–3.2 Å from host kinases. ITC analysis indicates that ATP binds to the protein with a K d of 45.6 ± 2.4 µM. Mutational studies confirm the role of Val‐244, Met‐245, Lys‐320, 324, and Glu‐366 for ATP binding. Co‐localization studies revealed FIKK9.1 in the parasite cytosol with a component trafficked to the apicoplast and also to IRBC. FIKK9.1 has 23 pockets to serve as potential docking sites for substrates. Correlation analysis of peptides from the combinatorial library concluded that peptide P277 (MFDFHYTLGPMWGTL) was fitting nicely into the binding pocket. The peptide P277 picked up candidates from parasite and key players from RBC cytoskeleton. Interestingly, FIKK9.1 is phosphorylating spectrin, ankyrin, and band‐3 from RBC cytoskeleton. Our study highlights the structural and biochemical features of FIKK9.1 to exploit it as a drug target. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Administrative coding in electronic health care record‐based research of NAFLD: an expert panel consensus statement

xloma.fota13 shared this article with you from Inoreader Administrative coding in electronic health care record‐based research of NAFLD: an expert panel consensus statement Via Hepatology Abstract Background and aims Electronic health record (EHR)‐based research allows the capture of large amounts of data, which is necessary in nonalcoholic fatty liver disease (NAFLD), where the risk of clinical liver outcomes is generally low. The lack of consensus on which International Classification of Disease (ICD) codes should be used as exposures and outcomes limits comparability and generalizability of results across studies. We aimed to establish consensus among a panel of experts on ICD codes that could become the reference standard and provide guidance around common methodological issues. Approach and results Researchers with an interest in EHR‐based NAFLD research were invited to collectively define which administrative codes are most appropriate for documenting exposures and outcomes. We used a modified Delphi approach to reach consensus on several commonly encountered methodological challenges in the field. After two rounds of revision, a high level of agreement (>67%) was reached on all items considered. Full consensus was achieved on a comprehensive list of administrative codes to be considered for inclusion and exclusion criteria in defining exposures and outcomes in EHR‐based NAFLD research. We also provide suggestions on how to approach commonly encountered methodological issues and identify areas for future research. Conclusions This expert panel consensus statement can help harmonize and improve generalizability of EHR‐based NAFLD research. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.