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Massive unemployment caused by Dnap !!!!! Labs around the country have no choice but to close their doors today. Sending all employees to the unemployment office.Orders have Just Stoped coming in said a Lab Director who did not want to be identify,its spookie he said.LOL No one wants a bunch of dots anymore they want Skin color
- Eye color
- Hair color
- Height
- Weight
- Nose shape
- Distance between eyes
- Distance between cheekbones
- Whether earlobes attached
- Longitude and latitude of face
- Depth of cranium
- Any unusual inherited traits e.g. skull shape
EVERYTHING THAT DNAP OFFERS.
Ming. you must know that if dnap Come out with-
Skin color
- Eye color
- Hair color
- Height
- Weight
- Nose shape
- Distance between eyes
- Distance between cheekbones
- Whether earlobes attached
- Longitude and latitude of face
- Depth of cranium
- Any unusual inherited traits e.g. skull shape
THEY WILL PUT EVERY LAB IN THE COUNTRY OUT OF BUSINESS.AND THIS IS NO JOKE
Have you notice Certain Universitys keep coming up. Stanford...
The Werner Syndrome Gene and Global Sequence Variation - http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WG1-458NN3T-89&_coverDate=01%2F01...
Next there is Dr. Passarino G. who also is a very powerful fiber in the Making of Dnap a reality. - The variability of the mitochondrial genome in human aging: a key for life and death?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_...
“Peopling of Three Mediterranean Islands (Corsica, Sardinia, and Sicily) Inferred by Y-Chromosome Biallelic Variability”
- http://hpgl.stanford.edu/publications/AJPA_2003_v121_p270-279.pdf
“Mutations arising in the wave front of an expanding population - http://hpgl.stanford.edu/publications/PNAS_2004_v101_n4_p975-979.pdf
“Inferring human history: Clues from Y-chromosome haplotypes - http://hpgl.stanford.edu/publications/Underhill_2004_p487-494.pdf
“Origin, diffusion and differentiation of Y-chromosome haplogroups E and J: inferences on the Neolithization of Europe and later migratory events in the Mediterranean area” - http://hpgl.stanford.edu/publications/AJHG_2004_v74_p1023-1034.pdf
The Effective Mutation Rate at Y Chromosome Short Tandem Repeats, with Application to Human Population-Divergence Time” - http://hpgl.stanford.edu/publications/AJHG_2004_v74_p000-000.pdf
The Levant versus the Horn of Africa: Evidence for Bidirectional Corridors of Human Migrations - http://hpgl.stanford.edu/publications/AJHG_2004_v74_p000-0130.pdf
Here also is Dr.Sukernik R.I - http://www.bionet.nsc.ru/ICIG/human/
You need to know about the team players and how they tie in and help to make Dnap strong, here is Dr.Lell, Jeffrey T along with his team of helpers take a look. It will help you understand who,what and why Tony is surrounding hime self with Powerfull people.
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Crawford, Dana
Savage A, Sun F, Crawford DC, Ashley A, Yang Q, Sherman SL. 1997. Sequential sibpair and association studies to detect genes in quantitative traits. Genetic Epidemiology, 14:885-890.
Crawford DC, Newman JL, Meadows KL, Taft LF, Sherman SL. 1997. FRAXA and haplotype associations: Significant differences between African-American and Caucasian populations. Abstract and poster presentation, American Society of Human Genetics, Baltimore MD, Oct. 28-Nov. 2, 1997.
Crawford DC, Sun F, Meadows KL, Newman JL, Taft LF, Ashley-Koch AE, Sherman SL. 1998. Approaches to investigating the mutational processes of the FMR1 gene: Coalescent modeling and haplotype associations in two populations. Poster presentation, European Molecular Biology Organization Workshop, April 1-3, 1998, London England.
Kokoszka, Jason E
Bergen AW, Kokoszka J, Peterson R, Long JC, Virkkunen M, Linnoila M, Goldman D. 1997. Mu opioid receptor gene variants: Lack of association with alcohol dependence. Molecular Psychiatry, 2(6):490-494.
Lell, Jeffrey T
Lell JT, Brown MD, Schurr TG, Sukernik RI, Starikovskaya YB, Torroni A, Moore LG, Troup GM, Wallace DC. 1997. Y chromosome polymorphisms in Native American and Siberian populations: Identification of Native American Y chromosome haplotypes. Hum Gen, 100:536-543.
Wallace DC, Brown MD, Schurr TG, Chen Y-S, Lell JT, Subernik RI, Starikovskaya YB, Olckers A. Mitochondrial DNA and Y chromosome variation in human evolution and disease. 1997. Abstract, Cold Spring Harbor Meeting, Oct. 4-8, 1997, Cold Spring Harbor NY.
Lell JT, Schurr TG, Brown MD, Sukernik RI, Starikovskaya YB, Scozarri R, Cruciani F, Wallace DC. Y chromosome compound haplotype analysis: Implications of the peopling of the Americas and elucidation of intra-Siberian relationships. 1997. Abstract, Am Jn Hum Genet, 61(suppl):A204.
Lell JT, Schurr TG, Brown MD, Sukernik RI, Starikovskaya YB, Scozarri R, Cruciani F, Wallace DC. Y chromosome compound haplotype analysis: Implications of the peopling of the Americas and elucidation of intra-Siberian relationships. 1997. Poster presentation, American Society for Human Genetics Meeting, October 1997, Baltimore MD.
Neal, Karama C
Sattah M, Gazitt T, Eisen A, Neal K, Szauter P, Lucchesi J. 1998. A Drosophila homolog of a putative murine DEAD box RNA helicase. Biological et Biochemica Acta. In press.
Savage, Amanda R
Savage A, Sun F, Crawford D, Ashley A, Yang Q, Sherman SL. 1997. Sequential sibpair and association studies to detect genes in quantitative traits. Genetic Epidemiology. In press.
Lamb N, Feingold E, Savage A, Avramopoulos D, Freeman S, Gu Y, Hallberg A, Hersey J, Karadima G, Pettay D, Saker D, Shen J, Taft L, Mikkelsen M, Petersen M, Hassold T, Sherman SL. 1997. Characterization of susceptible chiasma configurations that increase the risk for maternal nondisjunction of chromosome 21. Human Molecular Genetics, 6:1391-1399.
Savage A, Petersen MB, Mikkelsen M, Hassold T, Sherman SL. 1997. Elucidating the mechanism of paternal nondisjunction of chromosome 21 in humans. Abstract, American Society of Human Genetics, 265.
Feingold E, Savage A, Sherman SL. 1997. A unified method for creating genetic maps for trisomes. Abstract, American Society of Human Genetics, 1145.
Savage A, Petersen MB, Mikkelsen M, Hassold T, Sherman SL. 1997. Elucidating the mechanisms of paternal nondisjunction of chromosome 21 in humans. Oral presentation, American Society of Human Genetics, Oct. 28-Nov. 2, 1997, Baltimore MD.
Westerheide, Sandra
Westerheide SD, Boss JM. Anatomy of the major histocompatibility complex (MHC) Class II enhancer. 1998. Poster presentation, Keystone Symposium: Transcriptional Mechanisms, Feb. 21-26, 1998, Taos, New Mexico.
The strength of the selection barrier between populations.
Pylkov KV, Zhivotovsky LA, Christiansen FB.
N. I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
Genetic differences among populations exposed to selection form barriers against genetic exchange by mortality among hybrids. The strength of such a selection barrier, with which one (recipient) population reacts against immigration from another (donor) population, may be measured as the cumulative mean fitness of hybrids and their descendants relative to the fitness of the recipient population. Previous work analysed a case of weak selection with pairwise epistatic interactions by assuming small genetic distance between two populations in contact. The present study allows large genetic difference between the donor and recipient populations and considers weak multilocus selection with arbitrary epistatic interactions between two or more linked loci. An approximate analytical expression for the barrier strength is obtained as an expansion in which the strength of selection plays the role of a small parameter. It is shown that allele frequencies and gametic linkage disequilibria contribute in different ways to the strength of the selection barrier.
PMID: 11132411 [PubMed - indexed for MEDLINE]
Genetic structure of human populations.
Rosenberg NA, Pritchard JK, Weber JL, Cann HM, Kidd KK, Zhivotovsky LA, Feldman MW.
Molecular and Computational Biology, 1042 West 36th Place DRB 289, University of Southern California, Los Angeles, CA 90089, USA. noahr@usc.edu
We studied human population structure using genotypes at 377 autosomal microsatellite loci in 1056 individuals from 52 populations. Within-population differences among individuals account for 93 to 95% of genetic variation; differences among major groups constitute only 3 to 5%. Nevertheless, without using prior information about the origins of individuals, we identified six main genetic clusters, five of which correspond to major geographic regions, and subclusters that often correspond to individual populations. General agreement of genetic and predefined populations suggests that self-reported ancestry can facilitate assessments of epidemiological risks but does not obviate the need to use genetic information in genetic association studies.
PMID: 12493913 [PubMed - indexed for MEDLINE]
Role of apoptosis in pancreatic beta-cell death in diabetes.
Chandra J, Zhivotovsky B, Zaitsev S, Juntti-Berggren L, Berggren PO, Orrenius S.
Division of Toxicology, Institute for Environmental Medicine, Stockholm, Sweden.
Apoptosis is a physiological form of cell death that occurs during normal development, and critical mediators of this process include caspases, reactive oxygen species, and Ca2+. Excessive apoptosis of the pancreatic beta-cell has been associated with diabetes. Consequently, apoptosis research has focused on how infiltrating macrophages or cytotoxic T-cells might kill pancreatic beta-cells using cytokines or death receptor triggering. Meanwhile, the intracellular events in the target beta-cell have been largely ignored. Elucidation of such targets might help develop improved treatment strategies for diabetes. This article will outline recent developments in apoptosis research, with emphasis on mechanisms that may be relevant to beta-cell death in type 1 and type 2 diabetes. Several of the models proposed in beta-cell killing converge on Ca2+ signaling, indicating that the pancreatic beta-cell may be an ideal system in which to carefully dissect the role of Ca2+ during apoptosis.
PMID: 11272200 [PubMed - indexed for MEDLINE]
Another Dr. Who is helping to win the fight is Dr. Zhivotovsky LA The forensic DNA implications of genetic differentiation between endogamous communities.
Zhivotovsky LA, Ahmed S, Wang W, Bittles AH.
N.I. Vavilov Institute of General Genetics, Moscow, Russia.
In many indigenous minority populations, and among migrants from Asian and African populations now resident in western Europe, North America and Australia, there is a strong tradition of endogamy and a preference for consanguineous unions. These marriage practices can result in F(ST) values greatly in excess of the maximum value (0.01) currently recommended for forensic DNA purposes under guidelines established by the National Research Council (NRC) of the USA. To examine the possible extent of deviation from this accepted norm, three co-resident Pakistani communities were studied using 10 autosomal dinucleotide markers and six tetranucleotide markers on the Y-chromosome. The mean population subdivision coefficient (FST) value was 0.13 for the autosomal loci, and Y-chromosome loci exhibited even stronger differentiation with unique alleles identified in all three communities. The data indicate that even when sub-populations are virtually indistinguishable in terms of anthropology, geography, ethnicity or culture, they may still exhibit major genetic differentiation. Where significant population stratification is known to exist, more detailed genetic databases should be developed for forensic DNA purposes, based on reference data from each of the appropriate sub-populations and not on random or combined samples.
PMID: 11390138 [PubMed - indexed for MEDLINE]
Now Take a look here at Dr. Jonathan Pritchard he's a young man who has a great background and is helping to support the structure of Dnap Goals.He is another Fiber that make us strong. http://pritch.bsd.uchicago.edu/
DNA LEFT AT CRIME SCENE WILL REVEAL SKIN COLOUR
http://www.telegraph.co.uk/connected/main.jhtml?xml=/connected/2004/06/23/ecndna22.xml&sSheet=/c....
DNA left at crime scene will reveal skin colour
By Roger Highfield, Science Editor
(Filed: 22/06/2004)
Scientists have found a way to tell the eye and skin colour of a suspect from the DNA left at the scene of a crime, they report today.
They will soon be able to help police even further by using the same technology to predict hair colour.
The colour of eyes is influenced by the interaction of several genes, according to the study published in the journal Trends in Genetics by Dr Richard Sturm of Queensland University and Dr Tony Frudakis of the company Dnaprint Genomics, Florida.
Using special markers called AIMs that can identify the genetic differences between different populations they have identified the DNA sequences that explain most of the variations in eye colour in Europeans.
"Aside from the Forensic Science Service in Britain, which has a red hair test, there are no other genetic tests for physical characteristics commercially available yet," said Dr Sturm.
The research also questions the wisdom of many school biology textbooks.
Children are usually taught that brown is dominant, so if one parent has brown eyes so does their offspring, while two blue-eyed parents always have a blue-eyed child.
But the team found that, though uncommon, blue-eyed parents can have children with brown eyes. "This is because eye colour is determined by several interacting genes," said Dr Sturm.
You going to like this one on the Dr. Sturm - http://genepi.qimr.edu.au/staff/nick_pdf/CV345.pdf
Check this out on Dr. Sturm - http://genepi.qimr.edu.au/staff/nick_pdf/CV364.pdf
Dr. Sturm another POWER HOUSE or Stone to the foundation if you will.He brings to Dnap great strength he is a very strong FIBER that will help hold it all togeather.
Dr Sturm - Gu Zhu, David M. Evans, David L. Duffy, Grant W. Montgomery, Sarah E. Medland, Nathan A. Gillespie, Kelly R. Ewen, Mary Jewell, Yew Wah Liew, Nicholas K. Hayward, Richard A. Sturm, Jeffrey M. Trent, Nicholas G. Martin. A genome scan for eye colour in 502 twin families: most variation is due to a QTL on chromosome 15q. Twin Research
L. Jin, P. Underhill, V. Doctor, R. W. Davis, P. Shen, L. L. Cavalli-Sforza, and P. Oefner. "Distribution of haplotypes from a chromosome 21 region distinguishes multiple prehistorical human migrations." PNAS, Vol. 96, No. 7, 1999.
And this - Su, B., Xiao, J., Underhill, P., Deka, R., Zhang, W., Akey, J., Huang, W., Shen, D., Lu, D., Luo, J., Chu, J., Tan, J., Shen, P., Davis, R., Cavalli-Sforza, L., Chakraborty, R., Xiong, M., Du, R., Oefner, P., Chen, Z., Lin, J. (1999) Y chromosome evidence for northward migration of modern humans in East Asia during the last ice age. Am.J.Hum.Genet., 65, 1718-1724.
Dr. Underhill has done a lot of work on Ancestry for Dnap and I'm very glad he has.More powerful support to our cause.The Levant versus the Horn of Africa: evidence for bidirectional corridors of human migrations.
Luis JR, Rowold DJ, Regueiro M, Caeiro B, Cinnioglu C, Roseman C, Underhill PA, Cavalli-Sforza LL, Herrera RJ.
Department of Biological Sciences, Florida International University, Miami, 33199, USA.
Paleoanthropological evidence indicates that both the Levantine corridor and the Horn of Africa served, repeatedly, as migratory corridors between Africa and Eurasia. We have begun investigating the roles of these passageways in bidirectional migrations of anatomically modern humans, by analyzing 45 informative biallelic markers as well as 10 microsatellite loci on the nonrecombining region of the Y chromosome (NRY) in 121 and 147 extant males from Oman and northern Egypt, respectively. The present study uncovers three important points concerning these demic movements: (1) The E3b1-M78 and E3b3-M123 lineages, as well as the R1*-M173 lineages, mark gene flow between Egypt and the Levant during the Upper Paleolithic and Mesolithic. (2) In contrast, the Horn of Africa appears to be of minor importance in the human migratory movements between Africa and Eurasia represented by these chromosomes, an observation based on the frequency distributions of E3b*-M35 (no known downstream mutations) and M173. (3) The areal diffusion patterns of G-M201, J-12f2, the derivative M173 haplogroups, and M2 suggest more recent genetic associations between the Middle East and Africa, involving the Levantine corridor and/or Arab slave routes. Affinities to African groups were also evaluated by determining the NRY haplogroup composition in 434 samples from seven sub-Saharan African populations. Oman and Egypt's NRY frequency distributions appear to be much more similar to those of the Middle East than to any sub-Saharan African population, suggesting a much larger Eurasian genetic component. Finally, the overall phylogeographic profile reveals several clinal patterns and genetic partitions that may indicate source, direction, and relative timing of different waves of dispersals and expansions involving these nine populations.
Here's one on statins - Neurology. 2003 Jun 24;60(12):2006-7. Related Articles, Links
Correlation of statin-increased platelet APP ratios and reduced blood lipids in AD patients.
Baskin F, Rosenberg RN, Fang X, Hynan LS, Moore CB, Weiner M, Vega GL.
Department of Neurology, University of Texas Southwestern Medical Center at Dallas, TX 75390-9036, USA. Fred.Baskin@UTSouthwestern.edu
Platelets, like neurons, contain 120- to 130- and 110-kd amyloid precursor proteins (APPs). Their ratio is reduced in AD, further reductions correlating with reduced Mini-Mental Status Examination scores [r(11) = 0.69, p < 0.05]. As statins alter APP processing, platelet APPs were analyzed in patients with AD given anticholesterol drugs for 6 weeks. APP ratios increased [t(37) = -3.888, p = 0.0004], proportionally with reduced cholesterol [r(36) = -0.45, p = 0.005]. Longer trials may reveal slowed cognitive loss, validating this index.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 12821755 [PubMed - indexed for MEDLINE]
Progressive reversion of human immunodeficiency virus type 1 resistance mutations in vivo after transmission of a multiply drug-resistant virus.
Gandhi RT, Wurcel A, Rosenberg ES, Johnston MN, Hellmann N, Bates M, Hirsch MS, Walker BD.
Infectious Diseases Unit, Massachusetts General Hospital, Boston, MA 02114, USA. rgandhi@partners.org
Evolution and transmission of multiply drug-resistant human immunodeficiency virus type 1 (HIV-1) may limit therapeutic options as global treatment efforts expand. However, the stability of these mutants in the absence of drug selection pressure is not known. We performed a longitudinal analysis of plasma virus from a person who acquired HIV-1 that contained multiple reverse transcriptase (RT) and protease (PR) mutations. In the absence of therapy, 5 of 12 drug resistance mutations reverted in a stepwise fashion to wild type over the course of 52 weeks. Reversion of the M184V mutation alone did not change viral replicative capacity (RC), but it led to enhanced resistance to zidovudine and tenofovir. However, reversions of a second RT mutation and 3 PR mutations were associated with an increase in viral RC, and this was temporally correlated with a marked decrease in CD4 cell number. This study demonstrates the gradual stepwise back-mutation of certain drug resistance mutations in vivo in the absence of ongoing drug selection pressure. Moreover, it suggests that, despite initially impaired viral fitness, a transmitted HIV-1 isolate with multiple drug resistance mutations can evolve to develop increased RC and significant pathogenicity.
More from Dr.Rosenberg - Comparison of Alzheimer's disease in Native Americans and Whites.
Weiner MF, Rosenberg RN, Svetlik D, Hynan LS, Womack KB, White C 3rd, Good S, Fuller C, Wharton D, Richter R.
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA. myron.weiner@utsouthwestern.edu
OBJECTIVE: This study compared medical history and findings on initial clinical examination in Native Americans diagnosed with possible or probable Alzheimer's disease (AD) at Native American satellite clinics of the University of Texas (UT) Southwestern Medical Center's Alzheimer's Disease Center with those of Whites diagnosed with probable AD at the UT Southwestern Medical Center's Alzheimer's Disease Clinic. METHODS: The information reviewed was contained in the database of the UT Southwestern Alzheimer's Disease Center. RESULTS: In relation to Whites, Native Americans had slightly but significantly greater age at onset of symptoms (71.7 vs. 69.6 years, t = -2.08, p = .04) and equivalent cognitive scores at evaluation (Mini-Mental State Exam score = 17.4 vs. 18.5, t = 0.98, p = .33), despite significantly lower educational level (11.4 vs. 13.4 years, t = 5.63, p < .001). Native Americans were more frequently depressed on examination (22.8% vs. 9.5%, chi2 = 12, p = .001) and reported diabetes, hypertension, and heart disease significantly more often than did Whites (p < .01 for all), but their survival time after AD diagnosis was similar to that of Whites despite these comorbidities. CONCLUSIONS: With the exception of a greater prevalence of depression and cardiovascular risk factors in Native Americans than in Whites, Native Americans had a course of illness similar to that of Whites.
I the interest of Credibility i have to say Dr. Rosenberg is a fine pick. He is out of the Department of Neurology
University of Rochester NY. He is in Fact a powerful element to have on our side.
Reporting of Randomized Clinical Trials and Other Population-Based Research
A Priority of Archives of Neurology
Arch Neurol. 2004;61:20-21.
The maturation of neuroscience, insights into fundamental mechanisms, and applications of molecular genetics and cellular biology have fueled an unprecedented opportunity to carry out population-based clinical research aimed at identifying key risk factors and therapeutic interventions to relieve the burden of neurologic disease. The reporting of population-based clinical research, particularly of randomized controlled trials (RCTs), represents the final common pathway for translational research and the accrued knowledge base for our health and public policies. The Archives of Neurology editorial board is mindful of this importance and places high priority on the solicitation and publication of excellent reports of RCTs and other population-based neurologic research.
Excellent reporting is primarily dependent on the quality standards of the reported research. We seek well-conceived and scientifically grounded clinical research studies that are controlled and fashioned by statistical expertise, a documented protocol, and a prespecified plan of analysis. To aid comprehension and assessment of RCTs, we require a CONSORT1 (Consolidated Standards of Reporting Trials) format that includes a flow diagram depicting enrollment, intervention allocation, follow-up, and analysis. We also require declarations from authors about human subject protections, sponsors and their relationships to authors, access to study data, and potential conflicts of interest (see "Instructions to Authors" in this issue of the ARCHIVES). We depend on peer review to evaluate the submitted report for accuracy and balanced presentation. When appropriate, we engage critical editorial comment about the scientific rigor, interpretation of data, and public health implications of the study.
Successful reporting of clinical research is also dependent on effective solicitation of authors and manuscripts, scrupulous and balanced peer review, and timely publication of informative articles and comments. Many large-scale RCTs examining neurologic interventions involve lengthy enrollment and require longitudinal observation for many months or even years. As an initiative, we intend to identify promising RCTs (and other population-based research) that have completed enrollment with a well-characterized cohort, including baseline clinical features, a specified plan of follow-up and analysis, and relevant biomarkers when appropriate. Even prior to the completion of follow-up and analysis of the prespecified (therapeutic) outcomes, investigators of these trials are invited to submit concise preliminary reports describing the fully enrolled cohort and study methods. Such reports of the baseline population and its clinical characteristics, prespecified methods of study and analysis, and the plans and timetable for longitudinal follow-up will provide readers with requisite knowledge of important studies in progress and opportunities for critical review. These publications will also set the stage for the eventual reporting of longitudinal data, including the epidemiologic and therapeutic outcomes of interest. This initiative is in keeping with the unmet need to "register" RCTs2 and will help ensure that important negative as well as positive study results reach the scientific public.
The sister ARCHIVES and flagship JAMA publications have substantive resources and experience in the review, copyediting, and publication of RCTs and other population-based clinical research. As a member of the family of American Medical Association publications, Archives of Neurology enjoys distinct advantages in consortium reporting, including an accelerated process of editorial review. JAMA-Express and Archives Express provide authors with an opportunity for expedited review and publication of significant research reports that may affect public health. Submitted articles not judged to merit express publication but still worthy of regular publication do not ordinarily require another round of peer review. With the approval of the authors, submitted express or regular articles that are favorably reviewed but not best suited for JAMA may be considered without additional peer review for publication in Archives of Neurology. Like JAMA, Archives of Neurology will also accept group authorship in the authorship byline with a full appendix listing of all authors and their roles in the research.3 Archives of Neurology also maintains online electronic publishing and an interactive Web site (htttp://www.archneurol.com), inviting reader comments and containing links to other American Medical Association publication sites.
We trust that our initiatives in reporting excellent RCTs and other population-based research will benefit our authors and better inform our readers. We have assembled a subgroup of editors (Louis R. Caplan, MD; Mahlon R. DeLong, MD; James A. Ferendelli, MD; and John H. Growdon, MD) who are experienced in the conduct and reporting of clinical research and who will assist in facilitating this initiative and benchmarking our progress. We invite our authors and readers to comment to us directly (ira.shoulson@ctcc.rochester.edu or Roger.Rosenberg@UTSouthwestern.edu) on how to improve and expand our reporting of RCTs and other population-based clinical research. We believe that these new initiatives will become a vibrant centerpiece for Archives of Neurology and thus encourage submission and publication of the very best clinical research.
Ira Shoulson, MD
Department of Neurology
University of Rochester
1351 Mount Hope Ave, Suite 218
Rochester, NY 14618
Roger N. Rosenberg, MD, Editor
REFERENCES
1. Moher D, Schulz K, Altman D, for the CONSORT Group. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA. 2001;285:1987-1991. ABSTRACT/FULL TEXT
2. Dickersin K, Rennie D. Registering clinical trials. JAMA. 2003;290:516-523. ABSTRACT/FULL TEXT
3. Flanagin A, Fontanarosa PB, DeAngelis CD. Authorship for research groups. JAMA. 2002;288:3166-3168. FULL TEXT
Pharmacogenomics: Personalized Drugs And Personalized Medicine
Introduction:
Modern drug development is a complex process. The first step is the identification of a promising molecular target for drug action. This requires screening of the innumerable possibilities suggested by gene sequencing efforts, for example by the Human Genome Project. Validation aims to test the link between a target sequence and specific diseases. Then there is the need to clarify how the activity of the target sequence is regulated, its physiological relevance and the interaction of the products for which it codes. Advances in genomics (the systematic analysis of an entire genome) will eventually enable the identification of the genetic principles of most pathological and non-pathological phenotypes. It will also redefine the understanding and traditional definitions of diseases.
As the tools for identifying and understanding diseases become more sophisticated and precise, more specific treatments will clearly also have to be offered. Drugs that are precise enough to address a single gene within a gene-family need to be developed, otherwise ‘sledgehammers are created instead of the lasers that are needed’ (Cooke, 1998).
Pharmacogenomics aims to explore whether patients will respond to new drugs, and how. It aims to bridge the gap between gene discovery and drug development, and it is immediately applicable to clinical studies of existing drugs. The rapid growth in information and technology are stimulating enormous progress in this field (Lin, 1996). One important outcome of research in this area is the development of diagnostic tests that help identify the appropriate drug for a given individual.
The benefits of such tests are obvious: Patients avoid risky, painful and often extended investigative procedures to find the optimal treatment methods. A rapid test helps avoid harmful side effects. The systematic discovery and analysis of genetic variety in drug response should also lead to more cost effective drug development. Given that 80% of the compounds fail in clinical trials and industry spends $500-700 million for each new drug approval, considerable benefits may be reaped (Housman, 1998). Prescription based on a precise and rapid instrument for disease identification could also reduce treatment costs. "With this advancement in molecular technology and the financial implications of the results obtained, genotyping of patients before prescribing certain drug therapies is likely to become routine" (Prows, 1998).
The American National Institute for Health has already launched a $36-million programme to detect single nucleotide polymorphisms, so-called SNPs², which can be used in characterizing drug responses, disease susceptibilities, and to study population genetics (Stix, 1998).
New Therapeutic Approaches
Most therapeutic drugs undergo a biotransformation process that takes place, for example, in the liver. Typically, in a one or two-phase process, enzymes transform the lipophilic drug molecules to a more water-soluble metabolite which usually represents the active form of the drug. These metabolites are then further metabolized and eliminated from the body.
This idealized pathway, as it depends on the activity of biocatalysts, is determined by genetic parameters. Small differences or mutations in the genetic make-up, so-called polymorphisms, can cause modifications in the enzymes they encode. These modifications can subsequently be responsible for altered enzyme activity, the genotype determines the phenotype.
Three different drug-response phenotypes have been described (Johnsson, 1993).
Extensive metabolators, which represent the ‘normal’ population,
Slow metabolators, which show little or no ability to metabolize a drug, and
Ultra-extensive metabolators, which metabolize a drug far quicker than the ‘normal’ population.
Both slow metabolators and ultra-extensive metabolators show abnormal concentrations of drugs and their metabolites in their blood plasma. Those who are not able to metabolize these can accumulate high, possibly toxic doses. The ultra-extensive metabolators usually show no clinical response at all because of their tendency to eliminate drugs from body before they can take effect.
Biochemical tests can examine the patient’s phenotype. But these tests, which determine the metabolization ratio of a test drug, are complicated and often they do not exclude the risk of an adverse drug reaction (Prows, 1998). External conditions, such as interacting drugs or the overall disease process, can influence and distort the test.
Genetic tests can circumvent these problems. They do not try to detect the symptoms that are caused by a genetic alteration, they aim to detect the genetic alteration itself. In a subsequent process, this information can be used to draw conclusions about the phenotype.
A New Way For A Personalized Medicine
For the time being genotyping is only used in research. However, many companies are developing genetic tests for pharmacological purposes. In his review of the clinical implications of drugs based on genetic differences David Prows from the University of Cincinnati estimates that genotyping will become an accepted tool within the next five years (Prows, 1998).
The possibility of genotyping patients in order to estimate the risk of adverse drug reactions could pave the way for a more patient-centred health care model. Methods and tests developed by pharmaceogenomics will make it possible to identify groups of patients that will react positively to drugs prescribed to them. Disease-relevant drug-targets will be identified and used "to develop extremely efficacious, broadly tolerated drugs that can be prescribed to the largest possible population. New pharmaceutical products could be marketed alongside a corresponding diagnostic test kit, so as to permit the selective prescription of the drug" (Housman, 1998).
Together with new developments in protein analysis, where simultaneous assays of thousands of analytes will be possible, new integrated approaches in diagnostics can be foreseen. New fabrication technologies and progress in automation will support developments in diagnostics. Miniaturization and micro-fabrication technologies will make this new type of biosensor suitable for automation or even for implantation into the human body. The latter will enable on-line monitoring of high-risk patients. In order to detect the tiny differences in the human genome, which are responsible for diseases or variability in drug response, micro-chips, so-called SNP-chips will soon be on the market. They will definitely "mark the beginning of a personalized medicine" (Schmidt, 1998).
It is estimated that between 1.6 and 4.2 billion dollars are spent each year in the United States for additional treatments to deal with adverse reaction (Classen, 1997), and that they may have caused over 100,000 deaths during 1994 (Lazarou, 1998). Genetic tests would enable the physician to avoid some of these risks and so treat patients more effectively. Tests of this kind can also ensure patients have more information available to help them to make decision affecting their health. Such technologies and procedures will circumvent long-term trial-and-error measures and may reduce costs and risks tremendously. Patients could be checked before or even while a new drug is being administered. It may therefore strengthen the role of primary care, as more accurate diagnosis may reduce the need to consult experts.
In the US such targeted healthcare models have been predicted for 2008, (Poste, 1998), these include:
Genetic and pharmacogenomic profiling, to identify people at risk of developing serious illnesses because of their genetic predisposition
Diagnostics, to complement and support genetic tests
Smart cards for storage of patient information
Database applications for research, development and clinical care,
Counselling in clinical genetics
Pro-active disease management protocols for prophylactic therapy, lifestyle modification, and monitoring.
Although this model seems to be closely tailored to the US health market, some parts may also apply to some European health-care systems. Biotechnology, micro-and nano-technology, and information technology will drive new developments in diagnosis and treatment of disease.
However, despite the promising beneficial trends forecasted for the area of pharmacogenomics and the ability to personalize treatments and drugs, some concerns have been raised. Too sharply focused drugs and therapies may detract from the goal of medicine and pharmacy to find treatments for as many people as possible: pharmacogenomics should not be used to pinpoint the people who are ‘genetically right’ for the drugs pharmaceutical companies want to sell (Schmidt, 1998).
Such a trend would be worrying. It could be a source of new "rare" diseases, and possibly lead to "therapeutic discrimination" against patients with diseases and genotypes that are expensive to treat.
Other experts, however, argue that these fears are unfounded. They reply that both human genomes and diseases are polymorphic enough to make such a development unlikely to happen. The development of niche products for these markets could be an interesting and challenging market for SMEs given an appropriate intellectual property rights framework
In the USA, patient pressure resulted in the Orphan Drug Act in 1983, to stimulate the development of orphan drugs, which cannot be developed economically by industry without incentives. In 1999, the European Parliament approved, at the first reading, the proposed European Regulation on Orphan Medicinal Products, which might be implemented by mid 2000 in the EU Member States. Because of the emphasis on rare diseases, larger number of orphan drugs will result, but in addition the genetic origin of a number of more common diseases will be better understood.
Ethical, Legal And Social Implications
The information produced by pharmacogenomic tests, while potentially valuable for medical treatment, may also be used out of context in ways that are contrary to the interests of the patient. The interests of health-care providers, which-with best intentions – want to produce personalized and evidence based medicine, may be counter to those of the insurance companies, which want to reduce their risks. The risk is a genetic discrimination against people who, while currently healthy, may be genetically predisposed to various diseases. For example, Paul Seymur, of the Faculty and Institute of Actuaries in Great Britain, is concerned that a successful test for Alzheimer’s disease could create an "uninsurable underclass" (Financial Time 1997).
The ability to screen the genetic profile and the predisposition of humans to certain diseases caused by environmental or work related pollutants, for instance, raises the question of the confidentiality of these data and of the possible duty to life insurance. Examples given below show that the communication even of initially harmless information may ultimately have far-reaching consequences:
Some people are known to be "slow acetylators". Slow acetylators show an adverse drug reaction towards certain anaesthetics used in surgery. The adverse reactions can be severe or even fatal. For patients and physicians a genetic test determining the risk of an adverse reaction therefore is a very helpful and potentially life-saving tool. But at the same time insurance companies may be interested in the test result. "Slow acetylator"-women are known to have – under certain conditions – an increased risk of developing breast cancer (Schmidt, 1998).
Genotyping for the "apoE-gene" gives another example of this kind of cross-implication. The "apoE-gene" encodes a protein that is involved in the metabolism of cholesterol. The uptake and the adequate metabolism of cholesterol is directly related to risks of cardiovascular diseases. Testing for apoE genotypes therefore has diagnostic significance for their detection, particularly in the risk assessment of coronary artery disease. However, there is also some evidence that carriers of a certain apoE allele have a higher risk of developing Alzheimer’s Disease.
To Know or Not To Know
The two examples show the kinds of conflicts that may emerge in the near future. Pharmacognomics will definitely help us to sharpen our medical and pharmaceutical tools. Drugs will become more precise and efficient, the risk of toxic side effects will be reduced. But at the same time increasing amounts of information will be collected which may be put to a variety of uses. As shown above some ‘disorders’ which seem to have nothing common on the phenotype level are strongly interwoven on the genetic level. It is therefore possible for patients to become aware inadvertently that they harbour a gene which may have future consequences for their health. This is compounded by the fact that the information will not only affect patients’ own lives, but also those of their relatives. Thus the person affected may be forced to decide whether they should be told. Patients may wish to keep the test information secret, even if it is important information for relatives. Some people may find it hard to cope with this situation and may need properly-trained professional help.
Education And Training
The rapid pace of developments in this area is making it hard for education and training of health-care professionals, in genomics to keep pace. Lack of experience and competence in understanding the clinical implications of genomics may pose serious threats to the successful introduction of these new technologies (Post, 1998).
Educating health-care professionals about the implications and the potential impact of (pharmaco)genetic testing is of tremendous importance in order to ensure the proper evaluation of the data retrieved and to avoid malpractice and misuse. Taking for granted that genetic testing for diseases and physiological characteristics will increase, the need for more specialized doctors and genetic counsellors, is obvious. But, the role of genetic counsellors needs to be defined. Their task could be to examine the value of a test in a particular case and advice whether it makes sense and what information it may provide. They could then further analyse and evaluate the test results together with the experts from the testing laboratory or company (Euroscreen, 1998). The genetic counsellor could give advice and support to both physicians and patients. It could also be their function to prevent malpractice in both the application of tests and the handling of data.
The latter is of tremendous importance for the acceptance of genetically based therapy. Trust and confidence in the new technology is crucial, as the emotionally-charged debates surrounding genetically modified organisms in agriculture and food production have shown. The subjective perception of risks and threats associated with a certain technology can be decisive.
In order to avoid a backlash, protective measures and standards will be required to control the misuse of personal data and malpractice in testing procedures. Also, it will probably be prudent if patient profiling tools are not commercialized prematurely and without rigorous validation (Poste, 1998).
Conclusion
Progress in genomics will lead to the development of various genetic tests applicable in medical practice. They will expand the range of tools available to physicians and complement diagnostic methods. Pharmacogenomics will help to avoid the prescription of potentially toxic drugs, lead to more rapid diagnoses and enable the identification of more effective therapies.
For policy makers, though, there are a number of crucial issues at stake in these developments:
Genetic privacy and confidentiality.
To safeguard the potential benefits of new genetic testing and to enable its optimal use by society, more education and information is not just helpful but essential. A broad social dialogue will be needed on how to implement these new developments acceptably, covering discussions about privacy and confidentiality issues. Clear policies and guidelines are needed to avoid the enormous potential of human genetics being squandered.
Education and training
In contrast to most laboratory tests performed in clinical laboratories on blood or other body fluids or tissues, genetic tests may require extensive counselling before and/or after the test. With the growing availability of tests, the need for well-trained genetic counsellors will increase.
Insurance and the disclosure of information
The disclosure of genetic information needs to be regulated. A further major concern is the problem that in the future more, as yet unknown, conclusions, may be drawn from today’s test results.
Equal access to genetic testing
The availability of genetic tests for a variety of purposes will affect health-care costs. The new methods clearly imply additional costs for the funding system. The question whether the clinical utility of the information retrieved will be sufficient to justify additional payment needs to be addressed. Policy measurers should ensure that the positive trend towards a perosnalized medicine for many does not lead to the social exclusion of others.
For further details please contact: Thomas Munker, IPTS, Tel: +34 95 448 83 19 Fax: +34 95 448 83 26. E-mail: tomas.munker@jrc.es
Thomas Munker
Hay thanks everyone with the DD it was I must say a great and fun cat and mouse game today helping each other find clues,but the time has come for me to attend other matters,you will all have to do without me for a time. LOL Good buy and good night.
Slop. here is the guy who does work for the FBI he helping dnap - http://www.johndouglasmindhunter.com/home.php
This is profiling in crime this is the place - http://www.hermes-press.com/program1.htm
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No slop. Dnap is using these guys instead - http://www.veeco.com/html/product_bymarket_family.asp?exclude=196%2C195%2C197%2C194%2C198%2C132%2C98...
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Maybe Dnap is using these guys - http://www.ezcolor.com/worcesterpd.html
Worcester's Finest Use A Color Management Solution with MonacoPROOF Profiling to Solve and Prove Cases
The BCI (Bureau of Criminal Investigation), a unit within the Worcester Police Department, had to investigate the discovery of two bodies in the second week of May 2001. One of the bodies was ruled a homicide, while the other was undetermined. Worcester, Massachusetts-a city with a population of 180,000-is not considered unsafe. Those who know Worcester consider it to be a diverse yet close-knit, highly spiritual community populated with numerous religious affiliations. Worcester also boasts of having two of the best hospitals in the state, 10 colleges, and beautiful architecture. With all the city has going for it, it's no wonder Lieutenant David Grady of the BCI sounded weary and downtrodden when he said it was a very tough week in Worcester.
The BCI is responsible for conducting follow-up investigations of serious crimes against the person, crimes against property, check and credit fraud, arsons, homicides, and any criminal offenses which are committed within their jurisdiction or as requested by the Chief of Police and the District Attorney's Office.
Modern-day television and movies portray a detective arriving at the crime scene sporting a trench coat and a Polaroid instant or a standard 35mm camera in hand. NYPD Blue, a police drama that purports to be as accurate a police drama there is, shows its detectives taking pictures of the crime scene and victims with Polaroid cameras. Television shows like this are not far off the mark in terms of real-life police investigations, as detectives still use 35mm cameras and, on occasion, the relic Polaroid. Prints of crime scenes produced with these cameras are often used by the DA's Office as evidence in trying to gain a conviction. Or, in some cases, the prints are used for autopsies, where the medical examiner compares the photo from the crime scene to the condition of the victim.
What happens after the shots of the crime scenes are taken? Some police departments send their negatives to an outside photo lab, where color prints are produced and later used as evidence in court. Other police departments that want to avoid the time and cost of outsourcing their photography for color prints, produce their own prints in-house. They may have a workflow in place that includes devices like scanners, computer and monitors, and color printers. In addition to saving time and money, these police departments have complete control over the print process from beginning to end. The BCI had such a workflow, but it was not a perfect solution.
Workflow Was Not Perfect At First: Trial and Error Took It's Toll
Prior to adopting a workflow to produce its own prints, the BCI used a standard 35mm camera and sent the negatives to outside labs for one- to two-day service. The time it took the labs to produce the prints was problematic to the department, as was the quality expected from the unit. "Sometimes the DA's Office or the medical examiner wanted a picture that day," Lieutenant Grady says. "Or they wanted a certain aspect of a photo brought out or made lighter."
The BCI made the investment to purchase a digital camera, monitor, and color printer so that they could develop prints in-house. Although the unit no longer had to rely on outside services to develop their negatives, the workflow process didn't always go smoothly. There were times when a print was not adequate, so Lieutenant Grady would have to recreate a print, often many times. The problem he experienced was that he might see an image on the screen that looked perfect, but once printed, the photo was less than desirable. This trial and error resulted in a great deal of wasted time-time his busy unit didn't have. Lost time was not the only result of the trial and error of the process. Increased costs were also taking its toll on the unit, as the BCI often were forced to waste valuable paper and ink on the prints that were not deemed presentable for the DA's Office or the medical examiner.
Perhaps more importantly, the BCI realized that accurate color can make the difference between convicting a criminal and setting him/her free; therefore, quality of a print plays a large part in the outcome of cases. Lieutenant Grady states that a color-accurate print of an assault victim assures the court that the bruises and abrasions reflect the severity of the crime. For example, a victim may arrive in court healed and in better physical condition than when he/she was assaulted. The prints delivered to the DA's Office accurately depict the severity of the assault, and the jury is not swayed by the present condition of the victim. At first the quality of prints was unacceptable because matching the original with the output from the printer was dependent on human judgment. Initially, the quality of their prints relied on there being a person with a well-trained eye to determine whether the color, lightness, hue and saturation were of the highest quality.
Color Management Corrects The BCI's Workflow Problems: Improves Quality and Reduces Time and Costs
To improve its workflow, the BCI implemented a true CMS (color management system) that included device profiling with its workflow. An effective CMS allows the user to print exactly what he/she sees on the monitor. The profiling software the BCI implemented to make this possible was Monaco Systems MonacoPROOF.
The color management process begins with pictures (taken with a digital camera) being stored on the BCI's computer. In some cases photographs must be scanned and converted to digital files, but for the most part the BCI uses digital cameras. From the computer, the image files are outputted from a color printer. Profiling and device calibration are integral components of the CMS. To profile the scanner, monitor, and Fuji printer, an intuitive interface guides Lieutenant Grady through the process. Calibrating the devices for the best performance is also necessary, as their performance capabilities can change over time. A colorimeter is attached directly to the monitor where the target area flashes a series of colors. The instrument measures each patch, the profiling software collects the measurement data, and the data determines where any performance drift occurs. A spectrophotometer, in conjunction with profiling software, is used to ensure that the correct levels of cyan, magenta, yellow, and black colorants are printed-thus enabling Lieutenant Grady to accurately print the image he sees on his monitor. Color management also allows Lieutenant Grady to soft proof the image by correcting the saturation and/or lightness of the image so that the print can be presented clearly to the jury in court. Once he is satisfied with what he sees on his monitor, he prints the image, which looks exactly like the one on his monitor.
The CMS has made dramatic improvements over the previous workflow. First, it eliminated the vicious cycle of trial and error that existed before color management, thus saving the unit a great deal of time. Lieutenant Grady now sees an image on his screen and knows that the image and print will match each other. "I was trying to close the gap between the difference of what we were seeing on the monitor and what we were actually printing," states Lieutenant Grady. All developing of 8.5" x 11" prints can be done at the BCI within minutes. Larger prints must be sent to photo labs in Worcester, but this is rarely done.
Producing a higher quality print the first time not only saves time; it's a tremendous cost saver to the department. "There is very little guesswork between viewing an image on the monitor and printing it, which means we waste less paper and ink," says Lieutenant Grady. Moreover, there is no need to hire someone to profile the input and output devices in order to produce accurate prints. Lieutenant Grady states that profiling the devices is so easy that the BCI requires no dedicated employee to perform the procedures.
Finally, the department has better quality prints to present to the DA's Office and medical examiner. Says Lieutenant Grady, "MonacoPROOF has increased the accuracy of input to output dramatically. I was amazed with the difference the software made in the color management process." Lieutenant Grady maintains that inaccurate color in prints was, and still is, a serious problem in the outcome of many trials, as injuries suffered by victims or details of property crimes are not always accurately displayed in print. Lieutenant Grady believes this will change when other police departments implement CMS's and device profiling.
The City of Worcester Sets the Standard with Color Management and Device Profiling
The BCI of the Worcester Police Department is setting the standard for advanced forensic science. The unit switched from a 35mm to a digital camera and brought its film development in-house. This meant creating a workflow system that included scanners, monitors, and printers. Although there was some trial and error involved at first, Lieutenant Grady learned through reading articles and conducting research that color management with device profiling existed and that it could improve the unit's workflow tremendously. Lieutenant Grady knows that accurate color is important in the prosecutor's case, and he believes other police departments will come to that conclusion as well.
Color management has traditionally been a technology that serves the photo and art enthusiasts, newspapers, printers, service bureau, but, as Lieutenant Grady can contest, it has proven important to industries like law enforcement. Law enforcers like Lieutenant Grady, who have brought color management in-house, have complete control over the process. This control over photo processing assures Lieutenant Grady that he can present the most accurate prints to the DA's Office so that they can secure a conviction in court. Perhaps in the near future, we'll see Denis Franz of NYPD Blue clicking a digital camera instead of a Polaroid.
OT - R. Mirhashemi, J.F. Arena, T. Frudakis, N. Lambros, J. Arboleda, M. Hunt, M. Medranda, H. Averette, and M. Penalver. Candidate Gene in Predicting in-vivo Ovarian Cancer Response to Combination Therapy with Paraplatin and Paclitaxel
OT- Haplotypes predict therapeutic ovarian cancer response. R. Mirhashemi1, J.F. Arena1, N. Lambrou1, J. Arboleda1, M. Hunt1, H. Averette1, M. Penalver1, M. Thomas2, Z. Gaskin2, S. Gunjupulli2, V. Kondragunta2, P.K. Nachimuthu2, P. Visu2, S. Natarajan2, S. Gunturi2, T. Frudakis2. 1) Dept OB/GYN, D-52, Univ Miami Sch Medicine, Miami, FL; 2) DNAPrint Genomics, Inc., 900 Cocoanut Ave. Sarasota, FL 34236.
Thirty five percent of Ovarian Cancer (OC) patients fail to respond to first-line combination paclitaxel (taxol) and carboplatin (TC) therapy. Poor first line chemotherapy response portends significantly higher patient morbidity and mortality. Because OC patients exhibit wide variability in the TC metabolism, it is possible that some or all of this variable response can be explained in pharmacogenetic terms. To determine whether common polymorphisms are associated with variable TC response, we applied novel analytics and data resources for a candidate gene survey of several drug metabolism genes. After genotyping 42 ovarian cancer patients at 112 SNPs in xenobiotic metabolism genes, we used an empirical (lexigraphical) approach to screen all possible SNP combinations to identify those with haplotype alleles that were genetic features of variable TC response. At the present time, we have identified two such combinations. The first is comprised of 3-SNPs spanning 9.6Kb of the 3 half of the CYP3A4 gene (avg. p<0.004). The second combination contained 3-SNPs spanning a 7.5Kb segment of the 3 half of the CYP2C8 gene (avg. p<0.008). Approximately 61% (25/41) of the patients exhibited a positive Overall TC response during first line treatment. These TC response rates are roughly comparable to the 65% average positive response rate described in previous reports for TC combination therapy. Using an overall clinical response criteria for evaluation of response over the treatment line the accuracy of the responder classification was 96%, the sensitivity of the non-responder classification was 90% and the test overall efficiency was 81%. Our results suggest that first-line TC response is largely a function of xenobiotic metabolism in OC patients, rather than tumor type or stage, and that CYP3A4 and CYP2C8 haplotype combinations are potentially useful for pre-screening OC patients for an individualization of chemotherapy
I like this guy Jeffrey Trent He smart.