Metastasis is a critical factor contributing to poor prognosis in cancer, but the underlying mechanisms of metastasis are still poorly understood. We established a highly metastatic cell subline (HOC313-LM) derived from an oral squamous cell carcinoma cell line (HOC313) for uncovering the mechanisms of metastasis, and identified deoxyhypusine synthase (DHPS) as a metastasis-associated gene within the specific amplification at 19p13.2-p13.13 in HOC313-LM. DHPS-mediated hypusine-modification of eukaryotic translation factor 5A facilitated the translation of RhoA, resulting in the activation of the RhoA signaling pathway and leading to not only increased cell motility, invasion and metastasis of cancer cells in vitro, but also increased tumor growth in vivo. Moreover, the use of N1-Guanyl-1,7-diaminoheptane, a DHPS inhibitor, resulted in a significant decrease in tumor formation in vivo. In patients with esophageal squamous cell carcinoma (ESCC), overexpression of DHPS in ESCC tumors was significantly associated with worse recurrence-free survival, and correlated with distant metastasis. The elucidation of these molecular mechanisms within the hypusine cascade suggests opportunities for novel therapeutic targets in SCC.
Chromothripsis is the massive but highly localized chromosomal rearrangement in response to a one-step catastrophic event, rather than an accumulation of a series of subsequent and random alterations. Chromothripsis occurs commonly in various human cancers and is thought to be associated with increased malignancy and carcinogenesis. However, the causes and consequences of chromothripsis remain unclear. Therefore, to identify the mechanism underlying the generation of chromothripsis, we investigated whether chromothripsis could be artificially induced by ionizing radiation. We first elicited DNA double-strand breaks in an oral squamous cell carcinoma cell line HOC313-P and its highly metastatic subline HOC313-LM, using Single Particle Irradiation system to Cell (SPICE), a focused vertical microbeam system designed to irradiate a spot within the nuclei of adhesive cells, and then established irradiated monoclonal sublines from them, respectively. SNP array analysis detected a number of chromosomal copy number alterations (CNAs) in these sublines, and one HOC313-LM-derived monoclonal subline irradiated with 200 protons by the microbeam displayed multiple CNAs involved locally in chromosome 7. Multi-color FISH showed a complex translocation of chromosome 7 involving chromosomes 11 and 12. Furthermore, whole genome sequencing analysis revealed multiple de novo complex chromosomal rearrangements localized in chromosomes 2, 5, 7, and 20, resembling chromothripsis. These findings suggested that localized ionizing irradiation within the nucleus may induce chromothripsis-like complex chromosomal alterations via local DNA damage in the nucleus.
Two rat experiments were run to study the effects of a wide range of signal (CS) intensities on the suppression of licking. In Experiment I, a light CS was varied over five levels, including zero intensity. Conditioned suppression was found to vary directly with CS intensity, but basal lick rates were not different among groups. In Experiment 2, an attempt was made to disturb the basal rate of licking, while a tone CS was varied over four levels, including zero intensity. Here the suppression of the CS rates was found to be directly related and basal rates inversely related to CS intensity. The results as a whole were consistent with the Perkins-Logan hypothesis regarding the effects of CS intensity upon conditioning, but not with the Rescorla-Wagner model of classical conditioning.The intensity of the conditioned stimulus (CS) has been regarded as one of the important variables in both classical and instrumental conditioning experiments. Although the results of these studies are somewhat equivocal (Gray, 1965), they generally support the view that the relation between CS intensity and conditioned response magnitude is positive, a phenomenon known by the Hullian name of "stimulus intensity dynamism" (Hull, 1949).Stimulus intensity dynamism has also been reported in conditioned suppression (Kamin, 1965;Kamin & Brimer, 1963;Kamin & Schaub, 1963). The effects of CS intensity in an aversive conditioning situation, however, can be treated in a completely different manner, as suggested by recent developments in studies of aversive conditioning (lmada & Soga, 1971; Nageishi & lmada, 1974;Odling-Smee, 1975;Seligman, 1968Seligman, , 1969Weiss, 1970). Seligman (1968), for example, had demonstrated that unsignaled shocks produce greater suppression of basal rate of leverpressing than do signaled shocks, a result he explains with his safety signal hypothesis, which assumes that rats under a signaled shock condition learn to discriminate the signal (CS), or more correctly, the signal plus background cues (BC), from the BC alone, and the former comes to serve as a good predictor of danger and the latter of safety. When the shocks are given unsignaled or signaled by a cue of subliminal or zero intensity, no such discrimination should be possible, and hence animals in such a situation would be persistently fearful. Viewed in this way, it becomes immediately obvious that the problem of CS intensity in an on-the-baseline condiThe present research was supported by a grant in aid of research awarded to Hiroshi Imada by the Murao Foundation, Kobe, Japan. tioned suppression experiment can be discussed in terms of discriminability of the CS + BC from the BC alone. Decreasing CS intensity, therefore, should make this discrimination difficult, and thus should lead to the suppression of baseline responding. Unfortunately, in no previous studies of conditioned suppression dealing with CS intensity, has reference been made to the basal rate of responding. Also, in previous studies that dealt with the effect of predictability of shock upon...
In order to clarify the pathological localization of horizontal canal benign paroxysmal positional vertigo (HC-BPPV), we performed 3D analysis of positional nystagmus in 11 patients with HC-BPPV. In addition, these results were compared with 3D analysis data of pressure nystagmus in patients with HC fistula. 3D analysis of nystagmus was carried out using a video image analysis system. In seven patients with HC-BPPV, the velocity vectors were well aligned with the axes of the HC and in four patients they were not. In addition, the 3D velocity vectors of the slow phase of pressure nystagmus in all 11 subjects with HC fistula were closely aligned with the axes of the HC. The pathology of HC-BPPV in most patients with apogeotropic positional nystagmus has been considered to be localized in the HC. However, our results strongly suggest that the pathology of HC-BPPV with geotropic nystagmus is localized in the utricle. This is the first report concerning the pathological localization of HC-BPPV based on physiological evidence.
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