tbuckley/cabot-search huggingface dataset:
Abstract 2333: Integrin β1 contributes to metastasis and prognosis of squamous cell carcinoma of the head and neck (HNSCC)
Authors: Dongsheng Wang, Yuxiang Wang, A.r.m Ruhul Amin, Ling Su, Susan Muller, Donghai Huang, Sreenivas Nannapaneni, Lydia Koenig, Zhengjia Chen, Lin Pan, Mourad Tighiouart, Dong Moon Shin, Zhuo (Georgia) Chen
Journal: Cancer Research (2010)

Abstract Integrin β1 Contributes to Metastasis and Prognosis of Squamous Cell Carcinoma of the Head and Neck (HNSCC) It is known that integrin β1 is involved in metastasis of various tumor types. We have previously demonstrated that integrin β1 not only serves as a potential biomarker, but also plays a role in metastasis of squamous cell carcinoma of the head and neck (HNSCC), evidently by increasing tumor cell invasion (AACR poster 09-Abstract-6472). To determine the significance of integrin β1 expression in the prognosis of HNSCC and the mechanism underlying the association of integrin β1 with metastatic disease, tissue specimens obtained from 207 patients with HNSCC (101 from patients with lymph node metastasis and 106 from patients without lymph node metastasis) were analyzed for integrin β1 expression, scored as percentage expression. Furthermore, integrin β1 was knocked down by shRNA in two HNSCC cell lines to investigate its effect on invasion and metastasis-related signal transduction pathways. Finally, an orthotopic xenograft metastatic model was utilized to verify the clinical and in vitro biological findings. Both univariate and multivariate statistical analysis showed that integrin β1 expression was significantly higher in metastatic primary tumors than in non-metastatic tumors (42.7% vs 32.1%, p=0.01 and p=0.03 by univariate and multivariate analysis, respectively). Integrin β1 was also found to be highly associated with the primary cancer site (oral cavity : larynx : oropharynx = 43.5% : 33.3% : 28.2%, p=0.01). Integrin β1 showed a proportional correlation with tumor stage (25.9% vs 45.9% for Stage III vs Stage IV, respectively, p = 0.02). In patients with metastasis, integrin β1 expression was inversely correlated with overall survival (p=0.02). The in vitro study showed that in integrin β1 knock-down cells, phosphorylation of FAK and MMP2 activity were down-regulated, which was associated with reduced invasion activity of these cells. Finally, the xenograft metastatic model showed that knock-down of integrin β1 significantly prevented HNSCC cells from metastasizing to the lymph node and lung (p=0.001 and p=0.02, respectively). Our study indicates that integrin β1 has a major impact on HNSCC prognosis through, at least partially, its active involvement in the regulation of metastasis. (Supported by NIH/NCI R21 CA125062 and GCC Distinguished Cancer Scholar award to ZGC and DMS) 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 2333.
Abstract 3137: Epigenetic regulators influencing dual histone reader TRIM24 in estrogen receptor-mediated transcription in breast cancer
Authors: Teresa T. Yiu, Michelle C. Barton
Journal: Cancer Research (2012)

Abstract Nuclear receptor-mediated regulation of gene expression, including estrogen-receptor-alpha (ERα), relies on a complex network of proteins that impose either repression or activation of gene expression. Among these, epigenetic “reader” proteins recognize combinatorial PTMs on histones, through distinct structure domains such as tandem plant homeodomains (PHD) and bromodomains (Bromo). We recently reported that tripartite motif-containing 24 (TRIM24), by means of its C-terminal tandem PHD finger and Bromo domains, recognizes unmethylated histone H3 lysine K4 (H3K4me0) and acetylated histone H3 lysine K23 (H3K23ac) within the same histone tail. In the presence of estrogen, dual chromatin reader TRIM24 preferentially recognizes these two histone marks, binds to ERα and regulates estrogen-dependent target genes. Depletion of TRIM24 inhibits breast cancer cell growth and enhances tamoxifen-induced growth inhibition. In addition, overexpression of TRIM24 correlates with decreased overall survival in breast cancer patients. We believe that TRIM24 can be a potential biomarker for breast cancer development, as well as a target for therapeutic treatment. The goal of my research is to target TRIM24 in breast cancer by identifying upstream epigenetic regulators that may influence TRIM24's function in ERα-regulated transcriptional activation. For TRIM24-regulated ERα target genes, estrogen stimulation results in a global loss of H3K4me2 at estrogen-responsive elements (EREs), where TRIM24 and ERα are recruited. Global binding profile of TRIM24 by ChIP-seq also shows that TRIM24 preferentially binds to regions depleted of H3K4me2, suggesting that upstream regulators may determine TRIM24 binding to chromatin. Demethylation of histones is mediated by specific enzymes called histone demethylases (HDMs). When we increase H3K4me2 at EREs by inhibiting the enzymatic activity of HDM, recruitment of both TRIM24 and ERα to target genes is diminished. As a result, activation of TRIM24-regulated estrogen-responsive genes is impaired. Previous work has suggested that the presence of threonine T6 phosphorylation on histone H3 (H3T6ph) prevents HDMs from demethylating H3K4me2. H3T6ph may therefore impose an inhibitory mark for LSD1-mediated demethylation of H3K4me2, and serves as an added layer of regulation for TRIM24 binding to histones, affecting subsequent function of TRIM24 as an ERα coactivator. These results may give insights into future therapeutic studies of targeting TRIM24 in breast cancer. 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 3137. doi:1538-7445.AM2012-3137
Abstract 1646: Combining molecular target drugs to inhibit cancer-stromal cell interaction in gastric cancer.
Authors: Mieko Onoyama, Yasuhiko Kitadai, Kei Shinagawa, Ryo Yuge, Mayu Ohnishi, Shinji Tanaka, Wataru Yasui, Kazuaki Chayama
Journal: Cancer Research (2013)

Abstract Recent studies in molecular and cellular biology have shown that tumor growth and metastasis are not determined by cancer cells alone but also by various stromal cells. Many human tumors secrete platelet-derived growth factor (PDGF) ligands, and PDGF receptors (PDGF-Rs) are expressed by various stromal cell populations, including carcinoma-associated fibroblasts (CAFs). Tumor cells in surgical specimens and orthotopic tumors have been shown to express PDGF-B, whereas PDGF-Rβ has been shown to be expressed predominantly by stromal cells, including CAFs, pericytes, and lymphatic endothelial cells. mTOR (mammalian target of rapamycin) is a central regulatory kinase that increases the production of proteins that stimulate key cellular processes such as cell growth and proliferation, cell metabolism, and angiogenesis. mTOR also increases the translation of hypoxia-inducible factor-1a (HIF-1a), which drives the expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF), resulting in new vasculature. In the present study, we examined the effects of PDGF-R tyrosine kinase inhibitors (imatinib, nilotinib) and mTOR inhibitor (everolimus) on tumor stroma in an orthotopic nude mouse model of human gastric cancer. Treatment with PDGF-R tyrosine kinase inhibitors did not inhibit tumor growth but did significantly decrease the stromal reaction, lymphatic invasion, lymphatic vessel area, and pericyte coverage of tumor microvessels. In contrast, treatment with mTOR inhibitor reduced tumor growth and microvessel density but did not decrease the stromal reaction. PDGF-R inhibitor and mTOR inhibitor used in combination reduced both the growth rate and stromal reaction. (control (5/5, 0.3±0.1g), nilotinib (6/6, 0.3±0.1g), everolimus (4/6, 0.08±0.02g: p&amp;lt;0.05), combination (1/6, 0.04g)) Target molecule-based inhibition of cancer-stromal cell interaction may hold promise as an effective anti-tumor therapy. Citation Format: Mieko Onoyama, Yasuhiko Kitadai, Kei Shinagawa, Ryo Yuge, Mayu Ohnishi, Shinji Tanaka, Wataru Yasui, Kazuaki Chayama. Combining molecular target drugs to inhibit cancer-stromal cell interaction in gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1646. doi:10.1158/1538-7445.AM2013-1646
An Unusual Form of Diabetes Mellitus in Ataxia Telangiectasia
Authors: Don S. Schalch, Dale E. McFarlin, Mahlon H. Barlow
Journal: New England Journal of Medicine (1970)

Five of eight patients with documented ataxia telangiectasia had an unusual form of diabetes mellitus, characterized by marked hyperglycemia, resistance to ketosis, absence of glycosuria and markedly elevated plasma insulin levels in response to the administration of glucose or tolbutamide. Moreover, the blood glucose response to both exogenous and endogenous insulin was decreased, signifying insulin resistance similar to that found in pregnancy, acromegaly and obesity. In addition, the five subjects with diabetes had evidence of hepatic disease, which has not previously been reported in ataxia telangiectasia. Although the etiology of the hepatic dysfunction is not known, the immunologic deficiency commonly present in this disease may be responsible. Carbohydrate intolerance and the hypersecretion of insulin have been attributed to hepatic disease in some patients, or to certain lesions of the central nervous system in others, but it is not known if the diabetic state in ataxia telangiectasia results from dysfunction of either of these systems.
Abstract IA-12: Oncology drug discovery and development in the 21st century
Authors: William N. Hait
Journal: Cancer Research (2009)

Abstract Oncology drug discovery and development is poised to enter an era of unparalleled growth. Based on an increasingly detailed understanding of human genetics and cancer biology, new targets have emerged that go beyond nucleic acids and microtubules to members of signal transduction pathways that are upstream of these fundamental cellular structures. In addition, an appreciation of the effects of the tumor microenvironment on cancer cell pathophysiology and metabolism has focused increasing attention on targets in these areas. With more than 200 compounds in the Pharmaceutical Industry's pipeline, substantial improvements in the lives of cancer patients are anticipated. Yet major hurdles exist. Despite the increased knowledge and investment in drug development, the entry of new drugs into the clinic has not kept pace. Key barriers include but are not limited to: 1. Understanding the role of a drug target in the context of an individual's malignancy; 2. Predicting characteristics of a patient and his or her cancer that is most likely to benefit from a specific therapy; 3. Predicting the toxicity of new agents; 4. Outmoded clinical trial designs; 5. Developing rational drug combinations; 6. Accrual to clinical trials; 7. Appropriate resourcing of regulatory agencies and; 8. the price of developing cancer drugs. This presentation will address each of these challenges and suggest ways in which progress can be made. Citation Information: Cancer Res 2009;69(23 Suppl):IA-12.
Abstract 3125: KAP1 promotes malignant properties of breast cancer cells and regulates the expression of multiple KRAB-ZNFs.
Authors: Joseph B. Addison, Renata Galeeva, Dongquan Chen, Elena N. Pugacheva, Alexey V. Ivanov
Journal: Cancer Research (2013)

Abstract Background and Objective: Chromatin remodeling is fundamental for normal development and is universally affected in cancer cells. The largest family of human transcription factors, KRAB-ZNF repressors, and their essential cofactor KAP1 play important roles in chromatin organization and regulate multiple cellular processes such as cell differentiation, pluripotency, apoptosis, DNA repair and imprinting. Here, we explored the role of KAP1 and KRAB-ZNFs in breast cancer. Methods: Using cancer patient samples, in vitro and animal xenograft model we analyzed KAP1 role in cancer cell proliferation and primary tumor formation. Results: Patient sample analysis showed KAP1 and KRAB-ZNFs overexpression in significant proportion of breast tumors. KAP1 depletion in a panel of breast cancer cell lines inhibited cancer cell proliferation, while KAP1 overexpression stimulated cell growth. Concordantly, KAP1 knockdown in MDA-MB-231LN human breast cancer cells inhibited primary tumor growth in orthotopic xenograft mouse model, while KAP1 overexpression had an opposite, growth stimulatory effect. KAP1 depletion resulted in decreased expression of a number of cancer-associated genes. Functional in vitro studies provided evidence that KAP1 positively regulates expression of multiple KRAB-ZNFs. Discussion and Conclusions: These results thus establish KAP1 as an oncogenic factor in breast cancer. Grant support: NIH NCRR grant P20 RR16440 and Susan G. Komen for the Cure grant KG110350. Citation Format: Joseph B. Addison, Renata Galeeva, Dongquan Chen, Elena N. Pugacheva, Alexey V. Ivanov. KAP1 promotes malignant properties of breast cancer cells and regulates the expression of multiple KRAB-ZNFs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3125. doi:10.1158/1538-7445.AM2013-3125
Development and Validation of a Prediction Rule for Benefit and Harm of Dual Antiplatelet Therapy Beyond 1 Year After Percutaneous Coronary Intervention
Authors: Robert W. Yeh, Eric A. Secemsky, Dean J. Kereiakes, Sharon-Lise T. Normand, Anthony H. Gershlick, David J. Cohen, John A. Spertus, Philippe Gabriel Steg, Donald E. Cutlip, Michael J. Rinaldi, Edoardo Camenzind, William Wijns, Patricia K. Apruzzese, Yang Song, Joseph M. Massaro, Laura Mauri
Journal: JAMA (2016)

Dual antiplatelet therapy after percutaneous coronary intervention (PCI) reduces ischemia but increases bleeding.
Abstract 547: Inhibition of PI 3-K isoforms lead to reactivation of Akt signaling in a subset of breast cancer cell lines.
Authors: Emilie Collmann, Alex Toker
Journal: Cancer Research (2013)

Abstract The aggressive behavior of malignant breast cancer cells is determined by a complex array of signaling pathways that regulate functions such as growth, survival, and migration. Production of phosphatidylinositol-3,4,5-P3 (PIP3) by phosphoinositide 3-kinase (PI 3-K) results in activation of downstream targets including the protein kinase Akt that plays critical roles in cell survival and growth. Recent studies have highlighted alternate, PI 3-K independent pathways often associated with malignancy that lead to Akt reactivation. The goal of our studies is to investigate the role of PI 3-K catalytic subunits in Akt reactivation in breast cancer. Surprisingly, knock-down of the catalytic subunit of class I PI 3-K PIK3CA actually enhances phosphorylation of Akt, as well as the downstream targets S6K1 and GSK3β in a subset of triple negative breast cancer (TNBC) cell lines. The resulting increase in Akt phosphorylation is mTORC2-dependent and is insensitive to the class I PI 3-K inhibitors. Rescue experiments with wild type PIK3CA alleles reveal a further enhancement of Akt phosphorylation, when compared to PIK3CA knock-down alone. Moreover, silencing of distinct class I subunits PIK3CB and PIK3CD also enhanced Akt phosphorylation in TNBC. However, this effect is not universal and is not observed in numerous other breast cancer cell lines, or using specific PIK3CA inhibitors. This reactivation of Akt signaling suggests the interruption of a feedback loop similar to the mTOR-S6K-IRS1 negative feedback loop. It also indicates specific roles for individual PI 3-K isoforms in breast cancer and dependent on the mutational status of PTEN and PIK3CA. This research is supported by Susan G. Komen for the Cure postdoctoral fellowship KG111139 to EC and AT. Citation Format: Emilie Collmann, Alex Toker. Inhibition of PI 3-K isoforms lead to reactivation of Akt signaling in a subset of breast cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 547. doi:10.1158/1538-7445.AM2013-547
Unexpected finding of anticitrullinated protein antibodies in cerebrospinal fluid of RA patients with intact blood brain barrier
Authors: Erwan Le Maître, Karin Lundberg, Eva Kosek, Mohsen Khademi, Magnus Andersson, Jon Lampa
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> The authors have recently shown upregulation of inflammatory mediators in cerebrospinal fluid (CSF) from patients with rheumatoid arthritis (RA), with correlations to fatigue mechanisms. The authors have now sought to investigate potential specific intrathecal immune activation focusing on the detection of anticitrullinated protein antibodies (ACPA), known to be highly specific and predictive for the development of RA. <h3>Methods</h3> Thirteen female patients with ACPA-positive RA underwent lumbar puncture and collection of CSF and serum. CSF from 10 age-matched individuals with no inflammatory disease, and 26 age-matched patients with multiple sclerosis (MS) were included as controls. IgG ACPAs were measured using a commercial anti-CCP2 ELISA assay (Euro-Diagnostica, Malmö, Sweden). Serum samples were diluted 1:100 according to the protocol, while CSF samples were used undiluted. Analyses of CSF albumin and CSF/plasma albumin ratio were performed in clinical routine. <h3>Results</h3> As expected, all RA patients were anticyclic citrullinated peptide (CCP) positive in serum (threshold for positivity: 25 U/ml) with levels ranging from 34 U/ml to more than 3200 U/ml. Interestingly, 7/13 RA patients were anti-CCP positive also in CSF, with levels ranging from 29 U/ml to 154 U/ml in undiluted samples. Anti-CCP levels in controls, on the other hand, were significantly lower; 2.19 +/− 0.09 U/ml for non-inflammatory controls, and 2.54 +/− 0.16 U/ml for MS patients (undiluted samples). In RA patients, there was a correlation between presence of anti-CCP antibodies in CSF and significantly higher serum anti-CCP levels (1453 +/− 82 U/ml in RA with CCP positivity both serum/CSF versus 90 +/− 46 U/ml, CCP negative in CSF; p&lt;0.01). No difference in CSF albumin or the CSF/plasma albumin ratio could be detected between these groups. All patients had normal CSF albumin and CSF/plasma albumin ratios, consistent with an intact blood brain barrier. No RA patient had any history of or symptoms of neurologic disease. <h3>Conclusion</h3> Our data show, for the first time, the presence of ACPAs in CSF of RA patients. The association with high serum ACPA levels in these patients may suggest a leakage of antibodies, though data demonstrate intact blood brain barrier. Presence of autoantibodies like ACPA in the CSF may predispose for autoimmune reactions in the central nervous system, potentially affecting cerebral symptoms such as fatigue.
FRI0028 Efficacy of TOCILIZUMAB on MRI- Determined Bone Oedema in Rheumatoid Arthritis
Authors: N. Bensaoud, S. Rostom, R. Bahiri, B. Amine, F. Allali, N. Hajjaj-Hassouni
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> To assess the impact of Tocilizumab on bone oedema in rheumatoid arthritis as shown by MRI <h3>Methods</h3> In this longitudinal study, were included patients with rheumatoid arthritis RA according to the American College of Rheumatology ACR 1987 criteria with inadequate response or intolerance to DMARDs, treated with tocilizumab (TCZ).Sociodemographic characteristics, clinical and laboratory for the disease were collected at baseline (M0) and 06 months (M6) of treatment.Disease activity was assessed using DAS28, SDAI et CDAI.MRI of the dominant hand was performed at baseline and M6 of treatment.The primary outcome was the assessment of bone oedema by RAMRIS bone oedema (Rheumatoid Arthritis MRI Scoring system).Secondary outcomes included:RAMRIS synovitis, DAS28 CRP, CRP, and SDAI at baseline and M6. <h3>Results</h3> 22 patients with RA were included, 19 females (86.4%), with a mean of age 42±13.7. The mean disease duration was 8±5.2 years.The mean DAS28 was 5.8±0.94. The median CRP was 16 mg/l (6.7 to 36.3). The average SDAI was 90±34. Three patients were excluded from the study for serious side effects.At baseline, bone edema was present in 41% of patients (N=9), with a median bone oedema RAMRIS 0 (0 to 7.2). A M6, bone oedema decreased or disappeared in 32% (N=7) with a significant improvement in the score RAMRIS bone oedema (p=0.04). Moreover, there is a significant improvement RAMRIS synovitis (p&lt;0.0001) as well as activity parameters: DAS28CRP (p &lt;o, ooo1), CRP (p&lt;0.0001) and SDAI (p&lt;0.0001). <h3>Conclusions</h3> This study suggests that Tocilizumab is associated with a significant improvement in MRI- determined bone oedema in the short term. This improvement in bone oedema is correlated with improved parameters of disease activity, which could be discussed early structural effect. Further studies are needed to confirm these results. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5921
Lysyl oxidase is associated with increased thrombosis and platelet reactivity
Authors: Shinobu Matsuura, Rongjuan Mi, Milka Koupenova, Alexia Eliades, Shenia Patterson, Paul Toselli, Jonathan Thon, Joseph E. Italiano, Philip C. Trackman, Nikolaos Papadantonakis, Katya Ravid
Journal: Blood (2016)
Vesicocolic Fistula Detected by 99mTc-MAG3 Renogram
Authors: Lorenzo Mannelli, Serena Monti, Sarah Bastawrous, Ivano Lomabardo, Fatemeh Behnia
Journal: Clinical Nuclear Medicine (2014)

A 55-year-old man presented with 60-lb weight loss in 6 months. An abdominal CT demonstrated a large mass in the pelvis arising from the sigmoid colon and invading the urinary bladder. His elevated serum creatinine (1.25 mg/dL) triggered a request for a Tc-MAG3. Tc-MAG3 renogram demonstrated communication of the urinary bladder with the descending colon but no evidence of obstruction to drainage from the kidneys to the bladder. A retrograde cystogram confirmed a vesicocolic fistula. After multiple rounds of chemotherapy, the patient died 7 months later.
Atherosclerosis — An Inflammatory Disease
Authors: Russell Ross
Journal: New England Journal of Medicine (1999)

Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .