tbuckley/cabot-search huggingface dataset:
Abstract IA13: Mechanisms of chromatin regulation by the EWS-FLI1 fusion protein in Ewing sarcoma
Authors: Miguel N. Rivera
Journal: Cancer Research (2016)

Abstract Our laboratory uses genomic approaches to identify and characterize abnormalities in gene regulation in cancer. Large scale sequencing studies have shown that transcriptional regulators, including transcription factors, chromatin modifiers and histones, are frequently altered in cancer and may thus contribute to transformation through widespread changes in gene expression programs. This is particularly evident in pediatric tumors, which have low numbers of recurrent genetic events and where alterations in a transcriptional regulator may be the sole genetic “driver”. In the case of Ewing sarcoma, the second most common pediatric bone cancer, translocations involving EWS and the ETS transcription factor FLI1 generate a fusion protein that has been shown to be essential for the growth and survival of tumor cells. We recently used genome-wide chromatin profiling to study the mechanisms of action of EWS-FLI1 and found that it utilizes two distinct patterns of chromatin remodeling to either activate or repress enhancers. At repeats of the GGAA ETS recognition motif, which are poorly conserved in evolution, EWS-FLI1 multimers induce chromatin opening and create active enhancers de novo. These repeat enhancers can loop to physically interact with target promoters, as demonstrated by chromosome conformation capture assays. In contrast, at conserved enhancers containing canonical ETS motifs, EWS-FLI1 displaces wild-type ETS transcription factors and leads to significant reductions in enhancer activity. These different chromatin remodeling mechanisms are associated with the repression of tumor suppressors and mesenchymal lineage genes and the activation of oncogenes and potential therapeutic targets. Our studies thus illustrate how chromatin profiling can reveal mechanisms of chromatin regulation that are critical in establishing an oncogenic regulatory program in cancer. Citation Format: Miguel N. Rivera. Mechanisms of chromatin regulation by the EWS-FLI1 fusion protein in Ewing sarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA13.
Sensitivity, Specificity, PPV, and NPV for Predictive Biomarkers
Authors: Richard Simon
Journal: JNCI Journal of the National Cancer Institute (2015)

Molecularly targeted cancer drugs are often developed with companion diagnostics that attempt to identify which patients will have better outcome on the new drug than the control regimen. Such predictive biomarkers are playing an increasingly important role in precision oncology. For diagnostic tests, sensitivity, specificity, positive predictive value, and negative predictive are usually used as performance measures. This paper discusses these indices for predictive biomarkers, provides methods for their calculation with survival or response endpoints, and describes assumptions involved in their use.
Low level of response to alcohol as a predictor of future alcoholism
Authors: M A Schuckit
Journal: American Journal of Psychiatry (1994)

As part of a search for measurable attributes of an individual that might be related to the risk of alcoholism, the author's group previously compared 227 sons of alcoholics and 227 matched comparison subjects at the age of about 20 years. Forty percent of the men at high risk for alcoholism and less than 10% of the comparison subjects demonstrated a low intensity of response to alcohol challenge. This article reports the results of the follow-up of the first half of this study group almost a decade later.Of the men who had been tested at about age 20, 223 were about age 30 at this evaluation, which included personal and resource-person interviews, record searches, urine toxicology screens, and blood level markers of drinking.A low level of response to alcohol at age 20 was associated with a fourfold greater likelihood of future alcoholism in both the sons of alcoholics and the comparison subjects. Fifty-six percent of the sons of alcoholics with the lesser alcohol response developed alcoholism during the subsequent decade, compared to 14% of the men in this group who had highly sensitive alcohol responses. Neither family history of alcoholism nor response to alcohol predicted any other psychiatric diagnoses over the subsequent decade, and neither was a significant predictor of any other substance use disorder.In a heavy-drinking society, a lower sensitivity to modest doses of alcohol is associated with a significant increase in the risk of future alcoholism, perhaps through increasing the chances that a person will drink more heavily and more often.
Connective-Tissue Disease, Antibodies to Ribonucleoprotein, and Congenital Heart Block
Authors: James S. Scott, Peter J. Maddison, Pamela V. Taylor, Eva Esscher, Olive Scott, R. Paul Skinner
Journal: New England Journal of Medicine (1983)

The relation between congenital heart block and maternal connective-tissue disease was studied by antibody screening of serum samples obtained in connection with 45 cases of isolated congenital complete heart block. Serum was available from 41 mothers (17 who had connective-tissue disease and 24 who were healthy) and 21 children. Thirty-four mothers had antibody to a soluble tissue ribonucleoprotein antigen called Ro(SS-A), which was identified by immunodiffusion. Anti-Ro(SS-A) was found in seven of eight serum samples collected from affected children when they were less than three months old but in none of 13 samples obtained when these children were older. It appears that maternal anti-Ro(SS-A) antibody crosses the placenta and is a marker for risk of congenital complete heart block; its absence from maternal serum suggests that a child is unlikely to be affected. Anti-Ro(SS-A) or a related antibody is probably involved in the pathogenesis of congenital complete heart block.
Abstract B37: Detection of sarcoma circulating tumor cells using a size based microfiltration device
Authors: Masanori Hayashi, Peixuan Zhu, Catherine M. Albert, Diana Steppan, Gregory McCarty, Kyle W. Jackson, Cha-Mei Tang, David M. Loeb
Journal: Cancer Research (2016)

Abstract The inability to effectively treat hematogenous metastasis remains the largest challenge of sarcoma therapy. The ability to isolate, quantify, and study circulating tumor cells (CTC) in sarcomas has the potential to enhance our understanding of the biology of metastasis, altering the way we treat patients with high grade sarcomas. Using a size based filtration device, CellSieve™, we were able to successfully identify and quantify CTC in a metastatic xenograft model as well as in blood samples from patients with high grade sarcomas. In mice, we utilized our orthotopic implantation/amputation model of metastasis. Using a TdTomato-expressing Ewing sarcoma cell line and a cocktail of fluorescently labeled antibodies to vimentin and CD45, we were able to detect both CTC and circulating tumor clusters (CTCL) in mice with growing tumors and with metastatic disease, but not in mice immediately post-amputation. These experiments were augmented with samples collected from patients with high grade sarcomas. In 18 samples from 15 patients, we were able to identify both CTC and CTCL. Furthermore, we were also able to validate the presence of CTC by PCR amplification of sarcoma-associated chromosomal translocations. Future work will use this system to explore the biology of sarcoma metastasis by studying genetic, transcriptional, and epigenetic characteristics of CTC and CTCL and comparing these cells to those in the bulk primary tumor. We will also further explore the possibility that CTC and/or CTCL might serve as a biomarker of disease burden, response to treatment, or metastatic risk. Citation Format: Masanori Hayashi, Peixuan Zhu, Catherine M. Albert, Diana Steppan, Gregory McCarty, Kyle W. Jackson, Cha-Mei Tang, David M. Loeb. Detection of sarcoma circulating tumor cells using a size based microfiltration device. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B37.
Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer
Authors: David Hong, Jeffrey Infante, Filip Janku, Suzanne Jones, Ly M. Nguyen, Howard A. Burris, Aung Naing, Todd M. Bauer, Sarina Piha-Paul, Faye M. Johnson, Razelle Kurzrock, Lisa Golden, Scott Hynes, Ji Lin, Aimee Bence Lin, Johanna Bendell
Journal: Journal of Clinical Oncology (2016)

Purpose The primary objective was to determine safety, toxicity, and a recommended phase II dose regimen of LY2606368, an inhibitor of checkpoint kinase 1, as monotherapy. Patients and Methods This phase I, nonrandomized, open-label, dose-escalation trial used a 3 + 3 dose-escalation scheme and included patients with advanced solid tumors. Intravenous LY2606368 was dose escalated from 10 to 50 mg/m 2 on schedule 1 (days 1 to 3 every 14 days) or from 40 to 130 mg/m 2 on schedule 2 (day 1 every 14 days). Safety measures and pharmacokinetics were assessed, and pharmacodynamics were measured in blood, hair follicles, and circulating tumor cells. Results Forty-five patients were treated; seven experienced dose-limiting toxicities (all hematologic). The maximum-tolerated doses (MTDs) were 40 mg/m 2 (schedule 1) and 105 mg/m 2 (schedule 2). The most common related grade 3 or 4 treatment-emergent adverse events were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. Grade 4 neutropenia occurred in 73.3% of patients and was transient (typically &lt; 5 days). Febrile neutropenia incidence was low (7%). The LY2606368 exposure over the first 72 hours (area under the curve from 0 to 72 hours) at the MTD for each schedule coincided with the exposure in mouse xenografts that resulted in maximal tumor responses. Minor intra- and intercycle accumulation of LY2606368 was observed at the MTDs for both schedules. Two patients (4.4%) had a partial response; one had squamous cell carcinoma (SCC) of the anus and one had SCC of the head and neck. Fifteen patients (33.3%) had a best overall response of stable disease (range, 1.2 to 6.7 months), six of whom had SCC. Conclusion An LY2606368 dose of 105 mg/m 2 once every 14 days is being evaluated as the recommended phase II dose in dose-expansion cohorts for patients with SCC.
Roentgenographic Studies of the Gastrointestinal Tract Following Section of the Vagus Nerves for Peptic Ulcer
Authors: Max Ritvo, Irving A. Shauffer
Journal: New England Journal of Medicine (1948)

THERE is widespread interest in the surgical treatment of chronic, intractable peptic ulcer by section of the vagus nerves. Dragstedt and his co-workers1 in Chicago were the first to employ the procedure systematically, and since their publication of the results of supradiaphragmatic vagus resection in 2 patients in 1943 they have reported progressively larger series of cases, which reached a total of 90 in 1946.1,2 Moore3 has recorded 40 cases. Grimson and Ruffin4 5 6 have discussed a series of 57 cases. Previous reports of the findings in transthoracic, bilateral vagus-nerve resection have described changes in size, shape, motility and emptying of . . .
A Prospective Trial of D-Penicillamine in Primary Biliary Cirrhosis
Authors: Daniel S. Matloff, Elliott Alpert, Robert H. Resnick, Marshall M. Kaplan
Journal: New England Journal of Medicine (1982)

We evaluated D-penicillamine in the treatment of primary biliary cirrhosis. In a prospective double-blind trial, 26 patients received D-penicillamine (250 mg four times a day), and 26 received an identical placebo. Although the desired urinary excretion of copper was achieved in patients taking D-penicillamine, there was no improvement in survival or symptoms after 28 months. Serum bilirubin and alkaline phosphatase increased equally in both groups. Alanine and aspartate aminotransferases were lower in the D-penicillamine group, but serum albumin was also lower in this group. Liver histology worsened equally in both groups. Major side effects, some appearing more than 24 months after the start of treatment, occurred in 31 per cent of the patients receiving D-penicillamine. Less serious side effects occurred in an additional 46 per cent. We conclude that D-penicillamine at the dosage we used is not effective in the treatment of primary biliary cirrhosis and is associated with a high incidence of serious side effects.
Production of Antigens Associated With Epstein-Barr Virus in Experimentally Infected Lymphoblastoid Cell Lines&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Gary R. Pearson, Gertrude Henle, Werner Henle
Journal: JNCI Journal of the National Cancer Institute (1971)

Three lymphoblastoid cell lines responded in different ways to experimental infection by Epstein-Barr virus (EBV). The RPMI-6410 cell line yielded early antigen (EA)-producing cells but no membrane antigen (MA) or viral capsid antigen (VCA)-positive cells. All 3 groups of antigens were demonstrated in infected Raji and SKL-1 cultures. The SKL-1 cell line appeared to be the most permissive with respect to EBV infection, yielding the highest percentages of VCA- and MA-positive cells. In both infected SKL-1 and Raji cultures, EA synthesis became detectable within 6–8 hours after infection, whereas MA and VCA production were not evident until about 4 hours later. Neutralizing antibodies were removed from a high-titered serum by absorption with viable MA-positive but not MA-negative lymphoblastoid cells—further evidence that MA represents viral envelope components inserted in the cell membrane.
Phase II trial of GTX chemotherapy in metastatic pancreatic cancer
Authors: R. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz
Journal: Journal of Clinical Oncology (2009)

4623 Background: Preclinical studies suggest synergy between gemcitabine (G), docetaxel (T) and capecitabine (X). This GTX regimen was designed to inhibit MEK-ERK phosphorylation and increase BAX and BAK and also decrease BCL-2 in pancreatic cancer cell lines. Based on these findings, we pursued a prospective clinical trial evaluating the activity of GTX in previously untreated patients with metastatic pancreatic cancer. Methods: Patients with histologically confirmed metastatic adenocarcinoma of the pancreas, median age 60, 63% male, ECOG PS 0–2, received capecitabine 1500mg/m2/day total orally in divided doses, days 1 thru 14, gemcitabine 750mg/m2 IV over 75 minutes followed by docetaxel 30mg/m2 IV on days 4 and 11 on a 21 day cycle. Scans were completed every 9 to 10 weeks to assess for tumor response by RECIST criteria. Treatment was continued until evidence of disease progression, intolerable toxicity, surgery or a delay in treatment greater than 6 weeks. The primary endpoint was response rate. Secondary endpoints were overall survival (OS) measured as time from start of GTX to death, time to treatment failure (TTF) measured as time from start of GTX to disease progression or other reason for a halt in therapy. Results: Forty-three patients were enrolled at two centers between May 2004 and January 2007. Forty-one patients were eligible for assessment by intent to treat analysis. 35 patients (85%) had liver metastases. 9 patients (21.9%) had partial responses and 17 patients (41.5%) had stable disease. The one year survival rate was 56%. Two year survival rate was 14.6%. The median OS was 14.5 months. The median TTF was 6.9 months. Grade 3 and 4 toxicities included leukopenia (31.6%), neutropenia (29.2%), thrombocytopenia (12.2%), infection (12.5%), and mucositis (7.5%). Conclusions: The combination of gemcitabine, docetaxel, and capecitabine has activity in metastatic pancreatic cancer with a median survival over 1 year. A randomized phase III trial is in planning. [Table: see text]
Linkage of Dominant Hereditary Spherocytosis to the Gene for the Erythrocyte Membrane-Skeleton Protein Ankyrin
Authors: Fernando F. Costa, Peter Agre, Paul C. Watkins, John C. Winkelmann, Tang K. Tang, Katherine M. John, Samuel E. Lux, Bernard G. Forget
Journal: New England Journal of Medicine (1990)

HEREDITARY spherocytosis is a heterogeneous disorder characterized by hemolytic anemia, spheroidal red cells, and increased osmotic fragility of erythrocytes. The majority of the patients have an a...
A phase II trial of gemcitabine (gem) &amp; cisplatin (cis) in advanced esophageal cancer (AEC)
Authors: P. Scullin, J. Millar, D. Dunlop, A. Price, D. Cameron, H. Phillips, L. Wall, A. Morrison, M. Eatock
Journal: Journal of Clinical Oncology (2004)

4034 Background: Current cisplatin based regimens for the treatment of AEC are disappointing with response rates between 25 and 45% and median survival of around 9 months. Gemcitabine (Gem) is active against a range of tumour types. Preclinical models suggest synergistic cytotoxic activity for Gem and Cisplatin (Cis), and in phase II trials this combination is active in NSCLC, head & neck cancer and bladder cancer. Methods: This non-randomised open label phase II study evaluated the efficacy and safety of Gem 1250 mg/m2 on days 1, 8, and Cis 75 mg/m2 on day 1 every 21 days in AEC. Patients with; histologically proven, bidimensionally measurable, locally advanced or metastatic oesophageal carcinoma (squamous or adenocarcinoma), aged >18yrs, with a performance status 0–2 and life expectancy >3 months, and able to give informed consent were eligible. Interim review after 19 patients were enrolled suggested that this was unacceptably toxic, subsequent patients were treated with Gem 1000mg/m2 and Cis 75mg/m2. Response was assessed using WHO criteria. Results: Between March 2000 and August 2003, 42 patients ( M:F = 34:8), median age 60 years (range 37 – 79 years) were enrolled. Median number of cycles = 4 (range 1 – 6). 5 patients were non-evaluable for response. 4 patients had a complete radiologic response (9.5%), 15 pts had a partial response (36%) giving overall response rate (ORR) of 45%. In total 175 cycles were administered. Grade 3/4 haematological toxicity in all cycles was; neutropenia – 25%; thrombocytopenia – 9%, there was only 1 episode of neutropenic sepsis and no complicated thrombocytopenia. Grade 3/4 non-haematological toxicities were; nausea & vomiting 7 pts (despite 5HT3 antagonist and steroid premedication) and aesthenia 11pts. 4 pts discontinued therapy due to toxicity. Median survival is 13.7 months (95% CI 4.2 – 23.2 months). Conclusions: The combination of gem and cis is an active regimen for the treatment of advanced esophageal cancer. With a gem dose of 1000mg/m2 on day 1 and 8, toxicity is acceptable. The radiological complete response rate, overall response rate and median overall survival of 13.7 months suggest that this regimen is worthy of further study. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly
A Decade's Experience in the Operation of a Group Medical-Care Organization
Authors: Seymour Etkin
Journal: New England Journal of Medicine (1949)

THE National Health Assembly, which met last summer in Washington, D. C., reached agreement on everything except the question of national compulsory health insurance. Among the subjects agreed on was the proposal that voluntary prepayment was a sound method for financing health services.Ten years ago such an agreement would have been impossible. At that time a storm raged within and without the medical profession over the question of prepaid health programs. The focal point of the storm was Group Health Association of Washington, D. C., a medical-care organization operating on the principles of group medical practice and the prepaid . . .
Abstract 2188: Different gene expression between men and women patients with lung adenoarcinoma reveals enrichment of immune gene sets
Authors: Joseph A. Pinto, Jhajaira M. Araujo, Alexandra Prado, Claudio Flores, Nadezhda K. Cardenas, Mayer Zaharia, Gustavo Sarria, Alfredo Aguilar, Silvia Neciosup, Henry Gomez, Luis Mas
Journal: Cancer Research (2015)

Abstract INTRODUCTION: There is different susceptibility to DNA damage induced by tobacco smoking between women and men. In despite of the great advances in the knowledge of the genomic landscape of lung cancer, is not explored the molecular differences between man and women. Our aim was to evaluate differentially enriched gene sets between the two genders. METHODS: We evaluated 03 public databases containing gene expression values from lung adenocarcinoma patients: GSE50081 (HG-U133_Plus_2; n = 181 samples), GSE47115 (Illumina HumanHT-12 WG-DASL V4.0 R2; n = 46 samples), GSE10072 (HG-U133A; n = 107 samples). We perform the Gene Set Enrichment Analysis (GSEA) to find differences between the genders. Each dataset was analyzed individually and was divided in cohorts of smokers and non-smokers (and healthy tissues by smoking status when it was included in the dataset). Cases with unknown smoking status and former smokers were excluded from the analysis. We use the Gene Ontology biological process terms to find similar enriched pathways between cohorts. We consider enriched process with statistical differences (p&amp;lt;0.05) or trends (P&amp;lt;0.08) in at least a cohort. RESULTS: The analysis did show immune genes enrichment in women such as cytokine production, defense response to bacteria and response to other organisms. In another hand, regulation of JNK and MAPKKK cascades was enriched in tumors and healthy tissues from non-smokers women. In men, the oxidoreductase activity acting on sulfur group of donors was enriched in smoking men. CONCLUSION: There are differences between tumors from women and men that should be deeply explored. Citation Format: Joseph A. Pinto, Jhajaira M. Araujo, Alexandra Prado, Claudio Flores, Nadezhda K. Cardenas, Mayer Zaharia, Gustavo Sarria, Alfredo Aguilar, Silvia Neciosup, Henry Gomez, Luis Mas. Different gene expression between men and women patients with lung adenoarcinoma reveals enrichment of immune gene sets. [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 2188. doi:10.1158/1538-7445.AM2015-2188
Effect of genetic polymorphisms on erlotinib pharmacokinetics and toxicity in patients with non-small-cell lung cancer
Authors: Hiroto Kishi, Chihiro Endo, Ji-ichiro Sasaki, Sho Saeki, Norihiro Iwamoto, Megumi Inaba, Takeshi Isobe, Hirotsugu Kourogi, Hideyuki Saito, Akinobu Hamada
Journal: Annals of Oncology (2015)