tbuckley/cabot-search huggingface dataset:
Abstract LB-121: Identification of Carboxylesterase-2 as a determinant of response to irinotecan and neoadjuvant FOLFIRINOX therapy in pancreatic ductal adenocarcinoma
Authors: Michela Capello, Minhee Lee, Hong Wang, Ingrid Babel, Matthew H. Katz, Jason B. Fleming, Anirban Maitra, Huamin Wang, Weihua Tian, Ayumu Taguchi, Samir M. Hanash
Journal: Cancer Research (2015)

Abstract Background: Serine hydrolases (SHs) are among the largest classes of enzymes in human and play crucial role in many pathophysiological processes of cancer. We have undertaken a comprehensive proteomic analysis to assess the differential expression and cellular localization of SHs, which uncovered distinctive expression of Carboxylesterase 2 (CES2), the most efficient carboxyl esterase in activating the pro-drug irinotecan into SN-38, in pancreatic ductal adenocarcinoma (PDAC). We therefore assessed the extent of heterogeneity in CES2 expression in PDAC and its potential relevance to irinotecan based therapy. Methods: CES2 expression in PDAC and paired non-tumor tissues was evaluated by immunohistochemistry. CES2 activity was assessed by monitoring the hydrolysis of the substrate p-NPA. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CES2 expression in patients who underwent neoadjuvant FOLFIRINOX treatment. Results: Significant overexpression of CES2, both at the mRNA and protein levels, was observed in PDAC compared to paired non-tumor tissue (P &amp;lt; .0001), with 48/118 (40.7%) tumors exhibiting high CES2 expression. CES2 activity in PDAC cell lines was inversely correlated with irinotecan IC50 values (P = .021), while no molecule involved in irinotecan metabolism yielded a significant correlation between its expression and sensitivity to the drug. Remarkably, we recently found that high CES2 expression in tumor tissue was associated with longer overall survival in resectable and borderline resectable patients who underwent neoadjuvant FOLFIRINOX treatment (P = .024). Conclusion: Our findings suggest that CES2 expression and activity, by mediating the intra-tumoral activation of irinotecan, is a contributor to FOLFIRINOX sensitivity in pancreatic cancer and CES2 assessment may define a subset of patients likely to respond to irinotecan based therapy. Citation Format: Michela Capello, Minhee Lee, Hong Wang, Ingrid Babel, Matthew H. Katz, Jason B. Fleming, Anirban Maitra, Huamin Wang, Weihua Tian, Ayumu Taguchi, Samir M. Hanash. Identification of Carboxylesterase-2 as a determinant of response to irinotecan and neoadjuvant FOLFIRINOX therapy in pancreatic ductal adenocarcinoma. [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 LB-121. doi:10.1158/1538-7445.AM2015-LB-121
Abstract 4640: Andrographolide modulates cell cycle, cell migration and tumor growth in prostate cancer
Authors: Ingrid Forestier-Roman, Maria Sánchez, Joseph Casillas, Krizia Rohena, Magaly Martínez-Ferrer
Journal: Cancer Research (2015)

Abstract Prostate cancer is the most frequently diagnosed non-cutaneous cancer and is the second leading cause of cancer death in American men. Chemopreventive strategies have been tested to prevent the development of different types of cancer including prostate cancer. Andrographolide, a labdane diterpenoid that is the main bioactive component of the medicinal plant Andrographis paniculata, has been reported to have a wide range of biological activities including anticarcinogenic properties. In this study we aim to determine the role of Andrographolide in the progression of prostate cancer using in vitro and in vivo models. Andrographolide significantly inhibited PC3 cell growth at a concentration of 10μM after 24 h of treatment (P &amp;lt; 0.001), and inhibited LNCaP cell growth at a concentration of 15 μM after 24 h of treatment (P &amp;lt; 0.001). Wound healing assays and boyden chamber experiments showed that PC3 prostate cancer cells treated with Andrographolide (25uM) significantly reduced (P&amp;lt;0.001) their migration and invasion. Flow cytometry assays for Annexin V, cell cycle and cell count and viability were performed. Andrographolide (25uM) significantly increased apoptosis, decreased cell population in G1 phase, and reduced count and viability of PC3 cells treated for 48 hours. Immunofluorescence analysis showed that MMP-11 expression levels were significantly decreased and ZO-1 expression was significantly increased in PC3 cells treated with Andrographolide (25uM). Tumor progression was evaluated using a xenograft model in which the anterior prostate lobes of SCID mice were injected with 250,000 22RV1 cells or 500,000 PC3 cells. Andrographolide was administered bi-weekly at concentrations of 10uM and 25uM intraperitoneal injections during 4 weeks (22RV1) or 8 weeks (PC3). Tumor tissue was collected for gross examination, immunohistochemical analysis and gene expression analysis. In vivo results demonstrated that Andrographolide treatment significantly decreased tumor volume when compared with tumors generated in mice treated with vehicle. Our results suggest that the anti-migration and anti-invasion effects of andrographolide may be associated with alterations in the expression of ZO-1 and MMP-11. Citation Format: Ingrid Forestier-Roman, Maria Sánchez, Joseph Casillas, Krizia Rohena, Magaly Martínez-Ferrer. Andrographolide modulates cell cycle, cell migration and tumor growth in prostate cancer. [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 4640. doi:10.1158/1538-7445.AM2015-4640
Measuring tumor cell apoptosis and necrosis in blood samples of cancer patients during therapy
Authors: Frank Neumann, Klaus Mross, Marc Azemar, Vittorio Ziroli, Ulrich Massing, Clemens Unger, Bernd Hildenbrand
Journal: Clinical Cancer Research (2007)

A50  Clinical trials of new cancer drugs should ideally include measurements of parameters such as molecular target expression, pharmacokinetic (PK) behavior, and pharmacodynamic (PD) endpoints that can be linked to measures of clinical effect. Appropriate PK/PD biomarkers facilitate proof-of-concept demonstrations for target modulation; enhance the rational selection of an optimal drug dose and schedule, guide combination treatments and may explain or predict clinical outcomes.  Non-invasive assessment of treatment-induced tumour cell death is desirable both for accurate management of patients and for detailed characterisation of different treatment modalities.  Here we describe Cytokeratin 18 (CK18) as a suitable blood borne biomarker for non-invasive determination of apoptosis and necrosis of epithelial cells during breast and prostate cancer treatment.  Cytokeratin 18 is cleaved by caspases during apoptosis, and preclinical and clinical studies have shown that caspase-cleaved CK18 fragments are released from apoptotic cells into the extracellular compartment/blood circulation, where they accumulate with a favourable biological half-life.  In contrast to other biomarkers used to assess tissue damage during cancer treatment, caspase-cleaved CK18 is generated only during apoptosis and only by epithelium-derived cells, whereas the detection of increased levels of predominant uncleaved CK18 in patient serum samples is thought to be caused by necrotic tumor cell death.  Data will be presented that the non-invasive quantification of CK18 and caspase-cleaved CK18 (M30-antigen) biomarkers by ELISA can be useful to monitor individual patient response to therapy in early clinical studies.  References:  Cytokeratin-18 is a useful serum biomarker for early determination of response of breast carcinomas to chemotherapy. Olofsson MH, et al., Clin Cancer Res. (2007) 13:3198-206.  Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles. Kramer G, et al., Br J Cancer. (2006) 94:1592-8.  Validation of pharmacodynamic assays to evaluate the clinical efficacy of an antisense compound (AEG 35156) targeted to the X-linked inhibitor of apoptosis protein XIAP. Cummings J, et al. Br J Cancer. (2005) 92:532-8.  A novel assay for discovery and characterization of pro-apoptotic drugs and for monitoring apoptosis in patient sera. Apoptosis. Biven K, et al., (2003) 8:263-8.
173. Electroporation-Mediated FER Gene Delivery in the Resolution of Severe Gram Negative Pneumonia
Authors: Vladislav Dolgachev, Rebecca Goldberg, Suresh Madathilparambil, Krishnan Raghavendran, Mark R. Hemmila, Mark Johnson, David Machado-Aranda
Journal: Molecular Therapy (2016)

Introduction: The emergence of multi drug resistant bacterial pneumonia is a major concern among Intensive Care Units across the nation. Severely injured patients including those with lung contusion (LC) and requiring mechanical ventilation are particularly vulnerable in developing above forms of virulent pneumonia (PNA). The continued deterioration of these patients evolves into highly mortal Acute Respiratory Distress Syndrome. A recent GWAS study showed that FER expression, a non-receptor cytosolic tyrosine-kinase, was associated with survival from pneumonia and sepsis. We elected to study the role of FER gene in a murine model of bacterial PNA. We hypothesized that electroporation-mediated (EP) delivery of the FER gene would decrease mortality in severe PNA complicated by trauma. Methods: Two separate PNA models were created in C57Bl/6 mice by airway inoculation of 500 CFU of Klebsiella sp., in naive (Primary PNA) or after blunt trauma-induced lung contusion (Secondary PNA). Treatment group(s) consisted on delivering naked plasmid DNA encoding FER to the lung (pFER) followed by square wave EP at 200 V/cm, eight 10 ms pulses, 1 s apart using external forelimb flat electrodes, either before or after insult. These plasmids were delivered with appropriate controls (saline EP {EP-sham} and plasmids encoding the Na+/K+-ATPase- which has shown favorable response in sterile inflammatory conditions {pPump}). 7-day survival curves were recorded. Specific readouts included parameters of lung inflammation (Histology, Bronchial Alveolar Lavage [BAL], Taq-man PCR) and infection (blood-lung bacterial quantification) at 24 and 72 hrs. Results: Survival was markedly improved by pFER treatment, both in primary and secondary bacterial PNA as compared to EP-sham or pPump controls. (Figure 1 left). Assessed parameters of inflammation showed also favorable changes being more prominent in secondary bacterial PNA, as visualized by H-E staining (Figure 1 right). With pFER treatment there was a robust recruitment of monocytes in BAL (~20 fold increase over LC+PNA control, p<0.0001), with cells showing activation of bactericidal Fizz (~110 fold change over LC + PNA control, p<0.0001) and NOS (~160 fold change over LC + PNA, p<0.0001) genes. Blood and lung, bacterial counts were significantly decreased in the pFER group with some animals able to completely clear the lung of infection (Figure 2). Conclusion: EP-mediated delivery of the FER gene significantly improved mouse survival in severe primary and secondary models of bacterial PNA. Mechanisms include recruitment of monocytes, activation of lung immune cells and improved bacterial clearance.
Expression of Osteopontin in the Bone Marrow of Patients with Acute Myeloid Leukemia.
Authors: Ruediger Liersch, Michael Bayer, Christoph Biermann, Iris Appelmann, Christoph Schliemann, Christian Schwoeppe, Torsten Kessler, Carsten Mueller-Tidow, Wolfgang Berdel, Rolf Mesters
Journal: Blood (2009)
Uterine Rupture with Protruded Legs in a Large Amniocele
Authors: Pierre-Emmanuel Bouet, Charlyne Herondelle
Journal: New England Journal of Medicine (2016)

A 33-year-old woman presented at 22 weeks of gestation with a large herniation of the amniotic sac, detected by routine ultrasonography. MRI revealed a 2.5-cm rupture of the left uterine wall and a large amniocele that contained fetal legs.
Abstract 5121: Study of a synthetic peptide probe for apoptosis imaging
Authors: Shen Yang, Jie Meng, Huike Liu, Chuan Wang, Yanlian Yang, Hua Guo, Jian Liu, Chen Wang, Haiyan Xu
Journal: Cancer Research (2015)

Abstract Chemotherapy and radiotherapy can cause a great many apoptosis in the tumor mass. Thus, direct and fast observation for the therapy-induced apoptosis is important and valuable to evaluate the effectiveness of anti-tumor treatments. In this work, a peptide (named as P17) labeling apoptotic cells was designed and chemically synthesized. To validate the labeling function, different tumor cells (Jurkat, THP-1, K562, Hela and MDA-MB-231) were treated with TRAIL (the TNF-related apoptosis-inducing ligand) to induce apoptosis, followed by incubation with FITC-conjugated P17 and then co-stained with annexin v. Flow cytometry results indicate that P17 binding to the cells was markedly increased with apoptosis rates rising. Confocal microscopy observations show that only cells with annexin v staining were labeled by P17, while live cells were not. By pull-down assay and mass spectrometry, P17-binding protein was identified to be heat shock protein 60 (HSP60), a mitochondrial chaperoninm with accumulation in the cytoplasm during apoptosis. And this result is further confirmed by confocal microscopy with anti-hsp60 antibody and a native-gel-based analysis to investigate FITC-P17 binding to HSP60. To evaluate the apoptosis-binding ability of the peptide in vivo, BALB/c mice bearing 4T1 tumor were treated with cyclophosphamide (CTX) to induce apoptosis in the tumor mass, followed by intravenously injection of fluorescent P17 prior to sacrifice. The tumor was removed for ex vivo imaging immediately. It was observed that P17 accumulated in CTX-treated tumors. The tumor tissue was further stained with TUNEL assay, confirming that the fluorescent signal observed was resulted from the labeling of apoptotic cells in tumor, because of the colocalization of P17 and TUNEL. In conclusion, this study demonstrates that P17 is a promising probe for the apoptosis imaging for uses in the evaluation of cancer therapy, drug screening and monitoring the cytotoxicity of therapeutics. (This work is supported by National Key Basic Research Program of China (2011CB933504) and Key project of the Major Research Plan from National Natural Science Foundation of China (91127043).) Citation Format: Shen Yang, Jie Meng, Huike Liu, Chuan Wang, Yanlian Yang, Hua Guo, Jian Liu, Chen Wang, Haiyan Xu. Study of a synthetic peptide probe for apoptosis imaging. [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 5121. doi:10.1158/1538-7445.AM2015-5121
Abstract POSTER-CTRL-1208: A dualistic model for the origin of high-grade serous carcinoma: BRCA mutation status, histology and tubal intraepithelial carcinoma
Authors: Brooke E Howitt, Suchanan Hanamornroongruang, Douglas Lin, James E Conner, Stephanie Schulte, Judy Garber, Christopher P Crum, Emily E Meserve
Journal: Clinical Cancer Research (2015)

Abstract Extra-uterine high-grade serous carcinoma (HGSC) is linked to the fimbria via serous tubal intraepithelial carcinoma or STIC. Women with deleterious BRCA1/2 germ-line mutations (BRCA+) are at high risk for HGSC and ~5% of risk reducing salpingo-oophorectomies harbor a STIC. However, STIC is found in only~40% of the HGSC population and less frequently in endometrioid variants of HGSC (Roh 2009). Consecutively tested women with untreated HGSC, with detailed fallopian tube examination (SEE-FIM protocol), who had germ-line BRCA testing were studied. STIC status was determined by histologic exam, and tumors were classified as predominately SET (&amp;gt; 50% solid, endometrioid-like, or transitional, Soslow 2012) or classic histology. SET features trended towards a higher frequency in BRCA+ vs BRCA- women (50 vs 28%, p = .11). BRCA- subjects with SET morphology were significantly younger than those with classic HGSC (mean 56.2 vs 64.8 years; p=0.04), with a generally better clinical outcome. STIC was significantly more frequent in BRCA- tumors (66 vs 31%, p = 0.017) and more frequent in classic HGSCs in BRCA- (83 vs 22%, p = 0.003) women. Overall, several co-variables – histology, BRCA status, age, coexisting STIC, response to therapy - suggest two categories of HGSC with differences in speed of development, progression, outcome, histology, and possibly, precursor type. We introduce a dualistic HGSC model with a faster evolving tumor type that is not linked to a long-standing STIC. Resolving the nature of this second pathway is germane to both resolving the precursors and expectations from both screening and prevention of HGSC. Citation Format: Brooke E Howitt MD, Suchanan Hanamornroongruang MD, Douglas Lin MD PhD, James E Conner MD PhD, Stephanie Schulte MD, Judy Garber MD, Christopher P Crum MD, Emily E Meserve MD MPH. A dualistic model for the origin of high-grade serous carcinoma: BRCA mutation status, histology and tubal intraepithelial carcinoma [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1208.
Selective Loss of a Putative Precursor Population of B-Chronic Lymphocytic Leukemia Cells Following Immunization with hCD40L/IL-2 Expressing Autologous Tumor Cells
Authors: Aaron Foster, Fatma Okur, Gianpietro Dotti, Jessica Shafer, An Lu, Ettore Biagi, Eric Yvon, Catherine M Bollard, Barbara Savoldo, Michael Andreeff, Margaret A Goodell, Cliona M Rooney, Malcolm K Brenner
Journal: Blood (2008)
Abstract 1174: Exploiting glioma stem cell metabolism to abrogate radioresistance in glioblastomas
Authors: Elizabeth I. Spehalski, Keita Saito, Tamalee Kramp, Anita Tandle, Barbara Rath, Murali Cherukuri, Kevin Camphausen
Journal: Cancer Research (2015)

Abstract Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults and, even with aggressive treatment that includes surgical resection, radiation, and temozolomide administration, prognosis is poor due to tumor recurrence. There is evidence that within GBMs a small number of glioma stem cells (GSCs) exist, which are thought to be radiation resistant and may be capable of repopulating a tumor after treatment. Like most cancers, GBMs largely employ aerobic glycolysis to create ATP, a phenomenon known as the Warburg effect. Experiments have shown that the cellular metabolism of GSCs differs from that of differentiated cells, making them an attractive target for novel therapeutic approaches. Much work has been done to analyze the metabolic profiles of GSCs with the goal of identifying potential therapeutic targets, but little data exists linking metabolic changes to radiation resistance. The purpose of this study is to determine the impact of radiation on the cellular metabolism of GSCs and to identify changes that can be exploited for treatment in conjunction with radiation therapy. To this end, we analyzed three human GSC lines harboring unique sets of genetic mutations that were hypothesized to differentially impact cellular metabolism. Experimental approaches include in vitro examination of metabolic rates and mitochondrial stress of the GSC lines via Seahorse extracellular flux analysis with and without radiation administration as well as analysis of tumor xenografts in mice via 13C MR spectroscopic imaging using hyperpolarized [1-13C] pyruvate as a tracer. Additionally, we are employing genomic and proteomic profiling of the GSC lines both in culture and in vivo to categorize metabolic changes following radiation treatment. We show that the basal metabolic rates of GSC lines with distinctive genetic mutations can be differentiated using Seahorse analysis. This is confirmed in vivo by 13C MR spectroscopic imaging, thus revealing a potential non-invasive diagnostic modality. The underlying mechanism behind these metabolic differences and how this relates to each GSC's response to radiation is currently being examined. We expect that this data will result in the identification of molecular targets within the metabolic pathways of cells that can be exploited with drugs in conjunction with radiation therapy to improve the prognosis and survival of patients presenting with GBMs in the clinic. Citation Format: Elizabeth I. Spehalski, Keita Saito, Tamalee Kramp, Anita Tandle, Barbara Rath, Murali Cherukuri, Kevin Camphausen. Exploiting glioma stem cell metabolism to abrogate radioresistance in glioblastomas. [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 1174. doi:10.1158/1538-7445.AM2015-1174
Thrombotic Thrombocytopenic Purpura Triggered by Inflammatory Pseudotumor: A Report of a Rare Case
Authors: Fernanda Loureiro de Andrade Orsi, Thais Benevides, Muriel S Moura, Maria A Maria, Priscila O. Percout, Bruna m Mazetto, Margareth C Ozelo, Marina Pereira Colella, Erich V de Paula, Joyce Annichino-Bizzachi
Journal: Blood (2012)