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Journal of Controlled Release :... Apr 2024Modulating the metabolism of cancer cells, immune cells, or both is a promising strategy to potentiate cancer immunotherapy in the nutrient-competitive tumor...
Modulating the metabolism of cancer cells, immune cells, or both is a promising strategy to potentiate cancer immunotherapy in the nutrient-competitive tumor microenvironment. Glutamine has emerged as an ideal target as cancer cells highly rely on glutamine for replenishing the tricarboxylic acid cycle in the process of aerobic glycolysis. However, non-specific glutamine restriction may induce adverse effects in unconcerned tissues and therefore glutamine inhibitors have achieved limited success in the clinic so far. Here we report the synthesis and evaluation of a redox-responsive prodrug of 6-Diazo-5-oxo-L-norleucine (redox-DON) for tumor-targeted glutamine inhibition. When applied to treat mice bearing subcutaneous CT26 mouse colon carcinoma, redox-DON exhibited equivalent antitumor efficacy but a greatly improved safety profile, particularly, in spleen and gastrointestinal tract, as compared to the state-of-the-art DON prodrug, JHU083. Furthermore, redox-DON synergized with checkpoint blockade antibodies leading to durable cures in tumor-bearing mice. Our results suggest that redox-DON is a safe and effective therapeutic for tumor-targeted glutamine inhibition showing promise for enhanced metabolic modulatory immunotherapy. The approach of reversible chemical modification may be generalized to other metabolic modulatory drugs that suffer from overt toxicity.
Topics: Animals; Mice; Diazooxonorleucine; Prodrugs; Glutamine; Colonic Neoplasms; Oxidation-Reduction; Tumor Microenvironment
PubMed: 38403173
DOI: 10.1016/j.jconrel.2024.02.031 -
JAMA Network Open Feb 2024Training on the proper use of personal protective equipment (PPE) is critical for infection prevention among health care workers. Traditional methods, such as... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Training on the proper use of personal protective equipment (PPE) is critical for infection prevention among health care workers. Traditional methods, such as face-to-face and video-based training, can strain resources and present challenges.
OBJECTIVE
To determine the effectiveness of 360° virtual reality (VR) training for PPE donning and doffing compared with face-to-face and video training in enhancing the PPE use skills of prospective health care practitioners.
DESIGN, SETTING, AND PARTICIPANTS
A blinded, prospective, and randomized noninferiority clinical trial was conducted from August to December 2021 at Teikyo University School of Medicine in Tokyo, Japan, with a mixed population of medical students. Participants were second- to fourth-year medicine, medical technology, or pharmacy students aged 20 years or older with no prior PPE training. Participants were randomized into 1 of 3 training groups (VR, face-to-face, or video) based on their enrollment order. An intention-to-treat analysis was conducted.
INTERVENTION
A 30-minute lecture on PPE procedures was delivered to all participants before the training. After the lecture, the VR group trained with an immersive 360° VR tool, the face-to-face group trained with actual PPE, and the video group trained by watching video footage on a computer and a projector. After 3 days, a standardized practical skills test was administered.
MAIN OUTCOMES AND MEASURES
The primary outcome was the mean score on a 20-point practical skills test, and the secondary outcome was the percentage of correct execution.
RESULTS
A total of 91 participants were recruited and randomized into 3 groups: VR (n = 30), face-to-face (n = 30), and video (n = 31) training. After excluding 1 participant due to illness, 90 participants (mean [SD] age, 24.2 [3.15] years; 54 males [60.0%]) completed the assessment. The mean (SD) scores were 17.70 (2.10) points for the VR group, 17.57 (2.45) points for the face-to-face group, and 15.87 (2.90) points for the video group. The VR group demonstrated no significant difference in performance from the face-to-face group. However, the VR group had significantly higher effectiveness than the video group (17.70 vs 15.87 points; P = .02).
CONCLUSIONS AND RELEVANCE
Results of this trial indicate that VR training was as effective as face-to-face training in enhancing PPE donning and doffing skills and was superior to video training. The findings suggest that VR training is a viable resource-conserving training option.
TRIAL REGISTRATION
Japan Registry of Clinical Trials Identifier: jRCT103021029.
Topics: Adult; Humans; Male; Young Adult; Diazooxonorleucine; Health Facilities; Health Personnel; Personal Protective Equipment; Schools; Female
PubMed: 38353953
DOI: 10.1001/jamanetworkopen.2023.55358 -
Frontiers in Public Health 2023The global impact of Coronavirus Disease 2019 (COVID-19) has been profound, affecting public health, the global economy, and overall human life. Past experiences with...
BACKGROUND
The global impact of Coronavirus Disease 2019 (COVID-19) has been profound, affecting public health, the global economy, and overall human life. Past experiences with global pandemics underscored the significance of understanding the perception of HCWs and hospital staff in developing and implementing preventive measures. The World Health Organization (WHO) provided protocols to manage the spread of COVID-19 and assist healthcare workers and health systems globally in maintaining high-quality health services.
OBJECTIVE
This study aims to assess nurses' perception, awareness, and compliance regarding the implementation of COVID-19 protocols and explore factors influencing their perception.
METHODOLOGY
A quantitative cross-sectional survey-based study was conducted, distributing a constructed survey among nurses in the Eastern Province of Saudi Arabia.
RESULTS
Out of 141 participants, most adhered to protocols such as hand sanitization, social distancing, and proper personal protective equipment (PPE) usage. The predominant age group among respondents was 31 to 40 years ( = 71, 50%). A significant portion of participants reported holding a bachelor's degree ( = 86, 61%), with only 14% possessing advanced degrees ( = 19). Nearly a third of the nurses in the study had accumulated 6 to 10 years of professional experience ( = 49, 34.8%). A noteworthy percentage of nurses were engaged in daily shifts exceeding 8 h ( = 98, 70%). Gender differences were observed, with females exhibiting a higher tendency to avoid shaking hands and social gatherings. Saudi nationals were more inclined to shake hands and engage in gatherings. Non-Saudi nurses and those aged between <25 to 40 years demonstrated proper donning/doffing practices. Nurses with over 6 years of experience avoided social gatherings, while those working >8 h adhered better to PPE usage, proper donning/doffing, and disposal of PPE in designated bins.
CONCLUSION
Understanding COVID-19 protocols is crucial for tailoring interventions and ensuring effective compliance with COVID-19 preventive measures among nurses. More efforts should be made toward preparing the healthcare nursing to deal with the outbreak. Preparing healthcare nursing with the right knowledge, attitude, and precautionary practices during the COVID-19 outbreak is very essential to patient and public safety.
Topics: Female; Humans; Adult; Saudi Arabia; Cross-Sectional Studies; COVID-19; Diazooxonorleucine; Perception; Nurses
PubMed: 38249370
DOI: 10.3389/fpubh.2023.1291261 -
Journal of Medicinal Chemistry Nov 2023The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) exhibits remarkable anticancer efficacy; however, its therapeutic potential is hindered by its toxicity to...
The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) exhibits remarkable anticancer efficacy; however, its therapeutic potential is hindered by its toxicity to gastrointestinal (GI) tissues. We recently reported the discovery of DRP-104, a tumor-targeted DON prodrug with excellent efficacy and tolerability, which is currently in clinical trials. However, DRP-104 exhibits limited aqueous solubility, and the instability of its isopropyl ester promoiety leads to the formation of an inactive M1-metabolite, reducing overall systemic prodrug exposure. Herein, we aimed to synthesize DON prodrugs with various ester and amide promoieties with improved solubility, GI stability, and DON tumor delivery. Twenty-one prodrugs were synthesized and characterized in stability and pharmacokinetics studies. Of these, , -butyl-()-6-diazo-2-(()-2-(2-(dimethylamino)acetamido)-3-phenylpropanamido)-5-oxo-hexanoate, showed excellent metabolic stability in plasma and intestinal homogenate, high aqueous solubility, and high tumor DON exposures and preserved the ideal tumor-targeting profile of DRP-104. In conclusion, we report a new generation of glutamine antagonist prodrugs with improved physicochemical and pharmacokinetic attributes.
Topics: Humans; Prodrugs; Diazooxonorleucine; Glutamine; Esters; Neoplasms
PubMed: 37949450
DOI: 10.1021/acs.jmedchem.3c01681 -
Drug Discoveries & Therapeutics Nov 2023This work describes a novel artificial intelligence-based training and monitoring system (AITMS) that was used to control and prevent nosocomial infections (NIs) by...
This work describes a novel artificial intelligence-based training and monitoring system (AITMS) that was used to control and prevent nosocomial infections (NIs) by improving the skills of donning/removing personal protective equipment (PPE). The AITMS has two working modes, namely an AI-based protective equipment surveillance mode and an AI-based training mode, that were used for routine surveillance and training, respectively. Data revealed that the accuracy rate of donning/removing PPE improved as a result of the AITMS. Interestingly, the frequency of NIs decreased with the use of the AITMS. This study suggested the key role of using PPE in controlling and preventing NIs. Data preliminarily proved that appropriate donning/removing PPE may help to reduce the risk of NIs. In addition, the newest computerized technologies, such as AI, have proven to be useful in controlling and preventing NIs. These findings should helpful to formulate a better strategy against NIs in the future.
Topics: Humans; Artificial Intelligence; Pilot Projects; Cross Infection; Diazooxonorleucine; Hospitals
PubMed: 37673650
DOI: 10.5582/ddt.2023.01068 -
Brazilian Oral Research 2023The current study aims to assess the effectiveness of e-learning in compliance with the new biosafety recommendations in dentistry in the context of COVID-19 applied to...
The current study aims to assess the effectiveness of e-learning in compliance with the new biosafety recommendations in dentistry in the context of COVID-19 applied to the clinical staff of a dental school in Brazil. A quasi-experimental epidemiological study was carried out by means of a structured, pre-tested online questionnaire, applied before and after an educational intervention, using an e-learning format. After data collection, statistical tests were performed. A total of 549 members of the clinical staff participated in the study in the two collection phases, with a return rate of 26.9%. After the e-learning stage, a reduction was found in the reported use of disposable gloves, protective goggles, and surgical masks. The course had no impact on the staff's knowledge concerning the proper sequence for donning PPE and showed 100% effectiveness regarding proper PPE doffing sequence. Knowledge about avoiding procedures that generate aerosols in the clinical setting was improved. Despite the low rate of return, it can be concluded that online intervention alone was ineffective in significantly improving learning about the new clinical biosafety guidelines. Therefore, the use of hybrid teaching and repetitive training is highly recommended.
Topics: Humans; Computer-Assisted Instruction; COVID-19; Brazil; Diazooxonorleucine; Dentistry
PubMed: 37341233
DOI: 10.1590/1807-3107bor-2023.vol37.0060 -
Acta Biochimica Et Biophysica Sinica Mar 2023Ferroptosis is a type of programmed cell death closely related to amino acid metabolism. Pancreatic cancer cells have a strong dependence on glutamine, which serves as a...
Ferroptosis is a type of programmed cell death closely related to amino acid metabolism. Pancreatic cancer cells have a strong dependence on glutamine, which serves as a carbon and nitrogen substrate to sustain rapid growth. Glutamine also aids in self-protection mechanisms. However, the effect of glutamine on ferroptosis in pancreatic cancer remains largely unknown. Here, we aim to explore the association between ferroptosis and glutamine deprivation in pancreatic cancer. The growth of pancreatic cancer cells in culture media with or without glutamine is evaluated using Cell Counting Kit-8. Reactive oxygen species (ROS) are measured by 2',7'-dichlorodihydrofluorescein diacetate staining. Ferroptosis is assessed by BODIPY-C11 dye using confocal microscopy and flow cytometry. Amino acid concentrations are measured using ultrahigh-performance liquid chromatography-tandem mass spectrometry. Isotope-labelled metabolic flux analysis is performed to track the metabolic flow of glutamine. Additionally, RNA sequencing is performed to analyse the genetic alterations. Glutamine deprivation inhibits pancreatic cancer growth and induces ferroptosis both and . Additionally, glutamine decreases ROS formation via glutathione production in pancreatic cancer cells. Interestingly, glutamine inhibitors (diazooxonorleucine and azaserine) promotes ROS formation and ferroptosis in pancreatic cancer cells. Furthermore, ferrostatin, a ferroptosis inhibitor, rescues ferroptosis in pancreatic cancer cells. Glutamine deprivation leads to changes in molecular pathways, including cytokine-cytokine receptor interaction pathways ( , , , , , and ). Thus, exogenous glutamine is required for the detoxification of ROS in pancreatic cancer cells, thereby preventing ferroptosis.
Topics: Humans; Ferroptosis; Glutamine; Reactive Oxygen Species; Apoptosis; Pancreatic Neoplasms
PubMed: 36942991
DOI: 10.3724/abbs.2023029 -
Discover Oncology Feb 2023Carbohydrate antigen 19-9 (CA19-9) is the most widely used biomarker for pancreatic cancer. Since CA19-9 closely correlates with patient outcome and tumor stage in...
BACKGROUND
Carbohydrate antigen 19-9 (CA19-9) is the most widely used biomarker for pancreatic cancer. Since CA19-9 closely correlates with patient outcome and tumor stage in pancreatic cancer, the deciphering of CA19-9 biosynthesis provides a potential clue for treatment.
METHODS
Concentration of amino acids was detected by ultrahigh-performance liquid chromatography tandem mass spectrometry. Metabolic flux of glutamine was examined by isotope tracing untargeted metabolomics. Label-free quantitative N-glycosylation proteomics was used to examine N-glycosylation alterations.
RESULTS
Among all amino acids, glutamine was higher in CA19-9-high pancreatic cancers (> 37 U/mL, 66 cases) than in CA19-9-normal clinical specimens (≤ 37 U/mL, 37 cases). The glutamine concentration in clinical specimens was positively correlated with liver metastasis or lymphovascular invasion. Glutamine blockade using diazooxonorleucine suppressed pancreatic cancer growth and intraperitoneal and lymphatic metastasis. Glutamine promotes O-GlcNAcylation, protein glycosylation, and CA19-9 biosynthesis through the hexosamine biosynthetic pathway. UDP-N-acetylglucosamine (UDP-GlcNAc) levels correlated with the glutamine influx through hexosamine biosynthetic pathway and supported CA19-9 biosynthesis.
CONCLUSIONS
Glutamine is a substrate for CA19-9 biosynthesis in pancreatic cancer. Glutamine blockade may be a potential therapeutic strategy for pancreatic cancer.
PubMed: 36797531
DOI: 10.1007/s12672-023-00628-z -
Science Advances Nov 20226-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8 T cells....
6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8 T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl()-2-(()-2-acetamido-3-(1-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues. In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104's effect was CD8 T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.
Topics: Humans; Prodrugs; Diazooxonorleucine; Glutamine; CD8-Positive T-Lymphocytes; Neoplasms; Enzyme Inhibitors
PubMed: 36383674
DOI: 10.1126/sciadv.abq5925 -
British Journal of Anaesthesia Nov 2022Hypersensitivity to general anaesthetics predicts adverse postoperative outcomes in patients. Hypoxia exerts extensive pathophysiological effects on the brain; however,...
BACKGROUND
Hypersensitivity to general anaesthetics predicts adverse postoperative outcomes in patients. Hypoxia exerts extensive pathophysiological effects on the brain; however, whether hypoxia influences sevoflurane sensitivity and its underlying mechanisms remain poorly understood.
METHODS
Mice were acclimated to hypoxia (oxygen 10% for 8 h day) for 28 days and anaesthetised with sevoflurane; the effective concentrations for 50% of the animals (EC) showing loss of righting reflex (LORR) and loss of tail-pinch withdrawal response (LTWR) were determined. Positron emission tomography-computed tomography, O-glycoproteomics, seahorse analysis, carbon-13 tracing, site-specific mutagenesis, and electrophysiological techniques were performed to explore the underlying mechanisms.
RESULTS
Compared with the control group, the hypoxia-acclimated mice required higher concentrations of sevoflurane to present LORR and LTWR (EC50: 1.61 [0.03]% vs 1.46 [0.04]%, P<0.01; EC50: 2.46 [0.14]% vs 2.22 [0.06]%, P<0.01). Hypoxia-induced reduction in sevoflurane sensitivity was correlated with elevation of protein O-linked N-acetylglucosamine (O-GlcNAc) modification in brain, especially in the thalamus, and could be abolished by 6-diazo-5-oxo-l-norleucine, a glutamine fructose-6-phosphate amidotransferase inhibitor, and mimicked by thiamet-G, a selective O-GlcNAcase inhibitor. Mechanistically, O-GlcNAcylation drives de novo synthesis of glutamine from glucose in astrocytes and promotes the glutamate-glutamine cycle, partially via glycolytic flux and activation of glutamine synthetase.
CONCLUSIONS
Intermittent hypoxia exposure decreased mouse sensitivity to sevoflurane anaesthesia through enhanced O-GlcNAc-dependent modulation of the glutamate-glutamine cycle in the brain.
Topics: Animals; Mice; Acetylglucosamine; Sevoflurane; Glutamine; Diazooxonorleucine; Glutamate-Ammonia Ligase; Brain; Hypoxia; Glucose; Anesthetics, General; Oxygen; Glutamates
PubMed: 36031420
DOI: 10.1016/j.bja.2022.06.041