Synthesis, spectroscopic characterisation, corrosion inhibition studies and dyeing properties of lanthanide(III) complexes of 1-[(3-carboxyethyl-4,5-dimethylthiophen-2-yl)azo]-2-naphthol

Ligational behaviour of the heterocyclic ligand obtained by coupling of diazotized 2-amino-3-carboxyethyl-4,5-dimethylthiophene with β-naphthol towards some selected lanthanide(III) ions has been studied. Various spectral and physico-chemical techniques have been used to confirm the coordination sites of the ligand (HTAN) and its lanthanide(III) complexes. It has been observed that these ligands coordinate to the metal ions in a neutral tridentate fashion. Thermal stability of metal chelates and structural stability of the chelating agent has been studied by thermal analysis. As lanthanides and azo dyes are reported as good corrosion inhibitors we have examined the corrosion inhibition activities of HTAN and its metal complexes. Also dyeing properties of the azo dye and some of its selected complexes towards cotton fabrics has been evaluated, as the traditional application field of the synthetic azo dyes still remains in the textile industry

Citostatsko i protuupalno djelovanje polisaharida biljke Ganoderma lucidum

In this study, polysaccharides were isolated from Ganoderma lucidum (Polyporaceae) and their antitumor and anti-inflammatory activities were investigated using in vivo models. Potential antitumor activity was shown by G. lucidum polysaccharides (GLP) against solid tumor induced by Ehrlich’s ascites carcinoma cells. GLP at 100 mg kg–1 body mass showed 80.8 and 77.6 % reduction in tumour volume and tumour mass, respectively, when administered 24 h after tumour implantation. Again, GLP at the same dose but when administered prior to tumour inoculation, showed 79.5 and 81.2 % inhibition of tumour volume and tumour mass, respectively. GLP showed significant dose-dependent activity in carrageenean-induced (acute) and formalin-induced (chronic) inflammation assays. At 100 mg kg–1, GLP exhibited 57.6 and 58.2 % inhibition in carrageenean-induced and formalin-induced assays, respectively.U radu je ispitano in vivo citostatsko i protuupalno djelovanje polisaharida (GLP) izoliranih iz biljke Ganoderma lucidum (Polyporaceae). Ispitivani polisaharidi pokazali su potencijalno antitumorsko djelovanje na Ehrlichov ascitesni tumor. GLP su u dozi od 100 mg kg1 tjelesne mase inhibirali volumen tumora za 80,8, a njegovu masu za 77,6 %, kada su primijenjeni 24 h nakon implantacije tumora. Ako se GLP daju u istoj dozi prije inokulacije tumora, inhibiraju volumen tumora za 79,5, a njegovu masu za 81,2 %. GLP pokazuju značajno, o dozi ovisno, protuupalno djelovanje u karagenan testu (akutna upala) i formalin testu (kronična upala). U dozi od 100 mg kg1, GLP inhibiraju upalne procese za 57,6 odnosno 58,2 % u testu s karagenanom, odnosno formalinom

Citostatsko i protuupalno djelovanje polisaharida biljke Ganoderma lucidum

In this study, polysaccharides were isolated from Ganoderma lucidum (Polyporaceae) and their antitumor and anti-inflammatory activities were investigated using in vivo models. Potential antitumor activity was shown by G. lucidum polysaccharides (GLP) against solid tumor induced by Ehrlich’s ascites carcinoma cells. GLP at 100 mg kg–1 body mass showed 80.8 and 77.6 % reduction in tumour volume and tumour mass, respectively, when administered 24 h after tumour implantation. Again, GLP at the same dose but when administered prior to tumour inoculation, showed 79.5 and 81.2 % inhibition of tumour volume and tumour mass, respectively. GLP showed significant dose-dependent activity in carrageenean-induced (acute) and formalin-induced (chronic) inflammation assays. At 100 mg kg–1, GLP exhibited 57.6 and 58.2 % inhibition in carrageenean-induced and formalin-induced assays, respectively.U radu je ispitano in vivo citostatsko i protuupalno djelovanje polisaharida (GLP) izoliranih iz biljke Ganoderma lucidum (Polyporaceae). Ispitivani polisaharidi pokazali su potencijalno antitumorsko djelovanje na Ehrlichov ascitesni tumor. GLP su u dozi od 100 mg kg1 tjelesne mase inhibirali volumen tumora za 80,8, a njegovu masu za 77,6 %, kada su primijenjeni 24 h nakon implantacije tumora. Ako se GLP daju u istoj dozi prije inokulacije tumora, inhibiraju volumen tumora za 79,5, a njegovu masu za 81,2 %. GLP pokazuju značajno, o dozi ovisno, protuupalno djelovanje u karagenan testu (akutna upala) i formalin testu (kronična upala). U dozi od 100 mg kg1, GLP inhibiraju upalne procese za 57,6 odnosno 58,2 % u testu s karagenanom, odnosno formalinom

Cre recombinase expression cooperates with homozygous FLT3 internal tandem duplication knockin mouse model to induce acute myeloid leukemia

Murine models offer a valuable tool to recapitulate genetically defined subtypes of AML, and to assess the potential of compound mutations and clonal evolution during disease progression. This is of particular importance for difficult to treat leukemias such as FLT3 internal tandem duplication (ITD) positive AML. While conditional gene targeting by Cre recombinase is a powerful technology that has revolutionized biomedical research, consequences of Cre expression such as lack of fidelity, toxicity or off-target effects need to be taken into consideration. We report on a transgenic murine model of FLT3-ITD induced disease, where Cre recombinase expression alone, and in the absence of a conditional allele, gives rise to an aggressive leukemia phenotype. Here, expression of various Cre recombinases leads to polyclonal expansion of FLT3(ITD/ITD) progenitor cells, induction of a differentiation block and activation of Myc-dependent gene expression programs. Our report is intended to alert the scientific community of potential risks associated with using this specific mouse model and of unexpected effects of Cre expression when investigating cooperative oncogenic mutations in murine models of cancer

Toward identifying reproducible brain signatures of obsessive-compulsive profiles: rationale and methods for a new global initiative

Background Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2–3% and is a leading cause of global disability. Brain circuit abnormalities in individuals with OCD have been identified, but important knowledge gaps remain. The goal of the new global initiative described in this paper is to identify robust and reproducible brain signatures of measurable behaviors and clinical symptoms that are common in individuals with OCD. A global approach was chosen to accelerate discovery, to increase rigor and transparency, and to ensure generalizability of results. Methods We will study 250 medication-free adults with OCD, 100 unaffected adult siblings of individuals with OCD, and 250 healthy control subjects at five expert research sites across five countries (Brazil, India, Netherlands, South Africa, and the U.S.). All participants will receive clinical evaluation, neurocognitive assessment, and magnetic resonance imaging (MRI). The imaging will examine multiple brain circuits hypothesized to underlie OCD behaviors, focusing on morphometry (T1-weighted MRI), structural connectivity (Diffusion Tensor Imaging), and functional connectivity (resting-state fMRI). In addition to analyzing each imaging modality separately, we will also use multi-modal fusion with machine learning statistical methods in an attempt to derive imaging signatures that distinguish individuals with OCD from unaffected siblings and healthy controls (Aim #1). Then we will examine how these imaging signatures link to behavioral performance on neurocognitive tasks that probe these same circuits as well as to clinical profiles (Aim #2). Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, and religiosity) moderate these brain-behavior associations. Discussion Using harmonized methods for data collection and analysis, we will conduct the largest neurocognitive and multimodal-imaging study in medication-free subjects with OCD to date. By recruiting a large, ethno-culturally diverse sample, we will test whether there are robust biosignatures of core OCD features that transcend countries and cultures. If so, future studies can use these brain signatures to reveal trans-diagnostic disease dimensions, chart when these signatures arise during development, and identify treatments that target these circuit abnormalities directly. The long-term goal of this research is to change not only how we conceptualize OCD but also how we diagnose and treat it

Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia

Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML

Brain structural covariance networks in obsessive-compulsive disorder : a graph analysis from the ENIGMA Consortium

In the largest brain structural covariance study of OCD to date, Yun et al. show a less segregated organization of structural covariance networks and a reorganization of brain hubs, including cingulate and orbitofrontal regions, in OCD. The findings point to altered trajectories of brain development and maturation. Brain structural covariance networks reflect covariation in morphology of different brain areas and are thought to reflect common trajectories in brain development and maturation. Large-scale investigation of structural covariance networks in obsessive-compulsive disorder (OCD) may provide clues to the pathophysiology of this neurodevelopmental disorder. Using T-weighted MRI scans acquired from 1616 individuals with OCD and 1463 healthy controls across 37 datasets participating in the ENIGMA-OCD Working Group, we calculated intra-individual brain structural covariance networks (using the bilaterally-averaged values of 33 cortical surface areas, 33 cortical thickness values, and six subcortical volumes), in which edge weights were proportional to the similarity between two brain morphological features in terms of deviation from healthy controls (i.e. z -score transformed). Global networks were characterized using measures of network segregation (clustering and modularity), network integration (global efficiency), and their balance (small-worldness), and their community membership was assessed. Hub profiling of regional networks was undertaken using measures of betweenness, closeness, and eigenvector centrality. Individually calculated network measures were integrated across the 37 datasets using a meta-analytical approach. These network measures were summated across the network density range of K = 0.10-0.25 per participant, and were integrated across the 37 datasets using a meta-analytical approach. Compared with healthy controls, at a global level, the structural covariance networks of OCD showed lower clustering (P < 0.0001), lower modularity (P < 0.0001), and lower small-worldness (P = 0.017). Detection of community membership emphasized lower network segregation in OCD compared to healthy controls. At the regional level, there were lower (rank-transformed) centrality values in OCD for volume of caudate nucleus and thalamus, and surface area of paracentral cortex, indicative of altered distribution of brain hubs. Centrality of cingulate and orbito-frontal as well as other brain areas was associated with OCD illness duration, suggesting greater involvement of these brain areas with illness chronicity. In summary, the findings of this study, the largest brain structural covariance study of OCD to date, point to a less segregated organization of structural covariance networks in OCD, and reorganization of brain hubs. The segregation findings suggest a possible signature of altered brain morphometry in OCD, while the hub findings point to OCD-related alterations in trajectories of brain development and maturation, particularly in cingulate and orbitofrontal regions

The thalamus and its subnuclei—a gateway to obsessive-compulsive disorder

Larger thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population. Particular thalamic subregions may drive these differences. The ENIGMA-OCD working group conducted mega- and meta-analyses to study thalamic subregional volume in OCD across the lifespan. Structural T-1-weighted brain magnetic resonance imaging (MRI) scans from 2649 OCD patients and 2774 healthy controls across 29 sites (50 datasets) were processed using the FreeSurfer built-in ThalamicNuclei pipeline to extract five thalamic subregions. Volume measures were harmonized for site effects using ComBat before running separate multiple linear regression models for children, adolescents, and adults to estimate volumetric group differences. All analyses were pre-registered (https://osf.io/73dvy) and adjusted for age, sex and intracranial volume. Unmedicated pediatric OCD patients (<12 years) had larger lateral (d = 0.46), pulvinar (d = 0.33), ventral (d = 0.35) and whole thalamus (d = 0.40) volumes at unadjusted p-values <0.05. Adolescent patients showed no volumetric differences. Adult OCD patients compared with controls had smaller volumes across all subregions (anterior, lateral, pulvinar, medial, and ventral) and smaller whole thalamic volume (d = -0.15 to -0.07) after multiple comparisons correction, mostly driven by medicated patients and associated with symptom severity. The anterior thalamus was also significantly smaller in patients after adjusting for thalamus size. Our results suggest that OCD-related thalamic volume differences are global and not driven by particular subregions and that the direction of effects are driven by both age and medication status