Novel benzothiazole/benzothiazole thiazolidine-2,4-dione derivatives as potential FOXM1 inhibitors: In silico, synthesis, and in vitro studies.

The oncogenic transcription factor FOXM1 overexpressed in breast and other solid cancers, is a key driver of tumor growth and progression through complex interactions, making it an attractive molecular target for the development of targeted therapies. Despite the availability of small-molecule inhibitors, their limited specificity, potency, and efficacy hinder clinical translation. To identify effective FOXM1 inhibitors, we synthesized novel benzothiazole derivatives (KC10-KC13) and benzothiazole hybrids with thiazolidine-2,4-dione (KC21-KC36). These compounds were evaluated for FOXM1 inhibition. Molecular docking and molecular dynamics simulation analysis revealed their binding patterns and affinities for the FOXM1-DNA binding domain. The interactions with key amino acids such as Asn283, His287, and Arg286, crucial for FOXM1 inhibition, have been determined with the synthesized compounds. Additionally, the molecular modeling study indicated that KC12, KC21, and KC30 aligned structurally and interacted similarly to the reference compound FDI-6. In vitro studies with the MDA-MB-231 breast cancer cell line demonstrated that KC12, KC21, and KC30 significantly inhibited FOXM1, showing greater potency than FDI-6, with IC50 values of 6.13, 10.77, and 12.86 µM, respectively, versus 20.79 µM for FDI-6. Our findings suggest that KC12, KC21, and KC30 exhibit strong activity as FOXM1 inhibitors and may be suitable for in vivo animal studies.

Investigation of highly cited publications related to vaccines against COVID-19: current state and future predictions.

BACKGROUND: Since the date of declaring the COVID-19 outbreak a pandemic by the World Health Organization (March 11, 2020), vaccine studies have been initiated. In this article, we aimed to investigate highly cited articles on vaccines and guide researchers for future studies. MATERIAL AND METHODS: Publications with 6 or more citations (highly cited publications) were extracted from Web of Science (WoS) database. These publications were investigated according to the number of citations, language, publication year, WoS categories, publication types, organizations involved, authors, countries and research areas. Additionally, top 20 articles were investigated in detail. RESULTS: A total of 126 publications were determined. When WoS categories were investigated, 18 pertained to immunology (14.2 %), 17 to biochemistry (13.4 %) and 17 to multidisciplinary sciences (13.4 %). There were three types of publications, namely 80 original articles (63.4 %), 46 reviews (36.5 %) and 11 early access publications (8.7 %). Top universities were Harvard University (n=9, 7.1 %), Chinese Academy of Medical Sciences (n=7, 5.5 %) and University of California system (n=7, 5.5 %). Top authors were Qin CF with 4 articles (3.1 %), Wang L with 4 articles (3.1 %) and Baric RS with 3 articles (2.3 %). Top journals with the highest number of publications were Journal of Biomolecular Structure Dynamics (n=8, 6.3 %), Nature (n=8, 6.3 %) and Science (n=6, 4.7 %). Top countries were the United States of America (USA) with 45 articles (35.7 %), People's Republic of China with 44 articles (34.9 %), and India with 15 articles (11.9 %). Research areas of the publications were science technology other topics (n=21, 16.6 %), immunology (n=18, 14.2 %) and pharmacology (n=18, 14.2 %). CONCLUSION: Vaccine studies play a pivotal role in the warfare against COVID-19. Our results revealed that under the leadership of the USA, China and India, the number of scientists focusing on vaccines is increasing and gratifying results are obtained from vaccine studies (Tab. 3, Ref. 40).

Novel inhibitors of eukaryotic elongation factor 2 kinase: In silico, synthesis and in vitro studies.

Eukaryotic elongation factor 2 kinase (eEF2K) is an unusual alpha kinase whose expression is highly upregulated in various cancers and contributes to tumor growth, metastasis, and progression. More importantly, eEF2K expression is associated with poor clinical outcome and shorter patient survival in breast, lung and ovarian cancers. Therefore, eEF2K is an emerging molecular target for development of novel targeted therapeutics and precision medicine in solid cancers. Currently, there are not any available potent and specific eEF2K inhibitors for clinical translation. In this study, we designed and synthesized a series of novel compounds with coumarin scaffold with various substitutions and investigated their effects in inhibiting eEF2K activity using in silico approaches and in vitro studies in breast cancer cells. We utilized an amide substitution at position 3 on the coumarin ring with their pharmacologically active groups containing pyrrolidine, piperidine, morpholine and piperazine groups with (CH2)2 bridged for aliphatic amides. Due to their ability to form covalent binding to the target enzyme, we also investigated the effects of boron containing groups on functionalized coumarin ring (3 compounds) and designed novel aliphatic and aromatic derivatives of coumarin scaffolds (10 compounds) and phenyl ring with boron groups (4 compounds). The Glide/SP module of the Maestro molecular modeling package was used to perform in silico analysis and molecular docking studies. According to our combined results, structure activity relationship (SAR) was performed in detail. Among the newly designed, synthesized, and tested compounds, our in vitro findings revealed that several compounds displayed a highly effective eEF2K inhibition at submicromolar concentrations in in vitro breast cancer cells. In conclusion, we identified novel compounds that can be used as eEF2K inhibitors and that they should be further evaluated by in vivo preclinical tumor models studies for antitumor efficacy and clinical translation.

Delivery of Small Molecule EF2 Kinase Inhibitor for Breast and Pancreatic Cancer Cells Using Hyaluronic Acid Based Nanogels.

PURPOSE: To evalauted natural polymeric biomaterials including hyaluronic acid (HA) and its copolymeric form HA:Suc nanoparticles (NPs) as drug carrier systems for delivery of hydrophobic small molecule kinase EF2-kinase inhibitor in breast and pancreatic cancer cells. METHODS: In vitro cellular uptake studies of Rhodamine 6G labaled HA:Suc nanoparticles were evaluated by using flow cytometry analysis and fluorescent microscopy in breast (MDA-MB-231 and MDA-MB-436) and pancreatic cancer cells (PANC-1 and MiaPaca-2). Besides, in vitro release study of compound A (an EF2-kinase inhibitor) as a model hydrophobic drug was performed in the cancer cells. RESULTS: These biological evaluation studies indicated that HA and HA:Suc NPs provided a highly effective delivery of compound A were into breast and pancreatic cancer cells, leading to significant inhibition of cell proliferation and colony formation of breast and pancreatic cancer cells. CONCLUSION: HA-sucrose NPs incorporating an EF2-Kinase inhibitor demonstrate significant biologic activity in breast and pancreatic cancer cells. This is the first study that shows natural polymeric drug carriers succesfully deliver a hydrofobic cancer drug into cancer cells. Graphical Abstract Nanoparticles based on HA:Suc are effective in delivering hydrofobic cancer drugs in breast and pancreatic cancers.

Design, Synthesis, and Molecular Modeling Studies of Novel Coumarin Carboxamide Derivatives as eEF-2K Inhibitors.

Eukaryotic elongation factor-2 kinase (eEF-2K) is an unusual alpha kinase commonly upregulated in various human cancers, including breast, pancreatic, lung, and brain tumors. We have demonstrated that eEF-2K is relevant to poor prognosis and shorter patient survival in breast and lung cancers and validated it as a molecular target using genetic methods in related in vivo tumor models. Although several eEF-2K inhibitors have been published, none of them have shown to be potent and specific enough for translation into clinical trials. Therefore, development of highly effective novel inhibitors targeting eEF-2K is needed for clinical applications. However, currently, the crystal structure of eEF-2K is not known, limiting the efforts for designing novel inhibitor compounds. Therefore, using homology modeling of eEF-2K, we designed and synthesized novel coumarin-3-carboxamides including compounds A1, A2, and B1-B4 and evaluated their activity by performing in silico analysis and in vitro biological assays in breast cancer cells. The Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) area results showed that A1 and A2 have interaction energies with eEF-2K better than those of B1-B4 compounds. Our in vitro results indicated that compounds A1 and A2 were highly effective in inhibiting eEF-2K at 1.0 and 2.5 µM concentrations compared to compounds B1-B4, supporting the in silico findings. In conclusion, the results of this study suggest that our homology modeling along with in silico analysis may be effectively used to design inhibitors for eEF-2K. Our newly synthesized compounds A1 and A2 may be used as novel eEF-2K inhibitors with potential therapeutic applications.

Prodrugs for nitroreductase based cancer therapy-4: Towards prostate cancer targeting: Synthesis of N-heterocyclic nitro prodrugs, Ssap-NtrB enzymatic activation and anticancer evaluation.

In this study, various N-heterocyclic nitro prodrugs (NHN1-16) containing pyrimidine, triazine and piperazine rings were designed and synthesized. The final compounds were identified using FT-IR, 1H NMR, 13C NMR as well as elemental analyses. Enzymatic activities of compounds were conducted by using HPLC analysis to investigate the interaction of substrates with Ssap-NtrB nitroreductase enzyme. MTT assay was performed to evaluate the toxic effect of compounds against Hep3B and PC3 cancer cell lines and healthy HUVEC cell. It was observed that synthesized compounds NHN1-16 exhibited different cytotoxic profiles. Pyrimidine derivative NHN3 and triazine derivative NHN5 can be good drug candidates for prostate cancer with IC50 values of 54.75 µM and 48.9 µM, respectively. Compounds NHN6, NHN10, NHN12, NHN14 and NHN16 were selected as prodrug candidates because of non-toxic properties against three different cell models. The NHN prodrugs and Ssap-NtrB combinations were applied to SRB assay to reveal the prodrug capabilities of these selected compounds. SRB screening results showed that the metabolites of all selected non-toxic compounds showed remarkable cytotoxicity with IC50 values in the range of 1.71-4.72 nM on prostate cancer. Among the tested compounds, especially piperazine derivatives NHN12 and NHN14 showed significant toxic effect with IC50 values of 1.75 nM and 1.79 nM against PC3 cell compared with standart prodrug CB1954 (IC50: 1.71 nM). Novel compounds NHN12 and NHN14 can be considered as promising prodrug candidates for nitroreductase-prodrug based prostate cancer therapy.

Modification of existing antibiotics in the form of precursor prodrugs that can be subsequently activated by nitroreductases of the target pathogen.

The use of existing antibiotics in the form of prodrug followed by activation using enzymes of pathogenic origin could be a useful approach for antimicrobial therapy. To investigate this idea, a common antibiotic, sulfamethoxazole has been redesigned in the form of a prodrug by simple functional group replacement. Upon reductive activation by a type I nitroreductase from a pathogen, the drug displayed enhanced antimicrobial capacity. This strategy could improve the efficacy and selectively of antibiotics and reduce the incidence of resistance.

Antiproliferative activity of Humulus lupulus extracts on human hepatoma (Hep3B), colon (HT-29) cancer cells and proteases, tyrosinase, ß-lactamase enzyme inhibition studies.

The aims of this study were to examine the antiproliferation of Humulus lupulus extracts on human hepatoma carcinoma (Hep3B) and human colon carcinoma (HT-29) cell lines along with enzyme inhibitory effects of the crude extracts. Potential cell cytotoxicity of six different H. lupulus extracts were assayed on various cancer cells using MTT assay at 24, 48 and 72 h intervals. Methanol-1 extract has inhibited the cell proliferation with doses of 0.6-1 mg/mL in a time dependent (48 and 72 hours) manner in Hep3B cells with 70% inhibition, while inhibitory effect was not seen in colon cancer cells. Acetone extract has increased the cell proliferation at low doses of 0.1 mg/mL for 72 h in Hep3B cells and 0.1-0.2 mg/mL for 48 and 72 h in HT29 cells. The inhibitory effects of the extracts were compared by relative maximum activity values (V(max)) using proteases such as α-chymotrypsin, trypsin and papain, tyrosinase and ß-lactamase (penicillinase).

Levofloxacin-induced hepatotoxicity and death.

Drug-induced hepatotoxicity is a major cause of hepatocellular injury in patients admitting to emergency services with acute liver failure. Hepatic necrosis may be at varying degrees from mild elevations in transaminases to fulminant hepatitis, and even death. The case of a 53-year-old female patient with toxic hepatitis due to levofloxacin and multiple organ failure secondary to toxic hepatitis is presented. Patient suffered itching, redness, and rash after receiving a single dose of 750 mg of levofloxacin tablets for pulmonary infection 10 days ago. Skin lesions had regressed within 3 days, but desquamation formed all over the body. After the fifth day of drug intake, complaints of abdominal pain, vomiting, and yellowing in skin color had started. The patient was referred to our emergency department with these complaints 10 days after drug intake. Patient was thought as a candidate for liver transplant, but cardiopulmonary arrest occurred, and the patient died before she could be referred to a transplant center. This case is important because hepatotoxicity and death due to levofloxacin is uncommon in the literature.

The effectiveness of bedside point-of-care ultrasonography in the diagnosis and management of metacarpal fractures.

OBJECTIVE: We aimed to compare the effectiveness of point-of-care ultrasonography (POCUS) with direct radiography (DR) in the diagnosis and management of the patients with metacarpal fractures (MFs). METHODS: Patients between ages 5 and 55 years admitted to the emergency department with suspected MFs were included to the study. Emergency physicians (EPs) participating in the study were divided into 2 groups (POCUS, DR). Patients were evaluated by one of the EPs from each group. The EP performing the POCUS examination was blinded to the radiograph results. RESULTS: A total of 66 patients with MFs were included to the study. Fracture was determined in 36 (55%) patients with DR and in 37 (56%) patients with POCUS. When compared with radiography, the sensitivity of fracture detection with POCUS was 92%; specificity, 87%; positive predictive value, 89%; and negative predictive value, 90% (95% confidence interval, 80%-98%). Sensitivity of detecting localization of the fracture with POCUS was 92%; specificity, 87%; positive predictive value, 89%; and negative predictive value, 89% (95% confidence interval, 80%-98%). Of the patients with fracture, 69% have angulation and 24% have step-off determined with POCUS. Specificity of POCUS in the decision for treatment choice was 100%, and sensitivity was 99%. CONCLUSION: We found that POCUS could be applied easily with success by EPs in diagnosing MFs, determining the type of the fracture and required treatment methods correctly. Point-of-care US can be used to rule out a suspected MF, thereby avoiding the time and expense of radiography.

Evaluation of the effectiveness of bedside point-of-care ultrasound in the diagnosis and management of distal radius fractures.

OBJECTIVE: The aim of the study was to compare the effectiveness of point-of-care ultrasound (POCUS) with direct radiography in diagnosis and management of the patients with distal radius fractures (DRFs). METHODS: In this study, patients between ages 5 and 55 years admitted to the emergency department with low energy upper extremity trauma with suspected DRF were evaluated with POCUS and direct radiography by emergency physicians (EPs) trained in either musculoskeletal (MSK) imaging or x-ray interpretation of DRF. The EP performing the POCUS examination was blinded to the x-ray results. RESULTS: A total of 83 patients with DRF were included in the study. There were 18 (22%) females, and 65 (78%) males enrolled in the study. Mean age was 13 ± 14 years for males, and 15 ± 13 years for females. Compared with direct radiography, POCUS yielded 98% sensitivity, 96% specificity, 98% positive predictive value, 96% negative predictive value, and 98% accuracy of the test in detecting fractures. POCUS yielded 96% sensitivity, 93% specificity value in detecting linear fractures; 78% sensitivity, 98% specificity in detecting torus-type fractures, and 100% specificity and sensitivity for detecting fissure fractures. Specificity of POCUS in the decision for reduction was 100% and sensitivity was 98%; specificity was 100% for splint application. CONCLUSION: In our study, it was shown that POCUS could be applied easily by EPs trained in MSK POCUS imaging with success in diagnosing DRF and determining the correct fracture type and required treatment methods.

Comparison of the analgesic efficacy of dexketoprofen trometamol and meperidine HCl in the relief of renal colic.

In this study, the analgesic effects of dexketoprofen trometamol and meperidine hydrochloride were compared in patients diagnosed with renal colic. This study was a prospective, randomized, double-blind study. Fifty-two patients, between the ages of 18 and 70 years who were diagnosed with renal colic, were enrolled in the study after obtaining ethics committee approval. Before drug injection, dexketoprofen trometamol and meperidine hydrochloride were placed in closed envelopes, and the patients were randomly given a single dose of intravenous infusion for 20 minutes. Severity of pain and symptoms was evaluated with the numerical rating scale and renal colic symptom score for each patient immediately before administration of drugs and 30 minutes after the end of the application. At the same time, systolic arterial blood pressure, diastolic arterial pressure, respiratory rate, heart rate, nausea, vomiting, and reactions due to drug administration were recorded before and after drug administration. In statistical methods, t test, analysis of variance, and repeated measure analysis were used for the analysis of normally distributed continuous variables and the Mann-Whitney U, Kruskal-Wallis and Friedman tests were used for analysis of not-normally distributed continuous variables. In the analysis of discrete variables, the χ test was used. In both groups, a significant decrease was found in numerical rating scale values measured 30 minutes after drug administration, but the decline in dexketoprofen trometamol group (P = 0.02) was found to be more. Although a significant decrease was found in the renal colic symptom score (P < 0.001) values measured after drug administration in the dexketoprofen trometamol group, no significant decrease was found in the meperidine HCl (P = 0.058) group. After drug administration, a statistically significant decrease was found in the systolic arterial blood pressure, heart rate, and respiratory rate in both groups. Also, a statistically significant decrease was found in the diastolic arterial pressure in the meperidine group. But these changes in vital findings were not serious enough to disrupt patients' clinical status. With this study, we concluded that dexketoprofen trometamol, from the nonsteroidal anti-inflammatory drug group, can be within the primary treatment options for renal colic because of better analgesic efficacy, being well tolerated by patients compared with meperidine hydrochloride.

The relationship between inferior vena cava diameter measured by bedside ultrasonography and central venous pressure value.

OBJECTIVE: We aimed to present inferior vena cava (IVC) diameter as a guiding method for detection of relationship between IVC diameter measured noninvasively with the help of ultrasonography (USG) and central venous pressure (CVP) and evaluation of patient's intravascular volume status. METHODS: Patients over the age of 18, to whom a central venous catheter was inserted to their subclavian vein or internal jugular vein were included in our study. IVC diameter measurements were recorded in millimeters following measurement by the same clinician with the help of USG both at the end-inspiratory and end-expiratory phase. CVP measurements were viewed on the monitor by means of piezoelectric transducer and recorded in mmHg. SPSS 18.0 package program was used for statistical analysis of data. RESULTS: Forty five patients were included in the study. The patients had the diagnosis of malignancy (35.6%), sepsis (13.3%), pneumonia, asthma, chronic obstructive pulmonary disease (11.1%). 11 patients (24.4%) required mechanical ventilation while 34 (75.6%) patients had spontaneous respiration. In patients with spontaneous respiration, a significant relationship was found between IVC diameters measured by ultrasonography at the end of expiratory and inspiratory phases and measured CVP values at the same phases (for expiratory p = 0.002, for inspiratory p= 0.001). There was no statistically significant association between IVC diameters measured by ultrasonography at the end of expiration and inspiration and measured CVP values at the same phases in mechanically ventilated patients. CONCLUSIONS: IVC diameter measured by bedside ultrasonography can be used for determination of the intravascular volume status of the patients with spontaneous respiration.

A drug repurposing study identifies novel FOXM1 inhibitors with in vitro activity against breast cancer cells.

FOXM1, a proto-oncogenic transcription factor, plays a critical role in cancer development and treatment resistance in cancers, particularly in breast cancer. Thus, this study aimed to identify potential FOXM1 inhibitors through computational screening of drug databases, followed by in vitro validation of their inhibitory activity against breast cancer cells. In silico studies involved pharmacophore modeling using the FOXM1 inhibitor, FDI-6, followed by virtual screening of DrugBank and Selleckchem databases. The selected drugs were prepared for molecular docking, and the crystal structure of FOXM1 was pre-processed for docking simulations. In vitro studies included MTT assays to assess cytotoxicity, and Western blot analysis to evaluate protein expression levels. Our study identified Pantoprazole and Rabeprazole as potential FOXM1 inhibitors through in silico screening and molecular docking. Molecular dynamics simulations confirmed stable interactions of these drugs with FOXM1. In vitro experiments showed both Pantoprazole and Rabeprazole exhibited strong FOXM1 inhibition at effective concentrations and that showed inhibition of cell proliferation. Rabeprazole showed the inhibitor activity at 10 µM in BT-20 and MCF-7 cell lines. Pantoprazole exhibited FOXM1 inhibition at 30 µM and in BT-20 cells and at 70 µM in MCF-7 cells, respectively. Our current study provides the first evidence that Rabeprazole and Pantoprazole can bind to FOXM1 and inhibit its activity and downstream signaling, including eEF2K and pEF2, in breast cancer cells. These findings indicate that rabeprazole and pantoprazole inhibit FOXM1 and breast cancer cell proliferation, and they can be used for FOXM1-targeted therapy in breast or other cancers driven by FOXM1.

Semantic Harmonization of Alzheimer's Disease Datasets Using AD-Mapper.

Background: Despite numerous past endeavors for the semantic harmonization of Alzheimer's disease (AD) cohort studies, an automatic tool has yet to be developed. Objective: As cohort studies form the basis of data-driven analysis, harmonizing them is crucial for cross-cohort analysis. We aimed to accelerate this task by constructing an automatic harmonization tool. Methods: We created a common data model (CDM) through cross-mapping data from 20 cohorts, three CDMs, and ontology terms, which was then used to fine-tune a BioBERT model. Finally, we evaluated the model using three previously unseen cohorts and compared its performance to a string-matching baseline model. Results: Here, we present our AD-Mapper interface for automatic harmonization of AD cohort studies, which outperformed a string-matching baseline on previously unseen cohort studies. We showcase our CDM comprising 1218 unique variables. Conclusion: AD-Mapper leverages semantic similarities in naming conventions across cohorts to improve mapping performance.

Effectiveness of therapeutic plasma exchange in patients with intermediate syndrome due to organophosphate intoxication.

OBJECTIVE: We aimed to determine effectiveness of therapeutic plasma exchange (TPE) in patients with intermediate syndrome (IMS) due to organophosphate (OP) intoxication. METHODS: Patients diagnosed with IMS due to OP intoxication were included in this prospective study. Therapeutic plasma exchange procedure was performed with fresh frozen plasma as a replacement fluid via Fresenius-AS-TEC 204 device by Therapeutic Apheresis Unit to patients who developed IMS during follow-up. Samples were taken from patient's blood and waste plasma collected in the device before and after TPE procedure to be studied in laboratory for detection of organic phosphate and pseudocholinesterase (PChE) levels. In this study, SPSS 18.0 software package was used for statistical analysis of the data obtained. Level of statistical significance was taken as P < .05 for all tests. RESULTS: Of all 17 patients, 4 (23.5%) were female, and 13 (76.5%) were male. A statistically significant decrease was detected in organic phosphate levels in the plasma of patients after TPE procedure (P = .012). A statistically significant increase was detected in PChE levels in the plasma of patients after TPE procedure (P = .014). Of 17 patients included in the study, 13 patients showed clinical improvement and were discharged after the TPE process. CONCLUSION: In our study, it was observed that a significant decrease in the level of blood plasma OP and a significant increase in the level of PChE were achieved with TPE process in the early period of IMS due to OP poisoning. This study indicates that TPE is one of the effective treatment options for IMS due to OP intoxication.

Synthesis of new imine-/amine-bearing imidazo[1,2-a]pyrimidine derivatives and screening of their cytotoxic activity.

Imidazo[1,2-a]pyrimidine derivatives bearing imine groups (3a-e) were successfully synthesized in moderate to good yields using microwave-assisted heating. Corresponding amine derivatives (4a-e) were also obtained by the reduction reaction of the imine derivatives (3a-e). All synthesized products were characterized by FT-IR, 1H NMR, 13C NMR, and LC-MS spectroscopic techniques. In silico ADMET, Lipinski, and drug-likeness studies of the compounds were conducted and all were found to be suitable drug candidates. The cytotoxicity of the potential drug molecules was screened against the breast cancer cell lines MCF-7 and MDA-MB-231 and the healthy model HUVEC by the sulforhodamine B method. According to the antiproliferative studies, compounds 3d and 4d showed remarkable inhibition of MCF-7 cells with IC50 values of 43.4 and 39.0 µM and of MDA-MB-231 cells with IC50 values of 35.9 and 35.1 µM, respectively. In particular, compound 3d selectively inhibited the proliferation of MCF-7 1.6-fold and MDA-MB-231 2.0-fold relative to healthy cells. Moreover, the apoptotic mechanism studies indicated that compound 4d induced apoptosis by moderately increasing the ratio of Bax/Bcl-2 genes. Imidazo[1,2-a]pyrimidine derivative 3d, a promising cytotoxic agent, may be helpful in the discovery of new and more efficient anticancer agents for breast cancer treatment.

A prospective study of wake-up stroke patients presenting to the emergency department: a single-center cohort study.

INTRODUCTION: This study aims to prospectively examine patients with ischemic wake-up stroke (WUS) presenting to the emergency department, to investigate the risk factors affecting the mortality occurring within 28, 90, and 180 days, and to create a new scoring system for the prediction of 28-day mortality. MATERIALS AND METHOD: Patients who presented to the emergency department with WUS findings between 01.07.2019 and 30.06.2020 were prospectively analyzed. Logistic regression analysis was performed to determine the factors affecting mortality and the modified Rankin scale (mRS). RESULTS: A total of 161 patients were included. Of the patients, 22.4% died within 28 days and 40.4% within 180 days. The presence of coronary artery disease (CAD) increased the 28-day mortality risk (p = 0.009) 3.57 times, 90-day mortality risk 2.15 times (p = 0.033), and 180-day mortality risk 2.18 times (p = 0.045). In order to be used in the prediction of 28-day mortality in patients with WUS, we developed the ischemic WUS mortality score (IWUSMOS), which consists of the middle cerebral artery (45 points), internal carotid artery (60 points), basilar artery (39 points), superior cerebellar artery (66 points) occlusion, hypertension (33 points), CAD (28 points), malignancy (100 points), and arrhythmia (23 points). With this scoring system, the 28-day mortality risk was determined as 0.05% when the total score was "43" whereas the mortality risk was found to be 95.0% when the total score was "187." CONCLUSION: We propose that IWUSMOS, a new scoring system, can be used to predict the 28-day mortality risk of patients with WUS.

Structure prediction of eukaryotic elongation factor-2 kinase and identification of the binding mechanisms of its inhibitors: homology modeling, molecular docking, and molecular dynamics simulation.

Protein kinases emerged as one of the most successful families of drug targets due to their increased activity and involvement in mediating critical signal transduction pathways in cancer cells. Recent evidence suggests that eukaryotic elongation factor 2 kinase (eEF-2K) is a potential therapeutic target for treating some highly aggressive solid cancers, including lung, pancreatic and triple-negative breast cancers. Thus, several compounds have been developed for the inhibition of the enzyme activity, but they are not sufficiently specific and potent. Besides, the crystal structure of this kinase remains unknown. Hence, the functional organization and regulation of eEF-2K remain poorly characterized. For this purpose, we constructed a homology model of eEF-2K and then used docking methodology to better understanding the binding mechanism of eEF-2K with 58 compounds that have been proposed as existing inhibitors. The results of this analysis were compared with the experimental results and the compounds effective against eEF-2K were determined against eEF-2K as a result of both studies. And finally, molecular dynamics (MD) simulations were performed for the stability of eEF-2K with these compounds. According to these study defined that the binding mechanism of eEF-2K with inhibitors at the molecular level and elucidated the residues of eEF-2K that play an important role in enzyme selectivity and ligand affinity. This information may lead to new selective and potential drug molecules to be for inhibition of eEF-2K.Communicated by Ramaswamy H. Sarma.