Improving the Stability and Kinetic Inertness of Mn(II) Complexes by Increasing the Bridge Length in Bicyclic CDTA-Like Ligands.

Kinetic inertness of Mn(II)-based MRI contrast agents can be improved by increasing the rigidity of the polydentate ligand that tightly coordinate the metal ion. Taking inspiration from the remarkable increase in kinetic inertness of [Mn(CDTA)]2- compared to [Mn(EDTA)]2- due to the cyclohexyl backbone rigidity, we devised that bicyclic ligands would further improve the kinetic inertness of the Mn(II) complexes. The length of the alkyl bridge on the cyclohexane ring was varied from methylene (BCH-DTA), ethylene (BCO-DTA) to propylene (BCN-DTA) to evaluate the influence of the different trans-diaminotetraacetate ligands on relaxometric, thermodynamic and kinetic properties of the Mn(II) complexes. 1H and 17O NMR relaxometric studies showed a slight increase in relaxivity and a faster water exchange rate in these Mn(II)-complexes with respect to [Mn(CDTA)]2-. Solution studies revealed that the conditional stability (pMn) and dissociation half-life (t1/2) at pH 7.4 follow the order [Mn(BCH-DTA)]2-<[Mn(BCO-DTA)]2-<[Mn(BCN-DTA)]2- highlighting the effect of the bridge length on the overall stability of the Mn(II) complexes. Remarkably, [Mn(BCN-DTA)]2- shows an improved pMn value and a 7-times higher kinetic inertness than [Mn(CDTA)]2-. NMR studies on the Zn(II) analogues confirm the rigidity of the bicyclic complexes with an isomerization process at >313 K for the smaller bridged complex [Zn(BCH-DTA)]2-.

[Gd(HB-DO3A)]: Equilibrium, Dissociation Kinetic and Structural Differences in a Simple Homolog of [Gd(HP-DO3A)] (Prohance®).

[Gd(HP-DO3A)] (gadoteridol) as an active compound of ProHance® is a widely employed contrast agent in clinical MRI scans in the last 30 years. Recent concerns about the long-term retention of gadolinium-based contrast agents (GBCAs) led to a deeper investigation of the structural features underlying the integrity of the paramagnetic metal complex. Several human and nonclinical studies have noted marked differences among the macrocyclic GBCAs, with the least retention of Gd traces and most rapid elimination consistently being reported for [Gd(HP-DO3A)]. It was deemed of interest to assess how minor structural/electronic changes associated to the ligand structure may affect basic properties of the metal complex with several [Gd(HP-DO3A)] analogues synthesized and characterized in the last years. We recently reported that the closest homolog of [Gd(HP-DO3A)], i. e.: [Gd(HB-DO3A)], in which a (±)-2-hydroxy-1-propyl pendant arm is replaced by a (±)-2-hydroxy-1-butyl moiety, showed a significantly different retention behaviour in the model interaction with collagen, despite the apparently very minor structural difference. In this paper we report a comprehensive study of the structural, thermodynamic, kinetic and relaxation properties of [Gd(HB-DO3A)], compared to the parent [Gd(HP-DO3A)] and to other closely related macrocyclic GBCAs to assess whether very minor structural changes can modulate the physico-chemical properties of Gd3+ complexes.

EHDTA: a green approach to efficient Ln3+-chelators.

The rich coordination chemistry of lanthanoid ions (Ln3+) is currently exploited in a vast and continuously expanding array of applications. Chelating agents are central in the development of Ln3+-complexes and in tuning their physical and chemical properties. Most chelators for Ln3+-complexation are derived from the macrocyclic DOTA or from linear DTPA platforms, both of which arise from fossil-based starting materials. Herein, we report a green and efficient approach to a chelating agent (EHDTA), derived from cheap and largely available furfurylamine. The oxygenated heterocycle of the latter is converted to a stereochemically defined and rigid heptadentate chelator, which shows good affinity towards Ln3+ ions. A combination of NMR, relaxometric, potentiometric and spectrophotometric techniques allows us to shed light on the interesting coordination chemistry of Ln3+-EHDTA complexes, unveiling a promising ligand for the chelation of this important family of metal ions.

Radiolabeling of Platelets with 99mTc-HYNIC-Duramycin for In Vivo Imaging Studies.

Following the in vivo biodistribution of platelets can contribute to a better understanding of their physiological and pathological roles, and nuclear imaging methods, such as single photon emission tomography (SPECT), provide an excellent method for that. SPECT imaging needs stable labeling of the platelets with a radioisotope. In this study, we report a new method to label platelets with 99mTc, the most frequently used isotope for SPECT in clinical applications. The proposed radiolabeling procedure uses a membrane-binding peptide, duramycin. Our results show that duramycin does not cause significant platelet activation, and radiolabeling can be carried out with a procedure utilizing a simple labeling step followed by a size-exclusion chromatography-based purification step. The in vivo application of the radiolabeled human platelets in mice yielded quantitative biodistribution images of the spleen and liver and no accumulation in the lungs. The performed small-animal SPECT/CT in vivo imaging investigations revealed good in vivo stability of the labeling, which paves the way for further applications of 99mTc-labeled-Duramycin in platelet imaging.

Thermodynamic and Kinetic Stabilities of Al(III) Complexes with N2O3 Pentadentate Ligands.

Al(III) complexes have been recently investigated for their potential use in imaging with positron emission tomography (PET) by formation of ternary complexes with the radioisotope fluorine-18 (18F). Although the derivatives of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) are the most applied chelators for [Al18F]2+ labelling and (pre)clinical PET imaging, non-macrocyclic, semi-rigid pentadentate chelators having two N- and three O-donor atoms such as RESCA1 and AMPDA-HB have been proposed with the aim to allow room temperature labelling of temperature-sensitive biomolecules. The paucity of stability data on Al(III) complexes used for PET imaging instigated a complete thermodynamic and kinetic solution study on Al(III) complexes with aminomethylpiperidine (AMP) derivatives AMPTA and AMPDA-HB and the comparison with a RESCA1-like chelator CD3A-Bn (trans-1,2-diaminocyclohexane-N-benzyl-N,N',N'-triacetic acid). The stability constant of [Al(AMPDA-HB)] is about four orders of magnitude higher than that of [Al(AMPTA)] and [Al(CD3A-Bn)], highlighting the greater affinity of phenolates with respect to acetate O-donors. On the other hand, the kinetic inertness of the complexes, determined by following the Cu2+-mediated transmetallation reactions in the 7.5-10.5 pH range, resulted in a spontaneous and hydroxide-assisted dissociation slightly faster for [Al(AMPTA)] than for the other two complexes (t1/2 = 4.5 h for [Al(AMPTA)], 12.4 h for [Al(AMPDA-HB)], and 24.1 h for [Al(CD3A-Bn)] at pH 7.4 and 25 °C). Finally, the [AlF]2+ ternary complexes were prepared and their stability in reconstituted human serum was determined by 19F NMR experiments.

Characterization of the Fe(III)-Tiron System in Solution through an Integrated Approach Combining NMR Relaxometric, Thermodynamic, Kinetic, and Computational Data.

The Fe(III)-Tiron system (Tiron = 4,5-dihydroxy-1,3-benzenedisulfonate) was investigated using a combination of 1H and 17O NMR relaxometric studies at variable field and temperature and theoretical calculations at the DFT and NEVPT2 levels. These studies require a detailed knowledge of the speciation in aqueous solution at different pH values. This was achieved using potentiometric and spectrophotometric titrations, which afforded the thermodynamic equilibrium constants characterizing the Fe(III)-Tiron system. A careful control of the pH of the solution and the metal-to-ligand stoichiometric ratio allowed the relaxometric characterization of [Fe(Tiron)3]9-, [Fe(Tiron)2(H2O)2]5-, and [Fe(Tiron)(H2O)4]- complexes. The 1H nuclear magnetic relaxation dispersion (NMRD) profiles of [Fe(Tiron)3]9- and [Fe(Tiron)2(H2O)2]5- complexes evidence a significant second-sphere contribution to relaxivity. A complementary 17O NMR study provided access to the exchange rates of the coordinated water molecules in [Fe(Tiron)2(H2O)2]5- and [Fe(Tiron)(H2O)4]- complexes. Analyses of the NMRD profiles and NEVPT2 calculations indicate that electronic relaxation is significantly affected by the geometry of the Fe3+ coordination environment. Dissociation kinetic studies indicated that the [Fe(Tiron)3]9- complex is relatively inert due to the slow release of one of the Tiron ligands, while the [Fe(Tiron)2(H2O)2]5- complex is considerably more labile.

AAZTA-Like Ligands Bearing Phenolate Arms as Efficient Chelators for 68 Ga Labelling in†vitro and in†vivo.

The introduction of a phenolate pendant arm in place of an acetate on AAZTA- and DATA-like ligands resulted in hepta- and hexadentate chelators able to form Ga(III) complexes with thermodynamic stability and kinetic inertness higher than that of other Ga(III) complexes based on the parent 6-amino-6-methylperhydro-1,4-diazepine scaffold. In particular, the heptadentate AAZ3A-endoHB with a phenolate arm on an endocyclic N-atom shows a logKGaL of 27.35 and a remarkable resistance to hydroxide coordination up to basic pH (pH>9). This behaviour allows to also improve the kinetic inertness of the complex showing a dissociation half-life (t1/2 ) at pH 7.4 of 76 h. Although also the hexadentate AAZ2A-exoHB chelator forms a stable (logKGaL =24.69) and inert (t1/2 =33 h at pH 7.4) Ga(III) complex, the 68 Ga labelling showed a better radiochemical yield with AAZ3A-endoHB, especially at room temperature. Thus, a bifunctional chelator of AAZ3A-endoHB was synthesized bearing an isothiocyanate group that was conjugated to the N-terminus of a c(RGD) peptide for integrin receptor targeting. Finally, the conjugate was successfully labelled with 68 Ga isotope, and the resulting radiotracer tested for its stability in human serum and then in vivo for targeting B16-F10 tumours with miniPET imaging.

Boosting Bismuth(III) Complexation for Targeted α-Therapy (TAT) Applications with the Mesocyclic Chelating Agent AAZTA.

Targeted α therapy (TAT) is a promising tool in the therapy of cancer. The radionuclide 213 BiIII shows favourable physical properties for this application, but the fast and stable chelation of this metal ion remains challenging. Herein, we demonstrate that the mesocyclic chelator AAZTA quickly coordinates BiIII at room temperature, leading to a robust complex. A comprehensive study of the structural, thermodynamic and kinetic properties of [Bi(AAZTA)]- is reported, along with bifunctional [Bi(AAZTA-C4-COO- )]2- and the targeted agent [Bi(AAZTA-C4-TATE)]- , which incorporates the SSR agonist Tyr3 -octreotate. An unexpected increase in the stability and kinetic inertness of the metal chelate was observed for the bifunctional derivative and was maintained for the peptide conjugate. A cyclotron-produced 205/206 Bi mixture was used as a model of 213 Bi in labelling, stability, and biodistribution experiments, allowing the efficiency of [213 Bi(AAZTA-C4-TATE)]- to be estimated. High accumulation in AR42J tumours and reduced kidney uptake were observed with respect to the macrocyclic chelate [213 Bi(DOTA-TATE)]- .

The Correlation Between Platelet Count and Survival in Prostate Cancer.

Purpose: A number of studies have confirmed that elevated platelet count accompanying various solid tumours is associated with worse survival. However, only meagre data are available on the relationship between thrombocytosis and survival in prostate cancer. Methods: We conducted a retrospective analysis on clinical-pathological data accumulated from 316 patients during on average 51 months of follow-up after laparoscopic prostatectomy performed for prostate cancer. We analyzed the relationship between platelet count, risk factors, prostate-specific antigen (PSA) and cancer stage with use the Tumor, Node, Metastase system (TNM), as well as surgical margin, and prognosis. Results: Thrombocytosis occurred in only one out of the 316 patients. The multivariate Cox proportional hazard model showed that preoperative PSA, risk group, preoperative haemoglobin level, and surgical margin status were significant, independent predictors of biochemical progression-free survival. By contrast, age at diagnosis and thrombocytosis had no such predictive value. Conclusion: We could not demonstrate an association between elevated platelet count and worse survival in our study population of patients with prostate cancer.

Semi-Rigid (Aminomethyl) Piperidine-Based Pentadentate Ligands for Mn(II) Complexation.

Two pentadentate ligands built on the 2-aminomethylpiperidine structure and bearing two tertiary amino and three oxygen donors (three carboxylates in the case of AMPTA and two carboxylates and one phenolate for AMPDA-HB) were developed for Mn(II) complexation. Equilibrium studies on the ligands and the Mn(II) complexes were carried out using pH potentiometry, 1H-NMR spectroscopy and UV-vis spectrophotometry. The Mn complexes that were formed by the two ligands were more stable than the Mn complexes of other pentadentate ligands but with a lower pMn than Mn(EDTA) and Mn(CDTA) (pMn for Mn(AMPTA) = 7.89 and for Mn(AMPDA-HB) = 7.07). 1H and 17O-NMR relaxometric studies showed that the two Mn-complexes were q = 1 with a relaxivity value of 3.3 mM-1 s-1 for Mn(AMPTA) and 3.4 mM-1 s-1 for Mn(AMPDA-HB) at 20 MHz and 298 K. Finally, the geometries of the two complexes were optimized at the DFT level, finding an octahedral coordination environment around the Mn2+ ion, and MD simulations were performed to monitor the distance between the Mn2+ ion and the oxygen of the coordinated water molecule to estimate its residence time, which was in good agreement with that determined using the 17O NMR data.

Defining the conditions for the development of the emerging class of FeIII-based MRI contrast agents.

Fe(iii) complexes are attracting growing interest in chemists developing diagnostic probes for Magnetic Resonance Imaging because they leverage on an endogenous metal and show superior stability. However, in this case a detailed understanding of the relationship between the chemical structure of the complexes, their magnetic, thermodynamic, kinetic and redox properties and the molecular parameters governing the efficacy (relaxivity) is still far from being available. We have carried out an integrated 1H and 17O NMR relaxometric study as a function of temperature and magnetic field, on the aqua ion and three complexes chosen as reference models, together with theoretical calculations, to obtain accurate values of the parameters that control their relaxivity. Moreover, thermodynamic stability and dissociation kinetics of the Fe(iii) chelates, measured in association with the ascorbate reduction behaviour, highlight their role and mutual influence in achieving the stability required for use in vivo.

Investigation of IL6 expression in patients with colorectal adenocarcinoma / Az interleukin-6-expresszió vizsgálata colorectalis adenocarcinomában szenvedo betegeken

Összefoglaló. Bevezetés: A gyulladásos folyamatok és a tumorok kialakulása, illetve progressziója közötti összetett kapcsolat ismert. Az interleukin-6 (IL6) egy pleiotrop gyulladásos citokin, melynek tumorstimuláló és -gátló tulajdonsága is van. Célkituzés: Kutatásunk célja az IL6-expresszió vizsgálata volt colorectalis adenocarcinoma miatt reszekción átesett betegek szövettani metszetein. Módszer: Az Uzsoki Utcai Kórházban 2004 és 2011 között reszekált 64, colorectalis tumoros beteg demográfiai, sebészeti és patológiai adatait gyujtöttük össze. A betegek szövettani metszeteit IL6-antitesttel festettük. A digitalizált metszeteket kvantitatív színelemzéssel kiértékeltük, majd az eredményeket a betegek klinikai paramétereinek függvényében elemeztük. Eredmények: Elorehaladott stádiumú betegekben a tumorsejtek IL6-expressziója szignifikánsan magasabbnak bizonyult lineáris regresszióval. A tumorsejtek IL6-expressziója azonban nem korrelált a nemmel, az életkorral vagy a tumor differenciáltságával. Megbeszélés: Különbségek mutatkoztak a tumorsejtek és a stromasejtek IL6-kifejezodése között. Következtetés: Az IL6 hasznos marker és potenciális terápiás cél lehet az elorehaladottabb stádiumú colorectalis tumoros betegeknél. Orv Hetil. 2021; 162(37): 1502-1507. INTRODUCTION: It is well known that there is a complex correlation between inflammation and tumor development and tumor progression. Interleukin-6 (IL6) is a pleiotropic inflammatory cytokine with both tumor stimulating and inhibiting effect. OBJECTIVE: The goal of our study was to evaluate the IL6 expression of histological slides from patients after resection of colorectal adenocarcinoma. METHOD: Demographical, surgical, and pathological findings of 64 patients with colorectal cancer operated between 2004 and 2011 in Uzsoki Teaching Hospital were evaluated. Histopathological slides were stained with IL6 antibody. The digitalized slides were assessed with quantitative color analysis, and the results were evaluated according to patients' clinical parameters. RESULTS: Linear regression showed significantly higher IL6 expression in the tumor cells in patients with advanced stages. However, the IL6 expression of the tumor cells did not correlate with sex, age, or tumor grade. DISCUSSION: There were differences between the IL6 expression in tumor cells and stromal cells. CONCLUSION: IL6 may be a useful marker and potential therapeutic target in patients with advanced colorectal cancer. Orv Hetil. 2021; 162(37): 1502-1507.

Treatment of neglected gastric bands ­ review of the literature in relation to a case / Arrodált gyomorgyuruk kezelése - irodalmi áttekintés egy eset kapcsán

Introduction: Extreme obese (BMI: 50.1) 70 year old male patient after LAGB procedure in 2005, with abdominal wall and port infection underwent subcutaneous incision drainage of the area in December 2020. CT and Gastroscopy confirmed gastric penetration and intramural position of the Band. Using laparoscopic approach with incision of 2 cm of the stomach at the gastric greater curvature the band had been removed. Patient had been discharged without any complications. Discussion: LAGB was a very popular bariatric approach at the first decade of laparoscopic bariatric surgery. The increased incidence of short and long term complications reduced worldwide the number of LAGB procedures. Band penetration is a rare but dangerous complication. Laparoscopic removal is recommended. Usually, the intervention is followed by significant weight gain which can be treated with conversion of LAGB to Sleeve Gastrectomy or LGBP procedure.

Underlining the Importance of Peripheral Protic Functional Groups to Enhance the Proton Exchange of Gd-Based MRI Contrast Agents.

In this study, we report the synthesis and the equilibrium, kinetic, relaxation, and structural properties of two new GdIII complexes based on modified 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (HPDO3A) designed to modulate the relaxivity at acidic and basic pH due to intra- and intermolecular proton exchange. The presence of a carboxylic or ester moieties in place of the methyl group of HPDO3A allowed differentiation of a protic and nonprotic functional group, highlighting the importance of the formation of an intramolecular hydrogen bond between the coordinated hydroxyl and the carboxylate groups for proton exchange (kH = 1.5 × 1011 M-1 s-1, kOH = 1.7 × 109 M-1 s-1). The determination of the thermodynamic stability and kinetic inertness of the GdIII complexes confirmed that the modification of peripheral groups does not significantly affect the coordination environment and thus the stability (log KGdL = 19.26, t1/2 = 2.14 × 107 hours, pH = 7.4, 0.15 M NaCl, 25 °C). The relaxivity (r1) was measured as a function of pH to investigate the proton exchange kinetics, and as a function of the magnetic field strength to extrapolate the relaxometric parameters (r1GdL1 = 4.7 mM-1 s-1 and r1GdL2 = 5.1 mM-1 s-1 at 20 MHz, 25 °C, and pH 7.4). Finally, the X-ray crystal structure of the complex crystallized at basic pH showed the formation of a tetranuclear dimer with alkoxide and hydroxide groups bridging the GdIII ions.

Elevated platelet count as a possible prognostic marker of survival in patients with head and neck tumours / A magasabb vérlemezkeszám mint a fej-nyak tumoros betegek túléléssel kapcsolatos esetleges prognosztikai faktora.

Összefoglaló. Bevezetés: Régóta ismert, hogy a daganatokhoz társuló emelkedett vérlemezkeszám rosszabb túléléssel társul. Fej-nyak tumoros betegek esetében kevés információ áll rendelkezésünkre ezzel az összefüggéssel kapcsolatban. Célkituzés: Vizsgálatunk célja a fej-nyak daganatos betegek prognózisa és a thrombocytosis közötti összefüggés tanulmányozása volt. Módszer: Különféle stádiumú és lokalizációjú, 312, fej-nyak tumoros beteg retrospektív adatait elemeztük. A mutét elotti vérlemezkeszámokat vizsgáltuk, a 300 G/l feletti értéket tekintettük emelkedett thrombocytaszámnak. A vérlemezkeszám és a túlélés közötti kapcsolatot Kaplan-Meier-módszerrel és multivariáns Cox-regresszióval elemeztük. Eredmények: Emelkedett thrombocytaszám mellett szignifikánsan rosszabb túlélést észleltünk (5 éves túlélés: p = 0,007, betegségmentes túlélés: p = 0,192). Ez az összefüggés még akkor is fennállt, amikor multivariáns analízissel nemre, korra, stádiumra, differenciáltsági fokra, lokalizációra, valamint fehér- és vörösvérsejtszámra korrigáltuk az elemzést (5 éves túlélés: p = 0,027). A különféle anatómiai lokalizációkban eltéro mértékben észleltünk 300 G/l feletti vérlemezkeszámot (algarat: 43,6%, sub- és supraglottis: 35,8%, szájüreg: 35,7%, hangszalag: 22,5%, szájgarat: 19%, multiplex: 50%), ez azonban nem befolyásolta szignifikánsan a túlélést (p = 0,603). Következtetés: A daganathoz társuló thrombocytosis összefüggésbe hozható a fej-nyak tumoros betegek rosszabb túlélésével. Az egyes lokalizációkban talált különbözo vérlemezkeszámok nem befolyásolják eltéro mértékben a túlélést. Orv Hetil. 2021; 162(17): 676-682. INTRODUCTION: The association between cancer-related thrombocytosis and worse survival has been described with a variety of solid neoplasms. However, only limited data are available on the prognostic significance of elevated platelet count in head and neck tumours. OBJECTIVE: We aimed to investigate the correlation between the survival of patients with head and neck cancer and thrombocytosis. METHOD: We conducted an analysis of the data from 312 patients with head and neck squamous cell carcinoma of various stages and locations. Preoperative platelet counts were analysed; elevated platelet count was defined as 300 G/l or higher. The influence of platelet count on survival was calculated with the Kaplan-Meier method as well as with multivariate Cox regression. RESULTS: In patients with excessive thrombocytosis, survival was significantly worse (overall survival: p = 0.007, disease-free survival: p = 0.192). This association remained significant even after adjusting the multivariate analysis for age, gender as well as tumour stage, grade, location, red and white blood cell count (overall survival: p = 0.027). The magnitude of thrombocytosis differed among tumours of different anatomical locations (hypopharynx: 43.6%, sub- and supraglottis: 35.8%, oral cavity: 35.7%, vocal cord: 22.5%, oropharynx: 19%, multiple: 50%), but this did not affect survival significantly (p = 0.603). CONCLUSION: Elevated platelet count may be related to a worse prognosis in head and neck squamous cell carcinoma patients. The impact of thrombocytosis does not vary with the anatomical location of the tumour. Orv Hetil. 2021; 162(17): 676-682.

H-Bonding and intramolecular catalysis of proton exchange affect the CEST properties of EuIII complexes with HP-DO3A-like ligands.

Eu(HP-DO3A) is present in solution as a mixture of two diastereoisomers whose alcoholic groups are the source of the mobile protons for the CEST effect. The exchange is base catalyzed. Two novel EuIII complexes of HP-DO3A-like ligands containing an amino or a carboxylate functionality in the proximity of the -OH groups showed the occurrence of intramolecular catalysis of the prototropic exchange. New insights into the role of the intramolecular proton exchange on the CEST properties have been gained.

[Gd(AAZTA)]- Derivatives with n-Alkyl Acid Side Chains Show Improved Properties for Their Application as MRI Contrast Agents*.

Herein, the synthesis and an extensive characterization of two novel Gd(AAZTA) (AAZTA=6-amino-6-methylperhydro-1,4-diazepine tetra acetic acid) derivatives functionalized with short (C2 and C4 ) n-alkyl acid functions are reported. The carboxylate functionality is the site for further conjugations for the design of more specific contrast agents (CAs). Interestingly, it has been found that the synthesized complexes display enhanced properties for use as MRI contrast agents on their own. The stability constants determined by using potentiometric titration and UV/Vis spectrophotometry were slightly higher than the one reported for the parent Gd(AAZTA) complex. This observation might be accounted for by the larger sigma-electron donation of the acyl substituents with respect to the one provided by the methyl group in the parent complex. As far as concerns the kinetic stability, transmetallation experiments with endogenous ions (e.g. Cu2+ ) implied that the Gd3+ ions present in these Gd(AAZTA) derivatives show somewhat smaller susceptibility to chemical exchange towards these ions at 25 °C, close to the physiological condition. The 1 H NMR spectra of the complexes with EuIII and YbIII displayed a set of signals consistent with half the number of methylene protons present on each ligand. The number of resonances was invariant over a large range of temperatures, suggesting the occurrence of a fast interconversion between structural isomers. The relaxivity values (298 K, 20 MHz) were consistent with q=2 being equal to 8.8 mm-1 s-1 for the C2 derivative and 9.4 mm-1 s-1 for the C4 one, that is, sensibly larger than the one reported for Gd(AAZTA) (7.1 mm-1 s-1 ). Variable-temperature (VT)-T2 17 O NMR measurements showed, for both complexes, the presence of two populations of coordinated water molecules, one in fast and one in slow exchange with the bulk water. As the high-resolution 1 H NMR spectra of the analogs with EuIII and YbIII did not show the occurrence of distinct isomers (as frequently observed in other macrocyclic lanthanide(III)-containing complexes), we surmised the presence of two fast-interconverting isomers in solution. The analysis of the 17 O NMR VT-T2 profiles versus temperature allowed their relative molar fraction to be established as 35 % for the isomer with the fast exchanging water and 65 % for the isomer with the water molecules in slower exchange. Finally, 1 H NMRD profiles over an extended range of applied magnetic field strengths have been satisfactory fitted on the basis of the occurrence of the two interconverting species.

The relationship between IL-6 and thrombocytosis accompanying gastrointestinal tumours.

INTRODUCTION: Several reports have stated that thrombocytosis is associated with worse survival and higher rate of metastasis in solid tumours. A study in ovarian tumours implicated IL-6 produced by tumour cells as a key mechanistic factor. AIM: To evaluate the relevance of this paraneoplastic pathway in gastrointestinal cancer. MATERIAL AND METHODS: After excluding thromboembolic and inflammatory disorders, 161 patients were enrolled who had been operated due to various gastrointestinal cancer at the 1st Department of Surgery at the Semmelweis University between 2015 and 2017. Platelet counts and serum IL-6 levels were determined from preoperative blood samples. Thrombocytosis was defined as the upper limit of normal platelet count, e.g. 400 × 103/µl. RESULTS: A weak but significantly positive correlation was found between elevated platelet counts and serum IL-6 (correlation coefficient: R = 0.214, p = 0.006), which became more pronounced in colon and oesophageal cancer if evaluated in the different tumour types (R = 0.292 and R = 0.419, respectively). However, using a multivariant linear regression model (R 2 = 0.47) corrected with haemoglobin, white blood cell count, and advanced disease stage, the analysis showed no significant correlation between serum IL-6 and platelet counts. CONCLUSIONS: In gastrointestinal cancer our study did not support the paracrine-mediated paraneoplastic pathway described in ovarian tumors. Thrombocytosis showed significant correlation with white blood cells instead of serum IL-6, which implies that the inflammatory process may influence both parameters. Further studies are needed on larger patient cohorts.

Interaction of macrocyclic gadolinium-based MR contrast agents with Type I collagen. Equilibrium and kinetic studies.

The interactions of gadoterate meglumine, gadobutrol, gadoteridol and Gd(HB-DO3A) with bovine Type I collagen were investigated by ultrafiltration and dialysis. The affinity of the four agents to collagen is similar. However, the maximum adsorbed amount of GdIII-complexes decreases in the following order: gadoterate meglumine > gadobutrol > gadoteridol > Gd(HB-DO3A). Calculations with the open three-compartment model reveal that the structural homologs gadoteridol and Gd(HB-DO3A) have a lower adsorption onto collagen, which may explain the less prolonged in vivo retention of gadoteridol observed in soft tissues of rats.