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Lancet (London, England) Jan 2024The optimal target for systemic oxygenation in critically ill children is unknown. Liberal oxygenation is widely practiced, but has been associated with harm in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The optimal target for systemic oxygenation in critically ill children is unknown. Liberal oxygenation is widely practiced, but has been associated with harm in paediatric patients. We aimed to evaluate whether conservative oxygenation would reduce duration of organ support or incidence of death compared to standard care.
METHODS
Oxy-PICU was a pragmatic, multicentre, open-label, randomised controlled trial in 15 UK paediatric intensive care units (PICUs). Children admitted as an emergency, who were older than 38 weeks corrected gestational age and younger than 16 years receiving invasive ventilation and supplemental oxygen were randomly allocated in a 1:1 ratio via a concealed, central, web-based randomisation system to conservative peripheral oxygen saturations ([SpO] 88-92%) or liberal (SpO >94%) targets. The primary outcome was the duration of organ support at 30 days following random allocation, a rank-based endpoint with death either on or before day 30 as the worst outcome (a score equating to 31 days of organ support), with survivors assigned a score between 1 and 30 depending on the number of calendar days of organ support received. The primary effect estimate was the probabilistic index, a value greater than 0·5 indicating more than 50% probability that conservative oxygenation is superior to liberal oxygenation for a randomly selected patient. All participants in whom consent was available were included in the intention-to-treat analysis. The completed study was registered with the ISRCTN registry (ISRCTN92103439).
FINDINGS
Between Sept 1, 2020, and May 15, 2022, 2040 children were randomly allocated to conservative or liberal oxygenation groups. Consent was available for 1872 (92%) of 2040 children. The conservative oxygenation group comprised 939 children (528 [57%] of 927 were female and 399 [43%] of 927 were male) and the liberal oxygenation group included 933 children (511 [56%] of 920 were female and 409 [45%] of 920 were male). Duration of organ support or death in the first 30 days was significantly lower in the conservative oxygenation group (probabilistic index 0·53, 95% CI 0·50-0·55; p=0·04 Wilcoxon rank-sum test, adjusted odds ratio 0·84 [95% CI 0·72-0·99]). Prespecified adverse events were reported in 24 (3%) of 939 patients in the conservative oxygenation group and 36 (4%) of 933 patients in the liberal oxygenation group.
INTERPRETATION
Among invasively ventilated children who were admitted as an emergency to a PICU receiving supplemental oxygen, a conservative oxygenation target resulted in a small, but significant, greater probability of a better outcome in terms of duration of organ support at 30 days or death when compared with a liberal oxygenation target. Widespread adoption of a conservative oxygenation saturation target (SpO 88-92%) could help improve outcomes and reduce costs for the sickest children admitted to PICUs.
FUNDING
UK National Institute for Health and Care Research Health Technology Assessment Programme.
Topics: Child; Humans; Male; Female; Critical Illness; Hospitalization; Intensive Care Units, Pediatric; Oxygen; United Kingdom
PubMed: 38048787
DOI: 10.1016/S0140-6736(23)01968-2 -
British Journal of Anaesthesia Oct 2023We aimed at determining whether a 2-h session of high-flow nasal oxygen (HFNO) immediately after extubation improves oxygen exchange after major gynaecological surgery... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
We aimed at determining whether a 2-h session of high-flow nasal oxygen (HFNO) immediately after extubation improves oxygen exchange after major gynaecological surgery in the Trendelenburg position in adult female patients.
METHODS
In this single-centre, open-label, randomised trial, patients who underwent major gynaecological surgery were randomised to HFNO or conventional oxygen treatment with a Venturi mask. The primary outcome was the Pao/FiO ratio after 2 h of treatment. Secondary outcomes included lung ultrasound score, diaphragm thickening fraction, dyspnoea, ventilatory frequency, Paco, the percentage of patients with impaired gas exchange (Pao/FiO ≤40 kPa) after 2 h of treatment, and postoperative pulmonary complications at 30 days.
RESULTS
A total of 83 patients were included (42 in the HFNO group and 41 in the conventional treatment group). After 2 h of treatment, median (inter-quartile range) Pao/FiO was 52.9 (47.9-65.2) kPa in the HFNO group and 45.7 (36.4 -55.9) kPa in the conventional treatment group (mean difference 8.7 kPa [95% CI: 3.4 to 13.9], P=0.003). The lung ultrasound score was lower in the HFNO group than in the conventional treatment group (9 [6-10] vs 12 [10-14], P<0.001), mostly because of the difference of the score in dorsal areas (7 [6-8] vs 10 [9-10], P<0.001). The percentage of patients with impaired gas exchange was lower in the HFNO group than in the conventional treatment group (5% vs 37%, P<0.001). All other secondary outcomes were not different between groups.
CONCLUSIONS
In patients who underwent major gynaecological surgery, a pre-emptive 2-h session of HFNO after extubation improved postoperative oxygen exchange and reduced atelectasis compared with a conventional oxygen treatment strategy.
CLINICAL TRIAL REGISTRATION
NCT04566419.
Topics: Adult; Humans; Female; Oxygen; Lung; Respiration, Artificial; Pulmonary Atelectasis; Postoperative Complications; Gynecologic Surgical Procedures; Oxygen Inhalation Therapy
PubMed: 37543437
DOI: 10.1016/j.bja.2023.07.002 -
Seminars in Cancer Biology Dec 2023Disruption of oxygen homeostasis, resulting from an imbalance between O supply and demand during malignant proliferation, leads to the development of hypoxic tumor... (Review)
Review
Disruption of oxygen homeostasis, resulting from an imbalance between O supply and demand during malignant proliferation, leads to the development of hypoxic tumor microenvironments that promote the acquisition of aggressive cancer cell phenotypes linked to metastasis and patient mortality. In this review, the mechanistic links between tumor hypoxia and metastatic progression are presented. Current status and perspectives of targeting hypoxia signaling pathways as a strategy to halt cancer cell metastatic activities are emphasized.
Topics: Humans; Hypoxia; Tumor Hypoxia; Cell Hypoxia
PubMed: 37926346
DOI: 10.1016/j.semcancer.2023.11.001 -
Cell Death & Disease Oct 2023Hypoxia is an essential hallmark of solid tumors and HIF1α is a central regulator of tumor cell adaptation and survival in the hypoxic environment. In this study, we...
Hypoxia is an essential hallmark of solid tumors and HIF1α is a central regulator of tumor cell adaptation and survival in the hypoxic environment. In this study, we explored the biological functions of cell cycle division-related gene 8 (CDCA8) in bladder cancer (BCa) cells in the hypoxic settings. Specifically, we found that CDCA8 was significantly upregulated in BCa cell lines and clinical samples and its expression was positively correlated with advanced BCa stage, grade, and poor overall survival (OS). The expression of CDCA8 proteins was required for BCa cells to survive in the hypoxic condition. Mechanistically, CDCA8 stabilizes HIF1α by competing with PTEN for AKT binding, consequently leading to PTEN displacement and activation of the AKT/GSK3β signaling cascade that stimulates HIF1α protein stability. Significantly, HIF1α proteins bind to CDCA8 promoter for transcriptional activation, forming a positive-feedback loop to sustain BCa tumor cells under oxygen-deficient environment. Together, we defined CDCA8 as a key regulator for BCa cells to sense and prevail oxygen deprivation and as a novel BCa therapeutic target.
Topics: Humans; Cell Cycle Proteins; Cell Hypoxia; Cell Line; Cell Line, Tumor; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Oxygen; Proto-Oncogene Proteins c-akt; Urinary Bladder Neoplasms
PubMed: 37813876
DOI: 10.1038/s41419-023-06189-x -
Seminars in Cancer Biology Jan 2024Hypoxia is intrinsic to tumours and contributes to malignancy and metastasis while hindering the efficiency of existing treatments. Epigenetic mechanisms play a crucial... (Review)
Review
Hypoxia is intrinsic to tumours and contributes to malignancy and metastasis while hindering the efficiency of existing treatments. Epigenetic mechanisms play a crucial role in the regulation of hypoxic cancer cell programs, both in the initial phases of sensing the decrease in oxygen levels and during adaptation to chronic lack of oxygen. During the latter, the epigenetic regulation of tumour biology intersects with hypoxia-sensitive transcription factors in a complex network of gene regulation that also involves metabolic reprogramming. Here, we review the current literature on the epigenetic control of gene programs in hypoxic cancer cells. We highlight common themes and features of such epigenetic remodelling and discuss their relevance for the development of therapeutic strategies.
Topics: Humans; Cell Hypoxia; Epigenesis, Genetic; Hypoxia; Neoplasms; Oxygen
PubMed: 38029868
DOI: 10.1016/j.semcancer.2023.10.005 -
ELife Jul 2023The ability to sense and respond to changes in cellular oxygen levels is critical for aerobic organisms and requires a molecular oxygen sensor. The prototypical sensor... (Review)
Review
The ability to sense and respond to changes in cellular oxygen levels is critical for aerobic organisms and requires a molecular oxygen sensor. The prototypical sensor is the oxygen-dependent enzyme PHD: hypoxia inhibits its ability to hydroxylate the transcription factor HIF, causing HIF to accumulate and trigger the classic HIF-dependent hypoxia response. A small handful of other oxygen sensors are known, all of which are oxygen-dependent enzymes. However, hundreds of oxygen-dependent enzymes exist among aerobic organisms, raising the possibility that additional sensors remain to be discovered. This review summarizes known and potential hypoxia sensors among human O-dependent enzymes and highlights their possible roles in hypoxia-related adaptation and diseases.
Topics: Humans; Hypoxia; Oxygen; Gene Expression Regulation; Transcription Factors; Procollagen-Proline Dioxygenase; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Hypoxia
PubMed: 37494095
DOI: 10.7554/eLife.87705 -
The Journal of Biological Chemistry Sep 2023Iron-sulfur clusters (ISC) are essential cofactors that participate in electron transfer, environmental sensing, and catalysis. Amongst the most ancient ISC-containing...
Iron-sulfur clusters (ISC) are essential cofactors that participate in electron transfer, environmental sensing, and catalysis. Amongst the most ancient ISC-containing proteins are the ferredoxin (FDX) family of electron carriers. Humans have two FDXs- FDX1 and FDX2, both of which are localized to mitochondria, and the latter of which is itself important for ISC synthesis. We have previously shown that hypoxia can eliminate the requirement for some components of the ISC biosynthetic pathway, but FDXs were not included in that study. Here, we report that FDX1, but not FDX2, is dispensable under 1% O in cultured human cells. We find that FDX1 is essential for production of the lipoic acid cofactor, which is synthesized by the ISC-containing enzyme lipoyl synthase. While hypoxia can rescue the growth phenotype of either FDX1 or lipoyl synthase KO cells, lipoylation in these same cells is not rescued, arguing against an alternative biosynthetic route or salvage pathway for lipoate in hypoxia. Our work reveals the divergent roles of FDX1 and FDX2 in mitochondria, identifies a role for FDX1 in lipoate synthesis, and suggests that loss of lipoic acid can be tolerated under low oxygen tensions in cell culture.
Topics: Humans; Ferredoxins; Lipoylation; Thioctic Acid; Cell Hypoxia; Gene Knockout Techniques; Oxygen; Proteome; Sulfurtransferases; Binding Sites; Protein Stability; Protein Biosynthesis
PubMed: 37481209
DOI: 10.1016/j.jbc.2023.105075 -
ACS Nano Nov 2023Cancer with a complex pathological process is a major disease to human welfare. Due to the imbalance between oxygen (O) supply and consumption, hypoxia is a natural... (Review)
Review
Cancer with a complex pathological process is a major disease to human welfare. Due to the imbalance between oxygen (O) supply and consumption, hypoxia is a natural characteristic of most solid tumors and an important obstacle for cancer therapy, which is closely related to tumor proliferation, metastasis, and invasion. Various strategies to exploit the feature of tumor hypoxia have been developed in the past decade, which can be used to alleviate tumor hypoxia, or utilize the hypoxia for targeted delivery and diagnostic imaging. The strategies to alleviate tumor hypoxia include delivering O, in situ O generation, reprogramming the tumor vascular system, decreasing O consumption, and inhibiting HIF-1 related pathways. On the other side, hypoxia can also be utilized for hypoxia-responsive chemical construction and hypoxia-active prodrug-based strategies. Taking advantage of hypoxia in the tumor region, a number of methods have been applied to identify and keep track of changes in tumor hypoxia. Herein, we thoroughly review the recent progress of nanomedicine strategies in both conquering and utilizing hypoxia to combat cancer and put forward the prospect of emerging nanomaterials for future clinical transformation, which hopes to provide perspectives in nanomaterials design.
Topics: Humans; Nanomedicine; Neoplasms; Hypoxia; Tumor Hypoxia; Cell Hypoxia; Oxygen; Cell Line, Tumor
PubMed: 37871328
DOI: 10.1021/acsnano.3c07763 -
Nature Communications Jul 2023Skeletal muscle is more resilient to ischemia-reperfusion injury than other organs. Tissue specific post-translational modifications of cytochrome c (Cytc) are involved...
Skeletal muscle is more resilient to ischemia-reperfusion injury than other organs. Tissue specific post-translational modifications of cytochrome c (Cytc) are involved in ischemia-reperfusion injury by regulating mitochondrial respiration and apoptosis. Here, we describe an acetylation site of Cytc, lysine 39 (K39), which was mapped in ischemic porcine skeletal muscle and removed by sirtuin5 in vitro. Using purified protein and cellular double knockout models, we show that K39 acetylation and acetylmimetic K39Q replacement increases cytochrome c oxidase (COX) activity and ROS scavenging while inhibiting apoptosis via decreased binding to Apaf-1, caspase cleavage and activity, and cardiolipin peroxidase activity. These results are discussed with X-ray crystallography structures of K39 acetylated (1.50 Å) and acetylmimetic K39Q Cytc (1.36 Å) and NMR dynamics. We propose that K39 acetylation is an adaptive response that controls electron transport chain flux, allowing skeletal muscle to meet heightened energy demand while simultaneously providing the tissue with robust resilience to ischemia-reperfusion injury.
Topics: Animals; Swine; Lysine; Cytochromes c; Phosphorylation; Acetylation; Protein Processing, Post-Translational; Apoptosis; Cell Respiration; Reperfusion Injury; Muscle, Skeletal
PubMed: 37443314
DOI: 10.1038/s41467-023-39820-8 -
Cellular and Molecular Life Sciences :... Jul 2023The precise characterization of oxygen-sensing pathways and the identification of pO-regulated gene expression are both issues of critical importance. The O-sensing... (Review)
Review
The precise characterization of oxygen-sensing pathways and the identification of pO-regulated gene expression are both issues of critical importance. The O-sensing system plays crucial roles in almost all the pivotal human processes, including the stem cell specification, the growth and development of tissues (such as embryogenesis), the modulation of intermediate metabolism (including the shift of the glucose metabolism from oxidative to anaerobic ATP production and vice versa), and the control of blood pressure. The solid cancer microenvironment is characterized by low oxygen levels and by the consequent activation of the hypoxia response that, in turn, allows a complex adaptive response characterized mainly by neoangiogenesis and metabolic reprogramming. Recently, incredible advances in molecular genetic methodologies allowed the genome editing with high efficiency and, above all, the precise identification of target cells/tissues. These new possibilities and the knowledge of the mechanisms of adaptation to hypoxia suggest the effective development of new therapeutic approaches based on the manipulation, targeting, and exploitation of the oxygen-sensor system molecular mechanisms.
Topics: Humans; Gene Editing; Hypoxia; Oxygen; Cell Hypoxia; Neoplasms; Hypoxia-Inducible Factor 1, alpha Subunit; Von Hippel-Lindau Tumor Suppressor Protein; Tumor Microenvironment
PubMed: 37477829
DOI: 10.1007/s00018-023-04852-2