tbuckley/cabot-search huggingface dataset:
PARP1 in triple-negative breast cancer: Expression and therapeutic potential.
Authors: M. B. Cotter, A. Pierce, P. M. McGowan, S. F. Madden, L. Flanagan, C. Quinn, D. Evoy, J. Crown, E. McDermott, M. J. Duffy
Journal: Journal of Clinical Oncology (2011)

1061 Background: Triple negative breast cancers (TNBC) are so named as they lack expression of ER, PR and do not exhibit overexpression of HER2. Consequently, targeted therapy is currently unavailable for this subgroup of patients. The aims of this study were to investigate the expression of poly (ADP-ribose) polymerase 1 (PARP1) in TNBC and test the effect of the PARP inhibitor, Olaparib, on the growth of TNBC cell lines in vitro. Methods: PARP1 protein was measured in 90 breast cancers using Western blotting. Pooled data from 22 published gene expression databases (N=approx 4,000 patients) was used to relate PARP1 mRNA to patient outcome. The effect of Olaparib on the growth of TNBC lines was investigated using the acid phosphatase assay and Calcusyn software. Results: Using Western blotting, 4 forms of PARP1 were found in extracts of breast cancer, migrating at 116 kDa (main form), 65 kDa (necrotic form), 50 kDa (necrotic form) and 27 kDa (apoptotic form). The parental form of PARP, ie, the 116 kDa form was detected in all of 12 TN and in 73/78 (94%) of non TN samples. Using Kaplan-Meier analysis, high PARP1 mRNA expression was significantly related to adverse patient outcome (p=0.002). IC50 values for the inhibitory effect of Olaparib on the growth of the TNBC cell lines, MDA 231 and BT20 were 1.1 and 3.2 μM, respectively, while IC50 values for 5 non TN cell lines varied from 4.4 μM to16.7 μM. Conclusions: Our results suggest that PARP1 is expressed in the majority of TN and non-TN breast cancer and that high levels are associated with adverse outcome. Furthermore, our in vitro findings suggest that olaparib may be more effective in TN than non TN breast cancers. Acknowledgement: The authors thank SFI (SRC award, 08/SRC/B1410 to MTCI) for funding this work.
Antigen-specific immunity and tumor inflammation after vaccination with BPX-101, a drug-activated dendritic cell vaccine for metastatic castration-resistant prostate cancer (mCRPC).
Authors: T. M. Wheeler, B. Zhao, G. Sonpavde, J. D. McMannis, Y. Bai, N. Lapteva, M. Seethammagari, J. M. Levitt, D. M. Spencer, K. M. Slawin
Journal: Journal of Clinical Oncology (2011)

176 Background: We report evidence of antigen-specific immunity and severe prostate cancer inflammation and necrosis after vaccination in patients enrolled in a phase I-IIa clinical trial of BPX-101, a drug-activated DC vaccine for mCRPC. Methods: Twelve men with progressive, mCRPC were enrolled in a 3+3 dose escalation trial evaluating BPX-101 and activating agent AP1903. BPX-101, which targets prostate-specific membrane antigen (PSMA), was administered intradermally every 2 weeks for 6 doses, followed 24 hours after each dose by infusion of AP1903 (0.4 mg/kg). Injection site skin biopsies were performed after the fourth vaccination. T cells cultured from the skin biopsy ex vivo were stimulated with PSMA protein or control antigens, and were analyzed using Luminex microspheres for 30 inflammatory cytokines/chemokines. One patient (#1007) with an intact prostate developed lower urinary tract bleeding after the fifth vaccination and underwent a transurethral resection of bleeding prostate cancer tissue. Paraffin-embedded blocks were stained for hematoxylin and eosin (H&amp;E). Immunohistochemical stains for CD3, CD4, CD8 and CD34 were also performed. Results: Of 5 subjects with evaluable injection site biopsy results, all exhibited PSMA-specific immunity (3 T H 1-biased and 2 T H 2- biased). Subject 1007's injection site biopsy demonstrated a significant &gt;10-fold increase in IFN-gamma and IL-2 after stimulation by PSMA, compared to stimulation by ovalbumin, consistent with induction of a strong PSMA-specific CTL or T H 1-biased immune response. H&amp;E stained resected prostate tissue demonstrated Gleason 8 (4+4) prostate adenocarcinoma exhibiting a severe inflammatory response, consisting of infiltrating plasma cells and CD4 + and CD8 + T cells. Large areas of necrosis were seen adjacent to inflamed prostate cancer tissue. Conclusions: Vaccination with BPX-101 followed by AP1903 can induce a strong, PSMA-specific immune response. Furthermore, evidence of severe prostate cancer-specific inflammation and necrosis, associated with a strong PSMA-specific immune response has been observed after multiple doses of BPX-101. [Table: see text]
Implantable Cardioverter–Defibrillators in Nonischemic Cardiomyopathy
Authors: Rebecca E. Berger, Kenneth A. Ellenbogen, William G. Stevenson
Journal: New England Journal of Medicine (2016)

This interactive feature on treatment for nonischemic cardiomyopathy in patients who are receiving medical therapy offers a case vignette accompanied by essays that support either implantation of an ICD or no implantation. Share your comments and vote at NEJM.org.
PILLAR-1: Preliminary Results of a Phase II Study of mTOR Inhibitor Everolimus In Patients with Mantle Cell Lymphoma (MCL) Who Are Refractory or Intolerant to Bortezomib
Authors: Owen A. O'Connor, Leslie Popplewell, Jane N. Winter, RuiRong Yuan, Anna Robeva, Helene Cauwel, Quincy Chau, Michael Wang
Journal: Blood (2010)
The metabolomic signature of pancreatic cancer in urine.
Authors: Vanessa Wylie Davis, Dan E. Schiller, Michael B. Sawyer
Journal: Journal of Clinical Oncology (2012)

180 Background: Pancreatic cancer is one of the leading causes of cancer-related death, due partly to the lack of early detection and screening methods. Metabolomics, the newest of the “omics” sciences, provides a means for non-invasive screening of early tumor associated perturbations in cellular metabolism. We applied metabolomic techniques to identify urinary metabolites capable of facilitating diagnosis of pancreatic cancer. Methods: Urine samples from pancreatic cancer patients (n=55) and healthy volunteers (n=25) were collected and examined using 1H-NMR spectroscopy. Targeted profiling of spectra using Chenomx NMR Suite 7.0 software permitted quantification of 66 metabolites. Unsupervised (PCA) and supervised (PLS-DA) multivariate pattern recognition techniques were applied to discriminate between sample spectra of pancreatic cancer patients and healthy volunteers using SIMCA-P (version 11, Umetrics, Umeå, Sweden). Results: Significant differences were found when comparing concentrations of 66 metabolites in urines of healthy volunteers and pancreatic cancer patients. Those metabolites contributing the most class discriminating information included choline, 2-aminobutyrate, urea and 2-oxoglutarate. Clear distinctions between pancreatic cancer patients and healthy controls were noted when PLS-DA was applied to the data set. Model parameters for both goodness of fit R2, and predictive capability Q2, were high (R2 = 0.829; Q2 = 0.76). Model validity was tested using response permutation and results were suggestive of excellent predictive power. Application of PLS-DA to the data set also revealed clear discrimination of Stage I-III and Stage IV disease states, with the following model parameters, R2 = 0.62; Q2 =0.45. Conclusions: Urinary metabolomics detected clear differences in metabolic profiles of pancreatic cancer patients and healthy volunteers. Early results presented here suggest that metabolomic approaches may facilitate discovery of novel biomarkers capable of early disease detection.
Thymic Function Following Nonmyeloablative Allografting for the Treatment of Hematological Malignancies
Authors: Benedetto Bruno, Roberto Sorasio, Silvia Cena, Christian Sfiligoi, Luisa Giaccone, Marcella Spagnolo, Milena Gilestro, Fulvia Giaretta, Rainer F. Storb, Paola Omedè, Mario Boccadoro
Journal: Blood (2008)
Effect of PEDF on survival and in vivo antitumor activities of low-dose chemotherapy in castration-refractory prostate cancer.
Authors: Natalie Gaines, Thomas Nelius, Jessica Gillen, Katherine Rinard, Jose Lopez, Jennifer Hirsch, Everardo Cobos, C. Patrick Reynolds, Stephanie Filleur
Journal: Journal of Clinical Oncology (2012)

e15103 Background: The development of metronomic/low-dose treatment with conventional chemotherapeutic drugs has recently shown promise in the treatment of castration-refractory prostate cancer (CPRC). Pigment Epithelium-Derived Factor (PEDF) is a natural angio-inhibitor which is downregulated in prostate cancer. Previously we demonstrated that overexpression of PEDF in human CRPC PC3 cells decreased tumor growth in vivo. In the present study, we further validate PEDF anti-tumor properties in highly metastatic CRPC LNCaP-derivative CL1 cells. We also hypothesized that PEDF may enhance the cytotoxic effects of low-dose docetaxel (Doc) and cyclophosphamide (CTX) chemotherapies in vivo. Methods: Human PC3 and CL1 cell lines were genetically modified to stably express fluorescent DsRed Express protein with PEDF. Resulting cells were characterized in vitro for PEDF expression by western blot and for proliferation by growth curves and clone formation in Matrigel. PEDF anti-tumor effects were assessed on established SC xenografts in mice treated with Doc (5mg/kg IP every 4 days, 1mg/kg IP daily for 10 days, 0.5mg/kg IP every other day), CTX (10-20mg/kg in drinking water) or placebo. Survival studies were performed by injecting CL1 cells that express PEDF or control into the left lobe of the dorsal prostate of anesthetized mice. Results: We showed that PEDF inhibits proliferation and induces differentiation of all CPRC cells tested in vitro. Similarly, PEDF expression decreases by 85% and 70% the development of SC PC3 and CL1 tumors, respectively. In the survival study, we found that PEDF expression prolongs significantly (p=0.01; 95% confidence interval) median survival of CL1 tumor-bearing mice (53±0.001 days versus 57±1). Most importantly, we demonstrated that PEDF enhances the cytotoxic effects of low-dose chemotherapy on established tumors (best Doc dose: 1mg/kg for PC3 and 5mg/kg for CL1; best CTX dose: 10mg/kg for PC3 and CL1). Conclusions: This data reinforces the significance of PEDF as a potential new target when treating advanced prostate cancer. It also emphasizes PEDF as a promising new agent to enhance the anti-tumor efficacy of low-dose Doc and CTX chemotherapies.
Exploratory analysis of prognostic factors for patients (pts) with advanced soft tissue sarcoma (ASTS) receiving combination chemotherapy: A joined study of the EORTC Soft Tissue and Bone Sarcoma Group and the French Sarcoma Group.
Authors: N. Penel, M. M. Van Glabbeke, B. Bui Nguyen, M. Ouali, S. Mathoulin-Pelissier, S. Marreaud, A. Italiano, V. Brouste, P. C. W. Hogendoorn, J. Coindre, J. Blay, P. Hohenberger
Journal: Journal of Clinical Oncology (2011)

10090 Background: Even if all randomized trials failed to demonstrate significant advantage for combination, most of sarcoma experts are reluctant to administer single-agent regimen in all categories of pts and suspect that combination could be beneficial in some particular subsets of pts that need to be objectively identified. Methods: The aim of this study was to identify prognostic factors (PF) for 3 subsets of pts receiving different combination regimens: 469 pts having received CYVADIC regimen (1976-89), 925 pts having received doxorubicin + ifosfamide (AI) and 403 pts having received MAID regimen (1990-2009). “Other metastasis” termed non-lung, non-liver and non-bone metastasis. The primary endpoint was overall survival (OS). The PF have been identified using log-rank tests and Cox model. Results: The median OS of pts treated with CYVADIC was 10 months. The potential PF identified by univariate analysis were PS>0 (p<0.0001), grade>1 (0.0057), other metastasis (p=0.0005). The multivariate analysis retains the following independent F: PS=1 (HR=2.27), PS=2 (HR=3.48) and Grade III (OR=2.72). The median OS of pts treated with AI was 13.0 months. The potential PF were age ≥40 (p=0.0008), PS>0 (p<0.0001), grade (p=0.0019), other primary location than limbs or superficial trunk (p=0.0468), presence of liver metastasis (p=0.0016) and presence of other met. (p=0.0024). The multivariate analysis retained the following independent PF: grade III (HR=1.97), presence of liver met. (HR=1.44) and presence of other met. (HR=1.33). The median OS of pts treated with MAID was 26.3 months. The potential poor PF identified by univariate analysis were: PS>0 (p<0.0001), grade (p=0.0057) and presence of other met. (p=0.0005). The multivariate analysis retains the following independent PF: PS=1 (HR=2.27), PS=2 (HR=3.48) and Grade III (HR=2.72). Conclusions: Three PF seemed to be associated with longer OS in patients with ASTS and treated with combination regimens: good PS, low grade and absence of liver/other met. The role of poly-chemotherapy warrants further exploration in these subgroups of pts.
Antiretroviral Boosting Agent Cobicistat Increases the Pharmacokinetic Exposure and Anticoagulant Effect of Dabigatran in HIV-Negative Healthy Volunteers
Authors: Lori A. Gordon, Parag Kumar, Kristina M. Brooks, Anela Kellogg, Maryellen McManus, Raul M. Alfaro, Khanh Nghiem, Jomy M. George, Jay Lozier, Scott R. Penzak, Colleen Hadigan
Journal: Circulation (2016)
Phase I Trial of Rituximab, Cladribine and Temsirolimus (RCT) for Initial Therapy of Mantle Cell Lymphoma
Authors: David J. Inwards, Paul Fishkin, Betsy R. LaPlant, Matthew T. Drake, Paul Kurtin, Daniel Nikcevich, Donald Wender, Bradley Lair, Thomas E. Witzig
Journal: Blood (2012)
Allele-specific expression in the human heart and its application to postoperative atrial fibrillation and myocardial ischemia
Authors: Martin I. Sigurdsson, Louis Saddic, Mahyar Heydarpour, Tzuu-Wang Chang, Prem Shekar, Sary Aranki, Gregory S. Couper, Stanton K. Shernan, Jon G. Seidman, Simon C. Body, Jochen D. Muehlschlegel
Journal: Genome Medicine (2016)

Allele-specific expression (ASE) is differential expression of each of the two chromosomal alleles of an autosomal gene. We assessed ASE patterns in the human left atrium (LA, n = 62) and paired samples from the left ventricle (LV, n = 76) before and after ischemia, and tested the utility of differential ASE to identify genes associated with postoperative atrial fibrillation (poAF) and myocardial ischemia. Following genotyping from whole blood and whole-genome sequencing of LA and LV samples, we called ASE using sequences overlapping heterozygous SNPs using rigorous quality control to minimize false ASE calling. ASE patterns were compared between cardiac chambers and with a validation cohort from cadaveric tissue. ASE patterns in the LA were compared between patients who had poAF and those who did not. Changes in ASE in the LV were compared between paired baseline and post-ischemia samples. ASE was found for 3404 (5.1%) and 8642 (4.0%) of SNPs analyzed in the LA and LV, respectively. Out of 6157 SNPs with ASE analyzed in both chambers, 2078 had evidence of ASE in both LA and LV (p < 0.0001). The SNP with the greatest ASE difference in the LA of patients with and without postoperative atrial fibrillation was within the gelsolin (GSN) gene, previously associated with atrial fibrillation in mice. The genes with differential ASE in poAF were enriched for myocardial structure genes, indicating the importance of atrial remodeling in the pathophysiology of AF. The greatest change in ASE between paired post-ischemic and baseline samples of the LV was in the zinc finger and homeodomain protein 2 (ZHX2) gene, a modulator of plasma lipids. Genes with differential ASE in ischemia were enriched in the ubiquitin ligase complex pathway associated with the ischemia-reperfusion response. Our results establish a pattern of ASE in the human heart, with a high degree of shared ASE between cardiac chambers as well as chamber-specific ASE. Furthermore, ASE analysis can be used to identify novel genes associated with (poAF) and myocardial ischemia.
MEN1112/OBT357, an Anti Bst1/CD157 Humanized Antibody Inducing Acute Myelogenous Leukemia (AML) Blast Depletion in an Autologous Ex Vivo Assay: A Potential New Targeted Therapy for AML
Authors: Adriano Venditti, Francesco Buccisano, Luca Maurillo, Maria Ilaria Del Principe, Andrea Coppola, Patrizia Palomba, Roberto Arriga, Daniela Bellarosa, Alessandro Bressan, Keith Wilson, Stefano Manzini, Angela Capriati, Cecilia Simonelli, Monica Binaschi, Sergio Amadori, Giuseppe Sconocchia
Journal: Blood (2015)
Conflicts everywhere! Perceptions, actions, and cognition all entail memory and reflect conflict
Authors: Jerome S Jordan, David W Vinson
Journal: Behavioral and Brain Sciences (2016)

Morsella et al. assert that the function of consciousness is to determine which of many competing action options is expressed through the skeletomuscular system at any given moment. The present commentary addresses this issue from the first-person perspective and agrees with Morsella and colleagues, yet further proposes that the option-selection function of consciousness plays out in cognition as well.
Intracellular ERK Phosphorylation Levels after Ligation of the B Cell Receptor Are Associated with CD38 and Immunoglobulin Gene (VH) Germline Concordance in Chronic Lymphocytic Leukaemia
Authors: James R Bailey, Ria L Brathwaite, Gina L Eagle, Jo C Butt, Lynn Cawkwell, David J Allsup
Journal: Blood (2008)
MAGI2 Mutations Cause Congenital Nephrotic Syndrome
Authors: Agnieszka Bierzynska, Katrina Soderquest, Philip Dean, Elizabeth Colby, Ruth Rollason, Caroline Jones, Carol D. Inward, Hugh J. McCarthy, Michael A. Simpson, Graham M. Lord, Maggie Williams, Gavin I. Welsh, Ania B. Koziell, Moin A. Saleem
Journal: Journal of the American Society of Nephrology (2016)

Steroid–resistant nephrotic syndrome (SRNS), a heterogeneous disorder of the renal glomerular filtration barrier, results in impairment of glomerular permselectivity. Inheritance of genetic SRNS may be autosomal dominant or recessive, with a subset of autosomal recessive SRNS presenting as congenital nephrotic syndrome (CNS). Mutations in 53 genes are associated with human SRNS, but these mutations explain ≤30% of patients with hereditary cases and only 20% of patients with sporadic cases. The proteins encoded by these genes are expressed in podocytes, and malfunction of these proteins leads to a universal end point of podocyte injury, glomerular filtration barrier disruption, and SRNS. Here, we identified novel disease–causing mutations in membrane–associated guanylate kinase, WW, and PDZ domain–containing 2 ( MAGI2 ) through whole-exome sequencing of a deeply phenotyped cohort of patients with congenital, childhood–onset SRNS. Although MAGI2 has been shown to interact with nephrin and regulate podocyte cytoskeleton and slit diaphragm dynamics, MAGI2 mutations have not been described in human SRNS. We detected two unique frameshift mutations and one duplication in three patients (two families); two siblings shared the same homozygous frameshift mutation, whereas one individual with sporadic SRNS exhibited compound heterozygosity. Two mutations were predicted to introduce premature stop codons, and one was predicted to result in read through of the normal translational termination codon. Immunohistochemistry in kidney sections from these patients revealed that mutations resulted in lack of or diminished podocyte MAGI2 expression. Our data support the finding that mutations in the MAGI2 gene are causal for congenital SRNS.
Fluorescence In Situ Hybridization (FISH) Using a Subtelomeric 11q Probe as a New Diagnostic Tool for Congenital Thrombocytopenia Caused by Deletions in 11q.
Authors: Dorothea Gadzicki, Gudrun Michaelsen, Cornelia Rudolph, Doris Steinemann, Christoph M. Happel, Karl Welte, Christoph Klein, Holger Toennies, Peter Lichter, Udo Kontny, Charlotte Marie Niemeyer, Brigitte Schlegelberger
Journal: Blood (2004)
Tongue Fasciculations in Organophosphate Poisoning
Authors: Bharath A Chhabria, Ashish Bhalla
Journal: New England Journal of Medicine (2016)

A 15-year-old boy who lived with his family on a farm presented to the ED with vomiting, diarrhea, and altered sensorium. During insertion of a feeding tube, diffuse tongue fasciculations, shown in a video, were noted.
FDG-PET/CT for Monitoring Response of Melanoma to the Novel Oncolytic Viral Therapy Talimogene Laherparepvec
Authors: Matthew F. Covington, Clara N. Curiel, Lois Lattimore, Ryan J. Avery, Phillip H. Kuo
Journal: Clinical Nuclear Medicine (2016)

61-year-old woman with stage IIIa (T3a N1a M0) left lower leg melanoma with lesions suggestive of in-transit metastases 8 months following wide local excision and femoral nodal dissection. FDG-PET/CT demonstrated 5 FDG-avid in-transit nodal metastases in the distal left leg, confirmed on biopsy. Talimogene laherparepvec (T-VEC) oncolytic immunotherapy consisting of intralesional injections of modified herpes simplex virus–expressing granulocyte-macrophage colony-stimulating factor was completed over 6 months. Subsequent FDG-PET/CT demonstrated reduced or resolved FDG activity in the treated in-transit metastases and a new FDG-avid left thigh in-transit metastasis. FDG-PET/CT can monitor response to T-VEC and potentially other novel viral immunotherapies.
Late Relapses Following High Dose Chemotherapy and Autologous Stem Cell Transplant in Patients with Diffuse Large B Cell Lymphoma in the Rituximab Era
Authors: Carla Casulo, Hunter D Bradley, Megan M. Herr, Ferdous Barlaskar, Andrew Evans, Richard Burack, Jane L. Liesveld, Michael W. Becker, Laurie A. Milner, Paul M. Barr, Jonathan W. Friedberg
Journal: Blood (2014)
Immunophenotyping Features in Acute Myeloid Leukemia (AML) with NPM1+ and/or FLT3+
Authors: Pervin Topcuoglu, Klara Dalva, Sinem Civriz Bozdag, Onder Arslan, Muhit Ozcan, Osman Ilhan, Hamdi Akan, Meral Beksac, Gunhan Gurman
Journal: Blood (2011)