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A series of new 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their anti-AD potential. The results revealed that eleven compounds (1b, 2a-c, 3b, 4a-c, and 5a-c) exhibited excellent inhibitory potential against AChE, with IC 50 values ranging from 0.00098 to 0.07920 µM. Their potency was 1.55 to 125.47 times higher than that of donepezil (IC 50  = 0.12297 µM). In contrast, the newly synthesized oxadiazole derivatives with IC 50 values in the range of 16.64-70.82 µM exhibited less selectivity towards BuChE when compared to rivastigmine (IC 50  = 5.88 µM). Moreover, oxadiazole derivative 2c (IC 50  = 463.85 µM) was more potent antioxidant than quercetin (IC 50  = 491.23 µM). Compounds 3b (IC 50  = 536.83 µM) and 3c (IC 50  = 582.44 µM) exhibited comparable antioxidant activity to that of quercetin. Oxadiazole derivatives 3b (IC 50  = 140.02 µM) and 4c (IC 50  = 117.43 µM) showed prominent MAO-B inhibitory potential. They were more potent than biperiden (IC 50  = 237.59 µM). Compounds 1a, 1b, 3a, 3c, and 4b exhibited remarkable MAO-A inhibitory potential, with IC 50 values ranging from 47.25 to 129.7 µM. Their potency was 1.1 to 3.03 times higher than that of methylene blue (IC 50  = 143.6 µM). Most of the synthesized oxadiazole derivatives provided significant protection against induced HRBCs lysis, revealing the nontoxic effect of the synthesized compounds, thus making them safe drug candidates. The results unveiled oxadiazole derivatives 2b, 2c, 3b, 4a, 4c, and 5a as multitarget anti-AD agents. The high AChE inhibitory potential can be computationally explained by the synthesized oxadiazole derivatives' significant interactions with the AChE active site. Compound 2b showed good physicochemical properties. All these data suggest that 2b could be considered as a promising candidate for future development., (© 2024. The Author(s).)

A library of 16 3-benzyl- N 1 -substituted quinoxalin-2-ones was synthesized as N 1 -substituted quinoxalines and quinoxaline-triazole hybrids via click reaction. These compounds were tested for their anticancer activity via MTT assay on HCT-116 and normal colonocyte cell lines to assess their cytotoxic potentials and safety profiles. Overall, compounds 6 , 9 , 14 , and 20 were found to be promising anticolorectal cancer agents; they exhibited remarkable cytotoxicity (IC 50 0.05-0.07 μM) against HCT-116 cells within their safe doses (EC100) on normal colon cells. Their pronounced anticancer activities were observed as severe morphological alterations and shrinkage of the treated cancer cells. Besides, qRT-PCR analysis was conducted showing the potential of the promising hits to downregulate HIF-1a, VEGF, and BCL-2 as well as their ability to enhance the expression of proapoptotic genes p21, p53, and BAX in HCT-116 cells. In silico prediction revealed that most of our compounds agree with Lipinski and Veber parameters of rules, in addition to remarkable medicinal chemistry and drug-likeness parameters with no CNS side effects. Interestingly, docking studies of the compounds in the VEGFR-2' active site showed significant affinity toward the essential amino acids, which supported the biological results., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The EGFR/PI3K/Akt/mTOR pathway is important for metastasis, medication resistance, apoptosis prevention, and malignant transformation. Mutations in lung and colon cancer typically change this pathway's expression. As a result, a novel class of 1,2,4-oxdiazoles that are attached to 1,2,3-triazoles, 5-11, were created as possible anticancer drugs. The produced compounds are all examined by spectroscopic and micro-analytical techniques. MTT assay results on lung (A549) colon (Caco-2) and normal lung fibroblast (WI38) revealed that compounds 6a, 6b, 8a, and 11b demonstrated strong and selective antiproliferative activities against lung (A549) and colon (Caco-2) cancer cell lines while the remaining derivatives showed moderate to low activity. qPCR data revealed that the potential hits had large fold changes in the downregulation of EGFR, mTOR, and PI3K; they upregulate the amount of p53 to support their mode of action even more. Interestingly, docking investigations validated the biological outcomes by demonstrating a strong affinity of our compounds against EGFR active regions. Computational predictions of all the synthesized compounds' pharmacokinetic profiles, physicochemical characteristics, and drug-likeness data indicated that the promising hits might be taken into consideration as drug-like prospects., Competing Interests: The authors declare that none of their relationships or conflicting financial interests could have influenced the findings of this study., (This journal is © The Royal Society of Chemistry.)

A series of novel 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their potential anti-Alzheimer disease activity. The results revealed that compounds 2b, 2c, 2d, 3a, 4a, 6, 9a, 9b, and 13b showed excellent inhibitory activity against acetylcholinesterase (AChE) with IC 50 values in the range of 0.0158 to 0.121 μM. They were 1.01 to 7.78 times more potent than donepezil (IC 50 = 0.123 μM). The newly synthesized compounds exhibited lower activity towards butyrylcholinesterase (BuChE) when compared to rivastigmine. Compounds 4b and 13b showed the most prominent inhibitory potential against BuChE with IC 50 values of 11.50 and 15 μM, respectively. Moreover, 4b, and 9b were found to be more potent antioxidant agents (IC 50 values of 59.25, and 56.69 μM, respectively) in comparison with ascorbic acid (IC 50 = 74.55 μM). Compounds 2b and 2c exhibited monoamine oxidase-B (MAO-B) inhibitory activity with IC 50 values of 74.68 and 225.48 μM, respectively. They were 3.55 and 1.17 times more potent than biperiden (IC 50 = 265.85 μM). The prominent interactions of the compounds with the AChE active site can be used to computationally explain the high AChE inhibitory activity. The results unveiled 1,2,4-oxadiazole derivatives 2c and 3a as multitarget anti-AD agents. The predicted ADME properties for compounds 2b and 4a were satisfactory, and 4a had the highest likelihood of crossing the blood-brain barrier (BBB), making it the optimum compound for future optimization., Competing Interests: “The authors declare that none of their relationships or conflicting financial interests could have influenced the findings of this study”., (This journal is © The Royal Society of Chemistry.)

A series of new sulfonamide derivatives connected through an imine linker to five or seven membered heterocycles were designed and synthesized. All synthesized derivatives were characterized using a variety of spectroscopic methods, including IR, 1 HNMR, and 13 CNMR. In vitro α-glucosidase and α-amylase inhibition activities, as well as glucose uptake were assessed for each of the synthesized compounds. Four sulfonamide derivatives namely 3a, 3b, 3h and 6 showed excellent inhibitory potential against α-glucosidase with IC 50 values of 19.39, 25.12, 25.57 and 22.02 μM, respectively. They were 1.05- to 1.39-fold more potent than acarbose. Sulfonamide derivatives 3g, 3i and 7 (EC 50 values of 1.29, 21.38 and 19.03 μM, respectively) exhibited significant glucose uptake activity that were 1.62- to 27-fold more potent than berberine. Both α-glucosidase protein (PDB: 2QMJ) and α-amylase (PDB: 1XCW) complexed with acarbose were adopted for docking investigations for the most active synthesized compounds. The docked compounds were able to inhabit the same space as the acarviosin ring of acarbose. The docking of the most active compounds showed an analogous binding with the active site of α-glucosidase as acarbose. The superior activity of the synthesized compounds against α-glucosidase enzyme than α-amylase enzyme can be rationalized by the weak interaction with the α-amylase. The physiochemical parameters of all synthesized compounds were aligned with Lipinski's rule of five., Competing Interests: The authors have no conflict of interest concerning this work., (This journal is © The Royal Society of Chemistry.)

Monoamine oxidases (MAOs) and vascular endothelial growth factor receptor-2 (VEGFR-2) are promoters of colorectal cancer (CRC) and central signaling nodes in epithelial-mesenchymal transition (EMT) induced by activating hypoxia-inducible factors (HIFs). Herein, a novel series of rationally designed triazole-tethered quinoxalines were synthesized and evaluated against HCT-116 CRC cells. The tailored scaffolds combine the pharmacophoric themes of both VEGFR-2 inhibitors and MAO inhibitors. All the synthesized derivatives were screened utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay for their possible cytotoxic effects on normal human colonocytes, then evaluated for their anticancer activities against HCT-116 cells overexpressing MAOs. The hit derivatives 11 and 14 exhibited IC 50  = 18.04 and 7.850 µM, respectively, against HCT-116cells within their EC 100 doses on normal human colonocytes. Wound healing assay revealed their efficient CRC antimetastatic activities recording HCT-116 cell migration inhibition exceeding 75 %. In vitro enzymatic assays demonstrated that both 11 and 14 efficiently inhibited VEGFR-2 (IC 50  = 88.79 and 9.910 nM), MAO-A (IC 50  = 0.763 and 629.1 nM) and MAO-B (IC 50  = 0.488 and 209.6 nM) with observed MAO-B over MAO-A selectivity (SI = 1.546 and 3.001), respectively. Enzyme kinetics studies were performed for both compounds to identify their mode of MAO-B inhibition. Furthermore, qRT-PCR analysis showed that the hits efficiently downregulated HIF-1α in HCT-116cells by 3.420 and 16.96 folds relative to untreated cells. Docking studies simulated their possible binding modes within the active sites of VEGFR-2 and MAO-B to highlight their essential structural determinants of activities. Finally, they recorded in silico drug-like absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles as well as ligand efficiency metrics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Selective induction of breast cancer apoptosis is viewed as the mainstay of various ongoing oncology drug discovery programs. Passerini scaffolds have been recently exploited as selective apoptosis inducers via a caspase 3/7 dependent pathway. Herein, the optimized Passerini caspase activators were manipulated to synergistically induce P53-dependent apoptosis via modulating the closely related P53-MDM2 signaling axis. The adopted design rationale and synthetic routes relied on mimicking the general thematic features of lead MDM2 inhibitors incorporating multiple aromatic rings. Accordingly, the cyclization of representative Passerini derivatives and related Ugi compounds into the corresponding diphenylimidazolidine and spiro derivative was performed, resembling the nutlin-based and spiro MDM-2 inhibitors, respectively. The study was also extended to explore the apoptotic induction capacity of the scaffold after simplification and modifications. MTT assay on MCF-7 and MDA-MB231 breast cancer cells compared to normal fibroblasts (WI-38) revealed their promising cytotoxic activities. The flexible Ugi derivatives 3 and 4, cyclic analog 8, Passerini adduct 12, and the thiosemicarbazide derivative 17 were identified as the study hits regarding cytotoxic potency and selectivity, being over 10-folds more potent (IC 50 = 0.065-0.096 μM) and safer (SI = 4.4-18.7) than doxorubicin (IC 50 = 0.478 μM, SI = 0.569) on MCF-7 cells. They promoted apoptosis induction via caspase 3/7 activation (3.1-4.1 folds) and P53 induction (up to 4 folds). Further apoptosis studies revealed that these compounds enhanced gene expression of BAX by 2 folds and suppressed Bcl-2 expression by 4.29-7.75 folds in the treated MCF-7 cells. Docking simulations displayed their plausible binding modes with the molecular targets and highlighted their structural determinants of activities for further optimization studies. Finally, in silico prediction of the entire library was computationally performed, showing that most of them could be envisioned as drug-like candidates., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Although vaccines are obviously mitigating the COVID-19 pandemic diffusion, efficient complementary antiviral agents are urgently needed to combat SARS-CoV-2. The viral papain-like protease (PLpro) is a promising therapeutic target being one of only two essential proteases crucial for viral replication. Nevertheless, it dysregulates the host immune sensing response. Here we report repositioning of the privileged 1,2,4-oxadiazole scaffold as promising SARS-CoV-2 PLpro inhibitor with potential viral entry inhibition profile. The design strategy relied on mimicking the general structural features of the lead benzamide PLpro inhibitor GRL0617 with isosteric replacement of its pharmacophoric amide backbone by 1,2,4-oxadiazole core. Inspired by the multitarget antiviral agents, the substitution pattern was rationalized to tune the scaffold's potency against other additional viral targets, especially the spike receptor binding domain (RBD) that is responsible for the viral invasion . The Adopted facial synthetic protocol allowed easy access to various rationally substituted derivatives. Among the evaluated series, the 2-[5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl]aniline (5) displayed the most balanced dual inhibitory potential against SARS-CoV-2 PLpro (IC 50= 7.197 μM) and spike protein RBD (IC 50  = 8.673 μM), with acceptable ligand efficiency metrics, practical LogP (3.8) and safety profile on Wi-38 (CC 50  = 51.78 μM) and LT-A549 (CC 50  = 45.77 μM) lung cells. Docking simulations declared the possible structural determinants of activities and enriched the SAR data for further optimization studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Proline is water soluble amino acid extensively used in drug delivery systems. Compounds of cobalt (Co) transition metal have potent antimicrobial and anticancer activities. However, a drug delivery system combining proline cobalt is not reported yet. For the first time, new hybrid semi-organic single crystals of proline cobalt chloride (PCC) are prepared. The novelty of the article is also that single crystal proline cobalt chloride showed potent antimicrobial and antitumor activity. Doping of PCC by Ag 0 NPs significantly increased these biological activities. The anisotropic magnetic properties of single crystals can mitigate the cytotoxicity of Ag 0 NPs on normal cells. Silver nanoparticles (Ag 0 NPs) improved the crystal habits and physicochemical properties. Ag 0 NPs showed the best performance, paramagnetic materials n-type semiconductors due to delocalized excess electrons of Ag 0 NPs incorporated in the crystal lattice interstitially. Crystals have high absorptivity for UV-radiation electromagnetic radiation. Ag 0 NPs enhanced AC electrical conductivity up to 2.3 × 10 4 Ω cm -1 due to high electron density. Proline doped crystals are obtained in good purity as triclinic unit cell with having anisotropic magnetism. PCCAg 0 NPs crystal exhibited: high antimicrobial activities to various bacterial and fungal species, inhibition zone (mm): 21, 25, 24, 26, 30, 28, 12, and 46 for S. aureus , E. faecalis , S. typhi , E. coli , P. aerugino , K. pneumoniae , A. braselienses , and C. albicans , respectively, in comparison to ciprofloxacin antibiotic (23, 0, 26, 26, 25, 0, 0, 0) for the same tested species, respectively; higher cytotoxicity against breast cancer cells (IC 50 22.1 μM) than the reference drug cisplatin (IC 50 11.7 μM); and lower cytotoxicity to normal healthy lung cells MRC-5, (IC 50 145.5 μM) than cisplatin (IC 50 30.2 μM). Hence, this crystal is a candidate for chemotherapy of breast cancer., Competing Interests: The authors declare no conflict of interest.

We explored a new isonitrile, namely 4-( N -phthalimido)phenyl isonitrile, with extraordinary features. The novel isocyanide has a pharmacophore, the phthalimido (Pht) group, that possesses promising pharmaceutical activities. We found that the novel isonitrile is unexpectedly odorless as an extra bonus which makes its handling easy in organic synthesis to serve as a scaffold for building several new amide derivatives through multicomponent reactions, overcoming the stink of common aromatic isonitriles such as phenyl isonitrile, benzyl isonitrile, p -nitrophenyl isonitrile, and ethyl 4-isocyano benzoate. The novel isonitrile 9 serves as a source of N -protected isonitrile with a Pht group, where the Pht group can be easily removed via hydrazinolysis, affording the corresponding primary amine/alcohol scaffold which could be used as a precursor to synthesize Passerini products via acylation directly to afford Passerini adducts 14 and 15 without carrying out the traditional Passerini three-component reaction; this new isonitrile is considered as a novel convertible isocyanide analogue., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

The development of novel therapeutics promoting selective tumor elimination is the mainstay of clinical oncology. Emerging insights into tumor targeting reveal caspases activation, especially caspase-3, as a personalized anticancer strategy. Our on-going cancer research has exploited Passerini α-acyloxy carboxamides as caspase-3/7-dependent apoptotic inducers. Herein, we adopted scaffold hopping design to introduce new series of isoindole-based Passerini adducts as caspase-3/7 activators inspired by natural alkaloids from Lion's Mane mushroom promoting caspase-3-mediated apoptosis. Additional pharmacophoric motifs of lead caspase activators were merged into the tailored Passerini skeleton. The rationally designed adducts were synthesized utilizing one-pot reaction of the novel 4-(2'-phthalimido)phenylisonitrile 5, cyclohexanone and miscellaneous carboxylic acids under Passerini conditions. All derivatives were screened for their antiproliferative activities against lung A549, colorectal Caco-2 and breast MDA-MB 231 cancer cells compared to normal fibroblasts utilizing MTT assay. Most of the evaluated derivatives were superior to 5-fluorouracil. The 2-(1H-indol-3-yl)acetate derivative (8a) recorded the highest anticancer potency (IC 50  = 0.04-0.11 μM) and selectivity (SI = 42.59-125.53), followed by the 3-(4-(trifluoromethyl)phenyl)acrylate (8m), the 2-(phenylsulfonyl)glycinate (8q), and the 2-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)acetate (8c) derivatives, respectively. The four hits induced cancer cells apoptosis (up to 57.99%) via caspase-3/7 activation (up to 5.47 folds). Apoptosis-inducing factor1 (AIF1) quantification assay excluded their caspase-independent apoptosis induction potential via AIF1 signaling pathway. Docking simulations clarified the possible binding modes of the hit compounds with XIAP BIR2 domain; the specific receptor of caspase-3/7 activators, and aided identifying their structural determinants of activity. Finally, their practical LogP, efficiency metrics, in silico ADMET profiling were drug-like., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Selective elimination of tumors has always been the mainstay of oncology research. The on-going research underlying the cellular apoptotic mechanisms reveal caspases activation, especially the key effector caspase-3, as a personalized tumor-selective therapeutic strategy. Our continued research protocol has exploited new optimized Passerini α-acyloxy carboxamides as efficient apoptotic inducers via caspase-3/7 dependent mechanism with highly selective anticancer profiles. The adopted design rationale relied on excluding structural alerts of previous leads, while merging various pharmacophoric motifs of natural and synthetic caspase activators via optimized one-pot Passerini reaction conditions. The prepared compounds resulting from Passerini reaction were screened for their cytotoxic activities against colorectal Caco-2 and liver HepG-2 cancer cells compared to normal fibroblasts utilizing MTT assay. Notably, all compounds exhibited promising low-range submicromolar IC 50 against the studied cancer cell lines, with outstanding tumor selectivity (SI values up to 266). Hence, they were superior to 5-fluorouracil. Notably, 7a, 7g, and 7j conferred the highest potencies against Caco-2 and HepG-2 cells and were selected for further mechanistic studies. Caspas-3/7 activation assay of the hit compounds and flow cytometric analysis of the treated apoptotic cancer cells demonstrated their significant caspase activation potential (up to 4.2 folds) and apoptotic induction capacities (up to 58.7%). Further assessment of Bcl2 expression was performed being a physiological caspase-3 substrate. Herein, the three studied Passerini adducts were able to downregulate Bcl2 in the treated Caco-2 cells. Importantly, the mechanistic studies results of the three hits echoed their preliminary MTT antiproliferative potencies data highlighting their caspase-3 dependent apoptotic induction. Finally, the in silico predicted physicochemical and pharmacokinetic profiles, as well as ligand efficiency metrics were drug-like., (© 2022. The Author(s).)

In this study, a novel magnetic organic-inorganic composite was fabricated. Chitosan, sulfacetamide and ethylacetoacetae were used to prepare a new Sulfacetamide-Ethylacetoacetate hydrazone-chitosan Schiff-base (SEH-CSB) with a variety of active sites that capable of forming coordinate covalent bonds with Cr(VI). This was followed by modification of the formed SHE-CSB with NiFe 2 O 4 to obtain the magnetic Chitosan-Schiff-base composite (NiFe 2 O 4 @SEH-CSB). NiFe 2 O 4 @SEH-CSB was characterized using FTIR, zeta potential, SEM, VSM and XPS. Results clarified that SHE played a crucial role in the removal of Cr(VI). The removal of Cr(VI) on NiFe 2 O 4 @SEH-CSB was found to be more fitted to pseudo-second order kinetics model and Freundlich isotherm. Besides, the maximum adsorption capacity of NiFe 2 O 4 @SEH-CSB towards Cr(VI) was found to be 373.61 mg/g. The plausible mechanism for the removal of Cr(VI) by NiFe 2 O 4 @SEH-CSB composite suggested the domination of coulombic interaction, outer-sphere complexation, ion-exchange, surface complexation and coordinate-covalent bond pathways. The magnetic property enabled easy recycling of NiFe 2 O 4 @SEH-CSB composite for seven sequential cycles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Pancreatic cystic lesions (PCLs) are common in clinical practice. The accurate classification and diagnosis of these lesions are crucial to avoid unnecessary treatment of benign lesions and missed opportunities for early treatment of potentially malignant lesions., Aim: To evaluate the role of cyst fluid analysis of different tumor markers such as cancer antigens [ e.g. , cancer antigen (CA)19-9, CA72-4], carcinoembryonic antigen (CEA), serine protease inhibitor Kazal-type 1 (SPINK1), interleukin 1 beta (IL1-β), vascular endothelial growth factor A (VEGF-A), and prostaglandin E2 (PGE2)], amylase, and mucin stain in diagnosing pancreatic cysts and differentiating malignant from benign lesions., Methods: This study included 76 patients diagnosed with PCLs using different imaging modalities. All patients underwent endoscopic ultrasound (EUS) and EUS-fine needle aspiration (EUS-FNA) for characterization and sampling of different PCLs., Results: The mean age of studied patients was 47.4 ± 11.4 years, with a slight female predominance (59.2%). Mucin stain showed high statistical significance in predicting malignancy with a sensitivity of 87.1% and specificity of 95.56%. It also showed a positive predictive value and negative predictive value of 93.1% and 91.49%, respectively ( P < 0.001). We found that positive mucin stain, cyst fluid glucose, SPINK1, amylase, and CEA levels had high statistical significance ( P < 0.0001). In contrast, IL-1β, CA 72-4, VEGF-A, VEGFR2, and PGE2 did not show any statistical significance. Univariate regression analysis for prediction of malignancy in PCLs showed a statistically significant positive correlation with mural nodules, lymph nodes, cyst diameter, mucin stain, and cyst fluid CEA. Meanwhile, logistic multivariable regression analysis proved that mural nodules, mucin stain, and SPINK1 were independent predictors of malignancy in cystic pancreatic lesions., Conclusion: EUS examination of cyst morphology with cytopathological analysis and cyst fluid analysis could improve the differentiation between malignant and benign pancreatic cysts. Also, CEA, glucose, and SPINK1 could be used as promising markers to predict malignant pancreatic cysts., Competing Interests: Conflict-of-interest statement: No conflict of interest exists., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Facile synthesis of molecular hybrids containing a 2,4-dinitrophenyl moiety was achieved via nucleophilic aromatic substitution of the fluoride anion of Sanger's reagent (2,4-dinitrofluorobenzene) with various N , S , and O nucleophiles, considered as bioactive moieties. Antimicrobial evaluation of the new hybrids was carried out using amoxicillin and nystatin as antibacterial and antifungal reference standards, respectively. MIC test results identified the compounds 3, 4 , and 7 as the most active hybrids against standard strains and multidrug-resistant strains (MDR) of Staphylococcus aureus , Escherichia coli , and Pseudomonas aurginosa . Most of the hybrids displayed two times the antibacterial activity of AMOX against MDR Pseudomonas aeruginosa , E. coli , and a standard strain of P. aeruginosa (ATCC 29853), while demonstrating a weak antifungal profile against Candida albicans . Selectivity profiles of the promising compounds 3, 4, 6, 7, 8 , and 11 on WI-38 human cells were characterized, which indicated that compound 3 is the safest one (CC 50 343.72 μM). The preferential anti-Gram-negative activity of our compounds led us to do docking studies on DNA gyrase B. Docking revealed that the potential antimicrobial compounds fit well into the active site of DNA gyrase B. Furthermore, in silico absorption, distribution, metabolism, and excretion (ADME) predictions revealed that most of the new compounds have high gastrointestinal absorption and a good oral bioavailability with no BBB permeability., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Harnessing the antioxidant cellular machinery has sparked considerable interest as an efficient anticancer strategy. Activating Nrf2, the master switch of the cellular redox system, suppresses ROS, alleviates oxidative stress, and halts cancer progression. 1,2,4-oxadiazoles are iconic direct Nrf2 activators that disrupt Nrf2 interaction with its endogenous repressor Keap1. This study introduces rationally designed 1,2,4-oxadiazole derivatives that inhibit other Nrf2 suppressors (TrxR1, IKKα, and NF-kB) thus enhancing Nrf2 activation for preventing oxidative stress and carcinogenesis. Preliminary screening showed that the phenolic oxadiazoles 11, 15, and 19 were comparable to ascorbic acid (ROS scavenging) and EDTA (iron chelation), and superior to doxorubicin against HepG-2, MDA-MB231, and Caco-2 cells. They suppressed ROS by 3 folds and activated Nrf2 by 2 folds in HepG-2 cells. Mechanistically, they inhibited TrxR1 (IC 50 ; 13.19, 17.89, and 9.21 nM) and IKKα (IC 50 ; 11.0, 15.94, and 19.58 nM), and downregulated NF-κB (7.6, 1.4 and 1.9 folds in HepG-2), respectively. They inhibited NADPH oxidase (IC 50 ; 16.4, 21.94, and 10.71 nM, respectively) that potentiates their antioxidant activities. Docking studies predicted their important structural features. Finally, they recorded drug-like in silico physicochemical properties, ADMET, and ligand efficiency metrics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Multicomponent reactions (MCRs) are powerful synthetic tools in which more than two starting materials couple with each other to form multi-functionalized compounds in a one-pot process, the so-called "tandem", "domino" or "cascade" reaction, or utilizing an additional step without changing the solvent, the so-called a sequential-addition procedure, to limit the number of synthetic steps, while increasing the complexity and the molecular diversity, which are highly step-economical reactions. The Ugi reaction, one of the most common multicomponent reactions, has recently fascinated chemists with the high diversity brought by its four- or three-component-based isonitrile. The Ugi reaction has been introduced in organic synthesis as a novel, efficient and useful tool for the preparation of libraries of multifunctional peptides, natural products, and heterocyclic compounds with stereochemistry control. In this review, we highlight the recent advances of the Ugi reaction in the last two decades from 2000-2019, mainly in the synthesis of linear or cyclic peptides, heterocyclic compounds with versatile ring sizes, and natural products, as well as the enantioselective Ugi reactions. Meanwhile, the applications of these compounds in pharmaceutical trials are also discussed., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Matrix metalloproteinases (MMPs) are major modulators of the tumor microenvironment. They participate in extracellular matrix turnover, tumor growth, angiogenesis and metastasis. Accordingly, MMPs inhibition seems to be ideal solution to control cancer. Many MMPs inhibitors have been introduced ranging from hydroxamate-based peptidomimetics to the next generation non-hydroxamate inhibitors. Among MMPs, MMP-9 is attractive druggable anticancer target. Studies showed that inhibiting AKT, the central signaling node of MMP-9 upregulation, provides additional MMP-9 blockade. Furthermore, caspase-dependent AKT cleavage leads to cell death. Herein, Ugi MCR was utilized as a rapid combinatorial approach to generate various decorated bis-amide scaffolds as dual MMP-9/AKT inhibitors endowed with caspase 3/7 activation potential. The target adducts were designed to mimic the thematic structural features of non-hydroxamate MMP inhibitors. p-Nitrophenyl isonitrile 1 was utilized as structure entry to Ugi products with some structural similarities to amide-based caspase 3/7 activators. Besides, various acids, amines and aldehydes were employed as Ugi educts to enrich the SAR data. All adducts were screened for cytotoxicity against normal fibroblasts and three cancer cell lines; MCF-7, NFS-60 and HepG-2 utilizing MTT assay. 8, 11 and 28 were more active and safer than doxorubicin with single-digit nM IC 50 and promising selectivity. Mechanistically, they exhibited dual MMP-9/AKT inhibition at single-digit nM IC 50 with excellent selectivity over MMP-1,-2 and -13, and induced >51% caspase 3/7 activation. Consequently, they induced >49% apoptosis as detected by flow cytometric analysis, and inhibited cell migration (metastasis) up to 97% in cancer cells. Docking simulations were nearly consistent with enzymatic evaluation, also declared possible binding modes and essential structure features of active compounds. In silico physicochemical properties, ligand efficiency and drug-likeness metrics were reasonable for all adducts. Interestingly, 8 and 28 can be considered as drug-like candidates., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A wide range of endocrine disruptor compounds are routinely discharged to the ecosystem. Water contaminated with these compounds has a potential effect on the reproductive physiology of aquatic organisms as well as humans. In the present study, we tested the effect of the steroid estrogen, 17β-estradiol, on Biomphalaria alexandrina, a snail species that is widely distributed in Egypt and that acts as an intermediate host for the human blood fluke, Schistosoma mansoni. The effects of exposure to 0.3 mg/L and 1 mg/L 17β-estradiol on fecundity (M X ) and reproductive rate (R 0 ) of B. alexandrina were recorded. In addition, levels of steroid sex hormones and antioxidants in the hemolymph and ovotestis (OT) of exposed snails were measured. Histopathological changes in the OT of B. alexandrina were also investigated. Exposure to 0.3 mg/L and 1 mg/L 17β-estradiol caused a significant increase in the number of egg masses per snail after 3 weeks and 1 week of exposure for the two tested concentrations compared with unexposed controls. An increase in the levels of progesterone hormone was recorded in the hemolymph of exposed snails in comparison with unexposed controls. Additionally, levels of the antioxidant enzyme glutathione (GSH) were increased in the hemolymph and OT tissues of snails after 2 and 4 weeks of exposure. Histopathological sections in the OT revealed an increase in the oocyte and a decrease in the sperm densities after 2 weeks and this effect was restored to normal conditions after 4 weeks of exposure to both tested concentrations. The current results indicate that B. alexandrina is sensitive to 17β-estradiol and can therefore be used as bioindicator and model organism for the assessment of water pollution with endocrine disruptor compounds.

Evasion of apoptosis is a hallmark of cancer. Caspases; the key executors of apoptotic cascade are attractive targets for selective induction of apoptosis in cancer cells. Within this approach, various caspase activators were introduced as lead anticancer agents. In the current study, a new series of multifunctional Passerini products was synthesized and evaluated as potent caspase-dependent apoptotic inducers. The synthetic strategy adopted this isocyanide-based multicomponent reaction to possibly mimic the pharmacophoric features of various lead apoptotic inducers, where a series of α-acyloxy carboxamides was prepared from p-nitrophenyl isonitrile, cyclohexanone and various carboxylic acids. Accordingly, the main amide-based scaffold was decorated by substituents with varying nature and size to gain more information about structure-activity relationship. All the synthesized compounds were screened for cytotoxicity against normal human fibroblasts and their potential anticancer activities against three human cancer cell lines; MCF-7 (breast), NFS-60 (myeloid leukemia), and HepG-2 (liver) utilizing MTT assay. Among the most active compounds, 13, 21 and 22 were more potent and safer than doxorubicin with nanomolar IC 50 values and promising selectivity indices. Mechanistically, 13, 21 and 22 induced apoptosis by significant caspase activation in all the screened cancer cell lines utilizing flow cytometric analysis and caspase 3/7 activation assay. Again, 13 and 21 recorded higher activation percentages than doxorubicin, while 22 showed comparable results. Apoptosis-inducing factor1 (AIF1) quantification assay declared that 13, 21 and 22 didn't mediate apoptosis through AIF1-dependent pathway (i.e. only by caspase activation). Physicochemical properties, pharmacokinetic profiles, ligand efficiency metrics and drug-likeness data of all the synthesized compounds were computationally predicted and showed that 13, 21 and 22 could be considered as drug-like candidates. Finally, selected compounds were preliminarily screened for possible antimicrobial activities searching for dual anticancer/antimicrobial agents as an advantageous approach for cancer therapy., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was in [patients undergoing video-assisted thoracoscopic thymectomy for myasthenia gravis (MG)] is a [left-sided approach] superior to a [right-sided approach] in terms of [clinical outcome]? Two hundred and fifty-nine papers were found using the reported search. In looking at both procedures, we selected studies with a sizeable number of patients performing or studying both procedures and comparing their outcome. Hence, only 4 studies represented the best evidence to answer the clinical question. The authors, journal, date, country, study type, patient group, relevant outcomes and results of these papers are tabulated. Two studies compared their clinical experience with a right-sided versus a left-sided video assisted thoracoscopic surgery thymectomy approach, while 1 study compared using a bilateral versus a unilateral right-sided approach in patients with non-thymomatous MG. The number of patients studied included 31, 107 and 103 patients, respectively. All 3 studies demonstrated no difference regarding surgical time, intraoperative blood loss, postoperative hospital stay, postoperative complications and therapeutic effects (the last study compared the 5-year complete stable remission rate). All 3 studies concluded that both approaches are feasible, effective and comparable in operative and long-term results for the treatment of non-thymomatous MG. One anatomical study compared both approaches in 10 cadavers, 5 in each group. They studied the size of the specimen resected and visualization of different anatomic sites via each approach. Visualization was superior using the left-sided approach, while a right-sided approach resulted in slightly higher chances of an incomplete resection. The study concluded that a left-sided approach achieves a better chance of radical thoracoscopic thymectomy due to anatomic considerations. In conclusion, despite 1 cadaveric study suggesting that a left-sided approach may achieve more complete resection, possibly due to anatomical considerations, there are no differences in outcomes with either unilateral approach in terms of complications, hospital stay or long-term symptom relief., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

This work studied how pollution impacts the ecosystem of Lake Manzala by determination of physicochemical parameters, studying biodiversity of aquatic plants and macroinvertebrates, and determining bioaccumulation of Pb, Cu, Cd & Zn in some major organisms, Biomphalaria alexandrina and Melanoides tuberculata snails and Oreochromis niloticus fish. The more near to Mediterranean Sea and to the industrial area, Port-Said and Damietta sites showed higher dissolved oxygen and conductivity than Dakahlia sites. Distribution percentage of Eichhornia crassipes is high among Port-Said and Dakahlia sites of 100 and 88%, respectively, while Lemna giba is the most abundant among Damietta sites of 60%. The maximum macroinvertebrate taxa richness was obtained at Gammalya, Dakahlia of 16 species while the maximum abundance was registered at Annanya, Damietta of 591 organisms. Gastropoda are the most distributed organisms in Lake Manzala followed by Hemiptera and Plecoptera then shrimps and scud. All the medically important snails, B. alexandrina, B. truncatus and L. natalensis were recorded in Dakahlia, but only B. alexandrina was in Damietta and Port-Said sites. The collected water samples from Damietta sites showed the highest significant Cu & Cd concentration while Port-Said samples showed the highest Pb concentration and Dakahlia showed the highest Zn concentration. The metals concentrations were higher in snail tissue and in fish liver, kidney and most of muscle samples as compared in surface water. The higher metal bioaccumulation was determined in snails collected from sites showed higher water metals concentrations. Fish muscle showed the least residues than liver and kidney for all the measured metals. Pb and Cd were more accumulated in kidneys, Cu was more accumulated in liver and Zn was accumulated in all examined fish parts in descending order as follows Kidney > liver > muscle.

Introduction. Metal-on-metal (MoM) hip resurfacings have been associated with a variety of complications resulting from adverse reaction to metal debris. Pseudotumors have rarely been reported to cause deep venous thrombosis (DVT). Study Design. A case report and a review of the literature. Case Presentation. A 75-year-old female who had left metal-on-metal hip resurfacing 6 years ago presented with left groin pain associated with unilateral lower limb edema and swelling. By duplex and MRI studies, our patient had an extensive soft tissue necrosis associated with a large pelvic mass causing extensive DVT of the lower limb secondary to mechanical compression of the left iliac vein. Results. Our case was initially treated for DVT followed by dual surgical approach. The pseudotumor was excised through a separate iliofemoral approach and revision of the hip implant was undertaken through a posterior approach in the same setting. An inferior vena cava (IVC) filter was inserted to minimise the perioperative risks of handling the iliac veins. Conclusion. A combined approach with vascular surgeons is required. Combined resection of the pseudotumor and revision of the metal bearing surfaces is essential, in order to achieve a good surgical outcome in this rare complication.

Silver nanoparticles (AgPNs) extracts were prepared from seven Seven fungal isolates were evaluated through measuring their toxicity against Biomphalaria alexandrina snails. The effects of the two promising Paecilomyces variotii and Aspergillus niger AgNPs sublethal concentrations (LC10 & LC25) on the levels of steroid sex hormones, liver enzymes, total protein, lipids, albumhin, glucose, total and differential count of hemocytes and morphology of hemocytes, oocytes and sperms were studied in this work. The short period of snails' exposure (24h) to the two fungal AgNPs resulted in significant decrease in the levels of progesterone in B. alexandrina. The level of testosterone hormone showed significant increase in snails exposed to P. variotii AgNPs while no significant change was recorded at the exposure to A. niger AgNPs. Also, estradiol hormone concentration increased significantly in this investigation with the increase of the concentration of the two tested compounds. In addition, significant elevation in ALT, AST and Alkaline phosphatase was recorded. The total number of the hematocytes increased significantly by 17.4-47.8%. Snails' granulocytes were reduced by 19.1-43.8%, while hyalinocytes increased by 63.6-354.5%. The exposure of B. alexandrina to LC25 of both P. variotii and A. niger AgNPs showed apoptotic hemolymph cells, fragmented, vacuolated and degenerated cytoplasm, shrunken nucleus and phagocytosis in the light microscopy photographs of the hemocytes. Besides, the photographs showed also, abnormal nuclear division, degeneration and large fat vacuoles in the cytoplasm and swallowed atretic oocytes. Also, the photographs showed dead sperm head separated from its tail, other sperms showed abnormal swallowed head with severely nodded tail, dead sperms with wrinkled tails, hyperplasia and necrotic sperm heads led to overlapping of tails. In conclusion, applying the biosynthesized compounds which led to destruction of blood cells (the immune system), ova and sperms (the reproductive system) of snails is an important effective step to control schistosomiasis.

A 4-year-old girl presented to our tertiary care hospital with a complaint of lower extremity weakness and unsteady gait for 2 days. She was able to pull herself to stand, but could not stand unsupported. She had no sensory symptoms or pain. She did not complain of any weakness in her arms, trunk, face, or neck. She had no bowel or bladder incontinence or retention. On presentation to the emergency room, she had minimal antigravity strength of the lower extremities, but normal strength elsewhere. In addition, she was areflexic in both lower extremities and had a wide-based, unsteady gait but no appendicular dysmetria or titubation. Sensory examination was normal.

To investigate the structure-function relationship of plant cyclic nucleotide-gated ion channels (CNGCs), we identified a total of 29 mutant alleles of the chimeric AtCNGC11/12 gene that induces multiple defense responses in the Arabidopsis (Arabidopsis thaliana) mutant, constitutive expresser of PR genes22 (cpr22). Based on computational modeling, two new alleles, S100 (AtCNGC11/12:G459R) and S137 (AtCNGC11/12:R381H), were identified as counterparts of human CNGA3 (a human CNGC) mutants. Both mutants lost all cpr22-mediated phenotypes. Transient expression in Nicotiana benthamiana as well as functional complementation in yeast (Saccharomyces cerevisiae) showed that both AtCNGC11/12:G459R and AtCNGC11/12:R381H have alterations in their channel function. Site-directed mutagenesis coupled with fast-protein liquid chromatography using recombinantly expressed C-terminal peptides indicated that both mutations significantly influence subunit stoichiometry to form multimeric channels. This observation was confirmed by bimolecular fluorescence complementation in planta. Taken together, we have identified two residues that are likely important for subunit interaction for plant CNGCs and likely for animal CNGCs as well.

Purpose of Review: The study reviews recent advances in pharmacological management of muscular dystrophies. Similarities and differences among the pathophysiology of different forms of muscular dystrophy lead to a broad array of approaches to provide new treatments., Recent Findings: In this review, we include only those muscular dystrophies for which advances have been published in the past year. This represents the 'advancing edge' of a large body of research over more than 20 years. This runs the gamut of new discoveries in symptomatic management to mutation-specific strategies that attempt to correct the root cause of the disorder., Summary: The field of pharmacological therapies for the muscular dystrophies continues to steadily advance. It is encouraging that research into new therapies is increasingly exploring pharmacological strategies with the potential to ameliorate disease pathology to a clinically significant degree.

Irritable bowel syndrome (IBS) is common in western Europe and North America, and many aspects of its epidemiology, risk factors, and natural history have been described in these regions. Recent data suggest, however, that IBS is also common in the rest of the world and there has been some evidence to suggest some differences in demographics and presenting features between IBS in the west and as it is experienced elsewhere. The World Gastroenterology Organization, therefore, established a Task Force comprising experts on the topic from all parts of the world to examine IBS from a global perspective. IBS does, indeed, seem to be common worldwide though with some significant variations in prevalence rates between regions and countries and there may well be some potentially interesting variations in presenting symptoms and sex distribution. The global map of IBS is far from complete; community-based prevalence data is not available from many areas. Furthermore, while some general trends are evident in terms of IBS impact and demographics, international comparisons are hampered by differences in diagnostic criteria, study location and methodology; several important unanswered questions have been identified that should form the basis for future collaborative research and have the potential to shed light on this challenging disorder.

Recently, we reported the role of Arabidopsis cyclic nucleotide-gated ion channel (AtCNGC) 11 and 12 in Ca2+-dependent physiological responses. AtCNGC11 and 12 have been reported to be involved in plant immunity, but whether these channels play additional physiological roles was not clear before. Using single and double knockout mutants, we have found that these channels play significant roles in Ca2+ signaling, which mediates several physiological processes, such as gravitropic bending and senescence. Here, we conducted a high throughput, non-biased chemical screen using the gain-of-function mutant of AtCNGC11 and 12, cpr22. Our data presented here indicates that Ca2+ but not K+ channel blockers suppress AtCNGC11/12-induced lethality. Our data further suggest that AtCNGC11 and 12 are involved in Ca2+-dependent, but not K+-dependent physiological responses in planta.

To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ∼14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders.

Recently we have reported that the αC-helix in the cyclic nucleotide binding domain (CNBD) is required for channel regulation and function of cyclic nucleotide gated ion channels (CNGCs) in Arabidopsis. A mutation at arginine 557 to cysteine (R557C) in the αC-helix of the CNBD caused an alteration in channel regulation. Protein sequence alignments revealed that R557 is located in a region that is important for calmodulin (CaM) binding. It has been hypothesized that CaM negatively regulates plant CNGCs similar to their counter parts in animals. However, only a handful of studies has been published so far and we still do not have much information about the regulation of CNGCs by CaM. Here, we conducted in silico binding prediction of CaM and Arabidopsis CNGC12 (AtCNGC12) to further study the role of R557. Our analysis revealed that R557 forms salt bridges with both D79 and E83 in AtCaM1. Interestingly, a mutation of R557 to C causes the loss of these salt bridges. Our data further suggests that this alteration in CaM binding causes the observed altered channel regulation and that R557 plays an important role in CaM binding.

The involvement of cyclic nucleotide gated ion channels (CNGCs) in the signal transduction of animal light and odorant perception is well documented. Although plant CNGCs have recently been revealed to mediate multiple stress responses and developmental pathways, studies that aim to elucidate their structural and regulatory properties are still very much in their infancy. The structure-function relationship of plant CNGCs was investigated here by using the chimeric Arabidopsis AtCNGC11/12 gene that induces multiple defence responses in the Arabidopsis mutant constitutive expresser of PR genes 22 (cpr22) for the identification of functionally essential residues. A genetic screen for mutants that suppress cpr22-conferred phenotypes identified over 20 novel mutant alleles in AtCNGC11/12. One of these mutants, suppressor S58 possesses a single amino acid substitution, arginine 557 to cysteine, in the alphaC-helix of the cyclic nucleotide-binding domain (CNBD). The suppressor S58 lost all cpr22 related phenotypes, such as spontaneous cell death formation under ambient temperature conditions. However, these phenotypes were recovered at 16 degrees C suggesting that the stability of channel function is affected by temperature. In silico modelling and site-directed mutagenesis analyses suggest that arginine 557 in the alphaC-helix of the CNBD is important for channel regulation, but not for basic function. Furthermore, another suppressor mutant, S136 that lacks the entire alphaC-helix due to a premature stop codon, lost channel function completely. Our data presented here indicate that the alphaC-helix is functionally important in plant CNGCs.

Neurologic complications affect posttransplant recovery of more than 20% of transplant recipients. Etiology is usually related to surgical procedure of transplantation, primary disorders causing failure of transplanted organ, opportunistic infections, and neurotoxicity of immunosuppressive medications. Risk of opportunistic infections and immunosuppressant neurotoxicity is greatest within the first six months, but it persists along with long-term maintenance immunosuppression required to prevent graft rejection. Neurotoxicity may require alteration of immunosuppressive regimen, and prompt therapy of opportunistic infections improves outcomes.

Background: We describe a severe form of congenital myasthenic syndrome (CMS) associated with congenital nephrosis and ocular malformations caused by two truncating mutations in the gene encoding the laminin beta2 subunit (LAMB2)., Methods and Results: Mutational analysis in the affected patient, who has a history of a serious untoward reaction to treatment with acetylcholinesterase inhibition, revealed two frame-shifting heteroallelic mutations, a maternally inherited 1478delG and a paternally inherited 4804delC. An anconeus muscle biopsy demonstrated a profound distortion of the architecture and function of the neuromuscular junction, which was strikingly similar to that seen in mice lacking laminin beta2 subunit. The findings included: pronounced reduction of the axon terminal size with encasement of the nerve endings by Schwann cells, severe widening of the primary synaptic cleft and invasion of the synaptic space by the processes of Schwann cells, and moderate simplification of postsynaptic folds and intact expression of the endplate acetylcholinesterase. The endplate potential quantal content was notably reduced, while the frequencies and amplitudes of miniature endplate potentials were only moderately diminished and the decay phases of miniature endplate potentials were normal. Western blot analysis of muscle and kidney tissue and immunohistochemistry of kidney tissue showed no laminin beta2 expression., Conclusion: This case, which represents a new type of synaptic CMS, exemplifies the wide variability of phenotypes associated with LAMB2 mutations and underscores the fundamental role that laminin beta2 plays in the development of the human neuromuscular junction.

Hydroxychloroquine causes a vacuolar myopathy that is usually of mild to moderate severity. The myopathy may be underrecognized, especially in patients who receive multiple other medications for complex illnesses. We report two patients with connective tissue diseases and unusually severe, histopathologically proven hydroxychloroquine myopathy. Both had ventilatory failure; one also had primary pulmonary disease associated with scleroderma, but the other lacked a pulmonary etiology. The ventilatory failure and subsequent medical complications led to death despite discontinuation of hydroxychloroquine, thereby underscoring the potential severity of hydroxychloroquine myopathy and the need for its early recognition.

Regioselective alkylation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole (1) with hydroxy alkylating agents 2, 3, 13, and the 2,3-O-isopropylidene-1-O-(p-tolylsulfonyl)-glycerol (10) afforded the corresponding S-alkylated derivatives 6, 7, 11, and 14 under both conventional and microwave irradiation conditions; bentonite as a solid support gave better results, with no change in regioselectivity. A facile intramolecular dehydrative ring closure of 6, 7, 11, and 14 using K(2)CO(3) in DMF afforded the corresponding fused triazolo-thiazines and thiazolo-triazole 17-19. The isopropylidenes and acetyl derivatives of the products were prepared.

A comparative study of the gene expression profile in different developmental stages of Schistosoma mansoni has been initiated based on the expressed sequence tag (EST) approach. A total of 1401 ESTs were generated from seven different cDNA libraries constructed from four distinct stages of the parasite life cycle. The libraries were first evaluated for their quality for a large-scale cDNA sequencing program. Most of them were shown to have less than 20% useless clones and more than 50% new genes. The redundancy of each library was also analyzed, showing that one adult worm cDNA library was composed of a small number of highly frequent genes. When comparing ESTs from distinct libraries, we could detect that most genes were present only in a single library, but others were expressed in more than one developmental stage and may represent housekeeping genes in the parasite. When considering only once the genes present in more than one library, a total of 466 unique genes were obtained, corresponding to 427 new S. mansoni genes. From the total of unique genes, 20.2% were identified based on homology with genes from other organisms, 8.3% matched S. mansoni characterized genes and 71.5% represent unknown genes.

Background and Study Aims: Recently, tissue adhesive material has been used to improve the initial control of bleeding from huge esophagogastric varices, and to prevent them from rebleeding, in contrast to the conventional sclerotherapy. The present study assessed the value of the combined use of the tissue adhesive substance: N-butyl-2-cyanoacrylate and ethanolamine oleate 5% for management of bleeding esophagogastric varices., Patients and Methods: One hundred and fourteen patients with documented active variceal bleeding at the time of endoscopy were alternatively randomized into two groups. The combined therapy group included 58 patients who underwent injection using both cyanoacrylate for large esophageal and gastric varices and a sclerosant agent for remaining varices. The sclerosis, or control, group included 56 patients, who underwent injection with ethanolamine oleate., Results: This study proved the value of the combined therapy for the initial control of all bleeders (the follow-up period ranged from 12 to 32 months). In the sclerosis group, failure of the initial control of bleeding was reported in two cases (3.6%). Recurrent bleeding occurred in 8.6% in the combined therapy group compared to 25% in the sclerosis group (p < 0.01). Two months of therapy was required to achieve complete eradication of varices in 56.5% and 21.4% in the combined therapy and the sclerosis group, respectively. The mean number of sessions needed until the time of evaluation was 2.4 +/- 1.1 in the combined therapy group versus 5.1 +/- 2.3 sessions in the sclerosis group. The difference showed high statistical significance (p < 0.01). Minor complications occurred less frequently in the combined therapy group. Only one patient in the combined therapy group developed portal pyemia after extension of the tissue adhesive material from the site of injection into the portal vein. This patient died of hepatic failure. The mortality in the combined therapy group was lower than that in the sclerosis group (3.5% and 8.8% respectively, p > 0.05)., Conclusion: The combined use of tissue adhesive and sclerosant materials seems to be the best plan for rapid eradication of esophagogastric varices within a short time, requiring the lowest number of injection sessions and involving minor complications and low mortality.

Electrophilic compounds are widely used in industry. Plastic and dyeing industries are foremost examples of sites where workers are exposed to electrophilic compounds. Besides their immediate effect on different body systems, electrophilic compounds include most mutagenic and carcinogenic substances. The present study was carried out to elucidate the possibility of using nonselective assays in the biological monitoring of occupational exposure to electrophilic compounds. The study included a total number of 225 workers selected from the Plastic and Battery Company where workers are exposed to styrene (n = 70), and the Kafr El Dawar chemical and Dyeing Company where workers are exposed to aniline (n = 60) and benzidine (n = 25). Workers exposed to diesel engine exhaust were selected from a bus garage in Smoha (n = 70). A comparison group consisting of 141 subjects was selected from the administrative departments of the selected factories. The biochemical tests carried out on each subject included: (1) estimation of the biological indices of exposure: urinary mandelic acid and benzidine, blood methemoglobin, and carboxyhemoglobin, (2) liver and kidney function tests; and (3) nonselective biochemical parameters of early detection of carcinogenic and mutagenic risk: urinary thioether levels, urinary RNase and alpha esterase activities. The study revealed that two out of three nonselective assays have been affected by occupational exposure to electrophilic compounds. These were the urinary thioethers and RNase levels. Their determination is recommended in the biological monitoring of workers exposed to such agents especially in developing countries.

Magnetic resonance imaging (MRI) was used for the evaluation of the bony pelvis in 4 pregnant and 10 non-pregnant women. The anatomical details and shape of the bony pelvis were easily examined and the main pelvic measurements were estimated on the sections and programs. The end points were easily demonstrated. There was no need to correct for magnification. The study confirmed that MRI is a very valuable technique for assessment of the pelvis. Although it is expensive, it overcomes the technical difficulty of the other methods used for pelvimetry.

Sixteen women with clinically diagnosed uterine masses were studied by magnetic resonance imaging (MRI). Pelvic study was carried out in the coronal, sagittal and axial planes. Uterine leiomyomas were detected in 12 cases, while the remaining cases were one each of uterine sarcoma, invasive molar pregnancy, cervical malignancy with pyometra and haematometra with congenital cervical stenosis. The uterine origin of the masses could be clearly detected in all patients, as well as the nature of the masses, the presence of degenerative or malignant changes and the nature of the intrauterine fluid. MRI characteristic findings of the studied masses are presented and discussed.