tbuckley/cabot-search huggingface dataset:
Overexpression of C/EBP -LIP, a Naturally Occurring, Dominant-Negative Transcription Factor, in Human Breast Cancer
Authors: C. A. Cynthia A., P. Younes, R. Laucirica, J. M. Rosen
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: When cells fail to maintain a balance between proliferation, terminal differentiation, and programmed cell death, cancer often results. The CCAAT/enhancer-binding protein (C/EBP) family of transcription factors regulates many genes involved in the processes of proliferation and terminal differentiation. The messenger RNA for C/EBPβ is translated into two major isoforms, LAP (liverenriched activating protein) and LIP (liver-enriched inhibitory protein). LIP levels appear to be elevated in mouse mammary tumors but not in hyperplastic mammary tissues. We tested whether LIP expression is elevated in human breast cancer and whether elevated expression is associated with biologic predictors of the aggressiveness of the disease. Methods: Homogenates of infiltrating ductal carcinoma specimens from 39 women were analyzed for C/EBPβ protein content by western blot analysis, and the ratio of LAP to LIP in specimens containing high levels of LIP (i.e., levels approximately 15 times higher than those in tumor specimens that express little or no LIP) was also determined. Nonparametric statistical analyses were performed. Results: LIP was present at high levels in nine of 39 specimens of infiltrating ductal carcinoma. Eight of the nine specimens of infiltrating ductal carcinoma that contained high levels of LIP were negative for estrogen receptor and progesterone receptor (ER − /PR − ); all nine tumors were aneuploid and poorly differentiated, and eight of nine were highly proliferative. Of the tumors that contained LIP at low or nondetectable levels, six of 30 were ER − /PR- − , 17 of 29 were aneuploid, eight of 27 were highly proliferative, and 11 of 30 were poorly differentiated. Implication: LIP expression should be evaluated further as a prognostic marker for patients with breast cancer.
OP0271 Prevalence of Structural Lesions on MRI of the Sacroiliac Joints in Patients with Early Axial Spondyloarthritis and Patients with Back Pain
Authors: R. van den Berg, M. de Hooge, V. Navarro Compán, M. Reijnierse, F. van Gaalen, K. Fagerli, M. Turina, M. van Oosterhout, L. Punzi, T. Huizinga, D. van der Heijde
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Prevalence of structural lesions on MRI in recent onset axial spondyloarthritis (axSpA) patients (pts) and back pain pts is unknown <h3>Objectives</h3> To investigate the prevalence of structural lesions on MRI in these pts <h3>Methods</h3> Pts with back pain (≥3 months, ≤2 years, onset &lt;45 years) from the 5 centers were included in the SPondyloArthritis Caught Early (SPACE)-cohort. Pts underwent MRI of the sacroiliac joints (MRI-SI). MRIs-SI were scored by 3 well-calibrated readers independently for ankylosis, sclerosis, erosions, and fatty lesions (FL) (MRI T1-weighted images; STIR images viewed simultaneously). Erosions, sclerosis and FL were defined according to the MORPHO definition<sup>1</sup> (≥1 lesion on ≥2 consecutive slices or ≥2 lesion on 1 slice); ankylosis as 1 lesion on ≥1 slice. Lesions were considered present if 2/3 readers agreed. Prevalence based on several cut-offs of structural lesions were calculated. Pts were grouped according to the ASAS axSpA criteria<sup>2</sup> [imaging-arm (mNY+, mNY-), clinical arm], no-SpA and possible SpA <h3>Results</h3> Pts with MRI-SI data were included (n=299). If defined as ≥1, all structural lesions except ankylosis were frequent in all groups; in decreasing frequency in mNY+, MRI+mNY-, clinical-arm, possible SpA and no-SpA. The higher the cut-offs, the better discrimination between the imaging-arm and no/possible SpA; the clinical-arm close to no/possible SpA. To define a proper cut-off for the presence of structural lesions in axSpA, the false-positive percentage in no-SpA pts should be low. We defined possible cut-offs based on the acceptance of ≤10% (italics) and ≤5% (bold) false-positives (table). E.g. if ≥4 structural lesions are present, false-positives are 6.0% and 5.2% resp., with a frequency of 61.5% and 43.5% in the mNY+ and MRI+mNY- subgroups. <h3>Conclusions</h3> Prevalence of erosions, sclerosis and FL on MRI-SI is high in axSpA pts but also in no-SpA pts. Higher cut-offs than ≥1 lesion are needed to reduce false-positives; also with higher cut-offs structural lesions are frequent in early axSpA pts. These data suggest that with appropriate cut-offs, structural lesions might be helpful in defining sacroiliitis on MRI <h3>References</h3> Weber A&amp;R 2010;62:3048-58 Rudwaleit ARD 2009;68:777-83 <h3>Disclosure of Interest</h3> None Declared
GLP-1–Receptor Scanning for Imaging of Human Beta Cells Transplanted in Muscle
Authors: Francois Pattou, Julie Kerr-Conte, Damian Wild
Journal: New England Journal of Medicine (2010)

To the Editor: Cell therapy is emerging as a realistic treatment for type 1 diabetes, on the basis of the prolonged success of intraportal islet transplantation in selected patients.1 Key improvements include the development of alternative implantation sites and new tools for in vivo detection of transplanted cells. In the absence of reliable beta-cell markers, previous clinical attempts to visualize transplanted islets have relied on magnetic resonance imaging2 and positron-emission tomography.3 However, these techniques necessitate the in vitro manipulation of islets and are limited by the short half-life of available labeling agents. Glucagon-like peptide 1 (GLP-1)–receptor scanning has been successfully . . .
Abstract 769: Integrin-Linked Kinase (ILK) breaks Merlin's spell to inhibit the Hippo tumor suppressor pathway and activate the YAP oncogene.
Authors: Isabel Serrano, William J. Muller, Shoukat Dedhar
Journal: Cancer Research (2013)

Abstract The Hippo signalling pathway is gaining recognition as an important player in tumor progression. Components of the pathway, which include transcriptional co-activators YAP/TAZ, are dysregulated in a significant fraction of human cancers, and YAP activation has recently been shown to promote Epithelial to Mesenchymal Transition (EMT) and metastasis. However, how Hippo signalling is dysregulated in tumors remains unclear. Here, we demonstrate that Integrin-Linked Kinase (ILK), an actin-interacting, focal adhesion adaptor and serine/threonine protein kinase whose expression is also significantly upregulated in many types of cancers, inhibits the Hippo tumor suppressor pathway by stimulating the phosphorylation, and inhibiting the activity of Merlin, via the protein phosphatase inhibitor, CPI-17, an established target of ILK, and an inhibitor of Merlin (Deng JT et al. Biochem J 2002; Huang J et al. Biochem J 2006). We have assessed the pathway in human breast and prostate cancer cell lines, in which the Hippo pathway is switched OFF, as determined by the phosphorylation status of Merlin, MST1/2, LATS1/2, and YAP, and the nuclear YAP localization. We demonstrate that inhibition of ILK expression, or inhibition of its activity in these cells turns the Hippo pathway ON, resulting in the stimulation of YAP phosphorylation, sequestration in the cytoplasm, and inhibition of TEAD transcriptional activity. In addition, we have determined that YAP/TAZ protein expression is significantly upregulated in vivo in ErbB2 induced mammary tumors from transgenic mice, and that deletion of ILK from these tumors, which significantly delays tumor growth and inhibits metastasis, dramatically suppresses the expression of these transcription co-activators. Finally, we demonstrate that ILK plays a critical role in the suppression of the Hippo pathway by TGF-b, EGF and LPA. Treatment of human breast and prostate epithelial cells with these growth factors results in dephosphorylation of LATS 1/2, and YAP, and nuclear localization of YAP. However, inhibiting ILK activity under these conditions results in the stimulation of phosphorylation of LATS1/2 and YAP, as well as in the sequestration of YAP/TAZ in the cytoplasm. These novel data demonstrate that ILK inhibits the Hippo tumor suppressor pathway leading to nuclear activation of YAP/TAZ, thereby contributing to tumor progression and metastasis. Citation Format: Isabel Serrano, William J. Muller, Shoukat Dedhar. Integrin-Linked Kinase (ILK) breaks Merlin's spell to inhibit the Hippo tumor suppressor pathway and activate the YAP oncogene. [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 769. doi:10.1158/1538-7445.AM2013-769
Abstract 4072: Insulin and NADPH-generating enzymes as molecular targets to repress colon cancer cell proliferation
Authors: Ahmed Al-Dwairi, Adam R. Brown, Rosalia CM Simmen, Frank A. Simmen
Journal: Cancer Research (2011)

Abstract An increasing body of evidence implicates obesity and the attendant hyperinsulinemia as major risk factors for human colorectal cancers. The lipogenic pathway supports growth and survival of colon cancer cells. In particular, inhibition of Fatty Acid Synthase (FASN) or Acetyl-CoA Carboxylase α (ACCα) induces apoptosis of colon cancer cells. The relative involvement in colon cancer initiation, progression and pathogenesis of cytosolic NADPH that is used in lipogenesis remains less clear. In the present study, we have determined the effects of insulin and the involvement of the major NADPH-generating cytosolic enzymes on proliferation of human colon cancer cell lines. Insulin (1-10 nM; to mimic normo- to hyper-insulinemic states) induced a significant increase (7-15%, p &amp;lt; 0.05) in proliferation of HT-29 and HCT-116 colon cancer cell lines in vitro (assayed by MTT assay). Addition of insulin augmented (by 5-10%) proliferation of both cell lines upon concurrent treatment with cancer chemotherapeutic agents (5-fluorouracil, oxaliplatin, irinotecan; each added at a dose &amp;lt; EC50). The insulin-mediated increase in HT-29 cell growth was associated with a 2-3 fold elevation in FASN gene expression and a 50% decrease in expression of the FASN-targeting micro RNAs, miR-103 and miR-107. However, insulin did not induce mRNA abundance for the cytoplasmic NADPH-generating enzymes [Malic Enzyme 1 (ME1), Glucose 6-Phosphate Dehydrogenase (G6PD), 6-Phosphogluconate Dehydrogenase (6PGD), or Isocitrate Dehydrogenase-1 (IDH1]. siRNA-mediated knockdown of FASN or of the individual major cytosolic NADPH-generating enzymes caused decreases in proliferation of HT-29 and HCT-116 cells (15-30%, p &amp;lt; 0.05) compared to the control scrambled siRNA. Data highlight pro-proliferative roles for insulin, FASN and cytosolic NADPH-generating enzymes in colorectal cancer cell growth. Implementation of pharmacologic and/or nutritional means to reduce serum insulin levels, enhance FASN miR expression and inhibit tumor cell NADPH-generation may serve as useful adjuncts for future cancer treatment and prevention. Supported by NIH grant RO1 CA136493 and the Arkansas Biosciences Institute. 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 4072. doi:10.1158/1538-7445.AM2011-4072
Survival of patients with HER2+ metastatic breast cancer and use of trastuzumab following progression: analysis of RegistHER.
Authors: H Rugo, P Kaufman, E Tan-Chiu, M Ulcickas Yood, S Paik, D Yardley, A Brufsky, M Mayer, M Birkner, L Wang, M Brammer, D Tripathy
Journal: Cancer Research (2009)

Abstract Abstract #3142 Background: Most HER2+ metastatic breast cancer (MBC) patients who initially respond to trastuzumab (T)-based therapies will experience disease progression (PD). Standard practice is to discontinue the cytotoxic agent on which disease progressed, however there is evidence that tumors may remain sensitive to HER2 targeting and that there may be a potentiating effect of T on chemotherapy. We examined the treatment history of a large population of HER2+ MBC patients to assess outcomes associated with continuation of T beyond PD.&amp;#x2028; Methods: This analysis was carried out on patients enrolled in registHER, a prospective observational study of 1023 patients with newly diagnosed (within 6 months) HER2+ MBC. Median f/u from MBC diagnosis is 25 months at the time of data cut-off (12/31/07). For those treated with T prior to first PD, we compared demographics and baseline tumor characteristics for those patients treated with or without T following first PD. Treatment with T was defined as a minimum of 21 days of therapy prior to PD. In addition, we evaluated time to second PD, and overall survival post PD (both endpoints calculated from initial PD). Overall survival (OS) was also calculated from the date of treatment initiation to death for the entire treated cohort.&amp;#x2028; Results: Of 1023 evaluable patients, 873 (85%) were treated with any T-based first-line therapy. 622 T-treated patients progressed and 500 were subsequently treated with T following first PD. Patients who received T post first PD tended to be younger (&amp;lt;50 years of age, 45.2% vs 29.5%) and have hormone receptor positive disease (51.4% vs 42.0%) compared with patients who did not receive T post first PD. Among all treated patients the median overall survival was 35.6 mo (25th-75th-ile:18.6-63.1 mo). Median survival post PD in the 500 patients treated with trastuzumab following first PD was 21.2 mo (25th-75th-ile:11.8-35.8mo).&amp;#x2028; Conclusions: OS in patients on the prospective observational study registHER is longer than the OS of 25.1 months noted in the pivotal trial of first-line HER2+ MBC patients treated with T plus chemotherapy. We will present data on the association between various pre- and post-treatment factors, including the use of T beyond PD, and PFS and OS. This will include a multivariate analysis that specifically examines the association between T use in later lines and survival. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3142.
Abnormal Coronary Vasoconstriction as a Predictor of Restenosis after Successful Coronary Angioplasty in Patients with Unstable Angina Pectoris
Authors: Diego Ardissino, Paolo Barberis, Stefano De Servi, Piera Angelica Merlini, Ezio Bramucci, Colomba Falcone, Giuseppe Specchia
Journal: New England Journal of Medicine (1991)

High rates of restenosis after coronary angioplasty have been reported in patients with vasospastic angina. This study was designed to determine whether the occurrence of abnormal coronary vasoconstriction, detected by means of hyperventilation testing before angioplasty, influences the risk of restenosis after successful dilation.
Abstract 2418: Establishment and characterization of a primary chordoma xenograft
Authors: Preeti Shah, Varalakshmi Katuri, Ola Awad, Naheed Gul, Paul S. Metzer, David Loeb
Journal: Cancer Research (2011)

Abstract Chordomas are slow growing, malignant cancers believed to originate from notochord remnants. Chordoma accounts for 1% of cancers of the central nervous system with an annual incidence of 0.08 cases per 100,000 individuals. There are 3 different histologic subtypes- classic chordoma, chondroid chordoma, and dedifferentiated chordoma. Chordomas are characterized by the presence of physaliphorous cells with vacuolated cytoplasm and high expression of the transcription factor T Brachury. Management of chordoma is primarily surgical – chemotherapy and radiation therapy have limited effect. The development of effective treatments for this tumor is hampered by the lack of adequate animal models. We report here the establishment of the first primary xenograft model of chordoma. Tumor excised from a patient diagnosed with classic chordoma was implanted adjacent to the right proximal tibia in a NOD/SCID/IL2Rγ (null) mouse. The resulting tumor has been serially transplanted at least 10 times with no diminution in growth rate over time. Histologically, the xenograft does not appear to be a classic chordoma; interestingly, the patient from whom the xenograft was derived relapsed with a dedifferentiated morphology. To confirm the identity of the tumor xenograft, T brachyury expression was demonstrated by immunohistochemistry and PCR. We have begun to characterize this xenograft by gene expression profiling and comparative genomic hybridization. Expression profiling results were verified by RT-PCR. Cells isolated from xenografts were analyzed by the Aldefluor assay to assess the levels of expression of aldehyde dehydrogenase activity. A cell line was generated from this xenograft as well and is being characterized. In summary, we report here the establishment of the first primary chordoma xenograft. Initial molecular characterization of the xenograft and a cell line derived from this tumor is ongoing. These tools will shed valuable light on the pathophysiology of this rare tumor and allow the preclinical development of novel treatment strategies. 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 2418. doi:10.1158/1538-7445.AM2011-2418
Relation of Leisure-Time Physical Activity and Cardiorespiratory Fitness to the Risk of Acute Myocardial Infarction in Men
Authors: Timo A. Lakka, Juha M. Venalainen, Rainer Rauramaa, Riitta Salonen, Jaakko Tuomilehto, Jukka T. Salonen
Journal: New England Journal of Medicine (1994)

Previous studies have suggested that higher levels of regular physical activity and cardiorespiratory fitness are associated with a reduced risk of coronary heart disease. We investigated the independent associations of physical activity during leisure time and maximal oxygen uptake (a measure of cardiorespiratory fitness) with the risk of acute myocardial infarction.
Medical Treatment of Peripheral Arterial Disease and Claudication
Authors: W R Hiatt
Journal: New England Journal of Medicine (2001)

Peripheral arterial disease, which is caused by atherosclerotic occlusion of the arteries to the legs, is an important manifestation of systemic atherosclerosis. The age-adjusted prevalence of peripheral arterial disease is approximately 12 percent, and the disorder affects men and women equally (Table 1).7,8 Patients with peripheral arterial disease, even in the absence of a history of myocardial infarction or ischemic stroke, have approximately the same relative risk of death from cardiovascular causes as do patients with a history of coronary or cerebrovascular disease (Table 2).12,15 In patients with peripheral arterial disease, the rate of death from all causes . . .
Prostate-Specific–Antigen Testing for Early Diagnosis of Prostate Cancer
Authors: M J Barry
Journal: New England Journal of Medicine (2001)

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.A 65-year-old man with no risk factors for prostate cancer except his age has a normal digital rectal examination. Should a prostate-specific–antigen (PSA) test be ordered?The Clinical ProblemThe introduction of PSA testing in 1987 resulted in an enormous increase in the reported incidence of prostate cancer in the United States. After peaking in 1992, the incidence fell, presumably owing to the identification of preexisting cases among men who had been tested. The rate of death from prostate cancer has risen and fallen over the same period for reasons that are unclear (Figure 1).1 Advocates of screening attribute . . .
OP0175 Monocarboxylate Transporter (MCT)-4, Associated with the Decrease of Synovial Fluid Ph, is A Novel Therapeutic Target of Rheumatoid Arthritis
Authors: W. Fujii, E. Ashihara, H. Nagahara, Y. Kukida, R. Ishigaki, A. Kasahara, T. Sagawa, T. Seno, A. Yamamoto, M. Kohno, R. Oda, D. Tokunaga, T. Kubo, Y. Kawahito
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> It is well known that synovial fluid pH is decreased in rheumatoid arthritis (RA) patients (1), but the meaning and mechanism remain unclear. <h3>Objectives</h3> We investigate the correlation between synovial fluid pH and the disease activity of RA. We reveal the mechanism by which synovial fluid pH is regulated and explore the novel therapeutic strategy of RA by applying this mechanism. <h3>Methods</h3> We measured the values of pH and the concentration of L-lactate in synovial fluid of RA patients. Next, we investigated the expression of ion transporters regulating intracellular and extracellular pH in RA synovial fibroblasts (RASFs) obtained from the inflamed joints using quantitative RT-PCR and Western Blotting. Finally, we suppressed the ion transporter expression by small interfering RNA (siRNA) against the ion transporter increased in RASFs, and analyzed their viability and proliferative capacity of RASFs. <h3>Results</h3> Synovial fluid pH was decreased as the disease activity score (DAS)-28 CRP increased in RA patients (graph A, n=17, r = -0.81, p&lt;0.001), accompanied by increased level of synovial fluid L-lactate (graph B, n=11, r = -0.79, p&lt;0.01). The mRNA levels of Na<sup>+</sup>/H<sup>+</sup> exchanger (NHE)-1, vacuolar type H<sup>+</sup>-ATPase (V-ATPase), and monocarboxylate transporter (MCT)-1 were not altered. However, the mRNA and protein levels of MCT4, exporting intracellular lactate to extracellular space, were significantly increased in RASFs compared to those in osteoarthritis (OASFs) or normal synovial fibroblasts (graph C). Knockdown of MCT4 of RASFs induced apoptosis in RASFs and subsequently their proliferation was inhibited (graph D), indicating important roles of MCT4 in RASF proliferation. <h3>Conclusions</h3> Synovial fluid pH negatively correlated with DAS28-CRP, accompanied by increased level of L-lactate. We suggest that it is due to the increased expression of MCT4 in RASFs. Also, silencing of MCT4 induces apoptosis in RASFs and inhibits RASF proliferation, indicating that MCT4 could be a novel therapeutic target of RA. <h3>References</h3> Falchuk KH, Goetzl EJ, and Kulka JP. 1970. Respiratory gases of synovial fluids. An approach to synovial tissue circulatory-metabolic imbalance in rheumatoid arthritis. Am J Med. Aug;49(2):223-31. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1017
INCIDENCE OF CANCER INCREASED IN PATIENTS WITH CHRONIC HEART FAILURE
Authors: Mari Sakamoto, Masanori Asakura, Akira Funada, Makoto Amaki, Takahiro Ohara, Takuya Hasegawa, Yasuo Sugano, Hideaki Kanzaki, Toshimitsu HAmasaki, Toshihisa Anzai, Masafumi Kitakaze
Journal: Journal of the American College of Cardiology (2015)