Copper(II) Ions Originating from CuBTC MOF Act as a Soluble Catalyst in the Friedländer Synthesis.

The copper-based metal-organic framework (MOF), CuBTC (where H3BTC = benzene-1,3,5-tricarboxylate), has been reported as a reusable heterogeneous catalyst for the Friedländer synthesis of substituted quinolines, which are desirable targets in the pharmaceutical industry. Because of this application, we further investigated the CuBTC-catalyzed Friedländer synthesis of 3-acetyl-2-methyl-4-phenylquinoline. CuBTC was synthesized in-house and used as a catalyst for the Friedländer synthesis. Fresh and used CuBTC were analyzed using scanning electron microscopy (SEM), powder X-ray diffraction (pXRD), and X-ray photoelectron spectroscopy (XPS). The used CuBTC shows structural breakdown in pXRD patterns and SEM images. Despite the structural breakdown, the desired product, 3-acetyl-2-methyl-4-phenylquinoline, is still produced in a moderate yield (76.3% ± 0.2), as confirmed via time-of-flight mass spectrometry and nuclear magnetic resonance spectroscopy. Inductively coupled plasma atomic emission spectroscopy of the recovered supernatant solution indicates the presence of copper(II) ions in solution. Thus, we hypothesized that the standard Friedländer conditions may degrade the CuBTC framework, resulting in copper(II) ions in solution. Control experiments with copper(II) from Cu(NO3)2·3H2O catalyzes the Friedländer reaction in yields (75.6% ± 0.1) equal to that of the CuBTC MOF. Overall, our findings suggest that CuBTC acts as a copper(II) source, and the copper(II) ions originating from the CuBTC MOF are responsible for the observed catalysis.

Mixed Metal-Organic Framework Mixed-Matrix Membranes: Insights into Simultaneous Moisture-Triggered and Catalytic Delivery of Nitric Oxide using Cryo-scanning Electron Microscopy.

The fundamental chemical and structural diversity of metal-organic frameworks (MOFs) is vast, but there is a lack of industrial adoption of these extremely versatile compounds. To bridge the gap between basic research and industry, MOF powders must be formulated into more application-relevant shapes and/or composites. Successful incorporation of varying ratios of two different MOFs, CPO-27-Ni and CuBTTri, in a thin polymer film represents an important step toward the development of mixed MOF mixed-matrix membranes. To gain insight into the distribution of the two different MOFs in the polymer, we report their investigation by Cryo-scanning electron microscopy (Cryo-SEM) tomography, which minimizes surface charging and electron beam-induced damage. Because the MOFs are based on two different metal ions, Ni and Cu, the elemental maps of the MOF composite cross sections clearly identify the size and location of each MOF in the reconstructed 3D model. The tomography run was about six times faster than conventional focused ion beam (FIB)-SEM and the first insights to image segmentation combined with machine learning could be achieved. To verify that the MOF composites combined the benefits of rapid moisture-triggered release of nitric oxide (NO) from CPO-27-Ni with the continuous catalytic generation of NO from CuBTTri, we characterized their ability to deliver NO individually and simultaneously. These MOF composites show great promise to achieve optimal dual NO delivery in real-world medical applications.

Computational Insights into the Mechanism of Nitric Oxide Generation from S-Nitrosoglutathione Catalyzed by a Copper Metal-Organic Framework.

The controlled generation of nitric oxide (NO) from endogenous sources, such as S-nitrosoglutathione (GSNO), has significant implications for biomedical implants due to the vasodilatory and other beneficial properties of NO. The water-stable metal-organic framework (MOF) Cu-1,3,5-tris[1H-1,2,3-triazol-5-yl]benzene has been shown to catalyze the production of NO and glutathione disulfide (GSSG) from GSNO in aqueous solution as well as in blood. Previous experimental work provided kinetic data for the catalysis of the 2GSNO → 2NO + GSSG reaction, leading to various proposed mechanisms. Herein, this catalytic process is examined using density functional theory. Minimal functional models of the Cu-MOF cluster and glutathione moieties are established, and three distinct catalytic mechanisms are explored. The most thermodynamically favorable mechanism studied is consistent with prior experimental findings. This mechanism involves coordination of GSNO to copper via sulfur rather than nitrogen and requires a reductive elimination that produces a Cu(I) intermediate, implicating a redox-active copper site. The experimentally observed inhibition of reactivity at high pH values is explained in terms of deprotonation of a triazole linker, which decreases the structural stability of the Cu(I) intermediate. These fundamental mechanistic insights may be generally applicable to other MOF catalysts for NO generation.

Preoperative Evaluation of Thyroid Cancer: A Review of Current Best Practices.

OBJECTIVE: The incidence of thyroid cancer has significantly increased in recent decades. Although most thyroid cancers are small and carry an excellent prognosis, a subset of patients present with advanced thyroid cancer, which is associated with increased rates of morbidity and mortality. The management of thyroid cancer requires a thoughtful individualized approach to optimize oncologic outcomes and minimize morbidity associated with treatment. Because endocrinologists usually play a key role in the initial diagnosis and evaluation of thyroid cancers, a thorough understanding of the critical components of the preoperative evaluation facilitates the development of a timely and comprehensive management plan. The following review outlines considerations in the preoperative evaluation of patients with thyroid cancer. METHODS: A clinical review based on current literature was generated by a multidisciplinary author panel. RESULTS: A review of considerations in the preoperative evaluation of thyroid cancer is provided. The topic areas include initial clinical evaluation, imaging modalities, cytologic evaluation, and the evolving role of mutational testing. Special considerations in the management of advanced thyroid cancer are discussed. CONCLUSION: Thorough and thoughtful preoperative evaluation is critical for formulating an appropriate treatment strategy in the management of thyroid cancer.

Surface Modification of Oxygenator Fibers with a Catalytically Active Metal-Organic Framework to Generate Nitric Oxide: An Ex Vivo Pilot Study.

Coating all portions of an extracorporeal membrane oxygenation (ECMO) circuit with materials exhibiting inherent, permanent antithrombotic properties is an essential step to prevent thrombus-induced complications. However, developing antithrombotic coatings for oxygenator fibers within membrane oxygenators of ECMO systems has proven challenging. We have used polydopamine (PDA) to coat oxygenator fibers and immobilize a Cu-based metal-organic framework (MOF) on the surface to act as a nitric oxide (NO) catalyst. Importantly, the PDA/MOF coating will produce NO indefinitely from endogenous S-nitrosothiols and it has not previously been applied to ECMO oxygenator fibers.

Psychological adjustment to initial treatment for low-risk thyroid cancer: Preliminary study.

BACKGROUND: Low-risk papillary thyroid carcinoma (LR-PTC) can be managed by immediate surgery (IS) or active surveillance (AS). We compare the psychological impact of these treatments on patients with LR-PTC. METHODS: Psychological data were collected over 1 year, with assessments at the time of treatment decision (T1), at 6 months (T2) and 12 months (T3) follow-up. Assessments included 13 validated psychological tools. RESULTS: Of 27 enrolled patients, 20 chose AS and 7 chose IS. The average times to T2 and T3 were 5.7 and 11.3 months, respectively. For both groups, Impact of Events Scale scores significantly decreased (p = 0.001) at T2, and depressive/anxiety symptoms remained low. CONCLUSIONS: This study demonstrates the feasibility of assessing psychological outcomes among patients treated for LR-PTC. Further studies are needed to evaluate the impact of AS versus IS on quality of life and changes that patients experience over longer time periods following their treatment decision.

Active Surveillance of Papillary Thyroid Cancer: Frequency and Time Course of the Six Most Common Tumor Volume Kinetic Patterns.

Background: The change in size of the papillary thyroid cancer (PTC) nodule during active surveillance has traditionally been characterized as either stable, increasing, or decreasing based on changes in maximal tumor diameter or tumor volume. More recently, it has been observed that the changes in tumor size observed during observation are more complex with tumor volume kinetic patterns that can be characterized either as stable (Pattern I), early increase in volume (Pattern II), later increase in volume (Pattern III), early increase in volume followed by stability (Pattern IV), stability followed by an increase in volume (Pattern V), or a decrease in tumor volume (Pattern VI). Methods: The frequency, time course, and clinical correlates of these six tumor volume kinetic patterns were analyzed in a cohort of 483 patients with low-risk PTC up to 1.5 cm in maximal diameter followed with active surveillance at our center for a median of 3.7 years. Results: The cumulative incidence of an increase in tumor volume for the entire cohort was 15.9% [confidence interval (CI) 11.8-20.0] at 5 years. At 5 years, most tumors demonstrated stability (78.8%, Pattern I) with 10.0% showing early growth (Pattern II), 4.1% late growth (Pattern III), 1.9% growth then stability (Pattern IV), 0.6% stability then growth (Pattern V), and 5.6% with a decrease in tumor volume (Pattern VI). Tumor volume doubling time during exponential growth significantly differed across the kinetic patterns, with median values of 2.4, 7.1, and 3.3 years for Patterns II, III, and IV, respectively (p < 0.01). Similarly, the time to a change in tumor volume was significantly different across the kinetic patterns, with median values of 1.5, 3, 1.6, 4.7, and 4.1 years for Patterns II, III, IV, V, and VI, respectively (analysis of variance, p < 0.01). Clinical correlates at baseline were not associated with tumor volume kinetic pattern. Conclusions: These six kinetic tumor volume patterns provide a comprehensive description of the changes in PTC tumor volume observed during the first 5 years of active surveillance.

Clinicopathologic and Prognostic Features of Pediatric Follicular Cell-derived Thyroid Carcinomas: A Retrospective Study of 222 Patients.

Pediatric thyroid carcinomas (TCs) are rare and mainly approached based on data extrapolated from adults. We retrospectively reviewed 222 pediatric TCs (patient age less than or equal to 21 y). Lymph node (LN) disease volume at presentation was considered high if the largest positive LN measured ≥1 cm and/or >5 LNs were positive. High-grade follicular cell-derived thyroid carcinoma (HGFCTC) were defined by the presence of marked mitotic count and/or tumor necrosis and considered as high-risk histology along with papillary thyroid carcinomas (PTC) diffuse sclerosing variant (DSV). Disease-free survival (DFS) was analyzed. LN involvement at presentation was significantly associated with male sex, larger tumor size, lymphatic invasion, positive surgical margins, and distant metastases at presentation. Five- and 10-year DFS was 84% and 77%, respectively. Only 1 patient with HGFCTC died of disease. Within PTC variants, PTC-DSV was associated with adverse histopathologic parameters and higher regional disease spread, unlike PTC tall cell variant which did not portend worse behavior. The presence of necrosis conferred worse DFS ( P =0.006), while increased mitotic activity did not. While the entire HGFCTC group did not correlate with outcome ( P =0.071), HGFCTC with necrosis imparted worse DFS ( P =0.006). When restricted to PTC-DSV and HGFCTC with necrosis, high-risk histologic classification emerged as an independent prognostic parameter of DFS ( P =0.020). The excellent prognosis of pediatric TCs differs from that of adult TCs showing similar histologic features. While neither increased mitotic activity nor PTC tall cell variant histology predict adverse outcome, PTC-DSV and tumors with necrosis constitute high-risk histologic variants with an increased risk of protracted disease.

Radioactive iodine therapy: multiple faces of the same polyhedron

ABSTRACT The incidence of differentiated thyroid carcinoma (DTC) has increased in recent decades with early stage, low risk papillary thyroid cancer (PTC) being detected and diagnosed. As a result, the psychological, financial, and clinical ramifications of overdiagnosis and excessively aggressive therapy are being increasingly recognized with many authorities calling for a re-evaluation of the traditional "one size fits all" management approaches. To address these critical issues, most thyroid cancer guidelines endorse a more risk adapted management strategy where the intensity of therapy and follow up is matched to the anticipated risk of recurrence and death from DTC for each patient. This "less is more" strategy provides for a minimalistic management approach for properly selected patients with low-risk DTC. This has re-kindled the long-standing debate regarding the routine use of radioactive iodine therapy (RIT) in DTC. Although recent guidelines have moved toward a more selective use of RIT, particular in patients with low-intermediate risk DTC, the proper selection of patients, the expected benefit, and the potential risks continue to be a source of ongoing controversy and debate. In this manuscript, we will review the wide range of clinical, imaging, medical team, and patient factors that must be considered when evaluating individual patients for RIT. Through a review of the current literature evaluating the potential benefits and risks of RIT, we will present a risk adapted approach to proper patient selection for RIT which emphasizes peri-operative risk stratification as the primary tool that clinicians should use to guide initial RIT management recommendations.

Radioactive iodine therapy: multiple faces of the same polyhedron.

The incidence of differentiated thyroid carcinoma (DTC) has increased in recent decades with early stage, low risk papillary thyroid cancer (PTC) being detected and diagnosed. As a result, the psychological, financial, and clinical ramifications of overdiagnosis and excessively aggressive therapy are being increasingly recognized with many authorities calling for a re-evaluation of the traditional "one size fits all" management approaches. To address these critical issues, most thyroid cancer guidelines endorse a more risk adapted management strategy where the intensity of therapy and follow up is matched to the anticipated risk of recurrence and death from DTC for each patient. This "less is more" strategy provides for a minimalistic management approach for properly selected patients with low-risk DTC. This has re-kindled the long-standing debate regarding the routine use of radioactive iodine therapy (RIT) in DTC. Although recent guidelines have moved toward a more selective use of RIT, particular in patients with low-intermediate risk DTC, the proper selection of patients, the expected benefit, and the potential risks continue to be a source of ongoing controversy and debate. In this manuscript, we will review the wide range of clinical, imaging, medical team, and patient factors that must be considered when evaluating individual patients for RIT. Through a review of the current literature evaluating the potential benefits and risks of RIT, we will present a risk adapted approach to proper patient selection for RIT which emphasizes peri-operative risk stratification as the primary tool that clinicians should use to guide initial RIT management recommendations.

Specialized Metabolite-Mediated Predation Defense in the Marine Actinobacterium Salinispora.

The obligate marine actinobacterial genus Salinispora has become a model organism for natural product discovery, yet little is known about the ecological functions of the compounds produced by this taxon. The aims of this study were to assess the effects of live cultures and culture extracts from two Salinispora species on invertebrate predators. In choice-based feeding experiments using the bacterivorous nematode Caenorhabditis elegans, live cultures of both Salinispora species were less preferred than Escherichia coli. When given a choice between the two species, C. elegans preferred S. areniolca over S. tropica. Culture extracts from S. tropica deterred C. elegans, while those from S. arenicola did not, suggesting that compounds produced by S. tropica account for the feeding deterrence. Bioactivity-guided isolation linked compounds in the lomaiviticin series to the deterrent activity. Additional assays using the marine polychaete Ophryotrocha siberti and marine nematodes further support the deterrent activity of S. tropica against potential predators. These results provide evidence that Salinispora natural products function as a defense against predation and that the strategies of predation defense differ between closely related species. IMPORTANCE Bacteria inhabiting marine sediments are subject to predation by bacterivorous eukaryotes. Here, we test the hypothesis that sediment-derived bacteria in the genus Salinispora produce biologically active natural products that function as a defense against predation. The results reveal that cultures and culture extracts of S. tropica deter feeding by Caenorhabditis elegans and negatively affect the habitat preference of a marine annelid (Ophryotrocha siberti). These activities were linked to the lomaiviticins, a series of cytotoxic compounds produced by S. tropica. Microbial natural products that function as a defense against predation represent a poorly understood trait that can influence community structure in marine sediments.

Primary high-grade non-anaplastic thyroid carcinoma: a retrospective study of 364 cases.

AIMS: We aimed to study the clinicopathological and molecular features of high-grade non-anaplastic thyroid carcinomas (HGTCs), a carcinoma with a prognosis intermediate between those of well-differentiated carcinoma and anaplastic carcinoma. METHODS AND RESULTS: This study included 364 HGTC patients: 200 patients (54.9%) were diagnosed with poorly differentiated thyroid carcinoma (PDTC), based on the Turin consensus (HGTC-PDTC), and 164 were diagnosed with high-grade features that did not meet the Turin criteria (HGTC-nonPDTC). HGTCs are aggressive: the 3-year, 5-year, 10-year and 20-year disease-specific survival (DSS) rates were 89%, 76%, 60%, and 35%, respectively. Although DSS was similar between HGTC-PDTC and HGTC-nonPDTC patients, HGTC-PDTC was associated with higher rate of radioactive iodine avidity, a higher frequency of RAS mutations, a lower frequency of BRAF V600E mutations and a higher propensity for distant metastasis (DM) than HGTC-nonPDTC. Independent clinicopathological markers of worse outcome were: older age, male sex, extensive necrosis and lack of encapsulation for DSS; older age, male sex and vascular invasion for DM-free survival; and older age, necrosis, positive margins and lymph node metastasis for locoregional recurrence-free survival. The frequencies of BRAF, RAS, TERT, TP53 and PTEN alterations were 28%, 40%, 55%, 11%, and 10%, respectively. TP53, PTEN and TERT were independent molecular markers associated with an unfavourable outcome, independently of clinicopathological parameters. The coexistence of BRAF V600E and TERT promoter mutation increased the risk of DM. CONCLUSIONS: The above data support the classification of HGTC as a single group with two distinct subtypes based on tumour differentiation: HGTC-PDTC and HGTC-nonPDTC.

Monitoring a MOF Catalyzed Reaction Directly in Blood Plasma.

Herein, we establish a method to quantitatively monitor a metal-organic framework (MOF)-catalyzed, biomedically relevant reaction directly in blood plasma, specifically, the generation of nitric oxide (NO) from the endogenous substrate S-nitrosoglutathione (GSNO) catalyzed by H3[(Cu4Cl)3-(BTTri)8] (CuBTTri). The reaction monitoring method uses UV-vis and 1H NMR spectroscopies along with a nitric oxide analyzer (NOA) to yield the reaction stoichiometry and catalytic rate for GSNO to NO conversion catalyzed by CuBTTri in blood plasma. The results show 100% loss of GSNO within 16 h and production of 1 equiv. of glutathione disulfide (GSSG) per 2 equiv. of GSNO. Only 78 ± 10% recovery of NO(g) was observed, indicating that blood plasma can scavenge the generated NO before it can escape the reaction vessel. Significantly, to best apply and understand reaction systems with biomedical importance, such as NO release catalyzed by CuBTTri, methods to study the reaction directly in biological solvents must be developed.

NATIONAL SURVEY OF ENDOCRINOLOGISTS AND SURGEONS REGARDING ACTIVE SURVEILLANCE FOR LOW-RISK PAPILLARY THYROID CANCER.

OBJECTIVE: Active surveillance for low-risk papillary thyroid cancer (PTC) was endorsed by the American Thyroid Association guidelines in 2015. The attitudes and beliefs of physicians treating thyroid cancer regarding the active surveillance approach are not known. METHODS: A national survey of endocrinologists and surgeons treating thyroid cancer was conducted from August to September 2017 via professional society emails. This mixed-methods analysis reported attitudes toward potential factors impacting decision-making regarding active surveillance, beliefs about barriers and facilitators of its use, and reasons why physicians would pick a given management strategy for themselves if they were diagnosed with a low-risk PTC. Survey items about attitudes and beliefs were derived from the Cabana model of barriers to guideline adherence and theoretical domains framework of behavior change. RESULTS: Among 345 respondents, 324 (94%) agreed that active surveillance was appropriate for at least some patients, 81% agreed that active surveillance was at least somewhat underused, and 76% said that they would choose surgery for themselves if diagnosed with a PTC of ≤1 cm. Majority of the respondents believed that the guidelines supporting active surveillance were too vague and that the current supporting evidence was too weak. Malpractice and financial concerns were identified as additional barriers to offering active surveillance. The respondents endorsed improved information resources and evidence as possible facilitators to offering active surveillance. CONCLUSION: Although there is general support among physicians who treat low-risk PTC for the active surveillance approach, there is reluctance to offer it because of the lack of robust evidence, guidelines, and protocols.

Copper Metal-Organic Framework Surface Catalysis: Catalyst Poisoning, IR Spectroscopic, and Kinetic Evidence Addressing the Nature and Number of the Catalytically Active Sites En Route to Improved Applications.

The metal-organic framework (MOF) H3[(Cu4Cl)3-(BTTri)8, H3BTTri = 1,3,5-tris(1H-1,2,3-triazol-5-yl)benzene] (CuBTTri) is a precatalyst for biomedically relevant nitric oxide (NO) release from S-nitrosoglutathione (GSNO). The questions of the number and nature of the catalytically most active, kinetically dominant sites are addressed. Also addressed is whether or not the well-defined structural geometry of MOFs (as solid-state analogues of molecular compounds) can be used to generate specific, testable hypotheses about, for example, if intrapore vs exterior surface metal sites are more catalytically active. Studies of the initial catalytic rate vs CuBTTri particle external surface area to interior volume ratio show that intrapore copper sites are inactive within the experimental error (≤1.7 × 10-5% of the observed catalytic activity)-restated, the traditional MOF intrapore metal site catalysis hypothesis is disproven for the current system. All observed catalysis occurs at exterior surface Cu sites, within the experimental error. Fourier transform infrared (FT-IR) analysis of CN--poisoned CuBTTri reveals just two detectable Cu sites at a ca. ≥0.5% detection limit, those that bind three or one CN- ("Cu(CN)3" and "CuCN"), corresponding to the CN- binding expected for exterior surface, 3-coordinate (Cusurface) and intrapore, 5-coordinate (Cupore) sites predicted by the idealized, metal-terminated crystal structure. Two-coordinate Cu defect sites are ruled out at the ≥0.5% FT-IR detection limit as such defect sites would have been detectable by the FT-IR studies of the CN--poisoned catalyst. Size-selective poisoning studies of CuBTTri exterior surface sites reveal that 1.3 (±0.4)% of total copper in 0.6 ± 0.4 µm particles is active. That counting of active sites yields a normalized turnover frequency (TOF), TOFnorm = (4.9 ± 1.2) × 10-2 mol NO (mol Cusurface)-1 s-1 (in water, at 20 min, 25 °C, 1 mM GSNO, 30% loss of GSNO, and 1.3 ± 0.4 mol % Cusurface)-a value ∼100× higher than the TOF calculated without active site counting. Overall, Ockham's razor interpretation of the data is that exterior surface, Cusurface sites are the catalytically most active sites present at a 1.3 (±0.4)% level of total Cu.

Exploring the Parameter Space of p-Cresyl Sulfate Adsorption in Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) have high porosity and surface area, making them ideal candidates for adsorption-mediated applications. One high-value application is the removal of uremic toxins from solution for dialysis. Previous studies have reported adsorptive removal of the uremic toxin p-cresyl sulfate from solution via zirconium-based MOFs, but a specific analysis of parameters contributing to adsorptive uptake is needed to clarify differences in uptake performance between MOFs. We synthesized zirconium 1,3,5-benzenetricarboxylate (MOF-808) and an iron-based analog, MIL-100(Fe), and compared their adsorptive uptake with previously reported values of other zirconium-based MOFs. MIL-100(Fe) adsorbed three times more p-cresyl sulfate from solution on a per mass basis than MOF-808 and had a greater adsorption efficiency than 75% of previously reported Zr-based MOFs. We compared p-cresyl sulfate uptake by MOFs as a function of BET surface area, number of aromatic carbons in the organic linker, internal cage diameter, and pore window diameter. There is poor correlation between p-cresyl sulfate uptake and each of the variables considered, but the number of aromatic carbons of the MOF linker was a better predictor of uptake than BET surface area (R2 = 0.7034 and 0.1430, respectively), and pore window aperture was a better predictor of uptake than the pore cage diameter (R2 = 0.4780 and 0.0383, respectively). We hypothesize that the greater adsorptive capacity of MIL-100(Fe) compared to MOF-808 results from direct coordination of p-cresyl sulfate to vacant metal sites in the MOF, and the total adsorption may be accounted for by some combination of adsorptive interactions occurring at both metal and organic linker sites near to the exterior particle surface. The adsorptive uptake of p-cresyl sulfate by MIL-100(Fe) was observed to increase with p-cresyl sulfate content, mass of MIL-100(Fe), and volume of p-cresyl sulfate solution; the mass of MIL-100(Fe) had the greatest effect on total adsorption.

Thermogravimetric Analysis and Mass Spectrometry Allow for Determination of Chemisorbed Reaction Products on Metal Organic Frameworks.

Thermogravimetric analysis (TGA) is a technique which can probe chemisorption of substrates onto metal organic frameworks. A TGA method was developed to examine the catalytic oxidation of S-nitrosoglutathione (GSNO) by the MOF H3[(Cu4Cl)3(BTTri)8] (abbr. Cu-BTTri; H3BTTri = 1,3,5-tris(1H-1,2,3-triazol-5-yl)benzene), yielding glutathione disulfide (GSSG) and nitric oxide (NO). Thermal analysis of reduced glutathione (GSH), GSSG, GSNO, and Cu-BTTri revealed thermal resolution of all four analytes through different thermal onset temperatures and weight percent changes. Two reaction systems were probed: an aerobic column flow reaction and an anaerobic solution batch reaction with gas agitation. In both systems, Cu-BTTri was reacted with a 1 mM GSH, GSSG, or GSNO solution, copiously rinsed with distilled-deionized water (dd-H2O), dried (25 °C, < 1 Torr), and assessed by TGA. Additionally, stock, effluent or supernatant, and rinse solutions for each glutathione derivative within each reaction system were assessed by mass spectrometry (MS) to inform on chemical transformations promoted by Cu-BTTri as well as relative analyte concentrations. Both reaction systems exhibited chemisorption of glutathione derivatives to the MOF by TGA. Mass spectrometry analyses revealed that in both systems, GSH was oxidized to GSSG, which chemisorbed to the MOF whereas GSSG remained unchanged during chemisorption. For GSNO, chemisorption to the MOF without reaction was observed in the aerobic column setup, whereas conversion to GSSG and subsequent chemisorption was observed in the anaerobic batch setup. These findings suggest that within this reaction system, GSSG is the primary adsorbent of concern with regards to strong binding to Cu-BTTri. Development of similar thermal methods could allow for the probing of MOF reactivity for a wide range of systems, informing on important considerations such as reduced catalytic efficiency from poisoning, recyclability, and loading capacities of contaminants or toxins with MOFs.

Copper ion vs copper metal-organic framework catalyzed NO release from bioavailable S-Nitrosoglutathione en route to biomedical applications: Direct 1H NMR monitoring in water allowing identification of the distinct, true reaction stoichiometries and thiol dependencies.

Copper containing compounds catalyze decomposition of S-Nitrosoglutathione (GSNO) in the presence of glutathione (GSH) yielding glutathione disulfide (GSSG) and nitric oxide (NO). Extended NO generation from an endogenous source is medically desirable to achieve vasodilation, reduction in biofilms on medical devices, and antibacterial activity. Homogeneous and heterogeneous copper species catalyze release of NO from endogenous GSNO. One heterogeneous catalyst used for GSNO decomposition in blood plasma is the metal-organic framework (MOF), H3[(Cu4Cl)3-(BTTri)8, H3BTTri = 1,3,5-tris(1H-1,2,3-triazol-5-yl) benzene] (CuBTTri). Fundamental questions about these systems remain unanswered, despite their use in biomedical applications, in part because no method previously existed for simultaneous tracking of [GSNO], [GSH], and [GSSG] in water. Tracking these reactions in water is a necessary step towards study in biological media (blood is approximately 80% water) where NO release systems must operate. Even the balanced stoichiometry remains unknown for copper-ion and CuBTTri catalyzed GSNO decomposition. Herein, we report a direct 1H NMR method which: simultaneously monitors [GSNO], [GSH], and [GSSG] in water; provides the experimentally determined stoichiometry for copper-ion vs CuBTTri catalyzed GSNO decomposition; reveals that the CuBTTri-catalyzed reaction reaches 10% GSNO decomposition (16 h) without added GSH, yet the copper-ion catalyzed reaction reaches 100% GSNO decomposition (16 h) without added GSH; and shows 100% GSNO decomposition upon addition of stoichiometric GSH to the CuBTTri catalyzed reaction. These observations provide evidence that copper-ion and CuBTTri catalyzed GSNO decomposition in water operate through different reaction mechanisms, the details of which can now be probed by 1H NMR kinetics and other needed studies.

Phase 2 study of vascular endothelial growth factor trap for the treatment of metastatic thyroid cancer.

BACKGROUND: Several multitargeted tyrosine kinase inhibitors (TKIs) have demonstrated activity in patients with thyroid cancer that is refractory to radioactive iodine (RAI). The antitumor effect is attributed at least in part to the ability of these TKIs to inhibit angiogenesis in these vascular tumors. Vascular endothelial growth factor (VEGF) Trap (VT) is a recombinantly produced fusion protein consisting solely of human sequences for VEGF receptors 1 and 2 extracellular domains and human immunoglobulin 1. Evaluating VT in patients with thyroid cancer is reasonable considering the activity observed with TKIs targeting VEGF. METHODS: The current study was a single-institution, phase 2, Simon 2-stage design (21 to >41 patients) study based on the objective response rate and/or 6-month progression-free survival as the primary endpoints. Eligible patients were required to have progressive, RAI-refractory and/or [18 F]fludeoxyglucose-avid, recurrent and/or metastatic, nonmedullary, nonanaplastic thyroid cancer; disease that was measurable using Response Evaluation Criteria In Solid Tumors (RECIST) criteria; and adequate organ and bone marrow function. VT at a dose of 4 mg/kg intravenously was administered every 14 days. RESULTS: A total of 40 patients were included in the analysis. Of these patients, 24 had papillary thyroid cancer, 2 had follicular thyroid cancer, and 11 had Hurthle cell thyroid cancer. The final 3 tumors were classified as poorly differentiated. There were no complete and/or partial responses noted; 34 patients achieved stable disease and 6 patients experienced disease progression as their best response. Of the 34 patients with stable disease, 16 remained on the study for >6 months and 6 patients remained on the study for >12 months. The median duration on treatment was 4.1 months (range, 0.6-30.8 months). CONCLUSIONS: Unlike TKIs, which have shown responses in this setting, to the authors' knowledge there have been no responses observed with the use of single-agent VT to date. It does not appear to be a promising drug for the treatment of patients with thyroid cancer.