Melt-quenched porous organic cage glasses

The discrete molecular nature of porous organic cages (POCs) has allowed us to direct the formation of crystalline materials by crystal engineering. It has also been possible to create porous amorphous solids by deliberately disrupting the crystalline packing, either with chemical modification or by processing. More recently, organic cages were used to form isotropic porous liquids. However, the connection between solid and liquid states of POCs, and the glass state, are almost completely unexplored. Here, we investigate the melting and glass-forming behaviour of a range of organic cages, including both shapepersistent POCs formed by imine condensation, and reduced and synthetically post-modified amine POCs that are more flexible and lack shape-persistence. The organic cages exhibited melting and quenching of the resultant liquids provides molecular glasses. One of these molecular glasses exhibited improved gas uptake for both CO2 and CH4 compared to the starting amorphous cage. In addition, foaming of the liquid in one case resulted in a more stable and less soluble glass, which demonstrates the potential for an alternative approach to forming materials such as membranes without solution processing

Modular Type III Porous Liquids Based on Porous Organic Cage Microparticles

The dispersion of particulate porous solids in size-excluded liquids has emerged as a method to create Type III porous liquids, mostly using insoluble microporous materials such as metal–organic frameworks and zeolites. Here, the first examples of Type III porous liquids based on porous organic cages (POCs) are presented. By exploiting the solution processability of the POCs, racemic and quasiracemic cage microparticles are formed by chiral recognition. Dispersion of these porous microparticles in a range of size-excluded liquids, including oils and ionic liquids, forms stable POC-based Type III porous liquids. The flexible pairing between the solid POC particles and a carrier liquid allows the formation of a range of compositions, pore sizes, and other physicochemical properties to suit different applications and operating conditions. For example, it is shown that porous liquids with relatively low viscosities or high thermal stability can be produced. A 12.5 wt% Type III porous liquid comprising racemic POC microparticles and an ionic liquid, [BPy][NTf2], shows a CO2 working capacity (104.30 µmol gL−1) that is significantly higher than the neat ionic liquid (37.27 µmol gL−1) between 25 and 100 °C. This liquid is colloidally stable and can be recycled at least ten times without loss of CO2 capacity

Book Reviews

Professor Husband\u27s book deals with two problems, the date of the trial and crucifixion of Jesus, and the legal aspects of the proceedings against him. In both divisions of the subject his conclusions are novel and are supported by able argumentation

Opposing effects of inhibitors of Aurora-A and EGFR in autosomal-dominant polycystic kidney disease

© 2015 Nikonova, Deneka, Eckman, Kopp, Hensley, Egleston and Golemis. Aurora-A kinase (AURKA) overexpression in numerous tumors induces aneuploidy, in part because of cytokinetic defects. Alisertib and other small-molecule inhibitors targeting AURKA are effective in some patients as monotherapies or combination therapies. Epidermal growth factor receptor (EGFR) pro-proliferative signaling activity is commonly elevated in cancer, and the EGFR inhibitor erlotinib is commonly used as a standard of care agent for cancer. An erlotinib/alisertib combination therapy is currently under assessment in clinical trials, following pre-clinical studies that indicated synergy of these drugs in cancer. We were interested in further exploring the activity of this drug combination. Beyond well-established functions for AURKA in mitotic progression, additional non-mitotic AURKA functions include control of ciliary stability and calcium signaling. Interestingly, alisertib exacerbates the disease phenotype in mouse models for autosomal-dominant polycystic kidney disease (ADPKD), a common inherited syndrome induced by aberrant signaling from PKD1 and PKD2, cilia-localized proteins that have calcium channel activity. EGFR is also more active in ADPKD, making erlotinib also of potential interest in this disease setting. In this study, we have explored the interaction of alisertib and erlotinib in an ADPKD model. These experiments indicated erlotinib-restrained cystogenesis, opposing alisertib action. Erlotinib also interacted with alisertib to regulate proliferative signaling proteins, albeit in a complicated manner. Results suggest a nuanced role of AURKA signaling in different pathogenic conditions and inform the clinical use of AURKA inhibitors in cancer patients with comorbidities

Testing of a soft TED as a bycatch reduction device

A cooperative study was conducted with commercial fishermen in 1997 in which a soft Turtle Excluder Device was tested for its potential as a bycatch reduction device (BRD) for finfish and other marine fauna incidentally captured in commercial shrimp trawling operations. A pilot study conducted during spring 1997 indicated that a similar gear was successful in reducing bycatch while shrimp catches actually increased.This study further suggested that the inability of small fish to escape a BRD was because they were apparently incapable of maintaining swimming speeds that would allow them to find exits. We also found that the current BRD protocol is cumbersome and may dissuade fishermen and net designers from testing better BRDs. Specific problems and recommendations are provided

Trends in Radical Prostatectomy: Centralization, Robotics, and Access to Urologic Cancer Care

Robotic surgery has been widely adopted for radical prostatectomy. We hypothesize that this change is rapidly shifting procedures away from hospitals that do not offer robotics and consequently increasing patient travel

Correlations between capnographic waveforms and peak flow meter measurement in emergency department management of asthma

BACKGROUND The usual method for initial assessment of an acute asthma attack in the emergency room includes the use of peak flow measurement and clinical parameters. Both methods have their own disadvantages such as poor cooperation/effort from patients (peak flow meter) and lack of objective assessment (clinical parameters). We were looking into other methods for the initial asthma assessment, namely the use of capnography. The normal capnogram has an almost square wave pattern comprising phase 1, slope phase 2, plateau phase 3, phase 4 and angle alpha (between slopes 2 and 3). The changes in asthma include decrease in slope of phase 2, increase in slope 3 and opening of angle alpha. AIMS Our objective was to compare and assess the correlation between the changes in capnographic indices and peak flow measurement in non-intubated acute asthmatic patients attending the emergency room. METHODS We carried out a prospective study in a university hospital emergency department (ED). One hundred and twenty eight patients with acute asthma were monitored with peak flow measurements and then had a nasal cannula attached for microstream sampling of expired carbon dioxide. The capnographic waveform was recorded onto a PC card for indices analysis. The patients were treated according to departmental protocols. After treatment, when they were adjudged well for discharge, a second set of results was obtained for peak flow measurements and capnographic waveform recording. The pre-treatment and post-treatment results were then compared with paired samples t-test analysis. Simple and canonical correlations were performed to determine correlations between the assessment methods. A p value of below 0.05 was taken to be significant. RESULTS Peak flow measurements showed significant improvements post-treatment (p < 0.001). On the capnographic waveform, there was a significant difference in the slope of phase 3 (p < 0.001) and alpha angle (p < 0.001), but not in phase 2 slope (p = 0.35). Correlation studies done between the assessment methods and indices readings did not show strong correlations either between the measurements or the magnitude of change pre-treatment and post-treatment. CONCLUSION Peak flow measurements and capnographic waveform indices can indicate improvements in airway diameter in acute asthmatics in the ED. Even though the two assessment methods did not correlate statistically, capnographic waveform analysis presents several advantages in that it is effort independent and provides continuous monitoring of normal tidal respiration. They can be proposed for the monitoring of asthmatics in the ED

A novel HSP90 inhibitor-drug conjugate to SN38 is highly effective in small cell lung cancer

©2016 AACR.Purpose: Small cell lung cancer (SCLC) is a highly aggressive disease representing 12% to 13% of total lung cancers, with median survival of <2 years. No targeted therapies have proven effective in SCLC. Although most patients respond initially to cytotoxic chemotherapies, resistance rapidly emerges, response to second-line agents is limited, and dose-limiting toxicities (DLT) are a major issue. This study performs preclinical evaluation of a new compound, STA-8666, in SCLC. Experimental Design: To avoid DLT for useful cytotoxic agents, the recently developed drug STA-8666 combines a chemical moiety targeting active HSP90 (concentrated in tumors) fused via cleavable linker to SN38, the active metabolite of irinotecan. We compare potency and mechanism of action of STA-8666 and irinotecan in vitro and in vivo. Results: In two SCLC xenograft and patient-derived xenograft models, STA-8666 was tolerated without side effects up to 150 mg/kg. At this dose, STA-8666 controlled or eliminated established tumors whether used in a first-line setting or in tumors that had progressed following treatment on standard first- and second-line agents for SCLC. At 50 mg/kg, STA-8666 strongly enhanced the action of carboplatin. Pharmacokinetic profiling confirmed durable STA-8666 exposure in tumors compared with irinotecan. STA-8666 induced a more rapid, robust, and stable induction of cell-cycle arrest, expression of signaling proteins associated with DNA damage and cell-cycle checkpoints, and apoptosis in vitro and in vivo, in comparison with irinotecan. Conclusions: Together, these results strongly support clinical development of STA-8666 for use in the first- or second-line setting for SCLC

Systematic evaluation of underlying defects in DNA repair as an approach to case-only assessment of familial prostate cancer

Risk assessment for prostate cancer is challenging due to its genetic heterogeneity. In this study, our goal was to develop an operational framework to select and evaluate gene variants that may contribute to familial prostate cancer risk. Drawing on orthogonal sources, we developed a candidate list of genes relevant to prostate cancer, then analyzed germline exomes from 12 case-only prostate cancer patients from high-risk families to identify patterns of protein-damaging gene variants. We described an average of 5 potentially disruptive variants in each individual and annotated them in the context of public databases representing human variation. Novel damaging variants were found in several genes of relevance to prostate cancer. Almost all patients had variants associated with defects in DNA damage response. Many also had variants linked to androgen signaling. Treatment of primary T-lymphocytes from these prostate cancer patients versus controls with DNA damaging agents showed elevated levels of the DNA double strand break (DSB) marker ?H2AX (p < 0.05), supporting the idea of an underlying defect in DNA repair. This work suggests the value of focusing on underlying defects in DNA damage in familial prostate cancer risk assessment and demonstrates an operational framework for exome sequencing in case-only prostate cancer genetic evaluation