tbuckley/cabot-search huggingface dataset:
Stomach-Specific Activation of Oncogenic KRAS and STAT3-Dependent Inflammation Cooperatively Promote Gastric Tumorigenesis in a Preclinical Model
Authors: Stefan Thiem, Moritz F. Eissmann, Joachim Elzer, Anna Jonas, Tracy L. Putoczki, Ashleigh Poh, Paul Nguyen, Adele Preaudet, Dustin Flanagan, Elizabeth Vincan, Paul Waring, Michael Buchert, Andrew Jarnicki, Matthias Ernst
Journal: Cancer Research (2016)

Abstract About 5% to 10% of human gastric tumors harbor oncogenic mutations in the KRAS pathway, but their presence alone is often insufficient for inducing gastric tumorigenesis, suggesting a requirement for additional mutagenic events or microenvironmental stimuli, including inflammation. Assessing the contribution of such events in preclinical mouse models requires Cre recombinase–mediated conditional gene expression in stem or progenitor cells of normal and transformed gastric epithelium. We therefore constructed a bacterial artificial chromosome containing transgene (Tg), comprising the regulatory elements of the trefoil factor 1 (Tff1) gene and the tamoxifen-inducible Cre recombinase (CreERT2)–coding sequence. The resulting Tg(Tff1-CreERT2) mice were crossed with mice harboring conditional oncogenic mutations in Kras or Braf. The administration of tamoxifen to the resulting adult Tg(Tff1-CreERT2);KrasLSL-G12D/+ and Tg(Tff1-CreERT2);BrafLSL-V600E/+ mice resulted in gastric metaplasia, inflammation, and adenoma development, characterized by excessive STAT3 activity. To assess the contribution of STAT3 to the spontaneously developing gastric adenomas in gp130F/F mice, which carry a knockin mutation in the Il6 signal transducer (Il6st), we generated Tg(Tff1-CreERT2);Stat3fl/fl;gp130F/F mice that also harbor a conditional Stat3 knockout allele and found that tamoxifen administration conferred a significant reduction in their tumor burden. Conversely, excessive Kras activity in Tg(Tff1-CreERT2);KrasLSL-G12D/+;gp130F/F mice promoted more extensive gastric inflammation, metaplastic transformation, and tumorigenesis than observed in Tg(Tff1-CreERT2);KrasLSL-G12D/+ mice. Collectively, our findings demonstrate that advanced gastric tumorigenesis requires oncogenic KRAS or BRAF in concert with aberrant STAT3 activation in epithelial precursor cells of the glandular stomach, providing a new conditional model of gastric cancer in which to investigate candidate therapeutic targets and treatment strategies. Cancer Res; 76(8); 2277–87. ©2016 AACR.
Sequential Morphologic Changes During Methapyrilene-Induced Hepatocellular Carcinogenesis in Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN4"&gt;4&lt;/xref&gt;
Authors: H M Reznik-Schüller, M Gregg
Journal: JNCI Journal of the National Cancer Institute (1983)

Journal Article Sequential Morphologic Changes During Methapyrilene-Induced Hepatocellular Carcinogenesis in Rats Get access Robert D. Cardiff, Robert D. Cardiff Search for other works by this author on: Oxford Academic PubMed Google Scholar Hildegard M. Reznik-Schüller, Hildegard M. Reznik-Schüller 7 7Address reprint requests to Dr. Reznik-Schuller at Building 37, Room 5B22, National Institutes of Health, Bethesda, Md. 20205. Search for other works by this author on: Oxford Academic PubMed Google Scholar Marybelle Gregg Marybelle Gregg Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 71, Issue 5, November 1983, Pages 1021–1031, https://doi.org/10.1093/jnci/71.5.1021 Published: 01 November 1983 Article history Received: 18 February 1983 Accepted: 03 June 1983 Published: 01 November 1983
Oncogenic genes and their potential role in human malignancy.
Authors: P Lebowitz
Journal: Journal of Clinical Oncology (1983)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1983.1.10.657 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 6668487 Oncogenic genes and their potential role in human malignancy. P LebowitzxP LebowitzSearch for articles by this author https://doi.org/10.1200/JCO.1983.1.10.657 First Page PDF © 1983 by American Society of Clinical Oncology
Phase I/II study of docetaxel (D), gemcitabine (G), Carboplatin (C) in poor prognosis and previously treated patients (pts) with urothelial carcinoma (UTC)
Authors: A. C. Chen, E. Hovey, G. Shelton, J. Fitzsimmons, A. Randall, R. Taub, D. P. Petrylak
Journal: Journal of Clinical Oncology (2004)

4580 Background: Based on single agent activity of D, G, and C in UTC, we evaluated this combination in 2 pt cohorts: Group1 (G1): Chemotherapy-naive pts with at least 1 poor prognostic risk factor (visceral metastases, Karnofsky Performance Status <80%, alkaline phosphatase>normal, weight loss>10% over 6 months, age<60 years, non-transitional cell carcinoma (TCC) histology); Group 2 (G2): prior chemotherapy. Methods: A phase I/II study design assessed 2 dose regimens: Level 1: D 50 mg/m2 and C AUC=5 (AUC=4 for G2) day 1, dexamethasone 8mg bid orally x 3 days, G 800mg/m2 day 1 and 8, repeated every 21 days. Level 2: D 50 mg/m2, C AUC=5 (AUC=4 for G2) day 1; G 800 mg/m2 day 2, and repeated day 8 or 15. Prophylactic colony stimulating factors (CSF) were administered to 4 pts (1 G1, 3 G2) on dose level 2. Results: Pt characteristics: Median age 75 years (range 45–86);13 males, 9 females; 21 TCC, 1 squamous cell. Total cycles administered 118 (median 6, range 1–12). Twenty pts (11 G1, 9 G2) are evaluable for response and 22 for toxicity. Response rate 45% (95% confidence interval 32–78%) with 4 complete (CR) (3 G2 in lymph nodes and adrenal mass; 1 G1 in pelvic mass) and 5 partial responses (3 G1, 2 G2 in lymph nodes, liver, lung, presacral mass). Six pts had stable disease after 3 cycles which progressed by cycle 6. One G1 patient had a CR in liver but progression in bone. Major toxicities: neutropenia: grade 4 16 pts (9 G1, 7 G2), grade 3 5 pts (4 G2, 1 G1); febrile neutropenia 6 pts (2 G1, 4 G2); grade 3 anemia 5 pts (2 G1, 3 G2); grade 3 thrombocytopenia 11 pts (5 G1, 6 G2); grade 3 transaminitis 1 pt; grade 3 or 4 hyperglycemia 1 pt each; grade 3 nausea/vomiting 2 pts; and grade 3 diarrhea 1 pt. Among all pts, intermediate dose G was held in 67/118 cycles (35 of these in G2 pts). Among the 4 pts on level 2 who received prophylactic CSFs, intermediate dose G was held in 14/22 cycles. Intermediate dose G was reduced in 9 pts. No patient died on-study. Conclusions: DGC is active in UTC, with CRs in patients who failed prior chemotherapy. Intermediate dose G was frequently held due to neutropenia, even with the use of prophylactic CSF. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Eli Lilly; Aventis
Activity of oxaliplatin and 5-fluorouracil/folinic acid (FOLFOX2) in elderly patients with simultaneous advanced colon (ACC) and Hormone refractory prostate cancer (HRPC)
Authors: F. Campana, E. Raymond, J. L. Misset, E. Cvitkovic, F. Cvitkovic
Journal: Journal of Clinical Oncology (2004)

8241 Background. There is a likelihood of simultaneous colon and HRPC given the increased actual incidence of both cancers in elderly patients. HRPC has a high prevalence of epigenetic mismatch repair deficiency where oxaliplatin, unlike other alkylators, maintains activity. FOLFOX2 has been show active in HRPC (Droz JP, Ann Oncol 2003). We describe two cases of simultaneous advanced tumors treated with FOLFOX2. Methods. Two chemo-naïve patients with synchronous pathologically documented ACC and HRPC received the FOLFOX2 combination every 2 weeks (85 mg/m2 oxaliplatin with 400 mg/m2 bolus 5FU and 100 mg/m2 folinic acid day 1 followed by 2200 mg/m2 48h continuous infusion 5FU). Tumor response was evaluated clinically by ultrasound, CT-Scan and CEA. PSA was also used to assess the response of prostate cancer. Results. Two patients (pts) (PS 1; age:72 and 74) with measurable liver metastasis (colon cancer), non measurable but symptomatic bone metastasis (prostate cancer), and elevated baseline PSA values (12.5 and 255 ng/ml) were evaluable for toxicity and response. Pt 1 had 8 cycles and PT 2, 6 cycles; Grade 2 anemia, nausea, and weight loss were reported in both pts. Grade 3 asthenia was reported in one pt after 4 cycles. No peripheral neuropathy was reported. FOLFOX2 induced objective responses (60% and 70% tumor regression that lasted 8+ and 6 months) in colon cancer liver metastasis. Responses were associated with >50% sustained decrease in CEA levels in both pts. Chemotherapy was associated with pain relief and significant reductions of PSA values (90% decrease in one pt and normalization in the other). Duration of biological PSA responses was 3 months for one pt with partial PSA response and sustained for 8+ months in the pt with complete PSA response. Conclusion. Our clinical experience suggests that front-line FOLFOX2 chemotherapy is safe and active to control tumor progression of synchronous advanced colon and hormone-refractory prostate cancers in elderly males. No significant financial relationships to disclose.
Circulating tumor cells (CTCs) in metastatic breast cancer: Biological value beyond tumor burden
Authors: M. Cristofanilli, V. Guarneri, V. Valero, H. A. Fritsche, K. R. Broglio, J. M. Reuben, J. Lara, S. Krishnamurthy, G. N. Hortobagyi
Journal: Journal of Clinical Oncology (2006)

615 Background: The detection of circulating tumor cells (CTCs) can predict progression-free (PFS) and overall survival (OS) in patients with metastatic breast cancer (MBC). We evaluated the prognostic significance of baseline CTCs in relation to standard measures of tumor burden. Furthermore, we assessed if the prognostic value of CTCs was related to any particular molecular phenotype. Patients and Methods: One hundred twenty-three consecutive MBC patients (pts) evaluated prospectively between 12/2000 and 5/2005 were included in this analysis. CTCs from 7.5 mL of whole blood were isolated and enumerated using CellSearch system. Prognostic value was determined by analyzing the following factors, baseline level of CTCs (negative: &lt;5 CTCs/7.5 mL; positive: ≥ 5 CTCs/7.5 mL), age (50 yrs&lt;vs. &gt;/=50 yrs), hormonal receptor (HR), Her-2/neu status, metastatic site (visceral vs. non-visceral), Swenerton score, CA27.29 levels, and previous chemotherapy for MBC (none vs. pre-treated), Results: Median age was 52 years (range 24–88) and the median follow-up was 7.7 months (range 0–53.4 months). The median OS for the alive pts was 17.5 months. Fifty-two pts (42%) had positive CTCs and abnormal CA27.29 was detected in 80 pts (66%). The median OS for patients with negative vs. positive CTCs were 28.3 months (range 1.28 - 31.24) and 12.8 months (range 1.71 to 36.83) respectively (p=0.0001). In the multivariable model, HR status, CTCs, and CA27.29 level were the only factors significantly related to OS. CTCs demonstrated the strongest predictor for OS and were associated with 2.53 times the risk of death (p = 0.003). The prognostic value of CTCs was independent of line of treatment, site of recurrence and phenotype of the disease. Conclusions: CTCs demonstrated prognostic value independent of standard measures of tumor burden and phenotypic characteristics of the disease. CTCs are an important marker of tumor biology in metastatic breast cancer. No significant financial relationships to disclose.
Incidence and clinical implications of venous thromboembolism in advanced colorectal cancer patients: Findings from the ‘GISCAD-Alternating schedule‘ study
Authors: M. Mandala, S. Barni, L. Isa, I. Floriani, G. Fornarini, V. Torri, S. Mosconi, M. Marangolo, D. Corsi, R. Labianca
Journal: Journal of Clinical Oncology (2008)

20502 Background: The incidence of venous thromboembolism (VTE), as well as its prognostic role among advanced colorectal cancer (ACC) patients are still not completely understood. Methods: This survey regards a subgroup of patients from the sample enrolled in a randomized phase III study comparing LLV: 100/mg/m2 iv + 5FU: 400 mg/m2 iv bolus + 5FU: 600 mg/m2 22 hr continuous infusion, day 1 and 2 + CPT-11: 180 mg/m2 day 1, administered every 2 weeks 2 months on and 2 months off (ARM A) and the same regimen administered continuously (ARM B), until progression in both arms. Most patients received an oxaliplatin-based chemotherapy as second-line treatment. The occurrence of symptomatic, objectively documented, VTE was collected and its relationship with treatment duration and outcome was assessed using a proportional hazard model with time dependent variables. Results: At the time of this analysis we evaluated data regarding 203 patients from 9 participating centres. At a median follow-up of 57 months 23 (11.3%) patients developed a VTE and 181 (89.2%) died . Twenty-two VTEs occurred during chemotherapy, 1 VTE during follow-up. More VTEs events occurred in the continuous arm as compared to the intermittent arm, although at the time of this analysis the difference is not statistically significant. At a multivariate analysis, accounting for age, disease site and sex, no effect of treatment schedule was observed, while a detrimental effect of VTE occurrence on survival (HR: 1.6; 95% CI: 1.0–2.5, p < 0.05) was detected. Conclusions: These findings suggest for the first time in a randomised trial that the occurrence of VTE may be associated with a reduced overall survival among patients with ACC. VTE should be included as prognostic factor in future clinical trials. No significant financial relationships to disclose.
Can pseudomonas aeruginosa infection change the outecome of bronchectasis
Authors: Snen Houda, Daghfous Hafaoua, Kotti Amina, Saad Soumaya, Kahloul Olfa, Slim Leila, Tritar Fatma
Journal: European Respiratory Journal (2012)

Background:  Bronchiectasis patients are susceptible to infection with p seudomonas aeruginosa  (PA). Isolation of PA is associated with increased severity of disease, greater airflow obstruction and poorer quality of life. It is not known whether infection by PA is a marker of disease severity or contributes to disease progression.  Aim:  Determine frequency, clinical, biologic, manegment and outcome of PA infection complicated bronchectasis.  Patients and Methods:  Between 2005 - 2011, 24 PA infection occurred in patients with bronchectasis were retrospectively enrolled in the study.  Resultats:  The mean age of patients (13 women and 11 men) was 42 years (16-65 years).Twenty one patients have diffuse and bilateral bronchectasis. PA infection reveals bronchectasis in 3 cases (13%). Clinical manifestations included: acute respiratory failure (n= 15), fatal sepsis (n=1, increased suptum (n= 24) and fever (n=20). PA strain was isolated from suptum in 23 cases and from bronchial alveolar fluid in 1 case. All patients received continuous 2 antibiotics for more than 14 days: ceftazidin + aminosid or quinolone (96%) and imipenem + aminoside (4%). Following intravenous antibiotics, PA was eradicated in 22 cases and 2 patient was colonized with PA. Long term outcome complications were involved: chronic respiratory failure (12,5%), recurrent PA (12,5%) and Hemophilus perinfection (12,5%).  Conclusion:   Pseudomonas aeruginosa  lung infection in patients with bronchiectasis is associated with more severe disease and a higher utilization of health-care resources.
Abstract 182: Class I Histone Deacetylase Inhibition Represses the Upregulation of Sodium-Calcium Exchanger Expression in Cardiac Hypertrophy
Authors: Santhosh K Mani, Olga Chernysh, Mona S Li, Ludivine Renaud, Michael G Janech, Donald R Menick
Journal: Circulation Research (2012)

Background: Histone deacetylases (HDACs) play an important role in the alteration of gene expression during cardiac hypertrophy and failure. Our previous study demonstrated that acetylated Nkx2.5 is associated with the Class I/II HDAC complex, HDAC5/1/2 at the Ncx1 promoter, and deacetylated Nkx2.5 is associated with the transcriptional activator and histone acetylase, p300 in a mutually exclusive manner. Inhibition of HDACs by the Class I/II inhibitor, trichostatin A (TSA) prevents deacetylation of Nkx2.5 and recruitment of p300 to the Ncx1 promoter, thereby repressing its upregulation. Objective: To assess the specific roles of HDAC1, 2 and 5 in the regulation of Ncx1 gene expression and determine the specific Nkx2.5 lysine(s) undergoing acetylation or deacetylation, which mediates Ncx1 upregulation. Results: Treatment of isolated adult cardiomyocytes with the selective class I HDAC inhibitor, BML210, prevented alpha- and beta-adrenergic stimulated upregulation of Ncx1 expression, whereas treatment with the specific class II HDAC inhibitor, dPAHA did not. Interestingly, the HDAC5 knockout prevented NCX1 upregulation after 72 hr trans-aortic constriction (TAC) in mice. In order to determine which Nkx2.5 lysine(s) is deacetylated by HDAC1/2, we performed mass spectrometry analysis. The Nkx2.5 gene contains 15 lysine moieties, and LC-MS/MS analysis demonstrates that Nkx2.5 is acetylated on two conserved lysine residues. Conclusion: Class I HDAC activity is required for Ncx1 expression but not class II HDAC activity (HDAC5). However, the loss of HDAC5 prevents Ncx1 upregulation because it may act as a scaffold to recruit the factors required for Ncx1 promoter activation. These results suggest that HDAC inhibition may represent a novel therapeutic modality for hypertrophy and heart failure.
Factors predicting favorable outcome following autologous stem cell transplantation for primary refractory or relapsed Hodgkin’s disease: A prognostic model based on 20 year follow up
Authors: N. S. Majhail, D. J. Weisdorf, T. E. Defor, J. S. Miller, P. B. McGlave, A. Slungaard, M. Arora, N. K. Ramsay, P. J. Orchard, M. L. Macmillan, L. J. Burns
Journal: Journal of Clinical Oncology (2005)

6659 Background: Autologous stem cell transplant (ASCT) has become standard therapy for primary refractory (PR REF) or relapsed (REL) Hodgkin’s disease (HD); however more than half of these patients eventually relapse and die of HD. We studied long term outcome and evaluated factors influencing progression free survival (PFS) following ASCT for HD. Methods: Between 1985 and 2003, 141 patients with PR REF or REL HD underwent ASCT at our institution at a median of 25 (range, 7–220) months from diagnosis. Median age at ASCT was 30 (range, 7–60) years. 21 (15%) patients had PR REF and 120 (85%) had REL HD. Results: 68 (48%) patients are alive and disease free at a median 6.3 (range, 0.5–20) years follow up. Probability of PFS at 5 and 10 years was 41% (95% CI; 32–50%) and 38% (95% CI; 29–47%) and that of overall survival was 51% (95% CI; 42–60%) and 43% (95% CI; 33–53%) respectively. Transplant related mortality at 100 days was 1.4%; 8 (6%) patients developed MDS/AML at 1 to 6 years following ASCT. In multiple regression analysis, chemoresistant disease at pre-ASCT relapse (RR 2.9, 95% CI; 1.7–5.0, P<0.01), presence of B-symptoms at pre-ASCT relapse (RR 2.1, 95% CI; 1.3–3.4, P<0.01) and presence of residual disease at the time of ASCT (RR 2.3, 95%CI; 1.1–4.8, P=0.03) were independently predictive of poor PFS. Testing only the strongest two adverse prognostic factors (chemoresistant disease and B-symptoms at pre-ASCT relapse), PFS at 10 years was 60% (95% CI; 45–75%) with 0 adverse factors (low-risk group) compared to 28% (95% CI; 13–43%) with 1 (intermediate-risk group) and 0% with 2 (high-risk group) adverse factors (P<0.01). Of 24 patients alive beyond 10 years, 22 (92%) remain disease free. Conclusions: ASCT is associated with durable PFS in patients with PR REF or REL HD. Using a simple prognostic model, we identify patients with high-risk disease who have predictably unfavorable outcome following ASCT. Novel therapeutic approaches, including allogeneic stem cell transplantation, should be explored for this group of patients. No significant financial relationships to disclose.
Evolution of DNA-Binding Sites of a Floral Master Regulatory Transcription Factor
Authors: Jose M. Muiño, Suzanne de Bruijn, Alice Pajoro, Koen Geuten, Martin Vingron, Gerco C. Angenent, Kerstin Kaufmann
Journal: Molecular Biology and Evolution (2015)

Flower development is controlled by the action of key regulatory transcription factors of the MADS-domain family. The function of these factors appears to be highly conserved among species based on mutant phenotypes. However, the conservation of their downstream processes is much less well understood, mostly because the evolutionary turnover and variation of their DNA-binding sites (BSs) among plant species have not yet been experimentally determined. Here, we performed comparative ChIP (chromatin immunoprecipitation)-seq experiments of the MADS-domain transcription factor SEPALLATA3 (SEP3) in two closely related Arabidopsis species: Arabidopsis thaliana and A. lyrata which have very similar floral organ morphology. We found that BS conservation is associated with DNA sequence conservation, the presence of the CArG-box BS motif and on the relative position of the BS to its potential target gene. Differences in genome size and structure can explain that SEP3 BSs in A. lyrata can be located more distantly to their potential target genes than their counterparts in A. thaliana. In A. lyrata, we identified transposition as a mechanism to generate novel SEP3 binding locations in the genome. Comparative gene expression analysis shows that the loss/gain of BSs is associated with a change in gene expression. In summary, this study investigates the evolutionary dynamics of DNA BSs of a floral key-regulatory transcription factor and explores factors affecting this phenomenon.
Abstract 317: Pre-Hospital Predictors of Post-Cardiac Arrest Left Ventricle Dysfunction
Authors: Yuan Yao, Anne V Grossestreuer, Sarah M Perman, Vimal Ramjee, David F Gaieski
Journal: Circulation (2013)

Background: A proportion of patients with out-of-hospital cardiac arrest are initially resuscitated; however, few survive to hospital discharge. A common cause of this high mortality rate is post-cardiac arrest myocardial dysfunction, a temporal phenomenon that can be fully recovered from with appropriate treatment. Objectives: This study aims to explore the predictors of post-cardiac arrest myocardial dysfunction and evaluate their influence on survival and neurologic outcome. We hypothesized that there would be an association between pre-hospital resuscitative strategies (such as witnessed arrest, bystander CPR, and the use of a publicly accessible AED) and development of LV dysfunction after resuscitation. Methods: A retrospective chart review was performed of 238 out-of-hospital cardiac arrest patients who underwent echocardiography after resuscitation at three hospitals. Pre-hospital arrest characteristics and echocardiography results were abstracted. The primary outcome was left ventricular ejection fraction (LVEF; abnormal defined as &lt;40%) in the first 24 hours. Results: 191 (80%) patients had an echo completed in the first 24 hours, of which abnormal LVEF was observed in 90 (47%).Having a witnessed arrest predicted abnormal LVEF in first 24 hours (OR, 3.7; 95% CI, 1.04-13.22). No association was detected between initial rhythm, bystander CPR, use of AED, total downtime and the development of LVEF. No difference was observed in both neurologic outcome and survival in patients with a normal versus abnormal 24 hour echo. Among the 51 patients with serial echos, 28 (55%) patients had an abnormal initial LVEF; 15 (54%) of these patients had an LVEF that returned to normal by 72 hours. Conclusions: In survivors of out-of-hospital cardiac arrest, abnormal LVEF after resuscitation is not predictive of outcome; however, witnessed arrest is associated with the development of abnormal LVEF.