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Vascular damage, initiated by host inflammatory cells, is a component of the pathophysiology of many acute and chronic inflammatory disorders. Neutrophil-mediated tissue damage is mediated primarily hyproteinases, particularly elastase and cathepsin G. In this study we have identified endothelial binding of two key serine proteinase inhibitors (serpins), α1-antitrypsin, the inhibitor of elastase, and α1-antichymotrypsin, the inhibitor of cathepsin G. These serpins are shed from the endothelium into the supernatant when neutrophils adherent to the endothelium are activated. Endothelium activated by lipopolysaccharide (LPS) augments this process, Serpin-proteinase complexes activate neutrophils and induce further cytokine release, thereby amplifying inflammatory processes. Strategies aimed at preventing endothelial serpin depletion may help minimize vascular damage during inflammation. [ABSTRACT FROM AUTHOR]

The article presents a study of carbonyl iron as a tool for non-toxic iron loading of the mussel Mytilus edulis. It says that carbonyl iron can be used for the iron loading method, with the ability to maintain a relatively high iron concentration. It states that the method rejects the use of filter system to avoid the build up of iron hydroxide.

Objective: To describe the workflow, reach, cost, and self-reported quit rates for an opt-out tobacco treatment program (TTP) for patients seen in 43 oncology outpatient clinics., Methods: Between May 25, 2021, and December 31, 2022, adult patients (≥18 years) visiting clinics affiliated with the Medical University of South Carolina Hollings Cancer Center were screened for smoking status. Those currently smoking were referred to a telehealth pharmacy-assisted TTP. An attempt was made to contact referred patients by phone. Patients reached were offered free smoking cessation counseling and a 2-week starter kit of nicotine replacement medication. A random sample of 420 patients enrolled in the TTP were selected to participate in a telephone survey to assess smoking status 4 to 12 months after enrollment., Results: During the reference period 35,756 patients were screened and 9.3% were identified as currently smoking. Among the 3319 patients referred to the TTP at least once, 2393 (72.1%) were reached by phone, of whom 426 (12.8%) were ineligible for treatment, 458 (13.8%) opted out of treatment, and 1509 (45.5%) received treatment. More than 90% of TTP enrollees smoked daily, with an average of 13.1 cigarettes per day. Follow-up surveys were completed on 167 of 420 patients, of whom 23.4% to 33.5% reported not smoking; if all nonresponders to the survey are counted as smoking, the range of quit rates is 9.3% to 13.3%., Conclusion: The findings demonstrate the feasibility of reaching and delivering smoking cessation treatments to patients from a diverse set of geographically dispersed oncology clinics., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Objective: Describe the screening, referral, and treatment delivery associated with an opt-out tobacco treatment program (TTP) implemented in six hospitals varying in size, rurality and patient populations., Methods: Between March 6, 2021 and December 17, 2021, adult patients (≥ 18 years) admitted to six hospitals affiliated with the Medical University of South Carolina were screened for smoking status. The hospitals ranged in size from 82 to 715 beds. Those currently smoking were automatically referred to one of two tobacco treatment options: 1) Enhanced care (EC) where patients could receive a bedside consult by a trained tobacco treatment specialist plus an automated post-discharge follow-up call designed to connect those smoking to the South Carolina Quitline (SCQL); or 2) Basic care (BC) consisting of the post-discharge follow-up call only. An attempt was made to survey patients at 6-weeks after hospitalization to assess smoking status., Results: Smoking prevalence ranged from 14 to 49% across the six hospitals; 6,000 patients were referred to the TTP.The delivery of the bedside consult varied across the hospitals with the lowest in the Charleston hospitals which had the highest caseload of referred patients per specialist. Among patients who received a consult visit during their hospitalization, 50% accepted the consult, 8% opted out, 3% claimed not to be current smokers, and 38% were unavailable at the time of the consult visit. Most of those enrolled in the TTP were long-term daily smokers.Forty-three percent of patients eligible for the automated post-discharge follow-up call answered the call, of those, 61% reported smoking in the past seven days, and of those, 34% accepted the referral to theSCQL. Among the 986 of patients surveyed at 6-weeks after hospitalization quit rates ranged from 20%-30% based on duration of reported cessation and were similar between hospitals and for patients assigned to EC versus BC intervention groups., Conclusion: Findings demonstrate the broad reach of an opt-out TTP. Elements of treatment delivery can be improved by addressing patient-to-staffing ratios, improving systems to prescribe stop smoking medications for patients at discharge and linking patients to stop smoking services after hospital discharge., (© 2024. The Author(s).)

Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.

The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochemical properties. These studies culminated in the identification of compound 12 that showed improved cell potency, oral exposure, and in vivo activity in clinically relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.