Evaluation of in vitro and in vivo Cytotoxic Activities and Kinase Inhibition of Newly Synthesized Cyclo (Nα-Dinicotinoyl)-Bis-[(L-Valinyl)-L-Lysine Methyl Ester]

222-225Cancer is a major risk disease affecting human survival. The pharmaceutical companies are continuing searching for new drug candidates with promising anticancer activities, and reduced side effects. The current work aimed at synthesized a new tripeptide with potential pharmacological properties. L-Valine methyl ester was used to prepare cyclo (Nα-dinicotinoyl)-bis-[(L-valinyl)-L-lysine methyl ester. The new compound revealed promising in vitro cytotoxic activities against different neuroblastoma, cervical carcinoma, fibrosarcoma as well as hepatocellular carcinomas. Furthermore, we also found that the obtained IC50 of the compound decreased by about 50% during its in vivo anti-prostate cancer evaluation. Furthermore, the mechanism of action studies proposes that the new prepared derivative affects cancer cells trough the inhibition of VEGFR-2 kinase enzyme

Design and implementation of 2.6 GHz Phase shift using microstrip technology for mobile broadband application

This paper evolves transmission line phase shifting to optimize system cost. The design of a 1 x 2 microstrip (patch) array antenna which has an operating frequency of 2.6 GHz. Substrate FR4 dielectric with dielectric constant of 4.4 and thickness of 1.6 mm is utilized in array design. The study is performed in four steps: Firstly, through simulating radiation pattern on CST by altering two independent parameters; Spacing between patches and differential length of transmission line from source to each patch antenna. Secondly, a fabrication has been done on a sample deferential length to two ports that simulating two microstrip (patch) antennas array. Thirdly, testing of radiation fields has been performed to verify the correlation between actual records and the simulated designed antenna phase shifting. Fourth and finally, A comparison of results has been included between this paper results and previous works in sake of showing the introduced effort added value

Acacia senegal gum exudate offers protection against cyclophosphamide-induced urinary bladder cytotoxicity

Cylophosphamide (CYCL) is a strong anticancer and immunosuppressive agent but its urotoxicity presents one of the major toxic effects that limit its wide usage particularly in high dose regimens. Therefore, this study aimed to investigate Acacia Senegal gum exudate, Gum Arabic (GA), for its possible role as a natural, nontoxic agent against CYCL-induced urotoxicity. Male Swiss albino rats were exposed to CYCL (150 mg/kg BW, once i.p) with or without GA oral supplementation (7.5 g/kg/day for 6 days) through drinking water. Glutathione (GSH), Malondialdehyde (MDA) and Nitric oxide (NO) bladder contents were assessed. Responsiveness of the bladder rings to acetylcholine (ACh) in vitro, microscopic and macroscopic features are also investigated. CYCL produced pronounced harmful effects on bladder urothelial lining with significant increases in (MDA) and NO levels in the tissue homogenates. Bladder-GSH content is dropped by over 60% following CYCL injection. Bladder contractility, as measured by its responsiveness to ACh, recorded a marked reduction. The isolated bladders exhibited such macroscopic changes as severe edema, inflammation and extravasation. The bladder weight increased as well. Histological changes were evident in the form of severe congestion, petechial hemorrhage and chronic inflammatory reaction in the lamina propria accompanied with desquamated epithelia. GA, a potential protective agent, produced an almost complete reversal of NO induction, lipid peroxidation or cellular GSH bladder contents in the GA + CYCL-treated group. Likewise, bladder inflammation and edema were reduced. Bladder rings showed a remarkable recovery in their responsiveness to ACh. Bladder histological examination showed a near normal configuration and structural integrity, with a significant reduction in inflammation and disappearance of focal erosions. These remarkable effects of GA may be attributed to its ability to neutralize acrolein, the reactive metabolite of CYCL and/or the resultant reactive oxygen metabolites, through a scavenging action. GA may limit the cascading events of CYCL-induced damage, initiating a cytoprotective effect leading to structural and functional recovery of the bladder tissues

Evaluation of in vitro and in vivo Cytotoxic Activities and Kinase Inhibition of Newly Synthesized Cyclo (Nα-Dinicotinoyl)-Bis-[(L-Valinyl)-L-Lysine Methyl Ester]

Cancer is a major risk disease affecting human survival. The pharmaceutical companies are continuing searching for new drug candidates with promising anticancer activities, and reduced side effects. The current work aimed at synthesized a new tripeptide with potential pharmacological properties. L-Valine methyl ester was used to prepare cyclo (Nα-dinicotinoyl)-bis-[(L-valinyl)-L-lysine methyl ester. The new compound revealed promising in vitro cytotoxic activities against different neuroblastoma, cervical carcinoma, fibrosarcoma as well as hepatocellular carcinomas. Furthermore, we also found that the obtained IC50 of the compound decreased by about 50% during its in vivo anti-prostate cancer evaluation. Furthermore, the mechanism of action studies proposes that the new prepared derivative affects cancer cells trough the inhibition of VEGFR-2 kinase enzyme

Development, validation, and proof-of-concept implementation of a two-year risk prediction model for undiagnosed atrial fibrillation using common electronic health data (UNAFIED)

Background: Many patients with atrial fibrillation (AF) remain undiagnosed despite availability of interventions to reduce stroke risk. Predictive models to date are limited by data requirements and theoretical usage. We aimed to develop a model for predicting the 2-year probability of AF diagnosis and implement it as proof-of-concept (POC) in a production electronic health record (EHR). Methods: We used a nested case-control design using data from the Indiana Network for Patient Care. The development cohort came from 2016 to 2017 (outcome period) and 2014 to 2015 (baseline). A separate validation cohort used outcome and baseline periods shifted 2 years before respective development cohort times. Machine learning approaches were used to build predictive model. Patients ≥ 18 years, later restricted to age ≥ 40 years, with at least two encounters and no AF during baseline, were included. In the 6-week EHR prospective pilot, the model was silently implemented in the production system at a large safety-net urban hospital. Three new and two previous logistic regression models were evaluated using receiver-operating characteristics. Number, characteristics, and CHA2DS2-VASc scores of patients identified by the model in the pilot are presented. Results: After restricting age to ≥ 40 years, 31,474 AF cases (mean age, 71.5 years; female 49%) and 22,078 controls (mean age, 59.5 years; female 61%) comprised the development cohort. A 10-variable model using age, acute heart disease, albumin, body mass index, chronic obstructive pulmonary disease, gender, heart failure, insurance, kidney disease, and shock yielded the best performance (C-statistic, 0.80 [95% CI 0.79-0.80]). The model performed well in the validation cohort (C-statistic, 0.81 [95% CI 0.8-0.81]). In the EHR pilot, 7916/22,272 (35.5%; mean age, 66 years; female 50%) were identified as higher risk for AF; 5582 (70%) had CHA2DS2-VASc score ≥ 2. Conclusions: Using variables commonly available in the EHR, we created a predictive model to identify 2-year risk of developing AF in those previously without diagnosed AF. Successful POC implementation of the model in an EHR provided a practical strategy to identify patients who may benefit from interventions to reduce their stroke risk

Graphene‐Assisted Synthesis of 2D Polyglycerols as Innovative Platforms for Multivalent Virus Interactions

2D nanomaterials have garnered widespread attention in biomedicine and bioengineering due to their unique physicochemical properties. However, poor functionality, low solubility, intrinsic toxicity, and nonspecific interactions at biointerfaces have hampered their application in vivo. Here, biocompatible polyglycerol units are crosslinked in two dimensions using a graphene-assisted strategy leading to highly functional and water-soluble polyglycerols nanosheets with 263 ± 53 nm and 2.7 ± 0.2 nm average lateral size and thickness, respectively. A single-layer hyperbranched polyglycerol containing azide functional groups is covalently conjugated to the surface of a functional graphene template through pH-sensitive linkers. Then, lateral crosslinking of polyglycerol units is carried out by loading tripropargylamine on the surface of graphene followed by lifting off this reagent for an on-face click reaction. Subsequently, the polyglycerol nanosheets are detached from the surface of graphene by slight acidification and centrifugation and is sulfated to mimic heparin sulfate proteoglycans. To highlight the impact of the two-dimensionality of the synthesized polyglycerol sulfate nanosheets at nanobiointerfaces, their efficiency with respect to herpes simplex virus type 1 and severe acute respiratory syndrome corona virus 2 inhibition is compared to their 3D nanogel analogs. Four times stronger in virus inhibition suggests that 2D polyglycerols are superior to their current 3D counterparts.Peer Reviewe

The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer

PURPOSE: To investigate SGI-110 as a "chemosensitizer" in ovarian cancer and to assess its effects on tumor suppressor genes (TSG) and chemoresponsiveness-associated genes silenced by DNA methylation in ovarian cancer. EXPERIMENTAL DESIGN: Several ovarian cancer cell lines were used for in vitro and in vivo platinum resensitization studies. Changes in DNA methylation and expression levels of TSG and other cancer-related genes in response to SGI-110 were measured by pyrosequencing and RT-PCR. RESULTS: We demonstrate in vitro that SGI-110 resensitized a range of platinum-resistant ovarian cancer cells to cisplatin (CDDP) and induced significant demethylation and reexpression of TSG, differentiation-associated genes, and putative drivers of ovarian cancer cisplatin resistance. In vivo, SGI-110 alone or in combination with CDDP was well tolerated and induced antitumor effects in ovarian cancer xenografts. Pyrosequencing analyses confirmed that SGI-110 caused both global (LINE1) and gene-specific hypomethylation in vivo, including TSGs (RASSF1A), proposed drivers of ovarian cancer cisplatin resistance (MLH1 and ZIC1), differentiation-associated genes (HOXA10 and HOXA11), and transcription factors (STAT5B). Furthermore, DNA damage induced by CDDP in ovarian cancer cells was increased by SGI-110, as measured by inductively coupled plasma-mass spectrometry analysis of DNA adduct formation and repair of cisplatin-induced DNA damage. CONCLUSIONS: These results strongly support further investigation of hypomethylating strategies in platinum-resistant ovarian cancer. Specifically, SGI-110 in combination with conventional and/or targeted therapeutics warrants further development in this setting

A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer.

PURPOSE: Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer. PATIENTS AND METHODS: Patients received either G+C (guadecitabine 30 mg/m2 s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS). RESULTS: Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G+C and TC groups, respectively; P = 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group; P = 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group. CONCLUSIONS: Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection