Purine Nucleoside Phosphorylase mediated molecular chemotherapy and conventional chemotherapy: A tangible union against chemoresistant cancer

Background Late stage Ovarian Cancer is essentially incurable primarily due to late diagnosis and its inherent heterogeneity. Single agent treatments are inadequate and generally lead to severe side effects at therapeutic doses. It is crucial to develop clinically relevant novel combination regimens involving synergistic modalities that target a wider repertoire of cells and lead to lowered individual doses. Stemming from this premise, this is the first report of two- and three-way synergies between Adenovirus-mediated Purine Nucleoside Phosphorylase based gene directed enzyme prodrug therapy (PNP-GDEPT), docetaxel and/or carboplatin in multidrug-resistant ovarian cancer cells. Methods The effects of PNP-GDEPT on different cellular processes were determined using Shotgun Proteomics analyses. The in vitro cell growth inhibition in differentially treated drug resistant human ovarian cancer cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The involvement of apoptosis and implicated proteins in effects of different treatments was established using flow cytometry based detection of M30 (an early marker of apoptosis), cell cycle analyses and finally western blot based analyses. Results Efficacy of the trimodal treatment was significantly greater than that achieved with bimodal- or individual treatments with potential for 10-50 fold dose reduction compared to that required for individual treatments. Of note was the marked enhancement in apoptosis that specifically accompanied the combinations that included PNP-GDEPT and accordingly correlated with a shift in the expression of anti- and pro-apoptotic proteins. PNP-GDEPT mediated enhancement of apoptosis was reinforced by cell cycle analyses. Proteomic analyses of PNP-GDEPT treated cells indicated a dowregulation of proteins involved in oncogenesis or cancer drug resistance in treated cells with accompanying upregulation of apoptotic- and tumour- suppressor proteins. Conclusion Inclusion of PNP-GDEPT in regular chemotherapy regimens can lead to significant enhancement of the cancer cell susceptibility to the combined treatment. Overall, these data will underpin the development of regimens that can benefit patients with late stage ovarian cancer leading to significantly improved efficacy and increased quality of life

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Hybrid Dual Band High Gain Antenna

Abstract-This paper presents a hybrid high gain multi-resonance antenna. A rectangular split ring planar metamaterial antenna and rectangular slotted planar antenna are hybridized to achieve multiresonance and high gain. This work is based on a rectangular slotted antenna of three iterations. The single structure provides both the metamaterial and normal patch antenna performance. The hybrid structure provides a bandwidth of 210 MHz with metamaterial characteristics at 17.28 GHz and bandwidth of 430 MHz as slotted antenna at 21.90 GHz frequency. Antenna gain of 7dBi is achieved with overall dimensions of 40 mm×12 mm×0.787 mm. The simulated results are in good agreement with the experimental findings

Evaluation of chelating effect of chitosan as intracanal lubricant and an irrigant on smear layer removal – An in-vitro scanning electron microscope study

Aim: The aim of the study is to evaluate the chelating effect of chitosan as intracanal lubricant and an irrigant on smear layer removal. Objective: The objective of the study is to compare the effectiveness of smear layer removal with chitosan gel and ethylenediaminetetraacetic acid (EDTA) gel as an intracanal lubricant and to evaluate the cumulative outcome of chitosan gel and final rinse on smear layer removal compared to EDTA gel and solution. Materials and Methods: Forty single-rooted extracted human premolars were decoronated to a standard length. Cleaning and shaping were carried out using Mtwo rotary instrument and 3% sodium hypochlorite irrigant. Prepared specimens were divided into four equal groups (n = 10). In first two groups, 17% EDTA gel lubricant was used during instrumentation and final rinsing was carried out with 2 ml saline in one group and 2 ml 17% EDTA solution for 1 min in the other. In other two groups, 0.2% chitosan gel was used as lubricant, and final rinsing was carried out with 2 ml saline in one group and 2 ml 0.2% chitosan solution for 3 min in the other group. All the samples were then longitudinally sectioned which were then evaluated under scanning electron microscope for smear layer removal in three levels, i.e., cervical, middle, and apical third. Statistical Analysis Used: Comparison of mean smear layer scores in the coronal middle and apical thirds of the root canals between four study groups was done using Kruskal–Wallis test followed by Mann–Whitney Post hoc analysis for intergroup comparison with P < 0.05 as statistically significant. Results: In coronal, middle, and apical third sections of root canal, EDTA combination and chitosan combination groups demonstrated statistically significant smear layer removal compared to EDTA gel alone and chitosan gel alone groups. Among the gel groups, chitosan gel has shown a significant smear layer removal ability than EDTA gel. Conclusions: 0.2% chitosan gel lubricant and final rinse solution combination showed comparable smear layer removal as that of 17% EDTA gel lubricant and final rinse. While 0.2% chitosan gel lubricant with saline final rinse showed similar smear layer removal ability like 17% EDTA gel with saline final rinse in coronal and middle third, it performed better than EDTA gel in the crucial apical one-third of root canal

Sigmoid colon mucosal gene expression supports alterations of neuronal signaling in irritable bowel syndrome with constipation

Peripheral factors likely play a role in at least a subset of irritable bowel syndrome (IBS) patients. Few studies have investigated mucosal gene expression using an unbiased approach. Here, we performed mucosal gene profiling in a sex-balanced sample to identify relevant signaling pathways and gene networks and compare with publicly available profiling data from additional cohorts. Twenty Rome III+ IBS patients [10 IBS with constipation (IBS-C), 10 IBS with diarrhea (IBS-D), 5 men/women each), and 10 age-/sex-matched healthy controls (HCs)] underwent sigmoidoscopy with biopsy for gene microarray analysis, including differential expression, weighted gene coexpression network analysis (WGCNA), gene set enrichment analysis, and comparison with publicly available data. Expression levels of 67 genes were validated in an expanded cohort, including the above samples and 18 additional participants (6 each of IBS-C, IBS-D, HCs) using NanoString nCounter technology. There were 1,270 differentially expressed genes (FDR &lt; 0.05) in IBS-C vs. HCs but none in IBS or IBS-D vs. HCs. WGNCA analysis identified activation of the cAMP/protein kinase A signaling pathway. Nine of 67 genes were validated by the NanoString nCounter technology (FDR &lt; 0.05) in the expanded sample. Comparison with publicly available microarray data from the Mayo Clinic and University of Nottingham supports the reproducibility of 17 genes from the microarray analysis and three of nine genes validated by nCounter in IBS-C vs. HCs. This study supports the involvement of peripheral mechanisms in IBS-C, particularly pathways mediating neuronal signaling. NEW &amp; NOTEWORTHY Peripheral factors play a role in the pathophysiology of irritable bowel syndrome (IBS), which, to date, has been mostly evident in IBS with diarrhea. Here, we show that sigmoid colon mucosal gene expression profiles differentiate IBS with constipation from healthy controls. These profiling data and analysis of additional cohorts also support the concept that peripheral neuronal pathways contribute to IBS pathophysiology