tbuckley/cabot-search huggingface dataset:
Abstract 3652: Identification of cancer-specific signaling networks: what is “normal” control
Authors: Manjushree Anjanappa, Yangyang Hao, Howard J. Edenberg, Yunlong Liu, Harikrishna Nakshatri
Journal: Cancer Research (2016)

Abstract Success of precision medicine depends on definitive identification of cancer-specific alterations in signaling pathways. However, identifying cancer-specific signaling networks is challenging because of lack of proper control tissue for differential gene expression analyses. Most studies in breast cancer utilize tumor-adjacent normal tissue or reduction mammoplasty samples as “normal” controls. We recently reported that breast epithelial cells from healthy donors as well as tumor-adjacent normal are in different differentiation states compared with tumor cells and the differences in differentiation status alone could account for major transcriptome variations between normal and tumor. To overcome these limitations, we propagated breast epithelial cells from three healthy donors (healthy-normal), two high-risk patients, two tumor-adjacent normal (HR/AD-normal) and five tumor samples of different molecular subtypes. Phenotypically defined (CD49f+/EpCAM+) luminal progenitor cells were sorted from these cultures and subjected to RNA-seq analyses. Pathway analysis revealed activation of cell-intrinsic pro-inflammatory signaling in HR/AD-normal cells compared with healthy-normal cells. This signaling network was further amplified in tumor cells. The pro-inflammatory chemokine CCL2, which is overexpressed in highly aggressive breast cancer, and the cytokine TNFRSF11B were elevated in HR/AD-normal luminal progenitor cells. Despite using phenotypically defined cells in the transcriptome analyses, cancer-specific signaling network identification was directly influenced by the type of controls used; healthy-normal or HR/AD-normal. While cancer-enriched PI3K and NF-κB activation was observed when compared to any kind of control, SRC kinase activation was noted only when cells from healthy-normal were used as a control. In general, the number of tumor signaling networks identified using healthy-normal as a control was higher than when compared with HR/AD-normal as a control. These results suggest that considerable attention should be placed on the type of tissues used as control for definitive identification of cancer-specific signaling networks and therapies to target such pathways. Additionally, these data show that non-cancer tissues of breast cancer patients acquire a cell intrinsic pro-inflammatory phenotype, which may be prerequisite for cancer development and potentially an early-detection tool. Citation Format: Manjushree Anjanappa, Yangyang Hao, Howard J. Edenberg, Yunlong Liu, Harikrishna Nakshatri. Identification of cancer-specific signaling networks: what is “normal” control. [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 3652.
Abstract 3589: Nucleotide excision repair is elevated in stage IV commonly used breast cancer cell lines as compared to stage I breast tumor explants
Authors: Homood As Sobeai, Jennifer M. Johnson, Nancy Lalanne, Omar Ibrahim, Stephen G. Grant, Sharon L. Wenger, Jean J. Latimer
Journal: Cancer Research (2016)

Abstract Genomic instability is a hallmark of human carcinogenesis. We have previously published that sporadic stage I breast tumors exhibit deficient Nucleotide Excision Repair (NER) capacity relative to non-diseased breast reduction primary cultures (Latimer et al., 2010). In the present work, we hypothesized that this feature of early human breast cancer would not be maintained in cell lines established from late stage tumors. Our objective was to determine functional NER capacity and relative NER gene expression in a series of commonly used stage IV breast cancer-derived cell lines relative to stage I breast cancer explants and cell lines. NER capacity was determined using the functional unscheduled DNA synthesis (UDS) assay in six established breast cancer cell lines (MCF-7, MCF-7LY2, MDA-MB-231, SK-BR-3, CAMA-1, BT-20). JL BTL-12 (Jean Latimer Breast Tumor Line-12), derived from a stage III breast tumor, was included to represent an advanced stage tumor cell line established using our culture system. The NER capacity of the cell lines was compared to that of 19 stage I breast tumor primary cultures. NER gene expression was determined by expression microarray using the Affymetrix HG U-133 plus 2.0 chip in five of these established cell lines (MCF-7, MDA-MB-231, SK-BR-3, CAMA-1, BT-20), JL BTL-12 and a representative stage I tumor-derived cell line (JL BTL-8, Breast Tumor Line-8). The stage IV cell lines and JL BTL-12 all manifested significantly higher NER capacity than explants of stage I breast cancer. Unsupervised as well as supervised analyses, based on expression of the canonical 20 NER genes, placed JL BTL-12 and the five stage IV commercial cell lines in one cluster, while JL BTL-8 clustered separately. Four NER genes were significantly upregulated in JL BTL-12 and all commercial cell lines relative to JL BTL-8. In conclusion, based on NER these five cell lines commonly used in breast cancer research are more representative of late stage disease than early stage breast cancer, regardless of the type of breast cancer they represent. The most commonly diagnosed stage of breast cancer in the U.S. is now stage I, and it is now possible to study stage I cell lines or explants. Citation Format: Homood As Sobeai, Jennifer M. Johnson, Nancy Lalanne, Omar Ibrahim, Stephen G. Grant, Sharon L. Wenger, Jean J. Latimer. Nucleotide excision repair is elevated in stage IV commonly used breast cancer cell lines as compared to stage I breast tumor explants. [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 3589.
Ontario plans to stop funding high dose opioids
Authors: Owen Dyer
Journal: BMJ (2016)

The public health insurance programme in Canada’s most populous province, Ontario, will stop paying for high dose opioids in an effort to improve clinical outcomes and reduce the growing burden of opioid addiction.

The drugs due to be delisted are morphine 200 mg tablets; hydromorphone 24 mg and 30 mg capsules, sold under the brand name Hydromorph Contin; fentanyl 75 microgram/hr and 100 microgram/hr patches; and meperidine (Demerol) 50 mg tablets.

From January 2017 these will not be funded, even under the Exceptional Access Program …
Abstract 761: Specific inhibition of prostaglandin E2 production in medulloblastoma
Authors: Filip Bergqvist, Linda Ljungblad, Malin Wickström, Karin Larsson, Anna Kock, Marina Korotkova, John Inge Johnsen, Per Kogner, Per-Johan Jakobsson
Journal: Cancer Research (2016)

Abstract Introduction: Prostaglandin E2 (PGE2) is a key lipid mediator of inflammation and carcinogenesis. Apart from promoting direct growth of cancer cells, PGE2 has been shown to be crucial in maintaining the immunosuppressive tumor microenvironment. Drugs targeting cyclooxygenase (COX)-1 and -2, enzymes upstream in the production of PGE2 and other prostanoids, have successfully reduced tumor growth in many cancer models but these drugs are all associated with adverse long-term effects. The aim of this study is to demonstrate an anti-tumor effect in medulloblastoma by selective inhibition of microsomal prostaglandin E1 (mPGES-1), the enzyme downstream of COX-1/2 specifically required for the synthesis of PGE2. Experimental procedures: Human medulloblastoma cell lines (DAOY and D283) were treated with a selective small-molecule inhibitor against mPGES-1 or COX-2 in the presence or absence of pro-inflammatory interleukin (IL)-1â. Prostaglandins in supernatants were extracted and quantified with LC-MS/MS. Drug efficacy was determined and cell toxicity was measured with cell viability assay. Mice with human medulloblastoma xenograft will function as proof-of-concept for the anti-tumor activities associated with inhibition of PGE2 production. Key inflammatory enzymes were quantified with Western blot. Results: Medulloblastoma cells express high levels of COX-2, mPGES-1, and produce PGE2. The increased production of PGE2 by IL-1â was completely blocked when cells were co-treated with inhibitor for mPGES-1 or COX-2. Both inhibitors showed cell toxicity. We did not observe any shunting towards other prostanoids. Conclusion: We investigate the effect of selective inhibition of mPGES-1 or COX-2 on medulloblastoma growth. We aim to further characterize the mPGES-1 inhibitor and compare to selective COX-2 inhibitor in preclinical medulloblastoma models. Specific inhibition of PGE2 production, rather than general inhibition of prostanoid production, would potentially prove useful as a complement to current medulloblastoma treatments. Citation Format: Filip Bergqvist, Linda Ljungblad, Malin Wickström, Karin Larsson, Anna Kock, Marina Korotkova, John Inge Johnsen, Per Kogner, Per-Johan Jakobsson. Specific inhibition of prostaglandin E2 production in medulloblastoma. [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 761.
Absolute CVD risk, stratified by risk score, was 20% higher in primary care patients with CVD than in those without CVD
Authors: Tim Lancaster
Journal: Annals of Internal Medicine (2009)

ACP Journal Club19 May 2009Absolute CVD risk, stratified by risk score, was 20% higher in primary care patients with CVD than in those without CVDTim Lancaster, MDTim Lancaster, MDOxford University, UK National School for Primary Care Research, Oxford, England, UK (T.L.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-150-10-200905190-02015 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationKerr AJ, Broad J, Wells S, Riddell T, Jackson R. Should the first priority in cardiovascular risk management be those with prior cardiovascular disease? Heart. 2009;95:125-9. https://pubmed.ncbi.nlm.nih.gov/18381374Clinical Impact RatingsGIM/FP/GP: Author, Article, and Disclosure InformationAuthors: Tim Lancaster, MDAffiliations: Oxford University, UK National School for Primary Care Research, Oxford, England, UK (T.L.)This article was published at Annals.org on 5 May 2009. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 19 May 2009Volume 150, Issue 10 Page: JC5-15 Keywords Cardiovascular disease risk Cardiovascular diseases Databases Heart failure Hemorrhagic stroke Ischemic stroke Medical risk factors Research funding Risk management Stable coronary artery disease ePublished: 19 May 2009 Issue Published: 19 May 2009 Copyright & PermissionsCopyright © 2009 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Epidermal growth factor receptor is expressed and active in a subset of acute myeloid leukemia
Authors: Hasan Mahmud, Steven M. Kornblau, Arja ter Elst, Frank J. G. Scherpen, Yi Hua Qiu, Kevin R. Coombes, Eveline S. J. M. de Bont
Journal: Journal of Hematology & Oncology (2016)

The epidermal growth factor receptor (EGFR) inhibitor erlotinib has been shown to induce complete remission of acute myeloid leukemia (AML) in two patients with concurrent lung cancer and raised attention for a role of EGFR in AML whereas a recent phase II clinical study with gefitinib in AML demonstrated a negative result on the outcome. However, from several studies, EGFR expression in AML is poorly defined and the role of EGFR in AML remains unclear. Herein, we report the results of EGFR expression in AML of large cohorts of adult and pediatric AML patients with the data of total protein and phosphorylation levels of EGFR. Our data conclude that there is the expression of EGFR at the protein level in a subset of AML, which was identified to be functionally active in ~15 % of AML patients. This suggests that future studies need to be conducted with a subset of AML patients characterized by high EGFR expression.
Predictors of outcome in patients with advanced nonseminamatous germ cell testicular tumors.
Authors: Tarkan Yetisyigit, Nalan Babacan, Yuksel Urun, Selcuk Seber, Erkan Arpaci, Sener Cihan, Nuriye Yildirim, Omur Berna Oksuzoglu, Sercan Aksoy, Burcin Budakoglu, Banu cicek Yalcin, Suayib Yalcin, Nurullah Zengin, Necati Alkis
Journal: Journal of Clinical Oncology (2014)

e15528 Background: Predictorfactors determining complete response to treatment are still not clearly defined. We aimed to evaluate clinicopathological features, risk factors, treatment responses, and survival analysis of patient with advanced nonseminomatous GCTs (NSGCT). Methods: Between November 1999 and September 2011, 140 patients with stage II and III NSGCT were referred to our institutions and 125 patients with complete clinical data were included in this retrospective study. Four cycles of BEP regimen was given as a first-line treatment. Salvage chemotherapy and/or high-dose chemotherapy (HDCT) with autologous stem cell transplantation were given in patients who had progressed after BEP chemotherapy. Postchemotherapy surgery was performed in selected patients with incomplete radiographic response and normal tumor markers. Results: The median age was 28 years. According to good, intermediate, and poor risk group compete response rates (CRR) were as following respectively: 84.6%, 67.9%, and 59.4%.Extragonadal tumors, stage 3 disease, intermediate and poor risk factors, rete testis invasion were associated with worse outcomes. There were 32 patients (25.6%) with non-CR who were treated with salvage treatment. Thirty-one patients died from GCTs and 94% of them had stage III disease. Conclusions: Even though, response rate is high, some patients with GCTs still need salvage treatment and cure cannot be achieved in those patients. Non-complete response to platinium-based first-line treatment was a negative prognostic factor. Our study confirms the need for prognostic and predictive model and more effective salvage approach.
Sex differences in neuroanatomical and clinical correlations in schizophrenia
Authors: P E Cowell, D J Kostianovsky, R C Gur, B I Turetsky, R E Gur
Journal: American Journal of Psychiatry (1996)

The purpose of this study was to investigate sex differences in relationships between brain and behavior in schizophrenia.Frontal lobe, temporal lobe, and whole brain volumes were obtained from magnetic resonance images of 91 patients with schizophrenia (54 men and 37 women) and 114 healthy comparison subjects (62 men and 52 women). Four independent symptom scales, based on the following symptom clusters, were derived from clinical data: negative, disorganization, Schneiderian hallucinations-delusions, and suspicion-hostility. Regression analyses incorporating the four clinical scales and neuroanatomical volumes were performed to investigate possible interactions between brain region and sex.Significant interactive effects of sex and frontal lobe volume were found in regression analyses of the disorganization and suspicion-hostility symptom scales. In men, higher frontal lobe volume was associated with milder severity of disorganization but was not correlated with severity of suspicion-hostility. In women, higher frontal lobe volume was associated with more severe disorganization as well as more severe suspicion-hostility. No associations were found between brain volume and severity of negative or Schneiderian symptoms.Differences between male and female patients were observed in the relationships between frontal lobe volume and two of the four clinical dimensions examined. These findings suggest that aspects of the neuropathological basis for some symptoms of schizophrenia may be sexually dimorphic.
A randomized, open-label, multicenter, adaptive phase 2/3 study of trastuzumab emtansine (T-DM1) versus a taxane (TAX) in patients (pts) with previously treated HER2-positive locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (LA/MGC/GEJC).
Authors: Yoon-Koo Kang, Manish A. Shah, Atsushi Ohtsu, Eric Van Cutsem, Jaffer A. Ajani, Tina van der Horst, Marie-Laurence Harle-Yge, Yongzhe Piao, Betsy Althaus, Peter C. Thuss-Patience
Journal: Journal of Clinical Oncology (2016)

5 Background: Trastuzumab (H) + capecitabine/fluorouracil + cisplatin is standard of care for 1 st -line HER2-positive MGC/GEJC but there is no established HER2-targeted 2 nd -line regimen. T-DM1 (H linked to DM1) is approved for HER2-positive metastatic breast cancer previously treated with H + TAX (separately or in combination). This and preclinical HER2-positive GC models provided the rationale for GATSBY (NCT01641939). Methods: GATSBY is a 3-arm randomized, adaptive, seamless phase 2/3 global study of T-DM1 vs TAX in pts with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization-positive), unresectable LA/MGC/GEJC who progressed during or after 1 st -line fluoropyrimidine + platinum ± HER2-targeted therapy. Pts were initially randomized 2:2:1 to T-DM1 3.6 mg/kg every 3 weeks (q3w), T-DM1 2.4 mg/kg weekly (qw), or physician’s choice of paclitaxel 80 mg/m 2 qw or docetaxel 75 mg/m 2 q3w. An independent data monitoring committee selected T-DM1 qw for further study and subsequent patients were randomized 2:1 to this or TAX. The primary endpoint is overall survival (OS); all T-DM1 qw data are analyzed, including dose selection. Results: At clinical cutoff, 06/30/15, 415 pts had been randomized overall: 228 to T-DM1 qw, 117 to TAX (70 T-DM1 q3w pts reported separately); 77.4% had prior HER2-targeted therapy; 29.9% prior gastrectomy; 46.1% were Asian. Efficacy/safety are tabulated. Conclusions: T-DM1 2.4 mg/kg qw did not show an efficacy benefit over TAX. Grade ≥3 AE rates were numerically lower with T-DM1 vs TAX and rates of SAEs, fatal AEs, and treatment discontinuations due to AEs were comparable between arms. Clinical trial information: NCT01641939. [Table: see text]
Anaplastic oligodendroglial tumors: The Cleveland Clinic experience.
Authors: Neda Hashemi-Sadraei, Lizbeth Robles Irizarry, Mital Patel, Tanya M. Tekautz, Erin Sennett Murphy, Violette Recinos, Samuel T. Chao, John H. Suh, David M. Peereboom, Glen Stevens, Robert J. Weil, Michael A. Vogelbaum, Gene H. Barnett, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2012)

2100 Background: Anaplastic oligodendroglial tumors include both anaplastic oligodendroglioma (AO), and anaplastic oligoastrocytoma (AOA), histological categories of WHO grade 3 gliomas. There is limited data on specific prognostic factors for patients with these tumors. Methods: After obtaining IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify patients with histologically confirmed AO and AOA at the time of diagnosis. Multivariable analysis was conducted with use of a Cox proportional hazards model and a stepwise selection algorithm that used p&lt;0.05 both as the criteria for entry and retention in the model to identify independent predictors of survival. Results: Chart records of 139 patients, 52% of whom were male, diagnosed between 1992 and 2009 were included for analysis. Median age at presentation was 47 years (range, 18-83 years). 22% of patients had biopsy only, 35% had gross total resection, 43% had near total resection or subtotal resection. Following surgery, 30% of patients were treated with chemotherapy (CT) alone, 14% were treated with radiotherapy (RT) and 47% received both CT and RT. Median progression free survival and median overall survival (OS) were 29.0 and 58.7 months respectively. On multivariate analysis, four factors were identified as independent predictors of OS: age at diagnosis (≥50 vs. &lt;50, p=0.004), Hypothyroidism (p=0.009), multifocal disease (p=0.005) and 1p 19q co-deletion (p&lt;0.001). Choice of initial therapy did not impact survival in this cohort of patients. Conclusions: Older age, hypothyroidism and multifocal disease were associated with higher mortality. 1p, 19q co-deletion was associated with lower mortality. [Table: see text]
Adjuvant Dendritic Cell Vaccination in High-Risk Uveal Melanoma
Authors: Kalijn F. Bol, Thomas van den Bosch, Gerty Schreibelt, Hanneke W. Mensink, Jan E.E. Keunen, Emine Kiliç, Wouter J. Japing, Kaspar W. Geul, Harm Westdorp, Steve Boudewijns, Sandra A.J. Croockewit, Michelle M. van Rossum, Anna L. de Goede, Nicole C. Naus, Winette T.A. van der Graaf, Winald R. Gerritsen, Annelies de Klein, Cornelis J.A. Punt, Carl G. Figdor, Victoria M. Cohen, Dion Paridaens, I. Jolanda M. de Vries
Journal: Ophthalmology (2016)
A phase 1 study of ramucirumab (R) plus pembrolizumab (P) in patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, non-small cell lung cancer (NSCLC), or urothelial carcinoma (UC): Phase 1a results.
Authors: Roy S. Herbst, Johanna C. Bendell, Nicolas Isambert, Emiliano Calvo, Rafael Santana-Davila, Philippe Cassier, Jose Luis Perez-Gracia, Jing Yang, Jessicca Rege, David Ferry, Gu Mi, Ian Chau
Journal: Journal of Clinical Oncology (2016)

3056 Background: Hallmarks of tumor growth include angiogenesis and immunosuppression. This is the first study to combine R with P to target both processes simultaneously. Preliminary safety results from the dose-limiting toxicity (DLT) portion of the study (phase 1a) are reported. Methods: Eligible pts with advanced G/GEJ, NSCLC or UC and ECOG PS 0-1 who progressed on prior systemic therapy were enrolled. Two dosing regimens were evaluated in a phase 1a following a 3+3 design, schedule (S) 1 (R 8 mg/kg on Days 1&8 in G/GEJ only) and S2 (R 10 mg/kg on Day 1 in G/GEJ, NSCLC, and UC), given concomitantly with P 200 mg on Day 1 q3W. After phase 1A/DLT evaluation, each tumor type was expanded to 30 G/GEJ, 25 NSCLC, and 25 UC pts who will receive study treatment until confirmed disease progression or unacceptable toxicity (phase 1a). The primary objective was to assess safety and tolerability of two dosing regimens; preliminary efficacy will be examined in expansion cohorts. Results: As of data cutoff on 08-Jan-16, 10 pts were treated in phase 1a: 7 G/GEJ pts in S1 and 3 NSCLC pts in S2. S1 is currently ongoing, 1/5 evaluable pts had DLTs. In S2, no DLTs were observed and 3 expansion cohorts are fully enrolled. Treatment emergent adverse events (TEAEs) were reported for 9/10 pts, 5/10 pts had treatment-related AEs (TRAEs). The G/GEJ pt who experienced DLTs reported Grade (G) 3 TRAEs, including abdominal pain, hepatitis, pneumonia, colitis, peritonitis and G4 cholestasis; this pt discontinued study treatment. The other four pts reported G1-2 TRAEs including G1 fever, dysgeusia, dysphonia, asthenopia, and anorexia, and G2 hypothyroidism, dyspnea, pain, pruritus and asthenia; one of each, except pain (n = 2). Three deaths were reported (not related), 2 due to disease progression, and 1 sudden death. Conclusions: Preliminary data from the study did not reveal any unexpected safety signals. At the time of the phase 1a data cutoff, S2 was complete and the DLT observations for S1 are ongoing. An amendment is underway to explore additional tumor types. Additional safety and efficacy for S1 and S2 will be presented at the meeting. Clinical trial information: NCT02443324.