Citation Data Identify Alzheimer's, Breast Cancer As Hot Areas

Hot Papers In Medicine, Ranked By Citations Received In November And December 1996 Hot Papers In Biology, Ranked By Citations Received In November And December 1996 Editor's Note: Throughout the year, the newsletter Science Watch, published by the Institute for Scientific Information in Philadelphia, publishes lists of 10 research papers in biology and medicine that are the most cited at the time of publication. These rankings provide a glimpse of current trends in research. The most recent article on biology's hot papers (Science Watch, 8[2]:7, March/April 1997), written by Jeremy Cherfas, a science writer with the Biotechnology and Biological Sciences Research Council of the United Kingdom in Swindon, addresses Alzheimer's disease genetics. Meanwhile, the article on medical research-by David W. Sharp, deputy editor of Lancet-describes risk factors in breast cancer. Following are both Science Watch reports, along with their respective lists, reprinted here with the permission of the newsletter and ISI. For more information on the citation databases and papers discussed in the articles, contact Christopher King, editor of Science Watch, ISI, 3501 Market St., Philadelphia, Pa. 19104; (800) 523-1850, Ext. 1341. Fax: (215) 387-1266. E-mail: cking@isinet.com. World Wide Web: http://www.isinet.com. Molecular medicine took another huge stride forward with the paper at No. 7 in this period's hot paper collection. A vast team, headquartered at the University of Toronto, announced that it had cloned a gene responsible for Alzheimer's disease (AD) in cases in which the disease has an early onset and is strongly heritable. The gene, which is on chromosome 14, joined two other genes on chromosomes 19 and 21 that have also been implicated in AD. Alzheimer's is associated with a wide range of pathologies, but two features are of crucial importance: innumerable extracellular plaques of the small amyloid-ß protein and neurofibrillar tangles. These are intracellular bundles of abnormal filaments of highly phosphorylated forms of the protein tau, which is normally associated with microtubules. Hitherto, genes have been discovered that could have a role in both. On chromosome 19 a mutant form of the apolipoprotein E gene, known as e4, is associated with an increased likelihood of AD that first manifests when the patient is older than 60, a slightly earlier onset. Conversely, another allele, e2, seems to protect against AD. Just how these alleles work is unknown. What is clear is that patients with the e4 allele have even more amyloid-ß plaques in their brains. The other gene associated with AD codes for the ß-amyloid precursor protein. Several mutations have been found, each of which seems to alter the way in which the precursor protein is processed, resulting in the formation of more amyloid-b protein. These mutations have been found in a small number of families that show early-onset AD. The third gene is the one featured in paper No. 7. It was known to be associated with up to 70 percent of the early-onset cases of AD, and is particularly common in the most aggressive form of the disease, which strikes people between 30 and 60 years of age. According to the Toronto team, these findings indicate that this gene must involve a biologically fundamental process early in the path to AD. Using DNA from seven different pedigrees, the group homed in on a gene that gives their conjecture some substance. The gene, called AD3, codes for a large, 467-residue protein that includes seven transmembrane domains. Later, the Toronto group and others published evidence for a very similar gene on chromosome 1 (E.I. Rogaev et al., Nature, 376:775-8, 1995). What exactly the gene does, however, remains something of a mystery. It has a homologue in the much-studied nematode worm Caenorhabditis elegans, specifically in the sperm integral membrane protein SPE-4. The overall structure is roughly similar, with extensive sequence similarities. SPE-4 is involved in the formation of a complex structure that is bound to a bundle of parallel protein fibers and that may be involved in the transport and storage of small proteins. The similarities with Alzheimer's are seductive. AD3 could perhaps be involved in the transport or storage of ß-amyloid precursor protein, or indeed the tau protein, which is also implicated in AD. Patients with mutations in AD3 develop the AD pathology of plaques and tangles on average 10 years before patients with mutations to ß-amyloid precursor protein. Perhaps the mutant form of AD3 somehow promotes the transformation of ß-APP into the amyloid form. Alternatively, the AD3 protein could be a receptor or a channel protein. Mutations in this kind of protein have been linked to other neurological disorders, and even though the pathology of these disorders is not like AD, there is evidence of ion-channel malfunction in AD. Many mutations have been identified in the AD3 gene. The Toronto group found five: three in the transmembrane domains, two in acidic hydrophilic loops that probably lie on the inside of the membrane. Subsequent studies of 12 more pedigrees by a group in France (D. Campion et al., Human Molecular Genetics, 4:2373-7, 1995) found another six mutations in what they call the presenilin 1 gene. One problem is that the mutations so far identified in AD3 are not the kind of nonsense or deletion mutations that would cause instant disruption of function. While that squares with the observation that AD begins late in life, it does not make understanding the pathology of AD any easier. However, given the importance of the condition, and the number of researchers investigating it, further insights are bound to come soon. For 40 years or so, epidemiologists have been pointing to women's natural hormone status as some sort of risk factor for cancer of the breast. When a girl's menstrual cycles begin and when a woman's stop, and what happens in between with respect to timing of first sexual intercourse and childbirth, for example, have been exhaustively studied. The increasing popularity of oral contraception and hormone-replacement therapy (HRT) has complicated analyses and interpretation. Gradually, and for both types of exogenous hormonal manipulation, the balance between the risks and the benefits is becoming clearer. Last June, in a mammoth exercise, the Collaborative Group on Hormonal Factors in Breast Cancer looked at oral contraception (the "pill"). They had data on more than 150,000 women. The conclusion was that there is a slight increase in risk in pill users, but it does not persist when use stops, and disease may be diagnosed at a less advanced clinical stage. The Nurses' Health Study (paper No. 4) adds significantly to the other side of the argument, that relating to the postmenopausal use of estrogens and progestins. The nurses' study began in 1974 when more than 120,000 nurses aged 30 to 55 completed a detailed questionnaire. (The equivalent for men is the Physicians' Health Study.) These women have been followed up, the focus being cancers of various sorts and cardiovascular disease. The database must by now amount to about 1 million woman-years of observation. In June 1992, when this analysis was done, the figure was 725,550 years, with 1,935 newly diagnosed breast cancers. This paper is not groundbreaking, for there was a report a decade ago at the 12-year follow-up point, and there is similar evidence from European studies. Yet the paper clings to the No. 4 position it held in the previous top-10 ranking in the January/February issue of Science Watch (8[1]:5, 1997). That is not surprising. Size may not be everything, but it helps when, as here, there are important public-health implications. Relative to the incidence in women who had never used hormones, the risk of breast cancer was 1.32 times higher in those using estrogens alone and 1.41 in those on estrogens plus progestins. And considerable statistical confidence attaches to those results because of the huge study size. The risk seems greater in older women. Epidemiologists are getting much better at setting their results out in a way that the public can understand. The authors conclude that "women over 55 years of age should carefully consider the risks and benefits of estrogen therapy, especially if they have used estrogen for more than five years." In the same issue, Nancy E. Davidson editorializes that "all postmenopausal women should be apprised of our current understanding of the risks and benefits" (New England Journal of Medicine, 332:1638, 1995). It is not an easy information meal to digest, especially since women themselves will wish to add the less obviously medical advantages of freedom from tiredness and night sweats to the medical case of protection against heart disease and osteoporosis vs. slightly increased risk of cancer. Rank Paper CitationsNov.-Dec. 1996Total citationsthrough March 1997 1. J. Shepherd et al., "Prevention of coronary heart disease with pravastatin in men with hyper-cholesterolemia," New England Journal of Medicine, 333:1301-7, 1995. 43 211 2 A. Colombo et al., "Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance," Circulation, 91:1676-88, 1995. 26 165 3 E.M. Connor et al., "Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment," New Engl.J.Med. 331:1173-80, 1994. 20* 238 4 G.A. Colditz et al., "The use of estrogens and progestins and the risk of breast cancer in postmenopausal women," New Engl. J. Med., 332:1589-93, 1995. 20 180 5 B.M. Psaty et al., "The risk of myocardial infarction associated with antihypertensive drug therapies," JAMA-Journal of the American Medical Association, 274:620-5, 1995. 20 134 6 R.G. Will et al., "A new variant of Creutzfeldt-Jakob disease in the UK," Lancet, 347:921-5, 1996. 20 100 7 R.V. Considine et al., "Serum immunoreactive-leptin concentrations in normal-weight and obese humans," New Engl. J. Med., 334:292-5, 1996. 20 147 8 J.P. Vandenbroucke et al., "Increased risk of venous thrombosis in oral-contraceptive users who are carriers of V Leiden mutation," Lancet, 344:1453-7, 1994. 19 95 9 C.D. Furberg, B.M. Psaty, J.V. Meyer, "Nifedipine: Dose-related increase in mortality in patients with coronary heart disease," Circulation, 92:1326-31, 1995. 18 147 10 Y. Cao et al., "Virologic and immunologic characterization of long-term survivors of human immuno-deficiency virus type 1 infection," New Engl. J. Med., 332:201-8, 1995. 17 187 *Total citations through 1996 were used to rank citation ties for Nov.-Dec. 1996 Source: ISI's Hot Papers Database RankPaperCitationsNov - Dec 1996Total citationsthrough March 1997 1 R.D. Fleischmann et al., "Whole-genome random sequencing and assembly of Haemophilus influenzae Rd," Science, 269:496-512, 1995. 70 459 2 J.D. Thompson, D.G. Higgins, T.J. Gibson, "CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice," Nucleic Acids Research, 22:4673-80, 1994. 62 469 3 Y.Y. Zhang et al., "Positional cloning of the mouse obese gene and its human homologue," Nature, 372:425-32, 1994. 47 467 4 D.W. Nicholson et al., "Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis," Nature, 376:37-43, 1995. 46 308 5 X. Wel et al., "Viral dynamics in human immunodeficiency virus type 1 infection," Nature, 373:117-22, 1995. 44 601 6 D.D. Ho et al., "Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection," Nature, 373:123-6, 1995. 43 640 7 R. Sherrington et al., "Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease," Nature, 375:754-60, 1995. 42 313 8 A. Minden et al., "Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs," Cell, 81:1147-57, 1995. 38 240 9 M. Tewari et al., "Yama/CPP32b, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase," Cell, 81:801-9, 1995. 37* 277 10 C.M. Fraser et al., "The minimal gene complement of Mycoplasma genitalium," Science, 270:397-403, 1995. 37 212 *Total citations through 1996 were used to rank citation ties for Nov.-Dec. 1996 Source: ISI's Hot Papers Database

Citation Data Identify Alzheimer's, Breast Cancer As Hot Areas

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