The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation

Although targeted therapies are often effective systemically, they fail to adequately control brain metastases. In preclinical models of breast cancer that faithfully recapitulate the disparate clinical responses in these microenvironments, we observed that brain metastases evade phosphatidylinositide 3-kinase (PI3K) inhibition despite drug accumulation in the brain lesions. In comparison to extracranial disease, we observed increased HER3 expression and phosphorylation in brain lesions. HER3 blockade overcame the resistance of HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases to PI3K inhibitors, resulting in marked tumor growth delay and improvement in mouse survival. These data provide a mechanistic basis for therapeutic resistance in the brain microenvironment and identify translatable treatment strategies for HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases

Performance Evaluation of Fuzzy and PI Controller for Boost Converter with Active PFC

In this paper, the problem of controlling AC-DC full bridge converter is considered. The control objectives are two, one is guaranteeing a regulated voltage for the connected load and second one is enforcing power factor correction (PFC) with input current sinusoidal. Power factor correction of Boost converter is done by using fuzzy control technique. The inner loop has a current error amplifier which improves the power factor by properly shaping the input current in accordance with its reference. This reference signal is always synchronized and proportional to the line voltage hence the input current comes in phase with the input voltage. Thus by improving the power factor maximum active power can be delivered to the load. The voltage loop is being controlled by the fuzzy controller and the multiplier. Voltage regulation is done by the fuzzy controller and input distortion is minimized by the fuzzy controller. The desired features of an active PFC technique are close to Unity Power Factor operation, less than 10 % total harmonic distortion in line current and simple control strategy. The fuzzy control technique gives better performance during different line voltage and load. The results are verified through MATLAB/Simulink.DOI: http://dx.doi.org/10.11591/ijpeds.v2i4.52

A Convenient Synthesis of Some Novel Hydroxy Pyrazolines under Thermal Condition and Their Antimicrobial Activity 1

Abstract: In the present communication, a series of 1-hydro-2-pyrazolines 2(a-f) and 1-acetyl-2-pyrazoline 3(a-f) derivatives have been prepared by the treatment of chalcones 1(a-f) with hydrazine hydrate in ethyl alcohol under reflux condition. The newly synthesized products were confirmed by the spectral analysis. Furthermore, these compounds were evaluated for their antimicrobial activity

Photochemical oxidation of antibiotic gemifloxacin in aqueous solutions â A comparative study

The amount of organic micro pollutants like antibiotics detected in effluents, lakes, rivers, hospital wastewater, sewage water and ground water. These antibiotics are affecting aquatic organisms. Common wastewater treatment plants are not built to remove these substances. Thus there is a need for new technologies. The present study focuses on the application of a promising technology, that is the use of advanced oxidation processes (AOPs), which works based on the intermediacy of hydroxyl and other radicals to oxidized non-biodegradable compounds. Hence, in the present study treatment of certain gemifloxacin commonly used in day-to-day life has been carried out. The combination of UV, UV/H2O2, Fenton, and UV/Fenton systems has been studied. Gemifloxacin concentration degradation, Chemical Oxygen Demand (COD) and Total Organic Carbon (TOC) are monitored. Among all the processes studied photo-Fenton process has been found to be the maximum removal of gemifloxacin (97%). Keywords: Antibiotics, Pharmaceuticals, Oxidation technologies, Non-biodegradable, Gemifloxaci

New (E)-1-alkyl-1H-benzo[d]imidazol-2-yl)methylene)indolin-2-ones: Synthesis, in vitro cytotoxicity evaluation and apoptosis inducing studies

A new series of (E)-benzo[d]imidazol-2-yl)methylene)indolin-2-one derivatives has been synthesized and evaluated for their in vitro cytotoxic activity against a panel of selected human cancer cell lines of prostate (PC-3 and DU-145) and breast (BT-549, MDA-MB-231, MCF-7, 4T1), non-small lung (A549) and gastric (HGC) cancer cells along with normal breast epithelial cells (MCF10A). Among the tested compounds, 81 showed significant cytotoxic activity against MDA-MB-231 and 4T1 cancer cells with IC50 values of 3.26 +/- 0.24 mu M and 5.96 +/- 0.67 mu M respectively. The compounds 8f, 8i, 8l and 8o were also screened on normal human breast epithelial cells (MCF10A) and found to be safer with lesser cytotoxicity. The treatment of MDA-MB-231 cells with 81 led to inhibition of cell migration ability through disruption of F-actin protein assembly. The flow-cytometry analysis reveals that the cells arrested in G0/G1 phase of the cell cycle. Further, the compound 81 induced apoptosis of MDA-MB-231 cells was characterized by different staining techniques such as Acridine Orange/Ethidium Bromide (AO/EB), DAPI, annexin V-FITC/PI, Rhodamine-123 and MitoSOX red assay. Western blot studies demonstrated that the compound 81 treatment led to activation of caspase-3, increased expression of cleaved PARP, increased expression of pro-apoptotic Bax and decreased expression of anti-apoptotic Bcl-2 in MDA-MB-231 cancer cells

Synthesis of bis-1,2,3-triazolo-bridged unsymmetrical pyrrolobenzodiazepine trimers via ‘click’ chemistry and their DNA-binding studies

New conceivable synthetic approach for the construction of nitrogen-rich 1,2,3-triazolo-pyrrolo[2,1-c][1,4]benzodiazepine (TPBD, 3a–c) trimers has been developed. The first example of a bis-1,2,3-triazolo-bridged unsymmetrical PBD trimer has been successfully synthesized by employing a CuAAC type ‘click’ chemistry protocol. This efficient route generates tri-imine functionality in a single molecule. It has been envisaged that such tri-imine functionalities could bring in efficient interaction with DNA in a sequence-selective manner in the minor groove of duplex DNA. One of the representative analogues 3c has shown improved DNA-binding ability (&#x0394;T<SUB>m</SUB>23.7 °C) by thermal denaturation studies using CT-DNA and this data is also supported by molecular modeling (MD) studies

Multicomponent One-Pot Synthesis of Substituted Hantzsch Thiazole Derivatives Under Solvent Free Conditions

Thiazole derivatives were prepared by one-pot procedure by the reaction of α-haloketones, thiourea and substituted o-hydroxybenzaldehyde under environmentally solvent free conditions

Circulating miR-106b-3p, miR-101-3p and miR-1246 as diagnostic biomarkers of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common liver cancer and second leading cause of cancer related death worldwide. Most HCCs occur in a damaged cirrhotic background and it may be difficult to discriminate between regenerative nodules and early HCCs. No dependable molecular biomarker exists for the early detection of HCC. MicroRNAs (miRNAs) have attracted attention as potential blood-based biomarkers. To identify circulating miRNAs with diagnostic potential in HCC, we performed preliminary RNAseq studies on plasma samples from a small set of HCC patients, cirrhotic patients and healthy controls. Then, out of the identified miRNAs, we investigated miR-101-3p, miR-106b-3p, miR-1246 and miR-411-5p in plasma of independent HCC patients' cohorts. The use of droplet digital PCR (ddPCR) confirmed the aberrant levels of these miRNAs. The diagnostic performances of each miRNA and their combinations were measured using Receiver Operating Characteristic (ROC) curve analyses: a classifier consisting of miR-101-3p, miR-1246 and miR-106b-3p produced the best diagnostic precision in plasma of HCC vs. cirrhotic patients (AUC = 0.99). A similar performance was found when the levels of miRNAs of HCC patients were compared to healthy controls (AUC = 1.00). We extended the analyses of the same miRNAs to serum samples. In serum of HCC vs. cirrhotic patients, the combination of miR-101-3p and miR-106b-3p exhibited the best diagnostic accuracy with an AUC = 0.96. Thus, circulating miR-101-3p, miR-106b-3p and miR-1246, either individually or in combination, exhibit a considerable potential value as diagnostic biomarkers of HCC. KEYWORDS: circulating microRNA; cirrhosis; diagnostic biomarkers; hepatocellular carcinom

Synthesis and in vitro cytotoxicity evaluation of β-carboline-combretastatin carboxamides as apoptosis inducing agents: DNA intercalation and topoisomerase-II inhibition

To explore a new set of cytotoxic agents, β-carboline-combretastatin carboxamide conjugates were designed, synthesized and evaluated for their in vitro cytotoxicity potential, DNA binding affinity and Topoisomerase-II (topo-II) inhibition activity. Among the designed hybrids, 10v and 10af have shown significant cytotoxic effect against A549 (lung cancer) cell line having IC50 value 1.01 µM and 1.17 µM respectively. Further, it was speculated that treatment with compound 10v may induce apoptosis among A549 cells, which was supported by Hoechst staining, DCFDA, Annexin V-FITC and morphological assays. Flow cytometric analysis revealed that the hybrid 10v arrests A549 cells in G2/M phase of cell cycle in a dose dependent manner. Amongst the active hybrids, most potent hybrid 10v was tested for DNA topo-II inhibition activity. Moreover, to further support the biological activity and to infer the mode of interaction between ligands and DNA, spectroscopy and molecular docking studies were carried out. The docking and spectroscopy results showed that the ligands exhibited an intercalative mode of binding with DNA and could efficiently bind to DNA and form topo-II ternary complex. Based on these experiments, the hybrids 10v and 10af were identified as proficient new scaffolds which need to be developed as hit molecules for therapeutic interest