Synthesis, molecular docking and biological evaluation of 2-(thiophen-2-yl)-1H-indoles as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.

New 2-(thiophen-2-yl)-1H-indole derivatives bearing hydrophobic substituents at the 3-position were designed, synthesized and evaluated for their inhibition of HIV-1 reverse transcriptase (RT) enzyme. Dialkylphosphites (2a-c) or trialkylphosphites (3a-c) were reacted with 2-(thiophen-2-yl)-1H-indole-3-carbaldehyde (1) yielding the corresponding α-hydroxyphosphonate adducts (7a-7c). The reaction of compound 1 with the ylidenetriphenylphosphoranes (4a-4c) proceeds via Wittig mechanism giving the corresponding ethylenes (E, 8a-c). Compounds 8b,c were equally obtained upon reacting aldehyde 1 with the appropriate dialkylphosphonates 5a,b under the Horner-Wittig reaction conditions. On the other hand, the reaction of aldehyde 1 with diethyl cyanomethylene phosphonate (5c) yielded a mixture of the E-ethylene 10 and the cyanovinyl phosphonate 11. The thioaldehyde 12 was obtained upon refluxing aldehyde 1 with the Lawesson's reagent (LR, 6a) or with the Japanese reagent (JR, 6b) in dry toluene. Upon evaluation of HIV-1 Reverse Transcriptase enzyme inhibition, compound 8b (IC50 = 2.93 nM) exhibited the superior HIV-1 RT inhibition and its potency was about 3-folds that of Efavirenz (IC50 = 6.03 nM). Also, compounds 9a (IC50 = 4.09 nM) and 12 (IC50 = 3.54 nM) showed significantly higher inhibition potency. Moreover, compounds 7b (IC50 = 7.48 nM), and 8a (IC50 = 4.55 nM) showed potency not significantly different from that of Efavirenz. Molecular docking experiments on these potent compounds was in accordance with the in vitro data and confirmed binding of these compounds to the enzyme through ring-stacking and hydrogen bond interactions. According to these results, the new molecules would serve as potent HIV-1 NNRTIs inhibitors.

The role of next-generation sequencing in the differential diagnosis of composite neoplasms.

Composite neoplasms (CNs) are rare and diagnostically challenging lesions that require differentiating between mixed clonal tumors with divergent phenotypes (MT), collision of 2 independent tumors adjacent to each other (CT), and tumor-to-tumor metastasis (TTM). To that end, pathologists have traditionally used immunohistochemistry and limited molecular studies, such as Sanger sequencing. Herein we evaluate the potential application of NGS in the differential diagnosis of these rare neoplasms. Four CNs were included in the study. Two were diagnosed as MT (mixed adenoneuroendocrine carcinoma of the gallbladder and metastatic papillary thyroid carcinoma with squamous dedifferentiation) and 2 were interpreted as TTM (esophageal adenocarcinoma to lung adenocarcinoma and small cell carcinoma of the lung to meningeal melanoma). Diagnoses were made using clinical, histologic, and immunophenotypic information, with the aid of limited molecular studies in 2 cases. Formalin-fixed, paraffin-embedded tissue was dissected for DNA and RNA extraction, and NGS was performed using the Oncomine Comprehensive Panel. The 2 tumors initially interpreted as MT showed shared genetic aberrations in the different neoplastic components, supporting the pathologic diagnosis. NGS results for the lesion diagnosed as esophageal adenocarcinoma metastatic to lung adenocarcinoma did not support the histopathologic interpretation and were deemed inconclusive. However, the identification of an identical CDKN2A mutation in all components and in the adjacent benign lung parenchyma suggests a possible germline aberration. Sequencing results in the last case were clearly supportive of TTM. This study illustrates the role of NGS in the diagnostic workup of CNs, as an adjunct to light microscopy and immunohistochemistry.

Histological and immunohistochemical investigations of ovarian interstitial glands during non-breeding season in camels (Camelus dromedarius).

The aim of this was to investigate the histology and immunohistochemistry of interstitial glands during non-breeding season in camel ovaries. A total of 21 mature, non-pregnant and apparently healthy camels aged between 8 and 12 years were slaughtered. The ovaries were removed within 15 min, cleaned from adipose tissue, weighted and examined grossly. The histological preparation was made, and then, the blocks were cut at 3-5 microns thickness and stained by H&E for histological examinations. Moreover, some sections were stained with Sudan Black for lipid detection. Immunohistochemical analysis of paraffin-embedded ovarian tissues was performed to detect the localization of S-100, vimentin, progesterone receptors (PR) and oestrogen receptors (ER). Immunoreactive signals were detected using UltraVision Detection System. The results revealed that the interstitial glands were located in the cortical region and they were arranged in various arrangements either single, in couple or in groups rich in lipid droplet. All interstitial gland arrangements were enclosed by connective tissue capsules containing fibroblasts and collagenous fibres separated them from the surrounding ovarian structures. Both interstitial glands and their surrounding CT were penetrated by several blood vessels. There was a strong immunoreactive signal for S-100 in the nuclei of interstitial cells, and no signals were detected either in cells of the interstitial glands or their connective tissue with PR. We could conclude that the interstitial gland is distinct in ovary of camel and further studies are needed to elucidate its rule in steroid synthesis.

Tumor necrosis in radical prostatectomies with high-grade prostate cancer is associated with multiple poor prognostic features and a high prevalence of residual disease.

The Gleason grading system and the recently defined Grade Groups are strong, well-established predictors of outcome in prostate cancer. Each Gleason score, however, is the result of a sum of categories (Gleason patterns or GPs) that are intrinsically heterogeneous, as each individual pattern encompasses several tumor morphologies. Although the prognostic value of specific morphologic components of GP4 has recently been demonstrated, the significance of the different patterns of GP5 is largely unknown. We reviewed 344 consecutive prostatectomies performed at the Hospital of the University of Illinois at Chicago between 2011 and 2016 and selected 56 cases with primary or secondary GP5 with archival material available for review. Subsequently, we sorted the cases according to the presence or absence of tumor necrosis in invasive adenocarcinoma GP5-designated G5 (+N) and G5 (-N), respectively-for comparison of histopathologic and clinical characteristics. The GP5 (+N) group demonstrated higher prevalence of biochemical recurrence (P=.0006) and seminal vesicle invasion (P=.02), with a trend toward a higher frequency of lymph node metastases (P=.07) and multifocal surgical margin involvement (P=.09). Also, G5 (+N) patients showed higher preoperative prostate-specific antigen values (P=.005) and a larger percentage of submitted tissue involved by tumor (P<.0001). Our results show that GP5 with tumor necrosis is associated with poor prognostic histopathologic features and high rates of residual disease after prostatectomy.

The effect of some cryoprotectants on dromedary camel frozen-thawed semen.

The cryopreserved camel semen is often associated with poor quality and fertility. This study aimed to improve the dromedary frozen semen quality by comparing the efficiency of four cryoprotectant agents (CPAs) on sperm freezability. Semen samples were collected from seven male Maghrabi camels, diluted with Shotor diluent supplemented with glycerol (Sh-G), dimethyl formamide (DMF, Sh-DF), dimethyl sulfoxide (DMSO, Sh-DS) or ethylene glycol (EG, Sh-EG), all at 6% final concentration, and the samples were subjected to cryopreservation. The results revealed the superiority of Sh-DF over Sh-G and Sh-DS in terms of post-thaw motility (55.83 ± 2.20 vs. 47.50 ± 4.33 and 45.00 ± 2.89%, respectively), sperm membrane (49.00 ± 0.58, 39.33 ± 3.33 and 42.67 ± 1.45%, respectively) and acrosomal integrities (53.00 ± 0.58, 57.33 ± 0.88 and 52.33 ± 1.45%, respectively). Sh-EG group showed the lowest post-thaw motility, plasma membrane and acrosome integrities (12.50 ± 1.44, 22.67 ± 1.45 and 30.67 ± 1.45, respectively). In conclusion, the protocols of dromedary camel semen cryopreservation could be enhanced using 6% DMF as a cryoprotectant agent.

Association of endothelial nitric oxide synthase gene polymorphisms with classical risk factors in development of premature coronary artery disease.

Genetic polymorphism of the endothelial nitric oxide synthase (eNOS) affects the pathogenesis of atherosclerosis and associated with premature coronary artery disease (PCAD). We aimed to explore the association between Glu298Asp polymorphism of the eNOS gene and premature CAD in Egyptians, and the possible interaction between this polymorphism and other risk factors. The study population consisted of 116 patients with PCAD, and 119 controls. Glu298Asp polymorphism (rs1799983) of the eNOS gene was analyzed by polymerase chain reaction (PCR). We found that the TT genotype of the eNOS gene increased the risk of PCAD by 2.6. Hypertension, diabetes, smoking, total cholesterol, triglycerides, LDLc, HDLc and TT genotype of the eNOS gene were independent risk factors for the development of PCAD. We conclude that, the TT genotype of Glu298Asp polymorphism of eNOS gene is an independent risk factor of PCAD in Egyptians. The association of smoking, obesity, dyslipidemia and/or metabolic syndrome with the TT genotype increased the risk of the development of PCAD.

Effect of RAS inhibition on TGF-ß, renal function and structure in experimentally induced diabetic hypertensive nephropathy rats.

OBJECTIVE: Transforming growth factor-ß (TGF-ß) implicated in the pathogenesis of diabetic nephropathy. Hence, developing agents that antagonize fibrogenic signals is a critical issue facing researchers. MATERIAL AND METHODS: Fifty rats were allocated to five groups: 1=control rats, 2=diabetic hypertensive rats 3=diabetic hypertensive rats treated with spironolactone, 4=diabetic hypertensive rats treated with moexpril, 5=diabetic hypertensive rats treated with both spironolactone and moexpril. Measurement of TGF-ß, aldosterone, creatinine and ACE. Degree of fibrosis was calculated. RESULTS: Serum creatinine, mean arterial blood pressure (MAP), aldosterone, ACE, TGF-ß and renal fibrosis increased significantly in untreated diabetic hypertensive rats compared with control rats. Administration of spironolactone, moexpril, or both decreased these changes. CONCLUSIONS: Addition of the spironolactone to moexpril was more effective in reducing fibrosis and improvement of renal function than monotherapy with either drug, possibly due to a dual inhibitory effect on the RAS, and thus suppression of TGF-ß.

Polymer complexes. LIII. Supramolecular coordination modes and structural of novel sulphadrug complexes.

Novel polymer complexes of copper(II), palladium(II), platinum(II) and cadmium(II) containing homopolymer [4-acrylamido benzene sulphonyl guanidine; (HL)] and various anions (SO4²â», CH3COO⁻, NO3⁻, Br⁻ or Cl⁻) have been designed and carried out. Their structures were investigated by elemental analyses, spectral (IR, UV-vis, ¹H NMR and ESR) and magnetic moments. The modes of interactions between the ligand and the metals were discussed, where oxygen (of O=S=O group) and nitrogen atom [of imino nitrogen (NH/N) of the guanidine group] are involved in chelation. The homopolymer shows two types of coordination behaviour. In mononuclear polymer complexes 4 and 6-10, it acts as a neutral bidentate ligand chelated through the NH and O atoms, whereas in the polymer complexes 1-3, 5 and 11, monobasic bidentate ligand is coordinated through the -N and -O atoms. The poly-chelates are of 1:1/1:2 (metal-homopolymer) stoichiometry and exhibit four coordination. On the basis of electronic spectral data and magnetic susceptibility measurement square planar geometry has been proposed. The ESR spectral data provided information about their structure on the basis Hamiltonian parameters and degree of covalency. From the electron paramagnetic resonance and spectral data, the orbital reduction factors were calculated.