A New Mixed-Backbone Oligonucleotide against Glucosylceramide Synthase Sensitizes Multidrug-Resistant Tumors to Apoptosis

Enhanced ceramide glycosylation catalyzed by glucosylceramide synthase (GCS) limits therapeutic efficiencies of antineoplastic agents including doxorubicin in drug-resistant cancer cells. Aimed to determine the role of GCS in tumor response to chemotherapy, a new mixed-backbone oligonucleotide (MBO-asGCS) with higher stability and efficiency has been generated to silence human GCS gene. MBO-asGCS was taken up efficiently in both drug-sensitive and drug-resistant cells, but it selectively suppressed GCS overexpression, and sensitized drug-resistant cells. MBO-asGCS increased doxorubicin sensitivity by 83-fold in human NCI/ADR-RES, and 43-fold in murine EMT6/AR1 breast cancer cells, respectively. In tumor-bearing mice, MBO-asGCS treatment dramatically inhibited the growth of multidrug-resistant NCI/ADR-RE tumors, decreasing tumor volume to 37%, as compared with scrambled control. Furthermore, MBO-asGCS sensitized multidrug-resistant tumors to chemotherapy, increasing doxorubicin efficiency greater than 2-fold. The sensitization effects of MBO-asGCS relied on the decreases of gene expression and enzyme activity of GCS, and on the increases of C18-ceramide and of caspase-executed apoptosis. MBO-asGCS was accumulation in tumor xenografts was greater in other tissues, excepting liver and kidneys; but MBO-asGCS did not exert significant toxic effects on liver and kidneys. This study, for the first time in vivo, has demonstrated that GCS is a promising therapeutic target for cancer drug resistance, and MBO-asGCS has the potential to be developed as an antineoplastic agent

Hospital volume and post-operative mortality after resection for gastric cancer

Aims: In low-volume hospitals, expertise in gastric surgery is difficult to maintain because of the decreasing incidence of gastric cancer and the fall of surgery for ulcer disease. We evaluated the prognostic impact of hospital volume on post-operative mortality (POM) in a consecutive series of 1978 patients. Methods: Information on patients undergoing resection for gastric cancer in the period 1987-97 was retrieved from the Rotterdam Cancer Registry. The relationship between hospital volume and POM was analysed by logistic regression, adjusting for other prognostic factors. Results: POM was 7.9% on average but varied between the 22 hospitals from 3.1% to 15.1% (P = 0.15). Hospital volume had no prognostic influence (P = 0.74). Prognostic factors were age (70-79 years odds ratio (OR) = 3.8, 80 + years OR = 6.0), sex (male OR = 1.7), stage (IV OR = 1.8) and (partial) gastrectomy for cardia cancers (OR = 2.0). Conclusion: Variation in POM between hospitals was large but not related to hospital volume. For cardia cancer, POM rates were lower after oesophagogastrectonny. (C) 2002 Elsevier Science Ltd. All rights reserved

Transcriptional variability accelerates pre-leukemia by cell diversification and perturbation of protein synthesis

Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. scRNA-seq and bulk RNA-seq data were deposited in ArrayExpress with accession number E-MTAB-10853 and ERP006862, respectively. Code used for single-cell RNA-seq data analysis was deposited in Zenodo and can be accessed as G. Shikha and P. Cristina (2022). scRNA-seq analysis of RUNX1-RUNX1T1(9a) preleukemia, Zenodo; https://doi.org/10.5281/zenodo.6584118.Supplementary Materials: This PDF file includes: Figs. S1 to S7 avilable at: https://www.science.org/doi/suppl/10.1126/sciadv.abn4886/suppl_file/sciadv.abn4886_sm.pdf (223.69 MB).Other Supplementary Material for this manuscript includes the following: Supplementary Files S1 to S9 available at: https://www.science.org/doi/suppl/10.1126/sciadv.abn4886/suppl_file/sciadv.abn4886_supplementary_files_s1_to_s9.zip (2.34 MB).View/request a protocol for this paper from Bio-protocol available at: https://en.bio-protocol.org/cjrap.aspx?eid=10.1126/sciadv.abn4886Copyright © 2022 The Authors. Transcriptional variability facilitates stochastic cell diversification and can in turn underpin adaptation to stress or injury. We hypothesize that it may analogously facilitate progression of premalignancy to cancer. To investigate this, we initiated preleukemia in mouse cells with enhanced transcriptional variability due to conditional disruption of the histone lysine acetyltransferase gene Kat2a. By combining single-cell RNA sequencing of preleukemia with functional analysis of transformation, we show that Kat2a loss results in global variegation of cell identity and accumulation of preleukemic cells. Leukemia progression is subsequently facilitated by destabilization of ribosome biogenesis and protein synthesis, which confer a transient transformation advantage. The contribution of transcriptional variability to early cancer evolution reflects a generic role in promoting cell fate transitions, which, in the case of well-adapted malignancies, contrastingly differentiates and depletes cancer stem cells. That is, transcriptional variability confers forward momentum to cell fate systems, with differential multistage impact throughout cancer evolution.Wellcome: WT098051; Leuka: John Goldman Fellowship; Lady Tata Memorial Trust: International Scholarship 2017-2021; Cancer Research UK: C22324/A23015; Kay Kendall Leukaemia Fund: KKL888; Wellcome Trust / University of Cambridge ISSF: Bridging Funding 2019