tbuckley/cabot-search huggingface dataset:
Defining Septic Shock
Authors: Anja Kathrin Jaehne, Namita Jayaprakash, Sam Langberg
Journal: JAMA (2016)

To the Editor A panel of 19 experts conducted an extensive and complex analysis of current literature and sepsis databases to develop new SEPSIS-3 definitions and clinical criteria for sepsis and septic shock.1 Despite this effort, some concerns remain in regard to these definitions.
A dual Cys<scp>LT</scp><sub>1/2</sub> antagonist attenuates allergen‐induced airway responses in subjects with mild allergic asthma
Authors: G. M. Gauvreau, L.‐P. Boulet, J. M. FitzGerald, D. W. Cockcroft, B. E. Davis, R. Leigh, M. Tanaka, J. A. Fourre, M. Tanaka, T. Nabata, P. M. O'Byrne
Journal: Allergy (2016)

Abstract Background The cysteinyl leukotrienes (cys LT s) play a key role in the pathophysiology of asthma. In addition to functioning as potent bronchoconstrictors, cys LT s contribute to airway inflammation through eosinophil and neutrophil chemotaxis, plasma exudation, and mucus secretion. We tested the activity of the dual cys LT 1/2 antagonist, ONO ‐6950, against allergen‐induced airway responses. Methods Subjects with documented allergen‐induced early ( EAR ) and late asthmatic response ( LAR ) were randomized in a three‐way crossover study to receive ONO ‐6950 (200 mg) or montelukast (10 mg) or placebo q.d. on days 1–8 of the three treatment periods. Allergen was inhaled on day 7 two hours postdose, and forced expiratory volume in 1 s ( FEV 1 ) was measured for 7 h following challenge. Sputum eosinophils and airway hyperresponsiveness were measured before and after allergen challenge. The primary outcome was the effect of ONO ‐6950 vs placebo on the EAR and LAR . Results Twenty‐five nonsmoking subjects with mild allergic asthma were enrolled and 20 subjects completed all three treatment periods per protocol. ONO ‐6950 was well tolerated. Compared to placebo, ONO ‐6950 significantly attenuated the maximum % fall in FEV 1 and area under the % FEV 1 /time curve during the EAR and LAR asthmatic responses ( P &lt; 0.05) and allergen‐induced sputum eosinophils. There were no significant differences between ONO ‐6950 and montelukast. Conclusions Attenuation of EAR , LAR , and airway inflammation is consistent with cys LT 1 blockade. Whether dual cys LT 1/2 antagonism offers additional benefit for treatment of asthma requires further study.
Abstract 1212: Effect of metformin and insulin-/IGF1-receptor inhibitor combination drug therapy in triple negative breast cancer
Authors: Lei Xue, Laura Camacho, Sushma Kothapalli, Sao Jiralerspong
Journal: Cancer Research (2016)

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor survival outcomes. Chemotherapy is the only approved treatment, as there are no targeted therapies. Metformin is an anti-diabetic drug for Type 2 Diabetes. It has been shown to have anti-tumor effects by lowering serum levels of the mitogen insulin, and by pleiotropic effects on cancer cell signaling pathways. BMS-754807 is a potent and reversible inhibitor of the insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF-1R) family kinases that has been shown to have activity in a subset of TNBC. The aim of this study is to evaluate the hypothesis that the combination of metformin and BMS-754807 is more effective than single drug treatment in TNBC. Experimental design and methods: We treated TNBC cell lines with metformin and BMS-754807 alone and in combination and tested cell viability using MTS assays. Then we used CompuSyn software to analyze the dose-effect of drug combinations for additivity, synergism, or antagonism. We also examined the mechanism by performing Western blots of candidate pathways. Results: 5 out of the 9 cell lines tested (56%) showed synergism of metformin and BMS-754807 in the drug combination assays. Western blots showed significant inhibition of IR/IGF-1R and PI3K/Akt pathways with the drug combination. Conclusion: We conclude that the combination of metformin and BMS-754807 is more effective than single drug in a significant proportion of triple negative breast cancer cell lines. This combination may represent effective targeted therapy for a subset of TNBC. Further studies to evaluate this possibility are underway. Citation Format: Lei Xue, Laura Camacho, Sushma Kothapalli, Sao Jiralerspong. Effect of metformin and insulin-/IGF1-receptor inhibitor combination drug therapy in triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1212.
Impaired Platelet Responses to Thromboxane a2 and Thrombin in Mice Lacking Receptor-Interacting Protein Kinase 3
Authors: Yiwen Zhang, Jian Zhang, Rong Yan, Jie Zhang, Mengxing Chen, Miao Jiang, Zhenyu Li, Changgeng Ruan, Sudan He, Kesheng Dai
Journal: Blood (2014)
Abstract 4808: Identification of a novel compound, MO2455, that induces poly(ADP-ribose) (PAR) accumulation and inhibits the growth of cancer cells <i>in vitro</i> and <i>in vivo</i>
Authors: Tatsu Shimoyama, Takeshi Sawada, Mari Akimoto, Yuka Sasaki, Hiroaki Fujimori, Yoshinobu Ishikawa, Tadashi Okawara, Tetsumi Irie, Takeji Takamura, Kenji Matsuno, Kengo Inoue, Mitsuko Masutani, Fumiaki Koizumi
Journal: Cancer Research (2016)

Abstract Poly (ADP-ribose) chain (PAR) formed by poly (ADP-ribose) polymerase (PARP) is catabolized mainly by poly (ADP-ribose) glycohydrolase (PARG). PARG is emerging as a therapeutic target for cancer, because its inhibition leads to cell death in some kinds of cancer cell lines. In order to obtain small molecules that effectively inhibit PARG protein, an in-house collection of ∼10,000 small molecules were screened for their ability to accumulate the PAR in A549 cells at 5 μM. We identified ∼100 hit compounds. Among them, MO2282 and MO2455 induced the most significant accumulation of PAR. MO2455 is an analogue of MO2282 with improved water-solubility. MO2282 and MO2455 were evaluated in vitro for their ability to inhibit the catalytic activity of PARG. MO2282 and MO2455 showed modest inhibition activities against recombinant rat PARG. They also inhibited the growth of various kinds of cancel cell lines in vitro at an IC50 value of 0.05 - 3.0 μM and showed different spectrum of antitumor activity from conventional anticancer drugs, CDDP, ADM, PTX, and CPT-11. Next, we investigated the growth-inhibitory effect of MO2455 on A549 cells in a xenotransplanted model. A significant anti-tumor activity was observed in mice when treated with MO2455 at doses of 25 mg/kg every two days. Although treatment-related body weight loss was observed in mice treated with MO2455, body weight recovered by day 8. In conclusion, the present data suggest that MO2455 has potential as a cancer drug with different mechanisms of action from conventional anti-cancer drugs. Citation Format: Tatsu Shimoyama, Takeshi Sawada, Mari Akimoto, Yuka Sasaki, Hiroaki Fujimori, Yoshinobu Ishikawa, Tadashi Okawara, Tetsumi Irie, Takeji Takamura, Kenji Matsuno, Kengo Inoue, Mitsuko Masutani, Fumiaki Koizumi. Identification of a novel compound, MO2455, that induces poly(ADP-ribose) (PAR) accumulation and inhibits the growth of cancer cells in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4808.
Comparison Of Minimal Residual Disease As Outcome Predictor For AML Patients In First Complete Remission Undergoing Myeloablative Or Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation
Authors: Roland B. Walter, Boglarka Gyurkocza, Barry E. Storer, John M. Pagel, Sarah A. Buckley, Mohamed L. Sorror, Colleen Delaney, Brent L. Wood, H. Joachim Deeg, Rainer Storb, Frederick R. Appelbaum, Brenda M. Sandmaier
Journal: Blood (2013)
Abstract 3644: Optimization of library construction for massively parallel sequencing using low-input, FFPE-derived DNA without additional PCR amplification
Authors: Aaron R. Thorner, Liuda Ziaugra, Matthew D. Ducar, Ling Lin, Angelica Laing, Haley A. Coleman, Suzanne R. McShane, Andrea Clapp, Rachel R. Paquette, Bruce M. Wollison, Johann Hoeftberger, Neil A. Patel, Samuel S. Hunter, Monica D. Manam, Laura E. MacConaill, William C. Hahn, Matthew L. Meyerson, Paul van Hummelen.
Journal: Cancer Research (2016)

Abstract Massively parallel sequencing (MPS) is increasingly used in the laboratory and clinic to identify genomic factors contributing to tumorigenesis, such as somatic mutations, DNA insertions and deletions, transcriptome and epigenetic changes, and chromosomal abnormalities. Because tumor specimens are often quite limited or are from rare and precious samples, it is necessary to prepare sequencing libraries from minimal amounts of DNA. Indeed, it can be challenging to extract sufficient amounts of starting material from fresh-frozen paraffin embedded (FFPE) samples for library construction, and frequently samples are not processed because they do not reach minimum requirements. Therefore, it is of great importance to improve currently available protocols to process low yield FFPE-derived DNA for MPS. This will allow for the inclusion of more tumor samples to be sequenced per cohort, resulting in increased ability to identify genomic factors involved in tumorigenesis. Here, we optimized the KAPA Library Preparation Kit (Kapa Biosystems, Wilmington, MA) to successfully perform library construction from low-yield FFPE and fresh frozen samples. The kit normally requires an input of at least 100 ng of DNA. However, we were able to modify the protocol to prepare libraries from as little as 10 ng of starting material by optimizing the ratio of adapter:input DNA and SPRI-clean-up, performing low-volume reactions, and using IDT universal blockers during hybrid capture. Additional library enrichment PCR was not required. Library yields were sufficient for downstream hybrid capture and sequencing, and sequencing metrics were comparable to samples that were prepped using the manufacturer's recommendations. Experiments are underway to demonstrate that library complexity remains unchanged. Citation Format: Aaron R. Thorner, Liuda Ziaugra, Matthew D. Ducar, Ling Lin, Angelica Laing, Haley A. Coleman, Suzanne R. McShane, Andrea Clapp, Rachel R. Paquette, Bruce M. Wollison, Johann Hoeftberger, Neil A. Patel, Samuel S. Hunter, Monica D. Manam, Laura E. MacConaill, William C. Hahn, Matthew L. Meyerson, Paul van Hummelen. Optimization of library construction for massively parallel sequencing using low-input, FFPE-derived DNA without additional PCR amplification. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3644.
Abstract 441: Association of interferon inducible genes with tumor immune microenvironment and chemotherapy resistance in high-grade serous epithelial ovarian cancer
Authors: Katrina K. Au, Liliane Meunier, Cécile Le Page, Charles H. Graham, Andrew WB Craig, Timothy Childs, Julie-Ann Francis, Jeremy Squire, Anne-Marie Mes-Masson, Madhuri Koti
Journal: Cancer Research (2016)

Abstract Chemotherapy resistance is a major hurdle in high-grade serous epithelial ovarian cancer (HGSC) management. We previously reported differential expression of interferon inducible genes in pre-treatment tumours from chemoresistant and sensitive HGSC tumors. STAT1 expression was evaluated as a prognostic and predictive biomarker via immunohistochemistry in Phase I (n = 183) and Phase II (n = 550) biomarker validation studies conducted on HGSC tumours accrued from the Terry Fox Research Institute- Canadian Ovarian Experimental Unified Resource (TFRI-COEUR). Tumor STAT1 expression levels significantly correlated with the density of tumor infiltrating CD8+ T lymphocytes in both Phase I and Phase II cohorts. STAT1 expression significantly associated with progression free survival and response to chemotherapy in both Phase I and Phase II validation studies. Significant positive correlation between STAT1 expression levels and intratumoral CD8+ T cell density was observed. Intratumoral CD8+ T cell infiltration did not associate with progression free survival or response to chemotherapy in both cohorts. Interestingly, the prognostic relevance of CD8+ T cell was enhanced in combination with STAT1 in both cohorts. These findings provide evidence that STAT1 as an independent biomarker and a combination of CD8+ T cell infiltration with STAT1 could be novel immune-based prognostic and predictive biomarkers in HGSC. Findings from the current study will aid in patient stratification for novel immunomodulatory therapies for the management of chemotherapy resistance in HGSC. Citation Format: Katrina K. Au, Liliane Meunier, Cécile Le Page, Charles H. Graham, Andrew WB Craig, Timothy Childs, Julie-Ann Francis, Jeremy Squire, Anne-Marie Mes-Masson, Madhuri Koti. Association of interferon inducible genes with tumor immune microenvironment and chemotherapy resistance in high-grade serous epithelial ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 441.
Abstract 4452: Oxdative stress suppresses the expression of 15-hydroxyprostaglandin dehydrogenase via upregulation of DNMT3a/Snail in human colon epithelial cells
Authors: Ja-Young Lee, Jeong-Eun Lee, Hye Kyung Na
Journal: Cancer Research (2016)

Abstract Overproduction of prostaglandin E2 (PGE2) is implicated in pathogenesis of inflammation-associated carcinogenesis. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme that catalyzes the conversion of PGE2 to biologically inactive 15-keto-PGE2 metabolite. 15-PGDH has been considered to be a tumor suppressor as its expression is frequently repressed in human malignancies via hypermethylation of its promoter. In our previous study, oxidative stress caused by Helicobacter pylori infection suppressed the expression of 15-PGDH. Reactive oxygen species (ROS) can induce methylation as well as mutation of genes including those that encode tumor suppressor proteins, thereby contributing to carcinogenesis. This prompted us to investigate whether 15-PGDH expression could be down-regulated by oxidative stress in normal colon epithelial CCD841 cells. When CCD841 cells were treated with H2O2, the expression level of 15-PGDH was significantly reduced in both concentration and time dependent manners. Hydrogen peroxide (300 μM) induced the expression of DNA methyltransferase (DNMT) 3a, which was blocked by an inhibitor of DNMT, 5-Aza-2′-deoxycytidine (5-Aza). The 5-Aza abrogated the down-regulation of 15-PGDH expression induced by H2O2. The antioxidant, N-acetylcysteine (NAC) abrogated the down-regulation of 15-PGDH and upregulation of DNMT 3a expression induced by H2O2. The transcriptional repressor Snail plays a central role in the suppression of 15-PGDH expression. H2O2 treatment also elevated expression of Snail, which was abrogated by NAC and 5-Aza. Taken together, these finding suggest that ROS suppresses the expression of 15-PGDH through hypermethylation of CpG island in the 15-PGDH promoter. Citation Format: Ja-Young Lee, Jeong-Eun Lee, Hye Kyung Na. Oxdative stress suppresses the expression of 15-hydroxyprostaglandin dehydrogenase via upregulation of DNMT3a/Snail in human colon epithelial cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4452.
A novel proteomics biomarker panel as a diagnostic tool for patients with ovarian cancer.
Authors: C. K. Hogdall, E. Fung, I. J. Christensen, L. Nedergaard, S. A. Engelholm, A. L. Petri, S. Risum, L. Lundvall, A. T. Pedersen, E. V. Hogdall
Journal: Journal of Clinical Oncology (2010)

5061 Background: The frequency and poor prognosis of ovarian cancer (OC) emphasizes the need for better markers usable for both diagnostics and screening. Instead of a single marker could the wanted marker be the correct combination of more markers, which supplement each other. The serum proteomic biomarkers APOA1, TT, HEPC, ITIH4, TrF, CTAP3 and B2M have previously been found to be differently expressed in OC patients. The aims were to determine if these proteomic biomarkers alone or in combination with age and serum CA125, would be helpful in further triaging women according to likelihood that their mass was malignant. Methods: From a prospective collection of women from the Danish Pelvic Mass study we included 144 patients diagnosed with OC, 40 with a borderline and 469 with a benign ovarian tumor. All were candidates for surgery because of a suspicious pelvic mass. Proteominer technique and chromatographic SELDI-TOF-MS protocols were used to generate quantitative measurements of the proteomic biomarkers. A Danish Index (DK-Index) based on the proteomic data, age and CA125 was developed using a logistic regression model. Results: Area under the ROC curve for the DK-Index was 0.956 for OC vs. benign and borderline. At 90% specificity (SP) were the sensitivities (SN) 90% for all OC stages, 66% for FIGO stages I+II and 97% for stages III+IV. At 95% SP was SN 74% for all OC stages, 40% for stages I+II and 85% for stages III+IV. Demanding 99% SP was SN 53% for all OC stages, 23% for stages I+II and 64% for stages III+IV. The improved prediction by the DK-index compared to CA125 used alone is illustrated by ROC curves. Conclusions: All the proteomic biomarkers alone and in combination significantly discriminate between OC and benign or borderline tumors. Very high predictive values could be achieved in the DK-index. The DK-index deserves external validation in future studies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Vermillion, Inc. Vermillion, Inc. Vermillion, Inc.
Front-Line Treatment with Ofatumumab for Older Unfit Patients with Chronic Lymphocytic Leukemia
Authors: Candida Vitale, Maria Ciccone, Christina Hinojosa, Michael Keating, Naveen Pemmaraju, Susan O'Brien, William Wierda, Deborah A Thomas, Gautam Borthakur, Maro Ohanian, Jan A. Burger, Alessandra Ferrajoli
Journal: Blood (2015)
Case 20-1979
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, H. Franklin Bunn, Karl H. Proppe
Journal: New England Journal of Medicine (1979)

Presentation of CaseA 34-year-old man was admitted to the Eastern Maine Medical Center because of abdominal pain.He was well until four months earlier, when he was admitted to another hospital because of pneumonia. The hematocrit was 65 per cent. He was discharged after resolution of the pneumonia and a phlebotomy. Three months before admission he was referred to a hematologist. On examination the blood pressure was 140/90 mm Hg; the edge of the liver was palpable, and the spleen and kidneys were not felt. The urine was normal. The hematocrit was 67.3 per cent, and the hemoglobin 21.7 . . .
Evaluation of Alternative <i>In Vivo</i> Drug Screening Methodology: A Single Mouse Analysis
Authors: Brendan Murphy, Han Yin, John M. Maris, E. Anders Kolb, Richard Gorlick, C. Patrick Reynolds, Min H. Kang, Stephen T. Keir, Raushan T. Kurmasheva, Igor Dvorchik, Jianrong Wu, Catherine A. Billups, Nana Boateng, Malcolm A. Smith, Richard B. Lock, Peter J. Houghton
Journal: Cancer Research (2016)

Abstract Traditional approaches to evaluating antitumor agents using human tumor xenograft models have generally used cohorts of 8 to 10 mice against a limited panel of tumor models. An alternative approach is to use fewer animals per tumor line, allowing a greater number of models that capture greater molecular/genetic heterogeneity of the cancer type. We retrospectively analyzed 67 agents evaluated by the Pediatric Preclinical Testing Program to determine whether a single mouse, chosen randomly from each group of a study, predicted the median response for groups of mice using 83 xenograft models. The individual tumor response from a randomly chosen mouse was compared with the group median response using established response criteria. A total of 2,134 comparisons were made. The single tumor response accurately predicted the group median response in 1,604 comparisons (75.16%). The mean tumor response correct prediction rate for 1,000 single mouse random samples was 78.09%. Models had a range for correct prediction (60%–87.5%). Allowing for misprediction of ± one response category, the overall mean correct single mouse prediction rate was 95.28%, and predicted overall objective response rates for group data in 66 of 67 drug studies. For molecularly targeted agents, occasional exceptional responder models were identified and the activity of that agent confirmed in additional models with the same genotype. Assuming that large treatment effects are targeted, this alternate experimental design has similar predictive value as traditional approaches, allowing for far greater numbers of models to be used that more fully encompass the heterogeneity of disease types. Cancer Res; 76(19); 5798–809. ©2016 AACR.
Abstract 743: Tyrosine kinase discoidin domain receptor-1 (DDR1) regulates cytotoxicity of recombinant immunotoxin for cancer therapy
Authors: Fatima Ali-Rahmani, David Fitzgerald, Scott Martin, Paresma Patel, Marco Prunotto, Pinar Ormanoglu, Craig Thomas, Ira Pastan
Journal: Cancer Research (2016)

Abstract Discoidin domain receptor 1 (DDR1) is a collagen-activated tyrosine kinase that facilitates cell adhesion, migration, proliferation and matrix remodeling. The collagen/DDR1 axis is also thought to modulate tumor-stromal interaction and potentially affects tumor response to therapy. Mesothelin is a cell-surface protein over-expressed in several human cancers including mesothelioma, ovarian, lung, breast, and pancreatic cancers with limited expression on normal cells. RG7787 is a clinically optimized recombinant immunotoxin (RIT) consisting of a humanized anti-mesothelin Fab fused to domain III of Pseudomonas exotoxin A in which immunogenic B cell epitopes are silenced. To enhance therapeutic efficacy of RITs we conducted a kinome RNAi sensitization screen which identified DDR1 as a potential target. We hypothesized that DDR1 regulates RIT activity and its inhibition might enhance cell killing by RG7787. Knockdown of DDR1 by siRNA or treatment with inhibitor, ‘7rh’, greatly enhanced the cytotoxic activity of RG7787 in several cancer cell lines. Investigation into the mechanism of action showed DDR1 silencing was associated with a decrease in several ribosomal proteins and enhanced inhibition of protein synthesis. Induction of DDR1 expression or stimulation of DDR1 activity by collagen protected cancer cells from RG7787 killing, while DDR1 inhibition enhanced killing by RG7787. Moreover, the combination of immunotoxin and DDR1 inhibitor caused significantly more shrinkage of epithelial A431/H9 and pancreatic KLM1 tumor xenografts than either agent alone. These data demonstrate that DDR1 has a critical role in modulating immunotoxin activity. Inhibition of DDR1 represents a novel strategy to enhance therapeutic efficacy of RITs targeting mesothelin-expressing cancers. Citation Format: Fatima Ali-Rahmani, David Fitzgerald, Scott Martin, Paresma Patel, Marco Prunotto, Pinar Ormanoglu, Craig Thomas, Ira Pastan. Tyrosine kinase discoidin domain receptor-1 (DDR1) regulates cytotoxicity of recombinant immunotoxin for cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 743.