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Biomedical subjects

Jonathan Rees

Publications and source records attributed to Jonathan Rees.

16 recordsLinked to original sources
PubMed2007

DNA repair gene polymorphisms and genetic predisposition to cutaneous melanoma.

The incidence of cutaneous melanoma is rising rapidly in a number of countries. The key environmental risk factor is exposure to the ultraviolet (UV) component in sunlight. The nucleotide excision repair (NER) pathway deals with the main forms of UV-induced DNA damage. We have investigated the hypothesis that polymorphisms in NER genes constitute genetic susceptibility factors for melanoma. However, not all melanomas arise on sun-exposed sites and so we investigated the hypothesis that genes involved in other pathways for the repair of oxidative DNA damage may also be involved in susceptibility to melanoma. Scotland, with its high incidence of melanoma and stable homogeneous population, was ideal for this case-control study, involving 596 Scottish melanoma patients and 441 population-based controls. Significant associations were found for the NER genes ERCC1 and XPF, with the strongest associations for melanoma cases aged 50 and under [ERCC1 odds ratio (OR) 1.59, P = 0.008; XPF OR 1.69, P = 0.003]. Although an XPD haplotype was associated with melanoma, it did not contain the variant 751 Gln allele, which has been associated with melanoma in some previous studies. No associations were found for the base excision repair and DNA damage response genes investigated. An association was also found for a polymorphism in the promoter of the vitamin D receptor gene, VDR (OR 1.88, P = 0.005). The products of the two NER genes, ERCC1 and XPF, where associations with melanoma were found, act together in a rate-limiting step in the repair pathway.

Case-Control Studies↗
PubMed2006

Plenty new under the sun.

Variation at the melanocortin 1 receptor (MC1R) is very common in most non-African world populations. A range of variants predispose to skin cancer, including melanoma. What remains unclear are the mechanisms linking gene variation with sun sensitivity or tumor risk. In particular, it remains unclear whether pigmentary effects of the MC1R can account for all of the increase in cancer risk.

Humans↗
PubMed2005

The measurement of response shift in patients with advanced prostate cancer and their partners.

BACKGROUND: There is increasing evidence to support the phenomenon of response shift (RS) in quality of life (QoL) studies, with many current QoL measures failing to allow for this. If significant response shift occurs amongst prostate cancer patients, it will be necessary to allow for this in the design of future clinical research and to reassess the conclusions of previous studies that have not allowed for this source of bias. This study therefore aimed to assess the presence of RS and psychosocial morbidity in patients with advanced prostate cancer and their partners. METHODS: 55 consecutive advanced prostate cancer patients and their partners completed the Prostate Cancer Patient & Partner questionnaire (PPP), shortly after diagnosis and again at 3 months and 6 months. At the follow-up visits, both patients and partners also completed a then-test in order to assess RS. RESULTS: Partners consistently showed greater psychological morbidity than patients in relation to the prostate cancer. This was most marked on the General Cancer Distress (GCD) subscale (p < 0.001, paired t-test), and regarding worries about treatment (p = 0.01). Significant RS was identified in partners and patients by the use of the then-test technique, particularly on the GCD subscale, the concerns about treatment and the concerns about urinary symptoms items. CONCLUSION: These results suggest the presence of RS in patients with advanced prostate cancer and their partners, with higher levels of psychosocial morbidity noted amongst partners. This is the first study to identify RS in partners and calls into question the interpretation of all studies assessing changes in QoL that fail to allow for this phenomenon.

Aged↗
PubMed2005

Eumelanin and pheomelanin concentrations in human epidermis before and after UVB irradiation.

Pheomelanin is widely thought to be causally related to susceptibility to the harmful effects of ultraviolet radiation: epidemiological studies show that those with a higher ratio of pheomelanin to eumelanin in hair have higher rates of melanoma, and work in mouse and cell culture shows that pheomelanin generates excess free radicals after UVR exposure. By contrast, based on measurements of eumelanin and pheomelanin in human skin, before and following irradiation, we now report that both pheomelanin and eumelanin are positively related to skin colour, and by inference, inversely with cancer susceptibility. The ratio of melanin classes is similar in people with widely different cancer rates and UVR sensitivity. Although our numbers are small, our results extend previous work in man, and lead us to speculate that factors other than the amount of pheomelanin may be important in determining UVR susceptibility in persons with red hair.

Epidermis↗
PubMed2005

The photoadaptive response to ultraviolet exposure in human skin using ultraviolet spectrophotometry.

BACKGROUND: Both pigmentation and non-pigmentary processes contribute to the development of photoadaptation yet the exact contribution of either in the resting state and in response to ultraviolet (UV) radiation is unclear. The purpose of this study was to estimate independently these changes occurring in the epidermis following repeated exposure to UV in two groups with differing degrees of constitutive pigmentation. METHODS: We describe a mathematical model for explaining the spectral absorbance of excised human epidermis based on the absorbance of constituent chromophores. The model was applied to spectral absorbance data measured on samples of epidermis excised from pre-irradiated skin and from skin obtained following UV irradiation on 3 successive days. RESULTS: We found that in Asian skin there was only a mild photoadaptive response, principally by a small increase in pigmentation. On the other hand, the significant adaptive response in Caucasian skin was through hyperplasia of the epidermis, with tanning contributing only to a much smaller degree. CONCLUSION: This study has enabled us to study independently the pigmentary and non-pigmentary pathways and has shown that in those people with a lower degree of constitutive pigment, the primary mechanism of photoadaptation is via the non-pigmentary route.

Adaptation, Physiological↗
PubMed2004

Detection of activity centers in cellular pathways using transcript profiling.

We present a new computational method for identifying regulated pathway components in transcript profiling (TP) experiments by evaluating transcriptional activity in the context of known biological pathways. We construct a graph representing thousands of protein functional relationships by integrating knowledge from public databases and review articles. We use the notion of distance in a graph to define pathway neighborhoods. The pathways perturbed in an experiment are then identified as the subgraph induced by the genes, referred to as activity centers, having significant density of transcriptional activity in their functional neighborhoods. We illustrate the predictive power of this approach by performing and analyzing an experiment of TP53 overexpression in NCI-H125 cells. The detected activity centers are in agreement with the known TP53 activation effects and our independent experimental results. We also apply the method to a serum starvation experiment using HEY cells and investigate the predicted activity of the transcription factor MYC. Finally, we discuss interesting properties of the activity center approach and its possible applications beyond the comparison of two experiments.

Algorithms↗
PubMed2004

The fundamentals of clinical discovery.

There is a widespread view that clinical research is failing to advance appropriately, particularly in comparison with other aspects of biomedical science. I argue that this is due in part to an inadequate understanding of how medical advance occurs. The common usage of such terms as basic or fundamental, or the uncritical use of the term model is unhelpful--unhelpful, in that such terms tend to presuppose a certain model of clinical advance that is unusual, and furthermore, because they tend to exaggerate the importance of research in subjects such as biochemistry and genetics at the expense of other areas. I suggest that much medical research is best viewed as a form of engineering rather than science, and that the knowledge base and research funding for the amelioration of disease needs to be much more broadly based than at present.

Biomedical Research↗
PubMed2002

Complex disease and the new clinical sciences.

Medical research today is dominated by a genocentric point of view. At the same time, clinical discovery and patient-oriented research have become less common. Here, I suggest that these developments are interdependent, each representing the flip side of an inaccurate view of how clinical advance occurs.

Causality↗
PubMedDate not supplied

Clinical science: time for a new contract.

Academic clinical medicine is widely believed to be in crisis. In particular patient-orientated research is notable for its almost complete absence from the research portfolios of many institutions. A number of recent reports have suggested ways to improve recruitment into clinical academic medicine. Here I argue that, in addition, we should realise that any such crisis is not just confined to medicine but affects most of the university sector. In medicine the situation is compounded by, first, our inability to recognise how much clinical advance occurs and, second, by a refusal to acknowledge the changing organisation and sociology of science. If academic medicine is to continue to be attractive to the brightest and most interesting minds institutional change is unavoidable.

Academic Medical Centers↗