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Background: Vasopressin is recommended as a second-line vasoactive agent for the management of septic shock; however, a paucity of data to guide its optimal use remains. The aim was to evaluate the effect of time-to vasopressin initiation and norepinephrine (NE) dose at vasopressin initiation on clinical outcomes in patients presenting with septic shock. Methods: This was a multi-centered, retrospective, observational study conducted in patients with septic shock. Patients were divided into 2 groups: patients initiated on vasopressin when NE-equivalent dose (NEE) < 0.25 mcg/kg/min or ≥ 0.25 mcg/kg/min. The primary outcome was time-to-vasopressor discontinuation (hours). Secondary outcomes included 28-day in-hospital mortality, intensive care unit (ICU) length of stay (LOS), fluid balance after 72 hours, and the change in NEE at 12 hours. Results: A total of 302 patients were included in this study. After propensity-score matching, 73 patients in each group were identified for analysis. There was no significant difference in the time-to-vasopressor discontinuation (hours) between the groups (88.8 [55–187.5] vs 86.7 [47–172]); p = 0.7815). Fluid balance (mL) at 72 hours was significantly lower when vasopressin was initiated at NEE < 0.25 mcg/kg/min (1769 [71–7287] vs 5762 [1463–8813]; p = 0.0077). A multivariable linear regression showed shorter time to shock resolution with earlier vasopressin initiation, defined as within 4 hours (p < 0.05). Conclusion: In this propensity-score matched cohort, vasopressin initiation at NEE < 0.25 mcg/kg/min was not associated with shorter vasopressor duration. There was a lower fluid balance at 72 hours when vasopressin was initiated at lower NE doses. [ABSTRACT FROM AUTHOR]

Cancer cells frequently present elevated intracellular iron levels, which are thought to facilitate an enhanced proliferative capacity. Targeting iron metabolism within cancer cells presents an avenue to enhance therapeutic responses, necessitating the use of non-invasive models to modulate iron manipulation to predict responses. Moreover, the ubiquitous nature of iron necessitates the development of unique, non-invasive markers of metabolic disruptions to develop more personalized approaches and enhance the clinical utility of these approaches. Ferritin, an iron storage enzyme that is often upregulated as a response to iron accumulation, plays a central role in iron metabolism and has been frequently associated with unfavorable clinical outcomes in cancer. Herein, we demonstrate the successful utility, validation, and functionality of a doxycycline-inducible ferritin heavy chain (FtH) overexpression model in H1299T non-small-cell lung cancer (NSCLC) cells. Treatment with doxycycline increased the protein expression of FtH with a corresponding decrease in labile iron in vitro and in vivo, as determined by calcein-AM staining and EPR, respectively. Moreover, a subsequent increase in TfR expression was observed. Furthermore, T2* MR mapping effectively detected FtH expression in our in vivo model. These results demonstrate that T2* relaxation times can be used to monitor changes in FtH expression in tumors with bidirectional correlations depending on the model system. Overall, this study describes the development of an FtH overexpression NSCLC model and its correlation with T2* mapping for potential use in patients to interrogate iron metabolic alterations and predict clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Radiation therapy (RT) is an integral and commonly used therapeutic modality for primary lung cancer. However, radiation-induced lung injury (RILI) limits the irradiation dose used in the lung and is a significant source of morbidity. Disruptions in iron metabolism have been linked to radiation injury, but the underlying mechanisms remain unclear. Purpose: To utilize a targeted radiation delivery approach to induce RILI for the development of a model system to study the role of radiation-induced iron accumulation in RILI. Methods: This study utilizes a Small Animal Radiation Research Platform (SARRP) to target the right lung with a 20 Gy dose while minimizing the dose delivered to the left lung and adjacent heart. Long-term pulmonary function was performed using RespiRate-x64image analysis. Normal-appearing lung volumes were calculated using a cone beam CT (CBCT) image thresholding approach in 3D Slicer software. Quantification of iron accumulation was performed spectrophotometrically using a ferrozine-based assay as well as histologically using Prussian blue and via Western blotting for ferritin heavy chain expression. Results: Mild fibrosis was seen histologically in the irradiated lung using hematoxylin and eosin-stained fixed tissue at 9 months, as well as using a scoring system from CBCT images, the Szapiel scoring system, and the highest fibrotic area metric. In contrast, no changes in breathing rate were observed, and median survival was not achieved up to 36 weeks following irradiation, consistent with mild lung fibrosis when only one lung was targeted. Our study provided preliminary evidence on increased iron content and ferritin heavy chain expression in the irradiated lung, thus warranting further investigation. Conclusions: A targeted lung irradiation model may be a useful approach for studying the long-term pathological effects associated with iron accumulation and RILI following ionizing radiation. [ABSTRACT FROM AUTHOR]

Recently, the FDA-approved iron oxide nanoparticle, ferumoxytol, has been found to enhance the efficacy of pharmacological ascorbate (AscH−) in treating glioblastoma, as AscH− reduces the Fe3+ sites in the nanoparticle core. Given the iron oxidation state specificity of T2* relaxation mapping, this study aims to investigate the ability of T2* relaxation to monitor the reduction of ferumoxytol by AscH− with respect to its in vitro therapeutic enhancement. This study employed an in vitro glioblastoma MRI model system to investigate the chemical interaction of ferumoxytol with T2* mapping. Lipofectamine was utilized to facilitate ferumoxytol internalization and assess intracellular versus extracellular chemistry. In vitro T2* mapping successfully detected an AscH−-mediated reduction of ferumoxytol (25.6 ms versus 2.8 ms for FMX alone). The T2* relaxation technique identified the release of Fe2+ from ferumoxytol by AscH− in glioblastoma cells. However, the high iron content of ferumoxytol limited T2* ability to differentiate between the external and internal reduction of ferumoxytol by AscH− (ΔT2* = +839% for external FMX and +1112% for internal FMX reduction). Notably, the internalization of ferumoxytol significantly enhances its ability to promote AscH− toxicity (dose enhancement ratio for extracellular FMX = 1.16 versus 1.54 for intracellular FMX). These data provide valuable insights into the MR-based nanotheranostic application of ferumoxytol and AscH− therapy for glioblastoma management. Future developmental efforts, such as FMX surface modifications, may be warranted to enhance this approach further. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM), a highly lethal and aggressive central nervous system malignancy, presents a critical need for targeted therapeutic approaches to improve patient outcomes in conjunction with standard-of-care (SOC) treatment. Molecular subtyping based on genetic profiles and metabolic characteristics has advanced our understanding of GBM to better predict its evolution, mechanisms, and treatment regimens. Pharmacological ascorbate (P-AscH−) has emerged as a promising supplementary cancer therapy, leveraging its pro-oxidant properties to selectively kill malignant cells when combined with SOC. Given the clinical challenges posed by the heterogeneity and resistance of various GBM subtypes to conventional SOC, our study assessed the response of classical, mesenchymal, and proneural GBM to P-AscH−. P-AscH− (20 pmol/cell) combined with SOC (5 µM temozolomide and 4 Gy of radiation) enhanced clonogenic cell killing in classical and mesenchymal GBM subtypes, with limited effects in the proneural subtype. Similarly, following exposure to P-AscH− (20 pmol/cell), single-strand DNA damage significantly increased in classical and mesenchymal but not proneural GBM. Moreover, proneural GBM exhibited increased hydrogen peroxide removal rates, along with increased catalase and glutathione peroxidase activities compared to mesenchymal and classical GBM, demonstrating an altered H2O2 metabolism that potentially drives differential P-AscH− toxicity. Taken together, these data suggest that P-AscH− may hold promise as an approach to improve SOC responsiveness in mesenchymal GBMs that are known for their resistance to SOC. [ABSTRACT FROM AUTHOR]

Study Objective: Significant practice variation exists when selecting between hydrocortisone and vasopressin as second line agents in patients with septic shock in need of escalating doses of norepinephrine. The goal of this study was to assess differences in clinical outcomes between these two agents. Design: Multicenter, retrospective, observational study. Setting: Ten Ascension Health hospitals. Patients: Adult patients with presumed septic shock receiving norepinephrine prior to study drug initiation between December 2015 and August 2021. Intervention: Vasopressin (0.03–0.04 units/min) or hydrocortisone (200–300 mg/day). Measurements and Main Results: A total of 768 patients were included with a median (interquartile range) SOFA score of 10 (8–13), norepinephrine dose of 0.3 mcg/kg/min (0.1–0.5 mcg/kg/min), and lactate of 3.8 mmol/L (2.4–7.0 mmol/L) at initiation of the study drug. A significant difference in 28‐day mortality was noted favoring hydrocortisone as an adjunct to norepinephrine after controlling for potential confounding factors (OR 0.46 [95% CI, 0.32–0.66]); similar results were seen following propensity score matching. Compared to vasopressin, hydrocortisone initiation was also associated with a higher rate of hemodynamic responsiveness (91.9% vs. 68.2%, p < 0.01), improved resolution of shock (68.8% vs. 31.5%, p < 0.01), and reduced recurrence of shock within 72 h (8.7% vs. 20.7%, p < 0.01). Conclusions: Addition of hydrocortisone to norepinephrine was associated with a lower 28‐day mortality in patients with septic shock, compared to the addition of vasopressin. [ABSTRACT FROM AUTHOR]

Purpose: Ataxia telangiectasia mutated kinase (ATM) inhibitors are potent radiosensitizers that regulate DNA damage responses and redox metabolism, but they have not been translated clinically because of the potential for excess normal tissue toxicity. Pharmacologic ascorbate (P-AscH-; intravenous administration achieving mM plasma concentrations) selectively enhances H2O2-induced oxidative stress and radiosensitization in tumors while acting as an antioxidant and mitigating radiation damage in normal tissues including the bowel. We hypothesized that P-AscH- could enhance the therapeutic index of ATM inhibitor-based chemoradiation by simultaneously enhancing the intended effects of ATM inhibitors in tumors and mitigating off-target effects in adjacent normal tissues.Methods and Materials: Clonogenic survival was assessed in human (human colon tumor [HCT]116, SW480, HT29) and murine (CT26, MC38) colorectal tumor lines and normal cells (human umbilical vein endothelial cell, FHs74) after radiation ± DNA repair inhibitors ± P-AscH-. Tumor growth delay was assessed in mice with HCT116 or MC38 tumors after fractionated radiation (5 Gy × 3) ± the ATM inhibitor KU60019 ± P-AscH-. Intestinal injury, oxidative damage, and transforming growth factor β immunoreactivity were quantified using immunohistochemistry after whole abdominal radiation (10 Gy) ± KU60019 ± P-AscH-. Cell cycle distribution and ATM subcellular localization were assessed using flow cytometry and immunohistochemistry. The role of intracellular H2O2 fluxes was assessed using a stably expressed doxycycline-inducible catalase transgene.Results: KU60019 with P-AscH- enhanced radiosensitization in colorectal cancer models in vitro and in vivo by H2O2-dependent oxidative damage to proteins and enhanced DNA damage, abrogation of the postradiation G2 cell cycle checkpoint, and inhibition of ATM nuclear localization. In contrast, concurrent P-AscH- markedly reduced intestinal toxicity and oxidative damage with KU60019.Conclusions: We provide evidence that redox modulating drugs, such as P-AscH-, may facilitate the clinical translation of ATM inhibitors by enhancing tumor radiosensitization while simultaneously protecting normal tissues. [ABSTRACT FROM AUTHOR]