Identification of 33 candidate oncogenes by screening for base-specific mutations.

BACKGROUND: Genes with recurrent codon-specific somatic mutations are likely drivers of tumorigenesis and potential therapeutic targets. Hypermutable cancers may represent a sensitive system for generation and selection of oncogenic mutations. METHODS: We utilised exome-sequencing data on 25 sporadic microsatellite-instable (MSI) colorectal cancers (CRCs) and searched for base-specific somatic mutation hotspots. RESULTS: We identified novel mutation hotspots in 33 genes. Fourteen genes displayed mutations in the validation set of 254 MSI CRCs: ANTXR1, MORC2, CEP135, CRYBB1, GALNT9, KRT82, PI15, SLC36A1, CNTF, GLDC, MBTPS1, OR9Q2, R3HDM1 and TTPAL. A database search found examples of the hotspot mutations in multiple cancer types. CONCLUSIONS: This work reveals a variety of new recurrent candidate oncogene mutations to be further scrutinised as potential therapeutic targets.

Dynamics of cortical activation in a hemianopic patient.

Although residual vision in patients with cortical blindness is common, its brain mechanisms are poorly known. To study these mechanisms we measured neuromagnetic responses to visual stimuli in a patient with right posterior cerebral lesion and left visual field hemianopia. His vision had partially recovered with intensive training before our measurements. Compared with the processing in the healthy side, early occipital responses were attenuated for both passive viewing of checkerboard reversal patterns and a letter identification task. In both conditions there were prominent longer-latency responses at the right superior temporal cortex. We suggest that the activation in the superior temporal cortex can partially compensate for the failure to produce synchronized population responses at the early stages of visual cortical processing.

The imprint of action: motor cortex involvement in visual perception of handwritten letters.

Humans are able to recognize handwritten texts accurately despite the extreme variability of scripts from one writer to another. This skill has been suggested to rely on the observer's own knowledge about implicit motor rules involved in writing. To investigate the possible neural correlates of such an ability, we monitored with magnetoencephalography (MEG) the approximately 20-Hz oscillations originating from the motor cortex. The oscillations were more suppressed after visual presentation of handwritten than printed letters, indicating stronger excitation of the motor cortex to handwritten scripts. These results support the idea of embodied visual perception of handwritten scripts and the involvement of the motor cortex in the underlying action-perception link.

Neuromagnetic correlates of visual motion coherence.

In order to characterize cortical responses to coherent motion we use magnetoencephalography (MEG) to measure human brain activity that is modulated by the degree of global coherence in a visual motion stimulus. Five subjects passively viewed two-phase motion sequences of sparse random dot fields. In the first (incoherent) phase the dots moved in random directions; in the second (coherent) phase a variable percentage of dots moved uniformly in one direction while the others moved randomly. We show that: (i) visual-motion-evoked magnetic fields, measured with a whole-scalp neuromagnetometer, reveal two transient events, within which we identify two significant peaks--the 'ON-M220' peak approximately 220 ms after the onset of incoherent motion and the 'TR-M230' peak, approximately 230 ms after the transition from incoherent to coherent motion; (ii) in lateral occipital channels, the TR-M230 peak amplitude varies with the percentage of motion coherence; (iii) two main sources are active in response to the transition from incoherent to coherent motion, the human medial temporal area complex/V3 accessory area (hMT+/V3A) and the superior temporal sulcus (STS), and (iv) these distinct areas show a similar, significant dependence of response strength and latency on motion coherence.

Vagally mediated stimulation of gastric acid secretion by intravenously administered adenosine derivatives in anaesthetized rats.

The effects of adenosine and some of its analogues on gastric acid secretion were investigated in rats. These compounds increased gastric acid secretion in anaesthetized rats after intravenous injection, the order of potency being 5'-N-ethylcarboxamidoadenosine (NECA) greater than (-)N6-phenylisopropyladenosine (L-PIA), N6-cyclohexyladenosine (CHA) greater than (+)N6-phenylisopropyladenosine (D-PIA) greater than 2-chloroadenosine (2-CADO) greater than adenosine (ADO). The stimulation of acid secretion by L-PIA in anaesthetized rats was antagonized by theophylline and 8-phenyltheophylline and totally prevented by vagotomy and atropine. Intracerebroventricular administration of L-PIA had no effect on gastric acid secretion in anaesthetized rats, whereas in conscious rats it inhibited the output of acid, pepsin and fluid. These results indicate that adenosine derivatives stimulate gastric acid secretion in anaesthetized rats by activating the vagus nerve via adenosine receptors in afferent pathways.

Left minineglect in dyslexic adults.

We searched for a core mechanism underlying the diverse behavioural and sensorimotor deficits in dyslexic subjects. In psychophysical temporal order judgement and line motion illusion tasks, adult dyslexics processed stimuli in the left visual hemifield significantly (approximately 15 ms) more slowly than normal readers, indicating a left-sided 'minineglect'. Furthermore, abrupt stimuli captured attention in both visual hemifields less effectively in dyslexics than in normal readers. These abnormalities could reflect right parietal lobe hypofunction, a consequence of a general magnocellular deficit demonstrated previously. Based on these and previous data, we propose a causal chain which could result in several sensory and cognitive deficits observed in dyslexic subjects.

Coinciding early activation of the human primary visual cortex and anteromedial cuneus.

Proper understanding of processes underlying visual perception requires information on the activation order of distinct brain areas. We measured dynamics of cortical signals with magnetoencephalography while human subjects viewed stimuli at four visual quadrants. The signals were analyzed with minimum current estimates at the individual and group level. Activation emerged 55-70 ms after stimulus onset both in the primary posterior visual areas and in the anteromedial part of the cuneus. Other cortical areas were active after this initial dual activation. Comparison of data between species suggests that the anteromedial cuneus either comprises a homologue of the monkey area V6 or is an area unique to humans. Our results show that visual stimuli activate two cortical areas right from the beginning of the cortical response. The anteromedial cuneus has the temporal position needed to interact with the primary visual cortex V1 and thereby to modify information transferred via V1 to extrastriate cortices.