Mitomycin C versus 5-Fluorouracil for wound healing in glaucoma surgery.

BACKGROUND: Raised intraocular pressure is a risk factor for glaucoma. One treatment option is glaucoma drainage surgery (trabeculectomy). Antimetabolites are used during surgery to reduce postoperative scarring during wound healing. Two agents in common use are mitomycin C (MMC) and 5-Fluorouracil (5-FU). OBJECTIVES: To assess the effects of MMC compared to 5-FU as an antimetabolite adjunct in trabeculectomy surgery. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015 Issue 9), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to October 2015), EMBASE (January 1980 to October 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to October 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 2 October 2015. SELECTION CRITERIA: We included randomised controlled trials where wound healing had been modified with MMC compared to 5-FU. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and collected data. The primary outcome was failure of a functioning trabeculectomy one year after surgery. Secondary outcomes included mean intraocular pressure at one year. We considered three subgroups: high risk of trabeculectomy failure (people with previous glaucoma surgery, extracapsular cataract surgery, African origin and people with secondary glaucoma or congenital glaucoma); medium risk of trabeculectomy failure (people undergoing trabeculectomy with extracapsular cataract surgery) and low risk of trabeculectomy failure (people who have received no previous surgical eye intervention). MAIN RESULTS: We identified 11 trials that enrolled 687 eyes of 679 participants. The studies were conducted in the United States, Europe, Asia and Africa. Five studies enrolled participants at low risk of trabeculectomy failure, five studies enrolled participants at high risk of failure, and one study enrolled people with both high and low risk of failure. None of the included trials enrolled participants with combined trabeculectomy/cataract surgery.We considered one study to be at low risk of bias in all domains, six studies to be at high risk of bias in one or more domains, and the remaining four studies to be at an unclear risk of bias in all domains.The risk of failure of trabeculectomy at one year after surgery was less in those participants who received MMC compared to those who received 5-FU, however the confidence intervals were wide and are compatible with no effect (risk ratio (RR) 0.54, 95% confidence interval (CI) 0.30 to 1.00; studies = 11; I(2) = 40%). There was no evidence for any difference between groups at high and low risk of failure (test for subgroup differences P = 0.69).On average, people treated with MMC had lower intraocular pressure at one year (mean difference (MD) -3.05 mmHg, 95% CI -4.60 to -1.50), but the studies were inconsistent (I(2) = 52%). The size of the effect was greater in the high-risk group (MD -4.18 mmHg, 95% CI -6.73 to -1.64) compared to the low-risk group (MD -1.72 mmHg, 95% CI -3.28 to -0.16), but again the test for interaction was not statistically significant (P = 0.11).Similar proportions of eyes treated with MMC lost 2 or more lines of visual acuity one year after surgery compared to 5-FU, but the confidence intervals were wide (RR 1.05, 95% CI 0.54 to 2.06).Adverse events occurred relatively rarely, and estimates of effect were generally imprecise. There was some evidence for less epitheliopathy in the MMC group (RR 0.23, 95% CI 0.11 to 0.47) and less hyphaema in the MMC group (RR 0.62, 95% CI 0.42 to 0.91).None of the studies reported quality of life.Overall, we graded the quality of the evidence as low largely because of risk of bias in the included studies and imprecision in the estimate of effect. AUTHORS' CONCLUSIONS: We found low-quality evidence that MMC may be more effective in achieving long-term lower intraocular pressure than 5-FU. Further comparative research on MMC and 5-FU is needed to enhance reliability and validity of the results shown in this review. Furthermore, the development of new agents that control postoperative scar tissue formation without side effects would be valuable and is justified by the results of this review

A Genome-scale CRISPR Screen Identifies the ERBB and mTOR Signaling Networks as Key Determinants of Response to PI3K Inhibition in Pancreatic Cancer.

KRAS mutation is a key driver of pancreatic cancer and PI3K pathway activity is an additional requirement for Kras-induced tumorigenesis. Clinical trials of PI3K pathway inhibitors in pancreatic cancer have shown limited responses. Understanding the molecular basis for this lack of efficacy may direct future treatment strategies with emerging PI3K inhibitors. We sought new therapeutic approaches that synergize with PI3K inhibitors through pooled CRISPR modifier genetic screening and a drug combination screen. ERBB family receptor tyrosine kinase signaling and mTOR signaling were key modifiers of sensitivity to alpelisib and pictilisib. Inhibition of the ERBB family or mTOR was synergistic with PI3K inhibition in spheroid, stromal cocultures. Near-complete loss of ribosomal S6 phosphorylation was associated with synergy. Genetic alterations in the ERBB-PI3K signaling axis were associated with decreased survival of patients with pancreatic cancer. Suppression of the PI3K/mTOR axis is potentiated by dual PI3K and ERBB family or mTOR inhibition. Surprisingly, despite the presence of oncogenic KRAS, thought to bestow independence from receptor tyrosine kinase signaling, inhibition of the ERBB family blocks downstream pathway activation and synergizes with PI3K inhibitors. Further exploration of these therapeutic combinations is warranted for the treatment of pancreatic cancer

All clinically-relevant blood components transmit prion disease following a single blood transfusion: a sheep model of vCJD

Variant CJD (vCJD) is an incurable, infectious human disease, likely arising from the consumption of BSE-contaminated meat products. Whilst the epidemic appears to be waning, there is much concern that vCJD infection may be perpetuated in humans by the transfusion of contaminated blood products. Since 2004, several cases of transfusion-associated vCJD transmission have been reported and linked to blood collected from pre-clinically affected donors. Using an animal model in which the disease manifested resembles that of humans affected with vCJD, we examined which blood components used in human medicine are likely to pose the greatest risk of transmitting vCJD via transfusion. We collected two full units of blood from BSE-infected donor animals during the pre-clinical phase of infection. Using methods employed by transfusion services we prepared red cell concentrates, plasma and platelets units (including leucoreduced equivalents). Following transfusion, we showed that all components contain sufficient levels of infectivity to cause disease following only a single transfusion and also that leucoreduction did not prevent disease transmission. These data suggest that all blood components are vectors for prion disease transmission, and highlight the importance of multiple control measures to minimise the risk of human to human transmission of vCJD by blood transfusion

Validation and Use of 22Na Turnover to Measure Food Intake in Free-Ranging Lizards

As the food intake of free-ranging animals has proved to be difficult to measure by traditional means, the feasibility of using radioactive Na to measure food consumption in a small scincid lizard (Lampropholis guichenoti) was assessed. This technique has previously been used only for several species of mammal. A significant relationship between food intake and Na turnover was found in the laboratory, with Na turnover underestimating intake by 7.6%. The food intake of free-ranging members of a field population was estimated by 22Na turnover to be 9.55, 0.65, 9.39 and 13.75 mg dry weight (day)-1 during autumn, winter, spring and summer respectively. Estimates of assimilated and expended energy from these food intake values agree closely with data reported for other lizards using alternative techniques. This study also describes the technical innovations which were necessary to study lizards weighing less than 1 g; and it suggests that 22Na can provide an easy, reliable and inexpensive means of studying the energetics of many free-living animals

Co-Inhibition of BCL-W and BCL2 Restores Antiestrogen Sensitivity through BECN1 and Promotes an Autophagy-Associated Necrosis

BCL2 family members affect cell fate decisions in breast cancer but the role of BCL-W (BCL2L2) is unknown. We now show the integrated roles of the antiapoptotic BCL-W and BCL2 in affecting responsiveness to the antiestrogen ICI 182,780 (ICI; Fulvestrant Faslodex), using both molecular (siRNA; shRNA) and pharmacologic (YC137) approaches in three breast cancer variants; MCF-7/LCC1 (ICI sensitive), MCF-7/LCC9 (ICI resistant), and LY2 (ICI resistant). YC137 inhibits BCL-W and BCL2 and restores ICI sensitivity in resistant cells. Co-inhibition of BCL-W and BCL2 is both necessary and sufficient to restore sensitivity to ICI, and explains mechanistically the action of YC137. These data implicate functional cooperation and/or redundancy in signaling between BCL-W and BCL2, and suggest that broad BCL2 family member inhibitors will have greater therapeutic value than targeting only individual proteins. Whereas ICI sensitive MCF-7/LCC1 cells undergo increased apoptosis in response to ICI following BCL-W±BCL2 co-inhibition, the consequent resensitization of resistant MCF-7/LCC9 and LY2 cells reflects increases in autophagy (LC3 cleavage; p62/SQSTM1 expression) and necrosis but not apoptosis or cell cycle arrest. Thus, de novo sensitive cells and resensitized resistant cells die through different mechanisms. Following BCL-W+BCL2 co-inhibition, suppression of functional autophagy by 3-methyladenine or BECN1 shRNA reduces ICI-induced necrosis but restores the ability of resistant cells to die through apoptosis. These data demonstrate the plasticity of cell fate mechanisms in breast cancer cells in the context of antiestrogen responsiveness. Restoration of ICI sensitivity in resistant cells appears to occur through an increase in autophagy-associated necrosis. BCL-W, BCL2, and BECN1 integrate important functions in determining antiestrogen responsiveness, and the presence of functional autophagy may influence the balance between apoptosis and necrosis

Exploring the components, asymmetry and distribution of relationship quality in wild Barbary macaques (Macaca sylvanus)

Social relationships between group members are a key feature of many animal societies. The quality of social relationships has been described by three main components: value, compatibility and security, based on the benefits, tenure and stability of social exchanges. We aimed to analyse whether this three component structure could be used to describe the quality of social relationships in wild Barbary macaques (Macaca sylvanus). Moreover, we examined whether relationship quality was affected by the sex, age and rank differences between social partners, and investigated the asymmetric nature of social relationships. We collected over 1,900 hours of focal data on seven behavioural variables measuring relationship quality, and used principal component analysis to investigate how these variables clustered together. We found that relationship quality in wild Barbary macaques can be described by a three component structure that represents the value, compatibility and security of a relationship. Female-female dyads had more valuable relationships and same-age dyads more compatible relationships than any other dyad. Rank difference had no effect on the quality of a social relationship. Finally, we found a high degree of asymmetry in how members of a dyad exchange social behaviour. We argue that the asymmetry of social relationships should be taken into account when exploring the pattern and function of social behaviour in animal societies

Hybrid Mechanical Systems

We discuss hybrid systems in which a mechanical oscillator is coupled to another (microscopic) quantum system, such as trapped atoms or ions, solid-state spin qubits, or superconducting devices. We summarize and compare different coupling schemes and describe first experimental implementations. Hybrid mechanical systems enable new approaches to quantum control of mechanical objects, precision sensing, and quantum information processing.Comment: To cite this review, please refer to the published book chapter (see Journal-ref and DOI). This v2 corresponds to the published versio

Inferring predominant pathways in cellular models of breast cancer using limited sample proteomic profiling

<p>Abstract</p> <p>Background</p> <p>Molecularly targeted drugs inhibit aberrant signaling within oncogenic pathways. Identifying the predominant pathways at work within a tumor is a key step towards tailoring therapies to the patient. Clinical samples pose significant challenges for proteomic profiling, an attractive approach for identifying predominant pathways. The objective of this study was to determine if information obtained from a limited sample (i.e., a single gel replicate) can provide insight into the predominant pathways in two well-characterized breast cancer models.</p> <p>Methods</p> <p>A comparative proteomic analysis of total cell lysates was obtained from two cellular models of breast cancer, BT474 (HER2+/ER+) and SKBR3 (HER2+/ER-), using two-dimensional electrophoresis and MALDI-TOF mass spectrometry. Protein interaction networks and canonical pathways were extracted from the Ingenuity Pathway Knowledgebase (IPK) based on association with the observed pattern of differentially expressed proteins.</p> <p>Results</p> <p>Of the 304 spots that were picked, 167 protein spots were identified. A threshold of 1.5-fold was used to select 62 proteins used in the analysis. IPK analysis suggested that metabolic pathways were highly associated with protein expression in SKBR3 cells while cell motility pathways were highly associated with BT474 cells. Inferred protein networks were confirmed by observing an up-regulation of IGF-1R and profilin in BT474 and up-regulation of Ras and enolase in SKBR3 using western blot.</p> <p>Conclusion</p> <p>When interpreted in the context of prior information, our results suggest that the overall patterns of differential protein expression obtained from limited samples can still aid in clinical decision making by providing an estimate of the predominant pathways that underpin cellular phenotype.</p

Galactic and Extragalactic Samples of Supernova Remnants: How They Are Identified and What They Tell Us

Supernova remnants (SNRs) arise from the interaction between the ejecta of a supernova (SN) explosion and the surrounding circumstellar and interstellar medium. Some SNRs, mostly nearby SNRs, can be studied in great detail. However, to understand SNRs as a whole, large samples of SNRs must be assembled and studied. Here, we describe the radio, optical, and X-ray techniques which have been used to identify and characterize almost 300 Galactic SNRs and more than 1200 extragalactic SNRs. We then discuss which types of SNRs are being found and which are not. We examine the degree to which the luminosity functions, surface-brightness distributions and multi-wavelength comparisons of the samples can be interpreted to determine the class properties of SNRs and describe efforts to establish the type of SN explosion associated with a SNR. We conclude that in order to better understand the class properties of SNRs, it is more important to study (and obtain additional data on) the SNRs in galaxies with extant samples at multiple wavelength bands than it is to obtain samples of SNRs in other galaxiesComment: Final 2016 draft of a chapter in "Handbook of Supernovae" edited by Athem W. Alsabti and Paul Murdin. Final version available at https://doi.org/10.1007/978-3-319-20794-0_90-