EGFR Inhibition in Non-Small Cell Lung Cancer: Resistance, Once Again, Rears Its Ugly Head

Most patients with non-small cell lung cancer who initially respond to gefitinib or erlotinib (tyrosine kinase inhibitors) ultimately develop resistance and disease relapse. What is the mechanism for this resistance

Successful Pre-Rewarming Resuscitation after Cardiac Arrest in Severe Hypothermia: A Retrospective Cohort Study from the International Hypothermia Registry.

The aim of our study is to investigate successful pre-rewarming resuscitation after hypothermic cardiac arrest (HCA). The hypothermic heart may be insensitive to defibrillation when core temperature is below 30 °C and after successful defibrillation, sinus rhythm often returns into ventricular fibrillation. Recurrent defibrillation attempts may induce myocardial injury. Discrepancy exists concerning pre-rewarming defibrillation between the guidelines of the European Resuscitation Council and American Heart Association. The International Hypothermia Registry (IHR) gathers hypothermia cases. The primary outcome was survival. Secondary outcomes were the characteristics of defibrillation, the effect of Adrenaline administration under 30 °C, and the duration of CPR. Of the 239 patients, eighty-eight were in cardiac arrest at arrival of the rescue team. Successful pre-rewarming resuscitation was obtained in 14 patients. The outcome showed: seven deaths, one vegetative state, two patients with reversible damage, and four patients with full recovery. A total of five patients had a shockable rhythm, and defibrillation was successful in four patients. The response rate to Adrenaline was reported as normal in six patients. There were no statistically significant differences in the presence of a shockable rhythm, the success of defibrillation, and the effect on Adrenaline administration between the survivors and non-survivors. Successful resuscitation in severe hypothermia is possible before active rewarming and arrival in the hospital, thus improving the chance of survival

The m−m-dissimilarity map and representation theory of SLmSL_m

We give another proof that $m$-dissimilarity vectors of weighted trees are points on the tropical Grassmanian, as conjectured by Cools, and proved by Giraldo in response to a question of Sturmfels and Pachter. We accomplish this by relating $m$-dissimilarity vectors to the representation theory of $SL_m.$Comment: 11 pages, 8 figure

3D Microstructured Carbon Nanotube Electrodes for Trapping and Recording Electrogenic Cells

Electrogenic cells such as cardiomyocytes and neurons rely mainly on electrical signals for intercellular communication. Microelectrode arrays (MEAs) have been developed for long-term recording of cell signals and stimulation of electrogenic cells under low-cell-stress conditions, providing new insights in the behavior of electrogenic cells and the operation of the brain. To date, MEAs are relying on flat or needle-shaped electrode surfaces, mainly due to limitations in the lithographic processes. This paper relies on a previously reported elasto-capillary aggregation process to create 3D carbon nanotube (CNT) MEAs. This study shows that CNTs aggregate in well-shaped structures of similar size as cardiomyocytes are particularly interesting for MEA applications. This is because i) CNT microwells of the right diameter preferentially trap individual cardiomyocytes, which facilitates single cell recording without the need for clamping cells or signal deconvolution, and ii) once the cells are trapped inside of the CNT wells, this 3D CNT structure is used as an electrode surrounding the cell, which increases the cell-electrode contact area. As a result, this study finds that the recorded output voltages increase significantly (more than 200%). This fabrication process paves the way for future study of complex interactions between electrogenic cells and 3D recording electrodes.This work was supported by the Research Foundation—Flanders (FWO, Belgium) under Project No. 11S1214N. Michael De Volder was supported by the ERC Starting Grant (337739)—HIENA and the Marie Curie Grant CANA (618250). Davor Copic was supported by the Marie Curie Grant EmuCam (660351)

A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development

Disorders of sex development (DSD) are congenital conditions where chromosomal, gonad or genital development is atypical. In a significant proportion of 46,XY DSD cases it is not possible to identify a causative mutation, making genetic counseling difficult and potentially hindering optimal treatment. Here, we describe the analysis of a 46,XY DSD patient that presented at birth with ambiguous genitalia. Histological analysis of the surgically removed gonads showed bilateral undifferentiated gonadal tissue and immature testis, both containing malignant germ cells. We screened genomic DNA from this patient for deletions and duplications using an Illumina whole-genome SNP microarray. This analysis revealed a heterozygous deletion within the WWOX gene on chromosome 16, removing exons 6-8. Analysis of parental DNA showed that the deletion was inherited from the mother. cDNA analysis confirmed that the deletion maintained the reading frame, with exon 5 being spliced directly onto exon 9. This deletion is the first description of a germline rearrangement affecting the coding sequence of WWOX in humans. Previously described Wwox knockout mouse models showed gonadal abnormalities, supporting a role for WWOX in human gonad development

A novel substitution 1381V in the sterol 14alpha-demethylase (CYP51) of Mycosphaerella graminicola is differentially selected by azole fungicides

The recent reduction in the efficacy of azole fungicides in controlling Septoria leaf blotch of wheat, caused by Mycosphaerella graminicola, has prompted concerns over possible development of resistance, particularly in light of the recent emergence of widespread resistance to quinone outside inhibitors (QoIs). We have recently implicated alterations in the target-encoding sterol 14 alpha-demethylase protein (CYP51), and over-expression of genes encoding efflux pumps, in reducing sensitivity to the azole class of sterol demethylation inhibitors (DMIs) in M. graminicola. Here we report on the prevalence and selection of two CYP51 alterations, substitution I381V and deletion of codons 459 and 460 (Delta Y459/G460), in populations of M. graminicola. Neither alteration has previously been identified in human or plant pathogenic fungi resistant to azoles. The presence of Delta Y459/G460 showed a continuous distribution of EC50 values across isolates with either I381 or V381, and had no measurable effect on azole sensitivity. Data linking fungicide sensitivity with the presence of I381V in M. graminicola show for the first time that a particular CYP51 alteration is differentially selected by different azoles in field populations of a plant pathogen. Substitution I381V although not an absolute requirement for reduced azole sensitivity, is selected by tebuconazole and difenoconazole treatment, suggesting an adaptive advantage in the presence of these two compounds. Prochloraz treatments appeared to select negatively for I381V, whereas other azole treatments did not or only weakly impacted on the prevalence of this substitution. These findings suggest treatments with different members of the azole class of fungicides could offer a resistance management strategy

The Duchess of Malfi

Last revised 2002

CNTRICS Final Task Selection: Long-term Memory

Long-term memory (LTM) is a multifactorial construct, composed of different stages of information processing and different cognitive operations that are mediated by distinct neural systems, some of which may be more responsible for the marked memory problems that limit the daily function of individuals with schizophrenia. From the outset of the CNTRICS initiative, this multidimensionality was appreciated, and an effort was made to identify the specific memory constructs and task paradigms that hold the most promise for immediate translational development. During the second CNTRICS meeting, the LTM group identified item encoding and retrieval and relational encoding and retrieval as key constructs. This article describes the process that the LTM group went through in the third and final CNTRICS meeting to select nominated tasks within the 2 LTM constructs and within a reinforcement learning construct that were judged most promising for immediate development. This discussion is followed by each nominating authors' description of their selected task paradigm, ending with some thoughts about future directions.Psycholog