tbuckley/cabot-search huggingface dataset:
Abstract 312: P190-B RhoGAP overexpression disrupts mitosis, alters cell polarity, and increases adhesion and invasion in mammary epithelial cells
Authors: Peter R. McHenry, Clara Park, Peggy Chang, Erliang Zeng, James Sears, Tracy Vargo-Gogola
Journal: Cancer Research (2010)

Abstract Breast cancer causes approximately 40,000 deaths each year in the United States alone. Collective epithelial invasion is an important process in tumor progression, and it also occurs in the normal mammary gland (MG) through specialized structures called terminal end buds (TEBs) that proliferate and migrate to drive ductal outgrowth during MG development. P190-B RhoGAP is highly expressed in TEBs, suggesting it may regulate the invasive process of MG development. Indeed, tetracycline-inducible p190-B overexpression causes perturbations in TEB morphology, stromal composition, and MG branching morphogenesis. In the current study, we analyzed the gene expression patterns of MECs isolated from p190-B overexpressing mice to determine how p190-B regulates epithelial morphogenesis as well as stromal-epithelial interactions. We investigated the expression patterns of p190-B and investigated the effects of overexpression in MCF-7 breast cancer cells. We further investigated the effects of p190-B overexpression on primary MECs in a three-dimensional (3D) culture MEC morphogenesis assay in reconstituted basement membrane (rBM) and in adhesion assays. Microarray results demonstrated that a large number of genes involved in regulating mitotic cell division and the PI3K pathway of proliferation/survival signaling are altered in p190-B overexpressing primary MECs. Real-time PCR confirmed a number of genes are significantly up- or down-regulated in these pathways. Consistent with these findings, p190-B localizes to the mitotic spindle and kinetochores during metaphase of mitosis and to the midbody at cytokinesis. Furthermore, overexpression of p190-B caused abnormal centrosome formation, multipolar spindles, failed cytokinesis, and multinucleation in MCF-7 cells. In addition, primary MECs overexpressing p190-B demonstrated increased adhesion to laminin and type IV collagen, components of the basement membrane, and primary MECs overexpressing p190-B cultured in rBM showed increased disrupted acinar formation, loss of cell polarity, and invasion. P190-B overexpression alters cell polarity and mitosis and regulates adhesive and invasive properties in MECs. These phenotypes may be critical for TEB structure and function during MG branching morphogenesis. We propose that p190-B overexpression may contribute to tumorigenesis by disrupting mitosis and promoting invasion. 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 312.
Bronchogenic Carcinoma in Persons under Forty Years of Age
Authors: Harold W. Neuman, F. Henry Ellis, John R. McDonald
Journal: New England Journal of Medicine (1956)

BRONCHOGENIC carcinoma is generally considered a disease that affects predominantly middle-aged and elderly men. Younger persons, however, may be affected, and it is important that the clinician consider it as a possible diagnosis in any person, regardless of age or sex, whose thoracic roentgenogram discloses an abnormal pulmonary shadow.The present study was undertaken to review the experience at the Mayo Clinic with bronchogenic carcinoma occurring both in males and in females under forty years of age. Where indicated, comparisons are made between the findings in this group of cases and those of Kirklin and his associates,1 who reported on . . .
AB0851 Laboratory Abnormalities in Tuberculous Spondylodiscitis
Authors: H. Sahli, I. Cherif, R. Tekaya, A. Bachali, I. Mahmoud, O. Saidane, L. Abdelmoula, R. Zouari
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Tuberculous spondylodiscitis still frequent in our country. Biologic aspects can help diagnosis in some cases. <h3>Objectives</h3> Our objective is to describe laboratory features of tuberculous spondylodiscitis among monocentric experience. <h3>Methods</h3> This is a retrospective study which included medical records of patients treated for tuberculosis spondylodiscitis during the ten past years [2002-2012]. Biologic data were recorded and analysed. <h3>Results</h3> Fifty seven cases of 29 women and 28 men of tuberculous spondylitis were treated during the ten past years. The mean age was 56.6 years (range 20 to 86 years). A contact history of tuberculosis was reported by 2 patients. The predisposing conditions were present in the third of cases: diabetes mellitus (13 cases), hepatic cirrhosis (5 cases) and high-dose corticosteroid intake (2 cases). It was a progressive starting of disease in two thirds of cases with median duration from the onset of symptoms to the diagnosis about 5.4 months (0.7 range to 24 months). Fever was observed in 29% of cases. Night sweats were present in 40% of cases Anorexia and weight loss were present in 71.9% of cases. Stiffnes was noted in 70% of cases. Pulmonary tuberculosis was associated in 3 cases and cutaneous tuberculosis was noted in 1 case. Biological inflammatory tests were rised in 91% of cases with a mean erythrocyte sedimentation rate of 93mm (range 2 to 150) and an average value of c Reactive protein of 55mg/l (range 0,2 to 331). The blood count showed leukocytosis (15 cases), lymphocytosis (9 cases), leukopenia and anemia in one case each. Disturbance of liver function tests was noted in 5 cases: hepatic cholestasis (n=3), hepatic cytolisis (n=2). Hyerglycemia was noted in the 13 cases of diabetes mellitus. Identification of mycobacterium tuberculosis in sputum was positive in 1 case. <h3>Conclusions</h3> Inflammatory blood tests were rised in major of cases and leukocytosis was frequent among patients with tuberculous spondylodiscitis in this study. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2758
Abstract SY20-02: Role of Polycomb repressors in stem cells, cancer, DNA repair and iPS cell reprogramming
Authors: Maarten van Lohuizen
Journal: Cancer Research (2012)

Abstract Repressive Polycomb-group (Pc-G) protein complexes and the counteracting Trithorax-group (Trx-G) of nucleosome remodeling factors are involved in the dynamic maintenance of proper gene expression patterns during development, acting at the level of chromatin structure. As such, they are important controllers of cell fate. When deregulated, these master switches of gene expression are strongly implicated in formation of a diverse set of cancers, including leukemia, breast cancer, prostate cancer and glioblastoma. To identify critical Polycomb targets and pathways implicated in brain cancer we performed comprehensive Bmi1-ChIP-seq profiling of mouse and human glioma ‘stem-like’ cells followed by in vivo shRNAi-library screening. These studies revealed a critical cross-talk between the BMP/TGFβ signaling pathways and Bmi1 and also provided new candidate tumor suppressors and non-coding RNAs associated with gliomagenesis. Furthermore, we have characterized in detail an essential E3-ubiquitin ligase activity in the PRC1 Polycomb complex that consists of a functional Ring1B-Bmi1 heterodimer. This E3 ligase activity is required for maintenance of Polycomb repression in normal- and cancer stem cells and hence offers potential novel ways to target cancer stem cells or tumor reforming cells in which the activity of this E3 ligase is hyperactivated. This is further substantiated by dynamic regulation of the Ring1B.Bmi1 E3 ligase activity which also has implications for a novel link between Polycomb silencing and control of Double-Strand DNA repair. Lastly, our recent studies revealed an unanticipated important role for Polycomb repression in the process of cellular ‘iPS’ cell reprogramming. The implications of these findings for stem cell biology, development, and possibilities for new translational approaches to cancer 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 SY20-02. doi:1538-7445.AM2012-SY20-02
Abstract 1621: The proprotein convertase PCSK1 is a novel drug target in alveolar soft part sarcoma (ASPS)
Authors: David T. Vistica, Susan Kenney, Dominic A. Scudiero, Russell A. Reinhart, Michael H. Selby, Donna O. Butcher, Robert H. Shoemaker
Journal: Cancer Research (2011)

Abstract Proprotein convertases (PCs) are a family of calcium-dependent serine endoproteases which mediate the proteolytic cleavage, at pairs of dibasic amino acids, of many precursor proteins, including growth factors and pro-hormones, into their functionally active forms. One family member, PCSK1, was identified as a potential therapeutic target in ASPS. This was based on gene expression profiling of 4 primary and 3 metastatic ASPS tumors (BMC Cancer 9:22, 2009). Affymetrix 133 Plus 2 arrays revealed that PCSK1, but not PCSK2 or furin, was significantly up-regulated (range 18.6 to 131 fold) relative to universal RNA, a multi-organ pool of non-tumor RNA's. PCSK1 expression was confirmed by immunohistochemistry and Western Blot analysis in patient tumors, in an ASPS xenograft model, and in a cell line developed from the xenograft tumor (ASPS-1; J Pediatr. Hematol. Oncol., in press 2010) as well as in tumors produced by ASPS-1 in immunocompromised mice. ASPS-1 was utilized, in-vitro, to evaluate a panel of PCSK1 siRNA's, the most potent of these produced a 75% reduction in the PCSK1 RNA transcript, reduced expression of PCSK1 protein and produced a 50% reduction in ASPS-1 growth. As part of an effort to develop new therapeutic approaches toward the treatment of ASPS we have implemented a high-throughput screening effort to identify small molecule inhibitors of PCSK1. Utilizing recombinant PCSK1 and the fluorescent substrate (Pyr-Arg-Thr-Lys-Arg-MCA) a high-throughput screen of a small molecule library (∼15 K compounds) was initiated. Results of a pilot screen of ∼2400 compounds at concentrations ranging from 0.1 to 100 uM yielded several inhibitors of PCSK1 which were retested in a 20 concentration assay to confirm activity. Preliminary analysis of structure-activity relationships identified several active inhibitor chemotypes, comparable in potency to the known peptide PCSK1 inhibitor, Ac-Leu-Leu-Arg-Val-Lys-Arg-NH2, containing aryl groups linked by aliphatic chains containing peptide bonds. Such compounds may act as substrate mimetic inhibitors and will be further evaluated for inhibition of growth of ASPS-1. 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 1621. doi:10.1158/1538-7445.AM2011-1621
Is there still room for therapeutic drug monitoring of linezolid in patients with tuberculosis?
Authors: Mathieu S. Bolhuis, Simon Tiberi, Giovanni Sotgiu, Saverio De Lorenzo, Jos G. Kosterink, Tjip S. van der Werf, Giovanni Battista Migliori, Jan-Willem Alffenaar
Journal: European Respiratory Journal (2016)

We read with great interest the comments from D. Cattaneo and co-workers on our article describing a retrospective study in multidrug-resistant tuberculosis (MDR-TB) patients receiving linezolid tailored to the individual patient using therapeutic drug monitoring as part of their regular treatment [1]. Cattaneo and co-workers correctly summarise that one of our findings was that we did not observe any significant differences between exposure to linezolid and adverse events. Indeed, this observation may be surprising with a toxic drug like linezolid, but it is not a reason to rule out therapeutic drug monitoring as a tool for optimising the treatment regimens of TB patients. The explanation for this lies in the design of our study, the characteristics of the patient population, and the specific dosing regimen used for MDR-TB patients. A retrospective study demonstrates the clinical complexity of MDR-TB patient management: TDM of linezolid is useful <http://ow.ly/Xm2EA>
Abstract 2466: Characterization and development of on-target Mcl-1 inhibitors; BH3 profiling provides a valuable drug discovery tool.
Authors: David J. Richard, Nicole Carlson, William Pierceall, Ryan Lena, Thomas Bannister, Peter Hodder, Timothy Spicer, Michael Andreeff, Joseph Opferman, Brian Koss, Andrew Kung, Michael Cardone
Journal: Cancer Research (2013)

Abstract Anti-apoptotic Bcl-2 family proteins are central to the regulation of the intrinsic apoptotic pathway, and as such constitute an important group of targets with great potential as oncology therapeutics. The Bcl-2 family protein Mcl-1 has been demonstrated to facilitate survival and chemoresistance in multiple myeloma, AML, and other cancers, and agents which affect this pathway have become highly sought after. Currently, however, no therapies exist which directly target Mcl-1. We have identified compounds that target Mcl-1 which may be characterized as both Mcl-1-selective and pan-Mcl-1/Bcl-2 inhibitors. This effort has been facilitated by utilization of the BH3 profiling technology to guide SAR. This assay allows for determination of the mitochondrial priming state of both cell culture samples and primary patient samples. We have demonstrated a correlation between myeloma and leukemia cell line response to treatment with our inhibitors and the mitochondrial priming state of such cell lines. Such correlations have also been shown with respect to the extent of cytochrome C release. In the case of the selective Mcl-1 inhibitor, we have shown that cytochrome C release occurs preferentially in leukemia cell lines which are highly primed for Mcl-1 rather than Bcl-2. In addition, our Mcl-1 selective inhibitor demonstrates enhanced cell killing ability in leukemia cells which have been engineered to selectively express Mcl-1, Bcl-2, and Bcl-xL. Our current lead candidate possesses excellent drug-like properties and displays impressive efficacy in a multiple myeloma disseminated xenograft model. This work demonstrates the utility of the BH3 profiling assay as providing a functional biomarker for drug discovery tool and its ability to validate the on-target activity of Mcl-1 and Bcl-2 inhibitors. Citation Format: David J. Richard, Nicole Carlson, William Pierceall, Ryan Lena, Thomas Bannister, Peter Hodder, Timothy Spicer, Michael Andreeff, Joseph Opferman, Brian Koss, Andrew Kung, Michael Cardone. Characterization and development of on-target Mcl-1 inhibitors; BH3 profiling provides a valuable drug discovery tool. [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 2466. doi:10.1158/1538-7445.AM2013-2466
Evaluation of an Adrenal Mass in a Patient with Lung Cancer by FDG Coincidence Positron Emission Tomography Using a Dual-Head Gamma Camera
Authors: MOONSUN PAI, CHAN H. PARK, SEOK-NAM YOON, SUZY KIM, KYUNG-HOON WHANG
Journal: Clinical Nuclear Medicine (2000)

The proper management of primary lung cancer depends on accurate staging. Because a CT scan cannot reliably distinguish a metastasis from a benign nonfunctioning adrenal adenoma in most cases, many patients undergo percutaneous biopsy. The adrenal glands are common sites of metastases in patients with lung cancer. But most adrenal lesions incidentally discovered in patients with non–small-cell lung cancer are indeed benign. Camera-based FDG positron emission tomography (PET) may be as useful as conventional PET in the evaluation of adrenal metastases if the mass is within the resolution of camera-based PET (1.5 cm) or larger.
Gorham’s Disease
Authors: Rong-Hsin Yang, Paul Chih-Hsueh Chen, Cheng-Pei Chang, Shih-Jen Wang
Journal: Clinical Nuclear Medicine (2013)

Gorham’s disease is a rare disorder characterized by proliferation of vascular channels. The clinical presentation of Gorham’s disease is variable and depends on the site of involvement. A high index of clinical suspicion is needed for accurate diagnosis, and recognition of distinctive radiologic and histopathologic features can help facilitate and expedite diagnosis. The subsequent images were obtained from a 31-year-old male patient. Nuclear scintigraphy and computed tomography identified active bone destruction in the lower thoracic and upper lumbar spine in addition to the absence of the left lower rib cage. Gorham’s disease was subsequently confirmed by biopsy.
Abstract 3357: Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases
Authors: Yvonne Chao, Qian Wu, Marie Acquafondata, Rajiv Dhir, Alan Wells
Journal: Cancer Research (2011)

Abstract Epithelial to mesenchymal transition (EMT) is an oft-studied mechanism for the initiation of metastasis. We have recently shown that once cancer cells disseminate to a secondary organ, a mesenchymal to epithelial reverting transition (MErT) can occur, which we postulate is to enable metastatic colonization. Despite a wealth of in vitro and in vivo studies, evidence of MErT in human specimens is rare and difficult to document because clinically detectable metastases are typically past the micrometastatic stage at which this transition is most likely evident. We obtained specimens of primary and metastatic tumors from breast and prostate cancer patients and evaluated expression of various epithelial and mesenchymal markers by immunohistochemistry. Breast cancer metastases exhibited increased expression of membranous E-cadherin and β-catenin compared to primary tumors, consistent with EMT at the primary site and MErT at the metastatic site. Expression of epithelial markers connexins 26 and 43 was also increased, particularly in brain metastases. Despite the upregulation of epithelial markers in metastases, expression of mesenchymal markers vimentin and FSP1 was mostly unchanged or only slightly decreased. Furthermore, the switch in expression of E-cadherin to N-cadherin that is sometimes detected in EMT, was not found by our immunostaining. N-cadherin detection did not reveal a consistent pattern of expression in primary or metastastic tumors. We observed similar results in prostate cancer metastases; not only was E-cadherin expression increased but also expression inversely correlated with size of the metastasis, suggesting that a second EMT may occur in the ectopic site for tumor growth or to seed further metastases. In summary, we have observed an increased expression of epithelial markers and persistence of mesenchymal markers consistent with a partial MErT that may enable a second EMT at the metastatic site. Our results suggest that cancer cells continue to display phenotypic plasticity beyond the EMT that initiates metastasis. 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 3357. doi:10.1158/1538-7445.AM2011-3357
Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice
Authors: Hammoudi Alkaissi, Jimmy Ekstrand, Aksa Jawad, Jesper Bo Nielsen, Said Havarinasab, Peter Soderkvist, Per Hultman
Journal: Environmental Health Perspectives (2016)

Following human mercury (Hg) exposure, the metal accumulates in considerable concentrations in kidney, liver, and brain. Although the toxicokinetics of Hg have been studied extensively, factors responsible for interindividual variation in humans are largely unknown. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic interstrain variation regulating retention or/and excretion of Hg. A.SW, DBA/2 and BALB/C mouse strains accumulate higher amounts of Hg than B10.S.We aimed to find candidate genes associated with regulation of renal Hg concentrations.A.SW, B10.S and their F1 and F2 offspring were exposed for 6 weeks to 2.0 mg Hg/L drinking water. Genotyping with microsatellites was conducted on 84 F2 mice for genome-wide scanning with ion pair reverse-phase high-performance liquid chromatography (IP RP HPLC). Quantitative trait loci (QTL) were established. Denaturing HPLC was used to detect single nucleotide polymorphisms for haplotyping and fine mapping in 184 and 32 F2 mice, respectively. Candidate genes (Pprc1, Btrc and Nfkb2) verified by fine mapping and QTL were further investigated by real-time polymerase chain reaction. Genes enhanced by Pprc1 (Nrf1 and Nrf2) were included for gene expression analysis.Renal Hg concentrations differed significantly between A.SW and B10.S mice and between males and females within each strain. QTL analysis showed a peak logarithm of odds ratio score 5.78 on chromosome 19 (p = 0.002). Haplotype and fine mapping associated the Hg accumulation with Pprc1, which encodes PGC-1-related coactivator (PRC), a coactivator for proteins involved in detoxification. Pprc1 and two genes coactivated by Pprc1 (Nrf1 and Nrf2) had significantly lower gene expression in the A.SW strain than in the B10.S strain.This study supports Pprc1 as a key regulator for renal Hg excretion.Alkaissi H, Ekstrand J, Jawad A, Nielsen JB, Havarinasab S, Soderkvist P, Hultman P. 2016. Genome-wide association study to identify genes related to renal mercury concentrations in mice. Environ Health Perspect 124:920-926; http://dx.doi.org/10.1289/ehp.1409284.
Case 36-2013
Authors: Douglas E. Wright, Rachel P. Rosovsky, Mia Y. Platt
Journal: New England Journal of Medicine (2013)

A 38-year-old woman was admitted to this hospital because of fatigue, malaise, and lightheadedness, with dyspnea on exertion, bruising, dark urine, and headache. Laboratory tests revealed anemia and thrombocytopenia. Diagnostic tests were performed.
Abstract 346: Aspirin blocks EGF responsiveness in ovarian cancer cells
Authors: May Cho, Dineo Khabele, Deok-Soo Son
Journal: Cancer Research (2010)

Abstract Many ovarian cancers overexpress epidermal growth factor receptor (EGFR). EGFR over-expression in ovarian cancer has been associated with poor prognosis. EGFR inhibitors alone do not produce positive clinical results in ovarian tumors that lack a tyrosine kinase mutation or over-express EGFR. This suggests that downstream signaling pathways remained active. In other tumors, efficacy of EGFR inhibitors is improved with combination therapy . Recent evidence suggests that human epithelial ovarian cancers express elevated levels of COX-1, indicating COX-1 is a potential target for therapy. Aspirin (acetylsalicylate, ASA) is a more selective COX-1 inhibitor and is also known to have anti-tumor and anti-angiogenic properties. Our objective was to investigate the effects of ASA on EGF-induced ovarian cancer cell growth. ASA inhibited cell proliferation induced by EGF with a dose dependent manner in COX-1 positive OVCAR-3 ovarian cancer cells. In particular, ASA decreased phosphorylated Akt and Erk activated by EGF. Furthermore, we made COX-1 expressing cell line (SKCOX-1) by stably transfecting COX-1 expression vector into COX-1 negative SKOV-3 cells. SKCOX-1 cells were more responsive to ASA compared to cells transfected with pcDNA-3 (SKpcDNA). Taken together, ASA inhibits proliferation of COX-1 positive ovarian cancer cells by blocking phosphorylation of Akt and Erk, probably potentiating the efficacy to treat ovarian cancer. 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 346.