Incidence of HCC in chronic hepatitis C patients with advanced hepatic fibrosis who achieved SVR following DAAs: A prospective study

Liver cirrhosis is an important risk factor for hepatocellular carcinoma. The reported annual incidence of HCC is about 3%‐8% in CHC cirrhotic patients. Based on the Cochrane systematic review, there was no clear evidence, on the long‐term clinical effects of DAAs in patients achieving SVR, as regard liver cirrhosis‐related HCC incidence. The aim of the study was to determine the incidence of HCC in chronic hepatitis C patients genotype IV with liver cirrhosis and advanced liver fibrosis after achieving SVR following DAA treatment in a prospective large cohort of HCV patients with long follow‐up. This was a prospective observational cohort study including 2372 CHC patients with advanced liver fibrosis or cirrhosis receiving DAA therapy in outpatient clinics at the Egyptian Liver Research Institute and Hospital since January 2015. Liver fibrosis was assessed using transient elastography. Abdominal ultrasonography and AFP measurement were done at baseline and follow‐up visits every 6 months, in addition to triphasic abdominal MSCT when needed. Patients were followed up after achieving SVR12 for at least 12 months. HCC developed in 109 cases during the follow‐up period (mean 23.60 ± 8.25 months). Overall HCC incidence was 2.338/100 PY, 95% CI = 1.942‐2.814. In patients with cirrhosis, the incidence of HCC was 2.917/100 PY, 95% CI = 2.407‐3.535, while in patients with advanced liver fibrosis the incidence of HCC was 0.664/100 PY, 95% CI = 0.333‐1.326. In conclusion, the incidence of HCC was reduced in chronic hepatitis C genotype 4 patients with liver cirrhosis (F4) and advanced hepatic fibrosis (F3) who achieved SVR following DAA therapy.     

Noteworthy effect of slight variation in aliphatic chain length of trisubstituted imidazole inhibitors against epidermal growth factor receptor L858R/T790M/C797S mutant in cancer therapy

11h is a very potent inhibitor against epidermal growth factor receptor triple mutation L858R/T790M/C797S (EGFR^TM) with 13‐fold stronger potency than the FDA‐approved osimertinib. Recently, two new EGFR^TM inhibitors, 11d and 11e , were reported which revealed 2.8‐ and 2.3‐fold stronger potency than 11h , respectively. 11h , 11d, and 11e have the same structures but differ only in their aliphatic chain length. However, the exact effects of differential aliphatic chain length on the inhibitory potencies of these compounds require further elaboration at the atomistic level, hence the objective of this report. Various computational tools were employed for this purpose. From our findings, it was revealed that van der Waals (vdW) interactions modulate the binding mechanisms of these inhibitors and play the most important role in the differential inhibitory activities of 11d , 11h, and 11e . The strong hydrogen bond formation between the aliphatic chain of 11d and key residue ARG841 was recognized as the reason for its higher activity and inhibitory potency relative to 11h and 11e . Moreover, the extension of the N‐terminal loop into the active site for vdW interaction with the phenyl group of 11e and carbon–hydrogen bond formed between the aliphatic chain of 11e and LEU718 engendered a higher activity of 11e than 11h .     

Deciphering the canonical blockade of activated Hageman factor (FXIIa) by benzamidine in the coagulation cascade: A thorough dynamical perspective

The experimental inhibitory potency of benzamidine (BEN) paved way for further design and development of inhibitors that target β‐FXIIa. Structural dynamics of the loops and catalytic residues that encompass the binding pocket of β‐FXIIa and all serine proteases are crucial to their overall activity. Employing molecular dynamics and post‐MD analysis, this study sorts to unravel the structural and molecular events that accompany the inhibitory activity of BEN on human β‐FXIIa upon selective non‐covalent binding. Analysis of conformational dynamics of crucial loops revealed prominent alterations of the original conformational posture of FXIIa, evidenced by increased flexibility, decreased compactness, and an increased exposure to solvent upon binding of BEN, which could have in turn interfered with the essential roles of these loops in enhancing their procoagulation interactions with biological substrates and cofactors, altogether resulting in the consequential inactivation of FXIIa. A sustained interaction of the catalytic triad residues and key residues of the autolysis loop impeded their roles in catalysis which equally enhanced the inhibitory potency of BEN toward β‐FXIIa evidenced by a favorable binding. Findings provide essential structural and molecular insights that could facilitate the structure‐based design of novel antithrombotic compounds with enhanced inhibitory activities and low therapeutic risk.     

Improved Strength and Toughness of Carbon Woven Fabric Composites with Functionalized MWCNTs

This investigation examines the role of carboxyl functionalized multi-walled carbon nanotubes (COOH-MWCNTs) in the on- and off-axis flexure and the shear responses of thin carbon woven fabric composite plates. The chemically functionalized COOH-MWCNTs were used to fabricate epoxy nanocomposites and, subsequently, carbon woven fabric plates to be tested on flexure and shear. In addition to the neat epoxy, three loadings of COOH-MWCNTs were examined: 0.5 wt%, 1.0 wt% and 1.5 wt% of epoxy. While no significant statistical difference in the flexure response of the on-axis specimens was observed, significant increases in the flexure strength, modulus and toughness of the off-axis specimens were observed. The average increase in flexure strength and flexure modulus with the addition of 1.5 wt% COOH-MWCNTs improved by 28% and 19%, respectively. Finite element modeling is used to demonstrate fiber domination in on-axis flexure behavior and matrix domination in off-axis flexure behavior. Furthermore, the 1.5 wt% COOH-MWCNTs increased the toughness of carbon woven composites tested on shear by 33%. Microstructural investigation using Fourier Transform Infrared Spectroscopy (FTIR) proves the existence of chemical bonds between the COOH-MWCNTs and the epoxy matrix.     

Synthesis and biological evaluation of heteroalicyclic cyanoguanidines at histamine receptors

Recent studies on histamine receptor (HR) subtypes identified imidazolyl butyl cyanoguanidines, like UR‐PI376, as highly potent agonists at the human histamine H₄ receptor (hH₄R). While imidazole‐containing compounds display drawbacks in pharmacokinetics, we studied the possibility of replacing the heteroaromatic cycle by nonaromatic six‐membered heterocycles (piperidine, morpholine, thiomorpholine, and N‐methylpiperazine) as potential bioisosteres. Beyond that, this approach should give more information about the indispensability of the aromatic ring as a basic head group. Besides these changes, a variation of the spacer length (C₃–C₅) connecting the heterocycle and the cyanoguanidine moiety has been made to possibly trigger the selectivity towards the respective HRs. Investigations in radioligand‐binding assays exhibited only very weak activity at the hH₁R and hH₃R, while nearly all compounds were inactive at the hH₂R and hH₄R. In the case of piperidine‐containing compounds, moderate affinities at the hH₃R over the single‐digit micromolar range were detected.     

Association of PTPN22 gene polymorphism and systemic lupus erythematosus in a cohort of Egyptian patients: impact on clinical and laboratory results

To assess the possible association between the protein tyrosine phosphatases non-receptor 22 (PTPN22) gene 1858 CT polymorphism and the predisposition to systemic lupus erythematosus (SLE) in Egyptian patients and its influence on clinical and laboratory parameters. PTPN22 gene 1858 CT polymorphisms were analyzed in forty SLE patients and 20 normal controls by real-time polymerase chain reaction (PCR) technology, using the TaqMan 5-allele discrimination assay. Detailed history, clinical examination, and investigations were done to detect various organ involvement. The homozygous genotype TT was absent in both SLE and controls. The CC genotype was observed in 47.5% SLE and 80% controls; the CT genotype was found in 52.5% patients and 20% controls. The frequencies of the C and T alleles were 74 and 26% in SLE and 90 and 10% in controls, respectively. The presence of CT genotype increased the risk for developing SLE by 4.42. Renal involvement was significantly higher in SLE patients with CT (76.2%) compared to those with CC genotype (42.1%).     

Irrigation endoscopic discectomy: a novel percutaneous approach for lumbar disc prolapse

Purpose

The purpose of this study is to present a new endoscopic procedure, aiming to achieve the success rate equivalent to microsurgical discectomy, while addressing the drawbacks and limitations of other percutaneous techniques.

Methods

A series of 43 patients with uncontained lumbar disc herniation underwent surgery with irrigation endoscopic discectomy (IED). The endoscope and instruments are placed directly over the surface of the lamina through two posterior skin portals 5 mm each without any muscle retraction or dilatation. Pump irrigation is used for the opening of a potential working space. The rest of the procedure is performed endoscopically like the standard microsurgical discectomy.

Results

Outcome according to modified Macnab criteria was excellent in 78 %, good in 17 %, and poor in 5 % of patients. VAS for leg pain dropped from 78 preoperatively to 7, and the Oswestry Low-Back Pain Disability Questionnaire dropped from 76 to 19. The mean time for postoperative ambulation was 4 h, hospital stay was 8 h, and for return to work was 7 days.

Conclusions

Preliminary clinical experience with IED shows it to be as effective as microsurgical discectomy, and in comparison to other percutaneous procedures addressing noncontained herniations, a reduction in the cost, technical difficulty and surgical invasiveness has been demonstrated.