Design and synthesis of novel quinazoline-based EGFR kinase inhibitors and dual EGFR/NF-kappa B inhibitors as potential anti-cancer drugs with enhanced efficacy

The inhibition of signal transduction pathways, e.g. of EGFR kinase signaling, is a proven strategy in the treatment of cancers with several drugs clinically approved. Treatment with EGFR inhibitors suffers some limitations such as that certain cancers are originally insensitive or mutations emerge that cause drug resistance. The NF-κB pathway is also known to play a role in cell proliferation and survival and therefore, the inhibition of the NF-κB activation could be used in the treatment of cancer. Herein, a new class of quinazoline derivatives have been designed and synthesized to realize two strategies to overcome the above mentioned drawbacks. The first strategy included structural modifications which resulted in compounds that retain potency towards mutant EGFR. In addition, several compounds were identified to be more potent than Gefitinib towards cancer cell lines with wild-type and mutant EGFR. The second strategy involved the synthesis of compounds with dual inhibitory activity towards the EGFR and the NF-κB pathway. These compounds act as potent anticancer agents that are able to overcome the problem of cancers which are insensitive or resistant to the EGFR inhibitors. Several derivatives were obtained with enhanced potency towards both targets. The main structural requirements essential for activity for each target has been identified and the cellular mechanism of action was discovered for one of the potent compounds. The presented inhibitors open up new approaches to overcome the limitations associated with clinically approved EGFR inhibitors.Die Hemmung von Signaltransduktionswegen, z.B. der EGFR-Kinase-Signalweges, ist eine bewährte Strategie für die Krebstherapie und hat bereits einige klinisch zugelassene Medikamente hervorgebracht. Die Behandlung mit EGFR-Inhibitoren stößt oft an ihre Grenzen, so sprechen z.B. nicht alle Tumore an und einige werden aufgrund von Mutationen resistent. Der NF-kB-Signalweg spielt ebenfalls eine wichtige Rolle bei Zellproliferation und –überleben, so dass er ebenfalls ein vielversprechender Angriffspunkt bei Krebs sein könnte. In dieser Arbeit wurde eine neue Klasse von Chinazolinderivaten entworfen und synthetisiert, um zwei neue Strategien zur Überwindung der o.g. Nachteile umzusetzen. Die erste Strategie zielte auf die Einführung von Modifikationen ab, die auf eine Steigerung der Hemmaktivität gegenüber mutierter EGFR-Kinase abzielten. Dieses Ziel wurde erreicht, und zusätzlich wurde im Vergleich zu Gefitinib eine potentere Hemmung des Wachstums von Krebszellen mit Wildtyp- und mutierter EGFR-Kinase beobachtet. Die zweite Strategie beinhaltete die Synthese von Derivaten mit dualer Hemmwirkung sowohl auf den EGFR- als auch auf den NF-kB-Signalweg. Diese neuen Verbindungen versprechen eine gesteigerte Anti-Tumor-Wirkung und sind möglicherweise in der Lage, auch die gegen reine EGFR-Inhibitoren unempfindlichen oder resistenten Tumore zu bekämpfen. Einige Derivate mit verbesserter Wirksamkeit bei beiden Targets konnten entwickelt werden. Die wichtigsten strukturellen Voraussetzungen für die Aktivität bei jedem Target konnten identifiziert und der zelluläre Wirkmechanismus für eines der Derivate nachgewiesen werden. Die vorgestellten Inhibitoren könnten neue Wege zur Überwindung der eingeschränkten Wirksamkeit der bisherigen EGFR-Hemmstoffe aufzeigen

Design and synthesis of novel quinazoline-based EGFR kinase inhibitors and dual EGFR/NF-kappa B inhibitors as potential anti-cancer drugs with enhanced efficacy

The inhibition of signal transduction pathways, e.g. of EGFR kinase signaling, is a proven strategy in the treatment of cancers with several drugs clinically approved. Treatment with EGFR inhibitors suffers some limitations such as that certain cancers are originally insensitive or mutations emerge that cause drug resistance. The NF-κB pathway is also known to play a role in cell proliferation and survival and therefore, the inhibition of the NF-κB activation could be used in the treatment of cancer. Herein, a new class of quinazoline derivatives have been designed and synthesized to realize two strategies to overcome the above mentioned drawbacks. The first strategy included structural modifications which resulted in compounds that retain potency towards mutant EGFR. In addition, several compounds were identified to be more potent than Gefitinib towards cancer cell lines with wild-type and mutant EGFR. The second strategy involved the synthesis of compounds with dual inhibitory activity towards the EGFR and the NF-κB pathway. These compounds act as potent anticancer agents that are able to overcome the problem of cancers which are insensitive or resistant to the EGFR inhibitors. Several derivatives were obtained with enhanced potency towards both targets. The main structural requirements essential for activity for each target has been identified and the cellular mechanism of action was discovered for one of the potent compounds. The presented inhibitors open up new approaches to overcome the limitations associated with clinically approved EGFR inhibitors.Die Hemmung von Signaltransduktionswegen, z.B. der EGFR-Kinase-Signalweges, ist eine bewährte Strategie für die Krebstherapie und hat bereits einige klinisch zugelassene Medikamente hervorgebracht. Die Behandlung mit EGFR-Inhibitoren stößt oft an ihre Grenzen, so sprechen z.B. nicht alle Tumore an und einige werden aufgrund von Mutationen resistent. Der NF-kB-Signalweg spielt ebenfalls eine wichtige Rolle bei Zellproliferation und –überleben, so dass er ebenfalls ein vielversprechender Angriffspunkt bei Krebs sein könnte. In dieser Arbeit wurde eine neue Klasse von Chinazolinderivaten entworfen und synthetisiert, um zwei neue Strategien zur Überwindung der o.g. Nachteile umzusetzen. Die erste Strategie zielte auf die Einführung von Modifikationen ab, die auf eine Steigerung der Hemmaktivität gegenüber mutierter EGFR-Kinase abzielten. Dieses Ziel wurde erreicht, und zusätzlich wurde im Vergleich zu Gefitinib eine potentere Hemmung des Wachstums von Krebszellen mit Wildtyp- und mutierter EGFR-Kinase beobachtet. Die zweite Strategie beinhaltete die Synthese von Derivaten mit dualer Hemmwirkung sowohl auf den EGFR- als auch auf den NF-kB-Signalweg. Diese neuen Verbindungen versprechen eine gesteigerte Anti-Tumor-Wirkung und sind möglicherweise in der Lage, auch die gegen reine EGFR-Inhibitoren unempfindlichen oder resistenten Tumore zu bekämpfen. Einige Derivate mit verbesserter Wirksamkeit bei beiden Targets konnten entwickelt werden. Die wichtigsten strukturellen Voraussetzungen für die Aktivität bei jedem Target konnten identifiziert und der zelluläre Wirkmechanismus für eines der Derivate nachgewiesen werden. Die vorgestellten Inhibitoren könnten neue Wege zur Überwindung der eingeschränkten Wirksamkeit der bisherigen EGFR-Hemmstoffe aufzeigen

Frequency of hypoglycemia in Type 2 diabetic patients in sample of Egyptian people in clinic based study

Background: Hypoglycemia is a serious medical emergency that must be recognised and treated as soon as possible to avoid organ and brain damage. Hypoglycemia is not a sickness in and of itself; it is a symptom of a more serious health problem, the significance of which is determined by its impact on brain function. There is always a risk of a proportional increase in the incidence of hypoglycemia with a growing incidence of diabetes and various modalities of intense blood glucose management.Objective: We measured the frequency of hypoglycemic attacks in type 2 diabetic patients (T2DM) in clinic-based study and correlate the attacks of hypoglycemia with treatment regimens and duration of the diabetes mellitus (DM). Patients and Methods: Copies of pre-tested questionnaire were administered directly to 1000 patients with T2DM at the study site. This questionnaire was previously published as a part of the Workgroup of the American Diabetes Association and The Endocrine Society (ADA) on 2013. After translating it into public traditional Egyptian Arabic language. Results: Our main finding was that for people with T2DM the incidence of hypoglycemia was 36% (360 out of 1000 patients). 26.39% (95 out of 360 patients) were on oral hypoglycemic drugs compared to 71.94% (259 from 360 patients) on insulin. Hypoglycemia was 48.42% (46 out of 95 patients) in diabetic patients having diabetes for more than five years and on oral hypoglycemic drugs, compared to 76.83% (199 out of 259 patients) in diabetic patients on insulin. Conclusion: Hypoglycemia is common in T2DM (36%). It is a significant complication of diabetes therapy and although mild hypoglycemia causes unpleasant symptoms and disrupts patients' daily activities, severe hypoglycemia can result in coma, seizures, and death

On the Estimation of the Useful Lifespan of Lubrication Oil under Constrained Functioning Conditions an ANN / Fuzzy Logic Approach

Lubrication oil in automotives is a multi-billion-pound business but the non-optimization of its lifespan entails colossal harm to societies, global resources and the environment. Losses are caused by premature oil change or by machinery wearing due to deteriorated oil. The actual practice in the automotive field follows a predetermined routine-replacement policy that does not consider the wide spectrum of operating conditions. In this paper a decision support model is developed for the determination of the optimum life span of oil under specific working conditions. A data gathering scheme is set to capture the most relevant oils' characteristics from real samples over specific ranges of operation. The relationship between the causal factors and the resulting condition of oil is programmed in an ANN which is complemented with a fuzzy-logic approach in order to predict the optimum lifespan of oil under any set of causal factors. The approach is applied on a case study in Egypt; the model is tested, validated and is believed to fulfil its objectives satisfactorily

FLT3 receptor/CD135 expression by flow cytometry in acute myeloid leukemia: Relation to FLT3 gene mutations and mRNA transcripts

Background: Alterations of the FLT3 gene are the most frequent molecular aberrations seen at diagnosis of acute myeloid leukemia (AML). Two main types of FLT3 mutations have been the most commonly detected; internal tandem duplication (ITD) in the juxtamembrane domain and point mutation D835Y in the tyrosine kinase domain (TKD). Both classes of mutations result in constitutive activation of FLT3 receptor/CD135.Aim: To assess the frequency of FLT3 gene mutations (ITD and TKD D835Y) and the flow cytometric expression of FLT3 receptor/CD135 among AML patients to define the role for FLT3 receptor expression in predicting FLT3 gene mutational status and mRNA transcript level.Subjects and methods: Eighty AML patients at diagnosis and 20 control subjects were enrolled. FLT3 receptor/ CD135 expression, FLT3 gene mutations, and FLT3 transcript level were evaluated by flow cytometry, conventional polymerase chain reaction (PCR), and quantitative real-time reverse-transcription PCR, respectively. Fluorescence in situ hybridization was done to stratify patients into favorable, intermediate, and poor cytogenetic risk groups.Results: FLT3-ITD was detected in 22.5% AML patients, while none had FLT3-TKD D835Y mutation. A cutoff value of >17% was assigned to define FLT3 receptor/CD135+ cases. FLT3 receptor/CD135 and FLT3 transcripts were overexpressed in 100% AML patients; higher levels were found among AML-M5 subtype and poor cytogenetic group. AML patients harboring FLT3-ITD showed a trend for higher FLT3 receptor/CD135 expression and FLT3 transcript level than those with wild-type FLT3. FLT3 receptor/CD135 >49% was predictive for FLT3-ITD. A positive correlation was found between FLT3 receptor/CD135 expression and FLT3 transcript level.Conclusion: Evaluation of FLT3 receptor/CD135 expression by flow cytometry at diagnosis of AML could constitute a predictor for the FLT3-ITD mutational status and FLT3 transcript level.Keywords: Acute myeloid leukemia, CD135, FLT3 receptor, FLT3 mRNA, FLT3-ITD, FLT3-TK

Dacron Band versus de Vega Annuloplasty for Functional Tricuspid Regurgitation

Background: Typically Functional (secondary) tricuspid insufficiency is the most prevalent tricuspid valve disease on top of mitral diseases. Different repair techniques were introduced to deal with this problem. Objectives: The target of this study was to evaluate the repair of Tricuspid valves using a commonly used suture annuloplasty technique (DE VEGA) versus a patient-tailored synthetic band made of Dacron short-term results. Patients and methods: From January 2021 to October 2022, 40 patients with secondary tricuspid insufficiency participated in our prospective cohort single-center study. we equally split the patients into two different groups. A total of 20 patients were randomized to the flexible Dacron band group while the remaining 20 patients were allocated to the De-Vega annuloplasty technique group. Preoperative data, major intraoperative and immediate postoperative adverse events, and postoperative regurgitation were assessed. Results: studied groups’ properties regarding Demographic and Preoperative echo data were statistically comparable. The rate of acute postoperative morbidities and complications had no statistical significance. There was no significant difference in postoperative recurrence of tricuspid insufficiency Around (85%) of patients in the De-Vega group and (90 %) in the Band group did not have TR on discharge and after 6 months of follow-up. There was no statistical significance in the incidence of immediate post-operative complications. Conclusions: Tricuspid repair using a customized Dacron band is a reliable surgical technique for functional Tricuspid Regurgitation. Additional studies with a larger number of patients and a longer term of follow-up are needed to confirm our findings

The impact of adding fetal MRI to sonographically diagnosed intrauterine ventriculomegaly: a prospective cohort study

Objective: Intrauterine fetal ventriculomegaly (IVM) is one of the most commonly detected fetal anomalies. Prenatal diagnosis in IVM is considered a challenge with a significant impact on management. The current study aims to evaluate the added value of performing fetal MRI to sonographically diagnosed IVM. Methods: A prospective cohort study was conducted at a tertiary University Hospital in the period between January 2017 and March 2019. We included pregnant women with a single fetus sonographically diagnosed IVM (symmetrical or asymmetrical). First, a basic obstetric sonographic examination was done, followed by a detailed (2D/3D) fetal CNS anomaly scan for the detection of other associated anomalies. A fetal MRI brain scan was performed for all cases. Results: Sixty women were included in the study. Of the 60 fetuses with IVM, additional findings were seen on MRI in 14 cases (23%), and most of these findings were identified in fetuses with severe IVM (about 50%). No additional abnormalities were identified in fetuses of less than 24 weeks gestation. Callosal and septum pellucidum lesions (29%), along with posterior fossa abnormalities (28%) and cortical malformations (21%) accounted for the most common additional significant fetal MRI findings. Fetal MRI sensitivity, specificity, and positive and negative predictive values in correlation with those of prenatal ultrasound turned out to be notably higher, approaching nearly 100 %. Conclusions: Fetal MRI for sonographically diagnosed moderate or severe IVM is recommended to guide clinical management

TESTING AND ASSESSMENT OF SOME EGYPTIAN MARBLE TYPES

Marble is one of the most important materials in the field of interior design for houses and buildings. Marble is a natural material with aesthetic values that may vary from one type to another depending on its mineral compositions and its properties. In this research, the necessary tests were done for six types of Egyptian marble To compare the differences between geological, chemical, physicomechanical properties of the same marble type in the different areas and to quantify the different characteristics and uses of selected marble types. The tests were physical, mechanical (according to ASTM standards), chemical, as well as petrography analysis. South Sinai Teriesta marble samples had the highest values of major oxides, as SiO2 1.03%, MgO 0.638%, Al2O3 0.355%, Fe2O3 0.339%, and the lowest value of CaO 54.6%, compared with other studied marble types. Zaafarana marble samples had the lowest values of water absorption with average of 0.356% and the apparent porosity with average of 0.894%, the highest average values of: bulk density 2.729 gm/cm3, abrasion resistance 2.345, and compressive strength 100.29 MPa compared with other studied marble types. Elminya Selvia marble samples had the highest values of water absorption with average of 1.488% and the apparent porosity with average of 3.770%., the lowest average values of: bulk density with 2.468 gm/cm3, abrasion resistance 1.145, and compressive strength 41.37 MPa. Modulus of rupture ranged from 7.2 to 13.8 MPa, for dry and wet conditions and the flexural strength ranged from 6.4 to 12.25 MPa, for dry and wet conditions

Surgical Management of Split Depression Fracture of The Lateral Tibial Plateau

Background: Tibial plateau fractures are one of the commonest intra-articular fractures resulting from indirect coronal or direct axial compressive forces. Fractures of tibial plateau constitute 1% of all fractures and 8% of fractures in the elderly. Objective: In the present study, we aimed to prevent the development of osteoarthritis and to correlate the radiological findings with this type of tibial plateau fracture.Patients and methods: This study was an interventional study, where 18 patients were conducted with tibial plateau fracture Schatzker type 2 and were operated in the Department of Orthopedics, Faculty of Medicine, at Zagazig University Hospital. Results: Most of cases (55.6%) were operated upon 2 days after occurrence of fracture, followed by 27.8%, 16.6% were operated upon after 7 days and 10 days respectively. Seventeen (94.4%) cases were fixed by buttress plate while 1 case (5.6%) was fixed by proximal tibial plate and 16 cases (88.9%) needed bone graft. Significant improvement in time regard function score (knee society score) and radiological score (Rasmussen Assessment score) were found. No complication was found in 66.7% of studied group; 16.7% had infection, 11.1% had valgus deformity and only one case 5.6% had stiffness.Conclusion: It could be concluded that the surgical management of tibial plateau fractures is challenging and gives excellent anatomical reduction and rigid fixation to restore articular congruity, facilitate early knee motion by reducing post-traumatic osteoarthritis and thus achieving optimal knee function