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BACKGROUND: Over 50% of hospitalized patients have comorbid psychiatric diagnoses, resulting in increased risk of morbidity such as longer lengths of stay, worse health-related quality of life, and increased mortality. However, data regarding colorectal surgery postoperative outcomes in patients with psychiatric diagnoses (PD) are limited. METHODS: We queried a single institution's National Surgical Quality Improvement Program from 2013-2019 for major colorectal procedures. Postsurgical outcomes for patients with and without PD were compared. Primary outcomes were prolonged length of stay (pLOS) and 30-day readmission. RESULTS: From a total of 1447 patients, 402 (27.8%) had PD. PD had more smokers (20.9% vs 15%) and higher mean body mass index (29.1 kg/m2 vs 28.2 kg/m2). Bivariate outcomes showed more surgical site infections (SSI) (10.2% vs 6.12%), reoperation (9.45% vs 6.35%), and pLOS (34.8% vs 29.0%) (all P values <.05) in the PD group. On multivariate analysis, PD had higher likelihood of reoperation (OR 1.53, 95% CI: [1.02-2.80]) and SSI (OR 1.82, 95% CI: [1.25-2.66]). DISCUSSION: Psychiatric diagnoses are a risk factor for adverse outcomes after colorectal procedures. Further studies are needed to evaluate the benefit of perioperative mental health support services for these patients.
RESUMEN
The genetic principle of synthetic lethality is clinically validated in cancers with loss of specific DNA damage response (DDR) pathway genes (i.e. BRCA1/2 tumor suppressor mutations). The broader question of whether and how oncogenes create tumor-specific vulnerabilities within DDR networks remains unanswered. Native FET protein family members are among the earliest proteins recruited to DNA double-strand breaks (DSBs) during the DDR, though the function of both native FET proteins and FET fusion oncoproteins in DSB repair remains poorly defined. Here we focus on Ewing sarcoma (ES), an EWS-FLI1 fusion oncoprotein-driven pediatric bone tumor, as a model for FET rearranged cancers. We discover that the EWS-FLI1 fusion oncoprotein is recruited to DNA DSBs and interferes with native EWS function in activating the DNA damage sensor ATM. Using preclinical mechanistic approaches and clinical datasets, we establish functional ATM deficiency as a principal DNA repair defect in ES and the compensatory ATR signaling axis as a collateral dependency and therapeutic target in FET rearranged cancers. Thus, aberrant recruitment of a fusion oncoprotein to sites of DNA damage can disrupt normal DSB repair, revealing a mechanism for how oncogenes can create cancer-specific synthetic lethality within DDR networks.
RESUMEN
While oncogenes promote cancer cell growth, unrestrained proliferation represents a significant stressor to cellular homeostasis networks such as the DNA damage response (DDR). To enable oncogene tolerance, many cancers disable tumor suppressive DDR signaling through genetic loss of DDR pathways and downstream effectors (e.g., ATM or p53 tumor suppressor mutations). Whether and how oncogenes can help "self-tolerize" by creating analogous functional deficiencies in physiologic DDR networks is not known. Here we focus on Ewing sarcoma, a FET fusion oncoprotein (EWS-FLI1) driven pediatric bone tumor, as a model for the class of FET rearranged cancers. Native FET protein family members are among the earliest factors recruited to DNA double-strand breaks (DSBs) during the DDR, though the function of both native FET proteins and FET fusion oncoproteins in DNA repair remains to be defined. Using preclinical mechanistic studies of the DDR and clinical genomic datasets from patient tumors, we discover that the EWS-FLI1 fusion oncoprotein is recruited to DNA DSBs and interferes with native FET (EWS) protein function in activating the DNA damage sensor ATM. As a consequence of FET fusion-mediated interference with the DDR, we establish functional ATM deficiency as the principal DNA repair defect in Ewing sarcoma and the compensatory ATR signaling axis as a collateral dependency and therapeutic target in multiple FET rearranged cancers. More generally, we find that aberrant recruitment of a fusion oncoprotein to sites of DNA damage can disrupt physiologic DSB repair, revealing a mechanism for how growth-promoting oncogenes can also create a functional deficiency within tumor suppressive DDR networks.
RESUMEN
Limitations of Systematic Evolution of Ligands by Exponential Enrichment (SELEX) and related methods that depend upon combinatorial oligonucleotide libraries have hindered progress in this area. Our laboratory has introduced a new approach to aptamer discovery that uses oligonucleotides with sequences drawn from the human genome to capture proteins from biological samples. Specifically, we have focused on capture of proteins in nuclear extracts from human cell lines using G-quadruplex (G4) forming genomic sequences. Previous studies identified capture of several proteins both in vitro and in live cells by the Pu28-mer sequence from the ERBB2 promoter region. Here we provide a more comprehensive study of protein capture from BT474 and MCF7 human breast cancer cells using G4-forming sequences from the CMYC, RB, VEGF and ERBB2 human oncogene promoter regions. Mass spectrometric analysis and Western blot analysis of protein capture at oligonucleotide-modified surfaces revealed capture of nucleolin by all three of the oligonucleotides in BT474 and MCF7 cells, and also of ribosomal protein L19 (RPL19) in BT474 cells. Chromatin immunoprecipitation (ChIP) analysis confirmed the interaction of nucleolin with all three promoter sequences in MCF7 cells and with RB in BT474 cells. ChIP also revealed interactions of RPL19 with CMYC in BT474 cells and of both RPL19 and ribosomal protein L14 (RPL14) with ERBB2 in BT474 cells. These results offer the basis for development of new aptamers based on the G4 sequences from the CMYC, RB, VEGF, and ERBB2 promoters toward proteins including nucleolin, RPL19 and RPL14. These interactions also may have biological and therapeutic significance.
