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Background: Insersion of subcutaneous poracath is im-portant in some cancer cases for whom chemotherapy isindicated. It is done either through image guided techniquein Intrerventional Departement or through blind technique inthe Surgical Departement.Aim of Study: We aimed in our study to to evaluate thecomplications and advantages of the two methodes used forportacath insertion (image-guided inserion and anatomicallandmark blind technique) and compare both to detect thebetter one should be used for the pateints.Patients and Methods: 110 adult cancer patients referredfrom the Medical Oncology Department outpatient clinics forsubcutaneous port catheter insertion in the period from January2019 to January 2020. 55 pateints underwent image-guidedinserion technique, while the other 55 pateints underwent theanatomical landmark blind technique. Data were collectedand analyzed. We campared the feasibility, advantages andcomplications of each technique.Results: The results showed obvious decreased complica-tions in image guided port catheter insertion compared toanatomical landmark blind technique in adult cancer patientsindicated for chemotherapy.Conclusion: Image guided portacath insertion is moresafe than anatomical landmark blind insertion.

Targeting PCAF with small inhibitor molecules has emerged as a potential therapeutic strategy for the treatment of cancer. Recently, L-45 was identified as a potent triazolophthalazine inhibitor of the PCAF bromodomain. Here, we report the bioisosteric modification of the triazolophthalazine ring system of L-45 to its bioisosteric triazoloquinazoline while maintaining other essential structural fragments for effective binding with the binding site of PCAF. Consequently, a set of sixteen triazoloquinazoline derivatives were designed, synthesized, and investigated for their anticancer activity against four human cancer cell lines. Five derivatives demonstrated comparable cytotoxic activity with that of doxorubicin as a reference anticancer drug. Among them, compound 23 showed the most potent activity with IC50 values of 6.12, 4.08, 7.17, and 6.42 μM against HePG2, MCF-7, PC3, and HCT-116, respectively. Also, compound 21 exhibited comparable cytotoxic effects with that of doxorubicin against the selected cancer cell lines with IC50 values in the range of 7.41–9.58 μM. Molecular docking and pharmacokinetic studies were additionally performed to rationalize the binding affinities of the newly designed triazoloquinazolines toward the active site of histone acetyltransferase PCAF and to evaluate the druggability of new compounds. The results of these studies suggested that PCAF binding could be the mechanism of action of these derivatives.

The resistance of pathogenic microbes to currently available antimicrobial agents has been considered a global alarming concern. Hence, close attention should be paid to the development of novel potent antimicrobials. Herein, we report the synthesis, in vitro antimicrobial evaluation, of two novel sets of quinoline derivatives as potential DNA gyrase and DHFR inhibitors. The design of new compounds depended on modifying the structural aspects of previously reported fluoroquinolones. In both sets, the methyl group replaced the fluorine atom at C-6. In the first set, the diverse heterocyclic fragments of reported antimicrobial potentials, including pyrazole, isoxazole, and pyrimidine, were attached to C-3 of the quinoline scaffold. In the second set, the quinolone ring was replaced with the pyrazolo[3,4-b]quinoline scaffold to examine the effect of this action on the antimicrobial activity and the in silico virtual binding with DNA gyrase and DHFR. The preliminary antimicrobial activity of new compounds was assessed against a panel of pathogenic microbes including Gram-positive bacteria (Streptococcus pneumonia and Bacillus subtilis), Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus fumigatus, Syncephalastrum racemosum, and Geotriucum candidum). Six derivatives displayed relatively potent antimicrobial activity with a percent activity range of 80–113% relative to ampicillin, gentamicin, and amphotericin B as reference antimicrobial agents. Molecular docking studies were conducted to predict the binding affinities of new compounds toward the active sites of DNA gyrase and DHFR as proposed therapeutic targets.

Introduction: Prosthetic joint infection (PJI) is a rare complication of total knee replacement (TKR), yet it is a serious and debilitating condition. Bacterial infection accounts for the majority of cases and fungal infection is estimated to cause 1% of all prosthesis infection. Case Report: This case presents a 60years female, who presented to our outpatient orthopedic clinic complaining of right knee pain, swelling, and hotness. The physical examination revealed redness, hotness, restricted range of movement, and tibial loosening, 9 months following TKR revision. Culture of the joint aspirate showed growth of “Candida parapsilosis” and second aspirate confirmed the diagnosis. The patient then underwent two stages revision surgery with placement of amphotericin B loaded cement, to maintain high local antifungal concentration in addition to decrease the side effects of amphotericinB infusion such as thrombophlebitis and the more serious systemic effect as nephrotoxicity. The post-operative course was uneventful, with gradual improvement and restoration of normal movement range. Conclusion: Fungal PJI is a rare complication of TKR, yet it results in severe debilitating symptoms and impairment of the patient functional capacity. Careful evaluation of the patient followed by a detailed workup is necessary for the identification of the underlying causative micro-organism. Two-stage revision surgery with antifungal loaded cement spacer and antifungal therapy currently is the standard of management. To the best of our knowledge, this is the first fungal PJI following total knee arthroplasty reported in Jordan. Keywords: Fungal prosthetic joint infection, fungal infection, total knee replacement, total knee replacement complication.

Pharmaceutical and clinicians researchers are looking for novel drug carriers to maintain the drug level in the body in low and effective dose. Thus, the present research concerned with studying the behavior of some natural biomass materials, namely microcrystalline cellulose, MCC, nanocrystalline cellulose, NCC, nanomethylcellulose, MC, and carboxymethyl cellulose, CMC, as a drug carrier materials for the Gentamicin sulphate, GM, by following up their rate of releasing the loaded drug with the time. Knowing of the initial rate of the releasing to each one and the sustaining rate along the period of the treatment, helps in choosing the best carrier for the drug that matches the patients requirements either whom are in need for a rapid dose (high level) of the drug followed by slow (low level) dose or those in need to start with the low level of the drug followed by high level of the drug. We chose MCC, NCC, MC and CMC, as natural, nontoxic biodegradable and renewable biomass materials, beside their low cost, to carry out this study. The results of the drug release, which measured by UV spectra, showed that the MCC, NCC, MC and CMC loaded with 0.025 g of the GM drug released 27.2%, 42.1%, 29.7%, 28.5% of the drug, respectively, along 10 days. All of them achieved the slow of the drug release but their behavior were different, where MCC, NCC and CMC started with low release then increased, and inversely, MC gave high rate of drug release and then decreased. The cause of this behavior was concerned to the adsorbing of the drug particles on the surface of the biomass materials or absorbing of the drug particles into the pores of the biomass materials. This was indicated by the study of their morphological image using the SEM, as well as indicating the presence of the functional group using the FT-IR study. The XRD, EDX and Agar Diffusion Assay, i.e. antimicrobial activity, against Staphylococcus aureus, Escherichia Coli, Pseudomonas aeruginosa and Bacillus subtilis were carried out to make help in choosing of the best carrier convenient to the case of the illness requirement.

Background Up to 30% of patients with sickle cell disease (SCD) develop chronic liver disease via etiologies including sickle cell hepatopathy, acquired viral hepatitis, or secondary hemochromatosis. It is unclear how many patients with SCD ultimately undergo liver transplantation (LT) and what factors are associated with survival after LT. In this study, we examined LT outcomes in these patients by reviewing the Scientific Registry of Transplant Recipients (SRTR) and our institutional experience. Methods Analysis of the SRTR identified 23 LT recipients and five simultaneous liver and kidney transplantation (SLKT) recipients with SCD. Patient demographics and graft and patient survival were analyzed. Two patients with SCD at our institution underwent SLKT. Results Review of the SRTR revealed that recipients with SCD had significantly higher model for end-stage liver disease scores (33 versus 21, P = 0.004), preoperative intensive care unit admission (43.5% versus 19.1%, P = 0.007), preoperative dialysis (17.4% versus 4.9%, P = 0.009), and were more likely to be status 1 (26.1% versus 12.1%, P = 0.041) when compared with the reference population of African American LT recipients. Despite being higher risk at the time of LT, patients with SCD had equivalent posttransplant graft and patient survival when compared with the reference population (P = 0.5 and P = 0.2, respectively) and a 2:1 propensity score–matched group (P = 0.5 and P = 0.2, respectively). Two recent SLKT recipients with SCD from our institution have performed well with stable allograft function. Conclusions Data from the SRTR demonstrate that patients with SCD can expect equivalent graft and patient survival after LT despite exhibiting more comorbidities at the time of LT. The low number of patients with SCD who underwent LT in the SRTR in comparison with the rate of chronic liver disease in this population raises the question as to whether a disparity in access to LT exists for this complex population.

Standard prone position (PP) during percutaneous nephrolithotomy (PNL) has multiple drawbacks. We aimed to compare PNLs performed in split-leg (SL) modified lateral position (MLP) and those performed in standard PP. A prospective, randomized, unblind, double arm trial was conducted at a tertiary care academic medical center in Egypt, between November 2017 and October 2019. Adult patients with renal stones undergoing PNL were included. According to renal anatomy and stone complexity, stratified randomization was performed and study participants were allocated into either SL-MLP group or PP group. The stone free rate (SFR), total operative time, track formation time, fluoroscopy time, auxiliary procedures, and complications were compared. There were 61 patients in SL-MLP group and 63 patients in PP group. Both groups had similar baseline characteristics. The SFR was comparable between groups: 75.4% in SL-MLP group and 77.8% in PP group (p = 0.755). The mean total operative time was shorter and mean track formation time was longer in SL-MLP group (55.33 ± 20.73 vs. 98.49 ± 9.23, p

Background Many medications (including most antihypertensives) and physiological factors affect the aldosterone/renin ratio (ARR) when screening for primary aldosteronism (PA). We sought to validate a novel equilibrium angiotensin II (eqAngII) assay and compare correlations between the aldosterone/angiotensin II ratio (AA2R) and the current ARR under conditions affecting the renin-angiotensin system. Methods Among 78 patients recruited, PA was excluded in 22 and confirmed in 56 by fludrocortisone suppression testing (FST). Peripheral levels of eqAngII, plasma renin activity (PRA) and direct renin concentration (DRC) were measured. Results EqAngII showed good consistency with DRC and PRA independent of PA diagnosis, posture, and fludrocortisone administration. EqAngII showed close (P Conclusions Dynamic changes of eqAngII and the AA2R show good consistency and close correlations with renin and the ARR. The eqAngII assay shows better sensitivity than DRC and PRA assays, especially at low concentrations. Whether the AA2R can reduce the impact of some factors that influence the diagnostic power of the ARR warrants further study.

Aim: Highlighting the need for effective therapies for the treatment of ulcerative colitis, novel series of potential CB2 modulators (benzofuran and pyrrole carboxamides) were developed and tested for their functional activities on CB1/CB2 receptors. Results: In the benzofuran series, the cannabinoid (CB) receptor selectivity and the functional profile were dependent on the nature of the amide substituent and the position of the methoxy group, meanwhile the pyrrole derivatives, displayed an exclusive selectivity to the CB2 receptor and a functionality that is controlled by the nature of the pyrrole nitrogen substituent. Conclusion: Remarkably, we succeeded to develop potent and selective pyrrole-based CB2 receptor agonists, represented by compound 25a, which also demonstrated an exquisite anti-inflammatory effect in a dextran sodium sulfate-induced colitis model in mice.

Aims Due to the significant value held by medical records in terms of influencing patient care and medico-legal cases, this study aimed to investigate the quality of surgical notes and their improvement through periodic auditing during a six-year period at a major tertiary hospital. Methodology This study retrospectively evaluated surgical records of patients undergoing elective orthopedic surgeries at Jordan University Hospital from 2016 to 2021 using the Surgical Tool for Auditing Records (STAR) validated questionnaire. This questionnaire is composed of six distinct sections aimed to quantify the quality of medical records and demonstrate their associated deficiencies. Pre- and post-audit STAR scores were analyzed using the two independent sample t-test on Statistical Package for Social Sciences (SPSS) version 23.0 (IBM Corp. Armonk, NY). Results A total of 454 records were randomly selected and evaluated using the STAR questionnaire. There was an overall significant trend of improvement in the quality of records in all evaluated years compared to the 2016 baseline. The most pronounced improvements were in the records of 2021 as compared to the 2016 baseline (97.4 ± 0.7 vs. 94.3 ± 1.6; p

Aim of the Work To compare visual acuity, refractive and topographic outcome between small incision lenticule extraction (SMILE) and wavefront-guided femtosecond laser-assisted in situ keratomileusis (WFG FS-LASIK) in patients with myopic astigmatism. Patients and methods This prospective, non-randomized, comparative clinical study included 60 eyes of 30 patients with simple or compound myopic astigmatism presenting for refractive error correction. Femtosecond assisted LASIK group included 30 eyes and SMILE group included 30 eyes. The following tests were done for all patients preoperatively and at 3 months postoperatively: full ophthalmological examination, manifest refraction, UDVA, CDVA, corneal topography using combined schimflug and placcido disc imaging namely Pentacam. (Oculus Inc.) and wavefront analysis using ATLAS 9000 (Carl Zeiss Meditec) Main Outcome Measures: Uncorrected distance visual acuity (UDVA), corrected disctance visual acuity (CDVA), manifest refraction, Efficacy, safety, predictability, corneal higher order aberrations. Results At 3 months, the mean manifest refractive spherical equivalent (MRSE) in SMILE group was -0.33 ± 0.34 D and the mean MRSE in FS- LASIK group was 0.23 ± 0.35 D and there was a statistically significant difference between both groups (P < 0.05). mean postoperative cylinder was -0.56 ± 0.28 D in SMILE group and -0.53 ± 0.38D in FS-LASIK with statistically significant difference ( P = 0.254 ) 93% and 93% of eyes in the SMILE and FS-LASIK groups were within ± 0.5 D; 96.67% and 100% of eyes in the SMILE and FS-LASIK groups, respectively, were within ± 1 D. There were 86.66% of treated eyes in the SMILE group, and 93.33% treated eyes in the FS-LASIK group that had 20/25 or better UDVA. Regarding safety, the CDVA in the SMILE group, 20 eyes (66.67%) showed no change, 8 eyes (27%) gained 1 line, 2 eyes (7%) lost 1 line, and no eyes lost more than 1 line. whereas in the FS-LASIK group, 27 eyes (90%) exhibited no change, 2 eyes (6.66%) gained 1 line, 1 eye (3.33%) lost 1 line, and no eyes lost more than 1 line and There was no statistically significant difference between both groups (P = 0. 554 ). Regarding corneal asphericity, both procedures increased Q-value with no statistically significant difference between both groups (P = 0. 052). Regarding corneal higher order aberrations, both procedures significantly increased total corneal aberrations but there was no statistically significant difference in the change in RMS of total corneal higher order aberration (P = 0.434) .but SMILE increased RMS of coma aberration significantly more than FS-LASIK (P = 0. 029). Conclusion both SMILE and FS-LASIK procedures have shown excellent efficacy, safety, and predictability for the correction of myopia and myopic astigmatism. SMILE was closer to emmetropia regarding sphere and spherical equivalent, However, astigmatic undercorrection was noted after both surgeries with increased astigmatism. Both procedures increased the total corneal higher order aberrations with no statistically significant difference between both groups. A higher vertical coma was found in SMILE than WFG FS-LASIK.

Background Anemia is a severe complication of chronic kidney disease (CKD) that is seen in more than 80% of patients with impaired renal function. Although there are many mechanisms involved in the pathogenesis of anemia of renal disease, the primary cause is the inadequate production of erythropoietin by the damaged kidneys. Aim of the work to assess hepcidin level in non dialysis patients (CKD stage 4 &5) treated from Hepatitis C virus and its relation to iron parameters. Patients and Methods This study was conducted on 20 CKD patients (stage 4 and 5) treated from hepatitis C virus. All candidates included in this study subjected to careful history taking, full clinical examination and investigations (including complete blood count, renal chemistry, HCVAb, serum iron, total iron binding capacity, TSAT%, ferritin and hsCRP. Serum hepcidin was analyzed by ELISA technique. Results Serum hepcidin was 26.35±7.26; 40% in stage III, 37.8% in stage IV and 22.2% in stage V. There was statistically significant difference between GFR stages according to Hb., Drug intake ACE inhibitor/ARB, Plt., Creatinine, BUN, Iron, TIBC, Ferritin, T SAT%, CRP and Serum Hepcidin. We showed significant correlations between serum hepcidin and TIC, Iron, TIBC, Ferritin and TSAT%. Conclusion Median hepcidin value is elevated in nondialysis CKD patients due to increased inflammation and decreased clearance of hepcidin. Furthermore, iron status modifies serum hepcidin level and its association with Hb. Increased hepcidin level leads to iron-restricted erythropoiesis and recombinant human EPO (rhEPO) resistance by inhibiting iron absorption from gut and iron recycling from macrophages. Hence, elevated hepcidin can predict need for parenteral iron to overcome hepcidin-mediated iron-restricted erythropoiesis and need for relatively higher rhEPO doses to suppress hepcidin.

Pulmonary administration provides a useful alternative to oral and invasive routes of administration while enhancing and prolonging the accumulation of drugs into the lungs and reducing systemic drug exposure. In this study, chloroquine, as a model drug, was loaded into niosomes for potential pulmonary administration either via dry powder inhalation or intratracheally. Chloroquine-loaded niosomes have been prepared and extensively characterized. Furthermore, drug-loaded niosomes were lyophilized and their flowing properties were evaluated by measuring the angle of repose, Carr’s index, and Hausner ratio. The developed niosomes demonstrated a nanosized (100–150 nm) spherical morphology and chloroquine entrapment efficiency of ca. 24.5%. The FT-IR results indicated the incorporation of chloroquine into the niosomes, whereas in vitro release studies demonstrated an extended-release profile of the drug-loaded niosomes compared to the free drug. Lyophilized niosomes exhibited poor flowability that was not sufficiently improved after the addition of lactose or when cryoprotectants were exploited throughout the lyophilization process. In vivo, intratracheal administration of chloroquine-loaded niosomes in rats resulted in a drug concentration in the blood that was 10-fold lower than the oral administration of the free drug. Biomarkers of kidney and liver functions (i.e., creatinine, urea, AST, and ALT) following pulmonary administration of the drug-loaded nanoparticles were of similar levels to those of the control untreated animals. Hence, the use of a dry powder inhaler for administration of lyophilized niosomes is not recommended, whereas intratracheal administration might provide a promising strategy for pulmonary administration of niosomal dispersions while minimizing systemic drug exposure and adverse reactions.

The emergence of bacterial resistance has triggered a multitude of efforts to develop new antibacterial agents. There are many compounds in literature that were reported as potent antibacterial agents, however, they lacked the required safety to mammalian cells or no clear picture about their toxicity profile was presented. Inspired by discovered hit from our in-house library and by previously reported 2,4-diaminosubstituted quinazolines, we describe the design and synthesis of novel 2,4-disubstituted-thioquinazolines (3–13 and 36), 2-thio-4-amino substituted quinazolines (14–33) and 6-substituted 2,4-diamonsubstituted quinazolines (37–39). The synthesized compounds showed potent antibacterial activity against a panel of Gram-positive, efflux deficient E.coli and Mycobacterium smegmatis. The panel also involved resistant strains including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium, in addition to Mycobacterium smegmatis. The newly synthesized compounds revealed MIC values against the tested strains ranging from 1 to 64 µg/mL with a good safety profile. Most of the 2-thio-4-amino substituted-quinazolines showed significant antimycobacterial activity with the variations at position 2 and 4 offering additional antibacterial activity against the different strains. Compared to previously reported 2,4-diaminosubstituted quinazolines, the bioisosteric replacement of the 2-amino with sulfur offered a successful approach to keep the high antibacterial potency while substantially improving safety profile as indicated by the reduced activity on different cell lines and a lack of hemolytic activity.

Stress urinary incontinence (SUI) and cystocele often occur concomitantly and thus may potentially be treated via a single surgical procedure. This study evaluated the efficacy and safety of concomitant transobturator tape (TOT) with anterior colporrhaphy versus subvesical transobturator mesh (TOM) for cystocele-associated SUI. This prospective, clinical trial included women with cystocele-associated SUI. Patients were randomly allocated into either group I (anterior colporrhaphy with concomitant TOT “in-out” fixation) or group II (implantation of a subvesical four-armed TOM). All patients were followed up at 1, 3, 6, 9, and 12 months postoperatively. Statistical tests were performed to compare the group outcomes based on objective, subjective, and anatomical variables. There were 81 patients in group I and 83 in group II. Median follow-up duration was 12 months. The demographic data and baseline clinical characteristics of both groups were comparable. There were no significant differences between groups regarding the success rates of SUI and cystocele repair. Groups I and II had similar cure rates of SUI (82.9 and 88.4%, respectively; p = 0.369) and incidences of successful cystocele repair (85.4 and 97.7%, respectively; p = 0.055). No urethral or bladder injuries or mesh erosions were reported. Both groups had comparable postoperative complications, except the greater incidence of micturition difficulty in group I than group II, during the early follow-up (12.2% vs. 0.0%; p = 0.024). Transvaginal mesh was not superior to native tissue repair. Anterior colporrhaphy and TOT may be an appropriate alternative to four-armed TOM application for concomitant correction of SUI and cystocele.

The structure–activity and structure–kinetic relationships of a new tert-butylphenylthiazole series with oxadiazole linkers were conducted with the objective of obtaining a new orally available antibacterial compounds. Twenty-two new compounds were prepared, purified and identified. Their activity against methicillin-resistant Staphylococcus aureus were examined. Compound 20 with 3-hydroxyazetidine as a nitrogenous side chain showed promising activity against twenty-four clinical isolates, including vancomycin-resistant staphylococcal and enterococcal species with MIC values ranging from 4–8 μg mL−1. Additional advantages of this compound include an ability to eradicate staphylococcal biofilm mass in a dose-dependent manner as well as high metabolic stability after an oral dose of 25 mg kg−1 with a biological half-life that exceeds 5 hours and a plasma concentration (Cmax) that exceeds the MIC values.

Background: UROLOGIC pelvic surgery is the integration of surgical activities for the pelvis, the colon, urogenital, and gynecological organs primarily for the treatment of obstructions, dysfunction, malignancies, and inflammatory diseases.Aim of Study: To evaluate the efficacy of extracorporeal shock wave therpy on male coccydenia after urological surgery.Subjects: Thirty male patients who complain from coc-cydenia after urological surgery, their age range from 40-60 years old, choosen from El-Sahel Teaching Hospital and Police Hospital in Agoza, Cairo, Egypt during the period of June-2017 to November-2017.Methods: Patients assigned randomly into two groups of equal numbers, Group (A) control group which include 15 patients received routine medication only (anti-inflammatory drugs or NSAID), and Group (B) study group received shock wave therapy one session per week up to four weeks each session took 10 minutes the patients were received 2000 shots of ESWT in the coccyx, the frequency was 5Hz and the pressure was 3-4 bar in addition to traditional medications routine (anti-inflammatory drugs). Both groups were assessed pre and post-treatment for pain level by Visual Analogue Scale (VAS).Results: There was a significant decrease in the median values of visual analogue scale post-treatment of study group compared with control group (p=0.002) in favor of study group.Conclusion: Shock wave therapy is effective as a physical therapy program on improving coccydenia.

PURPOSE OF REVIEW: To review the indications for extra-corporeal membrane oxygenation (ECMO) in liver transplantation (LT) recipients and their optimal management on ECMO. RECENT FINDINGS: Recent studies have reported a 30–40% survival rate among LT recipients that receive ECMO. Increasingly, case reports have documented successful outcomes of LT performed for patients on pre-operative ECMO. Outcomes appear to be superior with patients in the immediate peri-LT period with reversible causes of severe, acute respiratory and/or cardiovascular collapse. Mortality is most commonly secondary to infection. Volume optimization with CRRT may improve outcomes and perfusion to the graft, especially for patients on veno-arterial (VA) ECMO. There is little consensus on management of anti-coagulation in these patients, but it can likely be held temporarily while the patient is coagulopathic and/or experiencing bleeding complications. SUMMARY: ECMO should be considered in the peri-LT period for patients with severe, acute, and reversible causes of respiratory and/or cardiovascular collapse, with acceptable outcomes in patients that would otherwise not be expected to survive. Management of the post-LT patient on ECMO is challenging with a slowly enlarging body of literature to inform decision making.

Hepatitis C virus (HCV) is an international challenge. Since the discovery of NS5A direct-acting antivirals, researchers turned their attention to pursue novel NS5A inhibitors with optimized design and structure. Herein we explore highly potent hepatitis C virus (HCV) NS5A inhibitors, the novel analogs share a common symmetrical prolinamide 2,7-diaminofluorene scaffold. Modification of the 2,7-diaminofluorene backbone included the use of (S)-prolinamide or its isostere (S,R)-piperidine-3-caboxamide, both bearing different amino acid residues with terminal carbamate groups. Compound 26 exhibited potent inhibitory activity against HCV genotype (GT) 1b (effective concentration (EC50) = 36 pM and a selectivity index of &gt, 2.78 × 106). Compound 26 showed high selectivity on GT 1b versus GT 4a. Interestingly, it showed a significant antiviral effect against GT 3a (EC50 = 1.2 nM). The structure-activity relationship (SAR) analysis revealed that picomolar inhibitory activity was attained with the use of S-prolinamide capped with R- isoleucine or R-phenylglycine residues bearing a terminal alkyl carbamate group.

Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases. A natural fragment of serum albumin, named EPI-X4, has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases. To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4. Subsequent rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4. The EPI-X4 derivative JM#21 bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100. EPI-X4 JM#21 did not exert toxic effects in zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model. Moreover, topical administration of the optimized EPI-X4 derivative efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis. Thus, rationally designed EPI-X4 JM#21 is a novel potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis. Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis, asthma and other CXCR4-associated diseases is highly warranted., Graphical abstract Dysregulation of CXCR4/CXCL12 signaling is associated with many inflammatory diseases. EPI-X4 is an endogenous peptide antagonist of CXCR4. Molecular docking and mutational analysis allowed to increase its anti-CXCR4 activity. The optimized EPI-X4 JM#21 derivative prevented inflammatory responses in mouse models of atopic dermatitis and allergen-induced asthma.Image 1

Herein, we report the synthesis and in vitro antimicrobial evaluation of novel quinoline derivatives as DNA gyrase inhibitors. The preliminary antimicrobial activity was assessed against a panel of pathogenic microbes including Gram-positive bacteria (Streptococcus pneumoniae and Bacillus subtilis), Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus fumigatus, Syncephalastrum racemosum, Geotrichum candidum, and Candida albicans). Compounds that revealed the best activity were subjected to further biological studies to determine their minimum inhibitory concentrations (MICs) against the selected pathogens as well as their in vitro activity against the E. coli DNA gyrase, to realize whether their antimicrobial action is mediated via inhibition of this enzyme. Four of the new derivatives (14, 17, 20, and 23) demonstrated a relatively potent antimicrobial activity with MIC values in the range of 0.66-5.29 μg/ml. Among them, compound 14 exhibited a particularly potent broad-spectrum antimicrobial activity against most of the tested strains of bacteria and fungi, with MIC values in the range of 0.66-3.98 μg/ml. A subsequent in vitro investigation against the bacterial DNA gyrase target enzyme revealed a significant potent inhibitory activity of quinoline derivative 14, which can be observed from its IC50 value (3.39 μM). Also, a molecular docking study of the most active compounds was carried out to explore the binding affinity of the new ligands toward the active site of DNA gyrase enzyme as a proposed target of their activity. Furthermore, the ADMET profiles of the most highly effective derivatives were analyzed to evaluate their potentials to be developed as good drug candidates.

The objective of this study is to compare the endothelial safety of femtosecond laser (FSL) energy at two different dissection depths in FSL-assisted deep anterior lamellar keratoplasty (FSDALK) for keratoconus. This prospective double-armed interventional study included 25 eyes from 21 patients with advanced keratoconus who underwent FSDALK (big bubble technique) at a trephination depth of 110 µm in group I (11 eyes) and 80 µm in group II (14 eyes)—all of which were anterior to the Descemet’s membrane (DM). Visual acuity measurement, anterior and posterior segment examination, corneal tomography, and specular microscopy were performed preoperatively and at 3, 6, and 12 months, postoperatively. Endothelial cell density, coefficient of variation, percentage of cell hexagonality, and pachymetry were used to evaluate endothelial safety. No statistically significant difference in any of the endothelial safety parameters was found between the two groups. The mean 12-month postoperative endothelial cell loss rate was 17.46% and 12.91% in group I and II, respectively (P = 0.345). Most of the endothelial cell loss occurred during the first 3 months after surgery. Group II showed statistically greater improvement in the mean keratometry values at all follow-up visits. The endothelial safety profiles of lamellar FSL cuts at 110 µm and 80 µm anterior to the DM are comparable. Cuts as deep as 80 µm anterior to the DM can be safely applied without causing significant injury to the endothelium. Further studies are needed to compare the endothelial safety profiles of different FSL platforms available in the market. Trial registration PACTR201901615323963. Registered 24 November 2018—retrospectively registered.

Detecting cognitive profiles is critical to efficient adaptive learning systems that automatically adjust the content delivered depending on the learner&rsquo, s cognitive states and skills. This study explores electroencephalography (EEG) and facial expressions as physiological monitoring tools to build models that detect two cognitive states, namely, engagement and instantaneous attention, and three cognitive skills, namely, focused attention, planning, and shifting. First, while wearing a 14-channel EEG Headset and being videotaped, data has been collected from 127 subjects taking two scientifically validated cognitive assessments. Second, labeling was performed based on the scores obtained from the used tools. Third, different shallow and deep models were experimented in the two modalities of EEG and facial expressions. Finally, the best performing models for the analyzed states are determined. According to the used performance measure, which is the f-beta score with beta = 2, the best obtained results for engagement, instantaneous attention, and focused attention are EEG-based models with 0.86, 0.82, and 0.63 scores, respectively. As for planning and shifting, the best performing models are facial expressions-based models with 0.78 and 0.81, respectively. The obtained results show that EEG and facial expressions contain important and different cues and features about the analyzed cognitive states, and hence, can be used to automatically and non-intrusively detect them.

A series of novel hybrid pyrazolo[3,4-d]pyramidine derivatives was designed and chemically synthesized in useful yields. The synthesized compounds were structurally characterized by the usual techniques. All the new synthesized compounds were biologically screened in vitro for their antiproliferative activities against a panel of four cancer cell lines, namely HepG-2, MCF-7, HCT-116, and Hela. The results of cytotoxic evaluation indicated that compound 14d was appeared to be the most prominent broad-spectrum cytotoxic activity and significantly more potent than sorafenib with IC50 values of 4.28, 5.18, 3.97, and 9.85 µM against four cell lines (HePG2, Hela, HCT-116 and MCF-7). In addition, compound 15 was displayed promising antiproliferative effect against all tested cell lines with IC50 value less than 11 µM compared with sorafenib as a control drug. Besides, structurally pharmacophoric features indicated that pyrazolo[3,4-d]pyrimidine scaffold having an amide linker and substituted with phenyl moiety at the 5-position was more potent than those possessing azomethine methyl, azomethine proton and carbomethene linkers, which lead to significant decrease in antiproliferative activity. The most potent compounds were further selected and evaluated for their activities against epidermal growth factor receptor (EGFR) kinase inhibitors according to homogenous time resolved fluorescence (HTRF) assay. The most potent compound 14d exhibited the most promising inhibitory activity against EGFRWT with IC50 value of 56.02 ± 1.38 µM compared with gefitinib as control drug with IC50 value of 41.79 ± 1.07 µM. Moreover, the inhibition of cell cycle progression and induction of apoptosis in the A549 cell line at G2/M and pre-G1 phases of cell cycle might contribute to cancer treatment that evaluated by Annexin V-FITC/PI double staining detection method. Finally, molecular docking studies were conducted to investigate that probable binding conformations of these anticancer agents and ADME properties were calculated to predict pharmacokinetics and toxic properties of the target compounds.

Three novel series of triazolophthalazine derivatives bearing hydrazone moiety were designed, synthesized, and evaluated for their anticancer activity against four human cancer cell lines by MTT assay. Six derivatives demonstrated comparable activity with Doxorubicin reference drug against the selected cancer cells. Especially, compound 16 showed the most potent activity with IC50 values of 5.70, 8.04, 11.15, and 4.25, µM against HePG2, MCF-7, PC3, and HCT-116 respectively. Also, compound 26 exhibited comparable inhibitory effect with that of Doxorubicin against the selected cancer cell lines with IC50 values of 6.45, 8.63, 12.28, and 7.03 µM against HePG2, MCF-7, PC3, and HCT-116 respectively. Investigation of the apoptotic activity of the two most active compounds revealed that compounds 16 and 26 could induce both the early and the late apoptosis of HePG2. Further mechanistic study of the HePG2 cell cycle confirmed the spectacular cytotoxic and apoptotic effects of both compounds. Compounds 16 and 26 showed a pronounced increase in cells in G2/M and Pre G1 phases with a concomitant reduction of cells in G0-G1 and S phases. A follow up enzymatic assay indicated that these two compounds have comparable activities with that of bromosporine as PCAF inhibitors with IC50 values of 8.13 and 5.31 µM respectively. Moreover, molecular docking study for all the synthesized compounds was performed to predict their binding affinities toward the active site of histone acetyltransferase GCN5. Results of molecular docking were strongly correlated with that of the cytotoxicity study.

Cognitive load refers to the used amount of working memory. It is very hard to be detected, especially in on-line and computer-supported learning. Thus, it is one of the most important challenges for educational technologists and instructional designers to address. Electroencephalogram (EEG) is a methodology that monitors the electric activity in the brain. EEG has been effective in detecting subjects’ emotional and cognitive states. In this paper, an approach for detecting the basic cognitive states that affect learning outcomes using EEG signals is proposed. Detected states include engagement, instantaneous attention, focused attention, working memory, planning, shifting and visual perception. The proposed approach consists of the following. First, 127 students in their undergraduate university-level studies undergo scientifically-validated cognitive assessment tests that evoke and measure their full cognitive profiles while putting on a 14-channel wearable EEG headset. Then, the collected data are used to train deep models as well as shallow classifiers to automatically predict the analyzed cognitive states. Although the main advantage of the deep learning models is avoiding the hand-crafted features needed for the shallow classifiers, the shallow classifiers outperformed the deep learning-based ones with a minimum accuracy of 92% as compared to the deep models with a maximum obtained accuracy of 78%.

Chronic knee dislocation is rare and debilitating for patient. Treatment for chronic knee dislocation is still debatable. There are two opposing goals of treatment which are obtaining stability and obtaining range of motion. We presented 2 patients with good clinical outcome using a gradual hexapodalic correction with Ortho-SUV system.

Background Transcatheter arterial chemoembolization is one of the effective therapeutic options for hepatocellular carcinoma (HCC). Ultraselective chemoembolization is an alternative approach to improve local control, and is associated with a reduced incidence of adverse effects. Objective It was to evaluate the sensitivity of cone beam computed tomography (CBCT) in detecting HCC tumors and their feeding vessels during transarterial chemoembolization (TACE). Patients and Methods All patients were suspected of having or confirmed to have HCC on the basis of clinical history, underlying liver disease and/or viral infection, the diagnosis of HCC was made by imaging findings. Between January 2016 and January 2018, Dyna CT was retrospectively used in 19 consecutive patients with HCC tumor with HCC tumor. Results The detectability of the tumor with DSA obtained at the common, proper, right, or left hepatic artery (i.e., nonselective DSA) and cone-beam CT was compared as taking pre imaging as a gold standard. Tumor stain and feeding branches were evaluated. The detectability of the tumor-feeding branch with non-selective DSA and Dyna CT HA images was compared. Conclusion Tumor detectability on cone-beam CT was significantly greater than on non-selective. Cone beam HA taking pre imaging as a gold standard was (94.4%) and its specificity (71.6%) with accuracy (76.97%). The sensitivity of DSA in detection of additional tumor as taking the pre imaging (CT/MRI) as a gold standard was (88.9%) and its specificity (84.5%) with accuracy (85.53%). Cone-beam CT has satisfactory ability to detect tumors; the detectability of tumor-feeding branches with Dyna CT was significantly higher than that with nonselective DSA (P less than 0.001). We believe the technical success rates of ultraselective transcatheter arterial chemoembolization may be improved by chemoembolization guidance software that uses cone-beam CT technology.

Background Lymphoid neoplasms are broadly divided into Hodgkin disease (HD) and non-Hodgkin’s lymphoma (NHL). Non-Hodgkin lymphoma accounts for about 5% of all cases of cancer with greater predilection to disseminate to extra-nodal sites. Extranodal lymphoma describes that there is neoplastic proliferation at sites other than the expected native lymph nodes or lymphoid tissue. Lymphomas that initially appear to have the bulk of the disease at extranodal sites are described as primary extranodal lymphoma and categorized as Stage I or II. In secondary extranodal lymphoma, there is secondary involvement of the extranodal sites from primary nodal disease, which is categorized as Stage III or IV. Aim and Objectives To assess the added value of hybrid Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in the evaluation of extranodal involvement in patients with non-Hodgkin lymphoma in comparison to contrast-enhanced CT (CECT). Patients and Methods All patients had Non-Hodgkin lymphoma, proved by histopathological and immunophenotyping examinations. They underwent CECT and F-18 FDG PET–CT studies. Results This study included 76 patients with pathologically confirmed lymphoma who underwent PET/CT study. The patients' ages ranged between 20 and 78 years old (mean age 51 ± 14.7 years). This study included 51 males and 21 females. Diffuse large B-cell lymphoma subtype had the highest prevalence 53% (40/76), whereas mucosa-associated lymphoid tissue lymphoma was the least prevalent 4%. The Spleen was the most common site as it was involved in 20 patients followed by bone and bone marrow 15 patients, lung 13, Liver 9, Nasopharynx 4, Muscular and Cutaneous Nodules 4 patients each, CNS, Adrenal, Renal and Pleural Affection 3 patients each, Tonsillar, stomach, Pancreas and Prostate 2 patients each, and finally only one patient had salivary gland, thyroid, breast, and testicular involvement. The overall sensitivity, specificity, PPV, NPV, and accuracy of PET/CT and CECT are 97%, 20%, 94.5%, 33.3%, 91, 6 % and 87.3%, 60 %, 93.9%, 10% and 87.5%, respectively. Conclusion Combined PET/CT using 18F-FDG is the best oncologic imaging modality at present time with indispensable role and valuable application in monitoring and management of the extranodal lymphoma. It can detect metabolically active lesions without CT structural changes and identify a viable tumor in normal size lymph nodes. PET/CT is more effective than CECT in evaluating extranodal Lymphomatous infiltration, especially in spleen, bone, and bone marrow.

Background: This study was conducted to evaluate the efficacy of whole-body vibration on strength of calf and quadriceps muscles post burn.Patients and Methods: Thirty patients (male and female) had second degree burn of lower limb with surface area about (20-35%) suffering from weakness of quadriceps and calf muscles. Their ages ranged between (20-35) years were participated in this study. The study conducted during the period between March and July (2017) at Makka Hospital and Al-Nada Hospital.They were assigned randomly into two Groups (A and B) equal in number: Group (A) Fifteen patients had received vibration training on vibration platform plus traditional physical therapy program (eight weeks, three times a week). Group (B) fifteen patients had received the same traditional physical therapy program only.Evaluation: Evaluations of both Groups (A and B) were done before starting the treatment and at the end of study after eight weeks using hand held dynamometer and manual muscle test.Treatment: Started immediately post wound closure. This study showed a statistically significant increase in calf and quadriceps muscle strength after eight weeks of receiving whole body vibration in addition to home based physical therapy program, compared with Group B who received traditional physical therapy program only.Results: Comparison between both Groups (A and B) before starting the study revealed that there was a statistically nonsignificant difference in calf and quadriceps muscle force between them. At the end of the study, there was a significant increase in the muscle force in the study group (Group A) compared with control groups (Group B).Conclusion: Participation in Whole Body Vibration (WBV) program resulted in a greater improvement in quadriceps and calf muscle strength in adults with healed thermal burn compared to base line values; a WBV program is an effective for strength gain in rehabilitation of burned patients.

Context Current threshold values for primary aldosteronism (PA) diagnostic testing are based on measuring aldosterone (PAC) using immunoassays. Quantification of PAC by liquid chromatography-tandem mass spectrometry (LC-MS/MS) yields lower values. Objective To compare aldosterone measurement by radioimmunoassay (RIA) with LC-MS/MS and evaluate performances of proposed LC-MS/MS–specific cutoffs for PA screening and confirmatory testing. Patients and Intervention Forty-one patients underwent aldosterone/renin ratio (ARR) testing to screen for, and fludrocortisone suppression testing (FST) to confirm or exclude, PA. Renin (DRC) was measured by chemiluminescent immunoassay. Results Median serum PACLC-MS/MS was 27.8% lower (P < 0.05) than plasma PACRIA in 164 pairs of FST samples. A positive correlation (Spearman coefficient, 0.894, P < 0.01; Pearson r coefficient, 0.861, P < 0.01) was observed between the two assays. Thirty-seven patients showed consistent FST diagnoses (29 positive, 8 negative), whereas four showed inconsistent FSTs by the two assays. Good agreement (κ coefficient, 0.736; P < 0.01) was observed between the current FST diagnostic PACRIA cutoff of 165 pmol/L and the proposed PACLC-MS/MS cutoff of 133 pmol/L. Among 37 patients with consistent FST results, no differences were observed in sensitivity (89.7% vs 93.1%) or specificity (87.5% vs 87.5%) for PA screening between the current ARR cutoff of 70 pmol/mU (PACRIA/DRC) and the proposed cutoff of 55 pmol/mU (PACLC-MS/MS/DRC). Conclusions Adjustment of the current cutoffs for PA diagnostic testing is necessary if PAC is measured by LC-MS/MS. Our preliminary results suggest that the proposed LC-MS/MS cutoffs for ARR and FST perform as well as current RIA cutoffs.

Supplemental Digital Content is Available in the Text., Purpose: To evaluate the effectiveness and safety of combined epithelium-off cross-linking (CXL) with photorefractive keratectomy (CXL Plus) for correction of the myopic and astigmatic components of keratoconus. Methods: Seventy-nine eyes of 46 patients who underwent CXL Plus were enrolled in this retrospective, multicenter, noncomparative clinical study. Uncorrected distance visual acuity, corrected distance visual acuity, refraction, keratometry, and pachymetry measurements were recorded preoperatively and at 3, 6, 12, and 18 months during follow-up. Results: The mean (±SD) preoperative uncorrected distance visual acuity and corrected distance visual acuity were 1.00 ± 0.22 logarithm of the minimum angle of resolution (logMAR) and 0.62 ± 0.38 logMAR, respectively, and improved to 0.71 ± 0.36 logMAR and 0.32 ± 0.18 logMAR postoperatively. The mean k value, mean corneal thickness at the thinnest location, and mean myopic and astigmatic components decreased from 46.58 ± 0.97 D, 473 ± 29 μm, 3.65 ± 1.72 D, and 1.83 ± 0.69 D preoperatively to 43.79 ± 1.17 D, 431 ± 38 μm, 1.02 ± 0.78 D, and 1.15 ± 0.26 D, respectively, during follow-up. Eleven eyes had delayed epithelial healing, 2 had stromal opacities, 1 had primary herpes simplex keratitis, and 5 showed progression of keratoconus. Conclusions: CXL Plus improved the refractive status of keratoconus during 18 months of follow-up, despite its potential early postoperative complications of delayed epithelial healing and corneal haze. CXL Plus reduced the myopic component more than the astigmatic component of keratoconus. However, the safety and stability of the procedure were offset by longer-term postoperative complications and a high rate of postoperative progression of keratoconus.

Much light has been shed on the vital role of protein kinase Czeta (PKCζ) in NF-κB activation and the potential use of PKCζ inhibitors as anti-inflammatory agents. We previously reported a series of 1,3,5-trisubstituted pyrazolines as potent and selective allosteric inhibitors of PKCζ; in that series of compounds, the phenolic OH at the 5-phenyl was essential for binding to the PKCζ PIF pocket. In the present study, we surprisingly found that replacing it by a halogen and at the same time moving the OH to the 3-phenyl still resulted in active compounds. An extension of this class of compounds with a new focused library is presented herein, where the phenolic OH at the 5-phenyl, which was reported to be an irreplaceable feature for activity, was moved to the 3-phenyl and replaced by halogen. The new set of compounds maintained the same level of potency against PKCζ and selectivity against PKC isoforms, and showed reduced potency against the PIF pocket mutant PKCζ[Val297Leu]. Of note, the repositioning of the key functional groups resulted in a marked enhancement of cellular potency. One of the most potent new PKCζ inhibitors, 2h, was able to suppress NO production in RAW 264.7 macrophage cells with 8 times higher efficacy than the previous series, and inhibited the NF-κB transcriptional activity in U937 cells with a sub-micromolar IC(50).

Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ERα) agonists or antagonists depending on the target issue. Tamoxifen (TAM) (a non-steroidal triphenylethylene derivative) was the first SERM approved as anti-estrogen for the treatment of metastatic breast cancer. On the hunt for novel SERMs with potential growth inhibitory activity on breast cancer cell lines yet no potential to induce endometrial carcinoma, we designed and synthesized 28 novel TAM analogs. The novel analogs bear a triphenylethylene scaffold. Modifications on rings A, B, and C aim to attenuate estrogenic/anti-estrogenic activities of the novel compounds so they can potentially inhibit breast cancer and provide positive, beneficial estrogenic effects on other tissues with no risk of developing endometrial hyperplasia. Compound 12 (E/Z-1-(2-{4-[1-(4-Chloro-phenyl)-2-(4-methoxy-phenyl)-propenyl]-phenoxy}-ethyl)-piperidine) showed an appreciable relative ERα agonistic activity in a yeast estrogen screen (YES) assay. It successfully inhibited the growth of the MCF-7 cell line with GI50 = 0.6 µM, and it was approximately three times more potent than TAM. It showed no potential estrogenicity on Ishikawa endometrial adenocarcinoma cell line via assaying alkaline phosphatase (AlkP) activity. Compound 12 was tested in vivo to assess its estrogenic properties in an uterotrophic assay in an ovariectomized rat model. Compared to TAM, it induced less increase in wet uterine wet weight and showed no uterotrophic effect. Compound 12 is a promising candidate for further development due to its inhibition activity on MCF-7 proliferation with moderate AlkP activity and no potential uterotrophic effects. The in vitro estrogenic activity encourages further investigations toward potential beneficial properties in cardiovascular, bone, and brain tissues.

Based on the biological importance of the thiazole nucleus, we decided to prepare and evaluate the biological activity of some new isatin derivatives containing thiazole moiety. The 5-(piperidin-1-ylsulfonyl)indoline-2,3-dione (1) was prepared and used as a starting material in the synthesis of many isatin derivatives for anticonvulsant evaluation. All the newly synthesized thiazlidino/thiosemicarbazide-indolin-2-one derivatives screened in vivo for their anticonvulsant activity against pentylenetetrazole-induced convulsions in mice. The results were compared with phenobarbitone sodium as a standard anticonvulsant drug. Most of the tested compounds exhibited anticonvulsant activity with relative potency ranging from 0.02 to 0.2 in comparison to standard drug phenobarbitone. The most active compounds 3, 6a, 6c and 8, were exposed to further investigations in rats to evaluate the effect of most active derivatives on the haematological, liver, kidney functions as well as histopathological studies of the liver and kidney tissues. Finally, the most potent compounds 3, 6a, 6c and 8 observed good toxic properties for both liver and kidney function with mild variability changes on RBCs, WBCs, Platelets, Hb, AST, ALT, and creatinine level, as well as kidney and liver tissue and these good results obtained rather than used low dose from phenobarbitone.

The upregulation of the CB2 receptors in neuroinflammation and cancer and their potential visualization with PET (positron emission tomography) could provide a valuable diagnostic and therapy-monitoring tool in such disorders. However, the availability of reliable CB2-selective imaging probes is still lacking in clinical practice. We have recently identified a benzothiazole-2-ylidine amide hit (6a) as a highly potent CB2 ligand. With the aim of enhancing its CB2 over CB1 selectivity and introducing structural sites suitable for radiolabeling, we herein describe the development of fluorinated and methoxylated benzothiazole derivatives endowed with extremely high CB2 binding affinity and an exclusive selectivity to the CB2 receptor. Compounds 14, 15, 18, 19, 21, 24 and 25 displayed subnanomolar CB2 Ki values (ranging from 0.16 nM to 0.68 nM) and interestingly, all of the synthesized compounds completely lacked affinity at the CB1 receptor (Ki > 10,000 nM for all compounds), indicating their remarkably high CB2 over CB1 selectivity factors. The fluorinated analogs, 15 and 21, were evaluated for their in vitro metabolic stability in mouse and human liver microsomes (MLM and HLM). Both 15 and 21 displayed an exceptionally high stability (98% and 91% intact compounds, respectively) after 60 min incubation with MLM. Contrastingly, a 5- and 2.8-fold lower stability was demonstrated for compounds 15 and 21, respectively, upon incubation with HLM for 60 min. Taken together, our data present extremely potent and selective CB2 ligands as credible leads that can be further exploited for 18F- or 11C-radiolabeling and utilization as PET tracers.

A new series of 8-methoxy-2-trimethoxyphenyl-3-substituted quinazoline-4(3)-one compounds were designed, synthesized, and screened for antitumor activity against three cell lines, namely, Hela, A549, and MDA compared to docetaxel as reference drug. The molecular docking was performed using Autodock Vina program and 20 ns molecular dynamics (MD) simulation was performed using GROMACS 2018.1 software. Compound 6 was the most potent antitumor of the new synthesized compounds and was evaluated as a VEGFR2 and EGFR inhibitor with (IC50, 98.1 and 106 nM respectively) compared to docetaxel (IC50, 89.3 and 56.1 nM respectively). Compounds 2, 6, 10, and 8 showed strong cytotoxic activities against the Hela cell line with IC50 of, 2.13, 2.8, 3.98, and 4.94 µM, respectively, relative to docetaxel (IC50, 9.65 µM). Compound 11 showed strong cytotoxic activity against A549 cell line (IC50, 4.03 µM) relative to docetaxel (IC50, 10.8 µM). Whereas compounds 6 and 9 showed strong cytotoxic activity against MDA cell line (IC50, 0.79, 3.42 µM, respectively) as compared to docetaxel (IC50, 3.98 µM).

Background: Plasma aldosterone/renin ratio (ARR) is the most popular screening test for primary aldosteronism (PA). Because both estrogen and progesterone (including in oral contraceptive agents) affect aldosterone and renin levels, we studied the effects of combined hormonal replacement therapy (HRT) on ARR; renin was measured as both direct renin concentration (DRC) and plasma renin activity (PRA). Methods: Fifteen normotensive, healthy postmenopausal women underwent measurement (seated, midmorning) of plasma aldosterone, DRC, PRA, electrolytes, and creatinine and urinary aldosterone, cortisol, electrolytes, and creatinine at baseline and after 2 weeks and 6 weeks of treatment with combined HRT (conjugated estrogens 0.625 mg and medroxyprogesterone 2.5 mg daily). Results: Combined HRT was associated with statistically significant increases in aldosterone [median (range): baseline, 150 (85 to 600); 2 weeks, 230 (129 to 790); 6 weeks, 434 (200 to 1200) pmol/L; P < 0.001 (Friedman test)] and PRA [2.3 (1.2 to 4.3), 3.8 (1.4 to 7.0), 5.1 (1.4 to 10.8) ng/mL/h, respectively; P < 0.001] but decreases in DRC [21 (10 to 31), 21 (10 to 39), and 14 (8.0 to 30) mU/L, respectively; P < 0.01], leading to increases in ARR calculated by DRC [7.8 (3.6 to 34.8), 11.4 (5.4 to 48.5), and 30.4 (10.5 to 90.2), respectively; P < 0.001]. The ARR calculated by DRC exceeded the cutoff value (70) in three patients after 6 weeks. There were no significant changes in ARR calculated by PRA [79 (26 to 184), 91 (23 to 166), and 88 (50 to 230), respectively; P = 0.282], plasma electrolytes and creatinine, or any urinary measurements. Conclusion: The combined oral HRT used in this study is capable of significantly increasing ARR with a risk of false-positive results during screening for PA but only if DRC (and not PRA) is used to calculate the ratio.