tbuckley/cabot-search huggingface dataset:
Sulindac Sulfide Selectively Induces Apoptosis of Human Breast Tumor Cells by Inhibiting PDE5A, Elevating cGMP, and Activating PKG.
Authors: H. Tinsley, B. Gary, A. Keeton, R. Reynolds, G. Piazza, G. Piazza
Journal: Cancer Research (2009)

Abstract Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX)-2 selective inhibitors display promising antineoplastic activity, but the gastrointestinal, renal, and cardiovascular toxicities that result from COX inhibition limit their clinical utility for cancer chemoprevention. Previous studies suggest that the pro-apoptotic activity of these drugs may be due to a COX-independent mechanism involving cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE) inhibition. However, the specific PDE isozyme(s) responsible has not yet been identified. Here we used the NSAID sulindac sulfide (SS) to further study cGMP PDE as a potential molecular target of the NSAIDs for breast cancer chemoprevention. SS inhibited growth and induced apoptosis of human SK-BR-3 and MDA-MB-231 breast tumor cells, while normal human mammary epithelial cells (HMEC) were less sensitive. SS also inhibited cGMP PDE activity from tumor cell lysates at concentrations comparable to those required for apoptosis, while appreciably higher concentrations were necessary to inhibit activity from HMEC lysates or cAMP PDE activity from any of the cell lysates. Additionally, SS increased intracellular cGMP concentrations and induced protein kinase G (PKG) activity in MDA-MB-231 cells as determined by ELISA and increased levels of phosphorylated VASP, a known PKG substrate, respectively. Moreover, pretreatment with the guanylyl cyclase inhibitor LY83583 desensitized the breast tumor cells to the growth-inhibitory activity of SS, likely by suppressing intracellular cGMP levels. The guanylyl cyclase activator NOR-3 and the cGMP PDE inhibitors MY5445 and trequinsin inhibited tumor cell growth, while the adenylyl cyclase activator forskolin and other PDE inhibitors had no effect. HMEC were found to express several cGMP hydrolyzing PDE isozymes (PDE1, 5, and 9), while the breast tumor cells expressed predominantly PDE5, which was confirmed to be sensitive to inhibition by SS using a recombinant enzyme. This work demonstrates that inhibition of PDE5A, elevation of cGMP, and activation of PKG are responsible for the pro-apoptotic effects of SS in human breast tumor cells and that differential expression of PDE isozymes between normal and tumor cells may explain the tumor selectivity of NSAIDs. These data also suggest that it may be feasible to develop NSAID derivatives with increased selectivity for inhibiting PDE5 and decreased COX-inhibitory activity, which would potentially improve safety and efficacy for breast cancer chemoprevention. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1041.
Abstract 5356: Inactivation of Foxo3a and increased expression of Id1 by the Epstein-Barr Virus-encoded LMP1 facilitates resistance to TGF-β-mediated growth inhibition in nasopharyngeal epithelial cells
Authors: Angela KF Lo, Christopher W. Dawson, Lawrence S. Young
Journal: Cancer Research (2010)

Abstract The universal association of Nasopharyngeal carcinoma (NPC) with EBV underscores the importance of EBV infection to the development of this disease. The EBV-encoded Latent Membrane Protein-1 (LMP1) is believed to be a key factor in NPC development due to its ability to induce cellular transformation in various cell types. As a viral mimic of CD40, LMP1 functions as a constitutively active TNF receptor, altering multiple signal cascades and activating a plethora of downstream targets. LMP1 has been shown to inactivate the transcriptional activity of Foxo3a, a tumor suppressor that can inhibit the proliferation of tumor cells. LMP1 has also been found to increase expression of Id1, a transcriptional repressor that can inhibit the expression of differentiation-linked genes. Here, we report that inactivation of Foxo3a by LMP1 facilitates Id1 induction. Using a panel of LMP1 mutants, we identified the CTAR1 domain of LMP1 as being responsible for Foxo3a inactivation and Id1 upregulation. Through the use of dominant negative proteins, shRNA silencing or selective pharmacological inhibitors, we demonstrate that Foxo3a inactivation by LMP1 is mediated through the LMP1 CTAR1 domain and requires activation of the Akt and Erk-MAPK signaling pathways. Whilst engagement of the Akt, Erk-MAPK and NIK-dependent noncanonical NF-κB pathways by LMP1 are involved in Id1 upregulation, we found that LMP1 CTAR2 domain-mediated IKKβ-dependent canonical NF-κB signaling negatively regulates Id1 expression, suggesting that CTAR2 may antagonize CTAR1-mediated regulation of Id1. LMP1 has been shown to inhibit TGFβ-mediated growth inhibition by disrupting various facets of TGFβ signaling. Here we show that stable “knock-down” of Id1 in LMP1 expressing NP69 cells after stable expression of Id1-specific shRNA, reduced the growth inhibitory effect of TGFβ. The interplay between LMP1, Foxo3a and Id1 is likely to contribute to the characteristic resistance of LMP1 to TGFβ-mediated signaling and cell growth arrest. The data presented in this study may offer a novel therapeutic approach for EBV associated epithelial cancers. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5356.
Comparison of laparoscopic versus open gastrectomy for gastric cancer: a phase III trial (KLASS trial): Interim reports on morbidity and mortality
Authors: H. Kim, W. Hyung, G. Cho, M. Kim, S. Han, W. Kim, S. Ryu, H. Lee, K. Song
Journal: Journal of Clinical Oncology (2008)

4641 Background: Recently, in technical aspects, almost all kinds of open gastric cancer surgeries can be reproduced laparoscopically. However, many controversies exist due to no evidence and no long-term results. There was no prospective multi-center large- scale randomized controlled trial in the world on the long-term outcome of laparoscopic gastric cancer surgery. Korean Laparoscopic Gastrointestinal Surgery Study Group, therefore, proposed a multi-institutional prospective randomized trial on comparing laparoscopy-assisted distal gastrectomy (LADG) versus open distal gastrectomy (ODG) for gastric cancer (KLASS Trial) after the feasibility and validity of these procedures had been evaluated by analyzing retrospective multi-center large series. Methods: Patient eligible criteria are as follows; pathologically proven gastric adenocarcinoma, age: 20 ∼ 80 years, preoperative stage: cT1N0M0, cT1N1M0, cT2aN0M0, no history of other cancer, no history of chemotherapy or radiotherapy, and written informed consent. Primary endpoint of this trial is to elucidate that there is no difference of overall survivals between LADG and ODG groups. The planned sample size per arm is 700 (1,400 in total). First of all, we compared morbidity and mortality between two groups by interim analysis in order to evaluate the safety of this trial. The time of interim analysis was decided on the hypothesis that the morbidity of this trial is not significantly different from that of previous reports on open gastric cancer surgeries (17%∼20%). Results: There were 179 LADG and 163 ODG patients. There was no significant difference between two groups in terms of age, gender, and comorbidity. Postoperative complication rates of LADG and ODG groups were 10.5% (17/179) and 14.7% (24/163), respectively (p=0.137). Reoperations were required in 3 cases of LADG and also 3 cases of ODG patients (p=1.000). Postoperative mortality was 1.1% (2/179) in LADG and 0% (0/163) in ODG patients (p=0.497). Conclusions: There was no significant difference of morbidity and mortality between LADG and ODG patients. This trial, therefore, is acceptable and should be ongoing. No significant financial relationships to disclose.
Abstract 1462: Targeting NAD+ biosynthesis combined with radiation to enhance cell death
Authors: Baukelien Van Triest, Shuraila F. Zerp, Ben Floot, Conchita Vens, Marcel Verheij
Journal: Cancer Research (2012)

Abstract Background and purpose: APO866 is a highly specific non-competitive inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the regulation of NAD+ biosynthesis. Inhibition of NAMPT reduces cellular NAD+ levels. Among NAD+ consuming enzymes are Poly(adenosine-diphosphate[ADP]-ribose)polymerases (PARPs) and Sirtuins. As a consequence, NAD+ is involved in numerous biochemical processes, including regulation of DNA repair, replication, transcription and apoptosis. APO866 is thought to preferentially target tumor cells because of their high NAD+ turnover rates and increased dependence on NAD+ as compared to normal cells. In the present study we investigated the cytotoxic effect of APO866 alone and in combination with radiation on tumor cells in vitro and in vivo. Results: APO866, in nanomolar concentrations, induces a time- and dose-dependent depletion of cellular NAD+ levels in a panel of human tumor cell lines (U937, J16, LNCaP, PC3 and A431). In vitro, under APO866-mediated reduced NAD+ conditions, solid tumor cell lines PC3 and LNCaP show besides a cytotoxic effect also a decrease in clonogenic survival in combination with ionizing radiation (Dose enhancement factor at 10% survival: 1.34 and 1.45 resp.), which was not caused by radiation-induced enhancement of dsDNA breaks as determined by γ-H2AX nuclear foci formation, nor by induction of apoptosis. In vivo experiments with PC3 xenografts, treated with the APO866/radiation combination, show the combination is more effective than APO866 or radiation treatment alone. The time to reach 300% of the initial tumor volume was in the control group 9.5 days, for APO866 treatment 28.6 days, radiation treatment 51.4 days and for the combined APO866/radiation treatment 76.6 days. Only the combination treatment caused complete initial growth regression. No significant toxicity was observed after any of these treatments. Tumors from animals treated with APO866 showed significant reduced NAD+ levels. Conclusion: APO866 treatment depletes NAD+ and enhances tumor cell kill in combination with radiation, in vitro and in vivo. Targeting NAD+ biosynthesis together with radiation is a promising strategy to enhance tumor response. 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 1462. doi:1538-7445.AM2012-1462
Surgical Treatment of Dissecting Aneurysm of the Thoracic Aorta
Authors: W. Gerald Austen, Roman W. DeSanctis
Journal: New England Journal of Medicine (1965)

DRAMATIC in onset and catastrophic in its consequences, dissecting aneurysm of the thoracic aorta is a common disease that poses difficult problems in management. The dismal outlook for patients with this lesion treated conservatively has led to a vigorous surgical attack on the problem; results have been encouraging although the many difficulties associated with surgical therapy are well known.1 2 3 4 5 6 7 During a one-year period 12 patients with such aneurysms have been treated at the Massachusetts General Hospital by resection of the diseased aorta and prosthetic graft replacement. Nine of these patients survive. It is the purpose of this report to review . . .
Case 14-2002
Authors: Jennifer S. Daly, Eugene J. Mark
Journal: New England Journal of Medicine (2002)

Presentation of CaseA 51-year-old woman was admitted to the hospital because of recurrent hemoptysis.The patient had been well until 18 months earlier, when she awoke from sleep with fluid in her mouth and spat out about 60 ml of blood. She had had a slight cough and two episodes of scanty hemoptysis about three months earlier. Her physician heard focal wheezing over the dorsal aspect of the region of the left upper lobe. The heart, abdomen, arms, and legs were normal. A chest radiograph showed slight calcification of hilar and mediastinal lymph nodes; the calcification was more prominent . . .
Abstract 1220: ErbB4: A novel therapeutic target in glioblastoma multiforme
Authors: Jacqueline Donoghue, Lauren Kerr, Anthony Longano, Paul Mischel, Terrance Johns
Journal: Cancer Research (2012)

Abstract Introduction: Glioblastoma Multiforme or glioma is amongst the most lethal and difficult to cancers to treat and kills 1,000 Australians and 12,000 Americans every year. The average age at diagnosis is 60 years and the death rate for glioma has remained relatively unchanged for the past 20 years; highlighting the need for new therapeutic options for its treatment. ErbB4, the fourth member of the EGFR family has both oncogenic and tumor suppressive activity dependent upon isoform expression and although ErbB4 is universally expressed in glioma, its functional role is somewhat unclear. Aims: The aim of this study was to characterize the expression of ErbB4 in a large cohort of glioma tissues at the protein and mRNA level and determine if ErbB4 expression relates to tumor biology and patient survival. Methods: Immunohistochemistry was performed on paraffin sections of glioma tissue (n=68) and normal brain (n=5) for the immunolocalisation of ErbB4 and EGFR (total and activated) and the ErbB4 ligand heregulin. Using a customized RT-qPCR assay, ErbB4 isoforms were identified in snap frozen glioma (n=23) and normal brain (n=15). Results: Patients diagnosed with glioma (n=68) had a median survival time of 15 months (range 1-120 months) with the average age of 63±2 years (range 21-80 years). ErbB4 and heregulin protein was demonstrated in all our glioma and normal brain samples. At the mRNA level however, ErbB4 expression was reduced in the glioma samples when compared to normal brain tissue. All six ErbB4 isoforms were demonstrated in all tissue samples and ErbB4 was preferentially expressed as the JMa/Cyt2 isoform in glioma. Histologically, ErbB4 activation (independent of EGFR activation) occurred in 16% of patient samples and was localized to sites like the leading edge of the tumor. The mean survival time for patients with high levels of activated ErbB4 was 12 months, while patients with low levels of activated ErbB4 had a mean survival time of 32 months. ErbB4, activated ErbB4 and heregulin were also demonstrated in the vasculature of the glioma but not normal brain. Conclusions: This study demonstrated the preferential expression of the JMa/Cyt-2 isoform of ErbB4 in glioma along with increased ErbB4 activation significantly shortening patient survival times. Due to a potential angiogenic role of ErbB4 in glioma and reduced patient survival times following ErbB4 activation, ErbB4 should be considered a new therapeutic target in glioma. 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 1220. doi:1538-7445.AM2012-1220
SCINTIGRAPHIC ASSESSMENT OF POSTNATAL MATURATION OF MYOCARDIAL SYMPATHETIC NERVES
Authors: Michael Dae, Michael Chin, Elias Botvinick, William OʼConnell, John Huberty
Journal: Clinical Nuclear Medicine (1987)

Dae, Michael; Chin, Michael; Botvinick, Elias; O'Connell, William; Huberty, John Author Information
Abstract 1382: Increased expression of placental growth factor is linked with shortened survival of patients with advanced ovarian cancer
Authors: Matthew S. Block, Matthew J. Maurer, Priya Ramar, Marshall D. Behrens, Courtney L. Erskine, Kimberly R. Kalli, Lynn C. Hartmann, Keith L. Knutson
Journal: Cancer Research (2012)

Abstract Background: Ovarian cancer (OC) is the leading cause of gynecologic cancer death in the United States. Survival in advanced OC is highly variable; some patients are cured of their disease with a combination of surgery and systemic chemotherapy, while the majority of patients develop recurrence and ultimately die of metastatic OC. While markers of poor prognosis within advanced OC exist, they have not translated to changes in therapy or outcomes. Vascular growth factors are important soluble mediators of tumor growth, vasculogenesis and angiogenesis that may be targeted therapeutically. We therefore explored the association between plasma levels of vascular growth factors and clinical outcomes in advanced OC. Methods: We enrolled 200 patients with OC or benign surgical conditions from the Mayo Ovarian SPORE Biospecimens Core. Presurgical plasma samples from patients with advanced OC (AJCC Stage III and IV, n = 100), early stage OC (Stage I and II, n = 50), and benign surgical conditions (n = 50) were assayed for vascular growth factors via multiplex electrochemiluminescence and by ELISA. Differences in plasma levels between benign, early, and advanced OC patient groups were assessed using plate-adjusted linear models. Associations between plasma levels of vascular growth factors and overall survival in advanced OC patients were assessed by Cox proportional hazards models. Results: Both vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) levels were increased in patients with advanced OC (mean ng/mL = 130.8, p = 0.004; mean ng/mL = 20.1, p = 0.025, respectively) compared to patients with early stage (mean ng/mL = 75.1 and 19.0 respectively) and benign conditions (mean ng/mL = 86.8 and 15.0, respectively). An increase in PlGF levels was associated with poor overall survival in patients with advanced OC (HR = 2.52, p = 0.005), while increase in VEGF levels were of borderline significance (HR = 1.21, p = 0.061) Conclusions: Soluble PlGF and VEGF are increased in the setting of advanced OC. Increased plasma PlGF is strongly linked to poor prognosis, while VEGF levels have a borderline association with prognosis. These data provide a rationale for therapeutic targeting of both VEGF and PlGF. 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 1382. doi:1538-7445.AM2012-1382
SP0036 Where Does Polymyalgia Rheumatica Fit in the Spectrum of Inflammatory Rheumatic Disease?
Authors: E.L. Matteson
Journal: Annals of the Rheumatic Diseases (2014)

<h3></h3> Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatic disease of the elderly; incidence of 700/100,000 in persons over the age of 50 years. Accurate diagnosis is difficult in PMR because proximal pain and stiffness syndrome, a commonly accepted phenotype of PMR, can occur in many other rheumatologic and inflammatory illnesses. There is significant overlap in the pathobiology of the disease with other rheumatic diseases, including synovitis, vasculitis inflammatory mechanisms and genetics. Polymyalgia symptoms are not uncommon as presenting manifestations of a wide spectrum of systemic conditions. These include malignancies, giant cell arteritis and other forms of vasculitis, rheumatoid arthritis, seronegative spondyloarthritis, metabolic and crystalline disorders and systemic infections. Special concern about the presence of diseases different from PMR or GCA must be considered in patients presenting with atypical symptoms of PMR. Similarities in initial clinical presentation often delays diagnosis, and over time, approximately 10 to 30% of patients initially diagnosed with PMR are found to have an alternative diagnosis. Laboratory tests tend to be unhelpful, although a positive rheumatoid factor or ACPA might indicate RA, and the presence of HLA-DRB1*04 may indicate underlying rheumatoid arthritis or giant cell arteritis. Response to corticosteroids is not a useful diagnostic test. Development of the EULAR/ACR provisional classification criteria for polymyalgia rheumatica have substantially improved disease classification and served to define the place of PMR among rheumatic diseases. There is a trade-off between sensitivity and specificity of the criteria. From the perspective of the patient, should we err on the side of overdiagnosing, or underdiagnosing PMR? Over diagnosis means subjecting patients to unwanted side effects of corticosteroids, while underdiagnosis may mean failure to treat correctly, with the attendant consequences. The morbidity of the disease and its limited treatment options are compelling reasons for better defining the place of PMR in the spectrum of systemic rheumatic diseases. Dasgupta B et al. American College of Rheumatology provisional classification criteria for polymyalgia rheumatica. Ann Rheumatic Dis,2012;71:484-492 doi:10.1136/annrheumdis-2011-200329 and Arthritis Rheum 2012; 64(4):943 <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.6139
Congenital Hemolytic Anemia with High Sodium, Low Potassium Red Cells
Authors: Harold S. Zarkowsky, Frank A. Oski, Ramadan Sha'afi, Stephen B. Shohet, David G. Nathan
Journal: New England Journal of Medicine (1968)

Evaluation of the erythrocytes of a child with hemolytic anemia of unknown cause showed that the intracellular concentrations of sodium and potassium were 100 mEq per liter of cells and 40 mEq per liter of cells respectively. Such values have never previously been recorded in human erythrocytes. Further studies showed that the cation abnormality was due to a vast increase in permeability to monovalent cations, with a concomitant massive increase in active cation pumping. Permeability to divalent cations and anions and to nonelectrolytes was normal. Thus, a defect in mean pore size or charge was not detected. Comparisons of these cells to erythrocytes in hereditary spherocytosis led to the conclusion that increased cation transport rates do not invariably result either in membrane phospholipid loss or in microspherocytic changes.