tbuckley/cabot-search huggingface dataset:
Abstract 3524: D-glucose exposure induced DNA damage and apoptosis in MCF-7 cells
Authors: Ibrahim O. Farah, Christine K. Tchounwou, Clement G. Yedjou, Paul B. Tchounwou
Journal: Cancer Research (2016)

Abstract D-glucose is the simple carbohydrate sugar that our bodies rely on to produce ATP energy. It has been shown that sustained high glucose burden is related to the promotion of many long-term health problems to various vital target organs including the kidneys, nervous system, eyes, heart (failure and stroke), erectile dysfunction in men and pregnancy complications in women. Epidemiological data have suggested an increased cancer rates in diabetic patients, for which the underlying mechanism is poorly understood. Furthermore, the D-glucose paradox as cancer-promoting energy source as well as being toxic to cancer cells is puzzling. Therefore in the present study, we will investigate the mechanisms of glucose-induced toxicity in MCF-7 cells as an in vitro cellular model to simulate diabetic complications in tumor cells using trypan blue exclusion and MTT assays. Mechanisms of DNA damage and apoptosis were tested by alkaline single cell gel electrophoresis (Comet) assay, and flow cytometry analysis using Annexin V FITC/PI and caspase-3 analysis. The MTT assay indicated that low dose (5 mg/mL) of D-glucose slightly increase cell viability upon 2 h of exposure. On the other hand, high doses (10-80 mg/mL) of D-glucose significantly reduced the viability of MCF-7 cells in a dose and time-dependent manner. Similar trends were seen with the trypan blue exclusion test. Data obtained from the comet assay indicated that D-glucose caused DNA damage in MCF-7 cells in a dose-dependent manner. The flow cytometry assessment (Annexin V FITC/PI) showed a strong dose-response relationship between high glucose exposure and Annexin V positive MCF-7 cells undergoing early stage apoptosis. Similarly, a statistically significant and concentration-dependent increase (p &amp;lt;0.05) were recorded for caspase-3 activity in MCF-7 cells undergoing late apoptosis. Based on these in vitro findings, our study provides clear evidence that elevated level of D-glucose induced cytotoxicity to MCF-7 cells via induction of DNA damage, externalization of phosphatidylserine and caspase-3 activation as indicators for the apoptotic mechanisms of D-glucose exposure. This research is supported by a grant from the National Institutes of Health-NIH (Grant No. NIMHD-G12MD007581). Citation Format: Ibrahim O. Farah, Christine K. Tchounwou, Clement G. Yedjou, Paul B. Tchounwou. D-glucose exposure induced DNA damage and apoptosis in MCF-7 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 3524.
The Ubiquitin Ligase Triad1 Is Involved in Myelopoiesis and Interacts with the Transcriptional Repressors Gfi1 and Gfi1b.
Authors: Bert A. Van der Reijden, Jurgen A.F. Marteijn, Liesbeth Van Emst, Theo De Witte, Joop H. Jansen
Journal: Blood (2004)
The importance of adjusting for treatment crossover bias in oncology clinical trials: An analysis of the EGF104900 trial in metastatic breast cancer (mBC).
Authors: Norman Paracha, Andrew Davies, Nicholas Latimer, Christopher Parker, Stuart Mealing, David Scott, Amie Padhiar, Mark Schulpher, Qing Wang
Journal: Journal of Clinical Oncology (2013)

636 Background: EGF104900 is a phase III trial in mBC that compared lapatinib + trastuzumab (LAPTRZ, n=146) with LAP monotherapy (LAP, n=145). The trial allowed LAP subjects to switch to LAPTRZ on documented disease progression (following ≥4 weeks of LAP). Conventional intent-to-treat (ITT) analysis does not control for potential bias due to treatment crossover. The Rank Preserving Structural Failure Time Model (RPSFTM) estimates event times had patients not switched, and performs re-censoring. The approach preserves randomization and ordering of patients’ observed survival times, assuming that patients switching benefit from the treatment effect seen in those initially randomized to the treatment arm. The method is recognized by NICE, UK, as an appropriate method for adjusting for crossover bias. Methods: 53% of LAP subjects crossed over to LAPTRZ. Analyses were stratified by hormone receptor status and visceral/non-visceral disease. RPSFTM was implemented in Stata (using White’s strbee procedure). Absolute overall survival (OS) was estimated using a parametric survival distribution fitted to the trial data with/without crossover adjustment. The unadjusted ITT Cox hazard ratio (HR) was compared with the crossover adjusted RPSFTM estimate, and the absolute gain in OS evaluated. Results: Median OS in the LAPTRZ and LAP arms was 61 and 41 weeks, respectively (ITT HR 0.74, 95% CI: 0.56, 0.96); RPSFTM crossover-adjusted median OS for LAP was 32 weeks (RPSFTM HR 0.52; 95% CI: 0.29, 0.92). Mean OS for LAPTRZ was estimated under a Weibull distribution as 74 weeks, compared with 57 (ITT) and 44 (RPSFTM) weeks for LAP. Treatment with LAPTRZ was estimated to extend mean OS by 30 weeks controlling for treatment crossover using RPSFTM compared with 17 weeks by ITT. Conclusions: Oncology trials are often subject to treatment crossover. Controlling for potential treatment crossover bias can result in greater estimates of gain in OS compared with ITT analysis. In the context of mBC such differences are of great importance to patients, clinicians, and healthcare payers. Treatment crossover-analyses are therefore also important for estimating cost-effectiveness in oncology.
Case 25-1969
Authors: David H. Alpers, Kilmer S. McCully
Journal: New England Journal of Medicine (1969)

Presentation of CaseA fifty-four-year-old man was found unconscious in the street and brought to the hospital.He was mentally retarded and had spent many years at a state school. He had recently been employed at a fruit market. Nine months before entry he was admitted to another hospital because of swelling of the abdomen. He was obese; a Grade 2 murmur was heard; the lungs were clear; the abdomen was tympanitic, and a large fecal impaction was found. The urine gave a trace-positive test for protein and contained 10 to 20 white cells per high-power field. The hematocrit was . . .
Subjects With Extreme-Duration Type 1 Diabetes Exhibit No Structural or Functional Abnormality on Cardiac MRI
Authors: Omar Asghar, Christopher Miller, Simon Ray, Matthias Schmitt, Rayaz A. Malik
Journal: Diabetes Care (2016)

Medalists represent a unique group of survivors of over 50 years of type 1 diabetes (T1D) (1,2). A subgroup of Medalists, escapers , remains free of micro- and macrovascular complications. To date, there are no published studies on cardiac structure and function in these subjects.

We have undertaken a comprehensive multiparametric cardiac MRI study (3,4) to quantify myocardial structure, function, deformation, perfusion, and fibrosis in a cohort of 13 subjects with extreme-duration T1D and 14 healthy control subjects (Table 1).

View this table:

Table 1 
Clinical characteristics and cardiac MRI data



The T1D group had a mean duration of diabetes of 47.4 ± 5.1 years (median 48.0 years). Eight participants had a history of retinopathy and 12 were receiving statin and ACE inhibitor therapy. The mean HbA1c over the previous 16 years was 8.3 ± …
Abstract 3861: Ruxolitinib inhibits STAT-3 activation in glioblastoma
Authors: Samuel Fehling, Braden McFarland, Etty Benveniste
Journal: Cancer Research (2016)

Abstract Glioblastoma (GBM), a primary Grade IV astrocytoma, is the most aggressive primary brain cancer in humans. Despite combined radiotherapy and chemotherapy, the median survival is 14 months. We and others have validated that levels of phosphorylated JAK1/2 and STAT-3 are increased in GBM tissues. When stimulated with IL-6 family members, JAK1/2 recruits and phosphorylates STAT-3. Phosphorylated STAT-3 dimerizes and translocates to the nucleus where it regulates genes involved in proliferation, angiogenesis, anti-apoptotic activity and immunosuppression. Elevated JAK/STAT activation is generated through an increase in IL-6 family cytokines as well as a decrease in JAK/STAT-3 negative regulators. To therapeutically inhibit the JAK/STAT-3 pathway in GBM we employed ruxolitinib, an FDA approved JAK1/JAK2 inhibitor. Human GBM cell lines U87-MG and U251-MG, as well as patient derived GBM xenograft lines JX6 and JX12, were treated with ruxolitinib in doses ranging from 0.01 to 10 μM. Ruxolitinib was observed to inhibit STAT-3 activation in a dose-dependent manner. Pre-treatment of U87-MG and U251-MG cells with ruxolitinib inhibited stimulus-induced STAT-3 activation and downstream gene expression in a dose-dependent manner. Future studies will examine ruxolitinib effects on migration, invasion, apoptosis and proliferation in vitro. Collectively, these data indicate the potential for ruxolitinib therapy for GBM patients. Citation Format: Samuel Fehling, Braden McFarland, Etty Benveniste. Ruxolitinib inhibits STAT-3 activation in glioblastoma. [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 3861.
Abstract 2034: Personalized chemotherapy regimen selection for breast cancer
Authors: Jinfeng Zhang, Kaixian Yu, Qingxiang Amy Sang, Winston Tan, Mayassa B. Dargham, Jun S. Liu, Ty Lively, Cedric Sheffield
Journal: Cancer Research (2016)

Abstract Despite the rapid progress in personalized cancer therapy (PCT) for breast cancer, no previous studies have used genomic predictors to choose among multiple chemotherapy regimens. It is unclear that given the current regimens how much PCT can improve the response rate for patients who will receive chemotherapy. In this study, we reanalyzed data from published studies of 1111 breast cancer patients who were treated with neoadjuvant chemotherapies. Those patients were divided into three regimen groups: an anthracycline alone, anthracycline plus paclitaxel, and anthracycline plus docetaxel. We developed a new strategy called PRES (Personalized REgimen Selection) to reassign the optimal regimen to each of the patients. First, a variable selection scheme was developed to identify significant genetic predictors for chemotherapy response. The selected genetic variables were then combined with clinical variables to build random forest models to predict the response of a patient to each regimen using pCR (pathological complete response) as the measure of response. The models were used to assign an optimal regimen to each patient to maximize the chance of pCR. We found that the expected rate of pCR was improved from 21.2% to 39.6% (95% CI: 34.6% - 43.0%). We also found that 31.1% of the patients may have been overtreated and 8.2% patients undertreated. A validation study on 21 cell lines showed that our prediction agrees with their paclitaxel-sensitivity profiles. We performed additional analysis on the Cancer Genome Atlas (TCGA) data and found that 18 of the 19 genes identified are significantly differentially expressed between normal and tumor tissues, and 2 of them, TAF6L and METRN (meteorin), are associated with overall survival. In conclusion, PRES could substantially increase response rates for breast cancer patients who will receive one of the widely-accepted chemotherapy regimens at present. Citation Format: Jinfeng Zhang, Kaixian Yu, Qingxiang Amy Sang, Winston Tan, Mayassa B. Dargham, Jun S. Liu, Ty Lively, Cedric Sheffield. Personalized chemotherapy regimen selection for 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 2034.
Abstract 3145: Clinical evaluation of streck cell-free DNA blood collection tubes for liquid profiling in oncology
Authors: Inga Medina Diaz, Stefan Holdenrieder, Annette Nocon, Makbule Kobilay, Dirk Skowasch, Stefanie Held, Johanna Weiland, Claudia Stamm, Frank Diehl, Frank Holtrup
Journal: Cancer Research (2016)

Abstract Liquid profiling based on circulating tumor DNA (ctDNA) extracted from blood has become a powerful diagnostic approach in oncology. Making ctDNA analysis broadly available requires shipping whole blood to a clinical laboratory while ensuring cell-free DNA (cfDNA) and blood cell integrity to prevent dilution of ctDNA with cellular genomic DNA. Since standard EDTA blood collection tubes cannot retain this integrity for a prolonged time, several laboratories have proposed Streck Cell-Free DNA blood collection tubes (Streck cfDNA BCTs) as an alternative for sample collection. Qualification data for the use of Streck cfDNA BCTs in oncology is limited and mainly based on blood collected from healthy individuals as well as data extrapolated from the prenatal field. However, the data generated from these samples may not represent the unique dynamics of clinical oncology specimens and therefore a study of true clinical oncology samples is required to support the use of Streck cfDNA BCT tubes in routine practice. In this study, we performed a clinical evaluation of cfDNA sample integrity from matched Streck cfDNA BCTs vs standard EDTA tubes from colorectal, pancreatic and non-small cell lung cancer patients (N &amp;gt; 50). Blood drawn into Streck cfDNA BCTs was either processed immediately or 3 days after phlebotomy. DNA quantification was followed by BEAMing digital PCR (OncoBEAM™) on KRAS, NRAS and EGFR mutations and compared to matching specimens collected in EDTA tubes. Our results suggest that cfDNA yield as well as the genomic DNA background is not affected by prolonged storage of clinical samples in Streck cfDNA BCTs for up to 3 days. In all sample sets containing mutated ctDNA, the detected mutational load was comparable between Streck cfDNA BCTs and EDTA tubes. In conclusion, this study represents a comprehensive clinical evaluation of Streck cfDNA BCTs vs EDTA tubes for ctDNA profiling. In conjunction with the findings of our previously presented Streck cfDNA BCT shipping condition studies, our data supports the compatibility of clinical oncology specimens collected in Streck cfDNA BCTs with the BEAMing technology. Citation Format: Inga Medina Diaz, Stefan Holdenrieder, Annette Nocon, Makbule Kobilay, Dirk Skowasch, Stefanie Held, Johanna Weiland, Claudia Stamm, Frank Diehl, Frank Holtrup. Clinical evaluation of streck cell-free DNA blood collection tubes for liquid profiling in oncology. [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 3145.
P1053 : Prevalence of patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 C/G polymorphism in patients with bona-fide post-NASH cirrhosis
Authors: P. Gallo, U. Vespasiani Gentilucci, G. Galati, A. De Vincentis, L. Piccioni, E. Riva, A. Picardi
Journal: Journal of Hepatology (2015)
Activity-Related Symptom Exacerbations After Pediatric Concussion
Authors: Noah D. Silverberg, Grant L. Iverson, Michael McCrea, Jennifer N. Apps, Thomas A. Hammeke, Danny G. Thomas
Journal: JAMA Pediatrics (2016)

Recovery from concussion generally follows a trajectory of gradual improvement, but symptoms can abruptly worsen with exertion. This phenomenon is poorly understood.To characterize the incidence, course, and clinical significance of symptom exacerbations (spikes) in children after concussion.This secondary analysis of clinical trial data analyzes 63 eligible participants prospectively recruited from an emergency department who were asked to complete a postconcussion symptom scale and record their activities in a structured diary for the next 10 days. They completed standardized assessments of symptoms (postconcussion symptom scale), cognition (Immediate Post-Concussion Assessment and Cognitive Testing), and balance (Balance Error Scoring System) 10 days following the injury. Eligible participants were aged 11 to 18 years and sustained a concussion (according to the Centers for Disease Control and Prevention criteria) that did not result in an abnormal computed tomography scan or require hospital admission. The trial was conducted from May 2010 to December 2012, and the analysis was conducted from November 2015 to February 2016.The occurrence of symptom spikes, defined as an increase of 10 or more points on the postconcussion symptom scale over consecutive days.Of the 63 participants, there were 41 boys (65.1%) and 22 girls (34.9%), and the mean (SD) age was 13.8 (1.8) years. Symptom spikes occurred in one-third of the sample (20 participants [31.7%]). Symptom spikes tended to partially resolve within 24 hours. An abrupt increase in mental activity (ie, returning to school and extracurricular activities) from one day to the next increased the risk of a symptom spike (relative risk, 0.81; 95% CI, 0.21-3.21), but most symptom spikes were not preceded by a documented increase in physical or mental activity. Patients with symptom spikes were initially more symptomatic in the emergency department and throughout the observation period but did not differ from the group without symptom spikes on cognition or balance 10 days following injury.Certain patients appeared susceptible to high and variable symptom reporting. Symptom spikes may not themselves be detrimental to recovery. The present findings support clinical guidelines for adolescents to return to school and activities gradually after concussion.clinicaltrials.gov Identifier: NCT01101724.
Abstract 1443: IL-18 is associated with the onset and progression of gastric cancer
Authors: Paul Nguyen, Rita Busuttil, Lisa Mielke, Gabrielle Belz, Alex Boussioutas, Matthias Ernst, Tracy Putoczki
Journal: Cancer Research (2016)

Abstract INTRODUCTION: Gastric cancer (GC) is the fourth most prevalent, and the third most common cause of cancer-related death worldwide. The disease is generally asymptomatic, and consequently is often diagnosed at an advanced stage when metastasis is present, and limited treatment options are available. Chronic inflammation is recognized as an integral component in the development and progression of GC, and is associated with increased infiltration of immune cells into the tumor microenvironment. The production of pro-inflammatory cytokines by these cells may contribute to tumor progression through activation of pathways promoting tumor cell survival and proliferation. Previous work from our lab has shown that therapeutic inhibition of the inflammatory cytokine interleukin (IL)-11 is effective in ameliorating disease progression in gastrointestinal cancer, however, it is unclear what role other pro-inflammatory cytokines, such as IL-18, might have in disease progression. METHODS: To characterize the role of different pro-inflammatory cytokines in GC, we first analyzed microarray and qRT-PCR data of from human GC specimens and adjacent non-tumor tissue. Following the generation of a candidate list of cytokines deregulated in human GC, the role of individual cytokines in disease progression was examined using a validated mouse model of intestinal-type GC, referred to as gp130Y757F, by crossing into cytokine knock-out strains and monitoring tumor burden and the expression of genes and proteins classically associated with tumorigenesis. RESULTS: We found that the expression pro-inflammatory cytokines including IL-1β and IL-18 were significantly elevated in the tumors of human GC patients compared to non-tumor tissue. In gp130Y757F mice, genetic ablation of IL-18, but not of IL-1β significantly reduced gastric tumor burden, which was associated with a reduction in the number of intratumoral macrophages, but not lymphocytes. This observation correlated with decreased expression of pro-inflammatory (Ifng, Tgfb1), antimicrobial (Reg3b, Reg3g), and tissue remodeling (Mmp9) genes, and a reduction in apoptosis in the gastric lesions in these mice. CONCLUSION: Our results demonstrate that IL-18 has an important role in GC disease progression, and may serve as a potential therapeutic target. Citation Format: Paul Nguyen, Rita Busuttil, Lisa Mielke, Gabrielle Belz, Alex Boussioutas, Matthias Ernst, Tracy Putoczki. IL-18 is associated with the onset and progression of gastric 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 1443.
P0588 : Immune response to hepatitis B vaccination in HIV infected individuals with isolated antibodies to HBV core antigen
Authors: G. Morsica, L. Della Torre, S. Bagaglio, S. Salpietro, E. Messina, M. Merli, H. Hasson, M. Maillard, S. Nozza, V. Spagnuolo, A. Castagna, A. Lazzarin, C. Uberti-Foppa
Journal: Journal of Hepatology (2015)
Function of microRNA activity by ActMiR in bladder cancer.
Authors: Ana Collazo Lorduy, Mireia Castillo-Martin, Eunjee Lee, Jun Zhu, Carlos Cordon-Cardo
Journal: Journal of Clinical Oncology (2016)

4531 Background: MicroRNAs (miRs) play a key role in cancer, in tumorigenesis and tumor progression. In the past years, miR expression signatures have been reported as prognostic biomarkers in bladder cancer (BC). However, miR’s expression does not always correlate with activity. We recently developed a novel computational method, named ActMiR, for explicitly inferring the activity of miRs based on the changes in expression levels of target genes. The objective was to validate the inferred miRs’ activity using BC as a model. Methods: We applied ActMiR in 405 BC cases from the TCGA database for which information from both mRNA and miR expression was available. Different BC cell lines (5637 and HT1376 for basal BC, SW780 and HT1197 for p53-like BC, and RT4 and RT112 for luminal BC) as well as the immortalized urothelial cell line (HUC) were used to perform the in vitro functional validation. RNA was extracted basally and after inhibition of miR106-5p with specific anti-miR inhibitor; miR and target genes’ expression was assessed by qRT-PCR. Results: ActMir analyses revealed that a subset of 306 out of 1044 miRNAs were differentially expressed between tumor and normal samples at p-value < 10-4. More importantly, at p-value < 10-4, 155 out of 556 miRNAs were functionally active. From these, only four (miR106b, miR532, mir556, and mir134) were significantly differentially expressed, functionally active and showed prognostic significance in the TCGA BC cohort. We chose to further analyze mir106b because it showed the biggest and most significant difference in activity between normal and cancer tissues (p-value < 2*10-11). As inferred by ActMir, mir106b-5p was significantly overexpressed in all cancer cells when compared to HUC. We used p53 cell lines to confirm that inhibition of mir106b-5p showed upregulation of the predicted target genes, because ActMir had predicted that miR106 expression and activity were both associated with overall survival in this BC subtype. Conclusions: Our results underscore the value of ActMir for inferring miR activity in BC from a systems biology perspective. It endorses ActMir as a promising tool for studying casual effects of miR activity on target genes, and ultimately for determining survival outcomes of BC patients.