A novel antifungal nanoemulsion based on reuterin-assisted synergistic essential oils: Preparation and in vitro/in vivo characterization.

This research aimed to develop, optimize, and evaluate a new antifungal nanoemulsion system based on the crude reuterin-synergistic essential oils (EOs) hybrid to overcome the EOs application limits. At first, the antifungal effects of the Lactobacillus plantarum and Lactobacillus reuteri cell-free extracts (CFE) were tested against the Botrytis cinerea, Penicillium expansum, and Alternaria alternata as indicator fungus using broth microdilution method. The L. reuteri CFE with the MIC of 125 µL/mL for B. cinerea and 250 µL/mL for P. expansum and A. alternata showed more inhibitory effects than L. plantarum. Next, reuterin as a significant antibacterial compound in the L. reuteri CFE was induced in glycerol-containing culture media. To reach a nanoemulsion with maximum antifungal activity and stability, the reuterin concentration, Tween 80 %, and ultrasound time were optimized using response surface methodology (RSM) with a volumetric constant ratio of 5 % v/v oil phase including triple synergistic EOs (thyme, cinnamon, and rosemary) at MIC concentrations. Based on the Box-Behnken Design, the maximum antifungal effect was observed in the treatment with 40 mM reuterin, 1 % Tween 80, and 3 min of ultrasound. The growth inhibitory diameter zones of B. cinerea, P. expansum, and A. alternata were estimated 6.15, 4.25, and 4.35 cm in optimum nanoemulsion, respectively. Also, the minimum average particle size diameter (16.3 nm) was observed in nanoemulsion with reuterin 40 mM, Tween 80 5 %, and 3 min of ultrasound treatment. Zeta potential was relatively high within -30 mV range in all designed nanoemulsions which indicates the nanoemulsion's stability. Also, the prepared nanoemulsions, despite initial particle size showed good stability in a 90-d storage period at 25 °C. In vivo assay, showed a significant improvement in the protection of apple fruit treated with reuterin-EOs nanoemulsions against fungal spoilage compared to free reuterin nanoemulsion. Treatment of apples with nanoemulsion containing 40 mM reuterin showed a maximum inhibitory effect on B. cinerea (5.1 mm lesion diameter compared to 29.2 mm for control fruit) within 7 d at 25 °C. In summary, the present study demonstrated that reuterin-synergistic EOs hybrid with boosted antifungal activities can be considered as a biopreservative for food applications.

Engineered Tumor-Immune Microenvironment On A Chip to Study T Cell-Macrophage Interaction in Breast Cancer Progression.

Evolving knowledge about the tumor-immune microenvironment (TIME) is driving innovation in designing novel therapies against hard-to-treat breast cancer. Targeting the immune components of TIME has emerged as a promising approach for cancer therapy. While recent immunotherapies aim at restoring antitumor immunity, counteracting tumor escape remains challenging. Hence there is a pressing need to better understand the complex tumor-immune crosstalk within TIME. Considering this imperative, this study aims at investigating the crosstalk between the two abundant immune cell populations within the breast TIME-macrophages and T cells, in driving tumor progression using an organotypic 3D in vitro tumor-on-a-chip (TOC) model. The TOC features distinct yet interconnected organotypic tumor and stromal entities. This triculture platform mimics the complex TIME, embedding the two immune populations in a suitable 3D matrix. Analysis of invasion, morphometric measurements, and flow cytometry results underscores the substantial contribution of macrophages to tumor progression, while the presence of T cells is associated with a deceleration in the migratory behavior of both cancer cells and macrophages. Furthermore, cytokine analyses reveal significant upregulation of leptin and RANTES (regulated on activation, normal T Cell expressed and secreted) in triculture. Overall, this study highlights the complexity of TIME and the critical role of immune cells in cancer progression.

Engineered Gold and Silica Nanoparticle-Incorporated Hydrogel Scaffolds for Human Stem Cell-Derived Cardiac Tissue Engineering.

Electrically conductive biomaterials and nanomaterials have demonstrated great potential in the development of functional and mature cardiac tissues. In particular, gold nanomaterials have emerged as promising candidates due to their biocompatibility and ease of fabrication for cardiac tissue engineering utilizing rat- or stem cell-derived cardiomyocytes (CMs). However, despite significant advancements, it is still not clear whether the enhancement in cardiac tissue function is primarily due to the electroconductivity features of gold nanoparticles or the structural changes of the scaffold resulting from the addition of these nanoparticles. To address this question, we developed nanoengineered hydrogel scaffolds comprising gelatin methacrylate (GelMA) embedded with either electrically conductive gold nanorods (GNRs) or nonconductive silica nanoparticles (SNPs). This enabled us to simultaneously assess the roles of electrically conductive and nonconductive nanomaterials in the functionality and fate of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Our studies revealed that both GNR- and SNP-incorporated hydrogel scaffolds exhibited excellent biocompatibility and similar cardiac cell attachment. Although the expression of sarcomere alpha-actinin did not significantly differ among the conditions, a more organized sarcomere structure was observed within the GNR-embedded hydrogels compared to the nonconductive nanoengineered scaffolds. Furthermore, electrical coupling was notably improved in GNR-embedded scaffolds, as evidenced by the synchronous calcium flux and enhanced calcium transient intensity. While we did not observe a significant difference in the gene expression profile of human cardiac tissues formed on the conductive GNR- and nonconductive SNP-incorporated hydrogels, we noticed marginal improvements in the expression of some calcium and structural genes in the nanomaterial-embedded hydrogel groups as compared to the control condition. Given that the cardiac tissues formed atop the nonconductive SNP-based scaffolds (used as the control for conductivity) also displayed similar levels of gene expression as compared to the conductive hydrogels, it suggests that the electrical conductivity of nanomaterials (i.e., GNRs) may not be the sole factor influencing the function and fate of hiPSC-derived cardiac tissues when cells are cultured atop the scaffolds. Overall, our findings provide additional insights into the role of electrically conductive gold nanoparticles in regulating the functionalities of hiPSC-CMs.

Engineered 3D ex vivo models to recapitulate the complex stromal and immune interactions within the tumor microenvironment.

Cancer thrives in a complex environment where interactions between cellular and acellular components, surrounding the tumor, play a crucial role in disease development and progression. Despite significant progress in cancer research, the mechanism driving tumor growth and therapeutic outcomes remains elusive. Two-dimensional (2D) cell culture assays and in vivo animal models are commonly used in cancer research and therapeutic testing. However, these models suffer from numerous shortcomings including lack of key features of the tumor microenvironment (TME) & cellular composition, cost, and ethical clearance. To that end, there is an increased interest in incorporating and elucidating the influence of TME on cancer progression. Advancements in 3D-engineered ex vivo models, leveraging biomaterials and microengineering technologies, have provided an unprecedented ability to reconstruct native-like bioengineered cancer models to study the heterotypic interactions of TME with a spatiotemporal organization. These bioengineered cancer models have shown excellent capabilities to bridge the gap between oversimplified 2D systems and animal models. In this review article, we primarily provide an overview of the immune and stromal cellular components of the TME and then discuss the latest state-of-the-art 3D-engineered ex vivo platforms aiming to recapitulate the complex TME features. The engineered TME model, discussed herein, are categorized into three main sections according to the cellular interactions within TME: (i) Tumor-Stromal interactions, (ii) Tumor-Immune interactions, and (iii) Complex TME interactions. Finally, we will conclude the article with a perspective on how these models can be instrumental for cancer translational studies and therapeutic testing.

Transcriptomic analyses reveal proinflammatory activation of human brain microvascular endothelial cells by aging-associated peptide medin and reversal by nanoliposomes.

Medin is a common vascular amyloidogenic peptide recently implicated in Alzheimer's disease (AD) and vascular dementia and its pathology remains unknown. We aim to identify changes in transcriptomic profiles and pathways in human brain microvascular endothelial cells (HBMVECs) exposed to medin, compare that to exposure to ß-amyloid (Aß) and evaluate protection by monosialoganglioside-containing nanoliposomes (NL). HBMVECs were exposed for 20 h to medin (5 µM) without or with Aß(1-42) (2 µM) or NL (300 µg/mL), and RNA-seq with signaling pathway analyses were performed. Separately, reverse transcription polymerase chain reaction of select identified genes was done in HBMVECs treated with medin (5 µM) without or with NFκB inhibitor RO106-9920 (10 µM) or NL (300 µg/mL). Medin caused upregulation of pro-inflammatory genes that was not aggravated by Aß42 co-treatment but reversed by NL. Pathway analysis on differentially expressed genes revealed multiple pro-inflammatory signaling pathways, such as the tumor necrosis factor (TNF) and the nuclear factor-κB (NFkB) signaling pathways, were affected specifically by medin treatment. RO106-9920 and NL reduced medin-induced pro-inflammatory activation. Medin induced endothelial cell pro-inflammatory signaling in part via NFκB that was reversed by NL. This could have potential implications in the pathogenesis and treatment of vascular aging, AD and vascular dementia.

Serum Alkaline Phosphate Level Associates with Metabolic Syndrome Components Regardless of Non-Alcoholic Fatty Liver; A Population-Based Study in Northern Iran.

Background: Serum alkaline phosphatase (ALP) is an indicator of hepatobiliary disorders, such as metabolic syndrome (MetS). To assess the association between serum ALP levels and MetS, with or without non-alcoholic fatty liver disease (NAFLD), in a cohort study in northern Iran. Methods: Data from approximately 5257 subjects aged more than 18 years participating in the Amol cohort were used. We extracted the required data and investigated the correlation between liver enzyme levels and MetS. Multiple logistic regression analyses based on the serum ALP quartiles were performed. Results: Of them, 2860 were male with a mean age of 42.11±16.1 years. A positive linear trend was observed between serum ALP levels and the number of MetS components in both sexes. In both sexes, systolic blood pressure, waist circumferences, and high-density lipoprotein (HDL) had a significant association with ALP. After adjusting for age, both sexes with NAFLD showed an increased risk of developing MetS. The risk of NAFLD increased in individuals with>2nd quartile of ALP. Furthermore, higher ALP levels were associated with an increased risk of MetS in males (1.1014 [0.782-1.315]) and females (1.441 [1.085-1.913]). Conclusion: There is a significant association between serum ALP levels and MetS, independent of fatty liver changes, suggesting that this marker can be considered as a feasible predictor of MetS.

Atypical Presentation of Adult-Onset Still's Disease.

Adult-onset Still's disease (AOSD) is a rare rheumatic disorder with various presentations. It is diagnosed based on the Yamaguchi criteria, besides the exclusion of infectious diseases and other rheumatic disorders and malignancies. Here, we describe a case of a young man, presenting with remittent fever, abdominal pain, and persistent nausea. Further evaluations showed elevated acute phase reactants, abnormal levels of liver transaminase, multiple lymphadenopathies, and pleural effusion. He was finally diagnosed with AOSD and responded well to corticosteroids and methotrexate. We describe the present case to alert gastroenterologists to AOSD as a rare differential diagnosis in patients with persistent gastrointestinal symptoms.

Cytochrome P2E1 (CYP2E1) Gene Polymorphism as a Potential Prognostic Biomarker in Colorectal Cancer.

BACKGROUND: Colon cancer is the most common type of gastrointestinal cancer. Genetic factors have been shown to have a role in the development of colorectal cancers. The aim of this study was to assess the expression of Cytochrome P2E1 (CYP2E1) gene polymorphism as a potential prognostic biomarker in the diagnosis, treatment, and prognosis evaluation of patients with colorectal cancer. METHODS: in this cross-sectional study, all of our 100 patients with colorectal cancer who underwent surgical operation were included. DNA was extracted from the tumor specimens to assess Cytochrome P2E1 (CYP2E1) Gene polymorphism by Conventional-PCR. RFLP-PCR method was used for RsaI polymorphism evaluation. Patients' characteristics were also recorded and their associations with CYP2E1 were assessed. RESULTS: One hundred tumor specimens were assessed. In total, 88 had wild-type, 8 had purely a 96 bp insertion in CYP2E1, and 4 were partially mutated by a single allele insertion. Generally, 10% of samples had positive results for the RsaI polymorphism. There were no statistically significant associations between CYP2E1 gene polymorphism and number of lymph nodes removed during the operation (P = 0.353), number of positive lymph nodes (P = 0.668), tumor specificity including mucinous or non-mucinous (P = 0.053), tumor invasion (P = 0.074), grading (P = 0.898), differentiation (P = 0.941), tumor location (P = 0.42) or staging (P = 0.182). CONCLUSION: There was no association between RsaI type CYP2E1 polymorphism and colorectal cancer risk. Our study does not support the use of this biomarker to evaluate the prognosis of colon cancer.

Nanoengineering of gold nanoribbon-embedded isogenic stem cell-derived cardiac organoids.

Cardiac tissue engineering is an emerging field providing tools to treat and study cardiovascular diseases (CVDs). In the past years, the integration of stem cell technologies with micro- and nanoengineering techniques has enabled the creation of novel engineered cardiac tissues (ECTs) with potential applications in disease modeling, drug screening, and regenerative medicine. However, a major unaddressed limitation of stem cell-derived ECTs is their immature state, resembling a neonatal phenotype and genotype. The modulation of the cellular microenvironment within the ECTs has been proposed as an efficient mechanism to promote cellular maturation and improve features such as cellular coupling and synchronization. The integration of biological and nanoscale cues in the ECTs could serve as a tool for the modification and control of the engineered tissue microenvironment. Here we present a proof-of-concept study for the integration of biofunctionalized gold nanoribbons (AuNRs) with hiPSC-derived isogenic cardiac organoids to enhance tissue function and maturation. We first present extensive characterization of the synthesized AuNRs, their PEGylation and cytotoxicity evaluation. We then evaluated the functional contractility and transcriptomic profile of cardiac organoids fabricated with hiPSC-derived cardiomyocytes (mono-culture) as well as with hiPSC-derived cardiomyocytes and cardiac fibroblasts (co-culture). We demonstrated that PEGylated AuNRs are biocompatible and do not induce cell death in hiPSC-derived cardiac cells and organoids. We also found an improved transcriptomic profile of the co-cultured organoids indicating maturation of the hiPSC-derived cardiomyocytes in the presence of cardiac fibroblasts. Overall, we present for the first time the integration of AuNRs into cardiac organoids, showing promising results for improved tissue function.

Serum cystatin C and inflammatory factors related to COVID-19 consequences.

BACKGROUND: Besides impaired respiratory function and immune system, COVID-19 can affect renal function from elevated blood urea nitrogen (BUN) or serum creatinine (sCr) levels to acute kidney injury (AKI) and renal failure. This study aims to investigate the relationship between Cystatin C and other inflammatory factors with the consequences of COVID-19. METHODS: A total of 125 patients with confirmed Covid-19 pneumonia were recruited in this cross-sectional study from March 2021 to May 2022 at Firoozgar educational hospital in Tehran, Iran. Lymphopenia was an absolute lymphocyte count of less than 1.5 × 109/L. AKI was identified as elevated serum Cr concentration or reduced urine output. Pulmonary consequences were evaluated. Mortality was recorded in the hospital one and three months after discharge. The effect of baseline biochemical and inflammatory factors on odds of death was examined. SPSS, version 26, was used for all analyses. P-vale less than 0.05 was considered significant. RESULTS: The highest amount of co-morbidities was attributed to COPD (31%; n = 39), dyslipidemia and hypertension (27%; n = 34 for each) and diabetes (25%; n = 31). The mean baseline cystatin C level was 1.42 ± 0.93 mg/L, baseline creatinine was 1.38 ± 0.86 mg/L, and baseline NLR was 6.17 ± 4.50. Baseline cystatin C level had a direct and highly significant linear relationship with baseline creatinine level of patients (P < 0.001; r: 0.926). ). The average score of the severity of lung involvement was 31.42 ± 10.80. There is a direct and highly significant linear relationship between baseline cystatin C level and lung involvement severity score (r = 0.890, P < 0.001). Cystatin C has a higher diagnostic power in predicting the severity of lung involvement (B = 3.88 ± 1.74, p = 0.026). The mean baseline cystatin C level in patients with AKI was 2.41 ± 1.43 mg/L and significantly higher than patients without AKI (P > 0.001). 34.4% (n = 43) of patients expired in the hospital, and the mean baseline cystatin C level of this group of patients was 1.58 ± 0.90 mg/L which was significantly higher than other patients (1.35 ± 0.94 mg/L, P = 0.002). CONCLUSION: cystatin C and other inflammatory factors such as ferritin, LDH and CRP can help the physician predict the consequences of COVID-19. Timely diagnosis of these factors can help reduce the complications of COVID-19 and better treat this disease. More studies on the consequences of COVID-19 and knowing the related factors will help treat the disease as well as possible.

Development and Characterization of Isogenic Cardiac Organoids from Human-Induced Pluripotent Stem Cells Under Supplement Starvation Regimen.

The prevalence of cardiovascular risk factors is expected to increase the occurrence of cardiovascular diseases (CVDs) worldwide. Cardiac organoids are promising candidates for bridging the gap between in vitro experimentation and translational applications in drug development and cardiac repair due to their attractive features. Here we present the fabrication and characterization of isogenic scaffold-free cardiac organoids derived from human induced pluripotent stem cells (hiPSCs) formed under a supplement-deprivation regimen that allows for metabolic synchronization and maturation of hiPSC-derived cardiac cells. We propose the formation of coculture cardiac organoids that include hiPSC-derived cardiomyocytes and hiPSC-derived cardiac fibroblasts (hiPSC-CMs and hiPSC-CFs, respectively). The cardiac organoids were characterized through extensive morphological assessment, evaluation of cellular ultrastructures, and analysis of transcriptomic and electrophysiological profiles. The morphology and transcriptomic profile of the organoids were improved by coculture of hiPSC-CMs with hiPSC-CFs. Specifically, upregulation of Ca2+ handling-related genes, such as RYR2 and SERCA, and structure-related genes, such as TNNT2 and MYH6, was observed. Additionally, the electrophysiological characterization of the organoids under supplement deprivation shows a trend for reduced conduction velocity for coculture organoids. These studies help us gain a better understanding of the role of other isogenic cells such as hiPSC-CFs in the formation of mature cardiac organoids, along with the introduction of exogenous chemical cues, such as supplement starvation.

Mediators of dietary diversity score (DDS) on NAFLD in Iranian adults: a structural equation modeling study.

BACKGROUND: The current study examines the association between the Dietary Diversity Score (DDS) and nonalcoholic fatty liver disease (NAFLD) in Iranian adults using structural equation modeling (SEM). METHODS: A sample of 3220 adults from the Amol Cohort Study was recruited for this cross-sectional study. Dietary acid load (DAL) and DDS were calculated using the data obtained from a validated food frequency questionnaire. Anthropometric parameters, blood pressure, biochemical measurements, and liver ultrasonography were evaluated according to standard protocols. RESULTS: DDS was neither directly nor indirectly associated with a greater prevalence of NAFLD. In the second model (DDS sub-scores model), the association of DAL with NAFLD was fully mediated through waist circumference (WC) (of DAL to WC: ß = 0.14, P < 0.0001, and of WC to NAFLD: ß = 0.50, P < 0.001). Vegetable and fruit diversity scores had a significant negative indirect relationship with NAFLD prevalence through DAL (ß = -0.06, P = 0.001, ß = -0.10, P < 0.001, respectively). Meat diversity score was positively associated with NAFLD prevalence in a full mediational process through DAL (ß = 0.12, P < 0.001). The SEM fit indices suggested a reasonably adequate fit of the data to the DDS model (Χ2/df = 4.76, GFI = 0.98, AGFI = 0.97, IFI = 0.97, CFI = 0.97, RMSEA = 0.03, and SRMR = 0.02) and its sub-scores model (Χ2/df = 4.72, GFI = 0.98, AGFI = 0.97, IFI = 0.95, CFI = 0.95, RMSEA = 0.03, and SRMR = 0.02). CONCLUSION: Meat diversity and lack of vegetable and fruit diversity were indirectly associated with NAFLD prevalence through DAL and WC mediators. Interventions for NAFLD may be more successful if they target a lower intake of animal protein sources and dietary diversity, particularly vegetable and fruit diversity.

Modeling long QT syndrome type 2 on-a-chip via in-depth assessment of isogenic gene-edited 3D cardiac tissues.

Long QT syndrome (LQTS) is a cardiovascular disease characterized by QT interval prolongation that can lead to sudden cardiac death. Many mutations with heterogeneous mechanisms have been identified in KCNH2, the gene that encodes for hERG (Kv11.1), which lead to onset of LQTS type 2 (LQTS2). In this work, we developed a LQTS2-diseased tissue-on-a-chip model, using 3D coculture of isogenic stem cell-derived cardiomyocytes (CMs) and cardiac fibroblasts (CFs) within an organotypic microfluidic chip technology. Primarily, we created a hiPSC line with R531W mutation in KCNH2 using CRISPR-Cas9 gene-editing technique and characterized the resultant differentiated CMs and CFs. A deficiency in hERG trafficking was identified in KCNH2-edited hiPSC-CMs, revealing a possible mechanism of R531W mutation in LQTS2 pathophysiology. Following creation of a 3D LQTS2 tissue-on-a-chip, the tissues were extensively characterized, through analysis of calcium handling and response to ß-agonist. Furthermore, attempted phenotypic rescue via pharmacological intervention of LQTS2 on a chip was investigated.

Passive and Flexible Wireless Electronics Fabricated on Parylene/PDMS Substrate for Stimulation of Human Stem Cell-Derived Cardiomyocytes.

In this paper, we report the development of a wireless, passive, biocompatible, and flexible system for stimulation of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMS). Fabricated on a transparent parylene/PDMS substrate, the proposed stimulator enables real-time excitation and characterization of hiPSC-CMs cultured on-board. The device comprises a rectenna operating at 2.35 GHz which receives radio frequency (RF) energy from an external transmitter and converts it into DC voltage to deliver monophasic stimulation. The operation of the stimulator was primarily verified by delivering monophasic voltage pulses through gold electrodes to hiPSC-CMs cultured on the Matrigel-coated substrates. Stimulated hiPSC-CMs beat in accordance with the monophasic pulses when delivered at 0.5, 1, and 2 Hz pulsing frequency, while no significant cell death was observed. The wireless stimulator could generate monophasic pulses with an amplitude of 8 V at a distance of 15 mm. These results demonstrated the proposed wireless stimulator's efficacy for providing electrical stimulation to engineered cardiac tissues. The proposed stimulator will have a wide application in tissue engineering where a fully wireless stimulation of electroconductive cells is needed. The device also has potential to be employed as a cardiac stimulator by delivering external stimulation and regulating the contractions of cardiac tissue.

Long-Term Follow-Up of Thalassemia Major Patients with Hepatitis C Virus Treated with Sofosbuvir and Daclatasvir: A Cohort Study.

BACKGROUND: Treatment of Chronic Hepatitis C virus (HCV) infection in patients suffering from hereditary ß-thalassemia major is a concern due to drug complications and liver malfunction. The aim of the present study was to evaluate treatment outcome of Direct-Acting Antiviral (DAA) therapy in thalassemia major patients infected with HCV in a three year follow-up. METHODS: In a cohort study, long-term safety and efficacy of DAA therapy were evaluated in a group of thalassemia major patients suffering from chronic HCV infection. Hematologic and biochemical parameters as well as liver Fibroscan monitoring were assessed at the onset and three years after the treatment. RESULTS: From among 84 patients enrolled in the study, 53.6% were males, 36.9% had cirrhosis, 96.4% had a history of Desferal usage, and 78.6% had a history of splenectomy. Unfortunately, 7 participants (8.3%) died prior to the end of follow-up with nearly half of them having Iron overload and heart failure complications. Fibroscan score, ALT, AST, and ferritin were significantly lower compared with baseline evaluation, while Hb, creatinine, and direct bilirubin increased significantly in the third year after the treatment. CONCLUSION: Safety and efficacy of Sofosbuvir and Daclatasvir in thalassemia patients assessed previously but our three year follow-up showed their mild complications and death into a long-term period after DAAs treatment and 91.7% three year survival rate, which may affected by other confounding factors, such as liver malfunction and Iron overload.

Predictive ability of six obesity measures to identify 7-year fatal and non-fatal cardiovascular events: A population-based cohort study.

Background: Globally, most people die from cardiovascular diseases. We aimed to compare predictive ability of six obesity indices, including body mass index, waist circumference, waist-to-hip ratio, waist-to-height ratio, conicity index, and abdominal volume index, to identify people at risk of fatal and non-fatal cardiovascular events, in a cohort study. Methods: We studied 5147 participants in a baseline population-based cohort study conducted in northern Iran. The obesity measures were calculated in enrollment phase (2009-2010), and the cardiovascular events were recorded during a 7-year follow-up phase (2010-2017). Receiver operating characteristic (ROC) analyses and Cox hazard regression models were applied, considering the obesity measures as predictors, and the 7-year cardiovascular events as outcomes. Multiple Cox models were adjusted by age, prior history of cardiovascular diseases, chronic kidney diseases, insulin resistance, diabetes mellitus, dyslipidemia, hypertension, and smoking status. Results: Conicity index showed the highest performance in predicting 7-year fatal and non-fatal cardiovascular events with areas under the ROC curve of 0.77 [95% confidence interval: 0.71-0.82], and 0.63 [0.59-0.68] in men, and 0.80 [0.74-0.87], and 0.65 [0.60-0.71] in women, respectively. In multiple Cox models, the obesity measures had no significant associations with cardiovascular events in women. In men, only waist-to-height ratio was independently associated with 7-year non-fatal cardiovascular events (hazard ratio: 1.19 [95% confidence interval: 1.01-1.38]). Conclusions: Although waist-to-height ratio had an independent association with 7-year non-fatal cardiovascular events in men, conicity index showed the best ability to predict 7-year fatal and non-fatal cardiovascular events in our study.

A randomized triple-blind controlled clinical trial evaluation of sitagliptin in the treatment of patients with non-alcoholic fatty liver diseases without diabetes.

The current study aimed to evaluate the efficacy of sitagliptin vs. placebo in treating non-alcoholic fatty liver disease (NAFLD). In a triple-blind randomized clinical trial, we assigned 120 eligible subjects with NAFLD to receive daily dosing of 50 mg sitagliptin (n = 60) or the placebo (n = 60) for 56 weeks and lifestyle modification in both groups. Laboratory and anthropometric outcomes were measured, and liver stiffness was assessed using a fibroscan. The primary outcome measures were changes from baseline in fibrosis scores and liver transferases. Out of 120 patients randomized into sitagliptin and placebo groups, 76 patients completed the trial, of whom 44 were in the sitagliptin and 32 in the placebo groups. Patients receiving sitagliptin showed a significant decrease in the fibrosis scores (P = 0.001). The reductions in the alanine aminotransferase (AST) (P = 0.036) and aspartate AST (P < 0.001) levels were also statistically significant. The effect of sitagliptin in reducing fibrosis scores was significantly greater in normal-weight and overweight individuals than in obese individuals (p = 0.036, and p = 0.018, respectively), whereas the effects of sitagliptin on AST levels were greater among overweight/obese patients (p = 0.028, and p = 0.016, respectively). Sitagliptin reduced fibrosis scores and liver enzymes in NAFLD patients after 56 weeks of therapy. The changes in fibrosis scores were more prominent in patients with normal weight and overweight than obese patients, whereas the effects on AST levels were greater among overweight/obese patients. Other randomized trials with larger sample sizes and longer treatment durations may be required before precise results can be reached. Clinical Trial Registration: [https://www.irct.ir/trial/46140], identifier [IRCT20140430017505N2].

Investigating the Interactions of Glioma Stem Cells in the Perivascular Niche at Single-Cell Resolution using a Microfluidic Tumor Microenvironment Model.

The perivascular niche (PVN) is a glioblastoma tumor microenvironment (TME) that serves as a safe haven for glioma stem cells (GSCs), and acts as a reservoir that inevitably leads to tumor recurrence. Understanding cellular interactions in the PVN that drive GSC treatment resistance and stemness is crucial to develop lasting therapies for glioblastoma. The limitations of in vivo models and in vitro assays have led to critical knowledge gaps regarding the influence of various cell types in the PVN on GSCs behavior. This study developed an organotypic triculture microfluidic model as a means to recapitulate the PVN and study its impact on GSCs. This triculture platform, comprised of endothelial cells (ECs), astrocytes, and GSCs, is used to investigate GSC invasion, proliferation and stemness. Both ECs and astrocytes significantly increased invasiveness of GSCs. This study futher identified 15 ligand-receptor pairs using single-cell RNAseq with putative chemotactic mechanisms of GSCs, where the receptor is up-regulated in GSCs and the diffusible ligand is expressed in either astrocytes or ECs. Notably, the ligand-receptor pair SAA1-FPR1 is demonstrated to be involved in chemotactic invasion of GSCs toward PVN. The novel triculture platform presented herein can be used for therapeutic development and discovery of molecular mechanisms driving GSC biology.

Association of breast cancer risk, density, and stiffness: global tissue stiffness on breast MR elastography (MRE).

PURPOSE: Quantify in vivo biomechanical tissue properties in various breast densities and in average risk and high-risk women using Magnetic Resonance Imaging (MRI)/MRE and examine the association between breast biomechanical properties and cancer risk based on patient demographics and clinical data. METHODS: Patients with average risk or high-risk of breast cancer underwent 3.0 T breast MR imaging and elastography. Breast parenchymal enhancement (BPE), density (from most recent mammogram), stiffness, elasticity, and viscosity were recorded. Within each breast density group (non-dense versus dense), stiffness, elasticity, and viscosity were compared across risk groups (average versus high). Separately for stiffness, elasticity, and viscosity, a multivariable logistic regression model was used to evaluate whether the MRE parameter predicted risk status after controlling for clinical factors. RESULTS: 50 average risk and 86 high-risk patients were included. Risk groups were similar in age, density, and menopausal status. Among patients with dense breasts, mean stiffness, elasticity, and viscosity were significantly higher in high-risk patients (N = 55) compared to average risk patients (N = 34; all p < 0.001). Stiffness remained a significant predictor of risk status (OR = 4.26, 95% CI [1.96, 9.25]) even after controlling for breast density, BPE, age, and menopausal status. Similar results were seen for elasticity and viscosity. CONCLUSION: A structurally based, quantitative biomarker of tissue stiffness obtained from MRE is associated with differences in breast cancer risk in dense breasts. Tissue stiffness could provide a novel prognostic marker to help identify high-risk women with dense breasts who would benefit from increased surveillance and/or risk reduction measures.

Empirically-Derived Dietary Patterns in Relation to Non-Alcoholic Fatty Liver Diseases Among Adult Participants in Amol, Northern Iran: A Structural Equation Modeling Approach.

Dietary modifications remain the mainstay in managing nonalcoholic fatty liver disease (NAFLD). Published data on the effect of overall dietary patterns on NAFLD is scarce. The present study aims to extract the dietary patterns and investigate their association to NAFLD by gender, using structural equation modeling, among adult participants in Amol, northern Iran. In this cross-sectional study, data from 3,149 participants in the Amol cohort study (55.3% men, n = 1,741) were analyzed. Usual dietary intake was assessed by a validated 168-items semiquantitative food frequency questionnaire. We classified major dietary patterns by explanatory factor analysis (EFA) and confirmatory factor analysis (CFA). NAFLD diagnosis was based on ultrasound scanning, including increased hepatic echogenicity, abnormal appearance of hepatic arteries, and diaphragm in the absence of excessive alcohol consumption. Multivariable logistic regression and structural equation modeling (SEM) were used to explore the relationship between dietary patterns and NAFLD. Three distinct dietary patterns, including western, healthy, and traditional/mixed dietary patterns, were identified. Adult male who adhere to the western dietary pattern were more affected with NAFLD risk [Q1, Q2, Q3, Q4, odds ratio (OR) = 1, 1.16, 1.34, 1.39; 95% confidence interval (CI) = 0.83-1.61, 0.96-1.85, 0.98-1.96, p trend = 0.04, respectively]. A full mediating effect of healthy dietary pattern, western dietary pattern, and traditional dietary pattern via dietary acid load (DAL) proxy (of dietary patterns to DAL: ßstd = -0.35, p < 0.006, ßstd = 0.15, p = 0.009, and ßstd = 0.08, p = 0.001, respectively), on NAFLD was found through mediation analysis using SEM. A western dietary pattern comprising frequent intake of salty and sweet snacks, soft drinks, refined grains, processed meats, cooked and fried potatoes, eggs, and coffee was associated with a higher odds of NAFLD in an Iranian male population. Additionally, our findings might provide a mechanistic explanation for the association between dietary patterns and NAFLD via DAL proxy. However, further prospective studies, including assessing acid-base biomarkers, are needed.