Evaluation of novel synthesized thiazole derivatives as potential aromatase inhibitors against breast cancer.

Background: 4-Methylacetophenone is used in the preparation of starting materials, 4-methylphenacyle bromide (2) and 4-methylacetophenone thiosemicarbazole (3). Results: Several novel 2,4-disubstituted-1,3-thiazole analogues were obtained via the treatment of starting materials with 4-methylphenacyl bromide, acetyl chloride, aromatic aldehydes and bromination providing thiazole derivatives 5-8 respectively. Conclusion: Compounds 5-8 were investigated for their cytotoxic activity on MCF-7 and normal breast cells. Active compounds were found and in contrast to staurosporine, compound 8 displayed the most potent cytotoxic action that showed a strong inhibitory effect (aromatase) and (protein tyrosine kinase) enzymes, proving that the novel thiazole derivatives promoted the effective anticancer drug candidates.

[Box: see text].

Applications of Proteomics in Probiotics Having Anticancer and Chemopreventive Properties.

Proteomics has grown in importance in molecular sciences because it gives vital information on protein identification, expression levels, and alteration. Cancer is one of the world's major causes of death and is the major focus of much research. Cancer risk is determined by hereditary variables as well as the body's immunological condition. Probiotics have increasing medical importance due to their therapeutic influence on the human body in the prevention and treatment of numerous chronic illnesses, including cancer, with no adverse effects. Several anticancer, anti-inflammatory, and chemopreventive probiotics are studied using different proteomic approaches like two-dimensional gel electrophoresis, liquid chromatography-mass spectrometry, and matrix-assisted laser desorption/ionization mass spectrometry. To gain relevant information about probiotic characteristics, data from the proteomic analysis are evaluated and processed using bioinformatics pipelines. Proteomic studies showed the significance of different proteomic approaches in characterization, comparing strains, and determination of oxidative stress of different probiotics. Moreover, proteomic approaches identified different proteins that are involved in glucose metabolism and the formation of cell walls or cell membranes, and the differences in the expression of critical enzymes in the HIF-1 signaling pathway, starch, and sucrose metabolism, and other critical metabolic pathways.

Impact of breath hold on regional nodal irradiation and heart volume in field in left breast cancer adjuvant irradiation.

PURPOSE: Compared to the free-breathing technique, adjuvant left breast irradiation after breast-conserving surgery or mastectomy using the breath-hold method significantly reduces the heart mean dose, Left anterior descending artery, and ipsilateral lung doses. Movement with deep inspiration may also reduce heart volume in the field and regional node doses. MATERIALS AND METHODS: Pre-radiotherapy planning CT was performed in the free-breathing, and breath-hold techniques using RPM, demographic information, clinicopathological data, heart volume in the field, heart mean dose, LAD mean dose, and regional nodal doses were calculated in both free breathing and DIBH. Fifty patients with left breast cancer receiving left breast adjuvant radiation were enrolled. RESULTS: There was no significant difference in axillary LN coverage between the two techniques, except for SCL maximum dose, Axilla I node maximum dose, and Axilla II minimum dose in favor of the breath hold technique. The mean age was 47.54 years, 78% had GII IDC, 66% had positive LVSI results, and 74% of patients had T2. The breath hold strategy resulted in considerably decreased mean heart dose (p = 0.000), LAD dose (p = 0.000), ipsilateral lung mean dose (p = 0.012), and heart volume if the field (p = 0.013). The mean cardiac dosage and the dose of the LAD were significantly correlated (p = 0.000, R = 0.673). Heart volume in the field and heart mean dosage was not significantly correlated (p = 0.285, r = - 0.108). CONCLUSION: When compared to free breathing scans, DIBH procedures result in considerably reduced dosage to the OAR and no appreciable changes in dose exposure to regional lymph node stations in patients with left-sided breast cancer.

Relation Between Baseline CXCR1 Expression And Neoadjuvant Chemotherapy Response In Breast Cancer Patients.

Objectives: To examine the C-X-C Motif Chemokine Receptor 1 expression in breast cancer tissues prior to neo-adjuvant chemotherapy, and its relationship to neo-adjuvant chemotherapy effectiveness and other prognostic variables. Method: The prospective study was conducted at Kafrelsheikh University Hospital, Egypt, from November 2018 to March 2021, and comprised patients with recent histopathologically proven breast cancer cases eligible for chemotherapy. Paraffin blocks of tumourspecimens were stained by immunohistochemicalstain using concentrating rabbit anti-human C-X-C Motif Chemokine Receptor 1 polyclonal antibody kits. C-X-C Motif Chemokine Receptor 1 expression was classified into low and high categories. Patients were followed for 2 years for treatment response, disease recurrence and mortality. Data was analysed using SPSS 25. RESULTS: Of the 100 females with mean age 50.2±12.1 years, 52(52%) had their left side affected, while 48(48%) had their rightside affected. There were 52(52%) cases with mean age 49.2±12.9 years having high C-X-C Motif Chemokine Receptor 1 expresssion, while 48(48%) with mean age 51.4±11.2 years had low expression. There was a significant association between high expression and advanced tumour grade, advanced tumourstage, higher frequency of triple negative breast cancer and higher frequency of Ki-67-positive cancers (p<0.05). Patients with high C-X-C Motif Chemokine Receptor 1 expression had significantly lower frequency of complete pathological response when compared with patients with low expression (p<0.001). Patients with high expression had higher frequency of recurrence, shorter disease-free survival, higher mortality and shorter overall survival, but the difference was not significant (p>0.05). Multivariate logistic regression analysis identified triple negative hormonal status (p=0.031) and high baseline C-X-C Motif Chemokine Receptor 1 expression (p<0.001) as significant predictors of complete pathological response. CONCLUSIONS: There was found to be a link between baseline C-X-C Motif Chemokine Receptor 1 expression in breast cancer tissues and pathological response to neoadjuvant therapy in breast cancer patients.

Clinical Significance Of Baseline And Post-Treatment CXCR1 Expression In Women With Breast Cancer Having Received Neoadjuvant Chemo Therapy.

Objectives: To examine the chemokine receptor type 1 expression in breast cancer tissues before and after neoadjuvant chemotherapy, and its relationship with pathological response to neoadjuvant chemotherapy and other clinical variables. Method: The prospective study was conducted at Kafrelsheikh University Hospital, Egypt, from November 2018 to March 2021, and comprised female patients with new histopathologically proven breast cancer eligible for chemotherapy. Paraffin blocks of tumourspecimens were stained immunohistochemically using concentrated rabbit anti-human chemokine receptor type 1 polyclonal antibody kits. The patients were followed up for treatment response, disease recurrence and mortality. Data was analysed using SPSS 25. RESULTS: Of the 100 patients with mean age 50.2±12.1 years, 40(40%) in group A with mean age 55.1±9.3 showed marked response and 60(60%) in group B with mean age 47.0±12.7 yearsshowed mild/moderate response (p<0.001). Group A patients had significantly lower baseline and post-treatment chemokine receptor type 1 expression compared to group B patients (p<0.05). The change in chemokine receptor type 1 expression was not significantly different (p>0.05). Patients with tumour grade 3 had significantly higher baseline chemokine receptor type 1 expression compared to patients with tumour grade 2. Tumourstage and post-treatment chemokine receptor type 1 expression were also significantly interlinked (p<0.05). Multivariate regression analysisidentified patients'age, baseline chemokine receptor type 1 and post-treatment chemokine receptor type 1 expressions as predictors of treatment response. CONCLUSIONS: There was found to be an association between baseline and post-treatment chemokine receptor type 1 expression in breast cancer tissues and pathological response to neoadjuvant chemo therapy in such patients.

Point-of-care diagnostics for rapid determination of prostate cancer biomarker sarcosine: application of disposable potentiometric sensor based on oxide-conductive polymer nanocomposite.

One of the most important reasons for an increased mortality rate of cancer is late diagnosis. Point-of-care (POC) diagnostic sensors can provide rapid and cost-effective diagnosis and monitoring of cancer biomarkers. Portable, disposable, and sensitive sarcosine solid-contact ion-selective potentiometric sensors (SC-ISEs) were fabricated as POC analyzers for the rapid determination of the prostate cancer biomarker sarcosine. Tungsten trioxide nanoparticles (WO3 NPs), polyaniline nanoparticles (PANI NPs), and PANI-WO3 nanocomposite were used as ion-to-electron transducers on screen-printed sensors. WO3 NPs and PANI-WO3 nanocomposite have not been investigated before as ion-to-electron transducer layers in potentiometric SC sensors. The designated sensors were characterized using SEM, XRD, FTIR, UV-VIS spectroscopy, and EIS. The inclusion of WO3 and PANI in SC sensors enhanced the transduction at the interface between the screen-printed SC and the ion-selective membrane, offering lower potential drift, a longer lifetime, shorter response time, and better sensitivity. The proposed sarcosine sensors exhibited Nernstian slopes over linear response ranges 10-3-10-7 M, 10-3-10-8 M, 10-5-10-9 M, and 10-7-10-12 M for control, WO3 NPs, PANI NPs, and PANI-WO3 nanocomposite-based sensors, respectively. From a comparative point of view between the four sensors, PANI-WO3 nanocomposite inclusion offered the lowest potential drift (0.5 mV h-1), the longest lifetime (4 months), and the best LOD (9.95 × 10-13 M). The proposed sensors were successfully applied to determine sarcosine as a potential prostate cancer biomarker in urine without prior sample treatment steps. The WHO ASSURED criteria for point-of-care diagnostics are met by the proposed sensors.

A Review of Endocrine Therapy in Early-stage Breast Cancer: The Journey From Crudeness to Precision.

Endocrine therapy (ET) is the standard of care for hormone receptor-positive early-stage breast cancer in the adjuvant setting. However, response to ET can vary across patient subgroups. Historically, hormone receptor expression and clinical stage are the main predictors of the benefit of ET. A "window of opportunity" trials has raised significant interest in recent years as a means of assessing the sensitivity of a patient's cancer to short-term neoadjuvant ET, which provides important prognostic information, and helps in decision-making regarding treatment options in a time-efficient and cost-efficient manner. In the era of genomics, molecular profiling has led to the discovery and evaluation of the prognostic and predictive abilities of new molecular profiles. To realize the goal of personalized medicine, we are in urgent need to explore reliable biomarkers or genomic signatures to accurately predict the clinical response and long-term outcomes associated with ET. Validation of these biomarkers as reliable surrogate endpoints can also lead to a revolution in the clinical trial designs, and potentially avoid the need for repeated tissue biopsies in the surveillance of disease response. The clinical potential of tumor genomic profiling marks the beginning of a new era of precision medicine in breast cancer treatment.

COVID-19 Vaccination in Pediatrics: Was It Valuable and Successful?

BACKGROUND: The mass vaccination of children against coronavirus 2019 disease (COVID-19) has been frequently debated. The risk-benefit assessment of COVID-19 vaccination versus infection in children has also been debated. AIM: This systematic review looked for answers to the question "was the vaccination of our children valuable and successful?". METHODS: The search strategy of different articles in the literature was based on medical subject headings. Screening and selection were based on inclusion/exclusion criteria. RESULTS AND DISCUSSION: The search results revealed that the majority of the reported adverse events after COVID-19 vaccination in pediatrics were mild to moderate, with few being severe. Injection site discomfort, fever, headache, cough, lethargy, and muscular aches and pains were the most prevalent side effects. Few clinical studies recorded significant side effects, although the majority of these adverse events had nothing to do with vaccination. In terms of efficacy, COVID-19 disease protection was achieved in 90-95% of cases for mRNA vaccines, in 50-80% of cases for inactivated vaccines, and in 58-92% of cases for adenoviral-based vaccines in children and adolescents. CONCLUSIONS: Based on available data, COVID-19 immunizations appear to be safe for children and adolescents. Furthermore, multiple studies have proven that different types of vaccines can provide excellent protection against COVID-19 in pediatric populations. The efficacy of vaccines against new SARS-CoV-2 variants and the reduction in vaccine-related long-term adverse events are crucial for risk-benefit and cost-effectiveness assessments; therefore, additional safety studies are required to confirm the long-term safety and effectiveness of vaccinations in children.

Impact of Extended Adjuvant Temozolamide Beyond 6 Months in the Management of Glioblastoma Patients.

OBJECTIVES: Our study aimed to assess the benefit of prolonging adjuvant temozolomide (TMZ) therapy beyond 6 cycles in glioblastoma multiform patients. MATERIALS AND METHODS: The medical records of 329 patients in 2 cancer centers in Egypt were reviewed from January 2008 to December 2018 who were diagnosed with diffuse gliomas. Data were collected on patient demographics, presenting complaints, tumor size, treatment modalities (extent of surgery, radiotherapy dose and technique, concomitant TMZ, and the number of adjuvant TMZ cycles), and reported adverse events. RESULTS: In the studied cohort, 105 patients were treated with adjuvant TMZ, 33 patients received <6 cycles (TMZL), 41 patients received the standard 6 cycles (TMZS), and 31 patients received >6 cycles (TMZE). Our results showed the median overall survival in the TMZL arm was 8.47 months compared with 15.83 months in the TMZS arm and 27.33 months in the TMZE arm ( P < 0.001). Furthermore, a median progression-free survival of 6.35 months was reported in the TMZL group versus, 12.7 and 22.90 months in (TMZS) and (TMZE) groups, respectively( P < 0.001). In the multivariate analysis, the extended adjuvant TMZ with a hazard ratio of 3.106 (95% CI: 2.43-14.46; P < 0.001) was statistically significantly associated with a better outcome. CONCLUSIONS: Extended adjuvant TMZ therapy beyond 6 cycles may significantly improve the progression-free survival and overall survival in patients with glioblastoma multiform.

Dietary-Induced Bacterial Metabolites Reduce Inflammation and Inflammation-Associated Cancer via Vitamin D Pathway.

Environmental factors, including westernised diets and alterations to the gut microbiota, are considered risk factors for inflammatory bowel diseases (IBD). The mechanisms underpinning diet-microbiota-host interactions are poorly understood in IBD. We present evidence that feeding a lard-based high-fat (HF) diet can protect mice from developing DSS-induced acute and chronic colitis and colitis-associated cancer (CAC) by significantly reducing tumour burden/incidence, immune cell infiltration, cytokine profile, and cell proliferation. We show that HF protection was associated with increased gut microbial diversity and a significant reduction in Proteobacteria and an increase in Firmicutes and Clostridium cluster XIVa abundance. Microbial functionality was modulated in terms of signalling fatty acids and bile acids (BA). Faecal secondary BAs were significantly induced to include moieties that can activate the vitamin D receptor (VDR), a nuclear receptor richly represented in the intestine and colon. Indeed, colonic VDR downstream target genes were upregulated in HF-fed mice and in combinatorial lipid-BAs-treated intestinal HT29 epithelial cells. Collectively, our data indicate that HF diet protects against colitis and CAC risk through gut microbiota and BA metabolites modulating vitamin D targeting pathways. Our data highlights the complex relationship between dietary fat-induced alterations of microbiota-host interactions in IBD/CAC pathophysiology.

Analytical dosimetric study of intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) for prostate cancer.

PURPOSE: The study aimed to compare the dosimetric results and treatment delivery efficiency among four techniques to explore the preferred technique in prostate treatment. MATERIALS AND METHODS: 7 IMRT, 9 IMRT, 1 ARC, and 2 ARC plans were created for 30 prostate cancer patients using the Eclipse™ treatment planning system (Varian Medical Systems). All the plans were designed to deliver 80.0 Gy in 40 fractions to the prostate planning target volume (PTV). Target coverage, organs at risk (OARs), number of monitor units, homogeneity, and conformity were compared across the four techniques to assess the quality of the plans. RESULTS: The study revealed better Planning Target Volume (PTV) dose coverage in the VMAT-2A than in the other plans. At the same time, VMAT-2A plans were found to be significantly lower in terms of Bladder and rectum doses than other techniques. In addition, VMAT has the advantage of considerably reducing the number of monitor units and treatment time. CONCLUSION: For prostate cancer, VMAT may offer a favorable dose gradient profile, conformity, and MU and treatment time compared to IMRT.

Combined anterior and posterior ring fixation versus posterior ring fixation alone in the management of unstable Tile B and C pelvic ring injuries: A randomized controlled trial.

PURPOSE: Combined anterior and posterior ring (APR) fixation is classically performed in Tile B2 and C1 injuries to achieve superior biomechanical stability. However, the posterior ring (PR) is the main weight bearing portion that is responsible for weight transmission from the upper parts of the body to the lower limbs through the sacrum and the linea terminalis. It is hypothesized that isolated PR fixation can achieve comparable radiological and clinical outcomes to APR fixation. Therefore, we conducted this study to compare the two fixation principles in managing Tile B2 and C1 injuries. METHODS: Our study included 20 patients with Tile B2 injuries and 20 patients with Tile C1 injuries. This study was a randomized control single-blinded study via computerized random numbers with a 1:1 allocation by using random block method. The study was performed at a level one trauma center. A total of 40 patients with Tile B2 and C1 injuries underwent combined APR or isolated PR fixation (Group A and B, respectively). Matta & Tornetta radiological principles and Majeed pelvic scoring system were used for the assessment of primary outcomes and postoperative complications. Secondary outcomes included operative time, amount of blood loss, intraoperative assessment of reduction, need of another operation, length of hospital stay, ability to weight bear postoperatively and pain control metrics. We used student t-test to compare the difference in means between two groups, and Chi-square test to compare proportions between two qualitative parameters. We set the confidence interval to 95% and the margin of error accepted to 5%. So, p ≤ 0.05 was considered statistically significant. RESULTS: The mean follow-up duration was 18 months. The operative time (mean difference 0.575 h) and the intraoperative blood loss (mean difference 97.5 mL) were lower in Group B. Also, despite the higher frequency of rami displacement before union in the same group, there were no significant differences in terms of radiological outcome (excellent outcome with OR = 2.357), clinical outcome (excellent outcome with OR = 2.852) and postoperative complications assessment (OR = 1.556) at last follow-up. CONCLUSION: The authors concluded that isolated PR fixation could favorably manage Tile B2 and C1 pelvic ring injuries with Nakatani zone II pubic rami fractures and intact inguinal ligament. Its final radiological and clinical outcomes and postoperative complications were comparable to combined APR fixation, but with less morbidity (shorter operation time, lower amount of blood, and no records of postoperative wound infection).

Impact of breath-hold technique on incidence of cardiac events in adjuvant left breast cancer irradiation.

BACKGROUND: This study aims to compare the incidence of cardiac events and to identify its predictors in left breast cancer patients receiving adjuvant radiotherapy using breath-hold technique (DIBH) versus free breathing technique (FB). METHODS: We conducted a retrospective multi-center study of two arms; the free breathing arm included 208 patients who were treated with traditional radiotherapy treatment technique, while DIBH arm included 224 patients who were treated with breath-hold technique using The Varian Real-time Position Management (RPM). We retrospectively reviewed the medical records of the patients from January 2010 to December 2017. RESULTS: The mean dose to the heart and left anterior descending artery were significantly lower in the DIBH arm (2.10 ± 0.39 and 6.16 ± 0.18 Gy) compared with (4.29 ± 0.60 Gy and 12.69 ± 0.93 Gy, respectively) in the FB arm. The incidence of cardiac events was higher in the FB arm than in the DIBH arm, but it was not statically significant. Our analysis revealed that age, diabetes, hypertension, smoking, mean LAD dose, and heart mean dose were significant prognostic factors for the occurrence of cardiac events in the breath-hold arm. Hypertension, smoking, as well as heart mean dose were independent risk factors for the occurrence of cardiac events. CONCLUSION: Use of the DIBH technique resulted in a significant reduction in doses to the heart, LAD and lesser cardiac events incidence compared to free breathing.

Acute and chronic metabolic effects of carvedilol in high-fructose, high-fat diet-fed mice: implication of ß-arrestin2 pathway.

We aimed to investigate the acute and chronic effects of carvedilol on insulin resistance in high-fructose, high-fat diet (HFrHFD) - fed mice and the implication of the ß-arrestin2 pathway. The acute effect of carvedilol (10 mg/kg, i.p.) on glucose tolerance and hepatic lipid signaling in normal and insulin resistant mice was investigated. Then, the chronic effect of carvedilol on insulin resistance and dyslipidemia in HFrHFD-fed mice was examined. Changes in ß-arrestin2 and its downstream signals in liver, skeletal muscle, and adipose tissue were measured. This involved measuring phosphatidylinositol 4,5-bisphosphate (PIP2) and diacylglycerol (DAG) levels and protein kinase B (AKT) activity. Carvedilol acutely reduced fasting blood glucose levels in both normal and insulin resistant mice without significantly affecting the glucose tolerance. These acute effects were associated with increased hepatic PIP2 but decreased hepatic DAG levels. Chronic administration of carvedilol significantly ameliorated insulin resistance and dyslipidemia in HFrHFD-fed mice. These chronic effects were associated with increased ß-arrestin2, PIP2, and AKT activity levels but decreased DAG levels in the classical insulin target tissues. In conclusion, carvedilol acutely maintains glucose homeostasis and chronically ameliorates insulin resistance and dyslipidemia in HFrHFD-fed mice. The insulin sensitizing effects of carvedilol are highly correlated with the upregulation of ß-arrestin2 pathway.

Indolin-2-one derivatives as selective Aurora B kinase inhibitors targeting breast cancer.

Aurora B is a pivotal cell cycle regulator where errors in its function results in polyploidy, genetic instability, and tumorigenesis. It is overexpressed in many cancers, consequently, targeting Aurora B with small molecule inhibitors constitutes a promising approach for anticancer therapy. Guided by structure-based design and molecular hybridization approach we developed a series of fifteen indolin-2-one derivatives based on a previously reported indolin-2-one-based multikinase inhibitor (1). Seven derivatives, 5g, 6a, 6c-e, 7, and 8a showed preferential antiproliferative activity in NCI-60 cell line screening and out of these, carbamate 6e and cyclopropylurea 8a derivatives showed optimum activity against Aurora B (IC50 = 16.2 and 10.5 nM respectively) and MDA-MB-468 cells (IC50 = 32.6 ± 9.9 and 29.1 ± 7.3 nM respectively). Furthermore, 6e and 8a impaired the clonogenic potential of MDA-MB-468 cells. Mechanistic investigations indicated that 6e and 8a induced G2/M cell cycle arrest, apoptosis, and necrosis of MDA-MB-468 cells and western blot analysis of 8a effect on MDA-MB-468 cells revealed 8a's ability to reduce Aurora B and its downstream target, Histone H3 phosphorylation. 6e and 8a displayed better safety profiles than multikinase inhibitors such as sunitinib, showing no cytotoxic effects on normal rat cardiomyoblasts and murine hepatocytes. Finally, 8a demonstrated a more selective profile than 1 when screened against ten related kinases. Based on these findings, 8a represents a promising candidate for further development to target breast cancer via Aurora B selective inhibition.

Impedimetric Sensors for Cyclocreatine Phosphate Determination in Plasma Based on Electropolymerized Poly(o-phenylenediamine) Molecularly Imprinted Polymers.

Cyclocreatine and its water-soluble derivative, cyclocreatine phosphate (CCrP), are potent cardioprotective drugs. Based on recent animal studies, CCrP, FDA-awarded Orphan Drug Designation, has a promising role in increasing the success rate of patients undergoing heart transplantation surgery by preserving donor hearts during transportation and improving the recovery of transplanted hearts in recipient patients. In addition, CCrP is under investigation as a promising treatment for creatine transporter deficiency, an X-linked inborn error resulting in a poor quality of life for both the patients and the caregiver. A newly designed molecularly imprinted polymer (MIP) material was fabricated by the anodic electropolymerization of o-phenylenediamine on screen-printed carbon electrodes and was successfully applied as an impedimetric sensor for CCrP determination to dramatically reduce the analysis time during both the clinical trial phases and drug development process. To enhance the overall performance of the proposed sensor, studies were performed to optimize the electropolymerization conditions, incubation time, and pH of the background electrolyte. Scanning electron microscopy, electrochemical impedance spectroscopy, and cyclic voltammetry were used to characterize the behavior of the developed ultrathin MIP membrane. The CCrP-imprinted polymer has a high recognition affinity for the template molecule because of the formation of 3D complementary cavities within the polymer. The developed MIP impedimetric sensor had good linearity, repeatability, reproducibility, and stability within the linear concentration range of 1 × 10-9 to 1 × 10-7 mol/L, with a low limit of detection down to 2.47 × 10-10 mol/L. To verify the applicability of the proposed sensor, it was used to quantify CCrP in spiked plasma samples.

Comparison of Long Term Outcomes After Endovascular Treatment Versus Bypass Surgery in Chronic Limb Threatening Ischaemia Patients with Long Femoropopliteal Lesions.

OBJECTIVE: There are currently two treatments available for patients with chronic limb threatening ischaemia (CLTI): open surgical bypass (OSB) and percutaneous transluminal angioplasty with/without stenting (PTA/S). The aim of this study was to compare short and long term outcomes between PTA/S and OSB in CLTI patients with long (GLASS grade III and IV) femoropopliteal disease. METHODS: This was a two centre retrospective study including all consecutive patients with CLTI undergoing first time lower extremity intervention at two distinct vascular surgical centres. Between 1 January 2012 and 1 January 2018, 1 545 CLTI consecutive limbs were treated for femoropopliteal GLASS grade III and IV lesions at two vascular surgical centres. Using covariables from baseline and angiographic characteristics, a propensity score was calculated for each limb. Thus, comparable patient cohorts (235 in PTA/S and 235 in OSB group) were identified for further analysis. The primary outcomes were freedom from re-intervention in the treated extremity and major amputation. Secondary outcomes were all hospital complications among the two patient groups. RESULTS: Total overall complication rates were significantly higher in the OSB group (20.42% vs. 5.96%, p < .001), especially wound infection/seroma rate that required prolonged hospitalisation and further treatment (7.65% vs. 0%, p < .001). After the median follow up of 61 months, re-intervention rates were significantly higher in the PTA/S group (log rank test, 44.68% vs. 29.79%, p = .002), but there was no significant difference in terms of major amputation rates between the two group of patients (log rank test, PTA/S 27.23% vs. OSB 22.13%, p = .17). CONCLUSION: Bypass surgery seems to be superior to PTA/S for GLASS grade III and IV femoropopliteal lesions in patients with CLTI in terms of long term re-intervention rates, but with considerably higher rates of post-operative complications. A larger cohort of patients in currently ongoing randomised trials, as well as prospective cohort studies are necessary to confirm these findings.

The renoprotective effect of glycyrrhizic acid in insulin-resistant rats exposed to aluminum involves the inhibition of TLR4/NF-κB signaling pathway.

Aluminum is well recognized as a nephrotoxic agent. Its hazardous effects arise from the high risk of daily exposure. The consumption of fructose also represents a critical health issue that might negatively impact different organs, including the kidneys. To pursue our previous work, this study aimed to investigate the potential renoprotective effects of glycyrrhizic acid (GLYA) on aluminum-induced nephrotoxicity in insulin-resistant rats. Insulin resistance (IR) was induced by adding fructose (10%) in drinking water for 18 weeks. Male Wistar rats were divided into five groups: control (CTRL), aluminum chloride (ALM, 34 mg/kg/day), fructose (FRCT), aluminum plus fructose (AL/FR), and GLYA (rats received AL/FR and treated with 40 mg/kg GLYA daily). AL/FR resulted in abnormal renal function tests and renal tissue injury. This was associated with increased oxidative stress and inflammation in the renal tissue. Moreover, the expressions of the toll-like receptor 4 (TLR4) and its adaptor proteins were increased in AL/FR group. The administration of GLYA mollified AL/FR-induced renal injury, oxidative stress, activation of the TLR4 signaling pathway, and inflammation. In conclusion, we provide evidence for the promising renoprotective effect of GLYA against AL/FR-induced kidney damage in rats. The renoprotection is attributed to the suppression of oxidative stress and inhibition of the TLR4/NF-κB signaling pathway in the kidneys.

Carvedilol Diminishes Cardiac Remodeling Induced by High-Fructose/High-Fat Diet in Mice via Enhancing Cardiac ß-Arrestin2 Signaling.

BACKGROUND: Insulin resistance (IR) is a well-known risk factor for cardiovascular complications. This study aimed to investigate the effect of a dietary model of IR in mice on cardiac remodeling, cardiac ß-arrestin2 signaling, and the protective effects of carvedilol as a ß-arrestin-biased agonist. METHODS AND RESULTS: Insulin resistance was induced by feeding mice high-fructose/high-fat diet (HFrHFD) for 16 weeks. Carvedilol was adiministered for 4 weeks starting at week 13. At the end of the experiment, body weight, heart weight, left and right ventricular thickness, visceral fat weight, fasting blood glucose (FBG), serum insulin, IR index, and serum endothelin-1 were measured. In addition, cardiac tissue samples were histopathologically examined. Also, cardiac levels of cardiotrophin-1, ß-arrestin2, phosphatidylinositol 4,5 bisphosphate (PIP2), diacylglycerol (DAG), and phosphoserine 473 Akt (pS473 Akt) were measured. Results showed significant increases in the FBG, serum insulin, IR index, serum endothelin-1, cardiac DAG, cardiac fibrosis, and degenerated cardiac myofibrils in HFrHFD-fed mice associated with a significant reduction in cardiac levels of cardiotrophin-1, ß-arrestin2, PIP2, and pS473 Akt. On the other hand, carvedilol significantly reduced the heart weight, FBG, serum insulin, IR index, serum endothelin-1, cardiac DAG, left ventricular thickness, right ventricular fibrosis, and degeneration of cardiac myofibrils. In addition, carvedilol significantly increased cardiac levels of cardiotrophin-1, ß-arrestin2, PIP2, and pS473 Akt. CONCLUSION: Carvedilol enhances cardiac ß-arrestin2 signaling and reduces cardiac remodeling in HFrHFD-fed mice.

The concurrent exposure to aluminium and fructose induces liver injury in rats: Protection by monoammonium glycyrrhizinate.

Aluminium is a ubiquitous element that occurs naturally in the soil making human exposure to it unavoidable. It is implicated in the aetiology of different neurodegenerative diseases and can induce liver injury. In addition, insulin resistance (IR) plays an essential role in the pathogenesis and the progression of liver disorders. The increased consumption of fructose contained in soft drinks and western pattern diet results in IR that along with the wide distribution of aluminium make the concurrent exposure conceivable and increase the risk of liver injury. Therefore, the present study explores the hepatotoxic effects of aluminium and fructose administered concurrently and evaluates the possible protection by monoammonium glycyrrhizinate (MAG). Liver injury was induced by the administration of aluminium chloride (34 mg/kg/d) plus 10% (w/v) fructose in drinking water. Male rats were treated with either MAG (40 mg/kg/d) or silymarin (SIL, 100 mg/kg/d). The concurrent administration of aluminium and fructose (FRUAL) induced liver injury manifested as a significant elevation of serum liver enzymes activities, bilirubin level, and prothrombin time, as well as reduction of albumin level. On the other hand, the administration of MAG improved the FRUAL-induced aberrations of liver function tests and hepatic cytoarchitecture. We assume that the MAG-induced suppression of oxidative stress, toll-like receptor 4 pathway activation, inflammation, and apoptosis might play a crucial role in the hepatoprotective effect of MAG in this model. Intriguingly, the hepatoprotective effect MAG against FRUAL-induced liver injury surpasses that of the gold standard SIL, suggesting MAG as a better alternative to SIL.