Overcoming resistance to rapalogs in gliomas by combinatory therapies

Glioblastoma is the most common and aggressive brain tumor type, with a mean patient survival of approximately 1 year. Many previous analyses of the glioma kinome have identified key deregulated pathways that converge and activate mammalian target of rapamycin (mTOR). Following the identification and characterization of mTOR-promoting activity in gliomagenesis, data from preclinical studies suggested the targeting of mTOR by rapamycin or its analogs (rapalogs) as a promising therapeutic approach. However, clinical trials with rapalogs have shown very limited efficacy on glioma due to the development of resistance mechanisms. Analysis of rapalog-insensitive glioma cells has revealed increased activity of growth and survival pathways compensating for mTOR inhibition by rapalogs that are suitable for therapeutic intervention. In addition, recently developed mTOR inhibitors show high anti-glioma activity. In this review, we recapitulate the regulation of mTOR signaling and its involvement in gliomagenesis, discuss mechanisms resulting in resistance to rapalogs, and speculate on strategies to overcome resistance. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).     

Harvey Cushing's ghosts: death and hauntings in modern medicine

The passing of Yale School of Medicine's 2010 Bicentennial occasions a moment of reflecting on the past, present, and future of medical education and research at Yale and beyond. Last June, a ribbon-cutting ceremony inaugurated the opening of the Cushing Center in the Cushing-Whitney Medical Library. Named after Harvey Cushing, an early 20th-century neurosurgeon and former Yale College alum, the dual education/exhibition space now houses hundreds of gross brain specimens constituting the Cushing Tumor Registry. Originally a personal collection, Cushing donated his numerous medical specimens, photographs, and other medical relics from his deathbed, relinquishing the brains to Yale only under the condition that a suitable space be erected to preserve the many specimens. Some 70 years later and after nearly being destroyed, Cushing's wish is fully realized: The once desiccated, hidden brains have been painstakingly restored and are now on view in the Cushing Center. The brains express Cushing's singular and spectral worldview as a surgeon, artist, athlete, soldier, book collector, and historian.     

A novel t(4;16)(q25;q23.1) associated with EGF and ELOVL6 deregulation in acute myeloid leukemia

About 50% of acute myeloid leukemia (AML) patients show the occurrence of non-random chromosome rearrangements. Most of the recurrent karyotypic rearrangements in AML have been defined as distinct disease entities in the 2008 World Health Organization (WHO) classification. In this paper we report an AML case showing a novel t(4;16)(q25;q23.1) rearrangement causing the activation of epidermal growth factor (EGF) and elongation of long-chain fatty acids family member 6 (ELOVL6) genes, rather than the generation of a novel fusion gene.     

Correlation of the plasma tyrosine to phenylalanine ratio with energy intake in self-selecting weanling rats

The relationship between changes in blood plasma amino acids and the quantity of protein and energy self-selected by the weanling rat, simultaneously offered two diets varying only in gluten (15 and 55%) concentration, was examined. Gluten and energy intakes were manipulated by additions of lysine, arginine or ammonia to gluten. In two experiments groups of ten weanling rats were fed the diets for a two week or four week period and food intake selection recorded. Blood samples were obtained between 0900–1100 hr at the end of the two week or four week period. Correlation coefficients of protein intake with the plasma TRP/NAA (Tyr+Phe+Leu+Val+Ile) ratios were ?0.97 and ?0.98, and of energy intake with TYR/PHE ratios were 0.77 and 0.70 in experiments 1 and 2, respectively. It is suggested that the plasma TRP/NAA and TYR/PHE ratios reflect the mechanisms regulating protein and energy intakes, respectively.     

Antiprogestational agents. The synthesis of 7-alkyl steroidal ketones with anti-implantational and antidecidual activity

A series of 7α- and 7β- alkyl derivatives of steroidal 4-en- and 5-en-3-ones were prepared by 1,6-conjugate addition of organocopper reagents to various steroidal 4,6-dien-3-ones of the androstane, estrane and gonane series. Biological study of these and related compounds revealed that 17β-hydroxy-7α-methyl-5-androsten-3-one (2), 17β-hydroxy-7α-methyl-5-estren-3-one acetate and 17β-hydroxy-7α-methyl-4-estren-3-one acetate had significant anti-implantational and antidecidual activities. The contragestative effects were associated with the latter antihormonal properties, and not with the androgenicity of these compounds.     

Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP)

The major hallmark of cellular senescence is an irreversible cell cycle arrest and thus it is a potent tumor suppressor mechanism. Genotoxic insults, e.g. oxidative stress, are important inducers of the senescent phenotype which is characterized by an accumulation of senescence-associated heterochromatic foci (SAHF) and DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS). Interestingly, senescent cells secrete pro-inflammatory factors and thus the condition has been called the senescence-associated secretory phenotype (SASP). Emerging data has revealed that NF-κB signaling is the major signaling pathway which stimulates the appearance of SASP. It is known that DNA damage provokes NF-κB signaling via a variety of signaling complexes containing NEMO protein, an NF-κB essential modifier, as well as via the activation of signaling pathways of p38MAPK and RIG-1, retinoic acid inducible gene-1. Genomic instability evoked by cellular stress triggers epigenetic changes, e.g. release of HMGB1 proteins which are also potent enhancers of inflammatory responses. Moreover, environmental stress and chronic inflammation can stimulate p38MAPK and ceramide signaling and induce cellular senescence with pro-inflammatory responses. On the other hand, two cyclin-dependent kinase inhibitors, p16INK4a and p14ARF, are effective inhibitors of NF-κB signaling. We will review in detail the signaling pathways which activate NF-κB signaling and trigger SASP in senescent cells.     

A dark business,full of shadows: Analogy and theology in William Harvey

In a short work called De conceptione appended to the end of his Exercitationes de generatione animalium (1651), William Harvey developed a rather strange analogy. To explain how such marvelous productions as living beings were generated from the rather inauspicious ingredients of animal reproduction, Harvey argued that conception in the womb was like conception in the brain. It was mostly rejected at the time; it now seems a ludicrous theory based upon homonymy. However, this analogy offers insight into the structure and function of analogies in early modern natural philosophy. In this essay I hope to not only describe the complex nature of Harvey’s analogy, but also offer a novel interpretation of his use of analogical reasoning, substantially revising the account offered by Guido Giglioni (1993). I discuss two points of conceptual change and negotiation in connection with Harvey’s analogy, understanding it as both a confrontation between the border of the natural and the supernatural, as well as a moment in the history of psychology. My interpretation touches upon a number of important aspects, including why the analogy was rejected, how Harvey systematically deployed analogies according to his notions of natural philosophical method, how the analogy fits into contemporary discussions of analogies in science, and finally, how the analogy must be seen in the context of changing Renaissance notions of the science of the soul, ultimately confronting the problem of how to understand final causality in Aristotelian science. In connection with the last, I conclude the essay by turning to how Harvey embeds the analogy within a natural theological cosmology.