tbuckley/cabot-search huggingface dataset:
The other triple-negative breast cancer: Immunohistochemical and clinicopathologic characterization of the Claudin-low subtype.
Authors: D. Voduc, M. C. U. Cheang, A. Prat, X. He, S. Tyldesley, J. Snider, K. DeSchryver, S. Davies, M. J. Ellis, C. M. Perou, T. O. Nielsen
Journal: Journal of Clinical Oncology (2011)

1129 Background: The triple-negative (TN) immunohistochemical (IHC) definition for basal-like breast cancer lacks specificity. This aggressive subtype is best identified with the addition of EGFR and CK5/6 biomarkers; however, the subgroup of TN breast cancers that lack expression of these biomarkers (5NP) is mostly uncharacterized. Recently, an additional intrinsic subtype, claudin-low, was identified using microarray-based gene expression data. These tumors are characterized by the low expression of ERBB2, ESR1, and cell-cell adhesion proteins such as claudins 3/4/7 and E-cadherin. Methods: Microarray gene expression and IHC data were collected from two independent cohorts: Washington University (WU, n=114) and University of North Carolina (UNC, n=98). Tumors were assigned as claudin-low or not using a genomic predictor. An IHC surrogate for the claudin-low subtype was developed, and applied to a tissue microarray (TMA) from the University of British Columbia (UBC, n=3473) linked with extensive clinicopathological and outcome data. Results: Against a gene expression gold standard, an IHC combination of ER(-), Her2(-), and E-cadherin(-) best identified claudin-low tumors (PPV=24% WU, 67% UNC; NPV=94% WU, 87% UNC). This IHC panel identified 226 claudin-low tumors (6.5%) from the UBC TMA. Compared to the basal-like tumors, claudin-low tumors had a similar distribution for patient age, tumor size and lymph node status. However, the claudin-low tumors were less often grade 3 (88% vs. 80%, p = 0.036) or high expressors of Ki67 (61% vs. 82%, p <0.001). Claudin-low subgroup had superior breast cancer specific survival when compared to the basal-like (10-yr BCSS 69% vs. 60%) with a multivariate HR of 0.69 (p = 0.030), adjusted for clinicopathological variables and adjuvant treatment. Conclusions: The ER(-)/Her2(-)/E-cadherin(-) IHC definition identified the claudin-low subtype of breast cancer, although with a PPV insufficient for clinical use. The addition of this definition to the standard IHC panel for intrinsic breast cancer subtypes (ER, PR, Her2, Ki67, EGFR and CK5/6) isolates a subgroup of TN tumors that are clinically distinct from basal-like breast cancers.
Abstract 4441: Intracellular delivery of therapeutic siRNA via an antennapedia-RNA-binding domain fusion peptide
Authors: Myrsini Tsimon, Angray Kang, Anatoliy Markiv, Christina Kousparou, Agamemnon Epenetos
Journal: Cancer Research (2011)

Abstract A key characteristic in tumorigenesis is the aberrant expression of various oncogenes, whose cellular products drive various anti-apoptotic/pro-survival pathways. The RNAi pathway is an endogenous cellular pathway that transiently inhibits the translation of mRNA into protein. It therefore has the potential to selectively arrest the production of mutated proteins. As the Intracellular delivery of bioactive molecules is still a major challenge, we are exploring the possible ability of the Antenapedia homeodomain (Antp) to act as an effective transporter of conjugated cargo across biological membranes. We have previously shown that Antp delivers both p21 into p21-null tumors in order to restore cell-cycle regulation, as well as a truncated form of MAML to inhibit Notch activation and induce apoptosis. To test whether in silico-designed siRNA has the ability to silence mutated forms of genes, we have created a bifunctional fusion protein, TR7, which incorporates Antp and an RNA-binding protein. TR7 attempts to both neutralize the anionic nature of siRNA as well as introduce it to the cytoplasm, thus initiating the RNAi process in a non-cytotoxic manner. In summary, this project, utilizing Antp, aims to solve the issue of systemic RNAi delivery, as well as harness the endogenous RNAi pathway to effectively halt the production of abnormal proteins in cancer and other life threatening illnesses. 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 4441. doi:10.1158/1538-7445.AM2011-4441
The Response of Symptomatic Neurosyphilis to High-Dose Intravenous Penicillin G in Patients with Human Immunodeficiency Virus Infection
Authors: Steven M. Gordon, Molly E. Eaton, Rob George, Sandra Larsen, Sheila A. Lukehart, Jane Kuypers, Christina M. Marra, Sumner Thompson
Journal: New England Journal of Medicine (1994)

Infection with the human immunodeficiency virus (HIV) may affect both the natural course of syphilis and the response to treatment. We examined the response to treatment with high-dose penicillin G in HIV-infected patients with symptomatic neurosyphilis.
Inactivating Variants in <i>ANGPTL4</i> and Risk of Coronary Artery Disease
Authors: Frederick E. Dewey, Viktoria Gusarova, Colm O’Dushlaine, Omri Gottesman, Jesus Trejos, Charleen Hunt, Cristopher V. Van Hout, Lukas Habegger, David Buckler, Ka-Man V. Lai, Joseph B. Leader, Michael F. Murray, Marylyn D. Ritchie, H. Lester Kirchner, David H. Ledbetter, John Penn, Alexander Lopez, Ingrid B. Borecki, John D. Overton, Jeffrey G. Reid, David J. Carey, Andrew J. Murphy, George D. Yancopoulos, Aris Baras, Jesper Gromada, Alan R. Shuldiner
Journal: New England Journal of Medicine (2016)

Higher-than-normal levels of circulating triglycerides are a risk factor for ischemic cardiovascular disease. Activation of lipoprotein lipase, an enzyme that is inhibited by angiopoietin-like 4 (ANGPTL4), has been shown to reduce levels of circulating triglycerides.
ZS-9 MAINTAINS NORMOKALEMIA IN HYPERKALEMIC PATIENTS DESPITE CONTINUING RAAS INHIBITORS: A SUBGROUP ANALYSIS FROM A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED TRIAL
Authors: Wajeh Qunibi, Henrik S. Rasmussen, Philip T. Lavin, Alex Yang, Bhupinder Singh
Journal: Journal of the American College of Cardiology (2015)
Accelerated Atherosclerosis in Prolonged Maintenance Hemodialysis
Authors: Armando Lindner, Bernard Charra, Donald J. Sherrard, Belding H. Scribner
Journal: New England Journal of Medicine (1974)

The survival experience of 39 patients receiving long-term regular hemodialysis in Seattle since 1960 was studied with particular reference to mortality and morbidity from arteriosclerotic cardiovascular complications. Mean age (± 1 S.D.) was 37.0 ± 9.5 years for the group at the start of dialysis. Mean duration of treatment was 6.5 years (range, one to 13). Overall mortality was 56.4 per cent at the end of the 13-year follow-up period, and 14 of 23 deaths could be attributed to arteriosclerotic complications: myocardial infarction was responsible for eight, strokes for three, and refractory congestive heart failure for three deaths. The incidence of these complications was many times higher than for normal and hypertensive groups of comparable age, and similar to rates found in Type 2 hyperlipoproteinemia. These results indicate that accelerated atherosclerosis is a major risk to long-term survivors on maintenance hemodialysis. (N Engl J Med 290:697–701, 1974)
P1108 EFFICACY AND TOLERABILITY OF TELAPREVIR-BASED TRIPLE THERAPY FOR ADVANCED FIBROSIS STAGE CHRONIC HEPATITIS C PATIENTS: RESULTS OF THE KYUSHU UNIVERSITY LIVER DISEASE STUDY GROUP
Authors: N. Furusyo, E. Ogawa, M. Nakamuta, E. Kajiwara, H. Nomura, K. Dohmen, K. Takahashi, T. Satoh, K. Azuma, A. Kawano, Y. Tanabe, K. Kotoh, S. Shimoda, J. Hayashi
Journal: Journal of Hepatology (2014)
Abstract LB-438: Proteomic analysis of aristolochic acid-induced nephrotoxicity in rats
Authors: Li-Rong Yu, Zhiguang Li, Yuan Gao, Tao Chen
Journal: Cancer Research (2011)

Abstract Aristolochic acids (AA) are a family of structurally related nitrophenanthrene carboxylic acids, mainly consisting of aristolochic acid I (AAI) and aristolochic acid II (AAII), and are the active component of some herbal medicines. Use of dietary supplements and other botanical products containing AA have resulted in severe nephrotoxicity and consequent renal replacement therapy. Aristolochic acids are potent carcinogens as well, inducing urothelial cancers in humans and kidney tumors in rats. Previous studies have shown that the tumorigenicity of AA could result from AA-induced DNA adduct formation and mutation induction. To further understand the molecular mechanisms underlying AA-induced nephrotoxicity (e.g., carcinogenesis) and identify disease biomarkers, a quantitative proteomic analysis was conducted on kidneys from AA-treated rats. Animal treatment was conducted according to the approved protocol and followed the recommendations of the NCTR Institutional Animal Care and Use Committee. Six-week-old Big Blue rats were treated with AA as its sodium salt at concentrations of 0.1, 1.0, and 10.0 mg/kg body weight by gavage five times/week for 12 weeks or with 0.9% sodium chloride as the control using the same schedule. Six rats from each treatment group were sacrificed 1 day after the last treatment. The kidneys were isolated, frozen quickly in liquid nitrogen, and stored at −80 °C. Kidney tissues from the control and the highest AA dose treatment (10 mg/kg body weight) were selected for proteomic analysis. Proteins were extracted and digested into peptides. Trypsin-catalyzed 16O/18O stable isotope labeling was performed for each pair of control/treatment samples, which were then analyzed using two-dimensional liquid chromatography coupled online with tandem mass spectrometry (LC-MS/MS). Approximately 3000 proteins were quantified from each pair of samples, and more than 150 proteins were concordantly over expressed or under expressed across all the AA-treated samples. Pathway analysis indicated that significant changes include proteins involving xenobiotic metabolism, response to stimulus including DNA damage, cell proliferation and neoplasm, etc. Intriguingly, proteins indicating kidney pathological changes such as nephron degeneration were identified as well. Although further verification is needed, the quantitative proteomic study identified proteins related to potential toxicity and oncogenic pathways and proteins that could serve as urinary biomarkers of renal damage inflicted by aristolochic acid exposure. The views presented do not necessarily reflect those of the U. S. Food and Drug Administration. 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 LB-438. doi:10.1158/1538-7445.AM2011-LB-438
PM-01 * NEURAL DERIVATIVES FROM HUMAN EMBRYONIC STEM CELLS: A CELLULAR SYSTEM TO STUDY THE ROLE OF Otx2 IN MEDULLOBLASTOMA PROGRESSION
Authors: R. Kaur, C. Aiken, L. C. Morrison, R. Rao, M. Del Bigio, S. Rampalli, T. Werbowetski-Ogilvie
Journal: Neuro-Oncology (2015)

Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor and is currently divided into 4 subtypes based on different genomic alterations, gene expression profiles and response to treatment: Wnt, Sonic Hedgehog (Shh), Group 3 and Group 4. This extensive heterogeneity has made it difficult to assess the functional relevance of genes to malignant progression. For example, expression of the transcription factor, Orthodenticle homeobox2 (Otx2) is frequently dysregulated in multiple MB variants; however, its role may be subtype-specific. We recently demonstrated that neural precursors derived from transformed human embryonic stem cells (trans-hENs), but not their normal counterparts (hENs), resemble Groups 3 and 4 MB in vitro and in vivo. These trans-hENs have >12-fold overexpression of Otx2. Here, we tested the utility of this model system as a means of dissecting the role of Otx2 in MB using gain and loss of function studies in hENs and trans-hENs respectively. Parallel experiments with MB cells revealed that Otx2 exerts tumor suppressive effects in hEN and Shh MB cells, likely by regulating self-renewal and decreasing expression of pluripotent genes such as Sox2, Lin28A, Oct4 and Nanog. Concomitant to the negative regulation of hESC genes, we observed a decrease in levels of the active histone mark, H3K4me3 at promoter loci of pluripotent genes as well as an increase in Otx2 recruitment at the Sox2 promoter by chromatin immunoprecipitation assays. This was supported by overexpression of Sox2 in Otx2+ Shh MB and hENs that resulted in significant rescue of self-renewal and cell migration. In contrast, Otx2 is oncogenic and promotes self-renewal of trans-hENs and Groups 3/4 MB independent of pluripotent genes. These results demonstrate a cell context-dependent function of Otx2. Our study underscores the value of hESC derivatives as developmental models of MB and for investigating key biological questions related to embryonal childhood cancers.
Abstract 800: Dysregulation of DLL4 gene expression in Li-Fraumeni syndrome and tumorigenesis
Authors: Zhixing Yao, Zaki A. Sherif
Journal: Cancer Research (2015)

Abstract Li-Fraumeni Syndrome (LFS), a clinically and genetically rare heterogeneous cancer syndrome, is characterized primarily by a p53 (TP53) gene mutation. This study is an attempt to understand why 30-40% of LFS patients who do not harbor p53 mutation are nonetheless besieged by the same preponderance of primary cancers, die at an early age, and at the same rate as those with the p53 mutation. LFS provides powerful insights into our understanding of the somatic mutations present in sporadic cancers influenced by p53. The p53 protein is a transcription factor that guards against genomic instability by inducing target genes that mediate its functions. Utilizing cytogenetic techniques, we previously discovered a novel balanced reciprocal translocation t(11;15)(q23;q15) between chromosomes 11 and 15 in the normal skin fibroblasts of a patient with LFS who had bilateral breast cancer but was homozygous for wild-type p53. Analysis of the breakpoint regions of this translocation yielded a number of genes; of particular interest was DLL4 (Delta-like ligand 4, locus 15q15.1), which encodes a ligand that binds to Notch receptors. Notch signaling controls cell fate specification during embryonic and postnatal development. DLL4 is a putative regulator of T cell lineage and thymopoiesis. In this study, we analyzed DLL4 gene expression and regulation in tumorigenesis. We also analyzed the transcriptional regulation of the DLL4 promoter. Our data reveal that DLL4 expression is abrogated in the normal skin fibroblasts of all LFS patients under study and markedly down-regulated in breast cancer cells and neuroblastoma cells due to TP53 mutation, DNA methylation or gene disruption caused by a balanced reciprocal translocation between chromosomes 11q23 and 15q15. Immunohistochemistry (IHC) staining corroborated the down-regulation of DLL4 in cancer tissue samples from different organs. These findings taken together not only have possible implications for karyotype-phenotype correlation in carcinogenesis, specifically of breast cancer, but also shed light on the possible implication of DLL4 in LFS and breast cancer initiation and progression. The drastic reduction or absence in the expression of DLL4 in normal skin fibroblasts of LFS patients as well as breast and brain cancer cells is significant and supports the concept that this ligand may play a role in cancer immune-surveillance and its resuscitation in the tumor microenvironment may stimulate T-cell immunity and suppress tumor growth. This demonstrates that DLL4 may provide a strong platform as an immuno-therapeutic target in LFS and breast cancer patients. Citation Format: Zhixing Yao, Zaki A. Sherif. Dysregulation of DLL4 gene expression in Li-Fraumeni syndrome and tumorigenesis. [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 800. doi:10.1158/1538-7445.AM2015-800
Abstract SY13-02: In vivo cancer theranostics
Authors: Martin G. Pomper
Journal: Cancer Research (2012)

Abstract A theranostic agent enables diagnosis and treatment concurrently. Although a relatively new concept to pharmaceutics, theranostics have been used in nuclear medicine for over 50 years - dating back to the iodine-131 thyroid scan. Today we most frequently associate theranostics with nanotechnology since nanomedicines tend to present an appropriate platform for complex, multifunctional capability such as simultaneous or sequential imaging and therapy. Unlike low molecular weight agents, nanomedicines can carry sufficient information to enable local control of imaging and therapeutic species. But not all theranostics are nanomedicines - they may also be multifunctional genes or suitably functionalized small molecules or serve as biomarkers themselves. Introduction to theranostics with examples of existing and emerging theranostic agents as well as their clinical potential and application will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY13-02. doi:1538-7445.AM2012-SY13-02
Effect of phospholipid methylation on beta-adrenergic receptors in the normal and hypertrophied rat myocardium.
Authors: C J Limas
Journal: Circulation Research (1980)

Abdominal aortic constriction in rats results in mild cardiac hypertrophy (20% increase in left ventricular weight compared to sham-operated controls) which is associated with increased numbers of beta-adrenergic receptors (123 +/- 7.3 fmol/mg protein (mean +/- SE) vs. 87 +/- 4.3 fmol/mg in controls, P < 0.01) without changes in their affinities for dihydroalprenolol. In vitro synthesis of phosphatidylcholine through successive methylation of phosphatidylethanolamine by S-adenosyl-L-methionine is enhanced in the hypertrophied myocardium) 0.38 +/- 0.03 nmol/mg per 30 minutes vs. 0.23 +/- 0.03 nmol/mg per 30 minutes in controls, P < 0.01). In both experimental groups, methyltransferase activity has a high affinity for S-adenosyl-L-methionine (Km = 6.8 microM), depends on Mg2+, is optimal around pH 9.0, and is inhibited by S-adenosyl-L-homocysteine (ki = 8.3 microM). The possible relationship between phospholipid methylation and changes in myocardial beta-adrenergic receptors was studied in both normal and hypertrophied hearts. Preincubation of cardiac membranes with S-adenosyl-L-methionine increased the numbers of b eta-adrenergic receptors in proportion to the duration of incubation and the concentration of S-adenosyl-L-methionine. In both groups, S-adenosyl-homocysteine, but not 5'-AMP or L-methionine, attenuated the increase in beta-adrenoreceptors. These results indicate that phospholipid methylation may be an important mechanism for regulation of beta-adrenergic mechanisms in both normal and hypertrophied myocardium.
Primary amelanotic malignant melanoma of the colon
Authors: H. Sashiyama, Y. Tsujinaka, Y. Hamahata, O. Tsutsumi, T. Hoshino, Y. Minami, Y. Tsunoda, M. Yano, Y. Sato
Journal: Endoscopy (2010)

Malignant melanomas in the gastrointestinal tract are usually metastases from cutaneous melanomas [1], and primary melanomas in the esophagus or anorectal lesions rarely occur. Primary colonic malignant melanoma is extremely rare, with only eight cases previously reported [2]. Although melanomas usually exhibit macroscopic pigmentation, 30 % are amelanotic [3]. Diagnosis of amelanotic melanoma of the gastrointestinal tract by endoscopic examination is difficult owing to its resemblance to gastrointestinal stromal tumor (GIST). We report the case of a patient with amelanotic melanoma of the cecum presenting as a submucosal tumor (SMT), detected by colonoscopy. To our knowledge, this is the first report of primary amelanotic melanoma of the colon.
P57 Comparative Cost-Effectiveness of IGRA to Detect Latent TB Infection in UK Inflammatory Bowel Disease Patients Initiating Anti-TNFα Agents: Abstract P57 Table 1
Authors: K Greveson, S Capocci, S Murthy, C Smith, S Morris, C Murray, I Cropley, M Hamilton, M Lipman
Journal: Thorax (2012)

<h3>Introduction</h3> Two commercial Interferon Gamma release assays (IGRA) are approved in the UK by NICE to detect M tuberculosis (Mtb) infection. They use different test platforms. Both may provide borderline (neither clear positive or negative) or indeterminate (failure of control samples) results, especially in people taking immunomodulatory therapy. Since 2008, we have applied a standard IGRA-based assessment for latent Mtb infection in inflammatory bowel disease (IBD) patients being considered for anti-TNFα therapy. Initially this involved T-Spot.TB (TSTB) but in December 2010, our service switched to Quantiferon Gold In-tube (QFGIT). Here we review the performance and cost-effectiveness of these assays within our protocol. <h3>Method</h3> Adult IBD patients were assessed using symptom review, chest radiograph (CXR) and IGRA Indeterminate/borderline IGRA were repeated and patients with persistently indeterminate/borderline results plus TB risk factors, or a positive result were referred to TB services. Cost per patient assessment used the average of assay costs and repeated assays plus onward referrals for those with indeterminate/borderline tests. Appointment costs were taken from standard NHS tariffs. Immunomodulators were defined as thiopurines, methotrexate or prednisolone &gt;20mg/day. <h3>Results</h3> Between October 2008 and November 2010, 90 patients were tested with TSTB, of which 2 had a positive TSTB result and 5 borderline/indeterminate. From December 2010 until July 2012, 82 patients were tested with QFGIT, of which 3 had a positive result and 12 indeterminate/borderline (Table). 170 (99%) had normal CXR and a negative clinical assessment. 4 of 13 patients had two sequential indeterminate IGRA and also required assessment in TB clinic. The average price per patient was £60.66 for TSTB and £52.41 for QFGIT. 88% (152/172) have subsequently received treatment with either infliximab or adalimumab. No subjects have gone on to develop active tuberculosis. <h3>Conclusion</h3> Using either platform, we find a comparable, low rate of LTBI in our IBD population. There appears to be a higher frequency of indeterminate results using QFGIT. This raises the average cost per patient, but overall, QFGIT remains more cost-effective than TSTB. Despite differing length of follow-up, the average time was sufficient in both, otherwise comparable, cohorts to detect likely development of active TB disease.