Biomedical subjects

Michael Khan

Publications and source records attributed to Michael Khan.

6 recordsLinked to original sources

PubMed2005

Can the location negative priming process operate in a proactive manner?

The location negative priming (NP) effect refers to the fact that the processing of a current target stimulus (probe trial) is delayed when it appears at a location that has recently contained a distractor event (prime trial), relative to when it occurs at a previously unoccupied position. One view is that the process causing the NP effect involves the inhibition of the internal representation of the prime-distractor event, and that the future processing of target stimuli that involve this event are prolonged because this distractor inhibition is persistent. In this study, we examined the possibility that the NP process (inhibition) could act proactively; specifically asking whether inhibition could be allocated to a location merely predicted to hold a future distractor event. To do this, we cued the probe distractor's location using an otherwise traditional location NP paradigm. No evidence of a proactive NP process was obtained. Probe-trial target latency was the same whether it appeared at the cued distractor location or at a new location, but was delayed when it occupied the prime-distractor location (NP effect). The location NP process is seemingly a reactive one, applying inhibition only when an actual distractor is present, much as past theories have implied.

Attention↗

PubMed2004

Brief inactivation of c-Myc is not sufficient for sustained regression of c-Myc-induced tumours of pancreatic islets and skin epidermis.

BACKGROUND: Tumour regression observed in many conditional mouse models following oncogene inactivation provides the impetus to develop, and a platform to preclinically evaluate, novel therapeutics to inactivate specific oncogenes. Inactivating single oncogenes, such as c-Myc, can reverse even advanced tumours. Intriguingly, transient c-Myc inactivation proved sufficient for sustained osteosarcoma regression; the resulting osteocyte differentiation potentially explaining loss of c-Myc's oncogenic properties. But would this apply to other tumours? RESULTS: We show that brief inactivation of c-Myc does not sustain tumour regression in two distinct tissue types; tumour cells in pancreatic islets and skin epidermis continue to avoid apoptosis after c-Myc reactivation, by virtue of Bcl-xL over-expression or a favourable microenvironment, respectively. Moreover, tumours progress despite reacquiring a differentiated phenotype and partial loss of vasculature during c-Myc inactivation. Interestingly, reactivating c-Myc in beta-cell tumours appears to result not only in further growth of the tumour, but also re-expansion of the accompanying angiogenesis and more pronounced beta-cell invasion (adenocarcinoma). CONCLUSIONS: Given that transient c-Myc inactivation could under some circumstances produce sustained tumour regression, the possible application of this potentially less toxic strategy in treating other tumours has been suggested. We show that brief inactivation of c-Myc fails to sustain tumour regression in two distinct models of tumourigenesis: pancreatic islets and skin epidermis. These findings challenge the potential for cancer therapies aimed at transient oncogene inactivation, at least under those circumstances where tumour cell differentiation and alteration of epigenetic context fail to reinstate apoptosis. Together, these results suggest that treatment schedules will need to be informed by knowledge of the molecular basis and environmental context of any given cancer.

Animals↗

PubMed2004

The use of a distractor-assigned response slows later responding in a location negative priming task.

Responding to a target's location takes longer when that location has recently contained a distractor event (ignored-repetition [IR] trial) relative to when it has been unoccupied (control trial). This is known as the location negative priming (NP) effect. We aimed to determine whether the elevated reaction time observed for IR trials was due to the reuse of a distractor location (location locus) and/or to the need to execute a (just inhibited) distractor response (response locus). We isolated these loci latency effects by using many-to-one and one-to-many location-response assignments. Our results showed that reusing a distractor location hastened target processing at that position (facilitative location locus), whereas the production of a distractor response was associated with a time cost (interfering response locus). Accordingly, part of the latency elevation seen with IR trials results from the need on these occasions to execute ajust inhibited (distractor) response, and, hence, the location NP effect has a response locus.

Attention↗

PubMed2003

Oxidised lipoproteins may promote inflammation through the selective delay of engulfment but not binding of apoptotic cells by macrophages.

During normal tissue homeostasis apoptotic cells (AC) are rapidly recognised and engulfed by neighbouring cells or macrophages (Mphi), thus preventing an inflammatory response. Conversely, in chronically inflamed tissues, including the atherosclerotic artery and rheumatoid joint, removal of AC is defective despite the co-localisation of seemingly adequate numbers of Mphi. Mechanisms preventing removal of AC in vivo remain obscure, but might include oxidised low-density lipoprotein (ox-LDL), which is abundant in chronic inflammatory lesions. Although implicated in their pathogenesis, defining the role of ox-LDL on inflammatory processes has proved complicated. In fact, seemingly contradictory results have previously been described, though these may in part reflect the heterogeneous nature of ox-LDL applied in these studies. We wished to investigate the effect of physiologically representative ox-LDL on the binding and engulfment of apoptotic vascular smooth muscle cells (VSMC) and fibroblasts, as these have previously been shown to co-localise with Mphi in chronically inflamed tissues in vivo. We show that Mphi recognition of AC in vitro is not affected at physiological levels of ox-LDL. However, engulfment of intact AC is dramatically reduced/delayed. Importantly, in the absence of ox-LDL rapid phagocytosis of intact AC suppresses Mphi inflammatory cytokine release. In striking contrast, in the presence of ox-LDL, despite binding of AC to Mphi, release of IL-6 and MCP-1 is no longer suppressed. We propose that ox-LDL could maintain an inflammatory response by inhibiting the engulfment of AC, required for Mphi de-activation. This mechanism may contribute to chronic persisting inflammation in the atherosclerotic artery and rheumatoid joint.

Apoptosis↗

PubMed2002

Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression.

To explore the role of c-Myc in carcinogenesis, we have developed a reversible transgenic model of pancreatic beta cell oncogenesis using a switchable form of the c-Myc protein. Activation of c-Myc in adult, mature beta cells induces uniform beta cell proliferation but is accompanied by overwhelming apoptosis that rapidly erodes beta cell mass. Thus, the oncogenic potential of c-Myc in beta cells is masked by apoptosis. Upon suppression of c-Myc-induced beta cell apoptosis by coexpression of Bcl-x(L), c-Myc triggers rapid and uniform progression into angiogenic, invasive tumors. Subsequent c-Myc deactivation induces rapid regression associated with vascular degeneration and beta cell apoptosis. Our data indicate that highly complex neoplastic lesions can be both induced and maintained in vivo by a simple combination of two interlocking molecular lesions.

3T3 Cells↗

PubMed2002

Influence of probe-trial selection on the location negative priming effect.

Using the location variant of the typical negative priming procedure, participants were cued (100% reliable) before (Experiment 1) or after (Experiment 2) the prime trial as to whether a distractor would or would not accompany the target on the probe trial. The crucial results were that on cued trials, the predictable absence, produced the removal of the negative priming effect (disengagement), and that this disengagement of the priming process, motivated by the predictable absence of a probe-trial distractor, could take place on-line. These findings demonstrated the "selection-state" dependency (probe trial) of the location negative priming process, supporting inhibition-based and episodic retrieval models in their contention that the ultimate function of this process is to enhance the efficiency of future distractor processing, and hence selection. The disengagement results revealed an adaptive feature of a process that can be detrimental or irrelevant to upcoming processing.

Adult↗