tbuckley/cabot-search huggingface dataset:
Abstract 1153: Effective treatment of cancer associated cachexia by AV-380, a GDF15 inhibitory antibody
Authors: Lorena Lerner, Nianjun Tao, Brian Krieger, Richard Nicoletti, Bin Feng, Nesreen Ismail, William Winston, Yanyu Zhang, Jinwei Jiang, Solly Weiler, Jeno Gyuris
Journal: Cancer Research (2015)

Abstract Background: One of the most lethal and debilitating effects of cancer is the development of cancer-related anorexia-cachexia syndrome (CACS). It affects the majority of advanced cancer patients and is thought to be responsible for up to ∼30% of all cancer deaths. CACS is a complex metabolic syndrome associated with malnutrition and severe involuntary weight loss due to the loss of muscle and fat tissue, as well as the clinical manifestation of anemia, inflammation and suppression of immune functions. The precise molecular mechanisms responsible for cancer cachexia are poorly understood, thus limiting the development of effective therapeutics. Current evidence suggests that a pro-inflammatory state may be responsible for many of the symptoms associated with CACS. Growth Differentiation Factor 15 (GDF15) is a pro-inflammatory cytokine whose circulating levels are significantly increased in cachectic cancer patients and several animal models of cancer cachexia. Here we demonstrate that the inhibition of GDF15 function results in the compete reversion of the phenotypic and metabolic changes associated with CASC. Methods: Mice bearing HT-1080 human fibrosarcoma xenografts have increased plasma GDF15 levels and develop cachexia were used in this study. Tumor bearing animals were treated either with AV-380, a GDF15 neutralizing antibody or IgG1 control. The effect on body weight, muscle/fat mass and organ sizes were assessed. Metabolic changes induced by the treatment were measured by a comprehensive laboratory animal monitoring system (CLAMS). Results: Treatment with AV-380 restored body weight, muscle and fat mass as well as normal organ sizes. Analyses of the CLAMS data demonstrated that mice receiving AV-380 reversed the phenotypic and metabolic changes associated with the cachexia induced by this tumor model. Moreover, AV-380 treated mice showed an increase in locomotor activity and energy expenditure, achieving levels similar to non tumor bearing control animals. Conclusions: Inhibition of GDF15 function completely reverted body weight loss, restored normal body composition and triggered a catabolic to anabolic metabolic switch in this cancer cachexia model. The data highlights the therapeutic potential of the GDF15 inhibitory antibody AV-380 for the treatment for CACS. Citation Format: Lorena Lerner, Nianjun Tao, Brian Krieger, Richard Nicoletti, Bin Feng, Nesreen Ismail, William Winston, Yanyu Zhang, Jinwei Jiang, Solly Weiler, Jeno Gyuris. Effective treatment of cancer associated cachexia by AV-380, a GDF15 inhibitory antibody. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1153. doi:10.1158/1538-7445.AM2015-1153
A New Method of Hip Coring Decompression for the Treatment of Femoral Avascular Necrosis In Sickle Cell Disease: Perioperative Safety and Preliminary Efficacy Data
Authors: Rakesh Donthineni, Janice Earl, Lynne Neumayr, Robert W Hagar, Keith C. Quirolo, Christine Aguilar, Elliott Vichinsky
Journal: Blood (2010)
Cerebral X-Linked Adrenoleukodystrophy: The University of Minnesota Hematopoietic Cell Transplantation Experience from 1991 to 2004.
Authors: Charles Peters, Lawrence R. Charnas, Todd DeFor, Elsa G. Shapiro, Satkiran S. Grewal, Paul J. Orchard, Susan L. Abel, Norma K.C. Ramsay, Kathryn E. Dusenbery, Daniel J. Loes, Lawrence A. Lockman, William Krivit
Journal: Blood (2004)
Rho‐kinase inhibition is beneficial in fibrosis
Authors: Jan Görtzen, Jonel Trebicka
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. To the Editor: In their recent work, Desai et al. discussed the effects of matrix rigidity on the hepatocyte nuclear factor 4 alpha (Hnf4α) transcriptional network and illuminated regulatory effects that maintain hepatocyte function in fibrotic liver tissue.1 This excellent contribution provides insight into the influence of the Rho‐associated kinase (ROCK) pathway on Hnf4α expression in hepatocytes cultured on polyacrylamide gels with matrix rigidity similar to liver fibrosis conditions. Importantly, the authors show that the inhibition of ROCK by Y‐27632 increased Hnf4α expression on a stiff matrix. Of note, RhoA is one of the key upstream regulators of Rho‐kinase, but the present work does not assess the effect of stiffness on RhoA expression in fibrotic liver. Moreover, RhoA expression is down‐regulated in hepatocytes cultured on stiff polyacrylamide gels, as was recently shown by our group.2 Regarding how the RhoA/ROCK pathway is tightly linked to stiffness,3 the present work does not elucidate whether ROCK is up‐regulated or down‐regulated in hepatocytes. Taking into account that RhoA is down‐regulated in hepatocytes, it remains unclear whether further inhibition of RhoA/ROCK may help preserve hepatocyte function. Moreover, the authors suggest a focal adhesion kinase–independent mechanism of RhoA/ROCK pathway regulation through matrix rigidity, possibly propagated through c‐SRC. While c‐SRC may directly decrease Hnf4α expression by phosphorylation,4 in their work the authors speculated that c‐SRC might regulate Hnf4α through RhoA/ROCK inhibition.1 Previously published evidence supports this hypothesis, showing that c‐SRC is up‐regulated and activated in hepatocytes cultured on stiff gels, which leads to RhoA down‐regulation and consecutively ROCK down‐regulation.2 Even though Desai et al. provided strong in vitro evidence using atomic force microscopy and gels with a tunable shear modulus, the study did not sufficiently address the gradient of matrix stiffness across the different zones between portal vein and hepatic vein, as well as the polarity of the hepatocytes. Finally, hepatic stellate cells cultured on stiff polyacrylamide gels induce RhoA expression,2 and RhoA and/or Rho‐kinase inhibition may ameliorate fibrosis and portal hypertension in experimental and human cirrhosis, especially as the overall expression of RhoA/Rho‐kinase expression and activity is up‐regulated in cirrhosis.5 Therefore, the inhibition of Rho‐kinase might be beneficial 2‐fold, as an antifibrotic mechanism and by preserving hepatocyte function; and it should be explored further in the human setting.
PWE-060 Prolonged QT interval and serum brain natriuretic peptide in cirrhotic cardiomyopathy
Authors: P Yap, D Das
Journal: Gut (2010)

<h3>Introduction</h3> Cirrhotic cardiomyopathy is a recently recognised cardiac complication of liver cirrhosis,1 characterised by blunting of the cardiac responses to stresses secondary to liver disease. The heart is unable to increase its cardiac output despite increased cardiac stresses due to a combination of diastolic dysfunction, from increased myocardial fibrosis and cardiomyocyte hypertrophy causing abnormal relaxation of the left ventricle and impaired left ventricular filling, abnormalities in the β-adrenergic conduction pathway and alteration to the membrane fluidity of the cardiomyocytes. This was a prospective study to measure the BNP levels and QT interval in patients with liver disease and cirrhosis, of all aetiology. <h3>Methods</h3> Prospective study over 6 months. 22 patients fulfilled inclusion criteria; acute decompensated liver disease of any cause with ascites. Patients excluded if they had a history of cardiac disease. All the patients had—ECGs on admission and serum BNP requested as in-patient. The QT interval was corrected using Bazetts formula. <h3>Results</h3> Of the 22 patients recruited, 16 were due to alcohol, 1 PBC, 2 NASH, 1 Hepatitis C and 2 unclear diagnosis. 17 of the 22 patients had a positively raised serum BNP. (normal &lt;300 ng/l) (min 13, max 4307; Mean 960). 18 of 22 patients had ECGs appropriate for analysis. The excluded patients had Atrial Fibrillation or ECG not done on latest admission. 14 of 18 patients ECG showed a prolonged QT interval, (normal QT interval &gt;0.44 ms) min 0.404 ms, max 0.558 ms; Mean 0.465 ms. <h3>Conclusion</h3> A large majority of the patients with cirrhosis had a raised BNP level and prolonged QT interval. This strongly suggests that they have underlying cardiac dysfunction in the form of cirrhotic cardiomyopathy and consequently lack the ability to increase their cardiac output in presence of stress, with the subsequent risk of developing acute heart failure and pulmonary oedema. Evidence shows that BNP levels and degree of QT interval prolongation are proportional to severity of cardiomyopathy in these patients1 and β-blockers have a beneficial role in normalising the QT interval.2 Given this background, we would advise routine assessment of all cirrhotics with electrocardiography and BNP estimations and a prospective trial be carried out to explore the protective role of β-blockers in these patients even in the absence of evidence of portal hypertension.
Pure erythroid leukemia
Authors: Wei Wang, Sa A. Wang, L. Jeffrey Medeiros, Joseph D. Khoury
Journal: American Journal of Hematology (2016)

Abstract The category of acute erythroid leukemia was significantly revised in the recently published 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms. In the previous 2008 WHO classification, acute erythroid leukemia was categorized into two subtypes: erythroleukemia and pure erythroid leukemia (PEL), whereas in the 2016 WHO update, erythroleukemia was merged into myelodysplastic syndrome, and PEL becomes the only type of acute erythroid leukemia. PEL is a rare and aggressive form of acute leukemia whose biology remains poorly characterized. In this review, we discuss the clinicopathologic features, diagnosis, putative pathogenesis, and molecular biology of PEL, with an overview of novel concepts and future directions in this area.
Abstract A40: Gene expression profiling of pancreatic cancer precursors directly from formalin fixed paraffin embedded (FFPE) tissue without nucleic acid extraction
Authors: Sheila Smiley, Celia Marginean, Bryan Lo
Journal: Cancer Research (2016)

Abstract Gene expression analysis of pancreatic intraepithelial neoplasia (PanINs), the pancreatic ductal adenocarcinoma precursor, has been challenging because extracting and purifying RNA from pancreatic tissue is difficult. Since the pancreas is rich in ribonucleases and PanINs are typically very small lesions, attempts to purify RNA of sufficient quality and quantity for microarray or RNAseq are usually unsuccessful. This is especially true if the starting material is formalin fixed paraffin embedded tissue, where the fixation process introduces further degradation of the RNA. We sought to solve this problem of PanIN gene expression profiling by using the HTG Edgeseq instrument platform. This instrument is designed to work with small FFPE specimens and perform RNA profiling even when RNA is partially degraded by employing a novel extraction free hybridization approach. In our pilot study, we show that the HTG Edgeseq can be used to profile ~2500 genes from a cohort of microdissected low and high grade PanIN from FFPE of human pancreatic adenocarcinoma resections. We speculate that most of these PanIN lesions would not have been amenable to other gene expression methodologies and that the PanIN data from the HTG Edgeseq will contribute to our understanding of the molecular pathways that underlie pancreatic cancer. Citation Format: Sheila Smiley, Celia Marginean, Bryan Lo.{Authors}. Gene expression profiling of pancreatic cancer precursors directly from formalin fixed paraffin embedded (FFPE) tissue without nucleic acid extraction. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A40.
Abstract 4318: Dexamethasone variably protects triple negative breast cancer cells against paclitaxel depending on relative cellular levels of glucocorticoid receptor alpha
Authors: Roselyne Labbe, Cecilia Speyer, Miriam Bukhsh, Austin Belfiori, Rafa Khansa, Mudgha Patki, Manohar Ratnam, David Gorski
Journal: Cancer Research (2015)

Abstract Introduction: Triple negative breast cancer (TNBC) comprises 15-20% of all breast cancer cases and is unresponsive to the drugs used to treat ER+/PR+ or HER2+ breast cancers. The only treatment option for TNBC is chemotherapy with paclitaxel being a major component. However, many patients respond poorly and develop side effects that are routinely treated with dexamethasone. In certain cancers, dexamethasone attenuates chemotherapy response by inhibiting apoptosis or temporarily arresting cell growth. Dexamethasone's actions are mediated through glucocorticoid receptor alpha (GR alpha), which is ubiquitous. Here we examine the protective effect of dexamethasone in TNBC cells and the relationship of this effect to variability in cellular GR alpha levels. Methods: GR alpha expression was measured in TNBC cell lines and related to dexamethasone's ability to affect their growth and resistance to paclitaxel. Cell lines analyzed included those expressing low levels of GR alpha and recombinant cells in which GR alpha expression was ectopically restored. Results: A positive association was observed between endogenous GR alpha expression and dexamethasone's ability to protect TNBC cells against paclitaxel. Overexpression of GR alpha in cells expressing low endogenous GR alpha conferred protection against paclitaxel in the presence of dexamethasone. In contrast to reported observations in other cancer cell types, dexamethasone increased cell proliferation and transcriptional activation of thymidylate synthase, an S-phase enzyme. These results suggest the use of dexamethasone may be one factor responsible for the poor response of TNBC patients to traditional chemotherapy and suggest using GR alpha expression level as a biomarker for predicting which TNBC patients should be given traditional chemotherapy. Citation Format: Roselyne Labbe, Cecilia Speyer, Miriam Bukhsh, Austin Belfiori, Rafa Khansa, Mudgha Patki, Manohar Ratnam, David Gorski. Dexamethasone variably protects triple negative breast cancer cells against paclitaxel depending on relative cellular levels of glucocorticoid receptor alpha. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4318. doi:10.1158/1538-7445.AM2015-4318
Abstract 2890: Single mouse trials, a concept using patient-derived tumor xenografts for large scale in vivo screens
Authors: Christina Gredy, Julia B. Schüler, Nina Zanella, Heinz-Herbert Fiebig, Thomas Metz
Journal: Cancer Research (2015)

Abstract Patient-derived xenografts (PDX) passaged in immunocompromised mice are a well-established system for preclinical efficacy testing of anti-cancer agents. Typically, PDXs are pre-screened either in vitro or via molecular analysis, and selected models are then tested in groups of 8 to 12 mice to confirm or evaluate the efficacy of a treatment relative to a vehicle control group. This approach results in highly reliable and reproducible efficacy data. However, it is often desirable to test large panels of tumor models in vivo in order to properly take genetic diversity into account. Such experiments can be cost-prohibitive in conventional study layouts, which results in fewer models being tested. The Single Mouse Trial (SMT) format addresses the need for compound testing in larger, more diverse tumor populations. This format employs a single mouse per PDX model and treatment arm, thereby enabling the investigation of efficacy in substantially larger panels of PDX models. In order to better mirror inter-patient response diversity observed in the clinic, less emphasis is put on the statistical robustness of response data for individual models. In the study presented here, six SoC drugs were tested in the SMT format in colorectal (cetuximab, oxaliplatin, irinotecan, 5-FU) and non-small-cell lung cancer (cetuximab, paclitaxel) PDXs, and results were compared to those obtained from standard format experiments with 5 - 10 mice per group. Dosing and schedules were adapted to clinical standards. Data for 19 CXF and 16 NSCLC models showed that in 77% of the cases, results obtained from the single mouse trial format were in line with results from standard efficacy tests. Furthermore, in 10% of the cases, efficacy was similar by trend between the two formats. Notable discrepancies were seen mainly in tumors exhibiting intermediate sensitivity. Our findings indicate that for the drugs tested here, the risk of misjudging the efficacy in a given PDX model based on SMT is low. This risk could be further lowered by increasing group sizes to 3 mice. For the identification of biomarkers which requires accurate efficacy data, such an intermediate format between the SMT and the standard format might be advantageous. Citation Format: Christina Gredy, Julia B. Schüler, Nina Zanella, Heinz-Herbert Fiebig, Thomas Metz. Single mouse trials, a concept using patient-derived tumor xenografts for large scale in vivo screens. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2890. doi:10.1158/1538-7445.AM2015-2890
Abstract 4080: Role of nuclear PKM2 in transcriptional regulation leading to EMT
Authors: Masamitsu Konno, Naohiro Nishida, Koichi Kawamoto, Jun Koseki, Yuichiro Doki, Masaki Mori, Hideshi Ishii
Journal: Cancer Research (2015)

Abstract Pyruvate kinase M2 (PKM2) maintains aerobic glycolysis in cancer cells and stimulates cell proliferation by controlling Warburg effect(Nature, 2008). In addition, PKM2 translocates to nucleus in response to EGFR signaling and up-regulates Cyclin D1 expression by controlling its transcription (Nature, 2011). PKM2 confers malignant potential by controlling both metabolism and transcriptional regulation. In this study, we investigated the correlation between PKM2 and invasion and metastasis of colorectal cancer in terms of nuclear function, which has yet to be investigated. Tumor invasion is initiated with the change of epithelial-mesenchymal transition (EMT) in cancer cell, and we induced EMT by adding TGF-β1 and EGF to SW 480. After EGF induction, in parallel with E-cadherin down-regulation and Vimentin up-regulation, the expression of PKM2 was increased both in transcriptional and translational level and PKM2 translocated into nucleus. PKM2 knock-down by siRNA suppressed E-cadherin decrease and invasion capacity in invasion assay. We created sh pyruvate kinase SW 480 with mouse PKM1 or PKM2 was overexpressed both of which have DNA sequence resistant to sh pyruvate kinase. PKM2 overexpression stimulated EMT induction by enhancing E-cadherin decrease. TGIF2 was identified which interacted with PKM2 in nucleus in response to EMT induction, which was considered to have a key role in controlling EMT induction. We performed immunohistochemical staining with specific antibody to PKM2 using clinical samples of colorectal cancers. Clinicopathological analysis showed that PKM2 positivity significantly correlated with lymph node metastasis and distant organ metastasis. In conclusion, our data suggested that PKM2 nuclear function had a crucial role in controlling invasion and metastasis. Citation Format: Masamitsu Konno, Naohiro Nishida, Koichi Kawamoto, Jun Koseki, Yuichiro Doki, Masaki Mori, Hideshi Ishii. Role of nuclear PKM2 in transcriptional regulation leading to EMT. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4080. doi:10.1158/1538-7445.AM2015-4080
Abstract 2925: WAVE3 is associated with chemoresistance in TNBC by activating tumor angiogenesis downstream of the STAT1/Hif-1α/VEGF-A signaling axis
Authors: Gangarao Davuluri, Edward F. Plow, William P. Schiemann, Khalid Sossey-Alaoui
Journal: Cancer Research (2015)

Abstract Chemoresistance is the main cause of disease recurrence and eventual death of breast cancer patients, particularly those harboring triple-negative breast cancer (TNBC) tumors for which effective FDA-approved drugs currently do not exist. However, a recent study determined that TNBCs can be segregated into 6 genetically distinct subtypes that do in fact exhibit differential rates of pathological complete response (pCR) to standard-of-care chemotherapies. Interestingly, the mesenchymal and mesenchymal stem-like subtypes of TNBCs exhibit the lowest rates of pCR when treated with standard-of-care chemotherapies. WAVE3 is an actin-cytoskeleton remodeling protein, and recent studies have highlighted a potential role for WAVE3 in promoting tumor progression and metastasis in TNBC. However, whether WAVE3 activity is involved in the development of chemoresistance in TNBCs, remains unclear. Here we show that loss of WAVE3 expression resensitizes human TNBC cells to Doxorubicin and Docetaxel, as measured by increased apoptosis and cell death. We also show that WAVE3 knockdown in the chemotherapy-treated TNBC cells results in inhibition of STAT1 phosphorylation, as well as a significant decrease in expression levels of its downstream effector Hif-1α. Since Hif-1α is a major activator of VEGF-A production, and therefore, a stimulator of tumor angiogenesis, loss of Hif-1α in the WAVE3-knocdown cells resulted in the inhibition the chemotherapy-mediated VEGF-A secretion and the downstream activation of angiogenesis, a phenomenon that often accompanies chemoresistance. Our data identify a critical role of WAVE3 in sensitizing TNBC to chemotherapy by inhibiting the STAT1⌠Hif-1α⌠VEGF-A signaling axis, and support the possibility of WAVE3 inhibition as a promising approach for TNBC cancer therapy. Citation Format: Gangarao Davuluri, Edward F. Plow, William P. Schiemann, Khalid Sossey-Alaoui. WAVE3 is associated with chemoresistance in TNBC by activating tumor angiogenesis downstream of the STAT1/Hif-1α/VEGF-A signaling axis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2925. doi:10.1158/1538-7445.AM2015-2925
RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer
Authors: Anne T. Schneider, Jérémie Gautheron, Maria Feoktistova, Christoph Roderburg, Sven H. Loosen, Sanchari Roy, Fabian Benz, Peter Schemmer, Markus W. Büchler, Ueli Nachbur, Ulf P. Neumann, Rene Tolba, Mark Luedde, Jessica Zucman-Rossi, Diana Panayotova-Dimitrova, Martin Leverkus, Christian Preisinger, Frank Tacke, Christian Trautwein, Thomas Longerich, Mihael Vucur, Tom Luedde
Journal: Cancer Cell (2016)