Multitopic Supramolecular Detection of Chemical Warfare Agents by Fluorescent Sensors

Two new naphthalimide derivatives (hosts), bearing one or two ethanolamine arms, respectively, were synthesized and tested as fluorescent probes for the detection of a chemical warfare agent simulant (guest). The resulting host–guest hydrogen bonds allowed a recognition mechanism based on supramolecular interactions. The sensor with two ethanolamine groups showed excellent sensibility and selectivity in a turn-on fluorescent response

Effects of SGLT2 Inhibitors and GLP-1 Receptor Agonists on Renin-Angiotensin-Aldosterone System

Sodium-glucose cotransporters inhibitors (SGLT2-i) and GLP-1 receptor agonists (GLP1-RA) are glucose-lowering drugs that are proved to reduce the cardiovascular (CV) risk in type 2 diabetes mellitus (T2DM). In this process, the renin-angiotensin-aldosterone system (RAAS) is assumed to play a role. The inhibition of SGLT2 improves hyperglycemia hampering urinary reabsorption of glucose and inducing glycosuria. This “hybrid” diuretic effect, which couples natriuresis with osmotic diuresis, potentially leads to systemic RAAS activation. However, the association between SGLT2-i and systemic RAAS activation is not straightforward. Available data indicate that SGLT2-i cause plasma renin activity (PRA) increase in the early phase of treatment, while PRA and aldosterone levels remain unchanged in chronic treated patients. Furthermore, emerging studies provide evidence that SGLT2-i might have an interfering effect on aldosterone/renin ratio (ARR) in patients with T2DM, due to their diuretic and sympathoinhibition effects. The cardio- and reno-protective effects of GLP-1-RA are at least in part related to the interaction with RAAS. In particular, GLP1-RA counteract the action of angiotensin II (ANG II) inhibiting its synthesis, increasing the inactivation of its circulating form and contrasting its action on target tissue like glomerular endothelial cells and cardiomyocytes. Furthermore, GLP1-RA stimulate natriuresis inhibiting Na+/H+ exchanger NHE-3, which is conversely activated by ANG II. Moreover, GLP1 infusion acutely reduces circulating aldosterone, but this effect does not seem to be chronically maintained in patients treated with GLP1-RA. In conclusion, both SGLT2-i and GLP1-RA seem to have several effects on RAAS, though additional studies are needed to clarify this relationship

Assessment of telomere length during post-natal period in offspring produced by a bull and its fibroblast derived clone

Objective: To investigate the telomere length in bovine offspring produced by a cloned and control bull, and the telomerase activity in embryos produced with the same technology. Methods: Five daughters of a control and five daughters of a bull cloned using a fibroblast of the control were produced by IVF using sperm of the two bulls. Blood samples of the offspring were collected at 2, 6, and 12 months of age and the relative telomere length (RTL) was assessed by flow cytometry. At same time the body growth, hematological profile, and clinical biochemistry of the same progeny was extensively surveyed, and results have been reported in a previous work. Thereafter, the telomerase activity was assessed using a real time PCR quantitative assay in groups of embryos produced with the same technology. Results: The offspring of the clone exhibited a modest, but significant (P<0.05), shortening of the telomeres (21.36%, 20.56% and 20.56%) compared to that of the control (23.78%, 23.53% and 22.43%) as mean values determined at 2, 6 and 12 months, respectively. Shortening of telomeres in respect to the age was not significant. No statistical difference was reported between telomerase activity assessed in 144 cloned (3.4−03 ± 2.4−03 amoles/μL) and 80 control (2.1−03 ± 1.8−03 amoles/μL) embryos. Conclusions: The results have revealed a moderate shortening of telomeres in the offspring of the clone with respect to control. However, this study did not evidence differences in the two progenies that suggest welfare problems during the first year of life

Characterization of human frataxin missense variants in cancer tissues

Human frataxin is an iron binding protein involved in the mitochondrial Fe-S clusters assembly, a process fundamental for the functional activity of mitochondrial proteins. Decreased level of frataxin expression is associated with the neurodegenerative disease Friedreich ataxia. Defective function of frataxin may cause defects in mitochondria, leading to increased tumorigenesis. Tumour initiating cells show higher iron uptake, a decrease in iron storage and a reduced Fe-S clusters synthesis and utilization. In this study we selected, from COSMIC database, the somatic human frataxin missense variants found in cancer tissues p.D104G, p.A107V, p.F109L, p.Y123S, p.S161I, p.W173C, p.S181F, and p.S202F to analyze the effect of the single amino acid substitutions on frataxin structure, function and stability. The spectral properties, the thermodynamic and the kinetic stability, as well as the molecular dynamics of the frataxin missense variants found in cancer tissues point to local changes confined to the environment of the mutated residues. The global fold of the variants is not altered by the amino acid substitutions, however some of the variants show a decreased stability and a decreased functional activity in comparison to that of the wild type protein. This article is protected by copyright. All rights reserved

New steps on an old path: Novel estrogen receptor inhibitors in breast cancer

: Estrogen receptor (ER) signaling represents the main driver of tumor growth and survival in hormone receptor positive (HR+) breast cancer (BC). Thus, endocrine therapy (ET) alone or in combination with targeted agents constitutes the mainstay of the treatment for this BC subtype. Despite its efficacy, intrinsic or acquired resistance to ET occurs in a large proportion of cases, mainly due to aberrant activation of ER signaling (i.e. through ligand-independent ER activation, in the presence of estrogen receptor 1 (ESR1) gene aberration or ER protein phosphorylation) and/or the upregulation of escape pathways, such as the PI3K/AKT/mTOR pathway. Therefore, the development of new ER pathway targeting agents remains essential to delay and overcome ET resistance, enhance treatment efficacy and tolerability, and ultimately prolong patient survival and improve their quality of life. Several novel ER targeting agents are currently under investigation. Among these, the oral selective ER degraders (SERDs) represent the pharmacological class at the most advanced stage of development and promise to enrich the therapeutic armamentarium of HR+&nbsp;BC in the next few years, as they showed promising results in several clinical trials, either as single ET agents or in combination with targeted therapies. In this manuscript, we aim to provide a comprehensive overview on the clinical development of novel ER targeting agents, reporting the most up-to-date evidence on oral SERDs and other compounds, including new selective ER modulators (SERMs), ER proteolysis targeting chimera (PROTACs), selective ER covalent antagonists (SERCAs), complete ER antagonists (CERANs), selective human ER partial agonists (ShERPAs). Furthermore, we discuss the potential implications of introducing these novel treatment strategies in the evolving and complex therapeutic scenario of HR+&nbsp;BC

High accuracy of genome-enabled prediction of belowground and physiological traits in barley seedlings

In plants, the study of belowground traits is gaining momentum due to their importance on yield formation and the uptake of water and nutrients. In several cereal crops, seminal root number and seminal root angle are proxy traits of the root system architecture at the mature stages, which in turn contributes to modulating the uptake of water and nutrients. Along with seminal root number and seminal root angle, experimental evidence indicates that the transpiration rate response to evaporative demand or vapor pressure deficit is a key physiological trait that might be targeted to cope with drought tolerance as the reduction of the water flux to leaves for limiting transpiration rate at high levels of vapor pressure deficit allows to better manage soil moisture. In the present study, we examined the phenotypic diversity of seminal root number, seminal root angle, and transpiration rate at the seedling stage in a panel of 8-way Multiparent Advanced Generation Inter-Crosses lines of winter barley and correlated these traits with grain yield measured in different site-by-season combinations. Second, phenotypic and genotypic data of the Multiparent Advanced Generation Inter-Crosses population were combined to fit and cross-validate different genomic prediction models for these belowground and physiological traits. Genomic prediction models for seminal root number were fitted using threshold and log-normal models, considering these data as ordinal discrete variable and as count data, respectively, while for seminal root angle and transpiration rate, genomic prediction was implemented using models based on extended genomic best linear unbiased predictors. The results presented in this study show that genome-enabled prediction models of seminal root number, seminal root angle, and transpiration rate data have high predictive ability and that the best models investigated in the present study include first-order additive × additive epistatic interaction effects. Our analyses indicate that beyond grain yield, genomic prediction models might be used to predict belowground and physiological traits and pave the way to practical applications for barley improvement

miR-34b/c Regulates Wnt1 and Enhances Mesencephalic Dopaminergic Neuron Differentiation

The differentiation of dopaminergic neurons requires concerted action of morphogens and transcription factors acting in a precise and well-defined time window. Very little is known about the potential role of microRNA in these events. By performing a microRNA-mRNA paired microarray screening, we identified miR-34b/c among the most upregulated microRNAs during dopaminergic differentiation. Interestingly, miR-34b/c modulates Wnt1 expression, promotes cell cycle exit, and induces dopaminergic differentiation. When combined with transcription factors ASCL1 and NURR1, miR-34b/c doubled the yield of transdifferentiated fibroblasts into dopaminergic neurons. Induced dopaminergic (iDA) cells synthesize dopamine and show spontaneous electrical activity, reversibly blocked by tetrodotoxin, consistent with the electrophysiological properties featured by brain dopaminergic neurons. Our findings point to a role for miR-34b/c in neuronal commitment and highlight the potential of exploiting its synergy with key transcription factors in enhancing in vitro generation of dopaminergic neurons.Peer reviewe

Genomic Prediction of Grain Yield in a Barley MAGIC Population Modeling Genotype per Environment Interaction

18 Pags.- 7 Figs.- 4 Tabls. © 2021 Puglisi, Delbono, Visioni, Ozkan, Kara, Casas, Igartua, Valè, Piero, Cattivelli, Tondelli and Fricano. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).Multi-parent Advanced Generation Inter-crosses (MAGIC) lines have mosaic genomes that are generated shuffling the genetic material of the founder parents following pre-defined crossing schemes. In cereal crops, these experimental populations have been extensively used to investigate the genetic bases of several traits and dissect the genetic bases of epistasis. In plants, genomic prediction models are usually fitted using either diverse panels of mostly unrelated accessions or individuals of biparental families and several empirical analyses have been conducted to evaluate the predictive ability of models fitted to these populations using different traits. In this paper, we constructed, genotyped and evaluated a barley MAGIC population of 352 individuals developed with a diverse set of eight founder parents showing contrasting phenotypes for grain yield. We combined phenotypic and genotypic information of this MAGIC population to fit several genomic prediction models which were cross-validated to conduct empirical analyses aimed at examining the predictive ability of these models varying the sizes of training populations. Moreover, several methods to optimize the composition of the training population were also applied to this MAGIC population and cross-validated to estimate the resulting predictive ability. Finally, extensive phenotypic data generated in field trials organized across an ample range of water regimes and climatic conditions in the Mediterranean were used to fit and cross-validate multi-environment genomic prediction models including G×E interaction, using both genomic best linear unbiased prediction and reproducing kernel Hilbert space along with a non-linear Gaussian Kernel. Overall, our empirical analyses showed that genomic prediction models trained with a limited number of MAGIC lines can be used to predict grain yield with values of predictive ability that vary from 0.25 to 0.60 and that beyond QTL mapping and analysis of epistatic effects, MAGIC population might be used to successfully fit genomic prediction models. We concluded that for grain yield, the single-environment genomic prediction models examined in this study are equivalent in terms of predictive ability while, in general, multi-environment models that explicitly split marker effects in main and environmental-specific effects outperform simpler multi-environment models.This research was carried out in the framework of the iBarMed project, which has been funded through the ARIMNet2 initiative and the Italian “Ministry of Agricultural, Food and Forestry Policies” under grant agreement “DM n. 20120.” ARIMNet2 has received funding from the EU 7th Framework Programme for research, technological development and demonstration under grant agreement no. 618127. The work was also supported by YSTEMIC_1063 (An integrated approach to the challenge of sustainable food systems: adaptive and mitigatory strategies to address climate change and malnutrition: From cereal diversity to plant breeding), a research project funded by Italian “Ministry of Agricultural, Food and Forestry Policies” in the frame of the Knowledge Hub on Food and Nutrition Security.Peer reviewe

Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study

BACKGROUND Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence. METHODS ADIUVO was a multicentre, open-label, parallel, randomised, phase 3 trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I-III, and Ki67 ≤10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14-20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14 study centres fulfilling the eligibility criteria of the ADIUVO trial who refused randomisation and agreed on data collection via the European Network for the Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete. FINDINGS Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67-94) in the mitotane group and 75% (63-90) in the surveillance group (hazard ratio 0·74 [95% CI 0·30-1·85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89-100] in the mitotane group and 86% [74-100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment. FUNDING AIFA, ENSAT Cancer Health F2-2010-259735 programme, Deutsche Forschungsgemeinschaft, Cancer Research UK, and the French Ministry of Health