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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 -
IEEE Transactions on Neural Systems and... 2024Highly impaired individuals stand to benefit greatly from cutting-edge bionic technology, however concurrent functional deficits may complicate the adaptation of such...
Highly impaired individuals stand to benefit greatly from cutting-edge bionic technology, however concurrent functional deficits may complicate the adaptation of such technology. Here, we present a case in which a visually impaired individual with bilateral burn injury amputation was provided with a novel transradial neuromusculoskeletal prosthesis comprising skeletal attachment via osseointegration and implanted electrodes in nerves and muscles for control and sensory feedback. Difficulties maintaining implant hygiene and donning and doffing the prosthesis arose due to his contralateral amputation, ipsilateral eye loss, and contralateral impaired vision necessitating continuous adaptations to the electromechanical interface. Despite these setbacks, the participant still demonstrated improvements in functional outcomes and the ability to control the prosthesis in various limb positions using the implanted electrodes. Our results demonstrate the importance of a multidisciplinary, iterative, and patient-centered approach to making cutting-edge technology accessible to patients with high levels of impairment.
Topics: Humans; Bionics; Prosthesis Implantation; Artificial Limbs; Amputation, Surgical; Diazooxonorleucine
PubMed: 38363669
DOI: 10.1109/TNSRE.2024.3366530 -
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 -
Cancer Research Feb 2024A promising approach to treat solid tumors involves disrupting their reliance on glutamine, a key component for various metabolic processes. Traditional attempts using...
A promising approach to treat solid tumors involves disrupting their reliance on glutamine, a key component for various metabolic processes. Traditional attempts using glutamine inhibitors like 6-diazo-5-oxo-L-norleucine (DON) and CB-839 were unsuccessful, but new hope arises with DRP-104, a prodrug of DON. This compound effectively targets tumor metabolism while minimizing side effects. In a recent study published in Nature Cancer, Encarnación-Rosado and colleagues demonstrated in preclinical models that pancreatic ductal adenocarcinoma (PDAC) responds well to DRP-104, although tumors adapt through the MEK/ERK signaling pathway, which can be countered by the MEK inhibitor trametinib. In a related study, Recouvreux and colleagues found that DON is effective against pancreatic tumors, revealing that PDAC tumors upregulate asparagine synthesis in response to DON, making them susceptible to asparaginase treatment. Both studies underscore the potential of inhibiting glutamine metabolism and adaptive pathways as a promising strategy against PDAC. These findings pave the way for upcoming clinical trials utilizing DRP-104 and similar glutamine antagonists in the battle against solid tumors.
Topics: Humans; Glutamine; Diazooxonorleucine; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Enzyme Inhibitors; Mitogen-Activated Protein Kinase Kinases
PubMed: 38117482
DOI: 10.1158/0008-5472.CAN-23-3954 -
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 -
Disaster Medicine and Public Health... Nov 2023Search and rescue teams and Antarctic research groups use protective cold-water anti-exposure suits (AES) when cruising on Zodiacs. Extremity tourniquet (ET)...
Search and rescue teams and Antarctic research groups use protective cold-water anti-exposure suits (AES) when cruising on Zodiacs. Extremity tourniquet (ET) self-application (SA) donned with AESs has not been previously studied. Our study therefore assessed the SA of 5 commercial ETs (CAT, OMNA, RATS, RMT, and SWAT-T) among 15 volunteers who donned these suits. Tourniquet's SA ability, ease of SA, tolerance, and tourniquet preference were measured. All ETs tested were self-applied to the upper extremity except for the SWAT, which was self-applied with the rest to the lower extremity. Ease- of- SA mean values were compared using the Friedman and Durbin-Conover post hoc tests < 0.001). Regarding the upper extremity, OMNA achieved the highest score of 8.5 out of 10, while RMT, and SWAT received lower scores than other options 0.001). For lower extremities, SWAT was found to be inferior to other options 0.01). Overall, OMNA was the best performer. The RATS showed significantly lower tolerance than the other groups in repeated- measures ANOVA with a Tukey post hoc test 0.01). Additionally, out of the 5 ETs tested, 60% of subjects preferred OMNA. The study concluded that SA commercial ETs are feasible over cold-water anti-exposure suits in the Antarctic climate.
Topics: Humans; Antarctic Regions; Tourniquets; Hemorrhage; Extremities; Diazooxonorleucine; Water
PubMed: 37937358
DOI: 10.1017/dmp.2023.179 -
Journal of Safety Research Sep 2023Worn shoes are an important contributor to occupational slip and fall injuries. Tools to assess worn tread are emerging; imaging tools offer the potential to assist. The...
PROBLEM
Worn shoes are an important contributor to occupational slip and fall injuries. Tools to assess worn tread are emerging; imaging tools offer the potential to assist. The aim of this study was to develop a shoe tread scanner and evaluate its effectiveness to predict slip risk.
METHODS
This study analyzed data from two previous studies in which worn or new slip-resistant shoes were donned during an unexpected slip condition. The shoe tread for each shoe was scanned using a portable scanner that utilized frustrated total internal reflection (FTIR) technology. The shoe tread parameters of the worn region size (WRS) for worn shoes and total contact area for new shoes were measured. These parameters were then used to predict slip risk from the unexpected slip conditions.
RESULTS
The WRS was able to accurately predict slip risk, but the contact area was not.
DISCUSSION
These findings support that increased WRS on the shoe outsole is associated with worse slip outcomes. Furthermore, the tool was able to offer robust feedback across a wide range of tread designs, but the results of this study show that the tool may be more applicable for slip-resistant shoes that are worn compared to their new counterparts.
SUMMARY
This study shows that FTIR technology utilized in this tool may be a useful and portable method for determining slip risk for worn shoes.
PRACTICAL APPLICATIONS
This tool has the potential to be an efficient, objective, end-user tool that improves timely replacement of shoes and prevention of injuries.
Topics: Humans; Shoes; Diazooxonorleucine; Technology
PubMed: 37718069
DOI: 10.1016/j.jsr.2023.05.014 -
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 -
Journal of Immunology (Baltimore, Md. :... Aug 2023Activated T cells undergo metabolic reprogramming to meet anabolic, differentiation, and functional demands. Glutamine supports many processes in activated T cells, and...
Activated T cells undergo metabolic reprogramming to meet anabolic, differentiation, and functional demands. Glutamine supports many processes in activated T cells, and inhibition of glutamine metabolism alters T cell function in autoimmune disease and cancer. Multiple glutamine-targeting molecules are under investigation, yet the precise mechanisms of glutamine-dependent CD8 T cell differentiation remain unclear. We show that distinct strategies of glutamine inhibition by glutaminase-specific inhibition with small molecule CB-839, pan-glutamine inhibition with 6-diazo-5-oxo-l-norleucine (DON), or by glutamine-depleted conditions (No Q) produce distinct metabolic differentiation trajectories in murine CD8 T cells. T cell activation with CB-839 treatment had a milder effect than did DON or No Q treatment. A key difference was that CB-839-treated cells compensated with increased glycolytic metabolism, whereas DON and No Q-treated cells increased oxidative metabolism. However, all glutamine treatment strategies elevated CD8 T cell dependence on glucose metabolism, and No Q treatment caused adaptation toward reduced glutamine dependence. DON treatment reduced histone modifications and numbers of persisting cells in adoptive transfer studies, but those T cells that remained could expand normally upon secondary Ag encounter. In contrast, No Q-treated cells persisted well yet demonstrated decreased secondary expansion. Consistent with reduced persistence, CD8 T cells activated in the presence of DON had reduced ability to control tumor growth and reduced tumor infiltration in adoptive cell therapy. Overall, each approach to inhibit glutamine metabolism confers distinct effects on CD8 T cells and highlights that targeting the same pathway in different ways can elicit opposing metabolic and functional outcomes.
Topics: Animals; Mice; Diazooxonorleucine; Glutamine; Neoplasms; CD8-Positive T-Lymphocytes
PubMed: 37341499
DOI: 10.4049/jimmunol.2200715