Antiproliferative Effect of Ascorbic Acid Is Associated with the Inhibition of Genes Necessary to Cell Cycle Progression

BACKGROUND: Ascorbic acid (AA), or Vitamin C, is most well known as a nutritional supplement with antioxidant properties. Recently, we demonstrated that high concentrations of AA act on PMP22 gene expression and partially correct the Charcot-Marie-Tooth disease phenotype in a mouse model. This is due to the capacity of AA, but not other antioxidants, to down-modulate cAMP intracellular concentration by a competitive inhibition of the adenylate cyclase enzymatic activity. Because of the critical role of cAMP in intracellular signalling, we decided to explore the possibility that ascorbic acid could modulate the expression of other genes. METHODS AND FINDINGS: Using human pangenomic microarrays, we found that AA inhibited the expression of two categories of genes necessary for cell cycle progression, tRNA synthetases and translation initiation factor subunits. In in vitro assays, we demonstrated that AA induced the S-phase arrest of proliferative normal and tumor cells. Highest concentrations of AA leaded to necrotic cell death. However, quiescent cells were not susceptible to AA toxicity, suggesting the blockage of protein synthesis was mainly detrimental in metabolically-active cells. Using animal models, we found that high concentrations of AA inhibited tumor progression in nude mice grafted with HT29 cells (derived from human colon carcinoma). Consistently, expression of tRNA synthetases and ieF2 appeared to be specifically decreased in tumors upon AA treatment. CONCLUSIONS: AA has an antiproliferative activity, at elevated concentration that could be obtained using IV injection. This activity has been observed in vitro as well in vivo and likely results from the inhibition of expression of genes involved in protein synthesis. Implications for a clinical use in anticancer therapies will be discussed

The Beginning, The Middle, and The End: New Tools for the Scholarly Edition

This article discusses a set of prototypes currently being designed and created by the Interface Design team of the Implementing New Knowledge Environments (INKE) project. These prototypes attempt to supplement the user experience in reading digital scholarly editions, by supporting a set of tasks that are straightforward in a digital environment but in a print edition would be sufficiently more difficult as to be prohibitive. We therefore offer these experimental prototypes as a collection of new affordances for the scholarly edition, although they may reasonably be extended, with some variation, to other kinds of digital text

The Beginning, The Middle, and The End: New Tools for the Scholarly Edition

This article discusses a set of prototypes currently being designed and created by the Interface Design team of the Implementing New Knowledge Environments (INKE) project. These prototypes attempt to supplement the user experience in reading digital scholarly editions, by supporting a set of tasks that are straightforward in a digital environment but in a print edition would be sufficiently more difficult as to be prohibitive. We therefore offer these experimental prototypes as a collection of new affordances for the scholarly edition, although they may reasonably be extended, with some variation, to other kinds of digital text

Effect of the Growth Assessment Protocol on the DEtection of Small for GestatioNal age fetus: process evaluation from the DESiGN cluster randomised trial

BACKGROUND: Reducing the rate of stillbirth is an international priority. At least half of babies stillborn in high-income countries are small for gestational-age (SGA). The Growth Assessment Protocol (GAP), a complex antenatal intervention that aims to increase the rate of antenatal detection of SGA, was evaluated in the DESiGN type 2 hybrid effectiveness-implementation cluster randomised trial (n = 13 clusters). In this paper, we present the trial process evaluation. METHODS: A mixed-methods process evaluation was conducted. Clinical leads and frontline healthcare professionals were interviewed to inform understanding of context (implementing and standard care sites) and GAP implementation (implementing sites). Thematic analysis of interview text used the context and implementation of complex interventions framework to understand acceptability, feasibility, and the impact of context. A review of implementing cluster clinical guidelines, training and maternity records was conducted to assess fidelity, dose and reach. RESULTS: Interviews were conducted with 28 clinical leads and 27 frontline healthcare professionals across 11 sites. Staff at implementing sites generally found GAP to be acceptable but raised issues of feasibility, caused by conflicting demands on resource, and variable beliefs among clinical leaders regarding the intervention value. GAP was implemented with variable fidelity (concordance of local guidelines to GAP was high at two sites, moderate at two and low at one site), all sites achieved the target to train > 75% staff using face-to-face methods, but only one site trained > 75% staff using e-learning methods; a median of 84% (range 78–87%) of women were correctly risk stratified at the five implementing sites. Most sites achieved high scores for reach (median 94%, range 62–98% of women had a customised growth chart), but generally, low scores for dose (median 31%, range 8–53% of low-risk women and median 5%, range 0–17% of high-risk women) were monitored for SGA as recommended. CONCLUSIONS: Implementation of GAP was generally acceptable to staff but with issues of feasibility that are likely to have contributed to variation in implementation strength. Leadership and resourcing are fundamental to effective implementation of clinical service changes, even when such changes are well aligned to policy mandated service-change priorities. TRIAL REGISTRATION: Primary registry and trial identifying number: ISRCTN 67698474. Registered 02/11/16. https://doi.org/10.1186/ISRCTN67698474

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Pemetrexed-cisplatin-bevacizumab combo in lung cancer models: impact on tumor immunity

International audienceDual chemotherapy (i.e., Pemetrexed and Cisplatin, CT) plus anti-VEGF Bevacizumab could be associated with anti-PD1 such as Pembrolizumab in NSCLC patients with low PDL1 levels. To support this new combination, to what extent those drugs could reshape tumor immunity remains to be evaluated, prior to establishing optimal scheduling or sequencing with Pembrolizumab. Both Pemetrexed and Cisplatin are expected to trigger immunogenic cell death, whereas Bevacizumab could help T lymphocytes to extravasate and better infiltrate tumor micro-environment. Here, we studied the impact of Cisplatin and Pemetrexed at two dose levels (i.e., low dose and Maximal Tolerated Dose, MTD) and fixed flat-dose Bevacizumab, alone or in combination (i.e., Cisplatin, Pemetrexed, Cisplatin + Pemetrexed, with our without Beva), on the immune repertoire of BalbC mice ectopically grafted with KLN-205 murine lung tumors. CD45, CD4, CD8, FoxP3-CD4 (Tregs), and MDSCs were monitored by FACS analysis in blood, spleen, and tumors on D2, D7, D14, and D21 after treatment. Results were normalized by CD45 counts. All treatments led to an increase in CD4+ T cells in blood as compared with control (i.e., untreated) animals. Little increase was observed in tumors, regardless of the treatments but mice treated with the Beva+CT combo (both low dose and MTD CT) showed an increase in CD4+ in the spleen on D14. Regarding CD8+ T cells, all treatments led to an increase from D2 to D7. Beva + CT low dose led to a continuous increase in CD8+ cells, whereas in Beva+CT MTD mice, after an initial increase, a reduction in CD8+ was observed after D7 eventually. In the spleen, CD8+ proved to be stable apart from the Beva + CT low dose group which showed an increase up to D14. In tumors, an increase in CD8+ cells was observed in all the groups. No change in MDSCs levels was observed, regardless of the drugs, the dosing and the organ. Conversely, Tregs decreased in the blood in the Beva + CT low-dose group on D14, and decreased in spleen and tumors as compared with Control mice, regardless of the drugs and the dosing. Overall, our data suggest that the triple combination between Beva, Pemetrexed, and Cisplatin has a stronger impact on immune cells than each drug used as a single agent. MDSCs were the only cells to be unaffected by the treatments. Dosing could be relevant as well since the reduction in CD8+ T cells observed with MTD CT could come from drug-related lymphopenia. The Beva followed by low dose Pemetrexed + Cisplatin group is thus the more likely to harness tumor immunity, with peaks in CD4+ and CD8+ T cells and drop in Tregs observed on D14. This pilot study suggests therefore that sequencing Beva + CT low dose followed by a two-week lag time prior to administrating anti-PD1 could lead to synergism in lung cancer models. Citation Format: Guillaume Sicard, Sarah Giacometti, Fabrice Barlesi, Raphaelle Fanciullino, Joseph Ciccolini. Pemetrexed-cisplatin-bevacizumab combo in lung cancer models: impact on tumor immunity [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 1856.</jats:p

Abstract 2099: Model-driven optimization of anti-angiogenics combined with chemotherapy: application to bevacizumab + pemetrexed/cisplatin doublet in NSCLC-bearing mice

International audienc