tbuckley/cabot-search huggingface dataset:
Protective Effect of Estrogen (E2) and Increased Risk of E2 Plus Progestin (Prog) on Breast Cancer (BrCa). The 2009 Review of the Women's Health Initiative (WHI) Hormone Replacement Therapy (HRT) Published Trials.
Authors: J. Ragaz, N. Le, J. Budlovsky, J. Spinelli
Journal: Cancer Research (2009)

Abstract INTRODUCTION &amp; METHODOLOGY.The objective of this review is to identify from the two WHI published randomized HRT trials the BrCa risk or benefit, with a special focus on different impact of E2-alone vs E2+Prog on human breast carcinogenesis (BrCa-genesis).In the 1st trial (JAMA 2002, 2007), healthy women age 50 - 79 were randomized to E2 plus Prog versus placebo (Plac). Reviewed were Hazard ratios (HRs) for all pts and also for those with or without prior Hormone use. Mean follow up was 5.2 years.In the 2nd trial (JAMA 2004, 2006), women with hysterectomy age 50 - 79 were randomized to E2 alone (without Prog) versus Plac. Mean follow up was 7.1 years. Reviewed were all pts, and also subsets with or without prior E2 or Prog; with or without prior history of Benign Breast Disease (PHBrD); and with or without prior history of a 1st degree relative with BrCa (PH1stRelBrCa).RESULTS.Invasive BrCa incidence:N (%)HR95% C.I.1st TrialAll participants:16,608 (100%)1.260.83 - 1.97No prior Hormone use:12,304 (74.1%)1.060.81 - 1.38Prior Hormone use &amp;lt;5 yrs:3,005 (18.1%)2.131.15 - 3.94*Prior Hormone use 5 - 10 yrs:783 (4.7%)4.611.01 - 21.02*2nd TrialAll participants:10,739 (100%)0.800.62 - 1.04No prior hormone use:5,763 (53.7%)0.650.46 - 0.92*Prior E2 use:4,976 (46.3%)0.980.67 - 1.44Prior E2 + PROG use:468 (4.4%)2.350.60 - 9.14No PHBrD:7,681 (71.5%)0.570.41 - 0.78*No PH1stRelBrCa8,554 (80.0%)0.680.50 - 0.92*CONCLUSION:1. Results from the 1st trial show that concomitant use of E2 with Prog, particularly in women with prior Hormone use, is associated with increased BrCa hazards.2. The results of the 2nd HRT trial indicate that use of HRT with E2 alone is associated with a reduction in BrCa incidence, significant in the majority of women with no prior BrCa risk factors. Also the results show that prior Prog but not prior E2 elevate the risk.3. These data indicate that HRT with E2 alone has a BrCa protective effect, while adding Prog increases the risk.4. These results are also compatible with a dual E2 effect on BrCa-genesis, where exogenous E2 are protective, but endogenous E2 [endE2] are carcinogenic, as shown from decades of anti-end E2 research with Tamoxifen, oophorectomy or Aromatase inhibitors.5. Based on these data we propose that in women with hysterectomy and no prior history of risk factors, the use of HRT with E2 alone as chemoprevention is plausible, and needs urgent verification.* significance, "p" &amp;lt;0.05. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 908.
Molecular pathologic diagnosis of epidermal growth factor receptor
Authors: C. L. Maire, K. L. Ligon
Journal: Neuro-Oncology (2014)

Epidermal growth factor receptor (EGFR) was one of the first oncogenes identified in glioblastoma (GBM) and remains one of the most attractive therapeutic targets. Genomic alterations in EGFR are present in 57% of patients and are strikingly diverse, including gene amplification, rearrangements, and point mutations. Each aberration class has important clinical implications for diagnosis, prognosis, or therapeutic investigation of EGFR in clinical trials. Somatic copy number alterations (SCNAs) are the most common abnormalities in EGFR, with gene amplification present in >43% of patients. The presence of EGFR amplification is often used now to support the diagnosis of GBM and discriminate GBM from other gliomas. It is currently detected in clinical labs using fluorescence in situ hybridization, colorimetric in situ hybridization or, more recently multiplex genomic technologies such as array CGH or targeted next-generation sequencing approaches. Rearrangements of EGFR are most commonly internal deletions leading to activation of the receptor including EGFRvIII and, less commonly, EGFRvII and other variants, which are collectively seen in 25% of GBM patients. EGFRvIII is readily detected via mutation-specific antibodies, but heterogeneity of this and other deletion variants has hindered reliable detection of these aberrations using genomic DNA-based methods. RNA expression profiling (Nanostring and anchored multiplex PCR) has additional potential as a rapid and reliable strategy for detecting EGFR rearrangements with high sensitivity. Single nucleotide variants in EGFR are relatively rare and diverse but are efficiently detected using the targeted or exome-sequencing assays that are now entering clinical pathology practice. The advent of multiplex technologies has revealed the fact that multiple aberrations of EGFR are present in at least 30% of patients with EGFR disruption, a fact recently highlighted by more quantitative sequencing techniques and single cell analysis of GBM. Diagnostic assays used to evaluate EGFR and other receptor tyrosine kinases will therefore be increasingly used to measure and resolve this heterogeneity in order to better understand their mechanisms of resistance. In summary, the diagnostic approaches for identifying clinically relevant EGFR aberrations have rapidly advanced and are providing insights into more effective inhibition of this familiar oncogene in GBM and other cancers.
Abstract 3862: Identification of a novel genetic variant in the <i>KLK3</i> gene which predisposes to prostate cancer
Authors: Zsofia Kote-Jarai, Ali Amin Al Olama, Daniel Leongamornlert, Malgorzata Tymrakiewicz, Ed Saunders, Michelle Guy, Nadiya Mahmud, Graham Giles, Gianluca Severi, John Hopper, Freddy Hamdy, David Neal, Jenny Donovan, Kenneth Muir, Jonathan Morrison, Douglas Easton, Rosalind Eeles
Journal: Cancer Research (2010)

Abstract Prostate cancer (PrCa) is the commonest solid tumour in men in developed countries. To identify common PrCa susceptibilility alleles, we conducted a multistage genome-wide association study (GWAS). In the first stage (stage 1) 541,129 SNPs were genotyped using the Illumina Infinium platform in 1,854 PrCa cases with clinically detected PrCa diagnosed at &amp;lt;60 years or a family history of disease, and 1,894 population screened controls with low (&amp;lt; 0.5ng/ml) prostate specific antigen (PSA) level from the UK. We identified 7 novel PrCa susceptibility loci (P=2.2×10−8 to P=8.1×10−29) one of which contains a strong candidate susceptibility gene KLK3 which codes for PSA. PSA is widely used as a biomarker for PrCa detection and disease monitoring. The tag-SNP in this region, rs2735839, was associated with both PrCa disease (P=1.33×10−20) and with PSA level (P =6× 10−8). To refine the association of PrCa with variants in this region we imputed genotypes for SNPs that were not in our GWAS study, using the Mach program and the HapMap 2 CEU population as a reference panel. Among SNPs in the KLK3 region, the strongest evidence for association with PrCa cancer was observed for rs17632542, (P =5.9×10−26), a SNP not typed in the GWAS. We genotyped this novel SNP in our stage 1 (as above) and an additional stage2 sample set of 3650 PrCa cases and 3940 controls from the UK and Australia, not selected for PSA level, using Taqman assay and ABIPrism 7900HT sequence detection system. rs1763542 showed stronger evidence of association than the original tag-SNP in both stages (stage 2 P=2×10−5, overall P=3.2×10−31). Whereas rs2735839 is intergenic between the KLK3 and KLK2 genes, rs17632542 is a non-synonymous coding SNP in the KLK3 gene causing an Ile to Thr substitution at aa179. We conclude that this SNP more strongly associated with PrCa then other known SNPs in the KLK3 region, and is a strong candidate for a causative variant influencing PrCa risk. Acknowledgements: This study was funded by Cancer Research UK, The Prostate Cancer Research Foundation, and NIHR support to the Biomedical Research Centre. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3862.
Cataract skills: how do we judge competency?
Authors: Richard Smith
Journal: Journal of the Royal Society of Medicine (2013)

The approach suggested by Ho and Claoue1 of using the rate of posterior capsule rupture (PCR) during cataract surgery as a surrogate marker for competency in cataract surgery for surgeons who are not in training programmes is a reasonable one. The occurrence of PCR considerably increases the likelihood of further complications and a poorer than expected visual outcome. A model has also been proposed for the adjustment of PCR rates to take account of known preoperative risk factors, which can increase the risk of PCT by a factor of 50 or more.2

However, considerable caution is required when interpreting the rate of an adverse event when the number of operations performed is small. A second occurrence of PCR in a sample of 50 cataract operations doubles the rate from 2% to 4%, for example. It is therefore important to consider not just the rate of PCR but the clinical course following each occurrence of PCR. If the complication is not recognized or not managed adequately during the procedure, the risk of further complications (e.g. macular oedema, retinal detachment) and a poor visual outcome increases greatly.
Evaluation of Serum Levels of Osteopontin and IgG Anti-Osteopontin Autoantibodies As Potential Biomarkers of Immune Activation in Patients with Allergic Diseases
Authors: Elisa Villa, Rosalba Minisini, Olaf Rötzschke, Kia Joo Puan, Boris Buenbrazo San Luis, Anand Andiappan, Nausicaa Clemente, Luca Gigliotti, Elena Boggio, Annalisa Chiocchetti, Umberto Dianzani, Mario Pirisi
Journal: Journal of Allergy and Clinical Immunology (2016)
Abstract LB-415: Polymorphisms in nucleotide excision repair genes and endometrial cancer risk
Authors: Jennifer A. Doherty, Noel S. Weiss, Sherianne Fish, Melissa M. Loomis, Mary A. Rossing, Chu Chen
Journal: Cancer Research (2010)

The increased risk of endometrial cancer associated with unopposed exogenous estrogens and high levels of endogenous estrogens (as are present in obesity) has been hypothesized to result, at least in part, via two possible mechanisms: 1) increased cellular proliferation, and 2) through the production of estrogen metabolites, which can result in DNA damage by directly binding to DNA and forming bulky DNA adducts, and/or indirectly through the production of reactive oxygen species. Thus, interindividual variation in the ability to repair such damage might influence a woman's risk of endometrial cancer. To test this hypothesis, we examined whether the presence of the minor alleles in 64 tag SNPs in the nucleotide excision repair genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, LIG1, XPA, and XPC was associated with risk of endometrial cancer in a population-based case-control study in Washington State, with 726 cases ages 50-74 years diagnosed between 1994-2005, and 736 controls frequency-matched to the cases by age. The analyses were restricted to non-Hispanic white women. Most of the genotypes that we investigated were not associated with endometrial cancer risk. However, the presence of the rs4150386 C allele (ERCC5), the rs3730865 C allele (LIG1), and the rs3731127 T allele (XPC) was associated with risk, with respective age-adjusted per-allele odds ratios (ORs) and 95% confidence intervals (CIs) of 0.68 (0.53-0.87), 1.50 (1.05-2.14) and 1.52 (1.10-2.10). The association between rs4150386 and endometrial cancer risk was considerably stronger among obese women (body mass index (BMI)≥30 kg/m2: per-C-allele OR=0.40, 95% CI 0.24-0.65) compared to women with BMI<30 kg/m2 (per-C-allele OR=0.86, 95% CI 0.64-1.14), while the association with rs3730865 was stronger among lighter versus heavier weight women (per-C-allele ORs and 95% CIs were: 1.69, 95% CI 1.12-2.56 for BMI<30 kg/m2, and 1.15, 95% CI 0.55-2.42 for BMI≥30 kg/m2). The association with rs3731127 did not vary by BMI, and the altered risk associated with the minor alleles of the three SNPs did not vary by use of long-term unopposed estrogens. Because of the multiple redundancies in DNA repair pathways and the large number of possible associations examined, there is the potential for false positive findings, both overall and in BMI subgroups. Any conclusions regarding the influence of NER genotypes on risk of endometrial cancer await the results of additional studies.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-415.
Evaluation of the incidence and of risk factors associated with trastuzumab-associated cardiac toxicity in routine clinical practice
Authors: J. Lemieux, M. Côté, L. Provencher, I. Simard, C. St-Pierre, E. Demers
Journal: Journal of Clinical Oncology (2009)

589 Background: Data on trastuzumab-associated cardiac toxicity (TACT) in routine clinical practice are scarce. Alcohol is a potential cardiotoxic but it has not been evaluated as a potential risk factor for TACT. Methods: This is a single institution retrospective study, conducted at the Centre des Maladies du Sein Deschênes-Fabia, Quebec City. Charts review was used to collect information on tumor, cardiovascular risk factors (coronary artery disease (CAD), heart failure, high blood pressure (HBP), obesity, diabetes), alcohol (yes/no), smoking (yes/no), type chemotherapy, anthracyclines doses, trastuzumab doses and left ventricular ejection fraction (LVEF). A questionnaire about smoking and use of alcohol (before chemotherapy, during chemotherapy and during trastuzumab alone) was administered to patients. TACT was defined as a decrease in the LVEF of ≥15% or ≥10% with a resulting LVEF &lt; 50% or any follow-up LVEF of &lt; 45%. Results: Data were collected on 117 patients with non-metastatic breast cancer who started adjuvant trastuzumab between 2002 and 2007. Questionnaires on alcohol use/smoking were administered to 61 patients from these 117 patients. Median age was 53 years old and 95.7% received anthracyclines-based chemotherapy. Median follow-up of LVEF was 16.3 months. TACT developed in 25.6% of patients (10.3 % with a decreased in the LVEF of ≥15%, 7.7% with a decreased in the LVEF of ≥10% with a resulting LVEF &lt; 50% and 7.7% with a LVEF &lt; 45%). None of the following risks factors for TACT were significant (using logistic regression): age (p =0.95), CAD (p = 0.29), HBP (p = 0.46), body mass index (p = 0.64), diabetes (p = 0.29), smoking (p = 0.9), anthracycline doses (p = 0.12), baseline LVEF (p = 0.26). Alcohol use was not associated with TACT (p = 0.76). Further data will be collected in next months about alcohol use. Conclusions: In routine clinical practice, TACT was observed in 25.6% of patients, which is higher than what was reported in trastuzumab phase III clinical trials. Results about alcohol use and TACT will be updated in the spring 2009. [Table: see text]
O121 SCI-B-VAC IS SUPERIOR TO ENGERIX-B FOR PREVENTING HBV VERTICAL TRANSMISSION
Authors: N. Saed, M. Hakim, Y. Nijim, N. Farah, J. Jamalia, T. Nuser, K. Ismael, R. Ghantous, J. Amer, R. Safadi
Journal: Journal of Hepatology (2014)
EXPERIENCIA SOBRE LA ULTILIZACIÓN DE LAS PRÓTESIS AUTOEXPANDIBLES METÁLICAS EN NEOPLASIAS ESOFÁGICAS
Authors: E Morcillo, M Bocanegra, L Vázquez, C Gónzalez, J Mostazo, R Olmedo, R González, R Manteca
Journal: Endoscopy (2014)

Introducción: En el carcinoma de esófago la disfagia constituye el síntoma principal. El tratamiento paliativo ideal debería solucionar la disfagia de forma simple, rápida, permanente, y segura.
Abstract 2608: HDAC-C1A: An irreversible HDAC inhibitor with significant anti-tumor activity
Authors: Maciej Kaliszczak, Meg Perumal, Eric Aboagye
Journal: Cancer Research (2011)

Abstract Histone deacetylase (HDAC) enzymes exert control over gene transcription and cell cycle progression and their inhibition has recently emerged as an efficacious strategy to treat cancer. However, current HDAC inhibitors have been linked to a shared undesirable toxicological profile that prompts the development of new entities. The present study evaluates the in vitro and in vivo PK/PD of a newly developed HDAC inhibitor, HDAC-C1A. HDAC-C1A inhibited class I, II and sirtuins, with highest affinity for HDAC6 (IC50 = 63 ng/mL), an HDAC subtype thought to be associated with low toxicity; HDAC6 knockout does not lead to embryonic lethality. The drug irreversibly inhibited HDAC from HeLa cell extract; in HCT116 cells inhibition of enzyme activity as assessed by levels of acetyl-histone H3, H4 and acetyl-tubulin was maintained after washout demonstrating an irreversible mechanism. HDAC-C1A treatment was associated with a dose and time dependent increase of histone and non-histone targets that was maintained at 4 hours after washout; acetylation was lost by 4 h with clinically licensed HDAC inhibitor SAHA. HDAC-C1A inhibited the growth of a panel of 7 cancer cell lines with a mean GI50 of 1.6 ± 0.6 µg/mL. The drug was relatively stable after parenteral administration for 4 h. The Cmax and AUC0-4h following i.p. injection (160 mg/kg) were 20.4 µg/mL and 50 µg/mL*h, respectively. Regarding efficacy, HDAC-C1A treatment was associated with a Tumor Growth Delay (TGD2x) of 5.7 ± 1.4 days and a Tumor Growth Inhibition (TGI) of 78% compared with vehicle when given i.p. at 20 mg/kg b.i.d. in a HCT116 human colon cancer xenograft model. This dose was non-toxic (no reduction in body weight). We also assessed the potential of [18F]fluorothymidine positron emission tomography ([18F]FLT-PET) to measure early response to HDAC-C1A treatment in HCT116 xenograft bearing mice. There was a 2-fold decrease in tumor [18F]FLT uptake compared to vehicle treated animals at 48 h post-treatment; the area under the normalized [18F]FLT time versus activity curve was 117 ± 6.9 at before treatment and decreased to 106 ± 5.5 (P = 0.02) at 24 hours and 54 ± 5 (P = 0.0001) at 48 h after initiating treatment. In summary, HDAC-C1A combines irreversible HDAC inhibition with a favourable pharmacokinetic profile leading to significant anti-tumor activity in the HCT116 tumor model. Early response to the drug was detectable by [18F]FLT-PET. These preclinical data support further development of HDAC-C1A. This work was supported in part by Cancer Research U.K.-Engineering and Physical Sciences Research Council Grant C2536/A10337. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2608. doi:10.1158/1538-7445.AM2011-2608
MULTIPLE INTRAVENOUS INFUSIONS OF VEPOLOXAMER (PURIFIED POLOXAMER −188) ELICIT PROGRESSIVE IMPROVEMENTS IN PLASMA BIOMARKERS IN DOGS WITH ADVANCED HEART FAILURE
Authors: Hani N. Sabbah, Ramesh C. Gupta, Vinita Sing-Gupta, Kefei Zhang, Marty Emanuele
Journal: Journal of the American College of Cardiology (2016)
1105 PHARMACOLOGICAL INHIBITION OF CCL2 LIMITS ANGIOGENESIS ASSOCIATED WITH CHRONIC TOXIC LIVER INJURY IN VIVO BY RESTRAINING INFILTRATION OF PROANGIOGENIC INFLAMMATORY MONOCYTES
Authors: M. Bartneck, J. Ehling, X. Wei, V. Fech, N. Gassler, D. Eulberg, C. Trautwein, T. Lammers, F. Tacke
Journal: Journal of Hepatology (2013)
SAT0143 Cardiovascular Events and Rheumatoid Arthritis in Latvia
Authors: E. Stumbra Stumberga, I. Stukena, R. Erts, G. Baltgaile
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> It is widely accepted that patients with rheumatoid arthritis (RA) have increased mortality and morbidity from premature cardiovascular disease. Up to 50% of this mortality excess is secondary to ischemic heart disease closely followed by cerebrovascular disease [1]. <h3>Objectives</h3> To investigate intima-media thickness (IMT) and plaque formation with relation to age, disease duration and disease severity, myocardial infarction (MI) and stroke in patients with RA in order to detect and estimate cardio and cerebrovascular risk factors and events. <h3>Methods</h3> Forty five patients (female 91.1%) with confirmed RA (aged 20-82) were selected. Carotid artery hemodynamic parameters, IMT and plaques were measured by using high resolution B-mode and Doppler–mode ultrasound to detect blood flow velocities, maximal IMT, size of atherosclerotic plaques. Rheumatoid arthritis severity was measured by DAS28, SDAI, CDAI scores and HAQ questionnaires. For cardiovascular risk detection Framingham risk score and AIP (Atherogenic Index of Plasma (log10 TG/HDLC)) were used. Data analysis was performed using IBM SPSS 21.0. <h3>Results</h3> Patients with previous MI were statistically significant older than patients without MI (69.0±10.6 and 52.7±15.7 years, respectively). Previous MI had 13.33% of patients, and previous stroke 4.44% of patients. There were no statistically significant correlations between atherosclerotic plaques on the right and left side of brachiocephalic vessels, IMT dx and sin, and the duration of RA and the age when diagnosis was confirmed (p&gt;0.05). Statistically significant correlation between IMT sin and age of patients was found (r=0.63; p&lt;0.001); IMT dx and age of patient (r=0.62; p&lt;0.001). No statistically significant correlations between IMT dx and sin, atherosclerotic plaques dx and sin and activity markers of RA (p&gt;0.05) were found. The duration of disease was not statistically longer for patient with MI than for patients without MI (p=0.34). Atherosclerotic lesions were not more pronounced to patients with MI than without (p=0.80). Anti CCP levels did not differ between patients with and without MI (p=0.900). <h3>Conclusions</h3> Previous MI did not show significant association with BMI, smoking habits, atherosclerotic lesions of vessels (atherosclerotic plaques), disease severity, activity markers and AIP. This preliminary observation indicates the changes of immune system long before appearance of RA, triggering severe cardiovascular events without traditional cardiovascular risk factors. <h3>References</h3> Wallberg-Jonsson S, Ohman ML, Dahlqvist SR:Cardiovascular morbidity and mortality in patients with seropositive rheumatoid arthritis in Northern Sweden. J. Rheumatol 1997;24:445–51. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5841
Initial Screening for Carcinogenicity of Commonly Used Drugs23
Authors: Gary D. Friedman, Hans K. Ury
Journal: JNCI Journal of the National Cancer Institute (1980)

Journal Article Initial Screening for Carcinogenicity of Commonly Used Drugs Get access Gary D. Friedman, M.D., M.S., Gary D. Friedman, M.D., M.S. 4Department of Medical Methods Research, Kaiser-Permanente Medical Care Program, 3700 Broadway, Oakland, Calif. 94611. Search for other works by this author on: Oxford Academic PubMed Google Scholar Hans K. Ury, Ph.D. Hans K. Ury, Ph.D. 4Department of Medical Methods Research, Kaiser-Permanente Medical Care Program, 3700 Broadway, Oakland, Calif. 94611. 5We thank Mrs. Donna Wells for computer programming and analysis; Miss Julie Bishop and Miss Marilyn Nelson for reviewing the records of all cancer cases; and Miss May Kuwatani, Ms. Joan Thomas, and Mrs. Betty Wong for additional technical assistance. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 65, Issue 4, October 1980, Pages 723–733, https://doi.org/10.1093/jnci/65.4.723 Published: 01 October 1980 Article history Received: 11 February 1980 Accepted: 05 May 1980 Published: 01 October 1980