tbuckley/cabot-search huggingface dataset:
DNA damage in breast cancer plus another primary cancer, early onset breast cancer, thyroid cancer and cancer-free individuals
Authors: Alice J. Sigurdson, Deirdre A. Hill, Michael Hauptmann, Bruce H. Alexander, Michele M. Doody, Cynthia B. Thomas, Jeffery P. Struewing, Irene M. Jones
Journal: Cancer Research (2004)

2889  Although a large number of DNA repair gene polymorphisms recently have been described, the relationship of these polymorphisms to DNA repair phenotype remains largely unknown. In an ongoing study, we are using the Comet assay to assess the DNA repair capacity of 90 EBV-transformed normal lymphoblastoid cell lines from the Polymorphism Discovery Resource (Coriell Cell Repository, NJ). These same cell lines have been re-sequenced as part of the Environmental Genome Project (EGP) in order to discover common polymorphisms and we have recently used this genotype data to construct haplotypes on a set of DNA repair and cell cycle control genes. We are combining haplotype and Comet data to assess whether DNA repair gene haplotypes determine DNA repair phenotype. We present here preliminary analysis on 57 cell lines for which we have Comet data along with the haplotypes of 5 DNA repair genes (ADPRT, LIG3, XRCC1, OGG1 and Polb). We used two DNA damaging agents, methyl-methanesulfonate (MMS), an alkylating agent, and hydrogen peroxide (H202) an oxidizing agent. DNA damage from both agents is repaired by the Base Excision Repair (BER) pathway. A modified version of the alkaline comet assay protocol was used as described by Singh et al (1988). Briefly, normal lymphoblastoid cell lines were tested in duplicate on two different days and exposed to 10 uM H202 for 20 min at 4° C or 1 mM MMS 30 minutes at 37 ° C. Komet 5.0 digital imaging and analysis software (ILS) was employed to measure Olive Tail Moment (OTM) on 100 cells/cell line (25 cells x 4 slides) before treatment (NT), immediately after treatment (T0), and after ∼50% repair (T1: 10 minutes for H2O2 and 4hrs for MMS). We estimated DNA repair between maximal damage at T0 and partial repair at T1 by analyzing the average base-2 logarithm of the post-repair median OTM, expressed as a proportion of the median OTM immediately after exposure. Preliminary analysis suggests that the overall exposure response correlation of cells to the two damaging agents (MMS vs H202) is moderately strong (Pearson correlation coefficient of .44, p=0.0007). For MMS, none of the gene haplotypes showed statistically significant association with the DNA repair response, nor did 4 of the 5 gene haplotypes for H2O2. However, we did find a significant association between DNA repair response to H2O2 and gene haplotypes of ADPRT (p=.0008). The ADPRT gene (ADP-ribosyltransferase (NAD+;poly (ADP-ribose) polymerase), otherwise known as PARP, is a nuclear zinc finger DNA-binding protein involved in the regulation of the molecular events in the recovery of cells from DNA damage and is important in the detection of single strand breaks. ADPRT knockout cells are known to be hypersensitive to MMS, but our preliminary findings suggest that ADPRT haplotype may affect H202 DNA damage response.
Prediction of outcome after anti-cancer immune stimulation by thermochemotherapy in a rat breast cancer model
Authors: Frederick Strebel, Manisha Singh, R. Wanda Rowe, Dorothy Lewis, Joan Bull
Journal: Cancer Research (2008)

2089  BACKGROUND: Whole-body fever-range thermal therapy (FR-WB-TT), when optimally scheduled with chemotherapy, enhances the anti-cancer activity of many chemotherapy drugs. In the clinically relevant MTLn3 rat mammary adenocarcinoma model, oxaliplatin (Ox) given at sub-maximally tolerated doses 24h before FR-WB-TT reproducibly results in a 50% cure rate. Cured rats are immune to re-challenge with the same tumor. After initial growth inhibition tumors regrow in all rats, but starting around 10-12 days post-treatment partially responding and ultimately cured rats begin to regress both their primary tumors and lymph node metastases. Acute response during the first 4-5 days, however, is not predictive of long term outcome. Are there early markers of response to predict cure? Can additional treatment turn non-responders into responders? To begin answering these questions, we investigated the proliferative and activation responses of CD8+ T-cells to Ox + FR-WB-TT thermochemotherapy. METHODS: Female Fischer 344 rats bearing an orthotopically implanted syngeneic MTLn3 tumor were treated with Ox (10 mg/kg i.v.) 24 h before FR-WB-TT (40°C for 6 h). Peripheral blood mononuclear cells (PBMC), Ficoll-separated from whole blood, and labeled with carboxyfluorescein succinylester (CSFE) were examined by flow cytometry for cell proliferation 6 and 10 days after Ox treatment. Separated lymphocytes were stimulated in vitro with MTLn3 breast or syngeneic 9L glioma brain tumor cells and CD25 expression was examined after 2 days of restimulation. Anti-tumor effect was assessed by comparing tumor volume in treated and control animals. RESULTS: 50% of treated animals were cured and lived a normal life-span. The other 50% either partially responded or had no response at all. Cured animals were immune to re-challenge with MTLn3 cells but not to 9L glioma cells. CD8+ cell counts, determined by a bead counting method directly from whole blood, were significantly higher for the eventual responder animals on days 6 and 10 after treatment. Partial responders had CD8+ cell counts intermediate between non-responders and cured animals. Rats that later rejected their tumors showed a loss of CFSE label compared to non-responding rats with later tumor progression. There was 56% CFSE loss in the eventual responders compared to 34% CFSE loss in rats that did not reject tumor. Percent CD25 activation after in vitro stimulation was also higher in cured animals than in non-responders or partial responders. CONCLUSIONS: CD8+ cell proliferation (increased numbers of CD8+ cells) and functional activation (CD25 expression) may be predictive of curative therapy early after treatment. Further work is ongoing to improve assays of CD8+ T-cell quantity and function, and to understand the mechanisms of immune stimulation of chemotherapy by thermal therapy with a view to curative intervention for non-responders.
Abstract 16803: Increasing Burden of Environmental Risk Factors for Congenital Heart Disease in the Current Era
Authors: Alan Fung, Mina Safi, Tanya Daljevic, Carly Ogaki, Priya Somascanthan, Ade Ajisebutu, John Smythe, Jane Lougheed, Herschel Rosenberg, Tapas Mondal, Seema Mital
Journal: Circulation (2010)

Congenital heart defects (CHD) are prevalent in up to 1.3 million Americans and occur in approximately 36,000 babies each year. We assessed the impact of maternal exposure to environmental risk fac...
Abstract 1962: CXCR4-mediated Bone Marrow Stem Cell Homing and Niche Maintenance Is Modulated by the Functional Status of c-kit
Authors: Min Cheng, Junan Zhou, Wuqiang Zhu, Toshikazu Tanaka, Qiutang Zeng, Raj Kishore, Douglas Losordo, Gangjian Qin
Journal: Circulation (2008)

Objective: The bone marrow (BM) “niche”, where the stem cells are dynamically maintained, is an attractive target for cell-based cardiovascular repair. Both CXCR4 antagonist and c-kit blocking antibody can rapidly mobilize BM stem cells; however, the functional interaction between CXCR4 and c-kit remains unclear. We hypothesize that CXCR4 crosstalk with c-kit to maintain BM stem cell niche. Methods and Results: We designed an in vitro adhesion assay to mimic BM niche. Mouse total BM cells were harvested and applied onto VCAM1-coated plates for 15 min, and followed by addition of CXCR4 agonist SDF-1 or antagonist AMD3100. The adhesion of BM cells to VCAM1 resulted in marked c-kit phosphorylation. Interestingly, AMD3100 significantly decreased while SDF-1 augmented the c-kit phosphorylation, suggesting that CXCR4 may regulate the functional status of c-kit. To determine the role of c-kit in CXCR4-regulated stem cell niche maintenance, we developed an in vivo homing assay. The c-kit mutant (c-kit W/W-V ) and WT mice (n=5) were first treated with AMD3100 to disrupt CXCR4-mediated niche, and 2 h later, transplanted with eGFP-transgenic BM cells. After 3 h, BM cells were isolated and analyzed by FACS. The percentages of donor-derived eGFP+, eGFP+Lin+, and eGFP+Lin− cells were similar between the two groups. However, the donor-derived primitive stem cells, including eGFP+Lin-Sca1+ and eGFP+Lin-ckit+ cells, were significantly fewer in c-kit W/W-V mice than in WT mice (c-kit W/W-V vs. WT: 94.1% vs. 96.0%, p&lt;0.05, and 33.82% vs. 55.27%, p&lt;0.01, respectively), indicating that c-kit-deficient BM niche specifically affects primitive stem cell homing and maintenance. Importantly, although donor-derived CXCR4-expressing total (eGFP+CXCR4+) cells were similar in both groups, CXCR4-expressing stem cells, including eGFP+Lin-CXCR4+, eGFP+Lin-Sca1+CXCR4+, and eGFP+Lin-ckit+CXCR4+ cells, were much fewer in c-kit W/W-V than in WT mice (c-kit W/W-V vs. WT: 19.7% vs. 30.6%, p&lt;0.01, 20.3% vs. 29.1%, P&lt;0.05, and 6.7% vs. 17.9%, p&lt;0.001, respectively), suggesting c-kit deficiency reduces the homing and maintenance of stem cells that express CXCR4. Conclusion: CXCR4-mediated BM stem cell homing and niche maintenance is modulated by the functional status of c-kit. This research has received full or partial funding support from the American Heart Association, AHA National Center.
Abstract P358: Discovery Loci and Generalization of Platelet Count Associations in the Hispanic Community Health Study: Study of Latinos (HCHS/SoL)
Authors: Chani J Hodonsky, Ursula Schick, Jean Morrison, Cathy Laurie, John H Eckfeldt, Timothy Thornton, Kari E North, Alex P Reiner
Journal: Circulation (2015)

Background: The biology of platelets_anuclear megakaryocyte fragments required for clotting_is well defined, with abnormalities resulting in clotting disorders ranging from asymptomatic to severe. Although platelet count (PLT) is highly heritable (h 2 =0.57 in NHANES), genetic regulation of this trait remains incompletely characterized. In particular, Hispanic Latinos are a diverse population in which the genetic variability of PLT has not been analyzed. We aimed to 1) identify novel loci associated with PLT in participants of HCHS/SoL; and 2) determine if previously identified PLT loci generalize to the Hispanic Latino population. Methods: We performed a genome-wide association study of PLT in 12,491 participants of HCHS/SoL, which includes individuals with Dominican, Puerto Rican, Mexican, Cuban, South American, and Central American ancestral origins residing in the United States. Participants were genotyped on the Illumina SoL Omni2.5M array and imputed to the 1000 Genomes Phase I Reference panel. We implemented linear mixed-model regression assuming an additive genetic model, adjusting for sex, age, study center, ancestry and sample weights, and including random effects for individual relatedness, household, and block group. Results: Ten independent loci were significantly (α = 5x10 -8 ) associated with PLT in HCHS/SoL and 13 of 57 previously identified platelet-count GWAS loci generalized to HCHS/SoL (+/-500kb, α = 8.78x10 -4 ). Discovery loci included a significant association near GABBR1 (rs3131857, MAF = 40%, β = -0.16) and a suggestive association near ETV7 (rs9470264, MAF = 20%, β = -0.19). Furthermore, a noncoding variant in ACTN1 was associated with increased PLT (rs117672662, MAF = 6%, β = 0.61); ACTN1 codes for alpha-actinin, a multi-isoform actin-binding protein involved in cytoskeleton organization and platelet/megakaryocyte structural integrity. Missense mutations in ACTN1 were recently implicated in congenital thrombocytopenia; exome sequencing also associated this locus with PLT, which supports a potential functional role in PLT for this gene. Conditional regression analyses to assess secondary association signals are in progress. Conclusions: Genetic associations in two discovery loci ( ETV7 and GABBR1 ) underscore the benefit of using diverse populations in GWAS. Expanding the number of loci associated with platelet count will help elucidate disease mechanisms and develop approaches to treat platelet disorders in populations of all ancestries.
Abstract 129: RAD17 loss of function is synthetically lethal with the checkpoint kinase inhibitors AZD7762 or MK-1775
Authors: John Paul Shen, Rohith Srivas, Ana Bojorquez-Gomez, Katherine Licon, Vignesh Sivaganesh, Jia L. Xu, Huwate Yeerna, Andrew Gross, Jian Feng Li, Robert Sobol, Trey Ideker
Journal: Cancer Research (2015)

Abstract Synthetic lethal interactions are a type of genetic interaction in which the simultaneous loss of function of two genes in combination results in cell death. Recently, there has been much interest in the discovery of drugs that are selectively toxic to cancer cells by targeting proteins that form synthetic lethal interactions with tumor specific mutations. He we have identified that RAD17 loss of function is synthetically lethal with AZD7762, an inhibitor of Chk1 and Chk2, and with MK-1775, an inhibitor of Wee1. HeLa or LN428 glioblastoma cells were selectively responsive to AZD7762 or MK-1775 following shRNA-mediated depletion of RAD17. Cells with dual knockdown of CHEK1 and CHEK2 or knockdown of WEE1 were also sensitized to RAD17 knockdown. At baseline, cells with RAD17 knockdown had greater expression of the DNA damage marker H2AX, an effect that was magnified by either chemical inhibition or siRNA-mediated knockdown of CHEK1/2 or WEE1. Accumulation of H2AX was observed primarily in S and G2 phases, RAD17 loss did not have a significant effect on cell cycle progression. The combination of AZD7762 and MK-1775 resulted in synergistic toxicity in RAD17 knockdown but not control cells. Collectively, these results demonstrate that RAD17 loss of function sensitizes cells to inhibition of S and G2/M checkpoint kinases, resulting in greater accumulation of DNA damage and ultimately cell death. We suggest that AZD7762 and MK-1775 may have greater clinical efficacy in tumors with RAD17 mutation or deletion. Citation Format: John Paul Shen, Rohith Srivas, Ana Bojorquez-Gomez, Katherine Licon, Vignesh Sivaganesh, Jia L. Xu, Huwate Yeerna, Andrew Gross, Jian Feng Li, Robert Sobol, Trey Ideker. RAD17 loss of function is synthetically lethal with the checkpoint kinase inhibitors AZD7762 or MK-1775. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 129. doi:10.1158/1538-7445.AM2015-129
Abstract 1684: Preclinical anti-tumor efficacy of FGFR2-ADC BAY 1187982 in patient-derived gastric, breast and ovarian cancer models
Authors: Anette Sommer, Charlotte Kopitz, Christoph Schatz, Ruprecht Zierz, Joachim Schuhmacher, Sabine Wittemer-Rump, Klaas Prins, Manuela Braun, Frank Reetz, Bertolt Kreft, Hung T. Huynh, Karl Ziegelbauer
Journal: Cancer Research (2015)

Abstract Antibody-drug conjugates (ADC) represent a promising therapeutic approach for treatment of cancer. We have developed a novel ADC directed against fibroblast growth factor receptor 2 (FGFR2). FGFR2 is overexpressed in several cancer indications, such as gastric, breast, and ovarian cancer and thus represents a potential therapeutic target for treatment of FGFR2-positive cancer patients with ADC-based therapy. FGFR2-ADC consists of a fully human anti-FGFR2-Ab (BAY 1179470) conjugated via a stable linker to a novel auristatin cytotoxic agent licensed from Seattle Genetics. FGFR2-ADC exhibits low nM to sub-nM potency in vitro in a panel of FGFR2-positive cancer cells lines (SNU-16, MFM-223, NCI-H716) while being inactive against FGFR2-low or -negative cell lines (MDA-MB-231, HEK-293, BaF/3) and highly selective versus a control ADC. FGFR2-ADC is highly efficacious in monotherapy and results in tumor growth inhibition in the gastric cancer xenograft model SNU-16 and tumor regression in the breast cancer xenograft model MFM-223. FGFR2-ADC induces tumor stasis in the colorectal cancer xenograft model NCI-H716 and regrown tumors are sensitive to a second treatment cycle of FGFR2-ADC. FGFR2-ADC shows high efficacy in vivo in monotherapy in patient-derived (PDX) FGFR2-positive murine xenograft models, e.g. in the ovarian cancer model OV30-0511A. FGFR2-ADC is also efficacious in the gastric cancer PDX model GC10-0608 and the breast cancer model MAXF857. The toxophore metabolite of FGFR2-ADC was more than 30-fold enriched in tumors versus other organs (liver, spleen, kidneys) in NCI-H716 tumor-bearing mice. Based on the preclinical efficacy, PK and tolerability data, evaluation of FGFR2-ADC in cancer patients appears warranted. A Phase I study is planned. Citation Format: Anette Sommer, Charlotte Kopitz, Christoph Schatz, Ruprecht Zierz, Joachim Schuhmacher, Sabine Wittemer-Rump, Klaas Prins, Manuela Braun, Frank Reetz, Bertolt Kreft, Hung T. Huynh, Karl Ziegelbauer. Preclinical anti-tumor efficacy of FGFR2-ADC BAY 1187982 in patient-derived gastric, breast and ovarian cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1684. doi:10.1158/1538-7445.AM2015-1684
Rapid tryptophan depletion in drug-free depressed patients with seasonal affective disorder
Authors: A Neumeister, N Praschak-Rieder, B Hesselmann, O Vitouch, M Rauh, A Barocka, S Kasper
Journal: American Journal of Psychiatry (1997)

Brain serotonin systems might be involved in the pathophysiology of seasonal affective disorder. The authors tested whether tryptophan depletion alters the mood of depressed patients with seasonal affective disorder.Eleven drug-free depressed patients with seasonal affective disorder underwent tryptophan depletion in a placebo-controlled, double-blind crossover study. Tryptophan depletion was induced by a 24-hour low-tryptophan diet and by ingestion of a tryptophan-free amino acid beverage. During control testing the diet and the beverage were supplemented with tryptophan. Behavioral ratings and plasma total and free tryptophan levels were obtained before the diet started and several times after administration of the beverages.The diet and the tryptophan-free amino acid drink reduced plasma total and free tryptophan levels by 79.0% and 87.5%, respectively. Both levels increased during control testing. No significant behavioral changes were induced by tryptophan depletion or control testing.The failure of tryptophan depletion to exacerbate the depressive syndrome suggests that dysfunctional serotonergic activity does not play a primary, direct role in the pathogenesis of winter depression.
Commentary: Cultural complexities should not be ignored
Authors: E. Webb
Journal: BMJ (1998)

There is no doubt that migrants experience cross cultural stress. Girls living in the West, but belonging to communities that are fiercely patrilineal and patriarchal, are perhaps particularly at risk. These girls do not live within one fixed culture with extrafamilial contact with another fixed culture. They live at the intersections of usually many cultures with widely different cultural norms, all of which change with time and place and influence one another. Members of …
Abstract 15085: Local Hemodynamic Forces and Aqueous Cigarette Smoke Extract Affect Development of Endothelial Dysfunction
Authors: Sindy Giebe, Coy Brunssen, Melanie Brux, Natalia Cockcroft, Katherine Hewitt, Henning Morawietz
Journal: Circulation (2014)

Endothelial dysfunction is one of the first steps in the development of atherosclerosis. This proinflammatory phenotype is associated with decreased bioavailability of nitric oxide and a corresponding expression profile in the endothelial cells. Tobacco smoking promotes development of atherosclerotic plaques and local hemodynamic forces are key stimuli in this process. Low laminar flow is involved in the development of an unstable plaque phenotype, while high laminar flow has atheroprotective role. The molecular mechanisms controlling plaque stability in response to tobacco smoking remain largely unknown so far. Therefore, we exposed human endothelial cells to cigarette smoke extract (CSEaq) under disturbed flow conditions.  Primary human endothelial cells were stimulated with increasing dosages of CSEaq for 24h. Cell viability was reduced by CSEaq in a dose-dependent manner. The impact of specific flow conditions and different doses of CSEaq on the expression of atherosclerosis-related genes was investigated using a cone-and-plate viscometer. High laminar flow induced elongation of endothelial cells in the direction of flow, increased eNOS expression and NO release in a time-dependent manner. This increase was inhibited by CSEaq. Low laminar flow showed no effect on eNOS expression and NO release. The NRF2 antioxidative defense system was also induced by high laminar flow. NRF2 and NRF2 target genes HMOX1 and NQO1 were strongly activated by CSEaq. Furthermore, we monitored the expression of proinflammatory genes. CSEaq strongly induced adhesion molecule ICAM-1. Interestingly, VCAM-1 was unaffected by CSEaq. Induction of endothelial NADPH oxidase isoform 4 by CSEaq was prevented by high laminar flow. Catalase expression was not affected by flow and CSEaq, whereas CSEaq transiently increased SOD1 expression. Endothelial wound healing was improved by atheroprotective high laminar flow. Low flow did not affect wound healing. Furthermore, high laminar flow decreased adhesion of monocytes to endothelial cells, compared to low flow.  We suggest novel molecular mechanisms how tobacco smoking promotes the development of endothelial dysfunction. This can contribute to the formation of an unstable atherosclerotic plaque phenotype.
Abstract 21411: Medium Term Prognosis in Non-st Segment Elevation Acute Coronary Syndromes in the Older Older. Clinical Outcomes Depending on Invasive vs. Conservative Strategies.
Authors: Inaki Villanueva, Itziar Solla, Emilio Paredes, Arturo Vilches, Oscar Diaz, Jose Antonio Baz, Francisco Calvo, Andres Iniguez
Journal: Circulation (2010)