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Background: Arterial blood gas (ABG) analysis is a vital diagnostic tool in clinical settings, particularly for assessing oxygenation, ventilation, and acid-base status in critically ill patients. Misinterpretation of ABG can lead to delayed or inappropriate management of critical conditions such as respiratory failure, metabolic disturbances, and sepsis, increasing morbidity and mortality. ABG interpretation is essential for timely and effective clinical decision-making. Accurate interpretation of ABG results is essential but challenging, especially when both respiratory and metabolic disturbances are present. This study aims to evaluate and enhance the quality of ABG interpretation among healthcare professionals at Aswan University Hospitals, following the American Thoracic Society (ATS) guidelines., Materials and Methods: This prospective cross-sectional study was conducted at Aswan University Hospitals from August to October 2024, involving 273 healthcare professionals, including house officers, medical officers, registrars, and residents. Participants were assessed in two audit cycles: the first without intervention and the second following targeted educational interventions. These interventions, implemented over two weeks, included lectures, educational posters, and focus group discussions focused on ABG interpretation. Data were collected using a validated questionnaire and analyzed to evaluate changes in ABG interpretation accuracy., Results: The results revealed significant improvements in ABG interpretation skills between the two cycles. The accuracy in verifying ABG results increased from 71.8% to 90.2%, distinguishing acidemia and alkalemia improved from 82.9% to 95.4%, and differentiating respiratory and metabolic disturbances rose from 82.1% to 96.7%. Additionally, proficiency in assessing compensatory mechanisms and calculating the anion gap showed substantial gains, with correct interpretation rates improving from 47% to 78.4% and 69.2% to 98%, respectively., Conclusion: The educational interventions effectively enhanced ABG interpretation skills among healthcare professionals, demonstrating the importance of targeted training in promoting accurate diagnosis and effective patient care. This study highlights the need for ongoing training in ABG analysis to improve diagnostic accuracy and clinical decision-making in critical care settings., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Aswan University Hospitals Institutional Review Board issued approval 1003/10/24. This clinical audit, titled "Evaluation and Improving the Quality of Arterial Blood Gases Interpretation Among House-Officers in Aswan University Hospital," was reviewed and approved by the Aswan University Hospitals Audit Committee under IRB number 1003/10/24. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Musa Hussain et al.)

Introduction: Heparins, naturally occurring glycosaminoglycans, are widely used for thrombosis prevention. Upon application as anticoagulants in cancer patients, heparins were found to possess additional antitumor activities. Ectonucleotidases have recently been proposed as novel targets for cancer immunotherapy., Methods and Results: In the present study, we discovered that heparin and its derivatives act as potent, selective, allosteric inhibitors of the poorly investigated ectonucleotidase NPP1 (nucleotide pyrophosphatase/phosphodiesterase-1, CD203a). Structure-activity relationships indicated that NPP1 inhibition could be separated from the compounds' antithrombotic effect. Moreover, unfractionated heparin (UFH) and different low molecular weight heparins (LMWHs) inhibited extracellular adenosine production by the NPP1-expressing glioma cell line U87 at therapeutically relevant concentrations. As a consequence, heparins inhibited the ability of U87 cell supernatants to induce CD4+ T cell differentiation into immunosuppressive Treg cells., Discussion: NPP1 inhibition likely contributes to the anti-cancer effects of heparins, and their specific optimization may lead to improved therapeutics for the immunotherapy of cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lopez, Schuh, Mirza, Vaaßen, Schmidt, Sylvester, Idris, Renn, Schäkel, Pelletier, Sévigny, Naggi, Scheffler, Lee, Bendas and Müller.)

We recently reported N 4 -substituted 3-methylcytidine-5'-α,β-methylenediphosphates as CD73 inhibitors, potentially useful in cancer immunotherapy. We now expand the structure-activity relationship of pyrimidine nucleotides as human CD73 inhibitors. 4-Chloro (MRS4598 16 ; K i = 0.673 nM) and 4-iodo (MRS4620 18 ; K i = 0.436 nM) substitution of the N 4 -benzyloxy group decreased K i by ∼20-fold. Primary alkylamine derivatives coupled through a p -amido group with a varying methylene chain length ( 24 and 25 ) were functionalized congeners, for subsequent conjugation to carrier or reporter moieties. X-ray structures of hCD73 with two inhibitors indicated a ribose ring conformational adaptation, and the benzyloxyimino group ( E configuration) binds to the same region (between the C-terminal and N-terminal domains) as N 4 -benzyl groups in adenine inhibitors. Molecular dynamics identified stabilizing interactions and predicted conformational diversity. Thus, by N 4 -benzyloxy substitution, we have greatly enhanced the inhibitory potency and added functionality enabling molecular probes. Their potential as anticancer drugs was confirmed by blocking CD73 activity in tumor tissues in situ.

Nucleoside triphosphate diphosphohydrolase1 (NTPDase1, CD39) inhibitors have potential as novel drugs for the (immuno)therapy of cancer. They increase the extracellular concentration of immunostimulatory ATP and reduce the formation of AMP, which can be further hydrolyzed by ecto-5'-nucleotidase (CD73) to immunosuppressive, cancer-promoting adenosine. In the present study, we synthesized analogs and derivatives of the standard CD39 inhibitor ARL67156, a nucleotide analog which displays a competitive mechanism of inhibition. Structure-activity relationships were analyzed at the human enzyme with respect to substituents in the N 6 - and C8-position of the adenine core, and modifications of the triphosph(on)ate chain. Capillary electrophoresis coupled to laser-induced fluorescence detection employing a fluorescent-labeled ATP derivative was employed to determine the compounds' potency. Selected inhibitors were additionally evaluated in an orthogonal, malachite green assay versus the natural substrate ATP. The most potent CD39 inhibitors of the present series were ARL67156 and its derivatives 31 and 33 with K i values of around 1 µM. Selectivity studies showed that all three nucleotide analogs additionally blocked CD73 acting as dual-target inhibitors. Docking studies provided plausible binding modes to both targets. The present study provides a full characterization of the frequently applied CD39 inhibitor ARL67156, presents structure-activity relationships, and provides a basis for future optimization towards selective CD39 and dual CD39/CD73 inhibitors., (Copyright © 2020 Schäkel, Schmies, Idris, Luo, Lee, Lopez, Mirza, Vu, Pelletier, Sévigny, Namasivayam and Müller.)

Ecto-5'-nucleotidase (CD73) catalyzes the hydrolysis of AMP to anti-inflammatory, immunosuppressive adenosine. It is expressed on vascular endothelial, epithelial, and also numerous cancer cells where it strongly contributes to an immunosuppressive microenvironment. In the present study we designed and synthesized fluorescent-labeled CD73 inhibitors with low nanomolar affinity and high selectivity based on N 6 - benzyl-α,β-methylene-ADP (PSB-12379) as a lead structure. Fluorescein was attached to the benzyl residue via different linkers resulting in PSB-19416 ( 14b , K i 12.6 nM) and PSB-18332 ( 14a , K i 2.98 nM) as fluorescent high-affinity probes for CD73. These compounds are anticipated to become useful tools for biological studies, drug screening, and diagnostic applications., Competing Interests: The authors declare the following competing financial interest(s): C.E.M. has given scientific advice to Arcus Biosciences Inc., a publicly traded biotechnology company.