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Structural, functional, and molecular-level changes in the aging heart are influenced by a dynamic interplay between immune signaling and cellular metabolism that is referred to as immunometabolism. This review explores the crosstalk between cellular metabolic pathways including glycolysis, oxidative phosphorylation, fatty acid metabolism, and the immune processes that govern cardiac aging. With a rapidly aging population that coincides with increased cardiovascular risk and cancer incidence rates, understanding the immunometabolic underpinnings of cardiac aging provides a foundation for identifying therapeutic targets to mitigate cardiac dysfunction. Aging alters the immune environment of the heart by concomitantly driving the changes in immune cell metabolism, mitochondrial dysfunction, and redox signaling. Shifts in these metabolic pathways exacerbate inflammation and impair tissue repair, creating a vicious cycle that accelerates cardiac functional decline. Treatment with cancer therapy further complicates this landscape, as aging-associated immunometabolic disruptions augment the susceptibility to cardiotoxicity. The current review highlights therapeutic strategies that target the immunometabolic axis to alleviate cardiac aging pathologies. Interventions include modulating metabolic intermediates, improving mitochondrial function, and leveraging immune signaling pathways to restore cardiac health. Advances in immunometabolism thus hold significant potential for translating preclinical findings into therapies that improve the quality of life for the aging population and underscore the need for approaches that address the immunometabolic mechanisms of cardiac aging, providing a framework for future research.

Radiation therapy (RT) is a cornerstone in cancer treatment (used in 50% of cases), yet challenges persist because damage to normal tissue through direct impact of radiation or bystander effects is inevitable. Injury of macrovessels by RT manifests as obstructive disease, which is akin to atherosclerotic disease. Historically observed in coronary arteries of patients treated for breast cancer and lymphoma, it also affects patients receiving contemporary therapy for lung and chest cancers. Moreover, radiation at various sites can lead to peripheral vascular disease. An aspect of radiation-induced injury that has received little attention is microvascular injury, which typically results from damage to the endothelium and is considered the primary driver of RT-induced toxicity in the skin, kidney, and brain. This review delves into the clinical manifestations of RT-induced vascular disease, signaling pathways, cellular targets affected by radiation injury, and preclinical models of RT-induced vascular injury. The goal is to inspire the development of innovative strategies to prevent RT-related cardiovascular disease., Competing Interests: None.

Background: Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have poor 5-year survival. Pharmacological ascorbate (P-AscH - , high dose, intravenous, vitamin C) has shown promise as an adjunct to chemotherapy. We hypothesized adding P-AscH - to gemcitabine and nab-paclitaxel would increase survival in patients with metastatic PDAC., Methods: Patients diagnosed with stage IV pancreatic cancer randomized 1:1 to gemcitabine and nab-paclitaxel only (SOC, control) or to SOC with concomitant P-AscH - , 75 g three times weekly (ASC, investigational). The primary outcome was overall survival with secondary objectives of determining progression-free survival and adverse event incidence. Quality of life and patient reported outcomes for common oncologic symptoms were captured as an exploratory objective. Thirty-six participants were randomized; of this 34 received their assigned study treatment. All analyses were based on data frozen on December 11, 2023., Results: Intravenous P-AscH - increased serum ascorbate levels from micromolar to millimolar levels. P-AscH - added to the gemcitabine + nab-paclitaxel (ASC) increased overall survival to 16 months compared to 8.3 months with gemcitabine + nab-paclitaxel (SOC) (HR = 0.46; 90 % CI 0.23, 0.92; p = 0.030). Median progression free survival was 6.2 (ASC) vs. 3.9 months (SOC) (HR = 0.43; 90 % CI 0.20, 0.92; p = 0.029). Adding P-AscH - did not negatively impact quality of life or increase the frequency or severity of adverse events., Conclusions: P-AscH - infusions of 75 g three times weekly in patients with metastatic pancreatic cancer prolongs overall and progression free survival without detriment to quality of life or added toxicity (ClinicalTrials.gov number NCT02905578)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Conventional cancer therapy strategies, although centered around killing tumor cells, often lead to severe side effects on surrounding normal tissues, thus compromising the chronic quality of life in cancer survivors. Hydrogen peroxide (H 2 O 2 ) is a secondary signaling molecule that has an array of functions in both tumor and normal cells, including the promotion of cell survival pathways and immune cell modulation in the tumor microenvironment. H 2 O 2 is a reactive oxygen species (ROS) crucial in cellular homeostasis and signaling (at concentrations maintained under nM levels), with increased steady-state levels in tumors relative to their normal tissue counterparts. Increased steady-state levels of H 2 O 2 in tumor cells, make them vulnerable to oxidative stress and ultimately, cell death. Recently, H 2 O 2 -producing therapies-namely, pharmacological ascorbate and superoxide dismutase mimetics-have emerged as compelling complementary treatment strategies in cancer. Both pharmacological ascorbate and superoxide dismutase mimetics can generate excess H 2 O 2 to overwhelm the impaired H 2 O 2 removal capacity of cancer cells. This review presents an overview of H 2 O 2 metabolism in the physiological and malignant states, in addition to discussing the anti-tumor and normal tissue-sparing mechanism(s) of, and clinical evidence for, two H 2 O 2 -based therapies, pharmacological ascorbate and superoxide dismutase mimetics.

The MR transverse relaxation rate, R2*, has been widely used to detect iron and myelin content in tissue. However, it is also sensitive to macroscopic B 0 inhomogeneities. One approach to correct for the B 0 effect is to fit gradient-echo signals with the three-parameter model, a sinc function-weighted monoexponential decay. However, such three-parameter models are subject to increased noise sensitivity. To address this issue, this study presents a two-stage fitting procedure based on the three-parameter model to mitigate the B 0 effect and reduce the noise sensitivity of R2* measurement in the mouse brain at 7T. MRI scans were performed on eight healthy mice. The gradient-echo signals were fitted with the two-stage fitting procedure to generate R2corr_t*. The signals were also fitted with the monoexponential and three-parameter models to generate R2nocorr* and R2corr*, respectively. Regions of interest (ROIs), including the corpus callosum, internal capsule, somatosensory cortex, caudo-putamen, thalamus, and lateral ventricle, were selected to evaluate the within-ROI mean and standard deviation (SD) of the R2* measurements. The results showed that the Akaike information criterion of the monoexponential model was significantly reduced by using the three-parameter model in the selected ROIs ( p = 0.0039-0.0078). However, the within-ROI SD of R2corr* using the three-parameter model was significantly higher than that of the R2nocorr* in the internal capsule, caudo-putamen, and thalamus regions ( p = 0.0039), a consequence partially due to the increased noise sensitivity of the three-parameter model. With the two-stage fitting procedure, the within-ROI SD of R2corr* was significantly reduced by 7.7-30.2% in all ROIs, except for the somatosensory cortex region with a fast in-plane variation of the B 0 gradient field ( p = 0.0039-0.0078). These results support the utilization of the two-stage fitting procedure to mitigate the B 0 effect and reduce noise sensitivity for R2* measurement in the mouse brain.

Soft tissue sarcomas (STSs) are mesenchymal malignant lesions that develop in soft tissues. Despite current treatments, including radiation therapy (RT) and surgery, STSs can be associated with poor patient outcomes and metastatic recurrences. Neoadjuvant radiation therapy (nRT), while effective, is often accompanied by severe postoperative wound healing complications due to damage to the surrounding normal tissues. Thus, there is a need to develop therapeutic approaches to reduce nRT toxicities. Avasopasem manganese (AVA) is a selective superoxide dismutase mimetic that protects against IR-induced oral mucositis and lung fibrosis. We tested the efficacy of AVA in enhancing RT in STSs and in promoting wound healing. Using colony formation assays and alkaline comet assays, we report that AVA selectively enhanced the STS (liposarcoma, fibrosarcoma, leiomyosarcoma, and MPNST) cellular response to radiation compared to normal dermal fibroblasts (NDFs). AVA is believed to selectively enhance radiation therapy by targeting differential hydrogen peroxide clearance in tumor cells compared to non-malignant cells. STS cells demonstrated increased catalase protein levels and activity compared to normal fibroblasts. Additionally, NDFs showed significantly higher levels of GPx1 activity compared to STSs. The depletion of glutathione using buthionine sulfoximine (BSO) sensitized the NDF cells to AVA, suggesting that GPx1 may, in part, facilitate the selective toxicity of AVA. Finally, AVA significantly accelerated wound closure in a murine model of wound healing post RT. Our data suggest that AVA may be a promising combination strategy for nRT therapy in STSs.

Purpose: Cisplatin contributes to acute kidney injury (AKI) and chronic kidney disease (CKD) that occurs with greater frequency and severity in older patients. Age-associated cisplatin sensitivity in human fibroblasts involves increased mitochondrial superoxide produced by older donor cells., Experimental Design: Young and old C57BL/6 J murine models of cisplatin-induced AKI and CKD were treated with the SOD mimetic avasopasem manganese to investigate the potential antioxidant and anti-inflammatory effects. Adverse event reporting from a phase 2 and a phase 3 randomized clinical trial (NCT02508389 and NCT03689712) conducted in patients treated with cisplatin and AVA was determined to have established the incidence and severity of AKI., Results: Cisplatin-induced AKI and CKD occurred in all mice, however, was more pronounced in older mice. AVA reduced cisplatin-induced mortality, AKI, and CKD, in older animals. AVA also alleviated cisplatin-induced alterations in mitochondrial electron transport chain (ETC) complex activities and NADPH Oxidase 4 (NOX4) and inhibited the increased levels of the inflammation markers, TNFα, IL1, ICAM-1, and VCAM-1. Analysis of age-stratified subjects treated with cisplatin from clinical trials (NCT02508389, NCT03689712) also supported that the incidence of AKI increased with age and AVA reduced age-associated therapy-induced adverse events (AE), including hypomagnesemia, increased creatinine, and AKI., Conclusions: Older mice and humans are more susceptible to cisplatin-induced kidney injury, and treatment with AVA mitigates age-associated damage. Mitochondrial ETC and NOX4 activities represent sources of superoxide production contributing to cisplatin-induced kidney injury, and pro-inflammatory cytokine production and endothelial dysfunction may also be increased by superoxide formation., Competing Interests: Declaration of competing interest Drs. Spitz and Allen acknowledge support for their laboratory efforts from a sponsored research agreement from Galera Therapeutics, Inc. Dr. Anderson is a paid consultant of Galera Therapeutics, helping them develop their patient and provider educational materials for clinical use of AVA. Dr. Beardsley is an employee of and owns stock in, Galera Therapeutics, Inc. No potential conflicts of interest were disclosed by the other authors., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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, T 2 * MR mapping effectively detected FtH expression in our in vivo model. These results demonstrate that T 2 * 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 T 2 * mapping for potential use in patients to interrogate iron metabolic alterations and predict clinical outcomes.

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.

Thioredoxin Reductase (TrxR) is a key enzyme in hydroperoxide detoxification through peroxiredoxin enzymes and in thiol-mediated redox regulation of cell signaling. Because cancer cells produce increased steady-state levels of reactive oxygen species (ROS; i.e., superoxide and hydrogen peroxide), TrxR is currently being targeted in clinical trials using the anti-rheumatic drug, auranofin (AF). AF treatment decreased TrxR activity and clonogenic survival in small cell lung cancer (SCLC) cell lines (DMS273 and DMS53) as well as the lung atypical (neuroendocrine tumor) NET cell line H727. AF treatment also significantly sensitized DMS273 and H727 cell lines in vitro to sorafenib, a multi-kinase inhibitor that was shown to decrease intracellular glutathione. The pharmacokinetic and pharmacodynamic properties of AF treatment in a mouse SCLC xenograft model was examined to maximize inhibition of TrxR activity without causing toxicity. AF was administered intraperitoneally at 2 mg/kg or 4 mg/kg (IP) once (QD) or twice daily (BID) for 1 to 5 days in mice with DMS273 xenografts. Plasma levels of AF were 10-20 μM (determined by mass spectrometry of gold) and the optimal inhibition of TrxR (50 %) was obtained at 4 mg/kg once daily, with no effect on glutathione peroxidase 1 activity. When this daily AF treatment was extended for 14 days a significant prolongation of median survival from 19 to 23 days (p=0.04, N=30 controls, 28 AF) was observed without causing changes in animal bodyweight, CBCs, bone marrow toxicity, blood urea nitrogen, or creatinine. These results show that AF is an effective inhibitor of TrxR both in vitro and in vivo in SCLC, capable of sensitizing NETs and SCLC to sorafenib, and supports the hypothesis that AF could be used as an adjuvant therapy with agents known to induce disruptions in thiol metabolism to enhance therapeutic efficacy.

Purpose: Pharmacologic ascorbate (P-AscH-) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH- with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH- in humans., Patients and Methods: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker., Results: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7-26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems., Conclusions: P-AscH- combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255., (©2023 American Association for Cancer Research.)

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 Fe 3+ 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 T 2 * mapping. Lipofectamine was utilized to facilitate ferumoxytol internalization and assess intracellular versus extracellular chemistry. In vitro T 2 * mapping successfully detected an AscH - -mediated reduction of ferumoxytol (25.6 ms versus 2.8 ms for FMX alone). The T 2 * relaxation technique identified the release of Fe 2+ 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 - (ΔT 2 * = +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.

Objective: Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Although tubular metabolism changes markedly following acute kidney injury (AKI), it remains unclear which metabolic alterations are beneficial or detrimental. By analyzing large-scale, publicly available datasets, we observed that AKI consistently leads to downregulation of the mitochondrial pyruvate carrier (MPC). This investigation aimed to understand the contribution of the tubular MPC to kidney function, metabolism, and acute injury severity., Methods: We generated tubular epithelial cell-specific Mpc1 knockout (MPC TubKO) mice and employed renal function tests, in vivo renal 13 C-glucose tracing, mechanistic enzyme activity assays, and tests of injury and survival in an established rhabdomyolysis model of AKI., Results: MPC TubKO mice retained normal kidney function, displayed unchanged markers of kidney injury, but exhibited coordinately increased enzyme activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, compared to WT control mice, MPC TubKO mice showed increased glycolysis, decreased kidney injury and oxidative stress markers, and strikingly increased survival., Conclusions: Our findings suggest that decreased renal tubular mitochondrial pyruvate uptake hormetically upregulates oxidant defense systems before AKI and is a beneficial adaptive response after rhabdomyolysis-induced AKI. This raises the possibility of therapeutically modulating the MPC to attenuate AKI severity., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

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 H 2 O 2 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.

Background: Extremity soft-tissue sarcomas (STS) are commonly treated with neoadjuvant radiation therapy followed by surgical resection. However, the pathological near-complete response rate is low (9-25%). Noninvasive imaging assessment that predicts treatment response before and during treatment is desirable to optimize treatment regimens. This pilot study aimed to investigate the application of a quantitative MRI parameter, T 2 *, in assessing neoadjuvant radiation therapy combined with pharmacological ascorbate in extremity STS., Methods: This prospective cohort study included seven patients diagnosed with extremity STS and scheduled to receive neoadjuvant radiation therapy combined with pharmacological ascorbate. T 2 * maps were obtained from each patient before treatment (baseline MRI), two weeks after initiating treatment (on-treatment MRI), and before surgery (pre-surgery MRI). The T 2 * values within the tumor region were transformed into z-scores with respect to the normal- appearing tissue region. The voxel-wise z-scores within the tumor region were thresholded to generate masks representing significantly high (z-score>1.96) and low z-score (z-score<-1.96) voxels. The means of the total z-scores and within each of the significantly high and low z-score mask were computed. Their correlations with percent necrosis from pathological examination were evaluated using Spearman's rank correlation coefficient r. A correlation was considered as moderate or strong when r is higher than 0.6 and 0.8, respectively. A correlation was considered as fair or weak when r is below 0.6., Results: For the baseline and on-treatment MRIs, the means of the significantly high z-scores of the T 2 * measurements showed moderate correlations with percent necrosis (r = 0.68 and 0.6; p = 0.11 and 0.24). For the pre-surgery MRI, the means of the total and significantly high z-scores showed strong correlations with percent necrosis (r = 0.8 and 0.9; p = 0.13 and 0.08). Tumor volume and baseline MRI-based percent necrosis showed fair or weak correlations (r = 0.3-0.54; p = 0.24-0.68)., Conclusion: T 2 * measurements prior to treatment, two weeks after initiating treatment, and before surgery showed moderate to strong correlations with percent necrosis. These results support the potential for using T 2 * mapping to predict and assess response to neoadjuvant radiation therapy combined with pharmacological ascorbate in extremity STS. Level of Evidence: IV ., Competing Interests: Disclosures: The authors report no potential conflicts of interest related to this study., (Copyright © The Iowa Orthopaedic Journal 2023.)

The intracellular redox-active labile iron pool (LIP) is weakly chelated and available for integration into the iron metalloproteins that are involved in diverse cellular processes, including cancer cell-specific metabolic oxidative stress. Abnormal iron metabolism and elevated LIP levels are linked to the poor survival of lung cancer patients, yet the underlying mechanisms remain unclear. Depletion of the LIP in non-small-cell lung cancer cell lines using the doxycycline-inducible overexpression of the ferritin heavy chain (Ft-H) (H1299 and H292), or treatment with deferoxamine (DFO) (H1299 and A549), inhibited cell growth and decreased clonogenic survival. The Ft-H overexpression-induced inhibition of H1299 and H292 cell growth was also accompanied by a significant delay in transit through the S-phase. In addition, both Ft-H overexpression and DFO in H1299 resulted in increased single- and double-strand DNA breaks, supporting the involvement of replication stress in the response to LIP depletion. The Ft-H and DFO treatment also sensitized H1299 to VE-821, an inhibitor of ataxia telangiectasis and Rad2-related (ATR) kinase, highlighting the potential of LIP depletion, combined with DNA damage response modifiers, to alter lung cancer cell responses. In contrast, only DFO treatment effectively reduced the LIP, clonogenic survival, cell growth, and sensitivity to VE-821 in A549 non-small-cell lung cancer cells. Importantly, the Ft-H and DFO sensitized both H1299 and A549 to chemoradiation in vitro, and Ft-H overexpression increased the efficacy of chemoradiation in vivo in H1299. These results support the hypothesis that the depletion of the LIP can induce genomic instability, cell death, and potentiate therapeutic responses to chemoradiation in NSCLC.

Diffuse intrinsic pontine gliomas (DIPG) are an aggressive type of pediatric brain tumor with a very high mortality rate. Surgery has a limited role given the tumor's location. Palliative radiation therapy alleviates symptoms and prolongs survival, but median survival remains less than 1 year. There is no clear role for chemotherapy in DIPGs as trials adding chemotherapy to palliative radiation therapy have failed to improve survival compared to radiation alone. Thus, there is a critical need to identify tissue-specific radiosensitizers to improve clinical outcomes for patients with DIPGs. Pharmacologic (high dose) ascorbate (P-AscH-) is a promising anticancer therapy that sensitizes human tumors, including adult high-grade gliomas, to radiation by acting selectively as a generator of hydrogen peroxide (H2O2) in cancer cells. In this study we demonstrate that in contrast to adult glioma models, P-AscH- does not radiosensitize DIPG. DIPG cells were sensitive to bolus of H2O2 but have faster H2O2 removal rates than GBM models which are radiosensitized by P-AscH-. These data support the hypothesis that P-AscH- does not enhance DIPG radiosensitivity, likely due to a robust capacity to detoxify and remove hydroperoxides., (©2023 by Radiation Research Society. All rights of reproduction in any form reserved.)

Background: Neuromuscular blocking agents are one of the few medication classes that have demonstrated a clinical benefit in patients with severe acute respiratory distress syndrome (ARDS). However, most literature utilized cisatracurium, and utilization of atracurium is limited to 1 small study. Objective: The purpose of this study was to provide further evidence comparing the safety and efficacy of atracurium versus cisatracurium for the treatment of ARDS. Methods: This multicenter, retrospective, observational cohort noninferiority study was conducted at 3 hospitals within a tertiary health care system. We included subjects diagnosed with ARDS who received either atracurium or cisatracurium for at least 12 hours. The primary outcome measured the change in PaO 2 /FiO 2 (P/F) ratio from baseline to 48 hours after initiation. Results: Baseline characteristics were similar between groups except for a higher median age and a higher proportion of subjects who were COVID-positive in the atracurium group. There were also some noted differences in the baseline P/F ratios. In a multivariable model adjusting for baseline characteristics, the change in the P/F ratio for atracurium was noninferior to cisatracurium at 24, 48, and 72 hours. A significant cost reduction, measured as cost per patient per day, was seen with the use of atracurium ($14.81-$25.16 vs $33.86-$41.91). Conclusion: Atracurium appears to be a safe and cheaper alternative agent in the management of ARDS., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Cisplatin, a potent chemotherapeutic agent, is marred by severe nephrotoxicity that is governed by mechanisms involving oxidative stress, inflammation, and apoptosis pathways. The transcription factor Nrf2, pivotal in cellular defense against oxidative stress and inflammation, is the master regulator of the antioxidant response, upregulating antioxidants and cytoprotective genes under oxidative stress. This review discusses the mechanisms underlying chemotherapy-induced kidney injury, focusing on the role of Nrf2 in cancer therapy and its redox regulation in cisplatin-induced kidney injury. We also explore Nrf2's signaling pathways, post-translational modifications, and its involvement in autophagy, as well as examine redox-based strategies for modulating Nrf2 in cisplatin-induced kidney injury while considering the limitations and potential off-target effects of Nrf2 modulation. Understanding the redox regulation of Nrf2 in cisplatin-induced kidney injury holds significant promise for developing novel therapeutic interventions. This knowledge could provide valuable insights into potential strategies for mitigating the nephrotoxicity associated with cisplatin, ultimately enhancing the safety and efficacy of cancer treatment.

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., (© 2023 Pharmacotherapy Publications, Inc.)

A distinctive feature of cancer is the upregulation of sirtuin proteins. Sirtuins are class III NAD+-dependent deacetylases involved in cellular processes such as proliferation and protection against oxidative stress. SIRTs 1 and 2 are also overexpressed in several types of cancers including non-small cell lung cancer (NSCLC). Sirtinol, a sirtuin (SIRT) 1 and 2 specific inhibitor, is a recent anti-cancer agent that is cytotoxic against several types of cancers including NSCLC. Thus, sirtuins 1 and 2 represent valuable targets for cancer therapy. Recent studies show that sirtinol functions as a tridentate iron chelator by binding Fe3+ with 3:1 stoichiometry. However, the biological consequences of this function remain unexplored. Consistent with preliminary literature, we show that sirtinol can deplete intracellular labile iron pools in both A549 and H1299 non-small cell lung cancer cells acutely. Interestingly, a temporal adaptive response occurs in A549 cells as sirtinol enhances transferrin receptor stability and represses ferritin heavy chain translation through impaired aconitase activity and apparent IRP1 activation. This effect was not observed in H1299 cells. Holo-transferrin supplementation significantly enhanced colony formation in A549 cells while increasing sirtinol toxicity. This effect was not observed in H1299 cells. The results highlight the fundamental genetic differences that may exist between H1299 and A549 cells and offer a novel mechanism of how sirtinol kills NSCLC cells., 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 Petronek, Bayanbold, Amegble, Tomanek-Chalkley, Allen, Spitz and Bailey.)

Chronic kidney disease (CKD) predisposes one toward end-stage renal disease (ESRD) and its associated morbidity and mortality. Significant metabolic perturbations in conjunction with alterations in redox status during CKD may induce increased production of reactive oxygen species (ROS), including superoxide (O 2 ●- ) and hydrogen peroxide (H 2 O 2 ). Increased O 2 ●- and H 2 O 2 may contribute to the overall progression of renal injury as well as catalyze the onset of comorbidities. In this review, we discuss the role of mitochondrial oxidative metabolism in the pathology of CKD and the recent developments in treating CKD progression specifically targeted to the mitochondria. Recently published results from a Phase 2b clinical trial by our group as well as recently released data from a ROMAN: Phase 3 trial (NCT03689712) suggest avasopasem manganese (AVA) may protect kidneys from cisplatin-induced CKD. Several antioxidants are under investigation to protect normal tissues from cancer-therapy-associated injury. Although many of these antioxidants demonstrate efficacy in pre-clinical models, clinically relevant novel compounds that reduce the severity of AKI and delay the progression to CKD are needed to reduce the burden of kidney disease. In this review, we focus on the various metabolic pathways in the kidney, discuss the role of mitochondrial metabolism in kidney disease, and the general involvement of mitochondrial oxidative metabolism in CKD progression. Furthermore, we present up-to-date literature on utilizing targets of mitochondrial metabolism to delay the pathology of CKD in pre-clinical and clinical models. Finally, we discuss the current clinical trials that target the mitochondria that could potentially be instrumental in advancing the clinical exploration and prevention of CKD., Competing Interests: The authors declare no conflicts of interest.

Purpose: Peripherally acting μ-opioid receptor antagonists (PAMORAs) are indicated to treat laxative-refractory opioid-induced constipation (OIC). While several PAMORAs exist, no head-to-head comparative data are available. This study evaluated the efficacy, safety, and cost of oral naloxegol vs subcutaneous methylnaltrexone for OIC in the hospital., Methods: In this multicenter retrospective chart review, patients who received oral naloxegol or subcutaneous methylnaltrexone as an inpatient were included if they were at least 18 years old, were still admitted to the hospital 48 hours after the first PAMORA dose, and either had an outpatient opioid prescription or received at least 30 morphine milligram equivalents in the 24 hours before the first PAMORA dose. The primary outcome was achievement of a bowel movement (BM) within 48 hours of the first dose. Secondary outcomes included a BM in 24 hours, time to the first BM, antimotility agent use, PAMORA cost per patient, and use of a second PAMORA due to failure of the first agent., Results: A total of 330 patients were included with 2:1 allocation (220 patients receiving methylnaltrexone vs 110 patients receiving naloxegol). Baseline characteristics were similar between the groups, except for body mass index and weight. Naloxegol met a prespecified noninferiority margin of 15% in production of a BM within 48 hours (risk difference, -4.6%; 90% confidence interval, -13.6% to 4.5%; P = 0.028). Achievement of a BM within 24 hours and time to first BM were also noninferior. Antimotility agent use was higher with naloxegol, naloxegol cost $193.16 less per patient, and 2 patients switched from naloxegol to methylnaltrexone., Conclusion: Oral naloxegol may be an effective, cost-efficient alternative to subcutaneous methylnaltrexone for treatment of OIC in the hospital setting., (© American Society of Health-System Pharmacists 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The study aims to create a model to predict survival outcomes for non-small cell lung cancer (NSCLC) after treatment with stereotactic body radiotherapy (SBRT) using deep-learning segmentation based prognostication (DESEP)., Methods: The DESEP model was trained using imaging from 108 patients with NSCLC with various clinical stages and treatment histories. The model generated predictions based on unsupervised features learned by a deep-segmentation network from computed tomography imaging to categorize patients into high and low risk groups for overall survival (DESEP-predicted-OS), disease specific survival (DESEP-predicted-DSS), and local progression free survival (DESEP-predicted-LPFS). Serial assessments were also performed using auto-segmentation based volumetric RECISTv1.1 and computer-based unidimensional RECISTv1.1 patients was performed., Results: There was a concordance between the DESEP-predicted-LPFS risk category and manually calculated RECISTv1.1 (φ=0.544, p=0.001). Neither the auto-segmentation based volumetric RECISTv1.1 nor the computer-based unidimensional RECISTv1.1 correlated with manual RECISTv1.1 (p=0.081 and p=0.144, respectively). While manual RECISTv1.1 correlated with LPFS (HR=6.97,3.51-13.85, c=0.70, p<0.001), it could not provide insight regarding DSS (p=0.942) or OS (p=0.662). In contrast, the DESEP-predicted methods were predictive of LPFS (HR=3.58, 1.66-7.18, c=0.60, p<0.001), OS (HR=6.31, 3.65-10.93, c=0.71, p<0.001) and DSS (HR=9.25, 4.50-19.02, c=0.69, p<0.001). The promising results of the DESEP model were reproduced for the independent, external datasets of Stanford University, classifying survival and 'dead' group in their Kaplan-Meyer curves (p = 0.019)., Conclusion: Deep-learning segmentation based prognostication can predict LPFS as well as OS, and DSS after SBRT for NSCLC. It can be used in conjunction with current standard of care, manual RECISTv1.1 to provide additional insights regarding DSS and OS in NSCLC patients receiving SBRT., Summary: While current standard of care, manual RECISTv1.1 correlated with local progression free survival (LPFS) (HR=6.97,3.51-13.85, c=0.70, p<0.001), it could not provide insight regarding disease specific survival (DSS) (p=0.942) or overall survival (OS) (p=0.662). In contrast, the deep-learning segmentation based prognostication (DESEP)-predicted methods were predictive of LPFS (HR=3.58, 1.66-7.18, c=0.60, p<0.001), OS (HR=6.31, 3.65-10.93, c=0.71, p<0.001) and DSS (HR=9.25, 4.50-19.02, c=0.69, p<0.001). DESEP can be used in conjunction with current standard of care, manual RECISTv1.1 to provide additional insights regarding DSS and OS in NSCLC patients., 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 Gainey, He, Zhu, Baek, Wu, Buatti, Allen, Smith and Kim.)

Background: Although not mentioned in the most recent guidelines, the 2016 Surviving Sepsis Campaign guidelines recommend to taper corticosteroids once vasopressors are no longer needed; however, at the time of publication, there were no studies comparing taper versus abrupt discontinuation of corticosteroids., Objectives: The purpose of this study was to further evaluate the impact of abrupt versus taper discontinuation of corticosteroids in septic shock., Methods: This was a retrospective cohort study that included patients who received an initial dose of 200 to 300 mg of hydrocortisone for septic shock. Participants were then divided into "abrupt" and "taper" groups. The primary outcome assessed was hemodynamic instability during taper or within 72 hours of the last corticosteroid dose. Secondary outcomes included intensive care unit (ICU) and hospital length of stay, incidence of hyperglycemia or hypernatremia, and in-hospital mortality., Results: The primary outcome of reinitiation of vasopressor therapy occurred in a larger proportion of patients in the taper group compared with the abrupt group (21.9% vs 10.7%). The ICU length of stay (7.6 days abrupt vs 9 days taper) and hospital length of stay (14.9 vs 15.3 days) were similar between groups. There was a statistically significant increase in patients who experienced hyperglycemia within 24 hours of the last corticosteroid dose in the abrupt group. All other secondary outcomes were similar between groups., Conclusions: The abrupt discontinuation of hydrocortisone in the treatment of septic shock was associated with a nonstatistically significant 50% absolute reduction in the need for vasopressor reinitiation.

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 H 2 O 2 -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 H 2 O 2 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 H 2 O 2 -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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to evaluate the effect of early intravenous (IV) calcium on systolic blood pressure (SBP) when administered with IV diltiazem in subjects with atrial fibrillation (AF) or flutter (AFL) with rapid ventricular response (RVR) in the Emergency Department (ED)., Methods: This was a multicenter, retrospective cohort study that evaluated adults admitted to the ED with documented AF or AFL, heart rate (HR) > 120 bpm, SBP 90 to 140 mmHg, and received treatment with IV diltiazem for rate control. The primary outcome was the change in SBP 60 min (+/- 30 min) after initial IV diltiazem administration. Secondary outcomes included time to initial rate control (HR < 100 bpm), time to sustained rate control (HR < 100 bpm for 3 h), change in HR, rates of hypotension, bradycardia, hypercalcemia, and line extravasation within 24 h of initial diltiazem administration., Results: There were 198 subjects in the diltiazem monotherapy group and 56 subjects in the diltiazem with calcium group meeting the inclusion criteria. The primary outcome, median change in SBP 60 min after initial IV diltiazem administration, was similar between groups (-2 mmHg vs -1.5 mmHg; p = 0.642), but this difference was not statistically significant. All secondary outcomes were found to be similar between groups. Although not statistically significant, hypotension occurred more often in the diltiazem with calcium group (20.2% vs 32.1%; p = 0.060) while bradycardia occurred more often in the diltiazem monotherapy group (4.5% vs 0%; p = 0.213). In terms of achieving rate control, the administration of calcium with diltiazem did not significantly change the time to initial rate control (1.4 h vs 1.8 h; p = 0.141) or time to sustained rate control (7.9 h vs 7.7 h; p = 0.570) compared to diltiazem alone., Conclusions: In the setting of AF/AFL with RVR, administration of IV calcium with IV diltiazem did not show a significant impact on clinical or safety outcomes compared to IV diltiazem monotherapy., Competing Interests: Declaration of Competing Interest The authors of this manuscript declare there are no known financial and personal relationships with other people or organizations that could be viewed as inappropriately influencing this work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Tubular metabolism changes markedly following acute kidney injury (AKI), but which changes are adaptive versus maladaptive remain poorly understood. In publicly available data sets, we noticed a consistent downregulation of the mitochondrial pyruvate carrier (MPC) after AKI, which we experimentally confirmed. To test the functional consequences of MPC downregulation, we generated novel tubular epithelial cell-specific Mpc1 knockout (MPC TubKO) mice. 13 C-glucose tracing, steady-state metabolomic profiling, and enzymatic activity assays revealed that MPC TubKO coordinately increased activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, MPC TubKO decreased markers of kidney injury and oxidative damage and strikingly increased survival. Our findings suggest that decreased mitochondrial pyruvate uptake is a central adaptive response following AKI and raise the possibility of therapeutically modulating the MPC to attenuate AKI severity., Competing Interests: COMPETING INTERESTS The authors declare no competing interests.

Background: Reactive oxygen species (ROS) contribute to platelet hyperactivation during aging. Several oxidative pathways and antioxidant enzymes have been implicated; however, their mechanistic contributions during aging remain elusive. We hypothesized that mitochondria are an important source of platelet ROS and that mitochondrial SOD2 (superoxide dismutase) protects against mitochondrial ROS-driven platelet activation and thrombosis during aging., Methods: We studied littermates of platelet-specific SOD2-knockout (SOD2 fl/fl Pf4Cre, pSOD2-KO) and control (SOD2 fl/fl ) mice at young (4-5 months) or old (18-20 months) ages. We examined agonist-induced platelet activation, platelet-dependent thrombin generation potential, and susceptibility to in vivo thrombosis., Results: Platelet α II b β3 activation, aggregation, and adhesion were increased to similar extents in aged mice of both genotypes compared with young mice. In contrast, the age-dependent increases in mitochondrial and total cellular ROS, calcium elevation, and phosphatidylserine exposure were augmented in platelets from pSOD2-KO mice compared with control mice. Aged pSOD2-KO mice showed increased platelet-dependent thrombin generation compared with aged control mice. In vivo, aged pSOD2-KO mice exhibited enhanced susceptibility to carotid artery and pulmonary thrombosis compared to aged control mice. Adoptive transfer of platelets from aged pSOD2-KO but not aged control mice increased thrombotic susceptibility in aged host mice, suggesting a prothrombotic effect of platelet pSOD2 deficiency. Treatment with avasopasem manganese (GC4419), a SOD mimetic, decreased platelet mitochondrial pro-oxidants, cellular ROS levels, and inhibited procoagulant platelet formation and arterial thrombosis in aged mice., Conclusions: Platelet mitochondrial ROS contributes to age-related thrombosis and endogenous SOD2 protects from platelet-dependent thrombin generation and thrombosis during aging.

Background We compared cardiac outcomes for surgery-eligible patients with stage III non-small-cell lung cancer treated adjuvantly or neoadjuvantly with chemotherapy versus chemo-radiation therapy in the Surveillance, Epidemiology and End Results-Medicare database. Methods and Results Patients were age 66+, had stage IIIA/B resectable non-small-cell lung cancer diagnosed between 2007 and 2015, and received adjuvant or neoadjuvant chemotherapy or chemo-radiation within 121 days of diagnosis. Patients having chemo-radiation and chemotherapy only were propensity-score matched and followed from day 121 to first cardiac outcome, noncardiac death, radiation initiation by patients who received chemotherapy only, fee-for-service enrollment interruption, or December 31, 2016. Cause-specific hazard ratios (HRs) and competing risks subdistribution HRs were estimated. The primary outcome was the first of these severe cardiac events: acute myocardial infarction, other hospitalized ischemic heart disease, hospitalized heart failure, percutaneous coronary intervention/coronary artery bypass graft, cardiac death, or urgent/inpatient care for pericardial disease, conduction abnormality, valve disorder, or ischemic heart disease. With median follow-up of 13 months, 70 of 682 patients who received chemo-radiation (10.26%) and 43 of 682 matched patients who received chemotherapy only (6.30%) developed a severe cardiac event ( P =0.008) with median time to first event 5.45 months. Chemo-radiation increased the rate of severe cardiac events (cause-specific HR: 1.62 [95% CI, 1.11-2.37] and subdistribution HR: 1.41 [95% CI, 0.97-2.04]). Cancer severity appeared greater among patients who received chemo-radiation (noncardiac death cause-specific HR, 2.53 [95% CI, 1.93-3.33] and subdistribution HR, 2.52 [95% CI, 1.90-3.33]). Conclusions Adding radiation therapy to chemotherapy is associated with an increased risk of severe cardiac events among patients with resectable stage III non-small-cell lung cancer for whom survival benefit of radiation therapy is unclear.

Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically targetable tumor, and 23% for the complete tumor extent, over a publicly trained model. We anticipate our study to: 1) enable more healthcare studies informed by large diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further analyses for glioblastoma by releasing our consensus model, and 3) demonstrate the FL effectiveness at such scale and task-complexity as a paradigm shift for multi-site collaborations, alleviating the need for data-sharing., (© 2022. The Author(s).)

Pharmacological ascorbate (i.e., intravenous infusions of vitamin C reaching ~ 20 mM in plasma) is under active investigation as an adjuvant to standard of care anti-cancer treatments due to its dual redox roles as an antioxidant in normal tissues and as a prooxidant in malignant tissues. Immune checkpoint inhibitors (ICIs) are highly promising therapies for many cancer patients but face several challenges including low response rates, primary or acquired resistance, and toxicity. Ascorbate modulates both innate and adaptive immune functions and plays a key role in maintaining the balance between pro and anti-inflammatory states. Furthermore, the success of pharmacological ascorbate as a radiosensitizer and a chemosensitizer in pre-clinical studies and early phase clinical trials suggests that it may also enhance the efficacy and expand the benefits of ICIs., 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 © 2022 Zaher, Stephens, Miller, Hartwig, Stolwijk, Petronek, Zacharias, Wadas, Monga, Cullen, Furqan, Houtman, Varga, Spitz and Allen.)

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Authors and Editor-in-Chief. Some of the data presented in Figure 6C, F and G of the paper to which this corrigendum relates were reported incorrectly in the published article. After being contacted by the Journal, the authors discovered an unintentional error in how the original data were analyzed that could affect the accuracy of the subsequent analysis. The raw data were incorrectly grouped in the analysis software, thereby altering the comparisons. Therefore the authors wish to retract the paper and corrigendum and will recollect and reanalyze the data appropriately. The authors apologize for any inconvenience., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Polyoxometalate nanoparticles (POMs) are a class of compounds made up of multiple transition metals linked together using oxygen atoms. POMs commonly include group 6 transition metals, with two of the most common forms using molybdenum and tungsten. POMs are suggested to exhibit antimicrobial effects. In this study, we developed two POM preparations to study anti-cancer activity. We found that Mo-POM (NH 4 )Mo 7 O 24 ) and W-POM (H 3 PW 12 O 40 ) have anti-cancer effects on glioblastoma cells. Both POMs induced morphological changes marked by membrane swelling and the presence of multinucleated cells that may indicate apoptosis induction along with impaired cell division. We also observed significant increases in lipid oxidation events, suggesting that POMs are redox-active and can catalyze detrimental oxidation events in glioblastoma cells. Here, we present preliminary indications that molybdenum polyoxometalate nanoparticles may act like ferrous iron to catalyze the oxidation of phospholipids. These preliminary results suggest that Mo-POMs (NH 4 )Mo 7 O 24 ) and W-POMs (H 3 PW 12 O 40 ) may warrant further investigation into their utility as adjunct cancer therapies.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Authors and Editor-in-Chief. Some of the data presented in Figure 6C, F and G of the above-titled paper were reported incorrectly in the published article. After being contacted by the Journal, the authors discovered an unintentional error in how the original data were analyzed that could affect the accuracy of the subsequent analysis. The raw data were incorrectly grouped in the analysis software, thereby altering the comparisons. Therefore the authors wish to retract the paper and will recollect and reanalyze the data appropriately. The authors apologize for any inconvenience., (Published by Elsevier Inc.)

Purpose: Platinum-based chemotherapy with or without immunotherapy is the mainstay of treatment for advanced stage non-small cell lung cancer (NSCLC) lacking a molecular driver alteration. Pre-clinical studies have reported that pharmacological ascorbate (P-AscH-) enhances NSCLC response to platinum-based therapy. We conducted a phase II clinical trial combining P-AscH- with carboplatin-paclitaxel chemotherapy., Experimental Design: Chemotherapy naïve advanced stage NSCLC patients received 75 g ascorbate twice per week intravenously with carboplatin and paclitaxel every three weeks for four cycles. The primary endpoint was to improve tumor response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 compared to the historical control of 20%. The trial was conducted as an optimal Simon's two-stage design. Blood samples were collected for exploratory analyses., Results: The study enrolled 38 patients and met its primary endpoint with an objective response rate of 34.2% (p = 0.03). All were confirmed partial responses (cPR). The disease control rate was 84.2% (stable disease + cPR). Median progression-free and overall survival were 5.7 months and 12.8 months, respectively. Treatment-related adverse events (TRAE) included one grade 5 (neutropenic fever) and five grade 4 events (cytopenias). Cytokine and chemokine data suggest that the combination elicits an immune response. Immunophenotyping of peripheral blood mononuclear cells demonstrated an increase in effector CD8 T-cells in patients with a progression-free survival (PFS) ≥ 6 months., Conclusions: The addition of P-AscH- to platinum-based chemotherapy improved tumor response in advanced stage NSCLC. P-AscH- appears to alter the host immune response and needs further investigation as a potential adjuvant to immunotherapy., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cancer cells often have altered iron metabolism relative to non-malignant cells with increased transferrin receptor and ferritin expression. Targeting iron regulatory proteins as part of a cancer therapy regimen is currently being investigated in various malignancies. Anti-cancer therapies that exploit the differences in iron metabolism between malignant and non-malignant cells (e.g. pharmacological ascorbate and iron chelation therapy) have shown promise in various cancers, including glioblastoma, lung, and pancreas cancers. Non-invasive techniques that probe tissue iron metabolism may provide valuable information for the personalization of iron-based cancer therapies. T 2 * mapping is a clinically available MRI technique that assesses tissue iron content in the heart and liver. We aimed to investigate the capacity of T 2 * mapping to detect iron stores in soft tissue sarcomas (STS)., Methods: In this study, we evaluated T 2 * relaxation times ex vivo in five STS samples from subjects enrolled on a phase Ib/IIa clinical trial combining pharmacological ascorbate with neoadjuvant radiation therapy. Iron protein expression levels (ferritin, transferrin receptor, iron response protein 2) were evaluated by Western blot analysis. Bioinformatic data relating clinical outcomes in STS patients and iron protein expression levels were evaluated using the KMplotter database., Results: There was a high level of inter-subject variability in the expression of iron protein and T 2 * relaxation times. We identified that T 2 * relaxation time is capable of accurately detecting ferritin-heavy chain expression (r = -0.96) in these samples. Bioinformatic data acquired from the KMplot database revealed that transferrin receptor and iron-responsive protein 2 may be negative prognostic markers while ferritin expression may be a positive prognostic marker in the management of STS., Conclusion: These data suggest that targeting iron regulatory proteins may provide a therapeutic approach to enhance STS management. Additionally, T 2 * mapping has the potential to be used a clinically accessible, non-invasive marker of STS iron regulatory protein expression and influence cancer therapy decisions that warrants further investigation. Level of Evidence: IV ., (Copyright © The Iowa Orthopaedic Journal 2022.)

Ferumoxytol (FMX) is an iron oxide nanoparticle that is FDA approved for the treatment of iron deficiency anemia. FMX contains an Fe3O4 core. Currently, the redox chemistry of Fe3O4 nanoparticles remains relatively unexplored. FMX has recently gained interest as an anti-cancer agent. Ionizing radiation (IR) is a treatment modality employed to treat several types of cancer. Utilizing electron paramagnetic resonance (EPR) spectroscopy, we found that the products produced from the radiolysis of water can oxidize the Fe3O4 core of FMX. Because of the limited diffusion of the HO2• and HO• produced, these highly oxidizing species have little direct effect on FMX oxidation. We have determined that H2O2 is the primary oxidant of FMX. In the presence of labile Fe2+, we found that reducing species generated from the radiolysis of H2O are able to reduce the Fe3+ sites of the Fe3O4 core. Importantly, we also have shown that IR stimulates the release of ferric iron from FMX. Because of its release of iron, FMX may serve as an adjuvant to enhance radiotherapy., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Purpose: The radiobiological benefits afforded by spatially fractionated (GRID) radiation therapy pairs well with the dosimetric advantages of proton therapy. Inspired by the emergence of energy-layer specific collimators in pencil beam scanning (PBS), this work investigates how the spot spacing and collimation can be optimized to maximize the therapeutic gains of a GRID treatment while demonstrating the integration of a dynamic collimation system (DCS) within a commercial beamline to deliver GRID treatments and experimentally benchmark Monte Carlo calculation methods., Methods: GRID profiles were experimentally benchmarked using a clinical DCS prototype that was mounted to the nozzle of the IBA-dedicated nozzle system. Integral depth dose (IDD) curves and lateral profiles were measured for uncollimated and GRID-collimated beamlets. A library of collimated GRID dose distributions were simulated by placing beamlets within a specified uniform grid and weighting the beamlets to achieve a volume-averaged tumor cell survival equivalent to an open field delivery. The healthy tissue sparing afforded by the GRID distribution was then estimated across a range of spot spacings and collimation widths, which were later optimized based on the radiosensitivity of the tumor cell line and the nominal spot size of the PBS system. This was accomplished by using validated models of the IBA universal and dedicated nozzles., Results: Excellent agreement was observed between the measured and simulated profiles. The IDDs matched above 98.7% when analyzed using a 1%/1-mm gamma criterion with some minor deviation observed near the Bragg peak for higher beamlet energies. Lateral profile distributions predicted using Monte Carlo methods agreed well with the measured profiles; a gamma passing rate of 95% or higher was observed for all in-depth profiles examined using a 3%/2-mm criteria. Additional collimation was shown to improve PBS GRID treatments by sharpening the lateral penumbra of the beamlets but creates a trade-off between enhancing the valley-to-peak ratio of the GRID delivery and the dose-volume effect. The optimal collimation width and spot spacing changed as a function of the tumor cell radiosensitivity, dose, and spot size. In general, a spot spacing below 2.0 cm with a collimation less than 1.0 cm provided a superior dose distribution among the specific cases studied., Conclusions: The ability to customize a GRID dose distribution using different collimation sizes and spot spacings is a useful advantage, especially to maximize the overall therapeutic benefit. In this regard, the capabilities of the DCS, and perhaps alternative dynamic collimators, can be used to enhance GRID treatments. Physical dose models calculated using Monte Carlo methods were experimentally benchmarked in water and were found to accurately predict the respective dose distributions of uncollimated and DCS-collimated GRID profiles., (© 2022 American Association of Physicists in Medicine.)

Background: Multiple publications demonstrate an association between time to initiation of corticosteroids and outcomes such as mortality and reversal of shock. However, the optimal time to initiate hydrocortisone remains unknown., Objective: To evaluate the impact of early versus late initiation of hydrocortisone in septic shock patients., Methods: A retrospective, multicentered, observational study was conducted. Adults admitted from July 1, 2014, to August 31, 2019, diagnosed with septic shock receiving vasopressors and low-dose hydrocortisone were evaluated. Participants were divided into the "early" group if hydrocortisone was initiated within 12 hours or "late" group if initiated after 12 hours of vasopressor initiation. The primary outcome was time to vasopressor discontinuation. Secondary outcomes included in-hospital mortality, intensive care unit (ICU) and hospital length of stay (LOS), vasopressor utilization, fluids administered, and need for renal replacement therapy., Results: A total of 198 patients were identified for inclusion in this propensity score-weighted cohort: 99 in the early group and 99 in the late group. Early initiation was associated with shorter time to vasopressor discontinuation compared with late initiation (40.7 vs 60.6 hours; P = 0.0002). There was also a reduction in ICU LOS (3.6 vs 5.1 days; P = 0.0147) and hospital LOS (8.9 vs 10.9 days; P = 0.0220) seen in the early group. There was no difference in mortality between groups., Conclusion and Relevance: In this propensity-matched cohort, administration of hydrocortisone within 12 hours from the onset of septic shock was associated with improved time to vasopressor discontinuation and reduced ICU and hospital LOS.

Background: Acute decompensated heart failure (ADHF) can present similarly to pulmonary infections. The additional volume and sodium received from intravenous antibiotics (IVAB) can be counterproductive, especially when strong evidence of infection is lacking., Objective: The objective was to evaluate the impact of potentially unwarranted IVAB on clinical outcomes in patients with ADHF., Methods: This multicenter, retrospective, cohort study evaluated adults admitted with ADHF, a chest radiograph within 24 hours, B-natriuretic peptide >100 pg/mL, and either received no IVAB or IVAB for at least 48 hours. Subjects with recent antibiotics, justification for antibiotics, or transferred to the intensive care unit (ICU) within 24 hours of admission were excluded. The primary outcome was hospital length of stay (LOS). Secondary outcomes included utilization of loop diuretics, administration of fluid and sodium, mortality, and 30-day readmissions., Results: Out of 240 subjects included, 120 received IVAB. LOS was significantly longer in the IVAB group (5.12 days vs 3.73 days; P < .001). LOS remained significantly longer in the IVAB group in a propensity score matched cohort (5.26 days vs 3.70 days; P < .001). The IVAB group received more volume and sodium from intravenous fluids ( P < .001). ICU admission greater than 24 hours after admission was higher with IVAB (20% vs 7.5%; P = .049). No significant differences in total loop diuretics, intubation rate, mortality, and 30-day readmissions were identified., Conclusion: ADHF patients who received potentially unwarranted IVAB had longer hospital LOS and were more likely to be admitted to the ICU after 24 hours of hospitalization., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Interest in the use of pharmacological ascorbate as a treatment for cancer has increased considerably since it was introduced by Cameron and Pauling in the 1970s. Recently, pharmacological ascorbate has been used in preclinical and early-phase clinical trials as a selective radiation sensitizer in cancer. The results of these studies are promising. This review summarizes data on pharmacological ascorbate (1) as a safe and efficacious adjuvant to cancer therapy; (2) as a selective radiosensitizer of cancer via a mechanism involving hydrogen peroxide; and (3) as a radioprotector in normal tissues. Additionally, we present new data demonstrating the ability of pharmacological ascorbate to enhance radiation-induced DNA damage in glioblastoma cells, facilitating cancer cell death. We propose that pharmacological ascorbate may be a general radiosensitizer in cancer therapy and simultaneously a radioprotector of normal tissue.

Purpose: The objective of this study was to examine feasibility of single- or hypo-fraction of high-dose-rate (HDR) electronic brachytherapy (eBT) in uveal melanoma treatment., Material and Methods: Biologically effective doses (BED) of organs at risk (OARs) were compared to those of iodine-125-based eye plaque low-dose-rate brachytherapy ( 125 I LDR-BT) with vitreous replacement (VR). Single- or hypo-fractionated equivalent physical doses (SFEDs or HFEDs) for tumor were calculated from tumor BED of 125 I LDR-BT using linear-quadratic (LQ) and universal survival curve (USC) models. BED OARs doses to retina opposite the implant, macula, optic disc, and lens were calculated and compared among SFED, HFED, and 125 I LDR-BT. Electronic BT of 50 kVp was considered assuming dose fall-off as clinically equivalent to 125 I LDR-BT. All OARs BEDs were analyzed with and without silicone oil VR., Results: For a single-fraction incorporating VR, the median/interquartile range of LQ (USC)-based BED doses of the retina opposite the implant, macula, optic disc, and lens were 16%/1.2% (33%/4%), 35%/19.5% (64%/17.7%), 37%/19% (75%/17.8%), and 27%/7.9% (68%/23.2%) of those for 125 I LDR-BT, respectively. SFED tumor values were 29.8/0.2 Gy and 51.7/0.5 Gy when using LQ and USC models, respectively, which could be delivered within 1 hour. SFED can be delivered within 1 hour using a high-dose-rate eBT. Even four-fraction delivery of HFED without VR resulted in higher OARs doses in the macula, optic disc, and lens (135 ~ 159%) than when using 125 I LDR-BT technique. A maximum p -value of 0.005 was observed for these distributions., Conclusions: The simulation of single-fraction eBT, including vitreous replacement, resulted in significantly reduced OARs doses (16 ~ 75%) of that achieved with 125 I LDR-BT., Competing Interests: The authors report no conflict of interest., (Copyright © 2021 Termedia.)

Cancer cells preferentially accumulate iron (Fe) relative to non-malignant cells; however, the underlying rationale remains elusive. Iron-sulfur (Fe-S) clusters are critical cofactors that aid in a wide variety of cellular functions (e.g., DNA metabolism and electron transport). In this article, we theorize that a differential need for Fe-S biogenesis in tumor versus non-malignant cells underlies the Fe-dependent cell growth demand of cancer cells to promote cell division and survival by promoting genomic stability via Fe-S containing DNA metabolic enzymes. In this review, we outline the complex Fe-S biogenesis process and its potential upregulation in cancer. We also discuss three therapeutic strategies to target Fe-S biogenesis: (i) redox manipulation, (ii) Fe chelation, and (iii) Fe mimicry.

Introduction: Management of massive pulmonary embolism in patients with hemodynamic instability encompasses the use of fibrinolytics. Use of fibrinolytic therapy is currently recommended in this patient population by ACCP, AHA, and EHA if treatment benefit outweighs the risk of bleeding. There is currently no data challenging or exploring the risk of using fibrinolytic therapy for the management of massive PE in patients with a history of intracranial hemorrhage., Case Presentation: A 38-year old female with suspected massive pulmonary embolism was admitted with a chief complaint of chest pain and right leg pain. Shortly after a confirmatory CT of bilateral PE, the patient had multiple cardiac arrests along with severe shock that led to a general agreement among the team to proceed with IV and then catheter-directed TPA as well as thrombectomy. Following fibrinolytic therapy, the patient was started on a heparin drip along with epinephrine for hemodynamic support. CT chest angiography showed the resolution of emboli following treatment with the fibrinolytic agent. CT of the head taken approximately 24 h post tPA initiation was used to rule out intracranial hemorrhage or other complications resulting from tPA administration., Conclusion: In patients with a history of intracranial hemorrhage, catheter guided fibrinolytic and thrombectomy may be effective treatment options of massive pulmonary embolism., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cisplatin is a chemotherapy agent commonly used to treat a wide variety of cancers. Despite the potential for both severe acute and chronic side effects, it remains a preferred therapeutic option for many malignancies due to its potent anti-tumor activity. Common cisplatin-associated side-effects include acute kidney injury (AKI) and chronic kidney disease (CKD). These renal injuries may cause delays and potentially cessation of cisplatin therapy and have long-term effects on renal function reserve. Thus, developing mechanism-based interventional strategies that minimize cisplatin-associated kidney injury without reducing efficacy would be of great benefit. In addition to its action of cross-linking DNA, cisplatin has been shown to affect mitochondrial metabolism, resulting in mitochondrially derived reactive oxygen species (ROS). Increased ROS formation in renal proximal convoluted tubule cells is associated with cisplatin-induced AKI and CKD. We review the mechanisms by which cisplatin may induce AKI and CKD and discuss the potential of mitochondrial superoxide dismutase mimetics to prevent platinum-associated nephrotoxicity.