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.

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.

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.

Novel etodolac derivatives as eukaryotic elongation factor 2 kinase (eEF2K) inhibitors for targeted cancer therapy.

Eukaryotic elongation factor 2 kinase (eEF2K) has been shown to be an important molecular driver of tumorigenesis and validated as a potential novel molecular target in various solid cancers including triple negative breast cancer (TNBC). Therefore, there has been significant interest in identifying novel inhibitors of eEF2K for the development of targeted therapeutics and clinical translation. Herein, we investigated the effects of indole ring containing derivatives of etodolac, a nonsteroidal anti-inflammatory (NSAID) drug, as potential eEF2K inhibitors and we designed and synthesized seven novel compounds with a pyrano[3,4-b] indole core structure. We evaluated the eEF2K inhibitory activity of seven of these novel compounds using in silico molecular modeling and in vitro studies in TNBC cell lines. We identified two novel compounds (EC1 and EC7) with significant in vitro activity in inhibiting eEF2K in TNBC cells. In conclusion, our studies indicate that pyrano[3,4-b] indole scaffold containing compounds demonstrate marked eEF2K inhibitory activity and they may be used as eEF2K inhibitors for the development of eEF2K-targeted therapeutics.

The effect of the shock index and scoring systems for predicting mortality among geriatric patients with upper gastrointestinal bleeding: a prospective cohort study

ABSTRACT BACKGROUND: Gastrointestinal (GI) bleeding is an important cause of mortality and morbidity among geriatric patients. OBJECTIVE: To investigate whether the shock index and other scoring systems are effective predictors of mortality and prognosis among geriatric patients presenting to the emergency department with complaints of upper GI bleeding. DESIGN AND SETTING: Prospective cohort study in an emergency department in Bursa, Turkey. METHODS: Patients over 65 years admitted to a single-center, tertiary emergency service between May 8, 2019, and April 30, 2020, and diagnosed with upper GI bleeding were analyzed. 30, 180 and 360-day mortality prediction performances of the shock index and the Rockall, Glasgow-Blatchford and AIMS-65 scores were evaluated. RESULTS: A total of 111 patients who met the criteria were included in the study. The shock index (P < 0.001) and AIMS-65 score (P < 0.05) of the patients who died within the 30-day period were found to be significantly different, while the shock index (P < 0.001), Rockall score (P < 0.001) and AIMS-65 score (P < 0.05) of patients who died within the 180-day and 360-day periods were statistically different. In the receiver operating characteristic (ROC) analysis for predicting 360-day mortality, the area under the curve (AUC) value was found to be 0.988 (95% confidence interval, CI, 0.971-1.000; P < 0.001). CONCLUSION: The shock index measured among geriatric patients with upper GI bleeding at admission seems to be a more effective predictor of prognosis than other scoring systems.

Effectiveness of the polyglycolic acid patch in preventing prolonged air leakage after pulmonary decortication.

AIM: This study aimed to investigate the effectiveness of an absorbable polyglycolic acid patch (PGA) in the early prevention of alveolar air leaks after pulmonary decortication operations. METHODS: Between January 2016 and December 2019, files of 185 patients with pleural effusion, empyema, or hemothorax were examined retrospectively. Thirty-five patients who underwent decortication surgery were included in the study. Two-way posteroanterior (PA) chest x-ray, computed tomography (CT), pulmonary function tests (PFT), arterial blood gas, hemogram, and biochemical tests were performed for all patients before the operation. The patients were divided into two groups. Group 1 was composed of 16 patients (45.7%) with standard decortication, and Group 2 was formed with 19 patients (54.3%) with standard decortication + PGA patch. RESULTS: The median age was 55 years (minimum = 25, maximum = 75) and the vast majority (82.9%; n = 29) of patients were males. There was no significant difference between groups in age, aetiology, or sex. The most common etiological cause in both Group 1 and Group 2 was nonspecific infection (56.3% and 73.7%, respectively). When Group 2 and Group 1 were compared regarding median times (day) of air leak cessation (Group 2 = 4; Group 1 = 8.5), chest drain removal (Group 2 = 5; Group 1 = 10), and hospital discharge times (Group 2 = 8; Group 1 = 13),the durations were statistically significantly shorter in Group 2 than in Group 1 (P < 0.001). CONCLUSION: Use of the PGA patch in pulmonary decortication operations significantly reduced the duration of air leaks, drain removal, and discharge time from the hospital in the postoperative period.

The effect of the shock index and scoring systems for predicting mortality among geriatric patients with upper gastrointestinal bleeding: a prospective cohort study.

BACKGROUND: Gastrointestinal (GI) bleeding is an important cause of mortality and morbidity among geriatric patients. OBJECTIVE: To investigate whether the shock index and other scoring systems are effective predictors of mortality and prognosis among geriatric patients presenting to the emergency department with complaints of upper GI bleeding. DESIGN AND SETTING: Prospective cohort study in an emergency department in Bursa, Turkey. METHODS: Patients over 65 years admitted to a single-center, tertiary emergency service between May 8, 2019, and April 30, 2020, and diagnosed with upper GI bleeding were analyzed. 30, 180 and 360-day mortality prediction performances of the shock index and the Rockall, Glasgow-Blatchford and AIMS-65 scores were evaluated. RESULTS: A total of 111 patients who met the criteria were included in the study. The shock index (P < 0.001) and AIMS-65 score (P < 0.05) of the patients who died within the 30-day period were found to be significantly different, while the shock index (P < 0.001), Rockall score (P < 0.001) and AIMS-65 score (P < 0.05) of patients who died within the 180-day and 360-day periods were statistically different. In the receiver operating characteristic (ROC) analysis for predicting 360-day mortality, the area under the curve (AUC) value was found to be 0.988 (95% confidence interval, CI, 0.971-1.000; P < 0.001). CONCLUSION: The shock index measured among geriatric patients with upper GI bleeding at admission seems to be a more effective predictor of prognosis than other scoring systems.

Identifying highly effective coumarin-based novel cholinesterase inhibitors by in silico and in vitro studies.

Inhibition of high cholinesterase levels including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), is one of the most important strategies for the treatment of Alzheimer's disease (AD). Clinically limited drugs are used in the treatment of AD, so there is a need to find new effective inhibitors today. Therefore, in this study, synthesized six coumarin carboxamides (A1, A2, B1-B4) were evaluated against AChE and BChE by combined in silico and in vitro studies. The in vitro assessment of studied compounds revealed that A1, A2, B3, and B4 showed highest inhibition potential against AChE and BChE. As demonstrated with our structure activity relationship (SAR) study, the promising inhibition result of AChE at nanomolar concentrations was obtained with heterocyclic amines including pyrrolidine and N-methyl piperazine moieties for tertiary amide substituted coumarin compounds B3 and B4, displaying KI values of 9.78 nM and 8.07 nM, respectively. Thus, compounds B3 and B4 had around 5.7- and 6.9-fold more potency compared to the reference molecule, neostigmine. Moreover, coumarin-3-carboxamide derivative A1 bearing benzylmorpholine moiety on coumarin scaffold at position 3 displayed stronger inhibition potential against BChE. Furthermore, in order to better understand their molecular mechanisms in these targets, we conducted molecular docking and MD simulations. Our promising preclinical results show that the lead compounds A1, A2, B3 and B4 have high potential as effective inhibitors for the treatment of AD.

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).

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.

Spontaneous pneumomediastinum incidence and clinical features in non-intubated patients with COVID-19.

OBJECTIVES: To evaluate the presentation characteristics and disease course of seven patients with COVID-19 who spontaneously developed pneumomediastinum without a history of mechanical ventilation. METHODS: A total of seven non-intubated patients with COVID-19, of age ranging from 18-67 years, who developed spontaneous pneumomediastinum between 01 April and 01 October 2020 were included in the study. Patients' demographic data, clinical variables, and laboratory values were examined. Spontaneous pneumomediastinum was evaluated using posteroanterior chest radiography and thorax computed tomography. RESULTS: During the research period, 38,492 patients reported to the emergency department of our hospital with COVID-19 symptoms. Of these, spontaneous pneumomediastinum was detected in seven patients who had no previous history of intubation. Chronic obstructive pulmonary disease (2/7) and asthma bronchiale (2/7) were determined as the most common causes of comorbidity. CONCLUSIONS: In our study, the frequency of spontaneous pneumomediastinum developing without pneumothorax was found to be high in non-intubated patients. Whether this is related to the nature of the disease or it is a result of the increase in cases diagnosed incidentally owing to the increasing use of low-dose computed tomography should be explored in further studies.

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.

New nimesulide derivatives with amide/sulfonamide moieties: Selective COX-2 inhibition and antitumor effects.

Seventeen new amide/sulfonamide containing nimesulide derivatives were synthesized and characterized by several spectroscopic techniques and primarily investigated for their inhibitory potential on COX enzymes and other pro-inflammatory factors. Experimental analyses showed that among seventeen compounds, N8 and N10 have remarkable potency and selectivity for the COX-2 enzyme over COX-1 at very low doses as compared to nimesulide. Moreover, both N8 and N10 selectively reduced the Lipopolysaccharide (LPS)-stimulated COX-2 mRNA expression level while the COX-1 level remained stable. Both PGE2 release and nitric oxide production in macrophage cells were significantly suppressed by the N8 and N10 treatment groups. In silico ADME/Tox, molecular docking and molecular dynamics (MD) simulations were also conducted. Additionally, all compounds were also screened in a panel of cancer cell lines for their antiproliferative properties by MTT and SRB assays. Compound N17 exhibited a considerable antiproliferative effect on the colon (IC50: 9.24 µM) and breast (IC50: 11.35 µM) cancer cell lines. N17 exposure for 48 h decreased expression of anti-apoptotic protein BCL-2 and increased the expression of apoptogenic BAX. Besides, the BAX/BCL-2 ratio was increased with visible ultrastructural changes and apoptotic bodies under scanning electron microscopy. In order to investigate the structural and dynamical properties of selected hits on the target structures, multiscale molecular modeling studies are also conducted. Our combined in silico and in vitro results suggest that N8 and N10 could be further developed as potential nonsteroidal anti-inflammatory drugs (NSAIDs), while cytotoxic N17 might be studied as a potential lead compound that could be developed as an anticancer agent.

Correction to "Target-Driven Design of a Coumarinyl Chalcone Scaffold Based Novel EF2 Kinase Inhibitor Suppresses Breast Cancer Growth In Vivo".

[This corrects the article DOI: 10.1021/acsptsci.1c00030.].

Target-Driven Design of a Coumarinyl Chalcone Scaffold Based Novel EF2 Kinase Inhibitor Suppresses Breast Cancer Growth In Vivo.

Eukaryotic elongation factor 2 kinase (eEF-2K) is an unusual alpha kinase involved in protein synthesis through phosphorylation of elongation factor 2 (EF2). eEF-2K is highly overexpressed in breast cancer, and its activity is associated with significantly shortened patient survival and proven to be a potential molecular target in breast cancer. The crystal structure of eEF-2K remains unknown, and there is no potent, safe, and effective inhibitor available for clinical applications. We designed and synthesized several generations of potential inhibitors. The effect of the inhibitors at the binding pocket of eEF-2K was analyzed after developing a 3D target model by using a domain of another α-kinase called myosin heavy-chain kinase A (MHCKA) that closely resembles eEF-2K. In silico studies showed that compounds with a coumarin-chalcone core have high predicted binding affinities for eEF-2K. Using in vitro studies in highly aggressive and invasive (MDA-MB-436, MDA-MB-231, and BT20) and noninvazive (MCF-7) breast cancer cells, we identified a lead compound that was highly effective in inhibiting eEF-2K activity at submicromolar concentrations and at inhibiting cell proliferation by induction of apoptosis with no toxicity in normal breast epithelial cells. In vivo systemic administration of the lead compound encapsulated in single lipid-based liposomal nanoparticles twice a week significantly suppressed growth of MDA-MB-231 tumors in orthotopic breast cancer models in nude mice with no observed toxicity. In conclusion, our study provides a highly potent and in vivo effective novel small-molecule eEF-2K inhibitor that may be used as a molecularly targeted therapy breast cancer or other eEF-2K-dependent tumors.

Spontaneous pneumomediastinum incidence and clinical features in non-intubated patients with COVID-19

OBJECTIVES: To evaluate the presentation characteristics and disease course of seven patients with COVID-19 who spontaneously developed pneumomediastinum without a history of mechanical ventilation. METHODS: A total of seven non-intubated patients with COVID-19, of age ranging from 18-67 years, who developed spontaneous pneumomediastinum between 01 April and 01 October 2020 were included in the study. Patients' demographic data, clinical variables, and laboratory values were examined. Spontaneous pneumomediastinum was evaluated using posteroanterior chest radiography and thorax computed tomography. RESULTS: During the research period, 38,492 patients reported to the emergency department of our hospital with COVID-19 symptoms. Of these, spontaneous pneumomediastinum was detected in seven patients who had no previous history of intubation. Chronic obstructive pulmonary disease (2/7) and asthma bronchiale (2/7) were determined as the most common causes of comorbidity. CONCLUSIONS: In our study, the frequency of spontaneous pneumomediastinum developing without pneumothorax was found to be high in non-intubated patients. Whether this is related to the nature of the disease or it is a result of the increase in cases diagnosed incidentally owing to the increasing use of low-dose computed tomography should be explored in further studies.

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.

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.

Successful Dialysis Treatment of Metformin Associated Lactic Acidosis, Report of Two Cases.

INTRODUCTION: Metformin-associated lactic acidosis is rare despite its widespread use. It is often associated with the use of metformin in the presence of chronic kidney disease, but it may also occur in people with normal renal function in the case of acute overdose. CASE REPORT: 20 years old (patient 1) and 37 years old (patient 2) women without any chronic disease took 40 gram (727 mg/ kg) and 60 gram (1200 mg/kg) metformin, respectively; for the suicidal attempt. Deep lactic acidosis was detected in patients. In patient 1, hemodialysis was performed for 4 hours. After the interruption, deep acidosis evolved again and another dialysis session was performed. In patient 2, hemodialysis was performed for 16 hours without any interruption and she did not need any other dialysis session. CONCLUSION: Metformin has a large distribution volume. It is not correct to make a final decision as to how long the dialysis will continue when dialysis begins. Dialysis should be continued without interruption until clinical and laboratory targets are achieved.

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.