Phase I Trial of [99mTc]Tc-maSSS-PEG2-RM26, a Bombesin Analogue Antagonistic to Gastrin-Releasing Peptide Receptors (GRPRs), for SPECT Imaging of GRPR Expression in Malignant Tumors.

The gastrin-releasing peptide receptor (GRPR) is overexpressed in prostate cancer (PCa) and in hormone-driven breast cancer (BCa). The aim of this phase I clinical trial was to evaluate safety, biodistribution, and dosimetry after the administration of the recently developed GRPR-targeting antagonistic bombesin analogue [99mTc]Tc-maSSS-PEG2-RM26 in PCa and BCa patients. Planar and whole-body SPECT/CT imaging was performed in six PCa patients and seven BCa patients 2, 4, 6, and 24 h post the intravenous administration of 40 µg of [99mTc]Tc-maSSS-PEG2-RM26 (600-700 MBq). No adverse events or pathological changes were observed. The rapid blood clearance of [99mTc]Tc-maSSS-PEG2-RM26 was observed with predominantly hepatobiliary excretion. The effective doses were 0.0053 ± 0.0007 for male patients and 0.008 ± 0.003 mSv/MBq for female patients. The accumulation of [99mTc]Tc-maSSS-PEG2-RM26 in tumors was observed in four out of six PCa and in seven out of seven BCa patients. In four BCa patients, a high uptake of the agent into the axillary lymph nodes was detected. Immunohistochemistry revealed positive GRPR expression in 60% of primary PCa, 71.4% of BCa tumors, and 50% of examined BCa lymph nodes. In conclusion, a single administration of [99mTc]Tc-maSSS-PEG2-RM26 was safe and well tolerated. [99mTc]Tc-maSSS-PEG2-RM26 SPECT may be useful for tumor detection in PCa and BCa patients, pending further studies.

The effect of resource-saving tillage technologies on the mobility, distribution and migration of trace elements in soil.

The influence of agricultural tillage technologies on the accumulation and distribution of trace elements in the soil is poorly studied. At the same time, intensive agriculture requires large amounts of fertilizers, growth stimulators, pesticides, and other substances, which can effect the ecological safety of the plant products and soil. This paper represents studying the effect of various agricultural techniques (including resource-saving technologies) on the mobility and profile distribution of Pb, Zn, and Cu in Haplic Chernozem. No significant influence of resource-saving tillage technologies was found on the total Pb content. Contrary, the resource-saving tillage technologies was observed to promote the growth of the total Zn and Cu content depending on the cultivation method (by 26% Zn, 34% Cu at minimal tillage, and 28% for both elements using No-till in Ap horizon). Amongst different applied agrotechnologies, there was no influence found on the profile distribution of total elements content. Only two horizons showed the total Pb content accumulation: biogenic (Ap-A) and carbonate (BC-C) horizon. In contrast, the only biogenic accumulation for Zn was determined. Copper characterizes by even distribution over the soil profile. The use of resource-saving agricultural technologies increases exchangeable fraction of Zn, Pb and Cu in soil almost by 1.5-2.0 times in the Ap horizon compared to moldboard ploughing. Despite the increase in the exchangeable fraction of Zn and Cu, this amount of micronutrients is not enough for adequate plant nutrition. The use of various agricultural technologies at Haplic Chernozem led to changes in the distribution of studied elements' exchangeable fraction over the soil profile. The study results suggested a need to increase the amount of Cu and Zn fertilizers applied to the soil with resource-saving cultivation technologies.

Effect of Al and Fe Doping on the Electrochemical Behavior of Li1.2Ni0.133Mn0.534Co0.133O2 Li-Rich Cathode Material.

This article studies the doping of Li-rich cathode materials. Aluminum and iron were chosen as dopants. Li-rich cathode materials for lithium-ion batteries, which were composed of Li1.2Ni0.133Mn0.534Co0.133O2 with a partial replacement of cobalt (2 at %) by iron and aluminum, were synthesized. The dopants were introduced at the precursor synthesis stage by co-precipitation. The presence of Fe and Al in the composition of the synthesized samples was proved by inductively coupled plasma mass spectrometry, X-ray diffraction analysis and X-ray microanalysis. The cathode materials were tested electrochemically. The incorporation of Al and Fe into the structure of lithium-enriched materials improved the cyclability and reduced the voltage fade of the cathodes. An analysis of the electrochemical data showed that the structural changes that occur in the initial cycles are different for the doped and starting materials and affect their cycling stability. The partial cation substitution suppressed the unfavorable phase transition to lower-voltage structures and improved the electrochemical performance of the materials under study.

Influence of the Composition and Testing Modes on the Electrochemical Performance of Li-Rich Cathode Materials.

Li-rich oxides are promising cathode materials for Li-ion batteries. In this work, a number of different compositions of Li-rich materials and various electrochemical testing modes were investigated. The structure, chemical composition, and morphology of the materials synthesized were studied by XRD with Rietveld refinement, ICP-OES, and SEM. The particle size distributions were determined by a laser analyzer. The galvanostatic intermittent titration technique and galvanostatic cycling with different potential limits at various current densities were used to study the materials. The electrochemical study showed that gradual increase in the upper voltage limit (formation cycles) was needed to improve further cycling of the cathode materials under study. A comparison of the data obtained in different voltage ranges showed that a lower cut-off potential of 2.5 V (2.5-4.7 V range) was required for a good cyclability with a high discharge capacity. An increase in the low cut-off potential to 3.0 V (3.0-4.8 V voltage range) did not improve the electrochemical performance of the oxides and, on the contrary, considerably decreased the discharge capacity and increased the capacity fade. The LMR35 cathode material (Li1.149Ni0.184Mn0.482Co0.184O2) demonstrated the best functional properties among all the compositions studied.

Phase I Clinical Trial Using [99mTc]Tc-1-thio-D-glucose for Diagnosis of Lymphoma Patients.

Similar to [18F]-FDG, [99mTc]Tc-1-thio-D-glucose ([99mTc]Tc-TG) also binds to GLUT receptors. The aim of this Phase I study was to evaluate the safety, biodistribution and dosimetry of [99mTc]Tc-TG. Twelve lymphoma patients were injected with 729 ± 102 MBq [99mTc]Tc-TG. Whole-body planar imaging was performed in 10 patients at 2, 4, 6 and 24 h after injection. In all 12 patients, SPECT/CT (at 2 h) and SPECT (at 4 and 6 h) imaging was performed. Vital signs and possible side effects were monitored during imaging and up to 7 days after injection. [99mTc]Tc-TG injections were well-tolerated and no side effects or alterations in blood and urine analyses data were observed. The highest absorbed dose was in the kidneys and urinary bladder wall, followed by the adrenals, prostate, bone marrow, lungs, myocardium, ovaries, uterus, liver and gall bladder wall. [99mTc]Tc-TG SPECT/CT revealed foci of high activity uptake in the lymph nodes of all nine patients with known nodal lesions. Extranodal lesions were detected in all nine cases. In one patient, a lesion in the humerus head, which was not detected by CT, was visualized using [99mTc]Tc-TG. Potentially, [99mTc]Tc-TG can be considered as an additional diagnostic method for imaging GLUT receptors in lymphoma patients.

Effects of Mg Doping at Different Positions in Li-Rich Mn-Based Cathode Material on Electrochemical Performance.

Li-rich Mn-based layered oxides are among the most promising cathode materials for next-generation lithium-ion batteries, yet they suffer from capacity fading and voltage decay during cycling. The electrochemical performance of the material can be improved by doping with Mg. However, the effect of Mg doping at different positions (lithium or transition metals) remains unclear. Li1.2Mn0.54Ni0.13Co0.13O2 (LR) was synthesized by coprecipitation followed by a solid-state reaction. The coprecipitation stage was used to introduce Mg in TM layers (sample LR-Mg), and the solid-state reaction (st) was used to dope Mg in Li layers (LR-Mg(st)). The presence of magnesium at different positions was confirmed by XRD, XPS, and electrochemical studies. The investigations have shown that the introduction of Mg in TM layers is preferable in terms of the electrochemical performance. The sample doped with Mg at the TM positions shows better cyclability and higher discharge capacity than the undoped sample. The poor electrochemical properties of the sample doped with Mg at Li positions are due to the kinetic hindrance of oxidation of the manganese-containing species formed after activation of the Li2MnO3 component of the composite oxide. The oxide LR-Mg(st) demonstrates the lowest lithium-ion diffusion coefficient and the greatest polarization resistance compared to LR and LR-Mg.

Phase I Trial of 99mTc-(HE)3-G3, a DARPin-Based Probe for Imaging of HER2 Expression in Breast Cancer.

Radionuclide molecular imaging of human epidermal growth factor receptor type 2 (HER2) expression may enable a noninvasive discrimination between HER2-positive and HER2-negative breast cancers for stratification of patients for HER2-targeted treatments. DARPin (designed ankyrin repeat proteins) G3 is a small (molecular weight, 14 kDa) scaffold protein with picomolar affinity to HER2. The aim of this first-in-humans study was to evaluate the safety, biodistribution, and dosimetry of 99mTc-(HE)3-G3. Methods: Three cohorts of patients with primary breast cancer (each including at least 4 patients with HER2-negative and 5 patients with HER2-positive tumors) were injected with 1,000, 2,000, or 3,000 µg of 99mTc-(HE)3-G3 (287 ± 170 MBq). Whole-body planar imaging followed by SPECT was performed at 2, 4, 6, and 24 h after injection. Vital signs and possible side effects were monitored during imaging and up to 7 d after injection. Results: All injections were well tolerated. No side effects were observed. The results of blood and urine analyses did not differ before and after studies. 99mTc-(HE)3-G3 cleared rapidly from the blood. The highest uptake was detected in the kidneys and liver followed by the lungs, breasts, and small intestinal content. The hepatic uptake after injection of 2,000 or 3,000 µg was significantly (P < 0.05) lower than the uptake after injection of 1,000 µg. Effective doses did not differ significantly between cohorts (average, 0.011 ± 0.004 mSv/MBq). Tumor-to-contralateral site ratios for HER-positive tumors were significantly (P < 0.05) higher than for HER2-negative at 2 and 4 h after injection. Conclusion: Imaging of HER2 expression using 99mTc-(HE)3-G3 is safe and well tolerated and provides a low absorbed dose burden on patients. This imaging enables discernment of HER2-positive and HER2-negative breast cancer. Phase I study data justify further clinical development of 99mTc-(HE)3-G3.

Chromatin Structure and "DNA Sequence View": The Role of Satellite DNA in Ectopic Pairing of the Drosophila X Polytene Chromosome.

Chromatin 3D structure plays a crucial role in regulation of gene activity. Previous studies have envisioned spatial contact formations between chromatin domains with different epigenetic properties, protein compositions and transcription activity. This leaves specific DNA sequences that affect chromosome interactions. The Drosophila melanogaster polytene chromosomes are involved in non-allelic ectopic pairing. The mutant strain agnts3, a Drosophila model for Williams-Beuren syndrome, has an increased frequency of ectopic contacts (FEC) compared to the wild-type strain Canton-S (CS). Ectopic pairing can be mediated by some specific DNA sequences. In this study, using our Homology Segment Analysis software, we estimated the correlation between FEC and frequency of short matching DNA fragments (FMF) for all sections of the X chromosome of Drosophila CS and agnts3 strains. With fragment lengths of 50 nucleotides (nt), CS showed a specific FEC-FMF correlation for 20% of the sections involved in ectopic contacts. The correlation was unspecific in agnts3, which may indicate the alternative epigenetic mechanisms affecting FEC in the mutant strain. Most of the fragments that specifically contributed to FMF were related to 1.688 or 372-bp middle repeats. Thus, middle repetitive DNA may serve as an organizer of ectopic pairing.

Nitrogen state of Haplic Chernozem of the European part of Southern Russia in the implementation of resource-saving technologies.

BACKGROUND: The prolonged use of traditional moldboard ploughing often results in soil degradation and, ultimately, has an impact on national food security. Therefore, the implementation of resource-saving technologies (minimal and No-till) is a promising approach in the development of agriculture, especially in drought regions. The present study reports the results of long-term research on the effect of various tillage methods (moldboard ploughing, minimal tillage and No-till technique) on the nitrogen content of Haplic Chernozem of the European part of Southern Russia. The revealed regularities can be used as a theoretical basis for the effective use of resource-saving technologies, including No-till, in the zone of insufficient moisture. RESULTS: Long-term (59 years) cultivation of winter wheat using traditional moldboard ploughing has decreased the soil organic material (SOM) by 35% and total nitrogen by 32% in the soil. Minimization of tillage, in contrast, recovers the nitrogen potential of the soil in winter wheat agrocenoses. There is a statistically confirmed dependence of the content of SOM and total nitrogen on the tillage method of the upper soil horizon, with no significant effect of the tillage methods on intensity ammonification and nitrification. However, the content of nitrate-nitrogen during resource-saving tillage methods (22.8-24.4 mg kg-1 ) was higher than that after ploughing (20.3 mg kg-1 ) during all the years of the study, indicating the higher content of easily mineralizable nitrogen-containing compounds in the soil after minimal tillage. CONCLUSION: The use of resource-saving tillage technologies under conditions of insufficient moisture stabilizes the nitrogen content in soil and can improve nitrogen nutrition of plants. © 2020 Society of Chemical Industry.

Phase I Study of 99mTc-ADAPT6, a Scaffold Protein-Based Probe for Visualization of HER2 Expression in Breast Cancer.

Radionuclide molecular imaging of human epidermal growth factor receptor type 2 (HER2) expression may help to stratify breast and gastroesophageal cancer patients for HER2-targeting therapies. Albumin-binding domain-derived affinity proteins (ADAPTs) are a new type of small (46-59 amino acids) protein useful as probes for molecular imaging. The aim of this first-in-humans study was to evaluate the biodistribution, dosimetry, and safety of the HER2-specific 99mTc-ADAPT6. Methods: Twenty-nine patients with primary breast cancer were included. In 22 patients with HER2-positive (n = 11) or HER2-negative (n = 11) histopathology, an intravenous injection of 385 ± 125 MBq of 99mTc-ADAPT6 was performed, randomized to an injected protein mass of either 500 µg (n = 11) or 1,000 µg (n = 11). Planar scintigraphy followed by SPECT imaging was performed after 2, 4, 6, and 24 h. An additional cohort (n = 7) was injected with 165 ± 29 MBq (injected protein mass, 250 µg), and imaging was performed after 2 h only. Results: Injections of 99mTc-ADAPT6 were well tolerated at all mass levels and not associated with adverse effects. 99mTc-ADAPT6 cleared rapidly from the blood and most other tissues. The normal organs with the highest accumulation were the kidney, liver, and lung. Effective doses were 0.009 ± 0.002 and 0.010 ± 0.003 mSv/MBq for injected protein masses of 500 and 1,000 µg, respectively. Injection of 500 µg resulted in excellent discrimination between HER2-positive and HER2-negative tumors as early as 2 h after injection (tumor-to-contralateral breast ratio, 37 ± 19 vs. 5 ± 2; P < 0.01). The tumor-to-contralateral breast ratios for HER2-positive tumors were significantly (P < 0.05) higher for an injected mass of 500 µg than for either 250 or 1,000 µg. Conclusion: Injections of 99mTc-ADAPT6 are safe and associated with low absorbed and effective doses. A protein dose of 500 µg is preferable for discrimination between tumors with high and low expression of HER2. Further studies are justified to evaluate whether 99mTc-ADAPT6 can be used as an imaging probe to stratify patients for HER2-targeting therapy in areas where PET imaging is not readily available.

Drosophila Model for the Analysis of Genesis of LIM-kinase 1-Dependent Williams-Beuren Syndrome Cognitive Phenotypes: INDELs, Transposable Elements of the Tc1/Mariner Superfamily and MicroRNAs.

Genomic disorders, the syndromes with multiple manifestations, may occur sporadically due to unequal recombination in chromosomal regions with specific architecture. Therefore, each patient may carry an individual structural variant of DNA sequence (SV) with small insertions and deletions (INDELs) sometimes less than 10 bp. The transposable elements of the Tc1/mariner superfamily are often associated with hotspots for homologous recombination involved in human genetic disorders, such as Williams Beuren Syndromes (WBS) with LIM-kinase 1-dependent cognitive defects. The Drosophila melanogaster mutant agnts3 has unusual architecture of the agnostic locus harboring LIMK1: it is a hotspot of chromosome breaks, ectopic contacts, underreplication, and recombination. Here, we present the analysis of LIMK1-containing locus sequencing data in agnts3 and three D. melanogaster wild-type strains-Canton-S, Berlin, and Oregon-R. We found multiple strain-specific SVs, namely, single base changes and small INDEls. The specific feature of agnts3 is 28 bp A/T-rich insertion in intron 1 of LIMK1 and the insertion of mobile S-element from Tc1/mariner superfamily residing ~460 bp downstream LIMK1 3'UTR. Neither of SVs leads to amino acid substitutions in agnts3 LIMK1. However, they apparently affect the nucleosome distribution, non-canonical DNA structure formation and transcriptional factors binding. Interestingly, the overall expression of miRNAs including the biomarkers for human neurological diseases, is drastically reduced in agnts3 relative to the wild-type strains. Thus, LIMK1 DNA structure per se, as well as the pronounced changes in total miRNAs profile, probably lead to LIMK1 dysregulation and complex behavioral dysfunctions observed in agnts3 making this mutant a simple plausible Drosophila model for WBS.

Non-coding RNA as a trigger of neuropathologic disorder phenotypes in transgenic Drosophila.

At most, many protein-misfolding diseases develop as environmentally induced sporadic disorders. Recent studies indicate that the dynamic interplay between a wide repertoire of noncoding RNAs and the environment play an important role in brain development and pathogenesis of brain disorders. To elucidate this new issue, novel animal models which reproduce the most prominent disease manifestations are required. For this, transgenic Drosophila strains were constructed to express small highly structured, non-coding RNA under control of a heat shock promoter. Expression of the RNA induced formation of intracellular aggregates revealed by Thioflafin T in embryonic cell culture and Congo Red in the brain of transgenic flies. Also, this strongly perturbed the brain control of locomotion monitored by the parameters of sound production and memory retention of young 5-day-old males. This novel model demonstrates that expression of non-coding RNA alone is sufficient to trigger neuropathology.

Role of non-coding RNAs in neurodegeneration and stress response in Drosophila.

The inherent limitations of genetic analysis in humans and other mammals as well as striking conservation of most genes controlling nervous system functioning in flies and mammals made Drosophila an attractive model to investigate various aspects of brain diseases. Since RNA research has made great progress in recent years here we present an overview of studies demonstrating the role of various non-coding RNAs in neurodegeneration and stress response in Drosophila as a model organism. We put special emphasis on the role of non-coding micro RNAs, hsr-omega transcripts, and artificial small highly structured RNAs as triggers of neuropathology including aggregates formation, cognitive abnormalities and other symptoms. Cellular stress is a conspicuous feature of many neurodegenerative diseases and the production of specialized proteins protects the nerve cells against aggregates formation. Therefore, herein we describe some data implicating various classes of non-coding RNAs in stress response in Drosophila. All these findings highlight Drosophila as an important model system to investigate various brain diseases potentially mediated by some non-coding RNAs including polyglutamine diseases, Alzheimer's disease, Huntigton's disease, and many others.

Pathogenic chaperone-like RNA induces congophilic aggregates and facilitates neurodegeneration in Drosophila.

Protein aggregation is a hallmark of many neurodegenerative diseases. RNA chaperones have been suggested to play a role in protein misfolding and aggregation. Noncoding, highly structured RNA recently has been demonstrated to facilitate transformation of recombinant and cellular prion protein into proteinase K-resistant, congophilic, insoluble aggregates and to generate cytotoxic oligomers in vitro. Transgenic Drosophila melanogaster strains were developed to express highly structured RNA under control of a heat shock promoter. Expression of a specific construct strongly perturbed fly behavior, caused significant decline in learning and memory retention of adult males, and was coincident with the formation of intracellular congophilic aggregates in the brain and other tissues of adult and larval stages. Additionally, neuronal cell pathology of adult flies was similar to that observed in human Parkinson's and Alzheimer's disease. This novel model demonstrates that expression of a specific highly structured RNA alone is sufficient to trigger neurodegeneration, possibly through chaperone-like facilitation of protein misfolding and aggregation.