tbuckley/cabot-search huggingface dataset:
Abstract 514: Effect of radiation therapy on breast epithelial cells in BRCA1/2 mutation carriers
Authors: Huai-Chin Chiang, Richard Elledge, Paula Larson, Ismail Jatoi, Rong Li, Yanfen Hu
Journal: Cancer Research (2016)

Abstract Women carrying BRCA1 and BRCA2 mutations have significantly elevated risk of developing breast and ovarian cancers. BRCA1-associated breast cancer likely originates from progenitors of the luminal epithelial lineage. Recent studies indicate that radiation therapy (RT) for BRCA1 cancer patients is associated with lower incidence of developing subsequent ipsilateral breast cancer. In the current study, we analyzed tumor-free breast tissue procured via prophylactic bilateral mastectomy from three BRCA1 and one BRCA2 mutation carriers, who had been previously treated with RT for unilateral breast cancers. Freshly isolated breast cells from the irradiated and non-irradiated breasts of the same individuals were subjected to flow cytometry, using established cell-surface markers. Two out of the three BRCA1 carriers and the BRCA2 carrier exhibited significantly diminished luminal cell population in the irradiated breast versus the non-irradiated side. The remaining BRCA1 carrier showed similar cell abundance between the two sides. Our finding suggests that prior RT could result in preferential depletion of the luminal epithelial compartment and thus reduced incidence of BRCA1-associated breast cancer. Further investigation may inform development of RT-based preventive approaches aimed at specifically decimating the source of BRCA1-associated tumors. Citation Format: Huai-Chin Chiang, Richard Elledge, Paula Larson, Ismail Jatoi, Rong Li, Yanfen Hu. Effect of radiation therapy on breast epithelial cells in BRCA1/2 mutation carriers. [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 514.
Abstract 240: Functional significance of co-occurring mutations in PIK3CA and MAP3K1 in breast cancer
Authors: Alvaro Avivar-Valderas, Robert McEwen, Amir Taheri-Ghahfarokhi, Ambar Ahmed, Daniel Stetson, Brian Dougherty, Marcello Maresca, Kevin Hudson, Francisco Cruzalegui
Journal: Cancer Research (2016)

Abstract PI3Kα signalling pathway is frequently hyper-activated in breast cancer (BrCa) with mutations of PIK3CA (∼45%) frequently found in luminal A BrCa samples. Genomic studies have also uncovered inactivating mutations in MAP3K1 (13-20%) and MAP2K4 (∼8%), two upstream kinases of the JNK apoptotic pathway in luminal A BrCa samples and co-occurring mutation of PIK3CA and MAP3K1 are found in ∼11% of PIK3CA mutants (TCGA). How these two alterations cooperate to promote tumorigenesis and impact the sensitivity to PI3Kα(AZD8835) and AKT (AZD5363) inhibitors is currently unknown. Using siRNA targeting and precise gene editing we have knocked down MAP3K1 in PIK3CA mutant cell lines to create in vitro models reflecting the mutational status of PIK3CA and MAP3K1 in BrCa patients. MAP3K1-deficient cells exhibited increased proliferation rate and decreased sensitivity to AZD8835 compared with parental control cells. In addition, mechanistic analysis revealed that siRNA mediated depletion of MAP3K1 enhances AKT phosphorylation and downstream signalling (i.e. pPRAS40, pFoxO1/FoxO3a) and provides resistance to AZD8835-mediated pathway inhibition. Using in vitro 3D-breast cancer organoid models we have found that MAP3K1 depletion increases overall acinar volume and counteracts AZD8835-mediated reduction of acinar growth. MAP3K1 deficient acini exhibited high pAKT levels in the presence of AZD8835 compared with control acini validating observations in 2D. Remarkably, whereas in control acini pAKT+ cells were restricted to the basal compartment, MAP3K1 deficient acini also exhibited pAKT+ cells in the luminal compartment suggesting anoikis resistance which is a hallmark in early stages of tumorigenesis. Elucidating the mechanistic basis for these clinically co-occurring mutations will provide insights into the mechanisms contributing to the oncogenic role of the PI3K pathway and future patient selection strategies. Citation Format: Alvaro Avivar-Valderas, Robert McEwen, Amir Taheri-Ghahfarokhi, Ambar Ahmed, Daniel Stetson, Brian Dougherty, Marcello Maresca, Kevin Hudson, Francisco Cruzalegui. Functional significance of co-occurring mutations in PIK3CA and MAP3K1 in 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 240.
Association Between Incretin-Based Drugs and the Risk of Acute Pancreatitis
Authors: Laurent Azoulay, Kristian B. Filion, Robert W. Platt, Matthew Dahl, Colin R. Dormuth, Kristin K. Clemens, Madeleine Durand, Nianping Hu, David N. Juurlink, J. Michael Paterson, Laura E. Targownik, Tanvir C. Turin, Pierre Ernst, Samy Suissa, Colin R. Dormuth, Brenda R. Hemmelgarn, Gary F. Teare, Patricia Caetano, Dan Chateau, David A. Henry, J. Michael Paterson, Jacques LeLorier, Adrian R. Levy, Pierre Ernst, Robert W. Platt, Ingrid S. Sketris
Journal: JAMA Internal Medicine (2016)

The association between incretin-based drugs, such as dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists, and acute pancreatitis is controversial.To determine whether the use of incretin-based drugs, compared with the use of 2 or more other oral antidiabetic drugs, is associated with an increased risk of acute pancreatitis.A large, international, multicenter, population-based cohort study was conducted using combined health records from 7 participating sites in Canada, the United States, and the United Kingdom. An overall cohort of 1 532 513 patients with type 2 diabetes initiating the use of antidiabetic drugs between January 1, 2007, and June 30, 2013, was included, with follow-up until June 30, 2014.Current use of incretin-based drugs compared with current use of at least 2 oral antidiabetic drugs.Nested case-control analyses were conducted including hospitalized patients with acute pancreatitis matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and follow-up duration. Hazard ratios (HRs) and 95% CIs for hospitalized acute pancreatitis were estimated and compared current use of incretin-based drugs with current use of 2 or more oral antidiabetic drugs. Secondary analyses were performed to assess whether the risk varied by class of drug (DPP-4 inhibitors and GLP-1 agonists) or by duration of use. Site-specific HRs were pooled using random-effects models.Of 1 532 513 patients included in the analysis, 781 567 (51.0%) were male; mean age was 56.6 years. During 3 464 659 person-years of follow-up, 5165 patients were hospitalized for acute pancreatitis (incidence rate, 1.49 per 1000 person-years). Compared with current use of 2 or more oral antidiabetic drugs, current use of incretin-based drugs was not associated with an increased risk of acute pancreatitis (pooled adjusted HR, 1.03; 95% CI, 0.87-1.22). Similarly, the risk did not vary by drug class (DPP-4 inhibitors: pooled adjusted HR, 1.09; 95% CI, 0.86-1.22; GLP-1 agonists: pooled adjusted HR, 1.04; 95% CI, 0.81-1.35) and there was no evidence of a duration-response association.In this large population-based study, use of incretin-based drugs was not associated with an increased risk of acute pancreatitis compared with other oral antidiabetic drugs.
Pre-surgical prediction of early biochemical recurrence with expressed prostatic secretion (EPS) biomarkers.
Authors: Jennifer Anne Linehan, Timothy G. Wilson, Mark H. Kawachi, Clayton S. Lau, Kristina Wittig, Katarzya Lamparska, Camille Amparo, Rosa Mejia, Daniel Jeske, Fang Lai, Steven S. Smith
Journal: Journal of Clinical Oncology (2016)

e16593 Background: A number of methods have been proposed for the prediction of earlybiochemical recurrence since recurrence within 2.5-3 yrs after surgery is associated with higher risk of prostate specific death. Most methods rely on post-surgical pathology; therefore they cannot be used to predict a favorable surgical outcome. Our objective was to develop biomarkers in EPS specimens obtained non-invasively that would improve the prediction of early biochemical recurrence prior to surgery defined as PSA ³ 0.2ng/ml detected within 2.5 years of surgery. Methods: We prospectively collected 855 EPS specimens prior to robot-assisted radical prostatectomy. Of those, 378 have been followed for biochemical recurrence over 2.5 years. RNA expression from PSA, Thioredoxin Reductases 1 and 2, PCA3, and TMPRSS2:ERG fusions were quantified with biomarker specific reverse transcription polymerase chain reactions. PSA Proteolytic Activity (PPA) was quantified using a novel method. The data was modeled using logistic regression, random forests and cross-validated. Results: A baseline using biopsy Gleason sum and PSA value was constructed with logistic regression. ROC analysis gave an AUC value of 0.8176 for the absence of biochemical recurrence within 2.5 yrs. A model containing the PCA3 RNA level normalized to the input RNA value, and PPA, improve the AUC of the model to 0.8820 (p value of 0.0046.) Random forest analysis was applied to the data using all variables available, however a statistical comparison showed that the logistic regression classifier was preferred. At 5% fixed false negative rate adding PPA and PCA3 values to Gleason sum and serum PSA improved the false positive rate by 33%. At a fixed false negative rate of 5%, the pre-surgical test also improved the false positive rate over a post-surgical test comprising, serum PSA, and post-surgical pathology values for major and minor pattern Gleason, extracapsular extension and seminal vesicle involvement. Conclusions: PSA proteolytic activity and PCA3 RNA are effective biomarkers in EPS specimens for the pre-surgical prediction of the early biochemical recurrence after surgery that should have utility in counseling patients prior to prostatectomy.
Risk of Hepatocellular Carcinoma in Patients with Hepatitis C Virus Who Achieved Sustained Virological Response
Authors: M Kudo
Journal: Liver Cancer (2016)

The recent development of interferon-free direct-acting antivirals (DAAs) has had a significant impact on the already great advances made in the treatment of hepatitis C. Combination therapy with pegylated interferon, ribavirin and simeprevir has achieved a sustained virological response (SVR) rate of approximately 70% in patients with hepatitis C caused by the genotype Ib virus. Combination therapy using daclatasvir and asunaprevir, which was approved in Japan in September 2014, has increased the SVR rate to approximately 95%. A clinical trial testing sofosbuvir-ledipasvir combination therapy (approved in September 2015 in Japan and October and November 2014 in the USA and EU, respectively) showed an SVR rate of nearly 100% in patients with genotype 1b hepatitis C virus. Combination therapy with ombitasvir and paritaprevir, which has a powerful therapeutic effect (SVR rate ≥95%), also became available in Japan from November 2015. Because interferon-based therapy is not possible in patients aged >70 years, in patients with cirrhosis, or in patients with a low platelet count, the above DAAs (which have extremely low rates of adverse effects) are extensively indicated. DAAs can be administered to almost all hepatitis C patients, including the elderly and those with compensated liver cirrhosis, and rapidly eradicate hepatitis C viruses; high SVR rates are achieved even in elderly cirrhotic patients with a high risk of liver cancer. Consequently, a new clinical problem has emerged, namely, the development of liver cancer after SVR [1,2,3,4,5,6,7,8,9,10,11,12]. Thus, two new unmet needs have arisen in the clinical setting: (1) finding the best possible way to assess the risk of liver cancer development after SVR is achieved and (2) establishing a liver cancer screening program for these patients [13,14].
Abstract 2525: Sema3C promotes glioma stem cell survival and radioresistance
Authors: Jianghong Man, Jocelyn Shoemake, Qiulian Wu, Jennifer Yu
Journal: Cancer Research (2016)

Abstract Introduction: Different cancer cell compartments often communicate through soluble factors to facilitate tumor growth. Glioma stem cells (GSCs) are a subset of tumor cells that resist standard therapy to contribute to disease progression. How GSCs employ a distinct secretory program to communicate with and nurture each other over the non-stem tumor cell (NSTC) population is not well defined. Methods/Materials: GSCs were enriched from patient specimens and functionally validated. We used a candidate approach to screen for secreted factors that were preferentially used by GSCs but not NSTCs. Expression was assessed by Western blot, and confirmed by immunohistochemistry and immunofluorescence in vitro and in human and mouse GBM tissues. Ligand-receptor interactions were confirmed by co-immunoprecipitation. Rac activity was assessed by Rac-GTP pulldown. Co-culture epistasis experiments were performed using knockdown and recombinant protein approaches. Glioma stem cell marker analysis (CD133, Sox2, Olig2), cell viability (ATP-dependent assays), apoptosis (TUNEL, PI/AnnexinV, cleaved caspase 3/7), self-renewal (tumorsphere formation and limiting dilution assay) and invasion (transwell migration assay) were performed. GSCs were separated in PlexinD1 hi and lo populations by FACS. Radiation (3 Gy) was delivered by Cs-137 irradiator. GSCs were used to establish orthotopic xenograft models of glioblastoma and tumor growth and animal survival were assessed. Results: We have found that GSCs preferentially secrete Sema3C and coordinately express PlexinA2/D1 receptors to activate Rac1/NF-κB signaling in an autocrine and paracrine loop to promote their own survival. Importantly, Sema3C is not expressed in neural progenitor cells (NPCs) or NSTCs. Disruption of Sema3C induced apoptosis of GSCs, but not NPCs or NSTCs, and suppressed tumor growth in orthotopic models of glioblastoma. Introduction of activated Rac1 rescued the Sema3C knockdown phenotype in vivo. Furthermore, GSCs that expressed high levels of Plexin receptors were more resistant to radiation, and Sema3C and Plexin receptors were upregulated after irradiation. Together, these data support that Sema3C signaling contributes to radiation resistance. Conclusions: Our study supports targeting Sema3C to break this GSC-specific autocrine/paracrine loop to improve glioblastoma treatment, potentially with a high therapeutic index. Citation Format: Jianghong Man, Jocelyn Shoemake, Qiulian Wu, Jennifer Yu. Sema3C promotes glioma stem cell survival and radioresistance. [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 2525.
Feasibility of a prospective host cell reactivation assay (HCRA) in non-small cell lung cancer (NSCLC) patients.
Authors: P. Mendez, M. Taron, T. Moran, E. Carcereny, V. Quiroga, P. Grassi, M. A. Fernandez, P. Gomez, J. Sanchez, R. Rosell
Journal: Journal of Clinical Oncology (2010)

10586 Background: DNA repair capacity (DRC)—the ability to repair BPDE-induced DNA adducts—measured in peripheral blood lymphocytes (PBLs) by the HCRA has been shown to correlate with survival in patients (p) treated with cisplatin-based chemotherapy. p with high DRC had significantly shorter survival (Bosken et al. JNCI 2002). However, the HCRA of DRC has not been tested prospectively. Methods: Cryopreserved PBLs from 41 NSCLC p were cultured for 96 hours under phytohaemagglutinin stimulation. The pmaxGFP plasmid was nucleoporated in the cells of the host under two different experimental conditions: (i) undamaged (GFP-UND) and (ii) 254nm UV light-damaged plasmid DNA (1,000 J/m2) (GFP-DAM). After transfection, the cells were incubated for 24 hours in culture media to allow, firstly, repair of UV-damaged plasmids, and secondly, reexpression of the GFP reporter protein. By flow cytometry, the dead cells (positively stained with propidium iodide) were excluded and DRC was calculated in alive cells as follows: percentage DRC = (pmaxGFP-DAM/pmaxGFP-UND) * 100, where pmaxGFP-DAM and pmaxGFP-UND correspond to the percentage of alive cells positive for GFP protein. Results: There were no differences in DRC according to gender, season of the year or histology. Median DRC was 8.77 for p with PS 0, 10.49 for p with PS 1, and 21.60 for p with PS 2 (p=0.009). p treated with chemotherapy, with or without surgery and/or radiotherapy, had a higher relative risk (RR) of death associated with increased DRC (p=0.07) (Table). Conclusions: HCRA measured in PBLs is feasible and can be useful in monitoring NSCLC p. Serial measurements to detect increments in DRC can provide a marker of acquired resistance to cisplatin-based chemotherapy. The correlation of DRC with the expression of DNA repair genes in the tumor should be investigated. Cox proportional hazards model of the RR of death associated with increased DRC Unadjusted RR (95%CI) 0.82 (0.66-1.02) p=0.07 Adjusted* RR (95%CI) (for age, sex, cigarettes/day, stage) 0.81 (0.65-1.02) p=0.07 No significant financial relationships to disclose.
Spleen Uptake on Bone Scan After Frequent Platelet and RBC Transfusions
Authors: Pierre De Marini, Annegret Laplace, Julien Matuszak, Luc-Matthieu Fornecker, Izzie Jacques Namer
Journal: Clinical Nuclear Medicine (2016)

A 21-year-old man, allogeneic hematopoietic stem cell transplantation recipient, was referred to our nuclear medicine department for a suspicion of knee osteonecrosis. Bone scan with Tc-HMDP did not show abnormal bone uptake but an intense spleen accumulation. F-FDG PET/CT performed on the same day showed no pathological spleen uptake. The patient had secondary hemochromatosis resulting from frequent transfusions in the setting of a chronic graft versus host disease with hemolysis and thrombocytopenia. The last RBC and platelet transfusions were performed 9 and 2 days before the examination, respectively. Secondary hemochromatosis and recent transfusions may explain our findings.
Management of Refractory Hemorrhage in a Kala-Azar Patient with Thrombocytopenia and Coagulopathy by Using Recombinant Factor VIIa (rFVIIa).
Authors: Goksel Leblebisatan, Ilgen Sasmaz, Bulent Antmen, Yurdanur Kilinc, Umit Sizmaz Celik, Kurthan Mert3, Necmi Aksaray
Journal: Blood (2005)
A Word From Our Sponsors
Authors: Paul Bergl
Journal: JAMA (2016)

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Low Expression of Nuclear Glucocorticoid Receptor Gene NR3C1 in Newly Diagnosed Myeloma Correlates with Inferior Prognosis and Is Rescued by Thalidomide
Authors: Christoph Heuck, Jackie Szymonifka, Qing Zhang, Saad Usmani, Bijay Nair, Sarah Waheed, Yazan Alsayed, Frits van Rhee, Elias J. Anaissie, Antje Hoering, John Crowley, John D Shaughnessy, Bart Barlogie
Journal: Blood (2011)
Abstract LB-158: Simultaneous targeting of the cell cycle and transcription through irreversible inhibition of CDK7: a novel, new therapeutic approach for high-grade glioma
Authors: Sameer Greenall, Terrance G. Johns
Journal: Cancer Research (2016)

Abstract High Grade Glioma (HGG), an incurable aggressive neoplasm of the brain, is characterised by a diverse array of genetic aberrations including those associated with receptor tyrosine kinase (RTK) signalling and cell cycle regulation pathways. Furthermore, HGG possess a highly heterogeneous intratumoral transcriptional profile, both at the global and subclonal levels, that allows for rapid resistance to a wide spectrum of therapeutics. Cyclin dependent kinase 7 (CDK7) presents an opportunity to target proliferation and global transcription simultaneously as it is the CDK activating kinase that controls multiple checkpoint progressions through the cell cycle as well as stabilising the RNA polymerase II-based transcriptional apparatus. Using a new irreversible inhibitor of CDK7, THZ1, we demonstrate that a panel of 10 patient-derived primary HGG cells lines, representing a diverse array of genotypes and phenotypes, were all exquisitely sensitive to THZ1 treatment at low nanomolar doses. THZ1 induced global transcription downregulation as measured by microarray analysis and resulted in potent caspase 3/7 activation, DNA damage and apoptosis. Cell cycle in all lines was arrested at the G2/M phase regardless of p53, CDKN2A/B or RB status, with substantial aneuploidy observed. Additionally, THZ1 treatment results in the dramatic loss of several RTKs critical in driving HGG including EGFR, EGFRvIII, PDGFR-α, PDGFR-β, MET, FGFR-3 and AXL, resulting in reduced PI3K/AKT, MAPK/ERK and STAT3 activation. Efficacy in ex vivo tumor slices and in vivo orthotopic experiments will be presented as well as insights into possible mechanisms of resistance. Our work suggest that irreversible inhibition of CDK7 represents a novel and effective treatment for HGG. Citation Format: Sameer Greenall, Terrance G. Johns. Simultaneous targeting of the cell cycle and transcription through irreversible inhibition of CDK7: a novel, new therapeutic approach for high-grade glioma. [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 LB-158.