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Shoulder strap fixation of LUCAS-2 to facilitate continuous CPR during non-supine (stair) stretcher transport of OHCAs patients
Early recognition and rapid initiation of high-quality cardiopulmonary resuscitation (CPR) are key to maximising chances of achieving successful return of spontaneous circulation in patients with out-of-hospital cardiac arrests (OHCAs), as well as improving patient outcomes both inside and outside hospital. Mechanical chest compression devices such as the LUCAS-2 have been developed to assist rescuers in providing consistent, high-quality compressions, even during transportation. However, providing uninterrupted and effective compressions with LUCAS-2 during transportation down stairwells and in tight spaces in a non-supine position is relatively impossible. In this study, we proposed adaptations to the LUCAS-2 to allow its use during transportation down stairwells and examined its effectiveness in providing high-quality CPR to simulated OHCA patients. 20 volunteer emergency medical technicians were randomised into 10 pairs, each undergoing 2 simulation runs per experimental arm (LUCAS-2 versus control) with a loaded Resusci Anne First Aid full body manikin weighing 60 kg. Quality of CPR compressions performed was measured using the CPRmeter placed on the sternum of the manikin. The respective times taken for each phase of the simulation protocol were recorded. Fisher’s exact tests were used to analyse categorical variables and median test to analyse continuous variables. The LUCAS-2 group required a longer time (~ 35 s) to prepare the patient prior to transport (p < 0.0001) and arrive at the ambulance (p < 0.0001) compared to the control group. The CPR quality in terms of depth and rate for the overall resuscitation period did not differ significantly between the LUCAS-2 group and control group, though there was a reduction in both parameters when evaluating the device’s automated compressions during transport. Nevertheless, the application of the LUCAS-2 device yielded a significantly higher chest compression fraction of 0.76 (p < 0.0001). Our novel adaptations to the LUCAS-2 device allow for uninterrupted compressions in patients being transported down stairwells, thus yielding better chest compression fractions for the overall resuscitation period. Whether potentially improved post-OHCA survival rates may be achieved requires confirmation in a real-world scenario study.
Journal Article
Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2
Most cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation to aerobic glycolysis for energy production. By reducing enzyme activity of pyruvate kinase M2 (PKM2), cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H
2
S) destabilizes the PKM2 tetramer into monomer/dimer through sulfhydration at cysteines, notably at C326, leading to reduced PKM2 enzyme activity and increased PKM2-mediated transcriptional activation. Blocking PKM2 sulfhydration at C326 through amino acid mutation stabilizes the PKM2 tetramer and crystal structure further revealing the tetramer organization of PKM2-C326S. The PKM2-C326S mutant in cancer cells rewires glucose metabolism to mitochondrial respiration, significantly inhibiting tumor growth. In this work, we demonstrate that PKM2 sulfhydration by H
2
S inactivates PKM2 activity to promote tumorigenesis and inhibiting this process could be a potential therapeutic approach for targeting cancer metabolism.
Low level of pyruvate kinase M2 (PKM2) activity in cancer cells is essential for the dependence on aerobic glycolysis. Here the authors show that PKM2 sulfhydration by hydrogen sulfide destabilizes the PKM2 tetramer, leading to reduced PKM2 enzyme activity and enhanced proliferation of breast cancer cells.
Journal Article
Urinary malate dehydrogenase 2 is a new biomarker for early detection of non‐small‐cell lung cancer
Reliable and noninvasive biomarkers for the early diagnosis of non‐small‐cell lung cancer (NSCLC) are an unmet need. This study aimed to screen and validate potential urinary biomarkers for the early diagnosis of NSCLC. Using protein mass spectrometry, urinary MDH2 was found to be abundant both in patients with lung cancer and lung cancer model mice compared with controls. Urine samples obtained as retrospective and prospective cohorts including 1091 NSCLC patients and 736 healthy controls were measured using ELISA. Patients with stage I NSCLC had higher urinary MDH2 compared with healthy controls. The area under the receiver‐operating characteristic curve (AUC) for the urinary MDH2 was 0.7679 and 0.7234 in retrospective and prospective cohorts to distinguish stage I cases from controls. Urinary MDH2 levels correlated with gender and smoking history. MDH2 expression levels were elevated in lung cancer tissues. MDH2 knockdown using shRNA inhibited the proliferation of lung cancer cells. Our study demonstrated that urinary MDH2 concentration was higher in early‐stage NSCLC patients compared with that in controls and that MDH2 could serve as a potential biomarker for early detection of NSCLC. Malate dehydrogenase 2 was significantly elevated both in urine and in cancer tissues of NSCLC patients. The level of MDH2 in urine could serve as an assistant biomarker for the early diagnosis of NSCLC.
Journal Article
Galectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington’s disease
Huntington’s disease (HD) is a neurodegenerative disorder that manifests with movement dysfunction. The expression of mutant Huntingtin (mHTT) disrupts the functions of brain cells. Galectin-3 (Gal3) is a lectin that has not been extensively explored in brain diseases. Herein, we showed that the plasma Gal3 levels of HD patients and mice correlated with disease severity. Moreover, brain Gal3 levels were higher in patients and mice with HD than those in controls. The up-regulation of Gal3 in HD mice occurred before motor impairment, and its level remained high in microglia throughout disease progression. The cell-autonomous up-regulated Gal3 formed puncta in damaged lysosomes and contributed to inflammation through NFκB- and NLRP3 inflammasome-dependent pathways. Knockdown of Gal3 suppressed inflammation, reduced mHTT aggregation, restored neuronal DARPP32 levels, ameliorated motor dysfunction, and increased survival in HD mice. Thus, suppression of Gal3 ameliorates microglia-mediated pathogenesis, which suggests that Gal3 is a novel druggable target for HD.
The authors show that Galectin-3 is up–regulated in brain tissues from patients and a mouse model of Huntington’s disease (HD) and correlates with disease severity. Galectin-3 accumulates at damaged lysosomes in HD microglia, prevents the clearance of damaged lysosomes, and promotes inflammation.
Journal Article
Mechanical stretch induces hair regeneration through the alternative activation of macrophages
Tissues and cells in organism are continuously exposed to complex mechanical cues from the environment. Mechanical stimulations affect cell proliferation, differentiation, and migration, as well as determining tissue homeostasis and repair. By using a specially designed skin-stretching device, we discover that hair stem cells proliferate in response to stretch and hair regeneration occurs only when applying proper strain for an appropriate duration. A counterbalance between WNT and BMP-2 and the subsequent two-step mechanism are identified through molecular and genetic analyses. Macrophages are first recruited by chemokines produced by stretch and polarized to M2 phenotype. Growth factors such as HGF and IGF-1, released by M2 macrophages, then activate stem cells and facilitate hair regeneration. A hierarchical control system is revealed, from mechanical and chemical signals to cell behaviors and tissue responses, elucidating avenues of regenerative medicine and disease control by demonstrating the potential to manipulate cellular processes through simple mechanical stimulation.
Mechanical stimulation is known to affect cell proliferation, differentiation, and regeneration. Here, the authors demonstrate that stretching mouse skin recruits macrophages and polarizes them into M2 cells that facilitate hair regeneration through the release of growth factors, including HGF and IGF-1
Journal Article