Management of ulcerative colitis by dichloroacetate: Impact on NFATC1/NLRP3/IL1B signaling based on bioinformatics analysis combined with in vivo experimental verification.

The inflammatory response in ulcerative colitis (UC) could be relieved by the conventional immunomodulatory agents; 5-aminosalicylic acid, corticosteroids, or azathioprine. However, the low remission rates and the intolerance to these agents necessitate investigation of gene expression signature in UC that could influence the therapeutic efficacy of drugs, as well as the interference with persistence genes by novel therapeutic option. Three microarray datasets (GSE66407, GSE38713 and GSE14580) from the NCBI-GEO database were utilized. Differentially expressed genes between samples of patients with UC and healthy ones were analyzed using R software. In addition, in vivo study using oxazolone-induced UC in BALB/c mice was carried out to investigate the proposed therapeutic efficacy of dichloroacetate (DCA). The bioinformatics analysis revealed the persistence of NLRP3, NFATC1, and IL1B in UC despite treatment with common therapeutic agents. DCA administration to oxazolone-treated mice showed remarkable interference with those persistence genes. Western blotting analysis for NLRP3, NFATC1, nuclear/total NF-κB, and cleaved caspase-1 revealed the ability of DCA to reduce the expression levels of these proteins in oxazolone-treated mice. Additionally, the inflammatory cytokines IL-1ß and IL-13 were reduced in colonic tissue by DCA treatment. The therapeutic efficacy of DCA was further confirmed by the apparent reduction in histopathological scoring, disease activity index, and the normalization of colon length. Therefore, DCA could be suggested as a novel and promising therapeutic option in UC based on its ability to interfere with the persistence of NFATC1/NLRP3/IL1B signaling. That merits further safety/toxicological pre-clinical assessment and update of bioavailability/metabolism data prior to clinical investigation.

Nicorandil mitigates amiodarone-induced pulmonary toxicity and fibrosis in association with the inhibition of lung TGF-ß1/PI3K/Akt1-p/mTOR axis in rats.

The long-term side effect of the antiarrhythmic drug, amiodarone (AMIO), such as lung toxicity, remains a critical clinical issue. The previous knowledge denotes diverse antioxidant, anti-inflammatory, and antifibrotic properties of the anti-anginal drug, nicorandil (NI). Therefore, we aimed to investigate the possible protective effect of NI on pulmonary tissue remodelling following AMIO-induced lung toxicity. The included rats were assigned into four equal groups (n = 8): (1) control, (2) control group that received NI 10 mg kg-1  day-1 , (3) model group that received AMIO in a dose of 60 mg kg-1  day-1 , and (4) treated group (AMIO-NI) that were treated with AMIO plus NI as shown above. Drug administration continued for 10 weeks. AMIO resulted in deteriorated (p < 0.001) pulmonary functions accompanied by respiratory acidosis. AMIO showed an obvious histological injury score with intense collagen deposition, disturbed nitric oxide synthase enzymes (NOS/iNOS), and increased alpha smooth muscle actin expression. Furthermore, AMIO upregulated the transforming growth factor (TGF-ß1)/phosphoinositide-3 kinase (PI3K)-Akt1-p/mammalian target of rapamycin (mTOR) axis, which determined the possible mechanism of AMIO on pulmonary remodelling. NI treatment significantly (p < 0.001) prevented the AMIO-induced lung toxicity, as well as inhibited the TGF-ß1/PI3K/Akt1-p/mTOR axis in the lung tissue of rats. The results were confirmed by an in-vitro study. CONCLUSION: The current results revealed that NI was effective in preserving the lung structure and functions. Amelioration of the oxidative stress and modulation of TGF-ß1/PI3K/Akt1-p/mTOR have been achieved. This study suggests NI administration as a preventive therapy from the serious pulmonary fibrosis side effect of AMIO.

Transcatheter closure of fenestrated atrial septal aneurysm in children: Feasibility and long-term results.

BACKGROUND: To date, extensive experience in transcatheter closure of fenestrated atrial septal aneurysm (ASA) in the pediatric population is limited. METHODS: To report on procedural feasibility, efficacy, and long-term outcome, we enrolled all children submitted to an attempt of transcatheter closure of fenestrated ASA at two, large volume, pediatric cardiology units (Naples and Massa, Italy) between April 2000 to May 2020. RESULTS: This retrospective study included 139 patients (median age 9 years [range 2-18] and weight 36 kg [range 10-102]); 19 (13.7%) children were ≤20 kg (range 10-20) and 14 (10.1%) were ≤5 years old. Single perforation was observed in 28 patients (20.1%), while 111 patients (79.9%) had multifenestrated ASA. The median size of the main defect was 15 mm (range 6-34) and 25 patients (18%) had a defect ≥20 mm. The procedural success rate was 99% (95% confidence interval [CI]: 94.9-99.8) using a single device in 75 (69%), two devices in 31 (28%), and three devices in 3 (3%) cases. Early minor adverse events (AEs) occurred in four patients (2.8%). Late minor AEs were recorded in one patient (0.7%) over a median follow-up of 5 years ([range 0-18 years; total 890.2 person-years, and with 30 patients (22%) followed ≥10 years). Neither mortality nor major AEs were recorded. Freedom from AEs was 99.1% at 10-15 years (95% CI: 93.5-99.8%), without any difference according to atrial septum anatomy or patient age and weight. CONCLUSION: Transcatheter closure of fenestrated ASA is technically feasible and effective in children with excellent long-term outcomes.

Musa sp. Leaves Extract Ameliorates the Hepato-Renal Toxicities Induced by Cadmium in Mice.

Heavy metals intoxication causes several health problems that necessitate finding new protective and therapeutic approaches. This study aimed to evaluate the impact of Musa sp. leaves extract (MLE) on hepato-renal toxicities induced by cadmium (Cd) in male mice. The phytochemical screening, metal chelating activity (MCA), and the median lethal dose (LD50) of MLE were determined. Fifty CD-1 male mice were used and intraperitoneally (i.p.) injected with MLE (1000 to 5000 mg/kg b.wt) for MLE LD50 determination. Another 50 mice were used for evaluating the effect of MLE on Cd toxicity. Blood samples were collected for hematological, liver, and kidney functions assessments. Liver tissue homogenates were used for determination of oxidant/antioxidant parameters. Liver and kidney tissues were harvested for histopathological and molecular investigations. MLE showed potent in vitro antioxidant activities. The MCA and LD50 of the MLE were 75 µg/mL and 3000 mg/kg b.wt, respectively. MLE showed beneficial therapeutic activity against hepato-renal toxicities in Cd-intoxicated mice, evidenced by improving the hematological, biochemical, histopathological, and molecular alterations.

Baseline plasma lipid levels in patients with acute coronary syndrome: Association with 20-year mortality. The ABC-5a* Study on Heart Disease.

BACKGROUND: The relationship between baseline plasma lipid levels during acute coronary syndrome and the outcome has clinical relevance. METHODS: To evaluate their long-term prognostic value, we examined 589 patients admitted with acute coronary syndrome at three hospitals. Baseline plasma lipids were assessed on days 1 and 7. Patients were followed for 20 years or until death. RESULTS: Virtually, all patients completed follow-up; 437 (74%) had died: 24% from coronary artery disease/heart failure (CAD/HF), 21% sudden cardiac death (SCD), 16% from other cardiovascular causes and 39% had non-cardiac death. The incidence rate (IR) of all-cause mortality was not different among patients with baseline plasma lipids less or greater than the median value. The IR of CAD/HF mortality was not significantly higher among patients with greater than median low-density lipoprotein (LDL) cholesterol and triglyceride (TG) levels. The IR of non-cardiac death tended to be lower among patients with greater than median total cholesterol (TC) and LDL levels. Using three levels of adjusted Cox survival models, baseline plasma lipids had no consistent independent or inverse association with all-cause mortality, even after excluding patients who received statins. Competitive risk survival models for each cause of death revealed that the only hazard of non-cardiac death was consistently higher among patients with less than or equal to median TC and LDL levels. CONCLUSION: In the present prospective long-term study, after acute coronary syndrome, baseline plasma lipid levels seem not to be associated with long-term global mortality. Only an independent inverse association between TC and LDL and non-cardiac death has been observed.

Association between plasma lipid levels during acute coronary syndrome and long-term malignancy risk. The ABC-4* study on heart disease.

BACKGROUND: Emerging evidence suggests that patients with coronary artery disease carry an increased risk of developing malignancy, with deleterious effects on long-term prognosis. Our aim was to ascertain whether baseline plasma lipid levels during acute coronary syndrome (ACS) are associated with malignancy in long-term. METHODS: This study included 589 patients admitted with ACS to three centers and discharged alive. Plasma lipid levels were assessed on the first morning after admission. Patients were followed for 17 years or until death. RESULTS: Five hundred seventy-one patients were free from malignancy at enrollment, of them 99 (17.3%) developed the disease during follow-up and 75 (13.1%) died due to it. Compared to patients without malignancy, those with malignancy showed lower plasma levels of total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TG). The groups showed similar statin use rates at any time in follow-up. The incidence rate of neoplasia and neoplastic mortality was higher in patients with baseline TC or LDL values ≤ median; they showed 85 and 72% increased incidence rate of developing malignancy and 133 and 122% increased incidence rate of neoplastic death respectively. No differences were observed relative to HDL and TG levels. In survival analysis using Cox regression with parsimonious models, patients with baseline TC or LDL values > median, respectively, showed risks of 0.6(95% CI 0.4-0.9; p = 0.01) and 0.6(95%CI 0.4-0.9; p = 0.02) for malignancy onset, and 0.5(95% CI 0.3-0.8; p = 0.005) and 0.5(95% CI 0.3-0.8; p = 0.004) for neoplastic death. Similar results were obtained using competitive risk analysis with parsimonious models. CONCLUSIONS: This long-term prospective study of an unselected real-world patient sample showed that neoplasia onset and mortality are independently associated with low plasma TC and LDL levels at admission for ACS.

Association of Osteopontin Gene Polymorphisms with Colorectal Cancer.

We investigated the association of the Osteopontin (OPN) (rs9138 and rs1126616) polymorphisms with colorectal cancer (CRC). One hundred CRC patients and 112 healthy individuals were subjected to OPN (rs9138 and rs1126616) genotyping and measurement of OPN protein plasma level. The C allele of OPN rs1126616 and the CC haplotype were significantly higher in CRC patient (p = 0.036, 0.003, respectively). In females, the C allele of OPN rs9318 (A/C) polymorphism was significantly associated with increased CRC risk (p = 0.036). The plasma OPN level >104.35 ng/mL was significantly associated with CRC. Our findings suggest a significant role played by OPN (rs9138 and rs1126616) in colorectal carcinogenesis.

Single-center experience in percutaneous closure of arterial duct with Amplatzer duct Occluder II additional sizes.

OBJECTIVES: This study aimed to report a large, single-center experience of percutaneous arterial duct (AD) closure using Amplatzer Duct Occluder II Additional Sizes device (ADO II-AS)(St. Jude Medical Corp, St. Paul, MN, USA). BACKGROUND: Transcatheter closure of AD remains challenging in low body weight patients and those who have a persisting shunt following a previous attempt at interventional closure. Recent technical advances in device design may address these issues. METHODS: From May 2011 to April 2016, 109 patients underwent attempted percutaneous closure of AD with ADO II-AS at our Institution. Mean age and weight were 4.8 ± 8.1 years (range 0-48) and 21.4 ± 20.6 kg (range 3-93), respectively. Fifteen patients (13.8%) were ≤6 kg (age 3.5 ± 2.0 months; weight 4.7 ± 1.1 kg). Arterial duct morphology was type A in 62 (57%), type B in 1 (1%), type C in 32 (29%), type D in 7 (6%) and type E in 6 patients (6%), respectively. Arterial approach was used to negotiate and deploy the occluding device in 103 patients (94.5%). RESULTS: AD diameter was 2.2 ± 0.6 (range 1.5-4.5) resulting in QP/QS of 1.9 ± 0.7 (range 1-3.3). Mean pulmonary artery pressure and PA/aortic pressure ratio were 19.3 ± 5.0 mm Hg (range 12-38) and 0.34 ± 0.14 (range 0.14-0.95), respectively. Successful device deployment was achieved in 107 patients (98.2%). Neither procedural morbidity nor mortality was recorded. Immediate, 24h and mid-term (30 ± 17 months) complete occlusion was recorded in 71%, 98.1%, and 100% of patients, respectively. CONCLUSION: In our experience, trans-catheter closure of AD of different sizes and morphologies using ADO II-AS is highly feasible, safe and effective also in challenging anatomic/clinical settings. © 2016 Wiley Periodicals, Inc.

Fate of Duct-Dependent, Discontinuous Pulmonary Arteries After Arterial Duct Stenting.

Significant and balanced PA growth following arterial duct (AD) stenting has already been consistently reported in literature. However, to date, no data are available about the role of this approach as palliation of congenital heart disease with a duct-dependent discontinuous pulmonary artery (dPA). The aim of this study was to evaluate the fate of a dPA of ductal origin following trans-catheter AD stabilization. Angiographic PA evaluation was performed in seven patients submitted to neonatal AD stenting as palliative recruitment of dPA. Five patients showed discontinuity of one PA, while two patients had both PAs served by bilateral ducts. PA growth was evaluated as per the Nakata index, McGoon ratio as well as dPA (n = 9) versus heart-dependent PA (hPA; n = 5) size and z-score changes. AD stabilization was performed using coronary stents dilated to 3.2 ± 0.3 mm (median 3.4), with significant increase of O2 saturation (from 83 ± 11 to 95 ± 5%, p < 0.02). Control angiography was performed 5.1 ± 2.8 months (median 6 months) after duct stenting, showing significant growth of the dPA (from 3.7 ± 1.0 to 7.6 ± 2.7 mm, p < 0.001; z-score from -0.7 ± 1.4 to 1.7 ± 2.2, p < 0.01). A trend toward better growth of the dPA as compared with the hPA was found (117 ± 87 vs. 54 ± 34%, p = NS). The final vessel size was still significantly different between the groups (dPA 7.6 ± 2.7 vs. hPA 11.9 ± 3.4 mm, p = 0.02), although the final z-score value did not significantly differ (dPA 1.7 ± 2.2 vs. hPA 3.8 ± 0.9 mm, p = NS). In conclusion, percutaneous AD stenting is effective in promoting a significant catch-up growth of duct-dependent dPA, being, therefore, advisable as a reliable alternative to surgical palliation.

The added value of pretreatment DW MRI in characterization of salivary glands pathologies.

OBJECTIVE: To evaluate the added value of diffusion weighted magnetic resonance imaging (DW-MRI) in characterization of salivary gland lesions. STUDY DESIGN: A prospective study was carried out between January 2013, and March 2015. METHODS: The study included 46 patients. The consultant radiologist, who reviewed the scans to comment on the apparent diffusion coefficient (ADC) value and ADC histogram was blind to the suspected pathology. Radiological findings were then compared to clinical and histological findings. RESULTS: The diagnostic performance of DW-MRI for identification of malignant lesions showed that the sensitivity, specificity, and positive and negative prediction value were 100%, 92%, 91.3%, and 100%, respectively. CONCLUSION: The specific ability of DW-MRI to probe tissue microstructures is an interesting complement to the currently used imaging procedures in the characterization, and even grading of malignancies. ADC mapping is an easy, cost effective promising tool that has neither radiation exposure, nor amalgam artifacts and can be used in helping characterization of salivary glands lesions. LEVEL OF EVIDENCE: 1B.

Language Profile in Congenital Hypothyroid Children Receiving Replacement Therapy.

OBJECTIVE: The aim of this work was to evaluate receptive and expressive language skills in children with congenital hypothyroidism receiving early hormonal replacement treatment before the age of 3 months and to identify any subtle areas of weaknesses in their language development to check the necessity for future language intervention. PATIENTS AND METHODS: The study was conducted on 30 hypothyroid children receiving hormonal replacement. They were subdivided into group I (5-8 years 11 months; 12 cases) and group II (9-12 years 11 months; 18 cases). All patients were subjected to a protocol of assessment applied in the Diabetes, Endocrine and Metabolism Pediatric Unit (DEMPU) and evaluation of language skills by the REAL scale. RESULTS: The younger group reached average Arabic language scores, while the older group showed moderate language delay. CONCLUSION: Early replacement therapy supports language development in young children. However, longitudinal and follow-up studies are required to identify difficulties presenting at older ages that may affect children in the academic settings.

Pulmonary metastatectomy in pediatric cancer patients at National Cancer Institute, Egypt: prognostic factors and outcome.

BACKGROUND: Metastatic tumors account for 80% of all lung tumors in children. Wilms tumour and osteosarcoma are the most tumors of childhood that produce lung metastases. The aim of the current study is to assess the prognostic factors of pulmonary metastatectomy in pediatric solid tumours as age, number, size, site,laterality, resectability of pulmonary nodules, and number of Thoracotomies. Calculate overall survival among patients who underwent pulmonary metastatectomy. METHODS: It is a retrospective study including all pediatric patients with metastatic solid tumors to lungs treated at pediatric oncology department, National Cancer Institute, Cairo University from 2008 to 2014. Fifty-five patients were included, 43 (78.2℅) patients of them had Osteosarcoma. RESULTS: Thirty (54.5℅)patients were male. The mean age was 15 years ranging from (4.5- 23) years. The site of primary disease was at lower limbs in 43 (78.2%) patients. All patients underwent complete surgical resection of the primary disease with negative margin, 22(51.1%) of the osteosarcoma patients did amputation with tumor necrosis less than 90%. All patients received chemotherapy and only 9 received radiation therapy. The patients were classified into four groups according to time of diagnosis of pulmonary metastasis: at time of diagnosis in 13 (21.8%) patients, within treatment in 16 (30.9%) patients, within first year follow up in 18 (32.7%) patients and detected late in 8 (14.5%) patients. Bilateral lung metastasis diagnosed by CT chest were detected in 42 (76.4%) patients. Size of metastatic nodules was ranging from (0.5 to 10 cm) with mean 3.4 cm. Number of metastatic nodules was ranging from (1 to 28) median 4.Metastatic complications were detected in 19 patients. 5-year OS was 74.8% in the study group, and 68% in osteosarcoma patients. Effect of prognostic factors as sex, time of respectability, laterality, tumor necrosis of the 1ry disease, Timing of lung metastasis, size and site of the primary, Surgical approach of metastatectomy, postoperative complications on overall survival of the studied patients was done with significant P-value of tumor necrosis of the 1ry disease and Timing of lung metastasis 0.017, 0.001 respectively. CONCLUSION: Resection of pulmonary metastases of pediatric solid tumours is a safe and effective treatment that offers better survival.

Balancing Risks versus Benefits: Vitamin C Therapy versus Copper Oxide Nanoparticles Toxicity in Albino Rats' Submandibular Salivary Gland.

OBJECTIVES: This study aimed to examine the suppressive effect of the natural antioxidant vitamin C (VC) against submandibular gland toxicity induced by copper oxide nanoparticles (CuO-NPs). MATERIALS AND METHODS: Three groups of 30 mature male albino rats (4 weeks old) weighing between 150 and 200 g were selected. The rats were randomly assigned for 6 weeks to receive: intraperitoneal injection (IP) of vehicle (control group); IP of 2.5 mg/kg body weight (bw) of CuO-NPs (CuO-NPs group); and IP of 2.5 mg/kg bw of CuO-NPs, combined with a daily oral dose of 100 mg/kg bw of VC in drinking water via gavage (CuO-NPs/VC group). The rats were euthanized, and their submandibular glands were dissected for histological evaluation, including hematoxylin and eosin staining and immunohistochemistry for Ki-67 and caspase-3. STATISTICAL ANALYSIS: The area expression for Ki-67 and caspase-3 was statistically analyzed using GraphPad Prism. Following analysis of variance analysis, Tukey's post hoc was used for multiple comparisons. The significance level was set at p < 0.05. RESULTS: CuO-NPs caused significant cytotoxic effects on submandibular salivary gland cells in albino rats. This led to an increase in Ki-67 and caspase-3 levels compared with the control group. VC administration improved tissue histology and reduced Ki-67 and caspase-3 levels in the VC/CuO-NPs group compared with rats treated with CuO-NPs alone. CONCLUSION: The study revealed significant cytotoxic effects of CuO-NPs on the submandibular salivary gland of albino rats. VC effectively mitigated these toxic effects, suggesting its potential as a readily available antioxidant.

Heart failure during acute coronary syndrome and the long-term cancer risk: the ABC-9 Study on heart disease.

AIMS: A higher risk of cancer among patients with heart failure (HF) has been suggested in recent community-based studies. This study aimed to investigate the impact of HF during hospitalization with acute coronary syndrome (ACS) on the long-term cancer risk. METHODS AND RESULTS: The study included 572 patients admitted with ACS to three Italian hospitals, discharged cancer-free, and prospectively followed for 24 years or until death. All but three patients completed the follow-up, which represented 6440 person-years (mean age: 66 ± 12 years; 70% males). Baseline HF was diagnosed in 192 (34%) patients. A total of 129 (23%) patients developed cancer (103 without HF and 26 with HF), and 107 (19%) patients died due to it (81 without HF and 26 with HF). The incidence rates for cancer onset and cancer death were not different according to HF status. Cox regression analysis revealed no association between HF or left ventricular ejection fraction (LVEF) and cancer risk. In addition, no difference in cancer risk was observed among patients with HF with preserved ejection fraction, HF with mildly reduced ejection fraction, and HF with reduced ejection fraction. In competing risk regression analysis, the risk of cancer onset associated with HF was sub-hazard ratio (SHR) 0.47 [95% confidence interval (CI): 0.30-0.72; P = 0.001] and SHR 1.02 (95% CI: 1.01-1.04; P = 0.002) with LVEF. Results were the same in the adjusted model. Yet the fully adjusted model showed an attenuated association between cancer death and HF (SHR: 0.63; 95% CI: 0.37-1.05; P = 0.08) and LVEF (SHR: 1.02; 95% CI: 0.99-1.06; P = 0.08). Consistent results were obtained after using propensity score matching analysis that created 192 pairs. A negative interaction between age and HF and a positive interaction between age and LVEF for cancer risk have also been found. CONCLUSIONS: An inverse association between baseline HF and long-term cancer risk has been observed among the ABC Study on heart disease patients who were followed for 24 years after ACS.

A comprehensive survey of warfarin-induced hepatic toxicity using histopathological, biomarker, and molecular evaluation.

Warfarin finds human application as anticoagulant therapy. Warfarin usage can cause liver damage and hemorrhage. Besides functioning as anticoagulant and causing continuous bleeding of pests, the mechanism of toxicity of warfarin is unknown. In this study, Wild female and male rats were administrated orally with warfarin for 18 days at 9, 18, 27.5, and 55 mg/kg, respectively. Hepatoxicity was determined by assessing, LD50, leukocyte counts, immunochemistry, histopathology, serum proteins, Western blotting, especially of markers of liver injury, such as AST, ALT & ALP, and markers of antioxidant and oxidative stress markers. Warfarin treatment decreased Nrf2 levels while it increased caspase 3, CYP2C9, COLL1A1. It caused cellular damage and fibrosis of liver. The plasma levels of markers of liver injury, AST, ALT, ALP, bilirubin and transferrin were increased. The plasma levels of albumin, IgG and antitrypsin were decreased. Warfarin treatment decreased RBC and total lymphocyte count while increasing selectively neutrophils. Warfarin exposure caused increased oxidative stress; increased LPO and decreased GSH, SOD, CAT and NO production. Oral exposure of rats with Warfarin leads to increased oxidative stress resulting into liver damage via CYP2C9 mediated by Nrf2 depletion.

Unlocking the miRNA-34a-5p/TGF-ß and HMGB1/PI3K/Akt/mTOR crosstalk participate in the enhanced cardiac protection of liraglutide against isoproterenol-induced acute myocardial injury rat model.

Liraglutide (LIRA), a drug used to treat type 2 diabetes mellitus that belongs to the glucagon-like peptide-1 class, has recently drawn attention for its potential cardioprotective properties because of its anti-oxidative and anti-inflammatory properties. This current investigation was designed to assess the impact of LIRA on myocardial injury induced by isoproterenol (ISO). The experiment included 24 male Wistar rats in total, and they were divided into four groups: Control, LIRA (200 µg/kg/12 hrs., S.C.), ISO (85 mg/kg, S.C.), and ISO + LIRA. To assess the results, various biochemical and histopathological analyses were carried out. The findings showed elevated serum enzyme levels, a sign of cardiac injury. ISO-treated rats showed an upregulation of oxidative stress and inflammatory biomarkers like MDA, MPO, nitrites, NADPH oxidase, TNF-α, IL-1ß, IL-6, 8-Hydroxyguanosine (8-OHdG), and TGF-ß, as well as altered gene expressions like TLR-1 and miRNA-34a-5p. According to western blotting analysis, protein levels of AKT, PI3K, and mTOR were obviously enhanced. Additionally, ISO-treated samples showed altered tissue morphology, elevated caspase 3, and decreased Bcl2 concentrations. The levels of these dysregulated parameters were significantly normalized by LIRA therapy, demonstrating its cardioprotective function against ISO-induced myocardial injury in rats. This protective mechanism was linked to anti-inflammatory properties, redox balance restoration, and modulation of the miRNA-34a-5p/TGF-ß pathway.

Evaluation of the Expression EGFR, HER2/NEU and the End Effector ERK of the RAS/RAF/MAP Kinase Pathway in Prostatic Adenocarcinoma for a Possible Role as New Target Therapy.

The alterations of EGFR and HER2/neu as growth factor receptors and the cytoplasmic signal transduction proteins of RAS/RAF/MAP kinases including its end effector molecule (ERK) are important in the carcinogenesis of many tumors. The activation of these protooncogenes in prostate cancer is still under investigation. The aim of this work was to study EGFR, HER2- neu, inactive (non-phosphorylated) and active (phosphorylated) ERK expression in prostatic adenocarcinomas in correlation to the clinical and pathological parameters. METHODS: Immunohistochemistry- using tissue microarrays- for EGFR, HER2/neu, non-phosphorylated, and phosphor-ERK, was performed on tissues from 166 patients- with primary prostatic adenocarcinoma with no prior treatment-. The results of different markers expression were correlated with the clinical and pathological parameters and were analyzed statistically. RESULTS: The prostatic tissue showed EGFR, HER2 neu, phosphorylated and non-phosphorylated ERK expression in 8.4%, 1.4%, 78.2%, and 83.4% respectively whether low (patchy) or high expression (diffuse).  There were no significant correlations found between patient characteristics and expression of the tested markers. The negative immune reactivity for non-phosphorylated ERK and EGFR- was significantly correlated with high tumor stage (p values 0.03 and 0.01, respectively). CONCLUSION: EGFR and HER2/neu may play a limited role in prostatic adenocarcinoma as they showed positive expression in a limited number of the examined tissues specifically HER2neu. The expression of non-phosphorylated ERK (mostly weak to moderate) and phosphorylated ERK (mostly moderate to strong)- was appreciated in most cases. Thus, we suggest that anti-EGFR drugs may have a limited role in the treatment of castrate-resistant prostate cancer, but anti-MEK/ERK drugs may have more promising role as a target therapy. It is recommended to perform further molecular testing to elucidate the exact mechanism and significance of these markers.

Microalbuminuria during acute coronary syndrome: Association with 22-year mortality and causes of death. The ABC-8* study on heart disease. (*ABC is an acronym for Adria, Bassano, Conegliano, and Padova Hospitals).

BACKGROUND: Microalbuminuria is associated with adverse outcomes in acute coronary syndrome (ACS) patients. METHODS: To evaluate the very long-term association between Microalbuminuria and the overall mortality and causes of death in this clinical setting, we prospectively studied 579 unselected ACS patients admitted to three hospitals. The baseline albumin-to-creatinine ratio (ACR) was measured on days 1, 3, and 7 in 24-h urine samples. Patients were followed for 22 years or until death. RESULTS: Virtually all patients completed follow-up; 449(78%) had died: 41% due to non-sudden cardiac death (non-SCD), 19% sudden cardiac death (SCD), 40% due to non-cardiac (non-CD) death. Using unadjusted Cox regression analysis, ACR was a significant predictor of all-cause mortality (hazard ratio [HR] 1.26;95%confidence interval [CI] 1.22-1.31; p˂0.0001) and the three causes of death (HR 1.40;95%CI 1.32-1.48; p˂0.0001), (HR 1.22;95%CI 1.12-1.32; p˂0.0001) and (HR 1.16;95%CI 1.09-1.23; p˂0.0001) for non-SCD, SCD and non-CD respectively. Using a fully adjusted model, ACR was a significant independent predictor of all-cause mortality (HR 1.12; 95%CI 1.08-1.16; p˂0.0001) and only non-SCD (HR 1.21; 95%CI 1.14-1.29; p˂0.0001). There was a positive interaction between ACR level and history of AMI (HR 1.15; 95%CI 1.03-1.29; p = 0.01) and the presence of heart failure at admission (HR 1.11; 95%CI 1.01-1.24; p = 0.04), and negative interaction with higher than median LVEF (HR 0.89; 95%CI 0.80-0.99; p = 0.03) for all-cause mortality at the multivariable level. CONCLUSION: Based on the present analysis, baseline urinary albumin excretion during ACS is a strong independent predictor of the very long-term mortality risk, chiefly due to non-sudden cardiac death.

Zafirlukast protects against hepatic ischemia-reperfusion injury in rats via modulating Bcl-2/Bax and NF-κB/SMAD-4 pathways.

Hepatic ischemia/reperfusion injury (IRI) is a clinical problem commonly during liver transplantation and other liver surgery. This study aimed to evaluate the protective effect of zafirlukast (ZFK) on IR-induced hepatic injury and investigate its relevant protective mechanism. Thirty-two male Wistar albino rats were randomly allocated to four groups: sham, IRI, ZFK, and ZFK + IR groups. ZFK was administered orally in a dose of 80 mg/kg/day for 10 consecutive days. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBL) levels, and gamma glutamyl transferase (GGT) activity were estimated. Liver tissues were used to assess oxidative stress biomarkers including malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NOx), and reduced glutathione (GSH) contents. Inflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-33 (IL-33), in addition to apoptosis biomarkers, BCL2 associated X protein (Bax), B-cell lymphoma 2 (Bcl2) and galactine-9 (GAL9) proteins were also assessed. Western blot analysis was performed for vascular endothelial growth factor (VEGF) and fibrinogen expressions. Immunohistochemical analysis for hepatic nuclear factor-kappa B (NF-κB) and SMAD-4 was done in addition to histopathological examination. Our study revealed that ZFK pre-treatment resulted in liver function restoration and oxidative stress correction. Moreover, inflammatory cytokines were significantly reduced and a remarkable reduction of apoptosis, angiogenesis, and clotting formation has been indicated. Additionally, a significant reduction in SMAD-4 and NF-kB protein expressions was observed. These results were supported by hepatic architecture improvement. Our findings revealed that ZFK possesses a potential protective effect against liver IR possibly through its antioxidant, anti-inflammatory and anti-apoptotic properties.