N- and s-substituted Pyrazolopyrimidines: A promising new class of potent c-Src kinase inhibitors with prominent antitumor activity.

In this work, readily achievable synthetic pathways were utilized for construction of a library of N/S analogues based on the pyrazolopyrimidine scaffold with terminal alkyl or aryl fragments. Subsequently, we evaluated the anticancer effects of these novel analogs against the proliferation of various cancer cell lines, including breast, colon, and liver lines. The results were striking, most of the tested molecules exhibited strong and selective cytotoxic activity against the MDA-MB-231 cancer cell line; IC50 1.13 µM. Structure-activity relationship (SAR) analysis revealed that N-substituted derivatives generally enhanced the cytotoxic effect, particularly with aliphatic side chains that facilitated favorable target interactions. We also investigated apoptosis, DNA fragmentation, invasion assay, and anti-migration effects, and discussed their underlying molecular mechanisms for the most active compound 7c. We demonstrated that 7c N-propyl analogue could inhibit MDA-MB-231 TNBC cell proliferation by inducing apoptosis through the regulation of vital proteins, namely c-Src, p53, and Bax. In addition, our results also revealed the potential of these compounds against tumor metastasis by downregulating the invasion and migration modes. Moreover, the in vitro inhibitory effect of active analogs against c-Src kinase was studied and proved that might be the main cause of their antiproliferative effect. Overall, these compelling results point towards the therapeutic potential of these derivatives, particularly those with N-substitution as promising candidates for the treatment of TNBC type of breast cancer.

Development of Novel Class of Phenylpyrazolo[3,4-d]pyrimidine-Based Analogs with Potent Anticancer Activity and Multitarget Enzyme Inhibition Supported by Docking Studies.

Phenylpyrazolo[3,4-d]pyrimidine is considered a milestone scaffold known to possess various biological activities such as antiparasitic, antifungal, antimicrobial, and antiproliferative activities. In addition, the urgent need for selective and potent novel anticancer agents represents a major route in the drug discovery process. Herein, new aryl analogs were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines: MCF-7, HCT116, and HePG-2. Some of these compounds showed potent cytotoxicity, with variable degrees of potency and cell line selectivity in antiproliferative assays with low resistance. As the analogs carry the pyrazolopyrimidine scaffold, which looks structurally very similar to tyrosine and receptor kinase inhibitors, the potent compounds were evaluated for their inhibitory effects on three essential cancer targets: EGFRWT, EGFRT790M, VGFR2, and Top-II. The data obtained revealed that most of these compounds were potent, with variable degrees of target selectivity and dual EGFR/VGFR2 inhibitors at the IC50 value range, i.e., 0.3-24 µM. Among these, compound 5i was the most potent non-selective dual EGFR/VGFR2 inhibitor, with inhibitory concentrations of 0.3 and 7.60 µM, respectively. When 5i was tested in an MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibited cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Molecular docking studies were performed to explore the binding mode and mechanism of such compounds on protein targets and mapped with reference ligands. The results of our studies indicate that the newly discovered phenylpyrazolo[3,4-d]pyrimidine-based multitarget inhibitors have significant potential for anticancer treatment.

Risk of Drug Resistance and Repeated Infection with Klebsiella pneumoniae and Escherichia coli in Intensive Care Unit Cancer Patients.

BACKGROUND: Bacterial infection is a frequent complication in cancer and immunocompromised patients. The emergence of antibiotic resistance is a significant health problem and cancer patients are at risk of repeated infections with drug-resistant bacteria. OBJECTIVE: This investigation aimed to identify predictors of repeat infections of Escherichia coli and Klebsiella pneumoniae and drug resistance in cancer patients admitted to the intensive care unit (ICU) in Upper Egypt. METHODS: Blood, urine, sputum, pus, and mouth and nose swabs were collected from patients at the Pediatric Oncology and Medical Oncology ICUs during the period from February 2017 to May 2018. The samples were assessed by antibiotic susceptibility test and further evaluated by genetic testing for the temoniera (TEM) gene of ß-lactamase. Samples positive for K. pneumoniae and E. coli were included and isolates positive for other microorganisms were excluded. RESULTS: The study included 107 patients with malignant neoplasms and 136 samples. Repeated infection with K. pneumoniae and E. coli occurred in 31% and 22.45% of patients, respectively. Patients who stayed for a longer period in the ICU were more likely to have repeated infections (OR 1.25, 95%CI 1.10-1.44, p=0.001) after control of other confounding factors. The type of malignant neoplasm, whether it was a hematologic or solid tumor (OR 7.46, 95% CI 2.56-21.7, p=0.0002) and a longer prior stay in the ICU (OR 1.14, 95% CI 1.02-1.28, p=0.025) remained the independent predictors for the drug resistance in the last infection. The TEM type of ß-lactamase was encoded in 48.68% and 66.67% of K. pneumoniae and E. coli, respectively. CONCLUSION: Reinfection with K. pneumoniae and E. coli in patients with cancer can occur as the number of days in the hospital increases. Total prior days spent in the ICU by cancer patients were independently associated with both repeated infections and drug resistance. Samples from patients with hematologic neoplasms were associated with drug resistance.

Design, Synthesis, biological Evaluation, and molecular docking studies of novel Pyrazolo[3,4-d]Pyrimidine derivative scaffolds as potent EGFR inhibitors and cell apoptosis inducers.

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

Pharmacophore-linked pyrazolo[3,4-d]pyrimidines as EGFR-TK inhibitors: Synthesis, anticancer evaluation, pharmacokinetics, and in silico mechanistic studies.

Targeting the epidermal growth factor receptors (EGFRs) with small inhibitor molecules has been validated as a potential therapeutic strategy in cancer therapy. Pyrazolo[3,4-d]pyrimidine is a versatile scaffold that has been exploited for developing potential anticancer agents. On the basis of fragment-based drug discovery, considering the essential pharmacophoric features of potent EGFR tyrosine kinase (TK) inhibitors, herein, we report the design and synthesis of new hybrid molecules of the pyrazolo[3,4-d]pyrimidine scaffold linked with diverse pharmacophoric fragments with reported anticancer potential. These fragments include hydrazone, indoline-2-one, phthalimide, thiourea, oxadiazole, pyrazole, and dihydropyrazole. The synthesized molecules were evaluated for their anticancer activity against the human breast cancer cell line, MCF-7. The obtained results revealed comparable antitumor activity with that of the reference drugs doxorubicin and toceranib. Docking studies were performed along with EGFR-TK and ADMET profiling studies. The results of the docking studies showed the ability of the designed compounds to interact with key residues of the EGFR-TK through a number of covalent and noncovalent interactions. The obtained activity of compound 25 (IC50 = 2.89 µM) suggested that it may serve as a lead for further optimization and drug development.

Coupled metamaterial optical resonators for infrared emissivity spectrum modulation.

We study the absorptivity of coupled metamaterial resonators in the mid-infrared range. We consider resonators supporting either a bright mode or a dark mode, introducing an additional degree of freedom for spectral modulation relative to bright modes alone. In a dark-bright coupled resonator system, we demonstrate tunable spectral splitting by changing the separation between resonators. We show via coupled mode theory that resonator separation can be mapped to coupling constant. We further introduce a dark-dark coupled resonator system, which gives rise to an emissive bright mode only in the presence of inter-resonator coupling. The dark-dark system yields a broadband emissivity that decays to zero exponentially with resonator separation, providing a design method for strong thermal emissivity control.

Design, synthesis, and molecular docking studies of new [1,2,4]triazolo[4,3-a]quinoxaline derivatives as potential A2B receptor antagonists.

Many shreds of evidence have recently correlated A2B receptor antagonism with anticancer activity. Hence, the search for an efficient A2B antagonist may help in the development of a new chemotherapeutic agent. In this article, 23 new derivatives of [1,2,4]triazolo[4,3-a]quinoxaline were designed and synthesized and its structures were confirmed by different spectral data and elemental analyses. The results of cytotoxic evaluation of these compounds showed six promising active derivatives with IC50 values ranging from 1.9 to 6.4 µM on MDA-MB 231 cell line. Additionally, molecular docking for all synthesized compounds was performed to predict their binding affinity toward the homology model of A2B receptor as a proposed mode of their cytotoxic activity. Results of molecular docking were strongly correlated with those of the cytotoxic study. Finally, structure activity relationship analyses of the new compounds were explored.

Experimental demonstration of dynamic thermal regulation using vanadium dioxide thin films.

We present an experimental demonstration of passive, dynamic thermal regulation in a solid-state system with temperature-dependent thermal emissivity switching. We achieve this effect using a multilayered device, comprised of a vanadium dioxide (VO2) thin film on a silicon substrate with a gold back reflector. We experimentally characterize the optical properties of the VO2 film and use the results to optimize device design. Using a calibrated, transient calorimetry experiment we directly measure the temperature fluctuations arising from a time-varying heat load. Under laboratory conditions, we find that the device regulates temperature better than a constant emissivity sample. We use the experimental results to validate our thermal model, which can be used to predict device performance under the conditions of outer space. In this limit, thermal fluctuations are halved with reference to a constant-emissivity sample.

Age and Tumor Location Predict Survival in Nonmetastatic Osteosarcoma in Upper Egypt.

AIM: The aims of this study were to assess survival outcome of pediatric patients with localized osteosarcoma of the extremities in Upper Egypt, identify factors of prognostic significance for survival, and to determine factors predictive of surgical methods used in these patients, as well as developing a clinical model for risk prediction. PATIENTS AND METHODS: A retrospective analysis of data assembled from medical records of 30 pediatric patients with a histologically verified nonmetastatic osteosarcoma of the extremities treated at South Egypt Cancer Institute with a unified chemotherapy protocol between January 2001 and December 2015 was carried out. Prognostic factors were determined using univariable and multivariable methods. A model for surgical outcomes in these patients based on the baseline clinical factors, and the parameters predictive of their tumor response to chemotherapy, was developed. RESULTS: With a median follow-up of 63 months for the study population, the estimates for event-free survival and overall survival (OS) at 3 and 5 years were 69.5% and 79% and 65.2% and 65.3%, respectively. Age 16 years or above was independently associated with both worse metastasis-free survival (hazard ratio [HR]=6.05, 95% confidence interval [CI]: 1.43-25.6, P=0.015) and OS (HR=7.9, 95% CI: 1.71-36.2, P=0.008). In the multivariable analysis, a proximal location within the limb gained a statistical significance to be independently associated with worse OS (HR=2.4, 95% CI: 1.13-22.1, P=0.003). Poor response to chemotherapy was marginally associated with worse metastasis-free survival (HR=4.9, 95% CI: 1.02-23.8, P=0.047) only in the univariable analysis. The patients found to be more likely to undergo an amputation surgery (odds ratio=14.1, 95% CI: 1.34-149.4, P=0.028) were those in whom a tumor was poorly responding to chemotherapy. CONCLUSION: In Upper Egypt, despite the reasonable survival outcomes in nonmetastatic osteosarcoma, a relatively high limb amputation rate has been encountered. The development of a clinical prediction model for future planning of possible outcome improvement in these patients, however, is still feasible.

Design of VO2-coated silicon microspheres for thermally-regulating paint.

Recent work has proposed an approach to design materials that regulate their own temperature. The concept is based on a temperature-dependent thermal emitter that has minimal emissivity below a target temperature, and maximal emissivity above it. Here we propose a microparticle approach suitable for scaling to large areas. We use electromagnetic and thermal simulations to show that the designed particles provide a 13x reduction in temperature variation relative to an uncoated aluminum substrate.

Pediatric Osteosarcoma of Extremities: A 15-year Experience From a Tertiary Care Cancer Center in Upper Egypt.

AIM: To assess the outcome and determine predictors of survival in pediatric patients with osteosarcoma of the extremities treated with a unified chemotherapy protocol at a single institution over a 15-year period. MATERIALS AND METHODS: We performed a retrospective analysis of medical records of 48 pediatric patients with histologically verified osteosarcoma of the extremities diagnosed at South Egypt Cancer Institute and received treatment between January 2001 and December 2015. RESULTS: With a median follow-up of 61 months for the entire cohort, estimates of overall survival (OS) for 3- and 5-year were 50.9% and 42.1%, respectively. While the estimates of OS for 3- and 5-year in the nonmetastatic group were 79% and 65.2%, respectively. In the multivariable analysis, both metastatic disease at diagnosis and poor response to chemotherapy retained their statistical significance as independent predictors for event-free survival. Whereas for OS, a metastatic disease at diagnosis remained as the lone predictor of a dismal outcome, while a poor response to chemotherapy became marginally associated with an inferior outcome. CONCLUSIONS: In Upper Egypt, whereas slightly less than two thirds of children with localized osteosarcoma of extremities survives their disease, metastasis at presentation remains the key predictor of dismal survival outcomes.

Highly selective ultraviolet aluminum plasmonic filters on silicon.

We report the use of aluminum patterning to make highly selective UV bandpass filters. We design and fabricate a periodic array of nanoholes in Al thin film on a bare silicon substrate as an analog for potential integration with a Si photodetector. Arrays were designed to operate in the wavelength range of 200-400 nm. Our results show that we can obtain a single dominant peak filter with a linewidth of 30 nm at normal incidence, in contrast to similar structures on glass substrates, where multiple modes influence the UV spectrum. Varying the angle of incidence is shown to split the plasmonic mode and further decrease the linewidth of the maximum wavelength mode down to 10 nm. Our results therefore show high potential for applications in solid-state image sensors for astronomy and planetary studies.

Design, synthesis and anticancer evaluation of 1H-pyrazolo[3,4-d]pyrimidine derivatives as potent EGFRWT and EGFRT790M inhibitors and apoptosis inducers.

In our attempt to develop effective EGFR-TKIs, two series of 1H-pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesized. All the newly synthesized compounds were evaluated in vitro for their inhibitory activities against EGFRWT. Compounds 15b, 15j, and 18d potently inhibited EGFRWT at sub-micro molar IC50 values comparable to that of erlotinib. Moreover, thirteen compounds that showed promising IC50 values against EGFRWT were tested in vitro for their inhibitory activities against mutant EGFRT790M. Compounds 17d and 17f exhibited potent inhibitory activities towards EGFRT790M comparable to osimertinib. Compounds that showed promising IC50 values against EGFRWT were further tested for their anti-proliferative activities against three cancer cell lines bearing EGFRWT (MCF-7, HepG2, A549), and two cancer cell lines bearing EGFRT790M (H1975 and HCC827). Compounds 15g, 15j, 15n, 18d and 18e were the most potent anticancer agents against the EGFRWT containing cells, while compounds 15e, 17d and 17f showed promising anti-proliferative activities against EGFRT790M containing cells. Furthermore, the most active compound 18d was selected for further studies regarding to its effects on cell cycle progression and induction of apoptosis in the HepG2 cell line. The results indicated that this compound is good apoptotic agent and arrests G0/G1and G2/M phases of cell cycle. Finally, molecular docking studies were performed to investigate binding pattern of the synthesized compounds with the prospective targets, EGFRWT (PDB: 4HJO) and EGFRT790M (PDB: 3W2O).

Sequential and selective localized optical heating in water via on-chip dielectric nanopatterning.

We study the use of nanopatterned silicon membranes to obtain optically-induced heating in water. We show that by varying the detuning between an absorptive optical resonance of the patterned membrane and an illumination laser, both the magnitude and response time of the temperature rise can be controlled. This allows for either sequential or selective heating of different patterned areas on chip. We obtain a steady-state temperature of approximately 100 °C for a 805.5nm CW laser power density of 66 µW/µm2 and observe microbubble formation. The ability to spatially and temporally control temperature on the microscale should enable the study of heat-induced effects in a variety of chemical and biological lab-on-chip applications.

Protective role of propolis against reproductive toxicity of triphenyltin in male rabbits.

Triphenyltin (TPT) is known to cause endocrine disruption, reproductive toxicity and a decrease in testosterone production. It is involved in the production of reactive oxygen species. Propolis has been reported to be an important antioxidant. Therefore, the present study aimed to elucidate the possible protective effects of propolis in alleviating the toxicity of triphenyltin chloride (TPTCl) on reproductive performance, testosterone levels, lipid peroxidation and enzyme activities in seminal plasma of male New Zealand white rabbits. Animals were orally administered the doses of propolis, TPTCl and propolis plus TPTCl every day for 12weeks. Results showed that semen quality was deteriorated following treatment with TPTCl. Also, testosterone levels, body weight (BW), relative weights of testes (RWT) and epididymis (RWE) were decreased. Thiobarbituric acid-reactive substances and lactate dehydrogenase were increased, while glutathione S-transferase, transaminases and phosphatases were decreased in seminal plasma of rabbits treated with TPTCl compared to control. Propolis alone significantly increased testosterone levels, BW, RTW, REW, semen characteristics and seminal plasma enzymes, and decreased the levels of free radicals and lactate dehydrogenase. Furthermore, the presence of propolis with TPTCl alleviates its toxic effects. From the present study, it can be concluded propolis can be effective in the protection of TPTCl-induced reproductive toxicity.

Aluminium-induced deterioration in reproductive performance and seminal plasma biochemistry of male rabbits: protective role of ascorbic acid.

Aluminium (Al) has been proposed as an environmental factor that may contribute to some diseases, affect several enzymes and other biomolecules and induced free radical-mediated cytotoxicity. Also, Al induced reproductive toxicity and exerted a significant adverse effect on the steroidogenesis. The antioxidant ascorbic acid (AA) plays an important role in various physiological processes in the body including detoxification of different toxic materials. Therefore, the present investigation aimed to elucidate possible protective effects of AA in alleviating the toxicity of aluminium chloride (AlCl3) on reproductive performance, lipid peroxidation and enzyme activities in seminal plasma of male New Zealand white rabbits. Six rabbits per group were assigned to one of four treatment groups: 0 mg AA and 0 mg AlCl3 /kg body weight (BW) (control); 40 mg AA/kg BW; 34 mg AlCl3 /kg BW; 34 mg AlCl3 plus 40 mg AA/kg BW. Rabbits were orally administered their respective doses every other day for 16 weeks. Results obtained showed that AlCl3 significantly (P<0.05) decreased libido (by increasing the reaction time), ejaculate volume, sperm concentration, total sperm output, sperm motility (%), total motile sperm per ejaculate (TMS), packed sperm volume (PSV), total functional sperm fraction (TFSF), normal and live sperm and semen initial fructose. While initial hydrogen ion concentration (pH) and dead and abnormal sperm were increased (P<0.05). Live body weight (LBW), feed intake (FI) and relative weights of testes (RTW) and epididymis (REW) were significantly (P<0.05) decreased. Concentrations of thiobarbituric acid-reactive substances (TBARS) were significantly (P<0.05) increased in seminal plasma of rabbits treated with AlCl3 compared with control. While, activities of glutathione S-transferase (GST), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and acid phosphatase (AcP) were significantly (P<0.05) decreased. Ascorbic acid alone significantly increased LBW, FI, RTW, REW, semen characteristics and seminal plasma enzymes, and decreased the levels of free radicals. Also, the present study showed that ascorbic acid might be effective in the protection of aluminium-induced reproductive toxicity. It was suggested that AlCl3 exerted a significant adverse effect on reproductive performance of male rabbits. Furthermore, AA could be able to antagonize the toxic effects of AlCl3 and improved semen quality of male rabbit.