Electronic isomerism in a heterometallic nickel-iron-sulfur cluster models substrate binding and cyanide inhibition of carbon monoxide dehydrogenase.

The nickel-iron carbon monoxide dehydrogenase (CODH) enzyme uses a heterometallic nickel-iron-sulfur ([NiFe4S4]) cluster to catalyze the reversible interconversion of carbon dioxide (CO2) and carbon monoxide (CO). These reactions are essential for maintaining the global carbon cycle and offer a route towards sustainable greenhouse gas conversion but have not been successfully replicated in synthetic models, in part due to a poor understanding of the natural system. Though the general protein architecture of CODH is known, the electronic structure of the active site is not well-understood, and the mechanism of catalysis remains unresolved. To better understand the CODH enzyme, we have developed a protein-based model containing a heterometallic [NiFe3S4] cluster in the Pyrococcus furiosus (Pf) ferredoxin (Fd). This model binds small molecules such as carbon monoxide and cyanide, analogous to CODH. Multiple redox- and ligand-bound states of [NiFe3S4] Fd (NiFd) have been investigated using a suite of spectroscopic techniques, including resonance Raman, Ni and Fe K-edge X-ray absorption spectroscopy, and electron paramagnetic resonance, to resolve charge and spin delocalization across the cluster, site-specific electron density, and ligand activation. The facile movement of charge through the cluster highlights the fluidity of electron density within iron-sulfur clusters and suggests an electronic basis by which CN- inhibits the native system while the CO-bound state continues to elude isolation in CODH. The detailed characterization of isolable states that are accessible in our CODH model system provides valuable insight into unresolved enzymatic intermediates and offers design principles towards developing functional mimics of CODH.

Hospital Price Transparency Rule Exposes Muddied Costs for Head and Neck Radiotherapy in One State.

OBJECTIVES: Financial toxicity due to cancer treatment is a significant concern for patients. To increase transparency related to treatment costs, the Hospital Price Transparency Final Rule (HPTFR) was passed on January 1, 2021. We used hospital pricing documentation to explore the costs of head and neck cancer (HNC) radiotherapy in Ohio, hypothesizing a large variance in cost based on geography. MATERIALS AND METHODS: Radiation oncology facilities were identified using the Ohio Hospital Association (OHA) website. The reported technical charges for Current Procedural Terminology (CPT) codes commonly billed in the definitive management of HNC with radiotherapy were recorded, and total treatment costs (TTCs) were calculated. RESULTS: Of 254 OHA-listed hospitals, 102 had radiation oncology facilities. Seven facilities were excluded due to a lack of pricing data, leaving 95 facilities in 40 of 88 counties. Median TTC was $176,496. Average TTC was $184,831 (SD: $83,982). The 22 rural hospitals charged less compared with nonrural hospitals, with a difference in medians of $72,084.38 (P<0.001). No difference was found between the TTCs of nonprofit and public hospitals (P=0.348) nor between academically affiliated and nonacademically affiliated hospitals (P=0.247). There is no correlation between county median household income and TTC (R2=0.0007). Rather, TTCs varied drastically across counties, regardless of income levels. CONCLUSIONS: There is a wide range of treatment costs for HNC patients receiving definitive radiotherapy in Ohio, and no variables fully explain this variance. Further policies are needed to improve the quality, quantity, and accessibility of health care data to address financial toxicity.

Reirradiation of Recurrent and Second Primary Cancers of the Head and Neck: a Review of the Contemporary Evidence.

OPINION STATEMENT: Recurrent and second primary head and neck cancers represent a clinical challenge due to frequently unresectable and/or locally advanced disease. Given that many of these patients have received definitive doses of radiation previously, reirradiation is associated with significant morbidity. Use of modern approaches such as conformal photon-based planning and charged particle therapy using protons or carbon ions allows for greater sparing of normal tissues while maintaining or escalating doses to tumor volumes. While the reirradiation data has consistently shown benefits to local control and even survival from escalation of radiotherapy dose, excessive cumulative doses can result in severe toxicities, including fatal carotid blowout syndrome. For all modalities, appropriate patient selection is of utmost importance. Large-scale trials and multi-institutional registry data are needed to standardize treatment modalities, and to determine optimal doses and volumes for reirradiation.

Normal tissue exposure and second malignancy risk in vertebral-body-sparing craniospinal irradiation.

The purpose of this study was to compare dose to anterior organs at risk (OARs) and quantify the risk of developing secondary malignancy (SMN) in pediatric patients treated with vertebral-body-sparing (VBS) vs vertebral body (VB) pencil beam scanning proton craniospinal irradiation (CSI). Comparative plans of VBS and VB CSI were created for 10 previously treated patients. Dose-volume histograms were used to evaluate dose to OARs. Absolute excess risk of SMN was calculated according to the organ-specific, radiation-induced cancer incidence based on the organ equivalent dose. OAR dosimetric parameters and absolute excess risk of SMN were compared for VBS and VB plans using the Kruskal-Wallis H test (α = 0.05). VBS CSI leads to significantly lower radiation dose to the heart, esophagus, kidney, liver and bowel. Excluding the vertebral body also significantly decreases the absolute excess risk of SMN for liver, esophagus and bowel. For these reasons, implementation of VBS pencil beam scanning proton CSI should be considered.

Enzyme Control Over Ferric Iron Magnetostructural Properties.

Fe3+ complexes in aqueous solution can exist as discrete mononuclear species or multinuclear magnetically coupled species. Stimuli-driven change to Fe3+ speciation represents a powerful mechanistic basis for magnetic resonance sensor technology, but ligand design strategies to exert precision control of aqueous Fe3+ magnetostructural properties are entirely underexplored. In pursuit of this objective, we rationally designed a ligand to strongly favor a dinuclear µ-oxo-bridged and antiferromagnetically coupled complex, but which undergoes carboxylesterase mediated transformation to a mononuclear high-spin Fe3+ chelate resulting in substantial T1 -relaxivity increase. The data communicated demonstrate proof of concept for a novel and effective strategy to exert biochemical control over aqueous Fe3+ magnetic, structural, and relaxometric properties.

Intensity Modulated Proton Therapy Better Spares Non-Adjacent Organs and Reduces the Risk of Secondary Malignant Neoplasms in the Treatment of Sinonasal Cancers.

This study compare dosimetric parameters and secondary malignancy risk (SMN) using intensity modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT) plans for the treatment of sinonasal cancer (SC). After IRB-approval, 10 patients previously treated with IMPT for cancers of the ethmoid, sphenoid, maxillary, or frontal sinuses were identified. Dosimetrists blinded to the IMPT plans generated VMAT plans for comparison. Volume coverage and dose to organs at risk (OAR) were recorded and compared. Organ equivalent dose (OED) of tissues outside of the treatment volume was used to define the excess absolute and relative risk of SMNs. In all cases, both VMAT and IMPT provided acceptable target volume coverage and were able to meet OAR constraints. IMPT was superior for brain V10, V30, and mean, brainstem D0.01 ipsilateral cochlea V30, contralateral cochlea mean, contralateral lacrimal gland mean, contralateral parotid mean, spinal cord D0.01 and body outside of the CTV V10, V20, and V30. VMAT was superior for ipsilateral eye mean, ipsilateral lens mean, CTV V100 and maximum hotspot. The relative risk of SMNs with VMAT compared to IMPT is 3.35 (95% CI, 1.92-5.89). For the treatment of SC, IMPT spares OARs that are not immediately adjacent to the treatment volume and reduces the risk of SMNs when compared to VMAT. VMAT spares OARs abutting the target volume better than IMPT and has more homogenous target coverage. Tumors of the ethmoid sinus, benefit more from IMPT, while tumors located elsewhere require application of our findings on a case by case basis.

Reversible Electron Transfer and Substrate Binding Support [NiFe3S4] Ferredoxin as a Protein-Based Model for [NiFe] Carbon Monoxide Dehydrogenase.

The nickel-iron carbon monoxide dehydrogenase (CODH) enzyme catalyzes the reversible and selective interconversion of carbon dioxide (CO2) to carbon monoxide (CO) with high rates and negligible overpotential. Despite decades of research, many questions remain about this complex metalloenzyme system. A simplified model enzyme could provide substantial insight into biological carbon cycling. Here, we demonstrate reversible electron transfer and binding of both CO and cyanide, a substrate and an inhibitor of CODH, respectively, in a Pyrococcus furiosus (Pf) ferredoxin (Fd) protein that has been reconstituted with a nickel-iron sulfide cluster ([NiFe3S4] Fd). The [NiFe3S4] cluster mimics the core of the native CODH active site and thus serves as a protein-based structural model of the CODH subsite. Notably, despite binding cyanide, no CO binding is observed for the physiological [Fe4S4] clusters in Pf Fd, providing chemical rationale underlying the evolution of a site-differentiated cluster for substrate conversion in native CODH. The demonstration of a substrate-binding metalloprotein model of CODH sets the stage for high-resolution spectroscopic and mechanistic studies correlating the subsite structure and function, ultimately guiding the design of anthropogenic catalysts that harness the advantages of CODH for effective CO2 reduction.

Rational Ligand Design Enables pH Control over Aqueous Iron Magnetostructural Dynamics and Relaxometric Properties.

Complexes of Fe3+ engage in rich aqueous solution speciation chemistry in which discrete molecules can react with solvent water to form multinuclear µ-oxo and µ-hydroxide bridged species. Here we demonstrate how pH- and concentration-dependent equilibration between monomeric and µ-oxo-bridged dimeric Fe3+ complexes can be controlled through judicious ligand design. We purposed this chemistry to develop a first-in-class Fe3+-based MR imaging probe, Fe-PyCy2AI, that undergoes relaxivity change via pH-mediated control of monomer vs dimer speciation. The monomeric complex exists in a S = 5/2 configuration capable of inducing efficient T1-relaxation, whereas the antiferromagnetically coupled dimeric complex is a much weaker relaxation agent. The mechanisms underpinning the pH dependence on relaxivity were interrogated by using a combination of pH potentiometry, 1H and 17O relaxometry, electronic absorption spectroscopy, bulk magnetic susceptibility, electron paramagnetic resonance spectroscopy, and X-ray crystallography measurements. Taken together, the data demonstrate that PyCy2AI forms a ternary complex with high-spin Fe3+ and a rapidly exchanging water coligand, [Fe(PyCy2AI)(H2O)]+ (ML), which can deprotonate to form the high-spin complex [Fe(PyCy2AI)(OH)] (ML(OH)). Under titration conditions of 7 mM Fe complex, water coligand deprotonation occurs with an apparent pKa 6.46. Complex ML(OH) dimerizes to form the antiferromagnetically coupled dimeric complex [(Fe(PyCy2AI))2O] ((ML)2O) with an association constant (Ka) of 5.3 ± 2.2 mM-1. The relaxivity of the monomeric complexes are between 7- and 18-fold greater than the antiferromagnetically coupled dimer at applied field strengths ranging between 1.4 and 11.7 T. ML(OH) and (ML)2O interconvert rapidly within the pH 6.0-7.4 range that is relevant to human pathophysiology, resulting in substantial observed relaxivity change. Controlling Fe3+ µ-oxo bridging interactions through rational ligand design and in response to local chemical environment offers a robust mechanism for biochemically responsive MR signal modulation.

Successful use of a therapeutic trial of graduated volume and dose escalation for postoperative head and neck radiotherapy in a Fanconi anemia patient.

BACKGROUND: Patients with the heritable disease, Fanconi anemia (FA), have a 500-fold risk of developing head and neck squamous cell carcinomas (HNSCC). However, the use of conventional cytotoxic agents including radiation therapy and cisplatin-based chemotherapy is contraindicated in patients with FA due to underlying DNA repair defects. METHODS/RESULTS: We present a young FA patient with recurrent HNSCC and high-risk pathologic features treated with a therapeutic trial of chemoradiation. This novel strategy employs a gentle radiation dose and volume escalation with concurrent pembrolizumab. The patient completed the entire course of therapy with no treatment delays or interruptions. CONCLUSIONS: The FA patient population has a clear need for adjuvant treatment regimens given their predilection for HNSCC. A therapeutic trial may allow FA and other radiosensitive patients to trial radiation with the option to terminate treatment before any severe side effects occur and for some to complete a full course of treatment.

The good, the neutral, and the positive: buffer identity impacts CO2 reduction activity by nickel(ii) cyclam.

Development of new synthetic catalysts for CO2 reduction has been a central focus of chemical research efforts towards mitigating rising global carbon dioxide levels. In parallel with generating new molecular systems, characterization and benchmarking of these compounds across well-defined catalytic conditions are essential. Nickel(ii) cyclam is known to be an active catalyst for CO2 reduction to CO. The degree of selectivity and activity has been found to differ widely across electrodes used and upon modification of the ligand environment, though without a molecular-level understanding of this variation. Moreover, while proton transfer is key for catalytic activity, the effects of varying the nature of the proton donor remain unclear. In this work, a systematic investigation of the electrochemical and light-driven catalytic behaviour of nickel(ii) cyclam under different aqueous reaction conditions has been performed. The activity and selectivity are seen to vary widely depending on the nature of the buffering agent, even at a constant pH, highlighting the importance of proton transfer for catalysis. Buffer binding to the nickel center is negatively correlated with selectivity, and cationic buffers show high levels of selectivity and activity. These results are discussed in the context of molecular design principles for developing increasingly efficient and selective catalysts. Moreover, identifying these key contributors towards activity has implications for understanding the role of the conserved secondary coordination environments in naturally occurring CO2-reducing enzymes, including carbon monoxide dehydrogenase and formate dehydrogenase.

Oxidative Stress in Youth and Adolescents With Elevated Body Mass Index Exposed to Secondhand Smoke.

INTRODUCTION: Our objective was to investigate the relationships between secondhand smoke (SHS) exposure and oxidative stress in a group of youth and adolescents with elevated body mass index. METHODS: Participants in this cross sectional study were healthy nonsmoking youth and adolescents ages 9 to 18 years old. Three-quarters of the participants were either overweight or obese. SHS exposure was determined by survey and hair nicotine level. Markers of oxidation were total antioxidant capacity and protein malondialdehyde adducts (MDA). RESULTS: Ninety subjects were studied; adequate hair samples were available for 86. The mean hair nicotine level was 0.75ng/mg, the median was 0.58ng/mg and the range was 0.09-2.88ng/mg. There was a significant relationship between MDA and the three survey questions regarding smoke exposure ([mother smokes, r = 0.29, P = .006], [smoker lives in the home, r = 0.31, P = .004], and [number of smokers in the home, r = 0.36, P = .002]). There was a significant positive relationship between log-hair nicotine and MDA (Pearson r = 0.233, P = .031), which remained significant after controlling for age, sex, race, and method of insurance. No relationship was found between log-hair nicotine and total antioxidant capacity. However, there was a significant relationship between number of smokers in the home (r = 0.24, P = .042) and total antioxidant capacity. CONCLUSIONS: We have demonstrated a significant positive relationship hair nicotine level and MDA in a group of youth with a high proportion of overweight/obese subjects. IMPLICATIONS: We have shown a significant relationship between objectively measured SHS exposure and one marker of oxidative stress in a sample of youth and adolescents with a high proportion of overweight/obese subjects, and who were nonsmokers with relatively low tobacco exposure. This finding remains significant after controlling for age, sex, race, and type of medical insurance. Since the cardiovascular effects of SHS exposure are related to oxidative stress, this finding adds to our knowledge that the sequence of deleterious effects of tobacco exposure on the cardiovascular system begins long before clinical disease is evident.