Abstract

Vasopressin and apelin are reciprocally regulated hormones which are implicated in the pathophysiology of heart failure and the regulation of metabolism; however, little is known about their interactions under pathological conditions. In this study, we determined how post-infarct heart failure (HF) and a high fat diet (HFD) affect expression of the apelin APJ receptor (APJR) and the V1a (V1aR) and V1b (V1bR) vasopressin receptors in the hypothalamus, the heart, and the retroperitoneal adipose tissue. We performed experiments in male 4-week-old Sprague Dawley rats. The animals received either a normal fat diet (NFD) or a HFD for 8?weeks, then they underwent left coronary artery ligation to induce HF or sham surgery (SO), followed by 4?weeks of NFD or HFD. The HF rats showed higher plasma concentration of NT-proBNP and copeptin. The HF reduced the APJR mRNA expression in the hypothalamus. The APJR and V1aR protein levels in the hypothalamus were regulated both by HF and HFD, while the V1bR protein level in the hypothalamus was mainly influenced by HF. APJR mRNA expression in the heart was significantly higher in rats on HFD, and HFD affected the reduction of the APJR protein level in the right ventricle. The regulation of APJR, V1aR and V1bR expression in the heart and the retroperitoneal adipose tissue were affected by both HF and HFD. Our study demonstrates that HF and HFD cause significant changes in the expression of APJR, V1aR and V1bR, which may have an important influence on the cardiovascular system and metabolism.

Abstract: Hepatocellular carcinoma (HCC) is the second common cause of cancer incidence and death amongEgyptian men. á-fetoprotein (AFP) may be elevated in many liver diseases and is not elevated in all patientswith HCC, So more sensitive serum markers are needed for HCC diagnosis. AFP glycoform measuring is moreimportant than measuring of AFP. There are three types of glycoforms, the most important one in diagnosis ofHCC is lens Culinaris agglutinin reactive 3 alpha fetoprotein (AFPL3), as it is generated from malignant livercells, its measurement helps to differentiate HCC from benign hepatic diseases. The aim of the present studywas to improve outcome of patients with HCC by early diagnosis, through detection of AFP L3 in patients withnormal level of AFP. This study included 82 patients divided into two groups: Group (A): 41 HCC patients withnormal Alpha fetoprotein level, Group (B): 41 HCC patients with high level of Alpha fetoprotein. Tri-phasic liverComputed Tomography (CT) is a standardized procedure for the detection and characterization of HCC.Measurement of Human AFP-L3 by ELISA in serum by the kit (AFPL3 EIAab®, Catalog No: E1117h). Resultsshowed that out of 82 patients 18 patients were females and 64 were males with mean age 63.5years old. AFPL3 at cutoff 2.89 had sensitivity of 100% and specificity of 87.8%, AUC=0.515 and accuracy of 93.2% accordingto this cutoff 95% of patients with AFP <30 ng/mL had AFP L3 =2.89 versus 5% of patients with AFP <30 ng/mLhad AFP L3 >2.89, while 100% of patients with AFP >30 ng/mL had AFP L3 >2.89 versus 0% of patients withAFP >30 ng/mL had AFP L3 =2.89, this indicates that AFP L3 is a good diagnostic marker for HCC when AFPlevel is more than 30 ng/ml. Conclusion: There is a significant direct correlation between AFP level and AFPL3level in patients with HCC. AFP L3 is a good diagnostic marker for HCC only when AFP level is more than 30ng/ml.
Key words: HCC · Alpha fetoprotein · Alpha fetoprotein L3

Context

EUTOS score is the prognostic score validated in the TKI era. This score can be influenced by many factors, especially in developing countries, like parasitic infestations, viral infections and allergic reactions. Refinement of this score is a need with the emergence of more potent TKIs and for better recognition of high-risk patients.

Objective
The main objective of this study is to see whether the replacement of the basophil percentage with serum tryptase as a marker of basophil cell mass may change the predictive power of this score.

Design
This observational study included newly diagnosed CML patients in the period from October 2016 to April 2017. Those patients were followed up till the reporting date in April 2019.

Setting
Patients were recruited from the Alexandria university hospital as a terminal referral center.

Patients
The 48 included patients were newly diagnosed chronic phase CML patients excluding accelerated phase and blastic crisis. The female to male ratio was 1:1 with the mean age at presentation 43.94 years. Nineteen age and sex match individuals were included as a control group for tryptase. Patients who completed the follow up were 100% and 2 patients died during the follow up.

Interventions
Serum tryptase was measured for patients and controls using quantitative sandwich ELISA technique (EIAab kit catalog no: E1070h, China). Then the prognostic scores Sokal, Hasford and EUTOS were calculated adding to this the proposed score EUTOS-T replacing the basophil percentage with the serum tryptase. The follow up was done at 3-month intervals measuring the BCR/ABL-1 transcripts and the results were correlated to the baseline scores.

Results
The results showed that EUTOS score had lower sensitivity and specificity of defining the high-risk group at the cut-off value of 87 suggesting the higher splenic measurements and basophilia in the studied group; however this score showed better sensitivity and specificity (86.67% and 84.85% respectively) at a cut-off value of 154. EUTOS-T score showed higher sensitivity of 93.33% and a negative predictive value of 95.7%. Besides, the correlation between the molecular failure at 12 months was the strongest with EUTOS-T giving p-value <0.001.

Conclusion
Using EUTOS-T score resulted in better prediction of molecular progression and shorter overall survival of high-risk patients that leads to better choice of the frontline treatment regimens.

Keywords
CML, chronic myelogenous leukemia, tryptase, EUTOS, prediction, TKI

Abstract

Leukocyte transendothelial migration is one of the most important step in launching an inflammatory immune response and chronic inflammation can lead to devastating diseases. Leukocyte migration inhibitors are considered as promising and potentially effective therapeutic agents to treat inflammatory and auto-immune disorders. In this study, based on previous trioxotetrahydropyrimidin based integrin inhibitors that suboptimally blocked leukocyte adhesion, twelve molecules with a modified scaffold were designed, synthesized, and tested in vitro for their capacity to block the transendothelial migration of immune cells. One of the molecules, namely, methyl 4-((2-(tert-butyl)-6-((2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene) methyl) phenoxy) methyl) benzoate, (compound 12), completely blocked leukocyte transendothelial migration, without any toxic effects on immune or endothelial cells (IC50=2.4 µM). In vivo, compound 12 exhibited significant therapeutic effects in inflammatory bowel disease (IBD)/Crohn’s disease, multiple sclerosis, fatty liver disease, and rheumatoid arthritis models. A detailed acute and chronic toxicity profile of the lead compound in vivo did not reveal any toxic effects. Such a type of molecule might therefore provide a unique starting point for designing a novel class of leukocyte transmigration blocking agents with broad therapeutic applications in inflammatory and auto-immune pathologies.

Abstract

Hepatic ischemia/reperfusion injury (H-IRI) is associated with irreversible liver damage. The current study aimed to investigate the protective effect of carvedilol against H-IRI in high fructose high fat diet (HFrHFD) fed mice and the role of G-protein coupled receptor kinase 2 and 5 (GRK2 and GRK5). Mice were fed HFrHFD for 16?weeks, at the end of feeding period, mice were subjected to 30?min of ischemia followed by 1?h of reperfusion. Carvedilol (20?mg/kg, i.p.) was administered 30?min before ischemia. To explore the role of GRK2 and GRK5 in mediating carvedilol effects, paroxetine (GRK2 inhibitor, 10?mg/kg, i.p.) and amlexanox (GRK5 inhibitor, 25?mg/kg, i.p.) were administered 30?min before carvedilol administration. Liver function, histopathology and hepatic oxidative stress, as well as inflammatory and apoptotic markers were measured at the end of the experiment. In addition, adrenergic receptors downstream signals were measured in the liver. Results showed increased markers of liver injury (ALT and AST) in mice subjected to H-IRI. Moreover, liver injury was associated with slight collagen deposits as revealed by histopathology and elevated hepatic levels of oxidative stress, inflammatory and apoptotic markers. On the other hand, carvedilol protected mice against H-IRI and improved all associated pathological changes. Furthermore, pre-injection of either GRK2i or GRK5i did not change carvedilol effects on serum ALT level and liver collagen deposits, while increased its antioxidant, anti-inflammatory and anti-apoptotic effects. In conclusion, carvedilol protects against H-IRI in HFrHFD-fed mice. GRK2 and GRK5 may not play a potential role in mediating this effect.