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Neuroendocrine Tumor Theranostics: An Update and Emerging Applications in Clinical Practice.
Sheikhbahaei, S, Sadaghiani, MS, Rowe, SP, Solnes, LB
AJR. American journal of roentgenology. 2021;(2):495-506
Abstract
OBJECTIVE. Theranostics have shown great promise for delivering precision medicine, particularly in neuroendocrine tumors (NETs). The clinical applications of radiolabeled somatostatin analogues in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and are currently integrated into the management guidelines of NETs. This article summarizes the available literature on different somatostatin receptor-targeting radiopharmaceuticals with theranostic potential in NETs, pheochromocytomas, and paragangliomas. We discuss the clinical application, administration, and toxicity of recent FDA-approved radionuclide therapies, including 177Lu-DOTATATE in advanced gastroenteropancreatic NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. CONCLUSION. Several studies support the safety and clinical efficacy of peptide receptor radionuclide therapies in disease control and quality-of-life improvement in patients with NETs and report potential benefits of combined radionuclide treatment approaches. The utility and pitfalls of functional imaging in therapy response assessment and surveillance of NETs remain to be established.
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High-Specific-Activity-131I-MIBG versus 177Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma.
Jha, A, Taïeb, D, Carrasquillo, JA, Pryma, DA, Patel, M, Millo, C, de Herder, WW, Del Rivero, J, Crona, J, Shulkin, BL, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(11):2989-2995
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Targeted radionuclide therapies (TRT) using 131I-metaiodobenzylguanidine (131I-MIBG) and peptide receptor radionuclide therapy (177Lu or 90Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity-131I-MIBG therapy was approved by the FDA and both 177Lu-DOTATATE and 131I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs.
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A Review of Zinc-L-Carnosine and Its Positive Effects on Oral Mucositis, Taste Disorders, and Gastrointestinal Disorders.
Hewlings, S, Kalman, D
Nutrients. 2020;(3)
Abstract
Zinc-L-carnosine (ZnC), also called polaprezinc known as PepZin GI™, is a chelated compound that contains L-carnosine and zinc. It is a relatively new molecule and has been associated with multiple health benefits. There are several studies that support ZnC's benefits in restoring the gastric lining, healing other parts of the gastrointestinal (GI) tract, improving taste disorders, improving GI disorders, and enhancing skin and liver. Oral mucositis is a common complication of cytotoxic radiotherapy and/or chemotherapy. It occurs in almost every person with head and neck cancer who receive radiotherapy. It is often overlooked because it is not considered life threatening. However, mucositis often leads to a decreased quality of life and cessation of treatment, ultimately decreasing positive outcomes. Therefore, solutions to address it should be considered. The primary mechanisms of action are thought to be localized and related to ZnC's anti-inflammatory and antioxidant functions. Therefore, the purpose of this review is to discuss the research related to ZnC and to explore its benefits, especially in the management of conditions related to damaged epithelial cells, such as oral mucositis. Evidence supports the safety and efficacy of ZnC for the maintenance, prevention, and treatment of the mucosal lining and other epithelial tissues. The research supports its use for gastric ulcers (approved in Japan) and conditions of the upper GI and suggests other applications, particularly for oral mucositis.
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The odyssey of cobaloximes for catalytic H2 production and their recent revival with enzyme-inspired design.
Dolui, D, Khandelwal, S, Majumder, P, Dutta, A
Chemical communications (Cambridge, England). 2020;(59):8166-8181
Abstract
Cobaloxime complexes gained attention for their intrinsic ability of catalytic H2 production despite their initial emergence as a vitamin B12 model. The simple, robust, and synthetically manoeuvrable cobaloxime core represents a model catalyst molecule for the investigation of optimal conditions for both photo- and electrocatalytic H2 production catalytic assemblies. Cobaloxime is one of the rare catalysts that finds equal applications in the analysis of homogeneous and heterogeneous catalytic conditions. However, the poor aqueous solubility and long-term instability of cobaloximes have severely impeded their growth. Lately, interest in the cobaloxime-based catalysts has been resuscitated with the rational use of extended enzymatic features. This unique enzyme-inspired catalyst design strategy has instigated the formation of a new genre of cobaloxime molecules that exhibit enhanced photo- and electrocatalytic H2 evolution with improved aqueous and air stability.
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Bridging the Imaging Gap: PSMA PET/CT Has a High Impact on Treatment Planning in Prostate Cancer Patients with Biochemical Recurrence-A Narrative Review of the Literature.
Ekmekcioglu, Ö, Busstra, M, Klass, ND, Verzijlbergen, F
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2019;(10):1394-1398
Abstract
68Ga- and 18F-labeled prostate-specific membrane antigen (PSMA) molecules have created new opportunities for the unmet diagnostic needs in prostate cancer. The purpose of this article is to give an overview of studies that have examined the role of PSMA PET in treatment planning for prostate cancer patients with biochemical recurrence (BCR). Methods: Medline, Embase, Web of Science, Google Scholar, and Cochrane Central were searched for relevant articles. After excluding the articles that did not fulfill the required criteria, we included in this review 12 publications that reported the impact of PSMA PET on the treatment plan for prostate cancer patients with BCR. Results: All studies in our review emphasized the impact of PSMA PET images on therapy management in prostate cancer patients with BCR. Overall, the impact of PSMA PET/CT on therapy management varied between 30% and 76% among the 1,346 patients included in the review. Upstaging was reported in 32%-67% of the patients. Patients with low prostate-specific antigen values (<0.5 ng/mL) also demonstrated positive lesions, which could not have been detected by means of conventional imaging techniques. Important modifications to the original treatment plan included avoidance of systemic therapy (17%-40%) and PET-directed local therapy (in ≤60% of the patients). Conclusion: PSMA imaging demonstrated a high clinical impact in patients with BCR, with modifications to the original treatment plan occurring among half the patients. Detecting recurrence in BCR can prevent unnecessary toxicity and lead to individualized therapy.
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Organic Chemistry Research on the Mechanistic Elucidation of Iron Acquisition in Barley.
Namba, K, Murata, Y
Biological & pharmaceutical bulletin. 2018;(10):1502-1507
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An organic chemistry approach to the mechanistic elucidation of iron acquisition in graminaceous plants is introduced here. To elucidate this detailed mechanism using phytosiderophores, the efficient synthesis of 2'-deoxymugineic acid (DMA), a phytosiderophore of rice, was established. The synthetic DMA was confirmed to have similar iron transport activity to that of natural mugineic acid (MA). It was also revealed that the addition of synthetic DMA, along with iron, to a rice hydroponic solution enabled the rice to grow well even under an alkaline condition, and DMA clearly showed its high potential as a fertilizer to improve food production. On the other hand, the 2'-hydroxy group of MA was confirmed to serve as a point of introduction for labeling, allowing the synthesis of various mugineic acid derivatives as molecular probes. The incorporation of fluorescent mugineic acid into cells allowed them to be clearly observed by fluorescence confocal analysis, and this provided the first direct experimental evidence of transporter-mediated internalization of mugineic acid into cells.
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Symptomatic Hyponatremia after Bowel Preparation: Report of Two Cases and Literature Review.
Costa, JM, Soares, JB
Acta medica portuguesa. 2017;(11):824-826
Abstract
INTRODUCTION Bowel preparation for colonoscopy and/or colorectal surgery can cause electrolyte imbalances. The risk of electrolyte imbalances seems to be related to the type of bowel cleansing solution, age of patients and comorbidities. CASE REPORT We report two cases of symptomatic hyponatremia (focal neurological signs and coma) after bowel preparation with sodium picosulfate/magnesium citrate for colonoscopy. In both cases, symptoms related to hyponatremia rapidly disappeared after sodium level correction with intravenous administration of hypertonic saline (3% NaCl). DISCUSSION Electrolyte imbalances are more common with sodium phosphate-based solutions (NaP) and sodium picosulfate/magnesium citrate, in patients older than 65, in patients treated with thiazide diuretics, angiotensin-converting-enzyme inhibitor, betablockers or antidepressants and in gastrectomized patients. These patients should use macrogol-based solutions (polyethylene glycol). CONCLUSION In patients at risk (patient > 65 years old, patients taking thiazide diuretics, angiotensin-converting-enzyme inhibitors, beta-blockers and antidepressants and with previous gastrectomy) we recommend macrogol-based solutions.
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[CuO](+) and [CuOH](2+) complexes: intermediates in oxidation catalysis?
Gagnon, N, Tolman, WB
Accounts of chemical research. 2015;(7):2126-31
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Characterization of monocopper intermediates in enzymes and other catalysts that attack strong C-H bonds is important for unraveling oxidation catalysis mechanisms and, ultimately, designing new, more efficient catalytic systems. Because initially formed 1:1 Cu/O2 adducts resulting from reactions of Cu(I) sites with O2 react relatively sluggishly with substrates with strong C-H bonds, it has been suggested that reductive O-O bond scission might occur instead to yield more reactive [CuO](+) or protonated [CuOH](2+) cores. Experimental and theoretical studies of [CuO](+) species in the gas phase have provided key insights into the possible reactivity of these species, but detailed information is lacking for discrete complexes with the [CuO](+) or [CuOH](2+) core in solution or the solid state. We describe herein our recent efforts to address this issue through several disparate approaches. In one strategy based on precedent from studies of enzymes and synthetic compounds with iron-α-ketocarboxylate motifs, reactions of O2 with Cu(I)-α-ketocarboxylate complexes were explored, with the aim of identifying reaction pathways that would implicate the intermediacy of a [CuO](+) species. A second approach focused on the reaction of N-oxides with Cu(I) complexes, with the goal being to elicit O-N bond heterolysis to yield [CuO](+) complexes. For both strategies, the course of the reactions depended on the nature of the supporting bidentate N-donor ligand, and indirect evidence in support of the sought-after [CuO](+) intermediates was obtained in some instances. In the final approach discussed herein, strongly electron donating and sterically encumbered pyridine-dicarboxamide ligands (L) enabled the synthesis of [LCu(II)OH](-) complexes, which upon one-electron oxidation formed complexes with the [CuOH](2+) core that were characterized in solution. Rapid hydrogen atom abstraction (HAT) from dihydroanthracene (DHA) was observed, yielding LCu(II)OH2. The O-H bond dissociation enthalpy (BDE) of ∼90 kcal/mol for this complex was determined through evaluation of its pKa (∼19) and the [LCu(II)OH](-)/LCu(III)OH reduction potential (approximately -0.08 V vs Fc/Fc(+)). Thus, the poor oxidizing power of the complex is offset by the high basicity of the hydroxide moiety to yield a strong O-H bond. This high BDE provided a thermodynamic rationale for the rapid HAT rate from DHA and suggested that stronger C-H bonds could be attacked. Indeed, using an inert solvent (1,2-difluorobenzene), substrates with C-H bond strengths as high as 99 kcal/mol were shown to react with the [CuOH](2+) complex, and a linear log k vs C-H BDE plot supported similar HAT pathways across the series. Importantly, these results provided key evidence in favor of the possible intermediacy of this core in oxidation catalysis, and we suggest that because it is a more energetically accessible intermediate than the [CuO](+) moiety, it should be considered as an alternative in proposed mechanisms for oxidations by enzymes and other synthetic systems.
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Bone-seeking radiopharmaceuticals as targeted agents of osteosarcoma: samarium-153-EDTMP and radium-223.
Anderson, PM, Subbiah, V, Rohren, E
Advances in experimental medicine and biology. 2014;:291-304
Abstract
Osteosarcoma is a cancer characterized by formation of bone by malignant cells. Routine bone scan imaging with Tc-99m-MDP is done at diagnosis to evaluate primary tumor uptake and check for bone metastases. At time of relapse the Tc-99m-MDP bone scan also provides a specific means to assess formation of bone by malignant osteosarcoma cells and the potential for bone-seeking radiopharmaceuticals to deliver radioactivity directly into osteoblastic osteosarcoma lesions. This chapter will review and compare a bone-seeking radiopharmaceutical that emits beta-particles, samarium-153-EDTMP, with an alpha-particle emitter, radium-223. The charged alpha particles from radium-223 have far more mass and energy than beta particles (electrons) from Sm-153-EDTMP. Because radium-223 has less marrow toxicity and more radiobiological effectiveness, especially if inside the bone forming cancer cell than samarium-153-EDTMP, radium-223 may have greater potential to become widely used against osteosarcoma as a targeted therapy. Radium-223 also has more potential to be used with chemotherapy against osteosarcoma and bone metastases. Because osteosarcoma makes bone and radium-223 acts like calcium, this radiopharmaceutical could possibly become a new targeted means to achieve safe and effective reduction of tumor burden as well as facilitate better surgery and/or radiotherapy for difficult to resect large, or metastatic tumors.
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Bioorganometallic chemistry with IspG and IspH: structure, function, and inhibition of the [Fe(4)S(4)] proteins involved in isoprenoid biosynthesis.
Wang, W, Oldfield, E
Angewandte Chemie (International ed. in English). 2014;(17):4294-310
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Abstract
Enzymes of the methylerythritol phosphate pathway of isoprenoid biosynthesis are attractive anti-infective drug targets. The last two enzymes of this pathway, IspG and IspH, are [Fe4 S4 ] proteins that are not produced by humans and catalyze 2 H(+) / 2 e(-) reductions with novel mechanisms. In this Review, we summarize recent advances in structural, mechanistic, and inhibitory studies of these two enzymes. In particular, mechanistic proposals involving bioorganometallic intermediates are presented, and compared with other mechanistic possibilities. In addition, inhibitors based on substrate analogues as well as developed by rational design and compound-library screening, are discussed. The results presented support bioorganometallic catalytic mechanisms for IspG and IspH, and open up new routes to anti-infective drug design targeting [Fe4 S4 ] clusters in proteins.