78 research outputs found
Suppression of TGFβ-mediated conversion of endothelial cells and fibroblasts into cancer associated (myo)fibroblasts via HDAC inhibition
Background: Cancer-associated fibroblasts (CAFs) support tumour progression and invasion, and they secrete abundant extracellular matrix (ECM) that may shield tumour cells from immune checkpoint or kinase inhibitors. Targeting CAFs using drugs that revert their differentiation, or inhibit their tumour-supportive functions, has been considered as an anti-cancer strategy. Methods: We have used human and murine cell culture models, atomic force microscopy (AFM), microarray analyses, CAF/tumour cell spheroid co-cultures and transgenic fibroblast reporter mice to study how targeting HDACs using small molecule inhibitors or siRNAs re-directs CAF differentiation and function in vitro and in vivo. Results: From a small molecule screen, we identified Scriptaid, a selective inhibitor of HDACs 1/3/8, as a repressor of TGFβ-mediated CAF differentiation. Scriptaid inhibits ECM secretion, reduces cellular contraction and stiffness, and impairs collective cell invasion in CAF/tumour cell spheroid co-cultures. Scriptaid also reduces CAF abundance and delays tumour growth in vivo. Conclusions: Scriptaid is a well-tolerated and effective HDACi that reverses many of the functional and phenotypic properties of CAFs. Impeding or reversing CAF activation/function by altering the cellular epigenetic regulatory machinery could control tumour growth and invasion, and be beneficial in combination with additional therapies that target cancer cells or immune cells directly
Distribution of Global Measures of Deviation Between the Empirical Distribution Function and Its Concave Majorant
Recommended from our members
The role of vibratory signals in mating behavior of Sunn Pest
Eurygaster integriceps Puton (Hemiptera; Scutelleridae) is the most damaging insect pest of wheat and barley in countries of West Asia. This study aimed to characterize vibratory signals produced by male and female E. integriceps and to investigate the role of these signals in intraspecific communication, both in the presence and absence of odor signals from the insects. The male "calling song" consists of short chirps repeated at regular intervals with a call rate of 4.6 chirps/sec, mean chirp duration of 0.085 sec and inter-chirp interval 0.17 sec. When approached, a second male typically produces a distinctive agonistic call or "rivalry song" in which chirps are repeated at a much faster rate of 10.4/sec. Females occasionally call spontaneously, but they are much more likely to do so in response to male calling song, or indeed when any other conspecific is nearby. The female song structure does not differ from the male calling song in its chirp rate, although it is generally produced at lower amplitude and the vibratory movements generating the calls are not always evident. Typically the chirp rate increases as the male gets close to the female, and once mounted with genitalia engaged, vibratory signals subside. A Y-track bioassay system was developed and when vibratory signals produced by live insects were used as source, male bugs were significantly attracted to signals from both females and males. Females were not attracted to signals from either sex. When recorded signals were used as source, rather different results were obtained in that females were significantly attracted to signals from males and males were not attracted to signals from males or females. In the presence of odor collected from male bugs on Porapak, females showed no preference for vibratory signals from live males or the recorded signal. The role of vibratory signaling in mate location in this species and the interaction of these signals with production of volatiles are discussed
Recommended from our members
Chemical and electrophysiological studies on Sunn Pest
The Sunn Pest, Eurygaster integriceps Puton (Hemiptera; Heteroptera; Scutelleridae) is the most damaging insect pest of wheat and barley in countries of West Asia. Previous work has shown that adult males produce a number of chemicals, and these have been implicated in attraction between the sexes. Volatiles were collected from insects by air aeration and trapping on Porapak resin and solid-phase microextraction (SPME) fibers. Males produced large amounts of homo-γ-bisabolene identified previously and smaller amounts of bisabolene and vanillin. Ethyl acrylate could not be detected, although reported previously. Females did not produce any of these compounds. These compounds were produced by males only during the light period and only after reaching sexual maturity. When disturbed, both males and females produced (E)-2-hexenal, tridecane, (E)-2-octenal and (E)-4-oxo-2-hexenal, compounds shown to be produced from glands in the thorax and thought to play a role in defense against predators. In analyses of volatiles from male or female bugs by gas chromatography linked to electroantennographic (EAG) recording, no significant responses were obtained from male antennae. In most analyses, no EAG responses were obtained from the antennae of female bugs, but in a very few cases a response to the homo-γ-bisabolene in collections from male bugs was observed. This indicates that receptors for this component are present on the antennae of the female bugs and suggests that the compound may have a role in intraspecific communication
Direct detection of the HCO photoproduct from the UV photolysis of HCHO: Absolute HCO quantum yields.
- …