tbuckley/cabot-search huggingface dataset:
Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma
Authors: Rosemarie Marchan, Bettina Büttner, Jörg Lambert, Karolina Edlund, Iris Glaeser, Meinolf Blaszkewicz, Gregor Leonhardt, Lisa Marienhoff, Darius Kaszta, Moritz Anft, Carsten Watzl, Katrin Madjar, Marianna Grinberg, Eugen Rempel, Roland Hergenröder, Silvia Selinski, Jörg Rahnenführer, Michaela S. Lesjak, Joanna D. Stewart, Cristina Cadenas, Jan G. Hengstler
Journal: Cancer Research (2017)

Abstract Glycerophosphodiesterase EDI3 (GPCPD1; GDE5; GDPD6) has been suggested to promote cell migration, adhesion, and spreading, but its mechanisms of action remain uncertain. In this study, we targeted the glycerol-3-phosphate acyltransferase GPAM along with choline kinase-α (CHKA), the enzymes that catabolize the products of EDI3 to determine which downstream pathway is relevant for migration. Our results clearly showed that GPAM influenced cell migration via the signaling lipid lysophosphatidic acid (LPA), linking it with GPAM to cell migration. Analysis of GPAM expression in different cancer types revealed a significant association between high GPAM expression and reduced overall survival in ovarian cancer. Silencing GPAM in ovarian cancer cells decreased cell migration and reduced the growth of tumor xenografts. In contrast to these observations, manipulating CHKA did not influence cell migration in the same set of cell lines. Overall, our findings show how GPAM influences intracellular LPA levels to promote cell migration and tumor growth. Cancer Res; 77(17); 4589–601. ©2017 AACR.
Investigating denosumab as add-on neoadjuvant treatment for hormone receptor-negative, RANK-positive or RANK-negative primary breast cancer and two different nab-Paclitaxel schedules - 2x2 factorial design (GeparX).
Authors: Sherko Kümmel, Gunter Von Minckwitz, Valentina Nekljudova, Serban Dan Costa, Carsten Denkert, Claus Hanusch, Jens Bodo Huober, Christian Jackisch, Stefan Paepke, Jens Uwe Blohmer, Michael Untch, Andreas Schneeweiss, Sibylle Loibl
Journal: Journal of Clinical Oncology (2016)

TPS635 Background: RANK ligand (RANKL) functions via its receptor RANK and pharmacologic inhibition attenuates breast cancer (BC) development and metastatic progression. High RANK expression is associated in hormone receptor negative (HR-) BC with higher pathological complete response (pCR) rates. Denosumab, an antibody against RANKL, will be tested in patients with HR- primary BC in addition to neoadjuvant chemotherapy (NACT). Methods: GeparX will randomize 778 patients to NACT +/- denosumab (120mg sc every 4 weeks for 6 cycles), stratified by lymphocyte predominant BC ( ≤ 50% vs > 50% stromal tumor infiltrating lymphocytes [TILs]), HER2 status, and epirubicin/cyclophosphamide (EC, q2w vs q3w). Secondarily patients will be randomized to the backbone treatment of nab-paclitaxel (nP) 125mg/m² weekly + EC or nP 125mg/m² day 1,8 q22 + EC, stratified by the first randomization. Carboplatin will be given in triple negative (TNBC) and trastuzumab + pertuzumab in HER2+ BC. Patients with primary cT1c-cT4a-d BC, centrally confirmed HR- and centrally assessed HER2, Ki-67, TIL and RANK status on core biopsy can be enrolled. Primary objective is to compare pCR (ypT0 ypN0) rates of NACT +/- denosumab plus backbone treatment and of backbone treatment alone. Secondary objectives are interaction of denosumab treatment with RANK expression; pCR rates per arm for both randomizations in TNBC and HER2+ BC; pCR rates in RANK high vs low; other pCR definitions for both randomizations; response rates; breast conservation rates; toxicity and compliance; and survival. A large translational program is also planned. Sample size (primary endpoint) planning assumed a pCR improvement by denosumab from 54% to 65% (OR = 1.58; 2-sided α = 0.10; 92% power) and by different NACT schedule from 55% to 64% (OR = 1.45; 2-sided α = 0.10; 80% power; overall α = 0.20), requiring 778 patients. Results: Recruitment will start in QII/2016 and is planned for 18 months in 60 sites in Germany. Conclusions: GeparX investigates if the addition of denosumab to standard NACT will increase the pCR rate and which nab-paclitaxel schedule to prefer in primary BC. Clinical trial information: EudraCT No.: 2015-001755-72.
A Critical Role of Presynaptic Cadherin/Catenin/p140Cap Complexes in Stabilizing Spines and Functional Synapses in the Neocortex
Authors: Min-Yin Li, Wan-Ying Miao, Qiu-Zi Wu, Shun-Ji He, Guoquan Yan, Yanrui Yang, Jia-Jia Liu, M. Mark Taketo, Xiang Yu
Journal: Neuron (2017)
Abstract 336: TAB1 Initiates p38α Autophosphorylation During Myocardial Ischemia
Authors: Rekha Bassi, Pelin Arabacilar, Mike Marber
Journal: Circulation Research (2012)

The p38 mitogen-activated protein kinase (MAPK) family has been implicated in many aspects of cell biology including inflammation, gene expression, cell cycle progression, differentiation and apoptosis. The canonical pathway of p38 activation results in dual phosphorylation of p38 induced via TGF-beta activated kinase 1 (TAK1) which is an upstream Ser/Thr kinase of the MAPK kinases (MKK) of p38; MKK3/6. However, a MKK-independent mechanism of activation is proposed as TAK 1 binding protein 1 (TAB1) appears to induce autophosphorylation of p38 through a direct interaction during myocardial ischaemia, worsening injury. When human embryonic kidney cells are transfected with wild-type TAB1, there is a marked increase in activating dual phosphorylation of p38 compared to untransfected cells (5.3 ± 1.9 normalised to untransfected). The ATP-competitive p38 inhibitor SB203580 (1µM) markedly reduced the phosphorylation of transfected p38 (20.4 ± 9.7 vs 5.4 ± 1.5). An SB203580-resistant form of p38 (T106M) was also co-transfected with TAB1, and the resulting p38 phosphorylation was no longer reduced by the presence of SB203580 (12.4 ± 7.5 vs 12.0 ± 6.7) but was reduced by another pharmacological inhibitor, BIRB796 (10µM) that does not depend on T106 for binding (5.6 ± 1.1 vs 1.6 ± 0.4, P&lt;0.05). In conclusion, these findings suggest that p38 activation by autophosphorylation is TAB1-mediated.
RNA-Seq to reveal mitochondrial gene fusions in breast cancer.
Authors: Vartika Agrawal, Yee Him Cheung, Payal Keswarpu, George Somlo, Maysa Abu-Khalaf, William M. Sikov, Vinay Varadan, Lyndsay Harris, Nevenka Dimitrova
Journal: Journal of Clinical Oncology (2017)

e13019 Background: Several mitochondrial DNA (mtDNA) mutations have been identified in various types of human cancer. While gene fusions encoded by the nuclear genome have an important role in tumorigenesis, the contribution of the mitochondrial genome to this process is unclear. mtDNA has limited protective mechanisms compared to that for nuclear DNA (nDNA), and hence more susceptible to genomic aberrations. Methods: We sequenced RNA from pre and post treatment breast cancer samples obtained from neoadjuvant clinical trials BrUOG 211A/211B. Seventy-three of these samples were considered baseline and 61 were from post-treatment samples, 54 samples at both time points. Patients were given a run-in dose of bevacizumab (B), nab- paclitaxel (N) or trastuzumab (T), followed by combination biologic/chemotherapy (HER2- with B/carboplatin/N; HER2+ with T/carboplatin/N). RNA was derived from biopsy pairs obtained pre/post 10-day exposure to run-in monotherapy. We used TopHat-Fusion and deFuse for fusion detection. Results: On average, in each patient 4.6 mtDNA gene fusions were detected at the baseline and 4 in the post treatment samples. In this cohort we detected in total 385 mtDNA fusions across the baseline and 344 across the post-treatment samples. A number of fusions had recurrently shown drastic increase from baseline to post-treatment, such as MT-ATP6:MT-ND2 ( N = 9), MT-ND6:MT-CO2 ( N = 6), MT-ND6:MT-CO1 ( N = 10), and MT-ND4:MT-ATP6 ( N = 9). We observe that some mitochondrial genes such as MT-ND6 have as many as 7 gene partners. MT-ND6 appeared in fusions that were most abundant among both baseline and post-treatment samples with MT:ND4 ( N = 39), MT:ND2 ( N = 37) and MD:ATP6 ( N = 36). Interestingly, gene fusions MT-ND6:J01415.25, MT-CYB:MT-ND2 and MT-ND6:MT-ND1 were observed respectively in 9, 5 and 4 baseline samples but not in their post treatment equivalent. Conclusions: While several studies have examined the presence of mtDNA mutations in breast cancer, the role of mitochondrial gene fusions is unknown in cancer. In our breast cancer cohort we observed quite a high number of mitochondrial fusions, and some of them seem to be recurrent in multiple samples. This could potentially have clinical implications as knowledge of fusions in solid tumours gains.
Use of targeted next generation sequencing (NGS) to assess mutational load in glioblastoma (GBM).
Authors: Stephen Joseph Bagley, Priya Velu, Ashkan Bigdeli, Paul Hess, Arati Suvas Desai, Gerald P. Linette, MacLean Nasrallah, Donald M. O'Rourke, Steven Brem, Jennifer J. Morrissette
Journal: Journal of Clinical Oncology (2017)

2027 Background: Trials of immune checkpoint inhibitors in GBM are ongoing. Evidence from other tumors suggests that high mutational load predicts response to these agents. We estimated mutational load in adults with newly diagnosed GBM using targeted NGS and assessed its association with other clinicopathologic parameters. Methods: NGS was performed for all patients diagnosed with isocitrate dehydrogenase wild-type (IDH-WT) GBM at our institution since September 1, 2016. Our panel performs targeted exome sequencing of 153 cancer-related genes (+/- 10 bp at intron/exon boundaries) and detects insertions, deletions, and single nucleotide variants at an allele frequency of 2%. Polymorphisms present in &gt; 0.1% of the population according to the ExAC database and 1000 Genomes Project were filtered to reduce germline variants in the absence of matched normals. To avoid upward skewing of mutational load due to the panel’s preferential detection of genes recurrently mutated in cancer, alterations with known or likely functional disruption per the COSMIC database and/or our internal variant knowledge base were also not counted. The number of mutations counted was divided by the coding region target territory of the NGS panel (~0.5 Mb) to extrapolate mutational load to the whole exome. The Mann-Whitney U test was used to compare mutational load according to sex, age (≥65 vs. &lt; 65), and MGMT methylation status (positive vs. negative). Results: Of 28 patients, median age was 65, 75% were male, and 37% were MGMT-methylated. Mean mutational load was 3.6 mutations/Mb (range 0-8, standard deviation 2.3) and was higher in males (4.3, 95% CI 3.3-5.3) compared to females (1.4, 95% CI 0.03-2.8) (p = 0.004). Mutational load did not differ according to age or MGMT methylation. Conclusions: In newly diagnosed IDH-WT GBM, targeted NGS revealed an estimated mutation rate similar to that reported in whole exome sequencing studies. In addition, we detected a higher mutational load in males compared to females. The latter finding adds to recent evidence suggesting sex-specific differences in the biology of GBM, and implies that future studies should account for sex when assessing mutational load as a predictive marker of immune checkpoint inhibition.
Ongoing complete remissions (CR) in the phase 1 of ZUMA-1: a phase 1-2 multicenter study evaluating the safety and efficacy of KTE-C19 (anti-CD19 CAR T cells) in subjects with refractory aggressive B-cell Non-Hodgkin Lymphoma (NHL).
Authors: Sattva Swarup Neelapu, Frederick Lundry Locke, Nancy L. Bartlett, Tanya Siddiqi, Julio C. Chavez, Chitra Hosing, Amanda F. Cashen, L. Elizabeth Budde, Adrian Bot, John Rossi, Lynn Navale, Yizhou Jiang, Jeff Aycock, Meg Elias, Jeffrey S. Wiezorek, William Y. Go
Journal: Journal of Clinical Oncology (2016)

7559 This study is supported in part by The Leukemia & Lymphoma Society Therapy Acceleration Program Background: Durable remissions with CD28/CD3z anti-CD19 CAR T cells have been observed in patients with relapsed/refractory B cell malignancies at the NCI (Kochenderfer, JCO 2015; NCT00924326). KTE-C19 utilizes the same CAR construct as the NCI trial, but is centrally manufactured in a streamlined 6 - 8 day process. We present updated data from the phase 1 portion of ZUMA-1. Methods: KTE-C19 was administered at a target dose of 2 x 106 anti-CD19 CAR T cells/kg after a fixed dose of cyclophosphamide/fludarabine conditioning chemotherapy (Locke, ASH 2015). The primary objective was to evaluate the safety of KTE-C19. Secondary objectives were to evaluate the overall response rate, duration of response, levels of CAR T cells in the blood, and levels of serum cytokines. Key inclusion criteria were ECOG 0-1 and chemotherapy-refractory disease defined as progressive disease or stable disease as best response to last line of therapy, or disease progression ≤ 12 months after autologous stem celltransplant (ASCT). Results: As of Jan 15, 2016, seven subjects were dosed with KTE-C19. As previously reported, one subject experienced a dose-limiting toxicity of grade 4 cytokine release syndrome (CRS) and neurotoxicity (NT). All other ≥ gr 2 adverse events of CRS and NT resolved within 1 mo. No additional KTE-C19 related AEs were observed after 1 mo from dosing. 71% of subjects had an objective response with a 57% CR rate. Three subjects who had disease progression within 6 mo of ASCT have ongoing CR at 3-6+ mo. CAR T cells peaked within two weeks and were detectable 1-6+ mo post infusion. Updated results as of Apr 2016 will be presented. Conclusions: Ongoing CRs have been observed after a single KTE-C19 dose in subjects with refractory aggressive NHL. No new KTE-C19 related adverse events were observed with additional follow up. The central manufacturing process and the KTE-C19 regimen evaluated was deemed safe and feasible for further study and the phase 2 portion of ZUMA-1 is ongoing. Clinical trial information: NCT02348216.
Primary Breast Lymphoma in the United States: 1975–2013
Authors: Alexandra Thomas, Brian K. Link, Sean Altekruse, Paul A. Romitti, Mary C. Schroeder
Journal: JNCI Journal of the National Cancer Institute (2017)

Primary breast lymphoma (PBL) has gained attention with the description of breast implant-associated anaplastic large cell lymphoma (ALCL). Less is known about PBL incidence, treatment, and survival by lymphoma subtype.The Surveillance, Epidemiology, and End Results (SEER) registry database was queried for patients with PBL as first malignancy, with attention to non-Hodgkin Lymphoma PBL subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma (MZL), and ALCL. Incidence was estimated by age and subtype with joinpoint analyses, along with initial local therapy. Five-year relative and overall survival estimates were compared using z and two-sided log-rank tests.PBL incidence (per 1 000 000 women) increased from 0.66 (1975-1977) to 2.96 (2011-2013) with an annual percentage change (APC) of 5.3% (95% confidence interval [CI] = 3.8% to 6.9%, P < .001) from 1975 to 1999 and no statistically significant change thereafter. Incidence continues to increase for women younger than age 50 years (APC = 2.8%, 95% CI = 1.0% to 4.6%, P = .003) and for ALCL-PBL (APC = 11.8%, 95% CI = 0.2% to 24.9%, P = .047) and MZL-PBL (APC = 2.3%, 95% CI = -0.2% to 4.9%, P = .07), with the latter increasing significantly from 1995 to 2013 (APC = 7.5%, 95% CI = 3.4% to 11.8%, P = .001). Surgery and surgery with radiation declined from 2000 to 2013 as initial local therapy for PBL. Five-year relative survival for PBL improved markedly over four decades and was superior for stage I DLBCL-PBL and stage I follicular PBL than for corresponding systemic presentations.PBL has increased in incidence over the last four decades and continues to increase for younger women and for some subtypes. The rise in imaging and procedures to the breast might enhance diagnostic sensitivity for PBL. Further study of the etiologies of PBL is needed.
Triple negative breast cancer (TNBC): Analysis of age and stage distribution and survival between African American and Caucasian women in a predominant low-income population.
Authors: Sheeba V. Tano, Mindie Michelle Kavanaugh, Prakash Peddi, Richard P. Mansour, Runhua Shi, Gary Von Burton
Journal: Journal of Clinical Oncology (2017)

e12586 Background: Triple negative breast cancers (TNBC) represent roughly 15% of all breast cancer and are associated with decreased overall survival. A higher incidence of TNBC has been seen in younger and African American patients. We investigated the effect of age and race relative to outcomes of patients with TNBC seen at a state charity hospital system. Methods: This retrospective review identified 194 pts with TNBC diagnosed between 1993-2011 at LSUHSC-Shreveport, a state charity hospital. TNBC was defined as ER/PR both &lt;1% and HER2neu not overexpressed by FISH analysis. The patient’s race, age at diagnosis, stage at diagnosis, treatment, relapse free survival (RFS), overall survival and survival following confirmed metastatic disease were analyzed. Results: There was no statistical difference in frequency of stage between groups. Although not statistically significant, there was a trend to worse RFS in AA and in young pts of both races. Younger age at diagnosis did have an inferior median survival as compared to older pts regardless of race or stage (p=0.0476). There was no difference in median survival following confirmation of metastatic disease between races (p=0.3574) or between age groups (p=0.8548); (median survival = 31 mos, 2.56-204 mos). Conclusions: In a predominantly low income patient population the incidence of TNBC was higher in the AA and in the young (age ≤ 50) as expected. There was no difference in stage or frequency within the populations. However, outcomes appeared to be worse in the younger pts and in AA patients with higher recurrence rate. Survival following first recurrence was similar regardless of age and race. Further analysis of etiologies for racial and age disparities is needed. [Table: see text]
Single- or double-unit UCBT following RIC in adults with AL: a report from Eurocord, the ALWP and the CTIWP of the EBMT
Authors: Frédéric Baron, Annalisa Ruggeri, Eric Beohou, Myriam Labopin, Mohamad Mohty, Didier Blaise, Jan J Cornelissen, Patrice Chevallier, Guillermo Sanz, Eefke Petersen, Bipin N Savani, Eliane Gluckman, Arnon Nagler
Journal: Journal of Hematology & Oncology (2017)

The feasibility of cord blood transplantation (CBT) in adults is limited by the relatively low number of hematopoietic stem/progenitor cells contained in one single CB unit. The infusion of two CB units from different partially HLA-matched donors (double CBT) is frequently performed in patients who lack a sufficiently rich single CB unit.We compared CBT outcomes in patients given single or double CBT following reduced-intensity conditioning (RIC) in a retrospective multicenter registry-based study. Inclusion criteria included adult (≥18 years) patients, acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), complete remission (CR) at the time of transplantation, first single (with a cryopreserved TNC ≥ 2.5 × 107/kg) or double CBT between 2004 and 2014, and RIC conditioning.Data from 534 patients with AML (n = 408) or ALL (n = 126) receiving a first single (n = 172) or double (n = 362) CBT were included in the analyses. In univariate analysis, in comparison to patients transplanted with a single CB, double CB recipients had a similar incidence of neutrophil engraftment but a suggestion for a higher incidence of grade II-IV acute GVHD (36 versus 28%, P = 0.08). In multivariate analyses, in comparison to single CBT recipients, double CBT patients had a comparable incidence of relapse (HR = 0.9, P = 0.5) and of nonrelapse mortality (HR = 0.8, P = 0.3), as well as comparable overall (HR = 0.8, P = 0.17), leukemia-free (HR = 0.8, P = 0.2) and GVHD-free, relapse-free (HR = 1.0, P = 0.3) survival.These data failed to demonstrate better transplantation outcomes in adult patients receiving double CBT in comparison to those receiving single CBT with adequate TNC after RIC.
<i>BRCA</i> mutation carriers undergoing combined mastectomy with immediate reconstruction and gynecologic risk-reducing surgery: An analysis of outcomes.
Authors: Olga Ivanov, Nicole Centers, Karen Wiercinski, Eva Reina, Cynthia Buffington, Aileen Caceres
Journal: Journal of Clinical Oncology (2017)

e13004 Background: The aim of this study was to assess outcomes of a multidisciplinary model for combined prophylactic and/or therapeutic mastectomy with immediate reconstruction and gynecologic risk-reducing surgery in patients with hereditary breast cancer syndromes. Methods: Between 2012 and 2016, 12 patients with documented BRCA1 and BRCA2 mutations underwent combined surgery at our facility. Procedures included bilateral mastectomy, axillary lymph node staging, immediate expander based reconstruction and minimally invasive salpingo-oophorectomy with added hysterectomy when indicated. All procedures were performed in a single operating room setting by rotating subspecialty teams. Results: Patient characteristics included a mean (+SD) BMI of 32.1±6.7 (23-44) kg/m 2 and ASA of 2.2±0.4 (2-3). Fifty-eight percent (7/12) were premenopausal. Patient’s average age was 45.8+10.8 (30-73). Therapeutic mastectomy for breast cancer was performed in 4/12 patients. Of the 4 affected patients 2 had neo-adjuvant chemotherapy for locally advanced cancer. The remaining 8/12 had prophylactic mastectomies. Risk-reducing salpingo-oophorectomy was performed in 12/12 patients. Seventy-five percent (9/12) underwent concurrent minimally invasive hysterectomy for suspected gynecologic malignancy, leiomyoma, complex endometrial hyperplasia, dysmenorrhea and menorrhagia. Two gynecologic specimens required mini-laparotomy for removal. Mean total operative time was 283.3±66.5 (206-447) minutes and estimated blood loss (EBL) was 209.2±139.2 (50-500) ml. Hospital length of stay (LOS) was 1.4±0.7 (1-3) days. There were no significant differences (p &gt; 0.05) in operative time, EBL, or LOS in comparing therapeutic to prophylactic mastectomies. Follow-up revealed no postoperative wound infections. Conclusions: Combined mastectomy with immediate reconstruction and gynecologic risk reducing surgery had no untoward surgical complications with a zero postoperative wound infection rate. Although a small study population, results indicate this approach is a prudent and feasible multidisciplinary model that can be offered to BRCA mutation carriers.
The importance of risk communication and documentation for patients with cutaneous adverse drug reactions
Authors: N.R. Adler, L.V. Graudins, A.K. Aung
Journal: British Journal of Dermatology (2017)

We read with interest Teo et al.'s recently published article examining cutaneous adverse drug reactions (cADR) referred to an inpatient liaison dermatology service.1 The authors assessed the number and types of cADR encountered and subsequent documentation.1 The diagnosis and management of cADR has been recognised by NICE Guidelines on Drug Allergy as a high-priority area for quality improvement.2 We commend Teo and colleagues1 for examining an essential, yet often overlooked, component of health service quality. We would like to further highlight the importance of risk communication, documentation and patient-centred care, aspects that are imperative for severe cADR.

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Dilatation pneumatique de l'achalasie après échec de la cardiomyotomie de Heller
Authors: A Tebaibia, D Boutarene, N Oumnia, M Lahcene, N Matougui, MA Boudjella, B Touchene
Journal: Endoscopy (2005)

La prise en charge thérapeutique de la dysphagie après cardiomyotomie de Heller pour achalasie est actuellement controversée. Elle repose sur la ré intervention ou la dilatation instrumentale. Peu d'études regroupant toutes un nombre limité de patients ont été rapportées.