Auto-degradable and biocompatible superparamagnetic iron oxide nanoparticles/polypeptides colloidal polyion complexes with high density of magnetic material

International audienceHypothesis: superparamagnetic iron oxide nanoparticles (SPIONs) are extensively used as building block of colloidal nanocomposites for biomedical applications. Strategies employed to embed them in a biodegradable and biocompatible polymer matrix often fail to achieve a high density of loading which would greatly benefit to applications such as imaging and hyperthermia. In this study, poly(acrylic acid) coated SPION (γ-Fe2O3-PAA) are self-assembled with hydrolysable poly(serine ester) by electrostatic complexation, leading to perfectly defined spherical particles with ultra-high density of magnetic material and an ability to auto-degrade into individual SPION and biocompatible byproducts.Experiments: self-assembly and auto-degradation of γ-Fe2O3-PAA/poly(serine ester) and γ-Fe2O3-PAA/poly(serine ester)-b-PEG colloidal particles are studied by light scattering and microscopy. Colloidal stability in bio-fluids, hyperthermia under alternating magnetic field, cellular uptake, cytotoxicity and degradation of γ-Fe2O3-PAA/poly(serine ester)-b-PEG in living cells are investigated.Findings: a remarkably slow electrostatic complexation leads to dense superparamagnetic γ-Fe2O3-PAA/poly(serine ester)-b-PEG polyion complexes (PICs) with controlled sizes (150 – 500 nm) and times of degradation in aqueous solvents (700 – 5000 h). The material shows good sustainability during hyperthermia, is well taken up by MC3T3 cells and non-cytotoxic. TEM images reveal a mechanism of degradation by “peeling” and fragmentation. In cells, PICs are reduced into individual SPIONs within 72 h

Sleeping More Hours Per Day Than Working Can Prevent New-Onset Diabetes

Objectives: We expressed the combined effect by the ratio of daily sleep time to daily work time. The aim of this study was to discussed the predictive ability of daily sleep hours/work hours (SH/WH) ratio for diabetes risk.Methods: Cox proportional hazards regression was used to calculate the hazard ratios (HRs) of new-onset diabetes. Restricted cubic spline analyses were performed to visualize the influence trend of SH/WH ratio and diabetes risk.Results: The RCS model revealed a non-linear and L-shaped correlation between SH/WH ratio and diabetes risk. Compared with the participates with SH/WH ratio <1, those with a ratio ≥1 had a lower risk of developing diabetes. The multivariable adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of new-onset diabetes in Q2, Q3, Q4 and Q5 groups compared with Q1 group were 0.82 (0.57, 1.19), 1.05 (0.69, 1.59), 0.57 (0.36, 0.91), 0.66 (0.42, 1.06). The Kaplan-Meier curve showed that Q4 group had lower cumulative incidence.Conclusion: Sleeping longer than working (SH/WH ratio ≥1) can reduce risk for developing diabetes. A minimal risk observed at 1.10–<1.37 (the fourth quintile) of SH/WH ratio

Association of Serum Uric Acid with Arterial Stiffness in Peritoneal Dialysis Patients

Background/Aims: Serum uric acid (SUA) has been proposed as a mediator associated with increased cardiovascular risk and arterial stiffness. However, evidence on the association between SUA and arterial stiffness in peritoneal dialysis (PD) patients is lacking. The aim of this study was to examine the relationship between SUA and arterial stiffness in PD patients. Methods: The patients who performed vascular profiler test from January 1, 2014 to October 31, 2016, and with SUA values were enrolled. Arterial stiffness was evaluated by brachial-ankle pulse wave velocity (baPWV). The relationship between SUA and baPWV was tested by multiple linear regression models. Results: Of 645 PD patients, mean SUA was 6.80 (±1.29) mg/dL, mean baPWV was 1713 (±505) cm/s. In fully adjusted linear regression models, higher SUA was significantly associated with higher baPWV in young [standardized coefficients (β), 0.085; 95% confidence interval (95% CI), 0.013 to 0.130; P=0.02] but not in elderly (β, -0.194; 95% CI, -0.774 to 0.093; P=0.1) PD patients. In gender-stratified models of young patients, there was a significant association between SUA and baPWV in male (β, 0.115; 95% CI, 0.015 to 0.182; P=0.02) but not in female. Male in the highest gender-specific SUA quartile had a higher baPWV than those in the lowest quartile (β, 0.132; 95% CI, 0.011 to 0.209; P=0.03). This gender difference was reversed when selecting male patients with lower SUA levels (quartile 1 and 2) and female patients with higher SUA levels (quartile 3 and 4). Conclusion: SUA was positively associated with baPWV in young PD patients, and this association was significant in males but not in females, which is possibly explained by the higher SUA level in males than in females

Quantitative determination of the orbital-selective Mott transition and quantum entanglement in the orbital-selective Mott phase

We examine the orbital-selective Mott transition in the non-hybridized two-band Hubbard model using the dynamical mean-field theory. We find that the orbital-selective Mott transition could be quantitatively depicted by the {local two-qubit fidelity}. Furthermore, within the orbital-selective Mott phase, the combined characteristics of the two orbitals lead to the presence of quantum entanglement, which is characterized by the non-semi-integer values of local two-qubit fidelity. It is demonstrated that the Hund\u27s coupling results in the ground states of both wide and narrow bands exhibiting the specific superposition states, indicating the existence of quantum entanglement within orbital-selective Mott phase. Without Hund\u27s coupling, there are no specific superposition states, nor does quantum entanglement occur within the orbital-selective Mott phase. The mechanisms underlying the orbital-selective Mott transition show prominent variations depending on the presence or absence of Hund\u27s coupling and its transverse terms.6 pages, 4 figure

Downregulation of ITGβ3 in colon adenocarcinoma reveals poor prognosis by affecting genome stability, cell cycle, and the tumor immune microenvironment

IntroductionAbnormal expression of integrin subunit beta 3 (ITGβ3), a gene-encoding protein, is related to the occurrence and development of cancers; however, the biological role of ITGβ3 in colon adenocarcinoma (COAD) remains unclear.MethodsWe used the Cancer Genome Atlas database to obtain the clinical data of patients with COAD, analyzed the mRNA gene clusters related to ITGβ3, and analyzed the interaction signal pathway and interaction protein network of the differentially expressed gene clusters. The results showed that ITGβ3 expression in COAD tumor tissues was significantly downregulated compared with that in paracancerous tissues. Low ITGβ3 expression in tumor tissues is associated with poor overall survival of patients with COAD. In multivariate analysis, stage IV and ITGβ3 low expression were independent prognostic factors. Gene Ontology analysis showed that differentially expressed genes (DEGs) were significantly enriched in leukocyte migration, cell adhesion, and extracellular matrix (ECM) organization. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the DEGs were mainly enriched in ECM-receptor interactions, focal adhesion, and the PI3K-Akt signaling pathway. Protein-protein interaction network analysis revealed the hub and seed genes of the key modules related to ITGβ3. Finally, we analyzed the correlation between TGβ3 and immune-related genes and found that ITGβ3 expression was significantly correlated with tumor purity and infiltration level of dominant immune cells.DiscussionThese findings indicate that ITGβ3 downregulation in COAD may profoundly affect genome stability and multiple steps of the cell cycle, alter the tumor immune microenvironment, and be related to the prognosis of patients with COAD

Clinicopathological Significance and Prognostic Value of DNA Methyltransferase 1, 3a, and 3b Expressions in Sporadic Epithelial Ovarian Cancer

Altered DNA methylation of tumor suppressor gene promoters plays a role in human carcinogenesis and DNA methyltransferases (DNMTs) are responsible for it. This study aimed to determine aberrant expression of DNMT1, DNMT3a, and DNMT3b in benign and malignant ovarian tumor tissues for their association with clinicopathological significance and prognostic value. A total of 142 ovarian cancers and 44 benign ovarian tumors were recruited for immunohistochemical analysis of their expression. The data showed that expression of DNMT1, DNMT3a, and DNMT3b was observed in 76 (53.5%), 92 (64.8%) and 79 (55.6%) of 142 cases of ovarian cancer tissues, respectively. Of the serious tumors, DNMT3a protein expression was significantly higher than that in benign tumor samples (P = 0.001); DNMT3b was marginally significant down regulated in ovarian cancers compared to that of the benign tumors (P = 0.054); DNMT1 expression has no statistical difference between ovarian cancers and benign tumor tissues (P = 0.837). Of the mucious tumors, the expression of DNMT3a, DNMT3b, and DNMT1 was not different between malignant and benign tumors. Moreover, DNMT1 expression was associated with DNMT3b expression (P = 0.020, r = 0.195). DNMT1 expression was associated with age of the patients, menopause status, and tumor localization, while DNMT3a expression was associated with histological types and serum CA125 levels and DNMT3b expression was associated with lymph node metastasis. In addition, patients with DNMT1 or DNMT3b expression had a trend of better survival than those with negative expression. Co-expression of DNMT1 and DNMT3b was significantly associated with better overall survival (P = 0.014). The data from this study provided the first evidence for differential expression of DNMTs proteins in ovarian cancer tissues and their associations with clinicopathological and survival data in sporadic ovarian cancer patients

Safety, tolerability, and efficacy of subcutaneous efgartigimod in patients with chronic inflammatory demyelinating polyradiculoneuropathy (ADHERE): a multicentre, randomised-withdrawal, double-blind, placebo-controlled, phase 2 trial

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system that can lead to severe disability from muscle weakness and sensory disturbances. Around a third of patients do not respond to currently available treatments, and many patients with a partial response have residual neurological impairment, highlighting the need for effective alternatives. Efgartigimod alfa, a human IgG1 antibody Fc fragment, has demonstrated efficacy and safety in patients with generalised myasthenia gravis. We evaluated the safety, tolerability, and efficacy of subcutaneous efgartigimod PH20 in adults with CIDP. Methods: ADHERE, a multistage, double-blind, placebo-controlled trial, enrolled participants with CIDP from 146 clinical sites from Asia-Pacific, Europe, and North America. Participants with evidence of clinically meaningful deterioration entered an open-label phase of weekly 1000 mg subcutaneous efgartigimod PH20 for no longer than 12 weeks (stage A). Those with confirmed evidence of clinical improvement (ECI; treatment responders) entered a randomised-withdrawal phase of 1000 mg subcutaneous efgartigimod PH20 weekly treatment versus placebo for a maximum of 48 weeks (stage B). Participants were randomised (1:1) through interactive response technology and stratified by their adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT) score change during stage A and their most recent CIDP medication within 6 months before screening. Investigators, the clinical research organisation, and participants were masked to the treatment. The primary endpoint in stage A, evaluated in the stage A safety population, was confirmed ECI (≥1 points aINCAT decrease, ≥4 points [centile metric] Inflammatory Rasch-built Overall Disability Scale increase, or ≥8 kPa grip strength increase after four injections and two consecutive visits). The primary endpoint in stage B, evaluated in the modified intention-to-treat population, was the risk of relapse (time to first aINCAT increase of ≥1 points). ADHERE is registered with ClinicalTrials.gov (NCT04281472) and EudraCT (2019-003076-39) and is completed. Findings: Between April 15, 2020, and May 11, 2023, 629 participants were screened; 322 (114 female, 208 male) entered stage A, of whom 214 (66%, 95% CI 61·0-71·6) had confirmed ECI. In stage B, 221 participants were randomised (79 female, 142 male; 111 to subcutaneous efgartigimod PH20, 110 to placebo). Subcutaneous efgartigimod PH20 significantly reduced the risk of relapse versus placebo (hazard ratio 0·39 [95% CI 0·25-0·61]; p<0·0001). 31 (27·9% [19·6-36·3]) participants given subcutaneous efgartigimod PH20 had a relapse versus 59 (53·6% [44·3-63·0]) given placebo. In stage A, treatment-emergent adverse events (TEAEs) occurred in 204 (63%) participants and serious TEAEs in 21 (7%). In stage B, TEAEs occurred in 71 (64%) participants on subcutaneous efgartigimod PH20 and 62 (56%) participants on placebo, and serious TEAEs in six (5%) on subcutaneous efgartigimod PH20 and six (5%) on placebo. Three deaths occurred: two in stage A (one non-related and one unlikely related to treatment) and one in stage B (placebo group). Interpretation: ADHERE showed the efficacy of subcutaneous efgartigimod PH20 in reducing the risk of relapse versus placebo in people with CIDP who responded to treatment. Further studies are needed to provide data on the longer-term effects of efgartigimod alfa and how it compares with currently available treatment options. Funding: argenx