Association Between the G82S Polymorphism of the Receptor Gene for Advanced Glycation End-products and Soluble Serum Levels RAGE with Diabetic Nephropathy in the White (Asian) Race.

INTRODUCTION: Diabetic nephropathy is one of the most common severe symptoms of diabetes mellitus. Hyperglycemia can lead to tissue damage and inflammation due to mediators such as receptor for advanced glycation end-products (RAGE). Therefore, in this study, we aimed to investigate the association between the G82S polymorphism of the RAGE gene and diabetic nephropathy in diabetic patients. METHODS: In this case-control study, 356 participants (158 men and 198 women) of Asian race, aged 45 to 65 years, who were diagnosed with type 2 diabetes mellitus based on their fasting plasma glucose levels were enrolled. DNA was isolated from the participants' blood samples and genotyped using TETRA -Primer ARMS-PCR. Serum protein concentration of soluble RAGE (sRAGE) was also determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Although we found differences in genotyping of participants between homozygous AA and GG and heterozygous GA in the studied groups, the differences were not significant (P = .568). In addition, we found no significant correlation between the G82S polymorphism of RAGE and the development of diabetic nephropathy. Serum levels of sRAGE were only slightly decreased in patients with diabetic nephropathy compared with diabetic patients (P > .05). CONCLUSION: The results of this study indicate no significant association between the G82S polymorphism in the gene RAGE and the development of diabetic nephropathy. Serum levels of sRAGE were only slightly decreased in patients with diabetic nephropathy compared to diabetic patients without nephropathy. Therefore, the study suggests that there is probably no association between the G82S polymorphism in the gene RAGE and the development of diabetic nephropathy. DOI: 10.52547/ijkd.7872.

Association of RARRES2 rs17173608 gene polymorphism and serum Chemerin with acute myocardial infarction and its risk factors: A case-control study in an Iranian population.

OBJECTIVE: The adipokine Chemerin and the retinoic acid receptor responder 2 (RARRES2) gene have been associated with an increased incidence of obesity, insulin resistance, endothelial dysfunction, type 2 diabetes mellitus, and coronary artery disease. The impact of RARRES2 rs17173608 gene polymorphism on acute myocardial infarction and Chemerin levels has not yet been entirely elucidated. This study aimed to assess the association of RARRES2 rs17173608 gene polymorphism and serum Chemerin with acute myocardial infarction (AMI) and its risk factors in an Iranian population. METHODS: In this case-control study, 134 AMI patients and 100 healthy controls were recruited from tertiary referral hospitals in Zanjan, Iran. Whole blood samples were collected for DNA extraction and Chemerin level determination. An enzyme-linked immunosorbent assay was used to quantify plasma levels of Chemerin. Tetra-primer amplification refractory mutation system-polymerase chain reaction and agarose gel electrophoresis techniques were used to detect gene polymorphism of Chemerin rs17173608 from DNA samples. RESULTS: Serum Chemerin levels were higher in the control group than in the AMI group. However, after adjusting for age, sex, and other risk factors, there was no significant association between serum Chemerin level and AMI occurrence. In the genotype analysis, 21.6% of patients had the TT genotype, and 78.4% had the TG genotype. The GG genotype was not detected in any patient. The genotype distribution of the healthy control group was 19.0% TT genotype, 80.0% TG genotype, and 1.0% GG genotype. Serum Chemerin levels in participants with TG genotype were statistically different between case and control groups. CONCLUSION: Serum Chemerin levels and RARRES2 rs17173608 gene polymorphism were not correlated with AMI occurrence after adjusting for AMI risk factors in Iranian patients. More research with a larger sample size and diverse ethnicities is needed to corroborate our findings.

Combination of Quercetin or/and siRNA-loaded DDAB-mPEG-PCL hybrid nanoparticles reverse resistance to Regorafenib in colon cancer cells.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer death. Although Regorafenib showed survival benefits in patients with CRC, reports imply the recurrence of malignant phenotype resulting from chemotherapy. Evidence demonstrated that a5ß1 integrin plays an important role in the Regorafenib treatment, which, may be led to resistance. In this study, the effects of /siRNA or/ and Quercetin loaded DDAB-mPEG-PCLnanoparticles could reverse this resistance phenotype in colon cancer cells in vitro. METHODS: Regorafenib-resistant Ls-180 colon cancer cell line was developed by long-term exposure to Regorafenib. Quercetin and Regorafenib were separately encapsulated into mPEG-PCL micelles through the nano-precipitation method and characterized by DLS. Optimized doses of Quercetin and Regorafenib were used for combination therapy of resistant cells followed cytotoxicity study using MTT. Gene expression levels of the ß1 subunit of integrin were determined by the real-time method of RT-PCR. RESULTS: Developed Regorafenib resistant LS-180 showed to have Regorafenib IC50 of 38.96 ± 1.72 µM whereas IC50 in non-resistant cells were 8.51 ± 0.29 µM, which meaningful was lower statistically compared to that of a resistant one. The ß1 mRNA level of whole α5ß1 integrin was significantly higher in the resistant cells compared to those of non-resistant ones. Gene expression levels in each siRNA-loaded nanoparticle and Quercetin-loaded one were lower than that in mock experiments. Finally, when these two types of nanoparticles were used to treat resistant cells, gene expression decrease of integrin indicated a greater effect that could be capable of reverse resistancy. CONCLUSION: Results of this study demonstrated another confirmation of involving integrins in cancer resistance following chemotherapy using Regorafenib. Also, it indicated how using siRNA targeting integrin could enhance the plant derivatives like Quercetin effects to reverse resistance in vitro.

The effect of EMPAgliflozin on markers of inflammation in patients with concomitant type 2 diabetes mellitus and Coronary ARtery Disease: the EMPA-CARD randomized controlled trial.

Systemic inflammation and oxidative burden in patients with type 2 diabetes mellitus (T2DM) causes deleterious cardiovascular outcomes. We sought to investigate the clinical antioxidative and anti-inflammatory effects of empagliflozin. Platelet function, oxidant and antioxidant biomarkers and pro-inflammatory agents at baseline and at 26 weeks were measured. A total of 95 patients (41.05% male, mean age 62.85 ± 7.91 years, mean HbA1c 7.89 ± 0.96%) with concomitant T2DM and coronary artery disease (CAD) were randomized (1:1) to receive empagliflozin (10 mg/daily) or placebo. Patients treated with empagliflozin had lower levels of interleukin 6 (IL-6) (adjusted difference (adiff): - 1.06 pg/mL, 95% CI - 1.80; - 0.32, P = 0.006), interleukin 1ß (IL-1ß) and high-sensitive C-reactive protein (Hs-CRP) (adiff: - 4.58 pg/mL and - 2.86 mg/L; P = 0.32 and 0.003, respectively) compared to placebo. There were elevations in super oxidase dismutase (SOD) activity, glutathione (GSHr), and total antioxidant capacity (TAC) with empagliflozin (adiff: 3.7 U/mL, 0.57 muM, and 124.08 mmol/L, 95% CI 1.36; 6.05, 0.19; 0.95, and 47.98; 200.18, P = 0.002, 0.004, and 0.002, respectively). While reactive oxygen species (ROS) improved significantly (adiff: - 342.51, 95% CI - 474.23; - 210.79, P < 0.001), the changes in catalase activity (CAT), malondialdehyde (MDA), or protein carbonyl groups (PCG) were not significant. Moreover, the P-selectin antigen expression on platelet surface was significantly reduced (adiff: - 8.81, 95% CI - 14.87; - 2.75, P = 0.005). Markers of glycemic status (fasting blood glucose, HbA1c, and HOMA-IR (homeostatic model assessment for insulin resistance) significantly improved (P < 0.001). Among patients with T2DM and CAD, 6-month treatment with empagliflozin can mitigate inflammation, platelet activity and oxidative stress and is associated with clinical cardiovascular benefits.Trial Registration Iranian Registry of Clinical Trials. www.IRCT.ir , Identifier: IRCT20190412043247N2. Registration Date: 6/13/2020. Registration timing: prospective.

Betanin alleviates oxidative stress through the Nrf2 signaling pathway in the liver of STZ-induced diabetic rats.

BACKGROUND: Continuing hyperglycemia causes and exacerbate oxidative stress. Betanin as the principal pigment of red beet root has antioxidant, anti-inflammatory, and anti-diabetic properties. The purpose of this study was to investigate the potency of betanin on antioxidant defense in STZ-induced diabetic rats' livers. METHODS: STZ at a single dose of 60 mg/kg body weight was intraperitoneally injected and betanin (10, 20, and 40 mg/kg/day) was administered orally for 28 days. Malondialdehyde (MDA), total antioxidant capacity (TAC), protein carbonyl (PC) levels, and the enzyme activity of superoxide dismutase (SOD), catalases and glutathione peroxidases (GPx) were evaluated in the liver. Furthermore, gene expression of Nrf2 and mentioned antioxidant enzymes were measured by Real-time PCR. RESULTS: Betanin (10 and 20 mg/kg) significantly reduced PC levels and increased antioxidant enzyme activity in diabetic rats compared to the control diabetic group (P < 0.01). In comparison to the diabetic control group, all studied genes expression in diabetic rats were increased significantly with betanin at doses of 10 and 20 mg/kg (P < 0.02). The increase in gene expression at 20 mg/kg of betanin was significantly stronger than others (P < 0.015) except for the catalase (P = 0.201), that was almost the same. Moreover, treatment of diabetic rats with 20 mg/kg of betanin could significantly increase TAC levels (P < 0.05) and decrease MDA levels (P < 0.001) compared to diabetic control group. CONCLUSIONS: Betanin could increase the antioxidant capacity of liver tissue associated with the Nrf2-mediated pathway in a dose-dependent manner.

Advanced Glycation End Product Blocker Drugs Have a Great Potential to Prevent Diabetic Cardiomyopathy in an Animal Model of Diabetes Mellitus Type-2.

Introduction: Sphingosine 1 phosphate (S1P) is a product of the sphingosine kinase 1 (SphK1) enzyme. Increased S1P can lead to tissue fibrosis that is also one of the pathways for developing diabetic cardiomyopathy. Advanced glycation end products (AGEs) increase S1P in cells. The study is aimed at using aminoguanidine (AG) as an AGEs blocker drug to prevent diabetic cardiomyopathy. Materials and methods. 210 rats were enrolled in the study. Diabetes mellitus type-2 was induced, and rats were divided into AG treated diabetic and nondiabetic groups. The heart histology was assessed with Masson's trichrome and hematoxylin-eosin staining. Cardiac function was measured with transthoracic echocardiography. S1P level and SphK1 gene expression were measured by western-blot and RT-qPCR, respectively. Results: Results showed that S1P level increases in diabetes, and its augmentation in cardiac tissue with K6PC-5 leads to cardiac fibrosis. 50 and 200 mg/kg of AG prevented cardiac fibrosis, but 100 mg/kg had no significant preventive effect. AG suppressed the SphK1 gene expression and reduced the fibrotic effect of S1P. AG preserved cardiac function by keeping ejection fraction and fractional shortening within the normal range in diabetic rats. Conclusion: AG has a suppressor effect on SphK1 gene expression besides its AGEs blocker role. AG is a potential drug to use in diabetic patients for preventing the development of diabetic cardiomyopathy. Other drugs that have AGEs or S1P blocker effects are a good choice for diabetic cardiomyopathy prevention.

Co-delivery of siRNA and lycopene encapsulated hybrid lipid nanoparticles for dual silencing of insulin-like growth factor 1 receptor in MCF-7 breast cancer cell line.

Insulin-like growth factor-1 receptor (IGF-1R) is expressed in malignant and normal breast tissue, and its intermittent activation by multiple IGF-1 signaling pathways leads to neoplasm cell proliferation, impaired apoptosis, increased survival, and resistance to cytotoxic therapeutic agents. Therefore, simultaneous suppression of the receptor and its cognate ligand would be a powerful promising strategy inhibiting malignant phenotypes of breast cancer cells. In the present study, Methoxypoly(ethylene glycol) - Poly(caprolactone) was hybridized with Dimethyldioctadecylammonium bromide (DDAB) cationic lipid (mPEG-PCL-DDAB) nanoparticles (NPs) and used as a carrier for simultaneous delivery of lycopene and insulin-like growth factor 1 receptor-specific lycopene encapsulated-mPEG-PCL-DDAB nanoparticle/siRNA to MCF-7 breast cancer cells. Then, the antitumor effects of this construct were evaluated in vitro. The results demonstrated that the synthesized mPEG-PCL-DDAB nanoparticle had suitable physicochemical properties. The use of mPEG-PCL-DDAB nanoparticle-loaded anti-insulin-like growth factor 1 receptor-siRNA and lycopene dramatically induced the process of apoptosis and arrested cell cycle in the MCF-7 tumor cell lines. In general, the findings of this study demonstrated the potency of mPEG-PCL-DDAB nanoparticles for dual delivery of siRNA, and lycopene in breast cancer cell lines followed the induction of apoptosis.

Study rationale and design of a study of EMPAgliflozin's effects in patients with type 2 diabetes mellitus and Coronary ARtery disease: the EMPA-CARD randomized controlled trial.

BACKGROUND: Recent trials have revealed that sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are effective against hyperglycemia and also reduce micro- and macro-vascular complications in patients with type 2 diabetes mellitus (T2DM). Most of the beneficial cardiovascular effects have been investigated in patients with heart failure and coronary artery disease (CAD). Yet, few human studies have been conducted to investigate the molecular mechanisms underlying these clinically beneficial effects in patients with CAD. Accordingly, the EMPA-CARD trial was designed to focus on the molecular effects of empagliflozin in patients with T2DM and CAD. METHODS: In this multicenter, triple-blind randomized controlled trial, patients with documented known T2DM and CAD will be recruited. They will be randomized on a 1:1 ratio and assigned into two groups of empagliflozin 10 mg/daily and placebo. The primary endpoint is the effect of empagliflozin on changes of plasma interleukin 6 (IL-6) after 26 weeks of treatment. The secondary endpoints will consist of changes in other inflammatory biomarkers (Interleukin 1-beta and high-sensitive C-reactive protein), markers of oxidative stress, platelet function, and glycemic status. DISCUSSION: The EMPA-CARD trial mainly tests the hypothesis that SGLT2 inhibition by empagliflozin may improve inflammatory status measured as reduction in inflammatory biomarkers in patients with T2DM and CAD. The results will provide information about the underlying mechanisms of SGLT2 inhibition that mediate the beneficial effects of this medication on clinical outcomes. TRIAL REGISTRATION: Iranian Registry of Clinical Trials. www.IRCT.ir , Identifier: IRCT20190412043247N2. Registration Date: 6/13/2020. Registration timing: prospective.

Apoptosis induction by siRNA targeting integrin-ß1 and regorafenib/DDAB-mPEG-PCL hybrid nanoparticles in regorafenib-resistant colon cancer cells.

Colorectal cancer (CRC) is regarded as the third most common cancer worldwide. Although Regorafenib as a receptor tyrosine kinase inhibitor (RTKI) disrupts tumor growth and angiogenesis in metastatic CRC (mCRC) patients, drug resistance leads to poor prognosis and survival. Integrin-ß1 overexpression has been proposed to be the major player in this regard. Herein, the Regorafenib-resistant human colon cancer cell line (SW-48) was induced, and the Integrin-ß1 gene expression, as well as apoptosis, was assessed through the combination of small interfering RNA (siRNA) targeting Integrin-ß1 and Regorafenib/Dimethyldioctadecylammonium bromide (DDAB)-methoxy poly (ethylene glycol) (mPEG)-poly-ε-caprolactone (PCL) hybrid nanoparticles (HNPs). In the current study, Regorafenib-resistant SW-48 cell line was generated in which the Regorafenib half-maximal inhibitory concentration (IC50) for non-resistant and resistant cells was 13.5±1.5 µM and 55.1±0.8 µM, respectively. The results of DLS also demonstrated that the size and the charge of the HNPs were equal to 66.56±0.5 nm and +29.5±1.2 mv, respectively. In addition, the Integrin-ß1 gene expression was significantly higher in resistant cells than in non-resistant ones (P<0.05). The siRNA/HNP complexes in combination with Regorafenib/HNPs were accordingly identified as the most effective treatment to decrease the Integrin-ß1 gene expression and to enhance the apoptosis rate in resistant cells (P<0.001). Overall, the study indicated that combination therapy using siRNA/HNP and Regorafenib/HNPs complex could down-regulate the Integrin-ß1 gene expression and consequently trigger apoptosis, and this may potentially induce drug sensitivity.

Clinicopathological, Immunohistochemical, and PMS2 Gene Expression Profiling of Patients with Sporadic Colorectal Cancer.

BACKGROUND: The DNA mismatch repair (MMR) system is one of the molecular pathways involved in colorectal cancer (CRC) carcinogenesis that consists of several genes, including MLH1 (MutL homolog 1), MSH6 (MutS homolog 6), MSH2 (MutS homolog 2), and MSH3 (MutS homolog 3). The protein encoded by PMS2 (post-meiotic segregation 2) is also essential for MMR. Here, we address the correlation between immunohistochemical and transcriptional expression of PMS2 with the tumor grade and clinical stage of non-hereditary/sporadic CRC disease. METHODS: This study retrospectively analyzed 67 colorectal resections performed for 38 male and 29 female patients. Random biopsies were taken by a gastroenterologist from patients referring to three hospitals in the cities of Zanjan, Urmia and Qazvin (Iran) during 2017-2019. All specimens were examined and classified for localization of tumor, pathological stage and grade. The PMS2 protein expression was studied immunohistochemically and analysis of mRNA expression was performed in the same tissue sections. RESULTS: Immunohistochemistry and quantitative real-time polymerase chain reaction (PCR) analysis showed a decrease in PMS2 expression compared with paracancerous tissue (P<0.001), which correlated with tumor stage. In addition, reduced PMS2 expression was correlated with the tumor differentiation grade, underlining a connection between downregulation of PMS2 and progression of CRC. Comparing the PMS2 mRNA levels in different groups showed the following results: 0.92 ± 0.18 in patients with Stage I CRC tumor, 0.86 ± 0.38 in Stage Ⅱ, 0.50 ± 0.29 in Stage Ⅲ, and 0.47 ± 0.23 in Stage Ⅳ. CONCLUSION: These findings suggest that PMS2 may provide a potential reliable biomarker for CRC classification by combined immunohistochemical and mRNA analysis.

Modeling and Reducing the Effect of Geometric Uncertainties in Intracranial Aneurysms with Polynomial Chaos Expansion, Data Decomposition, and 4D-Flow MRI.

PURPOSE: Variations in the vessel radius of segmented surfaces of intracranial aneurysms significantly influence the fluid velocities given by computer simulations. It is important to generate models that capture the effect of these variations in order to have a better interpretation of the numerically predicted hemodynamics. Also, it is highly relevant to develop methods that combine experimental observations with uncertainty modeling to get a closer approximation to the blood flow behavior. METHODS: This work applies polynomial chaos expansion to model the effect of geometric uncertainties on the simulated fluid velocities of intracranial aneurysms. The radius of the vessel is defined as the uncertainty variable. Proper orthogonal decomposition is applied to characterize the solution space of fluid velocities. Next, a process of projecting the 4D-Flow MRI velocities on the basis vectors followed by coefficient mapping using generalized dynamic mode decomposition enables the merging of 4D-Flow MRI with the uncertainty propagated fluid velocities. RESULTS: Polynomial chaos expansion propagates the fluid velocities with an error of 2% in velocity magnitude relative to computer simulations. Also, the bifurcation region (or impingement location) shows a standard deviation of 0.17 m/s (since an available reported variance in the vessel radius is adopted to model the uncertainty, the expected standard deviation may be different). Numerical phantom experiments indicate that the proposed approach reconstructs the fluid velocities with 0.3% relative error in presence of geometric uncertainties. CONCLUSION: Polynomial chaos expansion is an effective approach to propagate the effect of the uncertainty variable in the blood flow velocities of intracranial aneurysms. Merging 4D-Flow MRI and uncertainty propagated fluid velocities leads to more realistic flow trends relative to ignoring the uncertainty in the vessel radius.

Application of decoy oligodeoxynucleotides strategy for inhibition of cell growth and reduction of metastatic properties in nonresistant and erlotinib-resistant SW480 cell line.

Signal transducer and activator of transcription 3 (STAT3) is a critical regulator for angiogenesis, cell cycle progression, apoptosis, and drug resistance. Resistance toward EGF receptor (EGFR) inhibitors is a significant clinical concern for metastatic colon cancer patients. The present study aimed to evaluate the blocking influences of STAT3 decoy oligodeoxynucleotides (ODNs) on the STAT3 survival signaling pathway in nonresistant and erlotinib-resistant SW480 colon cancer cells. First, STAT3 decoy and scramble ODNs were designed according to STAT3 elements in the promoter region of MYCT1 gene and tested for the interaction of STAT3 protein with designed ODNs via in silico molecular docking study. Then, the efficiency of transfection and subcellular localization of ODNs were assessed using flow cytometry and fluorescence microscopy, respectively. Cell viability, cell cycle, and apoptosis tests, scratch and colony formation assays, and real-time PCR were also used to study the cancerous properties of cells. A considerable decrease in proliferation of colon cancer cells was observed with blockade of STAT3 signaling due to cell cycle arrest and induced apoptosis via downregulation of cyclin D1 and Bcl-XL, respectively. Furthermore, upon transfecting STAT3 decoy ODNs, colony formation potential and migration activity in both SW480 colon cancer cell lines were decreased compared to the control groups. From this study, it could be concluded that STAT3 is critical for cell growth inhibition and metastatic properties reduction of resistant SW480 colon cancer cells; therefore, STAT3 decoy ODNs could be considered as potential therapeutics along with current remedies for treating drug-resistant colon cancer.

Determination of carcinoembryonic antigen as a tumor marker using a novel graphene-based label-free electrochemical immunosensor.

In this work, a simple label-free electrochemical immunosensor for the detection of carcinoembryonic antigen (CEA) was developed. At first, the GC electrode was coated with partially reduced graphene oxide (rGO) to form a platform to bind the antibody. After activating the carboxyl groups of rGO through the EDC/NHS linker, the electrode surface was covered with the antibody. Then, the electrochemical behavior of the antibody-modified electrode and the parameters of the interactions of antibody-antigen immune complexes were investigated using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). This immune-complex layer was found to attenuate the electrochemical current which can be used as a good signal to determine the antigen concentration. The proposed immunosensor exhibited a good amperometric response to CEA within a concentration range of 0.1-5 ng mL-1 with a detection limit of 0.05 ng ml-1. Furthermore, the developed method was evaluated for the detection of CEA in the real sample (human blood serum), and the results were comparable with the reference values obtained by the standard enzyme-linked immunosorbent assay (ELISA). Our findings suggest the present immunosensor as a good candidate for application in clinical screening.

Oxidative toxic stress and p53 level in healthy subjects occupationally exposed to outdoor air Pollution - a cross-sectional study in Iran.

INTRODUCTION: It is suggested that air pollution exposure induces oxidative stress in the body and causes diseases. However, current evidence regarding the association of outdoor air pollution with some oxidative toxic stress (OTS) biomarkers in areas with different pollutant concentrations is equivocal. OBJECTIVE: The aim of study was to investigate the adverse effects of outdoor air pollution on human health, by evaluating potential oxidative and anti-oxidative biomarkers and p53 protein levels in subjects exposed to different outdoor air pollution from two polluted and less polluted cities of Iran. MATERIAL AND METHODS: In this cross-sectional study, a total of 203 healthy working men were selected from two cities. The activities of superoxide dismutase (SOD), catalase (CAT) and γ-glutamyltransferase (GGT) and the levels of malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS), were measured by the colorimetric method. The levels of p53 were measured by an ELISA method. RESULTS: The results showed a significant increase in the levels of p53 and MDA in the exposure group compared to the control group, while the activity of SOD and TAC was significantly decreased in the exposure group. No significant differences were found in activities of CAT and GGT, and levels of TOS between the two groups. CONCLUSIONS: The findings obtained confirmed the implication of air pollution in the development of OTS, and suggested useful biomarkers to evaluate the air pollution-induced harmful effects on human health in the polluted areas.

Super-resolution and denoising of 4D-Flow MRI using physics-Informed deep neural nets.

BACKGROUND AND OBJECTIVE: Time resolved three-dimensional phase contrast magnetic resonance imaging (4D-Flow MRI) has been used to non-invasively measure blood velocities in the human vascular system. However, issues such as low spatio-temporal resolution, acquisition noise, velocity aliasing, and phase-offset artifacts have hampered its clinical application. In this research, we developed a purely data-driven method for super-resolution and denoising of 4D-Flow MRI. METHODS: The flow velocities, pressure, and the MRI image magnitude are modeled as a patient-specific deep neural net (DNN). For training, 4D-Flow MRI images in the complex Cartesian space are used to impose data-fidelity. Physics of fluid flow is imposed through regularization. Creative loss function terms have been introduced to handle noise and super-resolution. The trained patient-specific DNN can be sampled to generate noise-free high-resolution flow images. The proposed method has been implemented using the TensorFlow DNN library and tested on numerical phantoms and validated in-vitro using high-resolution particle image velocitmetry (PIV) and 4D-Flow MRI experiments on transparent models subjected to pulsatile flow conditions. RESULTS: In case of numerical phantoms, we were able to increase spatial resolution by a factor of 100 and temporal resolution by a factor of 5 compared to the simulated 4D-Flow MRI. There is an order of magnitude reduction of velocity normalized root mean square error (vNRMSE). In case of the in-vitro validation tests with PIV as reference, there is similar improvement in spatio-temporal resolution. Although the vNRMSE is reduced by 50%, the method is unable to negate a systematic bias with respect to the reference PIV that is introduced by the 4D-Flow MRI measurement. CONCLUSIONS: This work has demonstrated the feasibility of using the readily available machinery of deep learning to enhance 4D-Flow MRI using a purely data-driven method. Unlike current state-of-the-art methods, the proposed method is agnostic to geometry and boundary conditions and therefore eliminates the need for tedious tasks such as accurate image segmentation for geometry, image registration, and estimation of boundary flow conditions. Arbitrary regions of interest can be selected for processing. This work will lead to user-friendly analysis tools that will enable quantitative hemodynamic analysis of vascular diseases in a clinical setting.

Circulating Irisin Levels and Redox Status Markers in Patients with Gastric Cancer: A Case-Control Study.

OBJECTIVE: Irisin, mostly known as an exercise-induced fat browning myokine, has been recently detected in several cancer cells, and its potential for being utilized as a biomarker for early diagnosis of some cancers, such as Gastric cancer (GC), is the subject of speculation. The present study aims to compare serum irisin levels in GC patients and healthy controls and assess the interrelation between irisin and oxidative stress markers. METHODS: In this case-control study, 22 newly diagnosed GC patients and 29 healthy controls were recruited based on the inclusion criteria. Serum levels of irisin were quantified in duplicates by ELISA. Oxidative stress indices, including total antioxidant power in sera, thiol group, malondialdehyde, and superoxide dismutase concentrations, were also measured in both groups. An independent-sample t-test was used to compare the means between the two studied groups. RESULTS: Serum levels of irisin were significantly higher in the GC group compared with those of their healthy counterparts (p =0.032). No significant differences were observed between the two groups in terms of the serum total antioxidant power or the oxidative stress marker, including MDA, thiol groups, and SOD concentration in sera. Furthermore, there was no significant association between irisin, FRAP, the Thiol group, and the SOD activity. CONCLUSION: According to the finding, the increased serum levels of irisin in GC patients can play a potential role in the early diagnosis of the GC patients; hence, this peptide can be employed as a new diagnostic indicator of GC.
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Towards multi-modal data fusion for super-resolution and denoising of 4D-Flow MRI.

4D-Flow magnetic resonance imaging (MRI) has enabled in vivo time-resolved measurement of three-dimensional blood flow velocities in the human vascular system. However, its clinical use has been hampered by two main issues, namely, low spatio-temporal resolution and acquisition noise. While patient-specific computational fluid dynamics (CFD) simulations can address the resolution and noise issues, its fidelity is impacted by accuracy of estimation of boundary conditions, model parameters, vascular geometry, and flow model assumptions. In this paper a scheme to address limitations of both modalities through data-fusion is presented. The solutions of the patient-specific CFD simulation are characterized using proper orthogonal decomposition (POD). Next, a process of projecting the 4D-Flow MRI data onto the POD basis and projection coefficient mapping using generalized dynamic mode decomposition (DMD) enables simultaneous super-resolution and denoising of 4D-Flow MRI. The method has been tested using numerical phantoms derived from patient-specific aneurysmal geometries and applied to in vivo 4D-Flow MRI data.

Crosstalk between Epidermal Growth Factor Receptors (EGFR) and integrins in resistance to EGFR tyrosine kinase inhibitors (TKIs) in solid tumors.

Cell adhesion to the extracellular matrix (ECM) is important in a variety of physiological and pathologic processes, including development, tumor invasion, and metastasis. Integrin-mediated attachment to ECM proteins has emerged to cue events primitively important for the transformed phenotype of human cancer cells. Cross-talk between integrins and growth factor receptors takes an increasingly prominent role in defining adhesion, motility, and cell growth. This functional interaction has expanded beyond to link integrins with resistance to Tyrosine kinase inhibitors (TKIs) of Epidermal Growth Factor Receptors (EGFRs). In this regard, integrin-mediated adhesion has two separate functions one as a clear collaborator with growth factor receptor signaling and the second as a basic mechanism contributing in Epithelial to Mesenchymal Transition (EMT) which affects response to chemotherapy. This review provides an overview of these mechanisms and describes treatment options for selectively targeting and disrupting integrin interaction to EGFR for cancer therapy.

The effect of resveratrol supplementation on C-reactive protein (CRP) in type 2 diabetic patients: Results from a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: C-reactive protein (CRP) is considered to be an inflammatory marker in type 2 diabetes (T2D) and it is produced by liver cells. The evidence has suggested that resveratrol has anti-inflammatory effect. This study aimed to evaluate the effect of resveratrol supplementation on CRP level in patients with T2D using a systematic review and meta-analysis of randomized controlled trials. METHODS: Electronic databases were completely searched using Medline, ISI Web of Science, EMBASE and Cochrane Library and Scopus until October 2019. Meta-analysis was performed using random-effects model and inverse variance method. Heterogeneity and publication bias were evaluated in selected studies. Sensitivity analyses and prespecified subgroup were conducted to evaluate potential heterogeneity. Meta-regression was performed to assess the effect of potential confounders on the estimated effect sizes. RESULTS: Six trials comprising a total of 491 subjects were included in this meta-analysis. The results showed significant reduction in the level of CRP [SMD (-0.34 mg/l) (95 % CI, -0.52, to -0.16) p < 0.05] in participants with T2D following supplementation with resveratrol. No significant publication bias was observed in the meta-analysis. Subgroup and sensitivity analyses indicated that the pooled effects of resveratrol supplementation on CRP level in T2D patients were affected by resveratrol dose and duration of resveratrol. Random-effects meta-regression did not indicate any significant association of CRP level with potential confounders including resveratrol dose, duration of treatment, age and gender of type 2 diabetic patients. CONCLUSION: We found a significant reduction in CRP level in patients with type 2 diabetes, who received resveratrol supplementation.

Capturing Upper Limb Gross Motor Categories Using the Kinect® Sensor.

IMPORTANCE: Along with growth in telerehabilitation, a concurrent need has arisen for standardized methods of tele-evaluation. OBJECTIVE: To examine the feasibility of using the Kinect sensor in an objective, computerized clinical assessment of upper limb motor categories. DESIGN: We developed a computerized Mallet classification using the Kinect sensor. Accuracy of computer scoring was assessed on the basis of reference scores determined collaboratively by multiple evaluators from reviewing video recording of movements. In addition, using the reference score, we assessed the accuracy of the typical clinical procedure in which scores were determined immediately on the basis of visual observation. The accuracy of the computer scores was compared with that of the typical clinical procedure. SETTING: Research laboratory. PARTICIPANTS: Seven patients with stroke and 10 healthy adult participants. Healthy participants intentionally achieved predetermined scores. OUTCOMES AND MEASURES: Accuracy of the computer scores in comparison with accuracy of the typical clinical procedure (immediate visual assessment). RESULTS: The computerized assessment placed participants' upper limb movements in motor categories as accurately as did typical clinical procedures. CONCLUSIONS AND RELEVANCE: Computerized clinical assessment using the Kinect sensor promises to facilitate tele-evaluation and complement telehealth applications. WHAT THIS ARTICLE ADDS: Computerized clinical assessment can enable patients to conduct evaluations remotely in their homes without therapists present.