Showing papers by "Fred Hutchinson Cancer Research Center published in 1996"
TL;DR: After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos.
Abstract: Background Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders. Methods We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial — the Beta-Carotene and Retinol Efficacy Trial — involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo. Results A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P = 0.02), as compared with the placebo group. There were no statistically significant ...
3,417 citations
TL;DR: The evidence for a protective effect of greater vegetable and fruit consumption is consistent for cancers of the stomach, esophagus, lung, oral cavity and pharynx, endometrium, pancreas, and colon, and the types of vegetables or fruit that most often appear to be protective against cancer are raw vegetables.
Abstract: In this review of the scientific literature on the relationship between vegetable and fruit consumption and risk of cancer, results from 206 human epidemiologic studies and 22 animal studies are summarized. The evidence for a protective effect of greater vegetable and fruit consumption is consistent for cancers of the stomach, esophagus, lung, oral cavity and pharynx, endometrium, pancreas, and colon. The types of vegetables or fruit that most often appear to be protective against cancer are raw vegetables, followed by allium vegetables, carrots, green vegetables, cruciferous vegetables, and tomatoes. Substances present in vegetables and fruit that may help protect against cancer, and their mechanisms, are also briefly reviewed; these include dithiolthiones, isothiocyanates, indole-3-carbinol, allium compounds, isoflavones, protease inhibitors, saponins, phytosterols, inositol hexaphosphate, vitamin C, D-limonene, lutein, folic acid, beta carotene, lycopene, selenium, vitamin E, flavonoids, and dietary fiber. Current US vegetable and fruit intake, which averages about 3.4 servings per day, is discussed, as are possible noncancer-related effects of increased vegetable and fruit consumption, including benefits against cardiovascular disease, diabetes, stroke, obesity, diverticulosis, and cataracts. Suggestions for dietitians to use in counseling persons toward increasing vegetable and fruit intake are presented. J Am Diet Assoc. 1996; 96:1027-1039.
2,316 citations
TL;DR: P27 deficiency may cause a cell-autonomous defect resulting in enhanced proliferation in response to mitogens, and in the spleen, the absence of p27 selectively enhanced proliferation of hematopoietic progenitor cells.
1,517 citations
Eugenia E. Calle1, Clark W. Heath1, H. L. Miracle-McMahill1, R. J. Coates2 +185 more•Institutions (41)
TL;DR: Breast cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53297 women with breast cancer and 100239 women without breast cancer from 54 epidemiological studies as mentioned in this paper.
1,253 citations
TL;DR: This review focuses on developments in the last 6-7 years, and cites data resulting from the isolation and characterization of SRC mutants, crystallographic studies of the structures of SH2, SH3 and tyrosine kinase domains, biochemical studies of Src kinase activity and binding properties, and the biology of transgenic and knockout mouse strains.
1,198 citations
TL;DR: Results based on the pre-specified analytic method are presented, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the intervention are presented.
Abstract: Risk Factors for Lung Cancer and for Intervention Effects in CARET, the Beta-Carotene and Retinol Efficacy Trial Gilbert S. Omenn, Gary E. Goodman, Mark D. Thornquist, John Balmes, Mark R. Cullen, Andrew Glass, James P. Keogh, Frank L. Meyskens, Jr., Barbara Valanis, James H. Williams, Jr., Scott Barnhart, Martin G. Cherniack, Carl Andrew Brodkin, Samuel Hammar* Background: Evidence has accumulated from observational studies that people eating more fruits and vegetables, which are rich in (3-carotene (a violet to yellow plant pigment that acts as an antioxidant and can be converted to vitamin A by enzymes in the intestinal wall and liver) and retinol (an al- cohol chemical form of vitamin A), and people having higher serum p-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg (3-carotene and 25 000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18 314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group (active = the daily combination of 30 mg P-carotene and 25 000 IU retinyl palmitate). Promptly after the January 18,1996, announcement that the CARET active in- tervention had been stopped, we published preliminary find- ings from CARET regarding cancer, heart disease, and total mortality. Purpose: We present for the first time results based on the pre-specified analytic method, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the interven- tion. Methods: CARET was a randomized, double-blinded, placebo-controlled chemoprevention trial, initiated with a pilot phase and then expanded 10-fold at six study centers. Cigarette smoking history and status and alcohol intake were assessed through participant self-report. Serum was collected from the participants at base line and periodically after randomization and was analyzed for p-carotene con- centration. An Endpoints Review Committee evaluated end- point reports, including pathologic review of tissue specimens. The primary analysis is a stratified logrank test for intervention arm differences in lung cancer incidence, with weighting linearly to hypothesized full effect at 24 months after randomization. Relative risks (RRs) were es- timated by use of Cox regression models; tests were per- formed for quantitative and qualitative interactions between the intervention and smoking status or alcohol intake. O'Brien-Fleming boundaries were used for stopping criteria at interim analyses. Statistical significance was set at the .05 1550 ARTICLES a value, and all P values were derived from two-sided statis- tical tests. Results: According to CARET'S pre-specified analysis, there was an RR of 136 (95% confidence interval [CI] = 1.07-1.73; P = .01) for weighted lung cancer incidence for the active intervention group compared with the placebo group, and RR = 1.59 (95% CI = 1.13-2.23; P = .01) for weighted lung cancer mortality. All subgroups, except former smokers, had a point estimate of RR of 1.10 or greater for lung cancer. There are suggestions of associa- tions of the excess lung cancer incidence with the highest quartile of alcohol intake (RR = 1.99; 95% CI = 1.28-3.09; test for heterogeneity of RR among quartiles of alcohol in- take has P = .01, unadjusted for multiple comparisons) and with large-cell histology (RR = 1.89; 95% CI = 1.09-3.26; test for heterogeneity among histologic categories has P = .35), but not with base-line serum p-carotene concentrations. Conclusions: CARET participants receiving the combination of P-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for p-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Preven- tion Study in 29 133 male smokers in Finland. Implications: Individuals at high risk of developing lung cancer, i.e., cur- rent smokers and asbestos-exposed workers, should be dis- couraged from taking supplemental P-carotene (and the combination of p-carotene with vitamin A). Safety and ef- ficacy should be demonstrated before recommending use of vitamin supplements in any population. [J Natl Cancer Inst * Affiliations of authors: G. S. Omenn, S. Bamhart, C A. Brodkin, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, and Departments of Environmental Health and Medicine, University of Washington, Seattle; G. E. Goodman, Division of Public Health Sciences. Fred Hutchinson Cancer Research Center, Departments of Environmental Health and Medicine, University of Washington, and Swedish Hospital Tumor Institute, Seattle; M. D. Thomquist, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, J. Balmes, Department of Medicine, University of California at San Francisco; M. R. Cullen, M. G. Chemiack, Department of Medicine, Yale University, New Haven, CT; A. Glass, B. Valanis, Kaiser Permanente Center for Health Research, Portland, OR; J. P. Keogh, Department of Medicine, University of Maryland, Baltimore; F. L Meyskens, Jr., J. H. Williams, Jr., Department of Medicine and Cancer Center, University of California/Irvine, Orange; S. Hammar, Departments of Environmen- tal Health and Pathology, University of Washington. Correspondence to: Gilbert S. Omenn, M.D., Ph.D., Fred Hutchinson Cancer Research Center, 1124 Columbia St., MP-859, Seattle, WA 98104. See Notes section following References. Journal of the National Cancer Institute, Vol. 88, No. 21, November 6, 1996
1,176 citations
TL;DR: A highly divergent human MHC class I molecule, MICA, encodes a cell surface glycoprotein, which is not associated with beta 2-microglobulin, is conformationally stable independent of conventional class I peptide ligands, and almost exclusively expressed in gastrointestinal epithelium.
Abstract: Conventional major histocompatibility complex (MHC) class I genes encode molecules that present intracellular peptide antigens to T cells. They are ubiquitously expressed and regulated by interferon gamma. Two highly divergent human MHC class I genes, MICA and MICB, are regulated by promoter heat shock elements similar to those of HSP70 genes. MICA encodes a cell surface glycoprotein, which is not associated with beta 2-microglobulin, is conformationally stable independent of conventional class I peptide ligands, and almost exclusively expressed in gastrointestinal epithelium. Thus, this MHC class I molecule may function as an indicator of cell stress and may be recognized by a subset of gut mucosal T cells in an unusual interaction.
1,036 citations
TL;DR: It is shown that expression of the human papillomavirus type 16 (HPV-16) E6 protein activates telomerase in early-passage human keratinocytes and mammary epithelial cells, indicating that telomerases activation is an intrinsic, but insufficient, component of transformation by HPV.
Abstract: Activation of telomerase, a ribonucleoprotein complex that synthesizes telomere repeat sequences, is linked to cell immortalization and is characteristic of most cell lines and tumours. Here we show that expression of the human papillomavirus type 16 (HPV-16) E6 protein activates telomerase in early-passage human keratinocytes and mammary epithelial cells. This activation was observed in cells pre-crisis, that is, before they became immortal, and occurred within one passage of retroviral infection with vectors expressing HPV-16 E6. Studies using HPV-16 E6 mutants showed that there was no correlation between the ability of the mutants to activate telomerase and their ability to target p53 for degradation, suggesting that telomerase activation by HPV-16 E6 is p53 independent. Keratinocytes expressing wild-type HPV-16 E6 have an extended lifespan, but do not become immortal, indicating that telomerase activation and E6-mediate degradation of p53 are insufficient for their immortalization. These results show that telomerase activation is an intrinsic, but insufficient, component of transformation by HPV.
821 citations
TL;DR: It is shown that the related chaperone, calreticulin, binds human class I-beta 2m dimers prior to peptide loading, suggesting that calretiulin remains associated with at least a subset of class I molecules when they, in turn, bind to TAP.
714 citations
TL;DR: In this paper, the ability of specific mitogens to allow transit through the restriction point paralleled their ability to downregulate p27, and antisense inhibition of p27 expression prevented cell cycle arrest in response to mitogen depletion.
Abstract: Cells deprived of serum mitogens will either undergo immediate cell cycle arrest or complete mitosis and arrest in the next cell cycle. The transition from mitogen dependence to mitogen independence occurs in the mid- to late G 1 phase of the cell cycle and is called the restriction point. Murine Balb/c-3T3 fibroblasts deprived of serum mitogens accumulated the cyclin-dependent kinase (CDK) inhibitor p27 Kip1 . This was correlated with inactivation of essential G 1 cyclin-CDK complexes and with cell cycle arrest in G 1 . The ability of specific mitogens to allow transit through the restriction point paralleled their ability to down-regulate p27, and antisense inhibition of p27 expression prevented cell cycle arrest in response to mitogen depletion. Therefore, p27 is an essential component of the pathway that connects mitogenic signals to the cell cycle at the restriction point.
713 citations
TL;DR: Two murine proteins, Mena and Evl, that are highly related to Enabled as well as VASP (Vasodilator-Stimulated Phosphoprotein) are identified, supporting a role for this protein in microfilament assembly and cell motility.
TL;DR: Results are in contrast to studies linking p53 loss with resistance to DNA damaging anticancer agents, as Surviving cells with intact p53 progressed through mitosis and transiently accumulated in the subsequent G1 phase, coincident with increased p53 and p21cip1,waf1 protein levels.
Abstract: The anticancer agent paclitaxel (Taxol) stabilizes tubulin polymerization resulting in arrest in mitosis and apoptotic cell death. Normal human fibroblasts depleted of functional p53 by SV40 T antigen or HPV-16 E6, and primary embryo fibroblasts from p53 null mice showed seven- to ninefold increased cytotoxicity by paclitaxel. Reduced levels of p53 correlated with increased G2/M phase arrest, micronucleation, and p53-independent paclitaxel-induced apoptosis. Surviving cells with intact p53 progressed through mitosis and transiently accumulated in the subsequent G1 phase, coincident with increased p53 and p21cip1,waf1 protein levels. These results are in contrast to studies linking p53 loss with resistance to DNA damaging anticancer agents.
TL;DR: Pregnancies among all women who received a marrow transplant are likely to be accompanied by preterm labor and delivery of LBW or VLBW babies who do not seem to be at an increased risk of congenital anomalies, but determination of possible adverse effects of parental exposure to high-dose alkylating agents with or without TBI on children born posttransplant requires longer, additional follow-up.
TL;DR: Delaying the start of ganciclovir until highgrade antigenemia and discontinuing gancIClovir based on negative antigenemia results in more CMV disease by day 100 than gancinglovir administered at engraftment, however, gancclovir at engRAFTment is associated with more early invasive fungal infections and more late CMV Disease resulting in similar survival rates.
TL;DR: The death of Brca1(5-6) mutant embryos prior to gastrulation may be due to a failure of the proliferative burst required for the development of the different germ layers, and the fact that mutant blastocyst growth is grossly impaired in vitro.
TL;DR: An immunotherapy trial in which individuals seropositive for human immunodeficiency virus receive CD8+ HIV–specific cytotoxic T cells modified by retroviral transduction to express a gene permitting positive and negative selection suggests that strategies to render gene–modified cells less susceptible to host immune surveillance will be required for successful gene therapy of immunocompetent hosts.
Abstract: The introduction and expression of genes in somatic cells is an innovative therapy for correcting genetic deficiency diseases and augmenting immune function. A potential obstacle to gene therapy is the elimination of such gene-modified cells by an immune response to novel protein products of the introduced genes. We are conducting an immunotherapy trial in which individuals seropositive for human immunodeficiency virus (HIV) receive CD8+ HIV-specific cytotoxic T cells modified by retroviral transduction to express a gene permitting positive and negative selection. However, five of six subjects developed cytotoxic T-lymphocyte responses specific for the novel protein and eliminated the transduced cytotoxic T cells. The rejection of genetically modified cells by these immunocompromised hosts suggests that strategies to render gene-modified cells less susceptible to host immune surveillance will be required for successful gene therapy of immunocompetent hosts.
TL;DR: It is shown that the ubiquitously expressed 11-zinc-finger factor CTCF is an exceptionally highly conserved protein displaying 93% identity between avian and human amino acid sequences, and provides the first feasible explanation of how certain homologous genes of different vertebrate species are regulated by the same factor and maintain similar expression patterns despite significant promoter sequence divergence.
Abstract: We have isolated and analyzed human CTCF cDNA clones and show here that the ubiquitously expressed 11-zinc-finger factor CTCF is an exceptionally highly conserved protein displaying 93% identity between avian and human amino acid sequences. It binds specifically to regulatory sequences in the promoter-proximal regions of chicken, mouse, and human c-myc oncogenes. CTCF contains two transcription repressor domains transferable to a heterologous DNA binding domain. One CTCF binding site, conserved in mouse and human c-myc genes, is found immediately downstream of the major P2 promoter at a sequence which maps precisely within the region of RNA polymerase II pausing and release. Gel shift assays of nuclear extracts from mouse and human cells show that CTCF is the predominant factor binding to this sequence. Mutational analysis of the P2-proximal CTCF binding site and transient-cotransfection experiments demonstrate that CTCF is a transcriptional repressor of the human c-myc gene. Although there is 100% sequence identity in the DNA binding domains of the avian and human CTCF proteins, the regulatory sequences recognized by CTCF in chicken and human c-myc promoters are clearly diverged. Mutating the contact nucleotides confirms that CTCF binding to the human c-myc P2 promoter requires a number of unique contact DNA bases that are absent in the chicken c-myc CTCF binding site. Moreover, proteolytic-protection assays indicate that several more CTCF Zn fingers are involved in contacting the human CTCF binding site than the chicken site. Gel shift assays utilizing successively deleted Zn finger domains indicate that CTCF Zn fingers 2 to 7 are involved in binding to the chicken c-myc promoter, while fingers 3 to 11 mediate CTCF binding to the human promoter. This flexibility in Zn finger usage reveals CTCF to be a unique "multivalent" transcriptional factor and provides the first feasible explanation of how certain homologous genes (i.e., c-myc) of different vertebrate species are regulated by the same factor and maintain similar expression patterns despite significant promoter sequence divergence.
TL;DR: Allogeneic stem-cell transplantation can be curative in young patients with symptomatic sickle cell disease and Kaplan-Meier estimates of survival and event-free survival at four years were 91 percent and 73 percent, respectively.
Abstract: BACKGROUND We investigated the risks and benefits of allogeneic bone marrow transplantation in children with complications of sickle cell disease. METHODS Twenty-two children less than 16 years of age who had symptomatic sickle cell disease received marrow allografts from HLA-identical siblings between September 1991 and April 1995. The indications for transplantation included a history of stroke (n = 12), recurrent acute chest syndrome (n = 5), and recurrent painful crises (n = 5). Patients were prepared for transplantation with busulfan, cyclophosphamide, and antithymocyte globulin. RESULTS Twenty of the 22 patients survived, with a median follow-up of 23.9 months (range, 10.1 to 51.0), and 16 patients had stable engraftment of donor hematopoietic cells. In three patients the graft was rejected and sickle cell disease recurred; in a fourth patient graft rejection was accompanied by marrow aplasia. In 1 of the 16 patients with engraftment, there was stable mixed chimerism. Two patients died of central nervous system hemorrhage or graft-versus-host disease. Kaplan-Meier estimates of survival and event-free survival at four years were 91 percent and 73 percent, respectively. Among patients with a history of acute chest syndrome, lung function stabilized; among patients with prior central nervous system vasculopathy who had engraftment, stabilization of cerebrovascular disease was documented by magnetic resonance imaging. CONCLUSIONS Allogeneic stem-cell transplantation can be curative in young patients with symptomatic sickle cell disease.
TL;DR: Fibrillar collagen specifically regulates early integrin signaling that may lead to up-regulation of cdk2 inhibitors and inhibition of SMC proliferation, a possible regulator of p27Kip1.
TL;DR: Results suggest that V HL regulates VEGF expression at a post-transcriptional level and that VHL inactivation in target cells causes a loss of VEGf suppression, leading to formation of a vascular stroma.
Abstract: The VHL tumor suppressor gene is inactivated in patients with von Hippel-Lindau disease and in most sporadic clear cell renal carcinomas. Although VHL protein function remains unclear, VHL does interact with the elongin BC subunits in vivo and regulates RNA polymerase II elongation activity in vitro by inhibiting formation of the elongin ABC complex. Expression of wild-type VHL in renal carcinoma cells with inactivated endogenous VHL resulted in unaltered in vitro cell growth and decreased vascular endothelial growth factor (VEGF) mRNA expression and responsiveness to serum deprivation. VEGF is highly expressed in many tumors, including VHL-associated and sporadic renal carcinomas, and it stimulates neoangiogenesis in growing solid tumors. Despite 5-fold differences in VEGF mRNA levels, VHL overexpression did not affect VEGF transcription initiation or elongation as would have been suggested by VHL-elongin association. These results suggest that VHL regulates VEGF expression at a post-transcriptional level and that VHL inactivation in target cells causes a loss of VEGF suppression, leading to formation of a vascular stroma.
TL;DR: How muscle necrosis can negatively impact the kidney, potentially culminating in tubular necrosis and ARF is discussed, to review current and possible future pharmacologic approaches for the management of this dramatic and often life threatening "myo-renal syndrome".
TL;DR: It is found that cyclin E is degraded by the ubiquitin-proteasome system, and that this degradation is regulated by both cdk2 binding andcdk2 catalytic activity.
Abstract: Cyclin E is a mammalian G1 cyclin that is both required and rate limiting for entry into S phase. The expression of cyclin E is periodic, peaking at the G1-S transition and then decaying as S phase progresses. To understand the mechanisms underlying cyclin E periodicity, we have investigated the regulation of cyclin E degradation. We find that cyclin E is degraded by the ubiquitin-proteasome system, and that this degradation is regulated by both cdk2 binding and cdk2 catalytic activity. Free cyclin E is readily ubiquitinated and degraded by the proteasome. Binding to cdk2 protects cyclin E from ubiquitination, and this protection is reversed by cdk2 activity in a process that involves phosphorylation of cyclin E itself. The data are most consistent with a model in which cdk2 activity initiates cyclin E degradation by promoting the disassembly of cyclin E-cdk2 complexes, followed by the ubiquitination and degradation of free cyclin E.
TL;DR: It is proposed that the Hat2p/Rbap48 family serve as escorts of histone metabolism enzymes to facilitate their interaction with histone H4.
TL;DR: This novel protein, p150(ship) (SH2-containing inositol phosphatase), identifies a component of a new growth factor-receptor signaling pathway in hematopoietic cells.
Abstract: The production, survival, and function of monocytes and macrophages is regulated by the macrophage colony-stimulating factor (M-CSF or CSF-1) through its tyrosine kinase receptor Fms. Binding of M-CSF to Fms induces the tyrosine phosphorylation and association of a 150-kD protein with the phosphotyrosine-binding (PTB) domain of Shc. We have cloned p150 using a modified yeast two-hybrid screen. p150 contains one SH2 domain, two potential PTB-binding sites, an ATP/GTP-binding domain, several potential SH3-binding sites, and a domain with homology to inositol polyphosphate-5-phosphatases. p150 antibodies detect this protein in FDC-P1 myeloid cells, but the same protein is not detectable in fibroblasts. The antibodies immunoprecipitate a 150-kD protein from quiescent or M-CSF-stimulated FDC-P1 cells that hydrolyzes PtdIns(3,4,5)P3, to PtdIns(3,4)P2. This activity is observed in Shc immunoprecipitates only after M-CSF stimulation. Retroviral expression of p15O in FD-Fms cells results in strong inhibition of cell growth in M-CSF and a lesser inhibition in IL-3. Ectopic expression of p150 in fibroblasts does not inhibit growth. This novel protein, p150(ship) (SH2-containing inositol phosphatase), identifies a component of a new growth factor-receptor signaling pathway in hematopoietic cells.
TL;DR: Analysis of the regulation of cyclin-dependent kinases in Drosophila has provided insights into how this embryonic program of cell proliferation is controlled at the molecular level and how it is linked to developmental cues.
Abstract: During early development in many species, maternally supplied gene products permit the cell cycle to run at maximum velocity, subdividing the fertilized egg into smaller and smaller cells. As development proceeds, zygotic controls are activated that first limit divisions to defined spatial and temporal domains, coordinating them with morphogenesis, and then halt proliferation altogether, to allow cell differentiation. Analysis of the regulation of cyclin-dependent kinases (Cdks) in Drosophila has provided insights into how this embryonic program of cell proliferation is controlled at the molecular level and how it is linked to developmental cues. Recent studies have also begun to reveal how cell proliferation is controlled during the second phase of Drosophila development, which occurs in imaginal tissues. In contrast to their embryonic progenitors, imaginal cells proliferate with a cycle that requires cell growth and is linked to patterning processes controlled by secreted cell signaling molecules. The functions of these signaling molecules appear to be nearly as conserved between vertebrates and invertebrates as the cell cycle control apparatus itself, suggesting that the mechanisms that coordinate growth, patterning, and cell proliferation in developing tissues have ancient origins.
TL;DR: The crystal structure of an unmodified hammerhead RNA in the absence of divalentMetal ions has been solved, and it was shown that this ribozyme can cleave itself in the crystal when divalent metal ions are added.
Abstract: The crystal structure of an unmodified hammerhead RNA in the absence of divalent metal ions has been solved, and it was shown that this ribozyme can cleave itself in the crystal when divalent metal ions are added. This biologically active RNA fold is the same as that found previously for two modified hammerhead ribozymes. Addition of divalent cations at low pH makes it possible to capture the uncleaved RNA in metal-bound form. A conformational intermediate, having an additional Mg(II) bound to the cleavage-site phosphate, was captured by freeze-trapping the RNA at an active pH prior to cleavage. The most significant conformational changes were limited to the active site of the ribozyme, and the changed conformation requires only small additional movements to reach a proposed transition-state.
TL;DR: This retrospective comparison suggests that compared to marrow transplantation from HLA-identical donors, allogeneic PBSC transplants from Hla-Identical donors is associated with faster engraftment, fewer transfusions, and no greater incidence of acute or chronic GVHD.
TL;DR: The highest risk of developing a solid tumor was associated with the diagnosis of Fanconi anemia, and better prevention of GVHD or omission of azathioprine as GV HD therapy (or both) may reduce the risk of late tumor development.
TL;DR: It is shown that pie-1 encodes a nuclear protein, PIE-1, that is localized to the germline blastomeres throughout early development and provides an example of a repressor-based mechanism for preserving pluripotency within a stem cell lineage.
Abstract: Totipotent germline blastomeres in Caenorhabditis elegans contain, but do not respond to, factors that promote somatic differentiation in other embryonic cells. Mutations in the maternal gene pie-1 result in the germline blastomeres adopting somatic cell fates. Here we show that pie-1 encodes a nuclear protein, PIE-1, that is localized to the germline blastomeres throughout early development. During division of each germline blastomere, PIE-1 initially associates with both centrosomes of the mitotic spindle. However, PIE-1 rapidly disappears from the centrosome destined for the somatic daughter, and persists in the centrosome of the daughter that becomes the next germline blastomere. The PIE-1 protein contains potential zinc-finger motifs also found in the mammalian growth-factor response protein TIS-11/NUP475 (refs 4-7). The localization and genetic properties of pie-1 provide an example of a repressor-based mechanism for preserving pluripotency within a stem cell lineage.
TL;DR: The data suggest that vegetables are associated with lower risk, and that fiber alone does not account for this association, but meat consumption is associated with increased risk but this, too, is not explained solely by its fat content.
Abstract: Epidemiologic evidence on the relation between nutrition and colorectal cancer is reviewed. Colon cancer varies approximately 20-fold internationally. Although there is clear evidence of genetic predisposition to colon cancer, much of this variation appears to be related to differences in dietary habits. At present, the data suggest that vegetables are associated with lower risk, and that fiber alone does not account for this association. Further, meat consumption is associated with increased risk but this, too, is not explained solely by its fat content. Several microconstituents of the diet may be associated with reduced risk--including folate and calcium--but phytochemicals of other sorts may be relevant. Mutagenic compounds, particularly heterocyclic amines, produced when protein is cooked, plausibly explain the meat association. The most consistent inverse association is with physical activity. Alcohol is associated, though inconsistently, with increased risk. Rectal cancer is less well studied but, at present, there are few data to suggest that the dietary risk factors are markedly different. Physical activity does not appear to be associated with a lower risk. Colorectal adenomatous polyps also appear to share the spectrum of risk factors seen with colon cancer, although, for adenomas, tobacco smoking is also a clear and consistent risk factor. There are a variety of links between the dietary epidemiology and physiology of colorectal neoplasia and the relevant pathologic and molecular changes. Other causal connections remain to be explicated.