tbuckley/cabot-search huggingface dataset:
Abstract 3514: A novel inhibitor of IDH1 abrogates 2-HG production and reverses aberrant epigenetic alterations in IDH1 mutant cells
Authors: Cynthia Rominger, Chad Quinn, Enoch Gao, Beth Pietrak, Alan Rendina, Angela Smallwood, Arthur Groy, Susan Korenchuk, Charles McHugh, Ken Wiggall, Alexander Reif, Stanley Schmidt, Hongwei Qi, Huizhen Zhao, Nestor Concha, Christopher Carpenter, Juan Luengo, Ryan Kruger, Benjamin Schwartz, Nicholas Adams, Michael T. McCabe
Journal: Cancer Research (2015)

Abstract The isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are mutated in acute myelogenous leukemia, low-grade glioma, intrahepatic cholangiocarcinoma, and chondrosarcomas. IDH1 and IDH2 normally function to convert isocitrate into alpha-ketoglutarate. However, when these enzymes are mutated at select residues the mutant enzymes now convert α-KG into 2-hydroxyglutarate (2-HG). In normal cells, 2-HG levels are typically extremely low, but IDH1/2 mutant cells can accumulate up to 10 mM 2-HG. In an effort to counteract the neomorphic activity of mutant IDH enzymes, we identified and developed potent inhibitors of IDH1. The compounds inhibit IDH1 catalytic activity in biochemical assays and reduce 2-HG production in IDH1-mutant cell lines. Consistent with the fact that 2-HG inhibits α-KG dependent enzymes including histone demethylases and Tet family hydroxylases, these IDH1 inhibitors induce a decrease in several histone methylation marks and also DNA methylation. These data demonstrate that small molecule inhibitors can reverse many of the epigenetic effects of mutant IDH1. Note: This abstract was not presented at the meeting. Citation Format: Cynthia Rominger, Chad Quinn, Enoch Gao, Beth Pietrak, Alan Rendina, Angela Smallwood, Arthur Groy, Susan Korenchuk, Charles McHugh, Ken Wiggall, Alexander Reif, Stanley Schmidt, Hongwei Qi, Huizhen Zhao, Nestor Concha, Christopher Carpenter, Juan Luengo, Ryan Kruger, Benjamin Schwartz, Nicholas Adams, Michael T. McCabe. A novel inhibitor of IDH1 abrogates 2-HG production and reverses aberrant epigenetic alterations in IDH1 mutant cells. [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 3514. doi:10.1158/1538-7445.AM2015-3514
Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation Represents a Feasible and Effective Treatment Strategy for Advanced Mycosis Fungoides and Sezary Syndrome.
Authors: Davide Soligo, Francesco Onida, Giorgia Saporiti, Aldo Della Volpe, Cristian Marino, Claudio Annaloro, Alessandro Rambaldi, Benedetto Bruno, Emilio Berti, Giorgio Lambertenghi Deliliers
Journal: Blood (2006)
Clinical and Molecular Significance of Peripheral Blood Cell-Free DNA in B-Cell Lymphomas for Detection of Genetic Mutations and Correlation with Disease Status
Authors: Yasuhiro Suzuki, Akihiro Tomita, Kenichi Yoshida, Kazuyuki Shimada, Chisako Iriyama, Masashi Sanada, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Seishi Ogawa, Hitoshi Kiyoi
Journal: Blood (2014)
PWE-049 Shotgun proteomics in the discovery of biomarkers of non-alcoholic fatty liver disease: an improved methodology
Authors: M Miller, H Jafferbhoy, M A J Ferguson, J Dillon
Journal: Gut (2010)

<h3>Introduction</h3> Non-alcoholic fatty liver disease is a common condition affecting up to one third of the US population. The current gold standard diagnostic tool is liver biopsy, which has associated morbidity and mortality concerns, as well as sampling error and inter-observer variability problems. There is an urgent need for the discovery and validation of non-invasive markers of this disease. Many studies have taken a targeted approach, examining the utility of various biochemical and clinical markers thought to be important in the pathogenesis of this condition. Shotgun proteomics offers an untargeted tool for the discovery of protein markers in complex clinical samples. <h3>Methods</h3> Materials: 30 patients with biopsy proven NAFLD were recruited. Patients had negative viral hepatitis screens, negative autoimmune screens, normal iron stores, and were taking no hepatotoxic medications. Biochemical and anthropological measurements were also recorded. <h3>Method</h3> Serum samples were pooled into three groups (SS/NASH/NASH fibrosis, <i>F</i><sub>1,2</sub>, with n=7 per group). The pooled samples were immunodepleted of the top 91 most abundant proteins. Buffer exchange and lyophilisation was performed before samples were reduced alkylated then digested with trypsin. The resultant peptide mixtures were labelled with iTRAQ tags as per the manufacturers9 protocol (Applied Biosystems), and then pooled together. Sample fraction was performed using a reverse phase C18 column at high pH. A total of 88 fractions were collected and combined to 47 fractions based on the appearance of the chromatogram. The 47 fractions were analysed by LC-MS/MS (QTOF, Agilent), using an optimised LC and MS methodology. The resultant MS data were processed using MASCOT Distiller software and the IPI_human database searched for matches. Only proteins with 2 peptide identification and a MASCOT score indicative of identity were included for analysis. <h3>Results</h3> A total of 557 proteins were identified and included for analysis. Previous iTRAQ technical replicate data indicated an error range of 1.13 (±0.10)–1.37 (±0.12). Proteins with fold changes out with this range were considered significantly differentially expressed. At least 10 proteins had a fold change &gt;5 in the NASH early fibrosis group. Interestingly, several protein markers of NAFLD fibrosis previously reported in the literature were also found to be appropriately unregulated in this experiment, including α-2-macroglobulin. <h3>Conclusion</h3> Discussion iTRAQ technology is a powerful tool, allowing analysis of up to 8 different samples simultaneously. We have improved our method of sample preparation and processing to increase the number of protein identifications. The findings from this study require further validation.
Abstract 1567: A mass spectrometry based serum test for the detection of hepatocellular carcinoma (HCC) in high risk patients
Authors: Devalingam Mahalingam, William K. Washburn, Glenn Halff, Leonidas Chelis, Stylianos Kakolyris, Stylianos Vradelis, Julia Grigorieva, Carlos Oliveira, Heinrich Roder, Joanna Roder
Journal: Cancer Research (2015)

Abstract Improved screening protocols (SP) for patients at high risk of developing HCC could lead to improved patient outcome and possibly cure if detected early. The current SPs, ultrasound with the possible addition of alphafetoprotein (AFP) measurement, suffer from insufficient sensitivity and specificity, and less than 30% of patients are diagnosed early enough to be suitable candidates for resection or transplantation. An easy to use biomarker for the early detection of HCC is clearly needed. We used mass spectrometry analysis of serum samples combined with specialized deep learning techniques to train and validate such a test. The development cohort consisted of patients undergoing transplant or resection for HCC (N = 52; median MELD = 14), and patients with advanced cirrhosis undergoing liver transplant (N = 53; median MELD = 25). Underlying cause of liver disease was 51% hepatitis C infection. The validation cohort consisted of patients with advanced HCC (N = 103; 70/26/7 Child-Pugh A/B/C) and liver disease but no HCC (N = 77; 68/7/2 Child-Pugh A/B/C), with 68% of patients having hepatitis B infection (HBV). The classifier was trained especially to avoid confounding by liver function. The resulting test showed a sensitivity/specificity of 73%/95% in cross validation in the development set overall. In the subset of T1 patients (or lesion size &amp;lt;2 cm) accuracy was 72% (75%). Performance was good across all represented causes of liver disease. The test was shown not to be confounded by liver function by classifying healthy patients (N = 17) as ‘no cancer’. In the validation set the performance was 89%/73%, with 91%/78% in the HBV subgroup and 90%/75% in the Child-Pugh A subgroup. The developed test shows promise in the early detection of HCC as a screening tool in high risk patients independent of the cause of underlying liver disease. While further validation will be necessary to conclusively prove its clinical validity, we believe such a test could substantially improve early detection of HCC. Citation Format: Devalingam Mahalingam, William K. Washburn, Glenn Halff, Leonidas Chelis, Stylianos Kakolyris, Stylianos Vradelis, Julia Grigorieva, Carlos Oliveira, Heinrich Roder, Joanna Roder. A mass spectrometry based serum test for the detection of hepatocellular carcinoma (HCC) in high risk patients. [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 1567. doi:10.1158/1538-7445.AM2015-1567
PTH-008 Faecal tumour M2 pyruvate kinase – a non-invasive marker for identifyinghigh-risk patients undergoing colorectal investigations in a district general hospital
Authors: D Majumdar, M Thornton, G Irving, A Soliman, K Kapur
Journal: Gut (2010)

<h3>Introduction</h3> Colorectal carcinoma is the second most common cause of cancer death in the western world. Alarm features such as weight loss, change in bowel habit, iron deficiency anaemia, rectal bleeding or a palpable abdominal mass have been proposed as the optimal method of identifying patients in primary care who need early assessment and investigations. However, the accuracy of these clinical features in identifying high-risk patients is quite variable. Tumour M2PK is the dimeric isoform of pyruvate kinase, which is upregulated in proliferating tissues. Several studies show good sensitivity and specificity of faecal M2PK for colorectal cancer. There is still a paucity of data for M2PK in identifying high-risk patients in secondary care. <h3>Methods</h3> To investigate the clinical utility of faecal M2PK in detection of colorectal cancer, colonic polyps or any other significant colonic pathology in routine clinical practice and assess its suitability as a tool for identifying patients referred to secondary care for early lower gastro-intestinal investigations. Patients undergoing colonoscopy or barium enema (routine/urgent/cancer pathway) were recruited from both general gastroenterology and surgical outpatient clinics. Patients returned a stool sample in the specimen container provided. A quantitative analysis by sandwich ELISA using two different monoclonal antibodies to specifically recognise the dimeric form of M2PK was used. A positive test result was defined as &gt;4 kU/l. Data were collected prospectively including demographics, clinical presentation and indication for colonoscopy as well as findings at lower GI investigations. The data were analysed for sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). <h3>Results</h3> 48 patients (60.4% females) were recruited from March to October 2007. The mean age was 59.6±15.1 years, with no significant difference in M2PK levels between males and females. Elevated M2PK levels were found in 43.8% of patients. Abnormal pathology was found in 58.3% of patients. The diagnoses included polyps (n=9), sigmoid colon cancer (n=1), diverticular disease (n=16), collagenous colitis (n=1), and miscellaneous (n=2). Raised stool M2PK was found in 55.6% of patients with polyps. The sensitivity of M2PK for detecting significant colorectal pathology (polyps/cancer) was 50%. Specificity was 57.9% at 4 kU/l, and increased to 84.2% with a modified cut-off of 8 kU/l (sensitivity unchanged). PPV was 23.8% and NPV 81.5% (8 kU/l: 45.5% and 86.5%, respectively). <h3>Conclusion</h3> In this highly selected cohort of patients referred to secondary care, a modified cut-off of M2PK may act as a useful adjunct in identifying high-risk patients.
Abstract LB-257: Discovery and characterization of novel, highly potent and selective USP7 inhibitors
Authors: Gerald Gavory, Colin O'dowd, Keeva McClelland, Ewa Odrzywol, Alan Brown, Stephanie Burton, Oliver Barker, Frank Burkamp, Matt Helm, Iain James, Jakub Flasz, Elias Arkoudis, Tim Harrison
Journal: Cancer Research (2015)

Abstract Over the past decade, protein ubiquitination has emerged as an important post-translational modification with roles in a plethora of cellular processes, and dysregulation in the ubiquitin proteasome system pathway (UPS) has been implicated in multiple human disorders including cancer. Ubiquitin specific proteases (USPs) are cysteine proteases that catalyse the de-ubiquitination of numerous protein substrates including tumor suppressors and oncogenes, hence regulating their levels and/or functions. USPs therefore represent a fast growing and attractive target class for pharmacological intervention. USP7 in particular has attracted considerable attention for its implications in multiple key oncogenic pathways including most notably MDM2/p53, PTEN and DNA damage. As part of a focussed effort towards targeting USPs, fragment screening was performed against a panel of family members, including USP7. Hits were identified by surface plasmon resonance and validated using orthogonal biophysical techniques (NMR, thermophoresis). Subsequent hit expansion identified molecules for which high-resolution co-crystal structures have been solved providing unique opportunities for structure-based design. Medicinal chemistry optimisation has yielded a series of novel, reversible and potent USP7 inhibitors (e.g. IC50 &amp;lt; 10 nM) with excellent selectivity profiles against deubiquitinating (DUBs) and other non-related enzymes. These inhibitors are cell-permeable and also exhibit potent target engagement in cells (e.g. EC50 &amp;lt; 30 nM). In line with the mechanism of action, further cellular profiling has demonstrated effects on p53, p21 and MDM2 levels in a concentration-dependant manner. From a translational viewpoint, initial studies aimed at identifying cell lines sensitive to these inhibitors will also be discussed. In summary, we report the discovery and detailed biochemical and cellular profiling of novel, potent and selective inhibitors of USP7. These molecules have drug-like properties and may provide opportunities for the development of new anticancer therapeutics. Citation Format: Gerald Gavory, Colin O'dowd, Keeva McClelland, Ewa Odrzywol, Alan Brown, Stephanie Burton, Oliver Barker, Frank Burkamp, Matt Helm, Iain James, Jakub Flasz, Elias Arkoudis, Tim Harrison. Discovery and characterization of novel, highly potent and selective USP7 inhibitors. [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-257. doi:10.1158/1538-7445.AM2015-LB-257
Prognostic Value of Immune Profiling Multiple Myeloma Patients during Minimal Residual Disease Monitoring in the Pethema/GEM2010MAS65 Study
Authors: Paula Arana, Bruno Paiva, Noemi Puig, Teresa Cedena, Lourdes Cordon, Maria Belen Vidriales, Joaquin Martinez-López, Enrique M. Ocio, Miguel T Hernandez, Ana Isabel Teruel, Mercedes Gironella, M Asuncion Echeveste, Laura Rosiñol, Rafael Martinez, Albert Oriol, Joan Blade, Juan Jose Lahuerta, Maria-Victoria Mateos, Jesus San Miguel
Journal: Blood (2015)
196. Nordihydroguaiaretic Acid (NDGA) Improves Function of Antigen-Specific T-Cells Stimulated by Capsid-Optimized AAV6 Vectors
Authors: Daniel Zhang, Chen Ling, George Aslanidi
Journal: Molecular Therapy (2016)

Cancer, a leading cause of death in the human population today, is generally treated with rigorous surgery followed by intensive chemotherapeutic methods, both of which have adverse toxic side effects. Immunotherapy represents an attractive alternative since it is based on activation of the host immune system. We recently showed that capsid-optimized AAV6-S663V+T492V vectors expressing a tumor-associated antigen are able to initiate specific peripheral T-cell response and suppress tumor progression as well as extend survival in a prostate cancer animal model (J Immunother., 38: 292-298, 2015). However, vaccination based on AAV6 vectors alone was not able to completely overcome the adverse effect of tumor microenvironment and tumor-induced immune dysfunction. Tumor-associated macrophages (TAMs) are prominent components of solid tumors. TAMs exhibit distinct phenotypes and function, and negatively contribute to immune system evasion. Previously published data indicate that inhibition of lipoxygenase (15-LOX2), a key enzyme contributing to TAM function, is critical to overcome tumor resistance and facilitate immunotherapy treatment. In our studies presented here, we first showed that 15-LOX2 is expressed in mouse prostate cancer cells, RM1, growing subcutaneously in C57BL/6 mice, but not in cells growing in culture. We also showed that LOX inhibitors, such as a plant-derived compound, nordihydroguaiaretic acid (NDGA), could restore the function of specific cytotoxic T-cells co-cultured with TAMs in a concentration-dependent manner. Splenocytes from C57BL/6 mice injected intra-muscularly with capsid-optimized AAV6 vectors expressing prostatic aid phosphatase (PAP) were isolated 14 days after vector injection. T-cells were incubated in the presence or absence of RM1 tumor cell extracts and NDGA for 2 hours and then used in killing assays against cultured RM1 cells. Two-color fluorescence assays of cell-mediated cytotoxicity was used to estimate the percentage of dead/alive target cells and a killing curve was generated with different effectors to target cell ratios. Our data indicated that the killing ability of T-cells initiated by capsid-optimized AAV6 vector injection and incubated with RM1 tumor-derived TAMs was approximately 3-fold lower than original activity T-cell. NDGA at a concentration of 10 uM had limited effect on the T-cell activity, but 25 µM NDGA restored the function of the T-cells to approximately 90% of the original activity. In our currently ongoing studies, we are using a combination of capsid-optimized AAV6 vector-mediated immune activation with the NDGA-treatment to corroborate whether a synergetic therapeutic effect can be achieved in an animal model. If successful, this approach could prove useful in the potential clinical application.
High Frequencies of Increased Interferon-γ-Producing and/or Skewed CD8+ T Lymphocyte Subfamilies in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH).
Authors: Akiko Shichishima, Hideyoshi Noji, Kazuhiko Ikeda, Yukio Maruyama, Tsutomu Shichishima
Journal: Blood (2006)
Abstract 2752: Prevalence of BAP1 germline mutations in asbestos-exposed malignant mesothelioma cases and controls
Authors: Mitchell Cheung, Jacqueline Talarchek, Suzanne E. Howard, Timothy Howard, Hongzhuang Peng, Mary Hesdorffer, Frank J. Rauscher, Jill A. Ohar, Joseph Testa
Journal: Cancer Research (2015)

Abstract Malignant mesothelioma (MM) is an uncommon but aggressive cancer that has been linked with asbestos exposure. Contributing genetic factors appear to play a role because familial clustering of MM has been observed and that only a small percentage of asbestos-exposed individuals have been documented to develop MM. Germline mutation of BAP1 has been identified as one such predisposing factor. However, the frequency of germline BAP1 mutations in MM cases is debatable due to small sampling sizes of studies from previous publications. Therefore, we decided to determine the prevalence of germline BAP1 mutations in a large set of asbestos-exposed MM cases and controls, the biggest such population study to date. BAP1 mutation status was compared between 150 MM cases with a family history of cancer and 153 asbestos-exposed controls without indications of familial cancers. Although no alterations of BAP1 were discovered in the controls, BAP1 mutations were identified in 9 of the MM cases (6%). These alterations included 2 splice site changes, 4 insertion/deletions, and 3 missense mutations. In vitro enzymatic assays showed decreased deubiquitinase activity for each of the three BAP1 missense mutant proteins. We observed a statistically significant lower age of MM onset as well as a higher incidence of peritoneal MMs among the 9 BAP1 mutation cases compared to the non-mutated MM cases. The other tumors identified in family members of the 9 individuals included additional MMs, ocular and cutaneous melanomas, renal, breast, lung, and gastric carcinomas, and lymphomas. Interestingly, six of the nine MM cases with a germline BAP1 mutation had two or more primary cancers, suggesting a widespread targeting of tissues of multiple organs caused by the mutation. In summary, these findings suggest that patients presenting with MM and a family history of cancer should be considered for BAP1 mutation testing to identify those who might benefit from screening and regular monitoring of family members to enable early detection and intervention. Citation Format: Mitchell Cheung, Jacqueline Talarchek, Suzanne E. Howard, Timothy Howard, Hongzhuang Peng, Mary Hesdorffer, Frank J. Rauscher, Jill A. Ohar, Joseph Testa. Prevalence of BAP1 germline mutations in asbestos-exposed malignant mesothelioma cases and controls. [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 2752. doi:10.1158/1538-7445.AM2015-2752
New therapeutic concepts in bile acid transport and signaling for management of cholestasis
Authors: Michael Trauner, Claudia Daniela Fuchs, Emina Halilbasic, Gustav Paumgartner
Journal: Hepatology (2016)

The identification of the key regulators of bile acid (BA) synthesis and transport within the enterohepatic circulation has revealed potential targets for pharmacological therapies of cholestatic liver diseases. Novel drug targets include the bile BA receptors, farnesoid X receptor and TGR5, the BA‐induced gut hormones, fibroblast growth factor 19 and glucagon‐like peptide 1, and the BA transport systems, apical sodium‐dependent bile acid transporter and Na + ‐taurocholate cotransporting polypeptide, within the enterohepatic circulation. Moreover, BA derivatives undergoing cholehepatic shunting may allow improved targeting to the bile ducts. This review focuses on the pathophysiological basis, mechanisms of action, and clinical development of novel pharmacological strategies targeting BA transport and signaling in cholestatic liver diseases. (H epatology 2017;65:1393‐1404).
Donor-Recipient Matching at the HLA-C Locus and Early Outcomes after Unrelated Umbilical Cord Blood Transplant (UCBT)
Authors: Mary Eapen, John Klein, Guillermo Sanz, Claudio Anasetti, Joan Garcia, Eliane Gluckman, Mary M. Horowitz, Gesine Koegler, Mary Laughlin, Gerard Michel, Stephen R Spellman, Franklin O. Smith, Vanderson Rocha
Journal: Blood (2008)
Preliminary Results From the US Zika Pregnancy Registry
Authors: William J. Muller, Emily S. Miller
Journal: JAMA (2016)

Margaret A. Honein, PhD; April L. Dawson, MPH; Emily E. Petersen, MD; Abbey M. Jones, MPH; Ellen H. Lee, MD; Mahsa M. Yazdy, PhD; Nina Ahmad, MD; Jennifer Macdonald, MPH; Nicole Evert, MS; Andrea Bingham, PhD; Sascha R. Ellington, MSPH; Carrie K. Shapiro-Mendoza, PhD; Titilope Oduyebo, MD; Anne D. Fine, MD; Catherine M. Brown, DVM; Jamie N. Sommer, MS; Jyoti Gupta, MPH; Philip Cavicchia, PhD; Sally Slavinski, DVM; Jennifer L. White, MPH; S. Michele Owen, PhD; Lyle R. Petersen, MD; Coleen Boyle, PhD; Dana Meaney-Delman, MD; Denise J. Jamieson, MD; for the US Zika Pregnancy Registry Collaboration