- Email: [email protected]
Focus on cancer prevention
Research Update
5 Brooks, P.C. et al. (1998) Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell 92, 391–400 6 Pike, S.E. et al. (1998) Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth. J. Exp. Med. 188, 2349–2356 7 Celerier, J. et al. (2002) Angiotensinogen and its cleaved derivatives inhibit angiogenesis. Hypertension 39, 224–228 8 Ferrara, N. et al. (1991) The 16K fragment of prolactin specifically inhibits basal or fibroblast growth factor stimulated growth of capillary endothelial cells. Endocrinology 129, 896–900 9 Colorado, P.C. (2000) Anti-angiogenic cues from vascular basement membrane collagen. Cancer Res. 60, 2520–2526 10 Kamphaus, G.D. (2000) Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. J. Biol. Chem. 275, 1209–1215 11 Petitclerc, E. et al. (2000) New functions for non-collagenous domains of human collagen type IV. Novel integrin ligands inhibiting angiogenesis and tumor growth in vivo. J. Biol. Chem. 275, 8051–8061
TRENDS in Molecular Medicine Vol.8 No.7 July 2002
12 Maeshima, Y. (2000) Distinct antitumor properties of a type IV collagen domain derived from basement membrane. J. Biol. Chem. 275, 21340–21348 13 Ramchandran, R. et al. (1999) Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin. Biochem. Biophys. Res. Commun. 255, 735–739 14 Xu, R. et al. (2001) NC1 domain of human type VIII collagen (alpha 1) inhibits bovine aortic endothelial cell proliferation and causes cell apoptosis. Biochem. Biophys. Res. Commun. 289, 264–268 15 Yi, M. and Ruoslahti, E. (2001) A fibronectin fragment inhibits tumor growth, angiogenesis, and metastasis. Proc. Natl. Acad. Sci. U. S. A. 98, 620–624 16 Kuroi, K. (2001) Circulating levels of endostatin in cancer patients. Oncol. Rep. 8, 405–409 17 Standker, L. (1997) Isolation and characterization of the circulating form of human endostatin. FEBS Lett. 420, 129–133 18 Sten-Linder, M. (1999) Angiostatin fragments in urine from patients with malignant disease. Anticancer Res. 19, 3409–3414
315
19 Wakasugi, K. and Schimmel, P. (1998) Two distinct cytokines released from a human aminoacyl-tRNA synthetase. EMBO J. 17, 297–305 20 Moses, M.A. et al. (1999) Troponin I is present in human cartilage and inhibits angiogenesis. Proc. Natl. Acad. Sci. U. S. A. 96, 2645–2650 21 O’Reilly, M. et al. (1999) Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance. J. Biol. Chem. 274, 29568–29571 22 O’Reilly, M.S. et al. (1996) Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat. Med. 2, 689–692 23 Folkman, J. (2001) Angiogenesis research: guidelines for translation to clinical application. Thromb. Haemost. 86, 23–33
Patricia A. D’Amore* Yin-Shan Ng Schepens Eye Research Institute, Depts of Ophthalmology and Pathology, Harvard Medical School, Boston, MA 02114, USA. *e-mail: [email protected]
Meeting Report
Focus on cancer prevention Rudolf Morant Tumor Prevention and Genetics 2002, the 2nd International Conference and 7th Annual Meeting of The International Society of Cancer Chemoprevention (ISCaC) was held in St. Gallen, Switzerland, 14–16 February 2002. Published online: 30 May 2002
This three-day conference at the University of St. Gallen attracted 230 participants from 30 countries. Co-sponsored by the International Society of Cancer Chemoprevention, the European School of Oncology and by the Swiss host, St. Gallen Oncology Conferences, the participants represented various backgrounds from basic scientists to clinical urologists, gynecologists, oncologists, surgeons and epidemiologists, offering an opportunity for interesting discussions on how to advance this field. The topics covered the search for and the assessment of new cancer-susceptibility genes and preclinical models of cancer chemoprevention. More detailed discussions involved clinical chemoprevention and screening efforts in skin tumors, breast cancer, prostate cancer and colorectal carcinomas. http://tmm.trends.com
Breast cancer
D. Lawrence Wickerham [The National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA] discussed the ongoing STAR trial, which compares tamoxifen with raloxifene in the prevention of breast cancer in high-risk women, and has already randomized more than 12 000 women (the target is 22 000). He noticed that the findings of the NSABP-P1 study, which showed a significant reduction with tamoxifen of nearly 50% in breast cancer incidence [1], have not yet been widely incorporated into clinical practice. Many practitioners are apparently reluctant to prescribe a drug with potential serious side-effects, such as thromboembolic events and
endometrial carcinoma, especially as other trials with similar designs in Europe have been negative so far. Trevor Powles (Royal Marsden Hospital, London, UK) warned that there were no data yet to prove the efficacy of tamoxifen in the subgroup of women with gene mutations that predispose high-penetrance breast cancer. Jack Cuzick (Cancer Research UK, London, UK) discussed the planned IBIS-2 trial, which will study the very promising drug anastrozole. This aromatase inhibitor has been recently proven superior to tamoxifen in the adjuvant setting [Arimidex and tamoxifen alone or in combination, (ATAC trial)] [2]. A very lively discussion on the value of mammography screening, chaired by Michael P. Osborne (Strang Cancer Prevention Center, New York, USA) and Jack Cuzick, highlighted the controversial views of Anthony B. Miller (Deutsches Krebsforschungszentrum, Heidelberg, Germany) and Stephen Feig (Mount Sinai Medical Center, New York, USA). The public controversy was initiated by two recent papers by Gotzsche and Olsen [3,4]. Discussion centered on whether it was justified to disregard the (positive) results
1471-4914/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S1471-4914(02)02370-5
Research Update
316
of some older studies because of minor methodological flaws. In spite of these controversies, the vast majority of active researchers in the field continue to support mammography screening. Gad Rennert (National Breast Cancer Screening Program, Haifa, Israel) discussed the political dimensions and influences on screening programs, for example the fact that the US congress forced the National Cancer Institute (NCI) to recommend mammography screening from the age of 40 (instead of 50, as in most other countries), contradictory to the conclusions of the scientific committee. Prostate cancer
Eric Klein (Cleveland Clinic, OH, USA), chairman of the current selenium and vitamin E cancer prevention trial (SELECT) trial, discussed the chemoprevention of prostate cancer. Results of this large randomized US trial of the South West Oncology Group (SWOG) (Seattle, WA, USA) are not expected before the year 2013. Georg Bartsch (Innsbruck, Austria) reported a significant drop in mortality from prostate cancer following the introduction in 1993 of prostatespecific antigen (PSA) mass screening at no cost in the federal state of Tyrol. He also gave a current update of the screening results among men aged 45–75 years. Hans-Peter Schmid (Kantonsspital St. Gallen, Switzerland) advised against
TRENDS in Molecular Medicine Vol.8 No.7 July 2002
introducing mass screening of PSA until the data from the large randomized trials in Europe (European Randomized Study of Screening for Prostate Cancer, ERSPC) and America (Prostate, Lung, Colon and Ovary Cancer Screening Project, PLCO) are available. Colorectal carcinomas
The session on colorectal carcinomas involved epidemiology (Peter Boyle, Istituto Europeo di Oncologia, Milano, Italy), genetics (Hansjakob Müller, Basle University, Switzerland) and potential approaches to chemoprevention (Martin Lipkin, Strang Cancer Prevention Center, New York, USA). The influence of diets, especially the Mediterranean diet, was discussed in terms of epidemiological data. Potential preventive methods using selective Cox-2 inhibitors, supplementation of calcium and folic acid were also reviewed. Gad Rennert reported the encouraging results of screening for fecal occult blood (FOB) in Israel. He stressed that centralized testing for hemoglobin in the stool samples by experienced technicians was essential for the success of the screening method. Stool samples were sent by mail with the participation of over 2000 primary care physicians. This low-technology, cost-effective measure has been shown to lower mortality from colorectal cancer in several randomized trials by 15–30% [6]. An alternative method
of screening was presented by Jack Cuzick with the use of flexible sigmoidoscopy in the current mass screening trial. The abstracts of the conference have been published in Supplement 1, vol 38 of the European Journal of Cancer, February 2002 and the full proceedings will be published in Recent Results in Cancer Research by Springer in the fall of 2002. The third international Conference on Tumor Prevention and Genetics is scheduled to be held on 12–14 February 2004, also in St. Gallen, Switzerland. References 1 Fisher, B. et al. (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl. Cancer Inst. 90, 1371–1388 2 Goss, P.E. (2001) Preliminary data from ongoing adjuvant aromatase inhibitor trials. Clin. Cancer Res. 7(Suppl 12), 4397s–4401s 3 Gotzsche, P.C. and Olsen, O. (2000) Is screening for breast cancer with mammography justifiable? Lancet 355, 129–134 4 Olsen, O. and Gotzsche, P.C. (2001) Cochrane review on screening for breast cancer with mammography. Lancet 358, 1340–1342 5 Bartsch, G. et al. (2001) Tyrol Prostate Cancer Screening Group. Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the Federal State of Tyrol, Austria. Urology 58, 417–424 6 Rennert, G. et al. (2001) Population colorectal cancer screening with fecal occult blood test. Cancer Epidemiol. Biomarkers Prev. 10, 1165–1168
Rudolf Morant ZeTuP, Rorschacherstrasse 150, 9006 St. Gallen, Switzerland. e-mail: [email protected]
New! BioMedNet Magazine The new online-only BioMedNet Magazine contains a range of topical articles currently available in Current Opinion and Trends journals, providing some of the finest material available on BioMedNet that deals with matters of daily importance: careers, funding policies, current controversy and changing regulations in the practice of research. You can choose to receive the BioMedNet Magazine delivered directly to your email address. Register now at http://news.bmn.com/magazine
http://tmm.trends.com
News & Comment
TRENDS in Molecular Medicine Vol.8 No.7 July 2002
317
Journal Club
Staphylococci, T cells and neurological function Infections show a panoply of effects on the nervous system, even when confined to a distant limb or organ. We are all aware of the distress of developing a high fever; most have experienced the grim sensations that accompany a bout of the ‘flu or food poisoning. Several mechanisms for these interactions are evident. Cells activated by infectious organisms can induce apoptosis in neural tissues. Cytokines released by far-off maternal sepsis can cross several barriers to damage the fetal brain. A route of morereversible change has been observed using staphylococcal superantigens, normally released from colonizing or infecting organisms in the skin, gut or respiratory tract. In a mouse model, Kawashima and Kusnecov now show that staphylococcal enterotoxin A causes the release of
corticotrophin-releasing hormone, steroid and adrenocorticotrophic hormone in a dose-dependent pattern. The response was unaffected if the T cells were previously suppressed with cyclosporin A, but it was not observed in RAG-1 mice, which have no T or B cells. These cells are therefore crucial, although their mediators and activation were not. The authors went on to examine behavioural effects of this interaction, observing reversible changes in mice exposed to toxin. Other enterotoxins have been associated with anxiety when tested in the mouse model. Perhaps this is relevant to enterotoxinmediated illnesses in children, in which behavioural changes have been documented. Precise parallels are difficult to draw, as the concentrations of enterotoxin used were
relatively high when compared with human equivalents. Questions now arise as to the role of the immune cells in the model. Might they ferry toxins or other mediators into the central nervous system? Staphylococcal toxins could bind to class II molecules expressed in the paraventricular nucleus, an area pivotal to regulation of host defences and the pituitary axis. It becomes tempting to speculate as to the evolutionary advantages to host and staphylococcus of this interplay at the core of the central nervous system. 1 Kawashima, N. and Kusnecov, A.W. (2002) Effects of staphylococcal enterotoxin A on pituitaryadrenal activation and neophobic behavior in the C57BL/6 mouse. J. Neuroimmunol. 123, 41–49
Colin Michie [email protected]
Does ICSI disrupt genomic imprinting? Intracytoplasmic sperm injection (ICSI) is a method of in vitro fertilization in which a sperm is physically introduced into the cytoplasm of the oocyte. It offers a means of circumventing problems of low sperm count or poor sperm motility, and has become a relatively common procedure to treat male infertility. However, along with the hope that it brings to infertile couples, there have inevitably been concerns about whether ICSI might predispose to birth defects. One very real concern is that men with a genetic cause for their infertility, such as Y-chromosome deletions, will pass on the problem to their sons, though this might be considered acceptable if the child is otherwise healthy. Recent studies have also shown evidence for an increase in chromosomal abnormalities and major birth defects in children conceived by ICSI. Now, a new paper raises the possibility that the risk for imprinting disorders might also be elevated.
Certain regions of the genome are imprinted, meaning that expression of genes in that region differs according to whether they were maternally or paternally derived. If the normal imprinting pattern is disrupted, either by deletion, abnormal methylation, or uniparental disomy (UPD) – where both chromosome homologues are derived from the same parent – then an abnormal phenotype can result. The best known examples of imprinting disorders are Prader–Willi syndrome and Angelman syndrome on chromosome 15. Cox et al. report on two unrelated children with Angelman syndrome, both of whom were conceived by ICSI. Molecular investigations showed that both cases were caused by a sporadic imprinting defect. This is a surprising finding, as the vast majority of Angelman cases result from maternal deletion or point mutation of the
UBE3A gene, or paternal UPD. Imprinting defects account for only a small percentage of Angelman cases, with an overall incidence of ~1/300 000 newborns. It is, of course, possible that these two cases represent a rare coincidence, but the authors raise the question of whether the process of artificial fertilization by ICSI might interfere with establishment of the normal methylation pattern in the oocyte. Further studies are most certainly needed, and given that these defects are usually quite rare, long-term follow-up of large cohorts from multiple centres will be needed to fully evaluate any increased risk.
insulin: patients must inject the hormone daily to prevent possibly life-threatening symptoms. Mark Peakman and colleagues (Guy’s, King’s and St. Thomas’ School of Medicine, London, UK) tested the blood of recently diagnosed diabetic patients for immune responses triggered by
Coxsackie B4 virus (CVB4). CVB4 is a common virus, especially prevalent in children. Previous research had indirectly linked CVB4 with type 1 diabetes. Peakman’s research, published in June’s edition of Diabetes, shows that the diabetic blood samples had much stronger
1 Cox, G.E. et al. (2002) Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am. J. Hum. Genet. (in press)
Micheala A. Aldred [email protected]
In Brief
Viral link to diabetes British scientists have unearthed new evidence suggesting that type 1 diabetes can be triggered by viral infection. Type 1 diabetes is an autoimmune condition affecting the body’s ability to produce http://tmm.trends.com
1471-4914/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
5 Brooks, P.C. et al. (1998) Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell 92, 391–400 6 Pike, S.E. et al. (1998) Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth. J. Exp. Med. 188, 2349–2356 7 Celerier, J. et al. (2002) Angiotensinogen and its cleaved derivatives inhibit angiogenesis. Hypertension 39, 224–228 8 Ferrara, N. et al. (1991) The 16K fragment of prolactin specifically inhibits basal or fibroblast growth factor stimulated growth of capillary endothelial cells. Endocrinology 129, 896–900 9 Colorado, P.C. (2000) Anti-angiogenic cues from vascular basement membrane collagen. Cancer Res. 60, 2520–2526 10 Kamphaus, G.D. (2000) Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. J. Biol. Chem. 275, 1209–1215 11 Petitclerc, E. et al. (2000) New functions for non-collagenous domains of human collagen type IV. Novel integrin ligands inhibiting angiogenesis and tumor growth in vivo. J. Biol. Chem. 275, 8051–8061
TRENDS in Molecular Medicine Vol.8 No.7 July 2002
12 Maeshima, Y. (2000) Distinct antitumor properties of a type IV collagen domain derived from basement membrane. J. Biol. Chem. 275, 21340–21348 13 Ramchandran, R. et al. (1999) Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin. Biochem. Biophys. Res. Commun. 255, 735–739 14 Xu, R. et al. (2001) NC1 domain of human type VIII collagen (alpha 1) inhibits bovine aortic endothelial cell proliferation and causes cell apoptosis. Biochem. Biophys. Res. Commun. 289, 264–268 15 Yi, M. and Ruoslahti, E. (2001) A fibronectin fragment inhibits tumor growth, angiogenesis, and metastasis. Proc. Natl. Acad. Sci. U. S. A. 98, 620–624 16 Kuroi, K. (2001) Circulating levels of endostatin in cancer patients. Oncol. Rep. 8, 405–409 17 Standker, L. (1997) Isolation and characterization of the circulating form of human endostatin. FEBS Lett. 420, 129–133 18 Sten-Linder, M. (1999) Angiostatin fragments in urine from patients with malignant disease. Anticancer Res. 19, 3409–3414
315
19 Wakasugi, K. and Schimmel, P. (1998) Two distinct cytokines released from a human aminoacyl-tRNA synthetase. EMBO J. 17, 297–305 20 Moses, M.A. et al. (1999) Troponin I is present in human cartilage and inhibits angiogenesis. Proc. Natl. Acad. Sci. U. S. A. 96, 2645–2650 21 O’Reilly, M. et al. (1999) Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance. J. Biol. Chem. 274, 29568–29571 22 O’Reilly, M.S. et al. (1996) Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat. Med. 2, 689–692 23 Folkman, J. (2001) Angiogenesis research: guidelines for translation to clinical application. Thromb. Haemost. 86, 23–33
Patricia A. D’Amore* Yin-Shan Ng Schepens Eye Research Institute, Depts of Ophthalmology and Pathology, Harvard Medical School, Boston, MA 02114, USA. *e-mail: [email protected]
Meeting Report
Focus on cancer prevention Rudolf Morant Tumor Prevention and Genetics 2002, the 2nd International Conference and 7th Annual Meeting of The International Society of Cancer Chemoprevention (ISCaC) was held in St. Gallen, Switzerland, 14–16 February 2002. Published online: 30 May 2002
This three-day conference at the University of St. Gallen attracted 230 participants from 30 countries. Co-sponsored by the International Society of Cancer Chemoprevention, the European School of Oncology and by the Swiss host, St. Gallen Oncology Conferences, the participants represented various backgrounds from basic scientists to clinical urologists, gynecologists, oncologists, surgeons and epidemiologists, offering an opportunity for interesting discussions on how to advance this field. The topics covered the search for and the assessment of new cancer-susceptibility genes and preclinical models of cancer chemoprevention. More detailed discussions involved clinical chemoprevention and screening efforts in skin tumors, breast cancer, prostate cancer and colorectal carcinomas. http://tmm.trends.com
Breast cancer
D. Lawrence Wickerham [The National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA] discussed the ongoing STAR trial, which compares tamoxifen with raloxifene in the prevention of breast cancer in high-risk women, and has already randomized more than 12 000 women (the target is 22 000). He noticed that the findings of the NSABP-P1 study, which showed a significant reduction with tamoxifen of nearly 50% in breast cancer incidence [1], have not yet been widely incorporated into clinical practice. Many practitioners are apparently reluctant to prescribe a drug with potential serious side-effects, such as thromboembolic events and
endometrial carcinoma, especially as other trials with similar designs in Europe have been negative so far. Trevor Powles (Royal Marsden Hospital, London, UK) warned that there were no data yet to prove the efficacy of tamoxifen in the subgroup of women with gene mutations that predispose high-penetrance breast cancer. Jack Cuzick (Cancer Research UK, London, UK) discussed the planned IBIS-2 trial, which will study the very promising drug anastrozole. This aromatase inhibitor has been recently proven superior to tamoxifen in the adjuvant setting [Arimidex and tamoxifen alone or in combination, (ATAC trial)] [2]. A very lively discussion on the value of mammography screening, chaired by Michael P. Osborne (Strang Cancer Prevention Center, New York, USA) and Jack Cuzick, highlighted the controversial views of Anthony B. Miller (Deutsches Krebsforschungszentrum, Heidelberg, Germany) and Stephen Feig (Mount Sinai Medical Center, New York, USA). The public controversy was initiated by two recent papers by Gotzsche and Olsen [3,4]. Discussion centered on whether it was justified to disregard the (positive) results
1471-4914/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S1471-4914(02)02370-5
Research Update
316
of some older studies because of minor methodological flaws. In spite of these controversies, the vast majority of active researchers in the field continue to support mammography screening. Gad Rennert (National Breast Cancer Screening Program, Haifa, Israel) discussed the political dimensions and influences on screening programs, for example the fact that the US congress forced the National Cancer Institute (NCI) to recommend mammography screening from the age of 40 (instead of 50, as in most other countries), contradictory to the conclusions of the scientific committee. Prostate cancer
Eric Klein (Cleveland Clinic, OH, USA), chairman of the current selenium and vitamin E cancer prevention trial (SELECT) trial, discussed the chemoprevention of prostate cancer. Results of this large randomized US trial of the South West Oncology Group (SWOG) (Seattle, WA, USA) are not expected before the year 2013. Georg Bartsch (Innsbruck, Austria) reported a significant drop in mortality from prostate cancer following the introduction in 1993 of prostatespecific antigen (PSA) mass screening at no cost in the federal state of Tyrol. He also gave a current update of the screening results among men aged 45–75 years. Hans-Peter Schmid (Kantonsspital St. Gallen, Switzerland) advised against
TRENDS in Molecular Medicine Vol.8 No.7 July 2002
introducing mass screening of PSA until the data from the large randomized trials in Europe (European Randomized Study of Screening for Prostate Cancer, ERSPC) and America (Prostate, Lung, Colon and Ovary Cancer Screening Project, PLCO) are available. Colorectal carcinomas
The session on colorectal carcinomas involved epidemiology (Peter Boyle, Istituto Europeo di Oncologia, Milano, Italy), genetics (Hansjakob Müller, Basle University, Switzerland) and potential approaches to chemoprevention (Martin Lipkin, Strang Cancer Prevention Center, New York, USA). The influence of diets, especially the Mediterranean diet, was discussed in terms of epidemiological data. Potential preventive methods using selective Cox-2 inhibitors, supplementation of calcium and folic acid were also reviewed. Gad Rennert reported the encouraging results of screening for fecal occult blood (FOB) in Israel. He stressed that centralized testing for hemoglobin in the stool samples by experienced technicians was essential for the success of the screening method. Stool samples were sent by mail with the participation of over 2000 primary care physicians. This low-technology, cost-effective measure has been shown to lower mortality from colorectal cancer in several randomized trials by 15–30% [6]. An alternative method
of screening was presented by Jack Cuzick with the use of flexible sigmoidoscopy in the current mass screening trial. The abstracts of the conference have been published in Supplement 1, vol 38 of the European Journal of Cancer, February 2002 and the full proceedings will be published in Recent Results in Cancer Research by Springer in the fall of 2002. The third international Conference on Tumor Prevention and Genetics is scheduled to be held on 12–14 February 2004, also in St. Gallen, Switzerland. References 1 Fisher, B. et al. (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl. Cancer Inst. 90, 1371–1388 2 Goss, P.E. (2001) Preliminary data from ongoing adjuvant aromatase inhibitor trials. Clin. Cancer Res. 7(Suppl 12), 4397s–4401s 3 Gotzsche, P.C. and Olsen, O. (2000) Is screening for breast cancer with mammography justifiable? Lancet 355, 129–134 4 Olsen, O. and Gotzsche, P.C. (2001) Cochrane review on screening for breast cancer with mammography. Lancet 358, 1340–1342 5 Bartsch, G. et al. (2001) Tyrol Prostate Cancer Screening Group. Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the Federal State of Tyrol, Austria. Urology 58, 417–424 6 Rennert, G. et al. (2001) Population colorectal cancer screening with fecal occult blood test. Cancer Epidemiol. Biomarkers Prev. 10, 1165–1168
Rudolf Morant ZeTuP, Rorschacherstrasse 150, 9006 St. Gallen, Switzerland. e-mail: [email protected]
New! BioMedNet Magazine The new online-only BioMedNet Magazine contains a range of topical articles currently available in Current Opinion and Trends journals, providing some of the finest material available on BioMedNet that deals with matters of daily importance: careers, funding policies, current controversy and changing regulations in the practice of research. You can choose to receive the BioMedNet Magazine delivered directly to your email address. Register now at http://news.bmn.com/magazine
http://tmm.trends.com
News & Comment
TRENDS in Molecular Medicine Vol.8 No.7 July 2002
317
Journal Club
Staphylococci, T cells and neurological function Infections show a panoply of effects on the nervous system, even when confined to a distant limb or organ. We are all aware of the distress of developing a high fever; most have experienced the grim sensations that accompany a bout of the ‘flu or food poisoning. Several mechanisms for these interactions are evident. Cells activated by infectious organisms can induce apoptosis in neural tissues. Cytokines released by far-off maternal sepsis can cross several barriers to damage the fetal brain. A route of morereversible change has been observed using staphylococcal superantigens, normally released from colonizing or infecting organisms in the skin, gut or respiratory tract. In a mouse model, Kawashima and Kusnecov now show that staphylococcal enterotoxin A causes the release of
corticotrophin-releasing hormone, steroid and adrenocorticotrophic hormone in a dose-dependent pattern. The response was unaffected if the T cells were previously suppressed with cyclosporin A, but it was not observed in RAG-1 mice, which have no T or B cells. These cells are therefore crucial, although their mediators and activation were not. The authors went on to examine behavioural effects of this interaction, observing reversible changes in mice exposed to toxin. Other enterotoxins have been associated with anxiety when tested in the mouse model. Perhaps this is relevant to enterotoxinmediated illnesses in children, in which behavioural changes have been documented. Precise parallels are difficult to draw, as the concentrations of enterotoxin used were
relatively high when compared with human equivalents. Questions now arise as to the role of the immune cells in the model. Might they ferry toxins or other mediators into the central nervous system? Staphylococcal toxins could bind to class II molecules expressed in the paraventricular nucleus, an area pivotal to regulation of host defences and the pituitary axis. It becomes tempting to speculate as to the evolutionary advantages to host and staphylococcus of this interplay at the core of the central nervous system. 1 Kawashima, N. and Kusnecov, A.W. (2002) Effects of staphylococcal enterotoxin A on pituitaryadrenal activation and neophobic behavior in the C57BL/6 mouse. J. Neuroimmunol. 123, 41–49
Colin Michie [email protected]
Does ICSI disrupt genomic imprinting? Intracytoplasmic sperm injection (ICSI) is a method of in vitro fertilization in which a sperm is physically introduced into the cytoplasm of the oocyte. It offers a means of circumventing problems of low sperm count or poor sperm motility, and has become a relatively common procedure to treat male infertility. However, along with the hope that it brings to infertile couples, there have inevitably been concerns about whether ICSI might predispose to birth defects. One very real concern is that men with a genetic cause for their infertility, such as Y-chromosome deletions, will pass on the problem to their sons, though this might be considered acceptable if the child is otherwise healthy. Recent studies have also shown evidence for an increase in chromosomal abnormalities and major birth defects in children conceived by ICSI. Now, a new paper raises the possibility that the risk for imprinting disorders might also be elevated.
Certain regions of the genome are imprinted, meaning that expression of genes in that region differs according to whether they were maternally or paternally derived. If the normal imprinting pattern is disrupted, either by deletion, abnormal methylation, or uniparental disomy (UPD) – where both chromosome homologues are derived from the same parent – then an abnormal phenotype can result. The best known examples of imprinting disorders are Prader–Willi syndrome and Angelman syndrome on chromosome 15. Cox et al. report on two unrelated children with Angelman syndrome, both of whom were conceived by ICSI. Molecular investigations showed that both cases were caused by a sporadic imprinting defect. This is a surprising finding, as the vast majority of Angelman cases result from maternal deletion or point mutation of the
UBE3A gene, or paternal UPD. Imprinting defects account for only a small percentage of Angelman cases, with an overall incidence of ~1/300 000 newborns. It is, of course, possible that these two cases represent a rare coincidence, but the authors raise the question of whether the process of artificial fertilization by ICSI might interfere with establishment of the normal methylation pattern in the oocyte. Further studies are most certainly needed, and given that these defects are usually quite rare, long-term follow-up of large cohorts from multiple centres will be needed to fully evaluate any increased risk.
insulin: patients must inject the hormone daily to prevent possibly life-threatening symptoms. Mark Peakman and colleagues (Guy’s, King’s and St. Thomas’ School of Medicine, London, UK) tested the blood of recently diagnosed diabetic patients for immune responses triggered by
Coxsackie B4 virus (CVB4). CVB4 is a common virus, especially prevalent in children. Previous research had indirectly linked CVB4 with type 1 diabetes. Peakman’s research, published in June’s edition of Diabetes, shows that the diabetic blood samples had much stronger
1 Cox, G.E. et al. (2002) Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am. J. Hum. Genet. (in press)
Micheala A. Aldred [email protected]
In Brief
Viral link to diabetes British scientists have unearthed new evidence suggesting that type 1 diabetes can be triggered by viral infection. Type 1 diabetes is an autoimmune condition affecting the body’s ability to produce http://tmm.trends.com
1471-4914/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.