Объем остаточной тиреоидной ткани и эффективность постоперационной радиойодтерапии больных с дифференцированными формами рака щитовидной железы

Резюме. У 210 больных с дифференцированными формами рака щитовидной железы изучено влияние массы участков остаточной ткани щитовидной железы (ОТЩЖ) на эффективность радиойодтерапии (РЙТ). Через 4–6 нед после хирургического лечения выполняли диагностическую сцинтиграфию с 70–80 МБк 131I, по данным которой на основании эллипсоидной модели рассчитывали объем ОТЩЖ. РЙТ проводили активностями 1,9–4,7 ГБк, контрольную сцинтиграфию выполняли через 4–6 мес. Эффективность первого курса РЙТ при объеме ОТЩЖ 1 см3 и менее составляла 88,9%, при объеме более 4 см3 — 69,3% (р < 0,05). Установлена достоверная корреляция между объемом ОТЩЖ и эффективностью первого курса РЙТ. При наличии нескольких участков ОТЩЖ эффективность РЙТ определяется не столько их количеством и суммарным объемом, сколько объемом каждого участка. Ключевые слова: дифференцированный рак щитовидной железы, тиреоидэктомия, радиойодтерапия, остаточная ткань щитовидной железы.Summary. The influence of the mass of the residual thyroid tissue (RTT) on the efficacy of radioiodine therapy (RT) was investigated in 210 patients with differentiated forms of thyroid cancer (DFTC). 4 to 6 weeks after surgery, diagnostic 131J scintigraphy (70–80 MBq) was applied. On the basis of data obtained, the RTT size was measured based on an ellipsoidal model. Activities applied in RT ranged between 1,9–4,7 GBq; control scintigraphy was performed in 4 to 6 months. The efficacy of the first RT course was 88,9% in patients with RTT of 1 cm3 or smaller and 69,3% in patients with RTT of 4 cm3 or larger (р<0,05). A significant correlation was found between the size of RTT and the efficacy of the first RT course. In cases where there were several RTT areas, the RT efficacy depended on the overall size of each area rather than on the number of such areas. Key Words: differentiated thyroid cancer, thyreoidectomy, radioiodine therapy, residual thyroid tissue

Studying the structure and dynamics of biomolecules by using soluble paramagnetic probes.

Characterisation of the structure and dynamics of large biomolecules and biomolecular complexes by NMR spectroscopy is hampered by increasing overlap and severe broadening of NMR signals. As a consequence, the number of available NMR spectroscopy data is often sparse and new approaches to provide complementary NMR spectroscopy data are needed. Paramagnetic relaxation enhancements (PREs) obtained from inert and soluble paramagnetic probes (solvent PREs) provide detailed quantitative information about the solvent accessibility of NMR-active nuclei. Solvent PREs can be easily measured without modification of the biomolecule; are sensitive to molecular structure and dynamics; and are therefore becoming increasingly powerful for the study of biomolecules, such as proteins, nucleic acids, ligands and their complexes in solution. In this Minireview, we give an overview of the available solvent PRE probes and discuss their applications for structural and dynamic characterisation of biomolecules and biomolecular complexes

Glycosylation of Conotoxins

Conotoxins are small peptides present in the venom of cone snails. The snail uses this venom to paralyze and capture prey. The constituent conopeptides display a high level of chemical diversity and are of particular interest for scientists as tools employed in neurological studies and for drug development, because they target with exquisite specificity membrane receptors, transporters, and various ion channels in the nervous system. However, these peptides are known to contain a high frequency and variability of post-translational modifications—including sometimes O-glycosylation—which are of importance for biological activity. The potential application of specific conotoxins as neuropharmalogical agents and chemical probes requires a full characterization of the relevant peptides, including the structure of the carbohydrate part. In this review, the currently existing knowledge of O-glycosylation of conotoxins is described

A compact native 24-residue supersecondary structure derived from the villin headpiece subdomain.

Many small proteins fold highly cooperatively in an all-or-none fashion and thus their native states are well protected from thermal fluctuations by an extensive network of interactions across the folded structure. Because protein structures are stabilized by local and nonlocal interactions among distal residues, dissecting individual substructures from the context of folded proteins results in large destabilization and loss of unique three-dimensional structure. Thus, mini-protein substructures can only rarely be derived from natural templates. Here, we describe a compact native 24-residues-long supersecondary structure derived from the hyperstable villin headpiece subdomain consisting of helices 2 and 3 (HP24). Using a combination of experimental techniques, including NMR and small-angle x-ray scattering, as well as all-atom replica exchange molecular-dynamics&nbsp;simulations, we show that a variant with stabilizing substitutions (HP24stab) forms a densely packed and compact conformation. In HP24stab, interactions between helices 2 and 3 are similar to those observed in native folded HP35, and the two helices cooperatively stabilize each other by completing the hydrophobic core lining the central part of HP35. Interestingly, even though the HP24wt fragment shows a more expanded and less structured conformation, NMR and simulations demonstrate a preference for a native-like topology. Thus, the two stabilizing residues in HP24stab shift the energy balance toward the native state, leading to a minimal folding motif

Identification, structural and pharmacological characterization of τ-CnVA, a conopeptide that selectively interacts with somatostatin sst3 receptor

Conopeptides are a diverse array of small linear and reticulated peptides that interact with high potency and selectivity with a large diversity of receptors and ion channels. They are used by cone snails for prey capture or defense. Recent advances in venom gland transcriptomic and venom peptidomic/proteomic technologies combined with bioactivity screening approaches lead to the identification of new toxins with original pharmacological profiles. Here, from transcriptomic/proteomic analyses of the Conus consors cone snail, we identified a new conopeptide called τ-CnVA, which displays the typical cysteine framework V of the T1-conotoxin superfamily. This peptide was chemically synthesized and its three-dimensional structure was solved by NMR analysis and compared to that of TxVA belonging to the same family, revealing very few common structural features apart a common orientation of the intercysteine loop. Because of the lack of a clear biological function associated with the T-conotoxin family, τ-CnVA was screened against more than fifty different ion channels and receptors, highlighting its capacity to interact selectively with the somatostatine sst3 receptor. Pharmacological and functional studies show that τ-CnVA displays a micromolar (Ki of 1.5 μM) antagonist property for the sst3 receptor, being currently the only known toxin to interact with this GPCR subfamily. -------------------------------------------------------------------------------

A novel µ-conopeptide, CnIIIC, exerts potent and preferential inhibition of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine receptors

BACKGROUND AND PURPOSE The µ-conopeptide family is defined by its ability to block voltage-gated sodium channels (VGSCs), a property that can be used for the development of myorelaxants and analgesics. We characterized the pharmacology of a new µ-conopeptide (µ-CnIIIC) on a range of preparations and molecular targets to assess its potential as a myorelaxant. EXPERIMENTAL APPROACH µ-CnIIIC was sequenced, synthesized and characterized by its direct block of elicited twitch tension in mouse skeletal muscle and action potentials in mouse sciatic and pike olfactory nerves. µ-CnIIIC was also studied on HEK-293 cells expressing various rodent VGSCs and also on voltage-gated potassium channels and nicotinic acetylcholine receptors (nAChRs) to assess cross-interactions. Nuclear magnetic resonance (NMR) experiments were carried out for structural data. KEY RESULTS Synthetic µ-CnIIIC decreased twitch tension in mouse hemidiaphragms (IC50= 150 nM), and displayed a higher blocking effect in mouse extensor digitorum longus muscles (IC = 46 nM), compared with µ-SIIIA, µ-SmIIIA and µ-PIIIA. µ-CnIIIC blocked NaV1.4 (IC50= 1.3 nM) and NaV1.2 channels in a long-lasting manner. Cardiac NaV1.5 and DRG-specific NaV1.8 channels were not blocked at 1 µM. µ-CnIIIC also blocked the 3β2 nAChR subtype (IC50= 450 nM) and, to a lesser extent, on the 7 and 4β2 subtypes. Structure determination of µ-CnIIIC revealed some similarities to -conotoxins acting on nAChRs. CONCLUSION AND IMPLICATIONS µ-CnIIIC potently blocked VGSCs in skeletal muscle and nerve, and hence is applicable to myorelaxation. Its atypical pharmacological profile suggests some common structural features between VGSCs and nAChR channels

Structure of the O-Glycosylated Conopeptide CcTx from Conus consors Venom

The glycopeptide CcTx, isolated from the venom of the piscivorous cone snail Conus consors, belongs to the kA-family of conopeptides. These toxins elicit excitotoxic re- ACHTUNGTRENUNGsponses in the prey by acting on voltage- gated sodium channels. The structure of CcTx, a first in the kA-family, has been determined by high-resolution NMR spectroscopy together with the analysis of its O-glycan at Ser7. A new type of glycopeptide O-glycan core structure, here registered as core type 9, containing two terminal l-galactose units {a-l-Galp-(1!4)-a-d- GlcpNAc-(1!6)-[a-l-Galp-(1!2)-b-d- Galp-(1!3)-]a-d-GalpNAc-(1!O)}, is highlighted. A sequence comparison to other putative members of the kAfamily suggests that O-linked glycosylation might be more common than previously thought. This observation alone underlines the requirement for more careful and in-depth investigations into this type of post-translational modification in conotoxins

Structure of the O-Glycosylated Conopeptide CcTx from Conus consors Venom

The glycopeptide CcTx, isolated from the venom of the piscivorous cone snail Conus consors, belongs to the kA-family of conopeptides. These toxins elicit excitotoxic re- ACHTUNGTRENUNGsponses in the prey by acting on voltage- gated sodium channels. The structure of CcTx, a first in the kA-family, has been determined by high-resolution NMR spectroscopy together with the analysis of its O-glycan at Ser7. A new type of glycopeptide O-glycan core structure, here registered as core type 9, containing two terminal l-galactose units {a-l-Galp-(1!4)-a-d- GlcpNAc-(1!6)-[a-l-Galp-(1!2)-b-d- Galp-(1!3)-]a-d-GalpNAc-(1!O)}, is highlighted. A sequence comparison to other putative members of the kAfamily suggests that O-linked glycosylation might be more common than previously thought. This observation alone underlines the requirement for more careful and in-depth investigations into this type of post-translational modification in conotoxins