tbuckley/cabot-search huggingface dataset:
The human chromosome 9 region orthologous to Mcs5a, a rat composite modifier locus, contains a breast cancer risk allele.
Authors: David J. Samuelson, Stephanie E. Nelson, Beth A. Aperavich, Jill D. Haag, Amy Trentham-Dietz, Robert Mau, Louis L. Gardner, J. M. Hampton, Paul D. Pharoah, M. Shah, R. N. Luben, A. Dunning, Bruce Aj Ponder, Michael N. Gould
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

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We have used a rat breast cancer model to identify and narrow an orthologous human genomic region for testing in a breast cancer case-control SNP-association study. Mcs5a , one of three subloci identified within the Wistar-Kyoto (WKy) Mcs5 QTL, confers resistance to DMBA-, NMU- and, HER2/ neu -induced mammary carcinomas in the rat. Congenic female rats (WF.WKy line O) with two Mcs5a WKy alleles developed 3.9±0.4, 2.2±0.4, and 9.9±1.1 mammary carcinomas/rat for DMBA, NMU, and HER2/ neu treatments, respectively. The WF.WKy females with two Mcs5a WF alleles averaged 8.9±0.8, 3.8±0.5, and 17.1±1.9 mammary carcinomas/rat when administered DMBA, NMU, or HER2/ neu , respectively. Mcs5a has been fine mapped, using a series of overlapping congenic lines, and shown to be a composite locus consisting of a genetic interaction between at least two adjacent genetic elements ( Mcs5a1 and Mcs5a2 ). Both Mcs5a1 and Mcs5a2 are required to be WKy alleles in order to confer the decreased mammary carcinoma susceptibility phenotype (i.e. the presence of WF alleles at either locus results in abrogation of the resistance phenotype). A recombinant congenic line (B3) from line O that is WKy-homozygous at Mcs5a1, but WF-homozygous at Mcs5a2 averaged 7.6±0.9 DMBA-induced mammary carcinomas/rat. Another line O recombinant congenic line (LL) that is WF-homozygous at Mcs5a1, but WKy-homozygous at Mcs5a2 averaged 7.1±0.5 DMBA-induced mammary carcinomas/rat. These phenotypes were not different from females of each line that were WF-homozygous at both loci and averaged 7.9±0.7 and 8.1±0.7 mammary carcinomas/rat, respectively. These DMBA-susceptible lines, B3 and LL, overlap by ∼400 bp on their opposing, distal and proximal ends. Two additional line O recombinant lines (WW and XX) that overlap by ∼116 Kb at their respective distal and proximal ends within this same genomic region have DMBA-resistance phenotypes similar to the parental Mcs5a line (O). Line WW females averaged 4.3±0.5 and line XX females averaged 5.3±0.3 DMBA-induced mammary carcinomas/rat. Respectively, the Mcs5a1 and Mcs5a2 orthologous regions are localized to 32 and 84 Kb on rat chromosome 5 ; and 30 and 63 Kb on human chromosome 9 . A SNP with a minor allele frequency of 12% in the human Mcs5a2 -region associated with a reduced breast cancer risk in two human case-control populations (n = 12,000) with an odds ratio of 0.86 (CI 0.78-0.94) for heterozygous women. SNPs located in the human Mcs5a1 region are currently being tested for an association to breast cancer.
A "Safer" Cigarette? Prove It, Say Critics
Authors: J Stephenson
Journal: JAMA (2000)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Toward Synthetic Viruses: Endosomal pH-Triggered Deshielding of Targeted Polyplexes Greatly Enhances Gene Transfer in vitro and in vivo
Authors: Greg F. Walker, Carolin Fella, Jaroslav Pelisek, Julia Fahrmeir, Sabine Boeckle, Manfred Ogris, Ernst Wagner
Journal: Molecular Therapy (2004)

Nonviral vectors should undergo "virus-like" changes compatible with the steps of gene delivery. Poly(ethylene) glycol (PEG) shielding of DNA/polycation polyplexes protects from nonspecific interactions with the extracellular environment. pH-triggered removal of the shield within the endosome may be advantageous. Polycation and PEG were linked via acylhydrazides or pyridylhydrazines. The pyridylhydrazone prepared from polylysine and propionaldehyde–PEG showed the greatest acid-dependent hydrolysis; at pH 5, 37°C for 10 min, 90% hydrolyzed, while at pH 7.4 the half-life was 1.5 h. Particle size and ζ potential measurements of the polyplexes showed complete deshielding within 1 h at pH 5, while at pH 7.4 the shield remained at 4 h, 37°C. For gene transfection a targeting conjugate was also included in the polyplex, transferrin as ligand for K562 and Neuro2A cells and epidermal growth factor for HUH-7 and Renca-EGFR cells. Marker gene expression showed that the reversibly shielded polyplexes exhibited up to 2 log orders of magnitude higher gene expression in vitro and 1 log magnitude higher gene expression in an in vivo mouse model, compared to the stably shielded control polyplexes. Engineering of polyplexes with more dynamic domains is an encouraging new direction in nonviral vector design.
Mosaic Epigenetic Inheritance as a Cause of Early-Onset Colorectal Cancer
Authors: Mathew A. Sloane, Andrea C. Nunez, Deborah Packham, Chau-To Kwok, Graeme Suthers, Luke B. Hesson, Robyn L. Ward
Journal: JAMA Oncology (2015)

Constitutional hypermethylation of 1 allele throughout the soma (constitutional epimutation) is an accepted mechanism of cancer predisposition. Understanding the origin and inheritance of epimutations is important for assessing cancer risk in affected families.We report a 29-year-old man with early-onset colorectal cancer who showed a constitutional MLH1 epimutation (approximately 50% of alleles methylated and allele-specific loss of MLH1 expression) that was stable over a 16-year period. The epimutation was inherited without a genetic alteration from his asymptomatic mother. She showed methylation on the same allele but in less than 5% of her somatic cells.These findings indicate that low-level somatic mosaicism for an epimutation in an asymptomatic parent can produce a nonmosaic constitutional epimutation in a child. Asymptomatic low-level methylation in some individuals may be associated with substantial cancer risk to their offspring.
Anterior Nongranulomatous Uveitis after Intravitreal HPMPC (Cidofovir) for the Treatment of Cytomegalovirus Retinitis
Authors: Eugenio Chavez-de la Paz, J. Fernando Arevalo, Leonard S. Kirsch, David Munguia, Firas M. Rahhal, Erik De Clercq, William R. Freeman
Journal: Ophthalmology (1997)
Encyclopaedia of Antibiotics.
Authors: John Stephen Glasby
Journal: Annals of Internal Medicine (1977)

PrefaceThe second edition has been expanded to include over 400 new antiIiotics which have been discovered since publication of the first edition. As in the previous edition, formulas, structures, melting points, origin, methods of purification and preparation, and patent references are given for the antibiotics. Toxicity and activity are indicated for many of the antibiotics. This book would be a valuable reference source for scientists and students working with antibiotics. In addition the structures of several of the antibiotics previously described have been elucidated and others have been revised in the light of further examination. The author also wishes to thank those research chemists and medical consultants who have provided him with additional data on the antibiotic activity of several important members of this class of compounds, particularly on their present use in human medicine.
Abstract P144: Race and Vitamin D Binding Protein Gene Polymorphisms Modify the Association between 25-Hydroxyvitamin D and Incident Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Jared P Reis, Erin D Michos, Elizabeth Selvin, James S Pankow, Pamela L Lutsey
Journal: Circulation (2015)

Background:  Low 25-hydroxyvitamin D [25(OH)D] levels are associated with diabetes, but few studies have examined racially diverse populations while also accounting for potential differences by race in common vitamin D binding protein (DBP) gene polymorphisms. DBP, the primary carrier protein for 25(OH)D, is associated with lower bioavailable vitamin D levels and may inhibit the action of vitamin D on target cells. We sought to evaluate whether the association between 25(OH)D and incident diabetes may vary by race and key DBP gene polymorphisms.   Methods:  We studied 8,120 white and 2,102 black adults aged 46-70 years at baseline (1990-92) from the ARIC Study with follow-up for incident diabetes during study visits conducted in 1993-95 and 1996-98. Adjusted hazard ratios (HR) and their 95% CIs for diabetes were estimated according to 25(OH)D. Potential effect modification by race or DBP gene polymorphisms was tested with the inclusion of multiplicative interaction terms.   Results:  During follow-up there were 750 incident cases of diabetes. The association of 25(OH)D with diabetes varied by race (p-interaction 0.004). Among whites, compared to those in the highest quintile of 25(OH)D, the adjusted HRs (95% CIs) for diabetes among those in quintiles 4 through 1 were 1.39 (1.06, 1.83), 1.06 (0.79, 1.42), 1.32 (0.99, 1.77), and 1.59 (1.17, 2.16), respectively (p-trend 0.01). No association was observed among blacks (p-trend 0.12). Presence of the rs4588 A allele, reported to be associated with high DBP levels, modified the association between 25(OH)D and diabetes among whites, but not blacks (p-interaction 0.01 and 0.38, respectively;  Table ).   Conclusions:  Low 25(OH)D levels were associated with risk for diabetes among whites, but not blacks, with the strongest associations observed among those genetically predisposed to high DBP levels. The effects of vitamin D supplementation for the prevention of diabetes may differ by race and bioavailable vitamin D levels.
Endocarditis in a Dutch patient caused by Bartonella quintana
Authors: A.M.C. Bergmans, J.L. Coenen, R. Bakhuizen, B.W. Moot, A.R. Ramdat Mister, B. Wilbrink, L.M. Schouls, M.J.H.M. Wolfhagen
Journal: Clinical Microbiology and Infection (1997)
Abstract 9603: Extreme Hypercholesterolemia Exacerbated by Breast Feeding: Infantile Cases of Sitosterolemia With Novel Mutations in ABCG5 Gene
Authors: Hayato Tada, Masa-aki Kawashiri, Tetsuo Konno, Kenshi Hayashi, Atsushi Nohara, Akihiro Inazu, Hiroshi Mabuchi, Masakazu Yamagishi
Journal: Circulation (2014)

Background: Sitosterolemia is an extremely rare inherited disease characterized by increased levels of plant sterols such as sitosterol, the cause of which is ATP-binding cassette (ABC) sub-family G member 5 or member 8 (ABCG5 or ABCG8) gene mutations. It has been described that infantile sitosterolemic cases exhibit clinical manifestations resembling homozygous FH, including severe hypercholesterolemia, the mechanism of which still remains unclear. In the present study, we tried to determine the molecular diagnosis for 6 Japanese infantile cases with severe hypercholesterolemia and systemic xanthomas without any mutations in LDL receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDL receptor adaptor protein 1 (LDLRAP1) genes, then evaluated their clinical features, especially the responsiveness to variety of therapies, including statins, ezetimibe, colestimide, and weaning from breast feeding. Methods and Results: We performed genetic analysis for ABCG5, and ABCG8 genes for those 6 cases, and identified 2 pairs of mutations in ABCG5 gene in each case, including 2 novel mutations (c.130C&gt;T and c.1813_1817delCTTTT) and 2 known mutations (c.1306G&gt;A and c .1336C&gt;T). During their clinical courses, significant reduction of their LDL cholesterol levels could be obtained through their weaning alone (from 540 ± 164 mg/dl to 147 ± 60 mg/dl, p &lt; 0.05). Also, a substantial reduction of their sitosterol levels were observed (from 90 ± 69 μg/ml to 52 ± 38 μg/ml, p &lt; 0.05) using ezetimibe without any apparent side effects, although statins and colestimide did not have any effects on their sitosterol levels. Interestingly, their cutaneous xanthomas completely disappeared associated with the reductions of their cholesterol levels rather than those of sitosterol levels. Conclusion: We have identified infantile Japanese sitosterolemic subjects with extreme hypercholesterolemia exacerbated by breast feeding. Their unique manner of responses to weaning as well as to ezetimibe could provide us novel insights into the metabolic basis for cholesterol and plant sterols in human.
Abstract P105: Dietary Acid Load of a Low Versus a High Protein Diet and Its Effect on Blood Pressure: A Fully Controlled Dietary Intervention Trial
Authors: Marielle F Engberink, Wieke Altorf-van der Kuil, Elizabeth J Brink, Stephan J Bakker, Marleen A van Baak, Johanna M Geleijnse
Journal: Circulation (2013)

Background: Mild metabolic acidosis may result in elevated blood pressure (BP). Several formulas to estimate dietary acid load have been developed. However, studies in which these formulas have been validated are limited. Objectives: To validate and/or improve existing formulas for dietary acid load and to examine the association between dietary protein, acid load and BP. Methods: We performed a randomized 14d crossover dietary intervention involving 37 healthy subjects (age: 21±2 y) who consumed individualized, isocaloric diets that were either low or high in protein (0.5 versus 2.0 g protein/kg BW/d). Duplicate portions of the provided diets were collected and analysed for energy and nutrients. We used two measures to characterize dietary acid load (i.e. PRAL and NEAP). Urinary Net Acid Excretion (NAE; i.e. titratable acid + ammonium - bicarbonate) was analysed. BP was measured according to standardized procedures. Results: Mean dietary intakes significantly differed between the low and high protein diet, resulting in significantly different acid load values (Table 1, all p&lt;0.001). The correlation between PRAL and NAE was 0.08 in the low protein diet and 0.62 in the high protein diet. For NEAP the correlations were 0.27 and 0.32. PRAL explained 69% of the variance of NAE, which could not be improved by adding other variables to the formula. Systolic BP was 108.4±7.5 and 109.5±8.0 mmHg on the low and high protein diet respectively (p=0.25). Conclusion: PRAL predicts NAE reasonably well in healthy adults for normal to high protein intake. PRAL can be influenced by diet, but this cannot be clearly attributed to protein intake alone. PRAL does not seem to influence short-term BP in healthy adults with normal BP.
Changes in bile acids, FGF-19 and sterol absorption in response to bile salt hydrolase active<i>L. reuteri</i>NCIMB 30242
Authors: Christopher J Martoni, Alain Labbé, Jorge G Ganopolsky, Satya Prakash, Mitchell L Jones
Journal: Gut Microbes (2015)

The size and composition of the circulating bile acid (BA) pool are important factors in regulating the human gut microbiota. Disrupted regulation of BA metabolism is implicated in several chronic diseases. Bile salt hydrolase (BSH)-active Lactobacillus reuteri NCIMB 30242, previously shown to decrease LDL-cholesterol and increase circulating BA, was investigated for its dose response effect on BA profile in a pilot clinical study. Ten otherwise healthy hypercholesterolemic adults, recruited from a clinical trial site in London, ON, were randomized to consume delayed release or standard release capsules containing L. reuteri NCIMB 30242 in escalating dose over 4 weeks. In another aspect, 4 healthy normocholesterolemic subjects with LDL-C below 3.4 mmol/l received delayed release L. reuteri NCIMB 30242 at a constant dose over 4 weeks. The primary outcome measure was the change in plasma BA profile over the intervention period. Additional outcomes included circulating fibroblast growth factor (FGF)-19, plant sterols and LDL-cholesterol as well as fecal microbiota and bsh gene presence. After one week of intervention subjects receiving delayed release L. reuteri NCIMB 30242 increased total BA by 1.13 ± 0.67 μmol/l (P = 0.02), conjugated BA by 0.67 ± 0.39 μmol/l (P = 0.02) and unconjugated BA by 0.46 ± 0.43 μmol/l (P = 0.07), which represented a greater than 2-fold change relative to baseline. Increases in BA were largely maintained post-week 1 and were generally correlated with FGF-19 and inversely correlated with plant sterols. This is the first clinical support showing that a BSH-active probiotic can significantly and rapidly influence BA metabolism and may prove useful in chronic diseases beyond hypercholesterolemia.
Preclinical discovery and clinical validation of predictive markers of response to cetuximab (Erbitux™) in metastatic colorectal cancer
Authors: Shirin Khambata Ford, Nancy-Anne Perkins, Xin Huang, Tai W. Wong, Suso Platero, Christiane Langer, Shelley Mayfield, Lynn Ploughman, Edwin A. Clark, David J. Mauro
Journal: Cancer Research (2006)

4032   Cetuximab (Erbitux™) is a chimeric monoclonal antibody that binds to the extracellular ligand-binding domain of the epidermal growth factor receptor (EGFR) and inhibits EGFR-dependent signaling. Clinical data has shown that whereas EGFR levels and EGFR mutations do not appear to correlate with response to Cetuximab in colorectal cancer (CRC), an increased number of gene copies for EGFR may be predictive. Our goal is to identify predictive markers of response that will ultimately be developed into molecular diagnostics to enhance the effectiveness of Cetuximab therapy in CRC. Preclinical approaches using transcriptional profiles of 164 primary CRC tumors and 21 sensitive and resistant CRC cell lines have identified a list of genes that may be predictive of response. A Phase II study of Cetuximab monotherapy in patients with metastatic CRC was conducted to examine whether preclinically identified markers could be validated in a clinical setting. Patients with metastatic CRC were enrolled in a study of Cetuximab monotherapy. RNA was isolated from the pre-treatment core biopsies of all patients and was profiled on Affymetrix gene chips. DNA isolated from the pre-treatment core biopsies is being used for EGFR gene copy number analysis as well as mutation analysis. An interim statistical analysis of transcriptional profiling data was performed to examine whether preclinically identified markers are differentially expressed between patients who derive clinical benefit (Partial Responders PR and Stable Disease SD) and those who do not (Progressive Disease PD). Pathway analysis tools were used to identify biological relationships between the predictive markers identified from this clinical study. Several preclinically identified candidates were able to distinguish between the PR/SD and PD patients with high accuracy. The top candidate sensitivity markers identified from this analysis are key players in the EGFR signaling pathway. Their strikingly higher expression levels in responders suggest that tumors addicted to the EGFR pathway respond to Cetuximab. Approximately twenty top response prediction markers are found to be associated with the EGFR network. The identified response prediction markers have the potential to be used either singly or in combination for patient selection to enhance the effectiveness of Cetuximab therapy. This analysis is currently being extended to include a larger set of patients from this study.
Modulation of platinum drug sensitivity by the Akt inhibitor LY294005 in MMR-proficient and MMR-deficient HCT116 colon tumor cells.
Authors: Andre Fedier, Rudiger A. Erdmann, Konstantin J. Dedes, Patrick Imesch, Teni Boulikas, Daniel Fink
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

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The Akt signaling pathway is believed to facilitate growth and survival and to block apoptosis, and its down-regulation has been shown to radio- and chemosensitize tumor cells. A role for Akt signaling in responding to DNA damage has also been suggested. We hypothesized that the Akt-specific inhibitor LY294005 has the potential to re-sensitize specifically HCT116 colon tumor cells to cisplatinum compounds to which these cells are resistant due to the defect in DNA mismatch repair (MMR) function. To that aim, the MMR-deficient HCT116+ch2 subline (lacking MLH1 protein expression) and the MMR-proficient HCT116+ch3 subline (expressing MLH1 protein) were used to (i) compare the efficacy of platinum compounds alone with that of the combination of these compounds with LY294005 against these sublines and to (ii) determine the effect of LY294005 on the level of phospho-Aktser473. Clonogenic data demonstrate that pre-incubation with 10 uM LY294005 substantially decreased the efficacy of Cisplatin and Lipoplatin against both sublines under the experimental conditions at which LY294005 markedly increased the efficacy of Docetaxel against these sublines or left the efficacy of 6-Thioguanine nearly unaffected. Notably enough, the extent of this decrease in efficacy imposed by LY294005 was 2 to 3-fold higher for the MMR-proficient subline than for the MMR-deficient subline, indicating that the LY294005-imposed effect was dependent on the presence of MLH1 protein. Moreover, LY294005 also produced a significant decrease in the efficacy of Oxaliplatin and Lipoxal the extent of which, however, was comparable in both sublines and therefore MLH1-independent. Immunoblot data showed that 10 uM LY294005 did not reduce the level of phospho-Aktser473 regardless of the MMR status and of whether the cells have been treated with the drugs or not, indicating that the LY294005-imposed changes in drug efficacy were not accompanied by alterations in the phosphorylation status of Aktser473. These results suggest that, at least under these experimental conditions, LY294005 has the potential to antagonize the cytostatic effect of platinum compounds, that this antagonizing effect occurs with a preference for MMR-proficient cells for Cisplatin and Lipoplatin and therefore in a MMR-dependent manner, and that the control of Akt signaling might not necessarily be dependent on the phosphorylation status of Akt. These observations may point to a possible presence of a relationship between MMR-mediated DNA damage signaling and the Akt pathway, and to a possible novel property for Akt signaling, at least for platinum drugs and perhaps under certain circumstances, to promote cell death and hence to aggravate the cytotoxic effect of platinum compounds rather than protecting from it.