Objectives Sepsis is associated with significant mortality. Telehealth may improve the quality of early sepsis care, but the use and impact of telehealth applications for sepsis remain unclear. We aim to describe the telehealth interventions that have been used to facilitate sepsis care, and to summarize the reported effect of telehealth on sepsis outcomes. Data Sources We identified articles reporting telehealth use for sepsis using an English-language search of PubMed, CINAHL Plus (EBSCO), Academic Search Ultimate (EBSCO), APA PsycINFO (EBSCO), Public Health (ProQuest), and Web of Science databases with no restrictions on publication date. Study Selection Included studies described the use of telehealth as an intervention for treating sepsis. Only comparative effectiveness analyses were included. Data Extraction and Synthesis Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) guidelines, two investigators independently selected articles for inclusion and abstracted data. A random-effects subgroup analysis was conducted on patient survival treated with and without telehealth. Results A total of 15 studies were included, involving 188,418 patients with sepsis. Thirteen studies used observational study designs, and the most common telehealth applications were provider-to-provider telehealth consultation and intensive care unit telehealth. Clinical and methodological heterogeneity was significantly high. Telehealth use was associated with higher survival, especially in settings with low control group survival. The effect of telehealth on other care processes and outcomes were more varied and likely dependent on hospital-level factors. Conclusions Telehealth has been used in diverse applications for sepsis care, and it may improve patient outcomes in certain contexts. Additional interventional trials and cost-based analyses would clarify the causal role of telehealth in improving sepsis outcomes.

Background: Chordoma is a cancer of spinal cord, skull base, and sacral area. Currently, the standard of care to treat chordoma is resection followed by radiation therapy. Since, chordoma is present in the spinal cord and these are very sensitive structures and often complete removal by surgery is not possible. As a result, chordoma has a high chance of recurrence and developing resistance to radiation therapy. In addition, treatment of chordoma by conventional radiation therapy can also damage normal tissues surrounding chordoma. Thus, current therapeutic options to treat chordoma are insufficient and novel therapies are desperately needed to treat locally advanced and metastatic chordoma. (2) Methods: In the present investigation, human chordoma cell lines of sacral origin MUG-Chor1 and U-CH2 were cultured and irradiated with Proton Beam Radiation using the clinical superconducting cyclotron and pencil-beam (active) scanning at Middle and End of the Spread-Out Bragg Peak (SOBP). Proton radiation was given at the following doses: Mug-Chor1 at 0, 1, 2, 4, and 8 Gy and U-CH2 at 0, 4, 8, 12, and 16 Gy. These doses were selected based on a pilot study in our lab and attempted to produce approximate survival fractions in the range of 1, 0.9, 0.5, 0.1, and 0.01, respectively, chosen for linear quadratic model fitting of the dose response. (3) Results: In this study, we investigated relative biological effectiveness (RBE) of proton radiation at the end of Spread Out Bragg Peak assuming that the reference radiation is a proton radiation in the middle of the SOBP. We observed differences in the survival of both Human chordoma cell lines, U-CH2 and MUG-Chor1. The data showed that there was a significantly higher cell death at the end of the Bragg peak as compared to middle of the Bragg peak. Based on the linear quadratic (LQ) fit for cell survival we calculated the RBE between M-SOBP and E-SOBP at 95% CI level and it was observed that RBE was higher than 1 at E-SOBP and caused significantly higher cell killing. Proton field at E-SOBP caused complex DNA damage in comparison to M-EOBP and the genes such as DNA topoisomerase 1, GTSE1, RAD51B were downregulated in E-SOBP treated cells. Thus, we conclude that there seems to be substantial variation in RBE (1.3–1.7) at the E-SOBP compared with the M-SOBP.

Chordoma is a rare, slow-growing sarcoma that is locally aggressive, and typically resistant to conventional chemo- and radiotherapies. Despite its low incidence, chordoma remains a clinical challenge because therapeutic options for chordoma are limited, and little is known about the molecular mechanisms involved in resistance to therapies. Furthermore, there are currently no established predictive or prognostic biomarkers to follow disease progression or treatment. Whole-genome sequencing of chordoma tissues has demonstrated a low-frequency mutation rate compared to other cancers. This has generated interest in the role of epigenetic events in chordoma pathogenesis. In this review, we discuss the current understanding of the epigenetic drivers of chordoma and their potential applications in prognosis and the development of new therapies.

Purpose/Objective(s): Pancreatic ductal adenocarcinoma (PDAC) is characterized by an unusually high degree of hypoxia in the tumor microenvironment, which activates hypoxic signaling pathways orchestrated by hypoxia-inducible factor 1α (HIF1α). It has been shown previously that HIF1α significantly increases PDAC radioresistance and growth, though its mechanism of action is unknown. Here, we test the hypothesis that HIF1α confers these traits in PDAC through involvement in DNA damage repair and KRAS signaling in vitro. Materials/Methods: We performed studies with the KPC cell line (KrasLSL-G12D/+;TP53LSL-R172H/+). We used CRISPR-Cas9, a genome editing tool, to generate a HIF1α knockout (KO) cell line. Hypoxic microenvironments were induced using 100uM of the oxygen scavenger CoCl2. Radioresistance and double-strand DNA damage was evaluated and compared between wild-type (WT) and KO cells after treatment with increasing doses of ionizing radiation using neutral comet assays. Tumor signaling pathways were mapped and analyzed using western blot and co-immunoprecipitation. The KRASG12D inhibitor, BI-2852, was obtained from Boehringer-Ingelheim. Cancer cells were evaluated for growth and migration using cell proliferation assays and scratch wound assays following treatment with 50 uM BI-2852. Bioinformatic analysis was conducted using TCGA (The Cancer Genome Atlas) data; high and low expression were defined as samples with mRNA expression z-scores ≥ 1 and ≤ -1, respectively, Results: HIF1α KO cells demonstrated significantly increased radioresistance compared to WT cells following 8 and 10 Gy of radiation in hypoxic conditions (t-test, P<0.05). The olive moment of KO cells treated with the IC50 radiation dose (4 Gy) was significantly higher than that of WT cells (t-test, P<0.0001), suggesting that the DNA damage repair was upregulated by HIF1α. In addition, WT cells demonstrated higher tumor proliferation (t-test, P<0.01) and migration (t-test, P<0.05) compared to KO cells under hypoxia, suggesting HIF1α promoted tumor growth. WT cells treated with BI-2852 demonstrated significantly lower levels of TP53; using coimmunoprecipitation, we show that TP53 was likely degraded through Mdm2. HIF1α KO was necessary to induce high levels of apoptosis in cells treated with BI-2852. Our results suggest that HIF1α may act synergistically with KRAS to promote tumor survival through anti-apoptotic pathways that target TP53 for degradation. TCGA data also suggest that tumors with high expression of HIF1α is are associated with significantly poorer prognosis coimpared to tumors with low expression of HIF1α (Logrank test, P=0.003). Conclusion: Overall, this study demonstrates that HIF1α promotes DNA damage repair in PDAC and reveals a HIF1α/KRAS/p53 signaling axis. Future studies will test anti-HIF1α and anti-KRAS combination therapies in PDAC mouse models. Citation Format: Kevin J. Tu, Sanjit K. Roy, Amit Sawant, Hem D. Shukla. HIF1α is involved in radiation-induced DNA damage repair and anti-apoptotic pathways in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4810.

Cancer arises through clonal evolution, in some cases selecting change of metabolic function (COMF) mutations that functionally alter proteins to affect cellular metabolism. COMF mutations can impart new catalytic functions that can be applied to enable novel chemical synthesis and metabolic engineering techniques. We previously showed that the oncogenic COMF mutation IDH1 p.R132H could also be used to enable a bio-based method of adipic acid production, a valuable commodity chemical used to synthesize nylon that erstwhile required petroleum-substrates for synthesis. However, there is no high-throughput method to identify COMF mutations. Here, we present METIS (Mutated Enzymes from Tumors In silico Screen), a bioinformatic pipeline to identify COMF mutations from cancer mutational data based on the recurrence rate, genetic conservation, and predicted functionality of the mutations. We applied METIS to 210,354 cancer-derived missense mutations from the COSMIC (Catalogue Of Somatic Mutations In Cancer) database. We identified 4 candidate COMF mutations: the Cbl proto-oncogene E3 ubiquitin ligase (CBL) p.Y371H, Polypeptide N-Acetylgalactosaminyltransferase 17 (GALNT17) p.R228C, solute carrier family 17 member 5 (SLC17A5) p.R364C, and 2-oxoglutarate dehydrogenase-like (OGDHL) p.A400T. To determine these mutations’ effect on the cellular metabolome, we performed unbiased global metabolite profiling using LC-MS/MS and GC/MS of HeLa cells exogenously expressing COMF candidates. OGDHL p.A400T demonstrated significant metabolic changes after FDR correction (q<0.05, two-tailed Welch’s unequal variances t-test with Bonferroni correction). In particular, xanthosine, a key intermediate in purine metabolism commonly used in pharmaceutical development, was increased 2.9-fold (P = 1.2 x 10-9, q = 3.2 x 10-7). Thus, our data suggest OGDHL p.A400T could be used to improve production methods for a useful biochemical. We then deployed METIS2, which featured improved statistical, pathogenicity, and structural analysis tools to all 49 million currently-available cancer mutations within COSMIC, providing a refined panel of six candidate mutations. Consistent with the findings from initial METIS metabolomic screen, METIS2 identified OGDHLp.A400T as a COMF mutation candidate. Overall, our results detail an approach to filter cancer data for mutations that confer metabolic functions, validate that mutations identified in this way can alter the cellular metabolome, and catalog potentially-useful candidate mutations. Moreover, prediction of COMF mutations through METIS can also be applied to elucidate mechanisms of cancer initiation, progression, and/or maintenance to identify potential therapeutic targets. As cancer mutation and structural data continue to accumulate, we expect METIS to increase in its predictive power to accurately find COMF mutations. Citation Format: Kevin J. Tu, Bill H. Diplas, Joshua A. Regal, Matthew S. Waitkus, Christopher J. Pirozzi, Zachary J. Reitman. A bioinformatic pipeline for identifying change-of-metabolic-function cancer mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3143.