tbuckley/cabot-search huggingface dataset:
Abstract POSTER-CTRL-1216: Profile of BRCA testing in ovarian cancer patients in the US and EU
Authors: JE Tyczynski, S Moss, P De Richter
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Around 13% of patients with ovarian cancer harbor mutations in the BRCA genes. Their disease has distinct characteristics which may impact treatment pathways. However, currently only a selected subset of ovarian cancer patients are offered testing for BRCA mutation, based largely upon family history of BRCA-related tumors. Frequencies of, and barriers to testing are not well characterized; therefore, our objective was to describe the current BRCA testing practices among women diagnosed with ovarian cancer. Methods: A survey of 465 oncologists, 513 pathologists and 97 laboratory directors, including detailed questionnaires for 435 ovarian cancer patients, across the US, UK, France, Germany, Italy and Spain was conducted during 2013 by Ipsos Healthcare syndicated MDx Monitor. Results: Physician awareness of BRCA testing in ovarian cancer patients varies: 61–86% in EU and over 90% in US. 50–67% of oncologists in EU, compared with over 80% in US, claim to have used BRCA testing within 6 months from diagnosis. On average, between 24% (US) to 7% (UK) of ovarian cancer patients were tested for BRCA post-diagnosis with large variations between physicians. Guidelines and patient requests were drivers for testing; barriers included perceived lack of clinical utility/targeted therapies (~35%), lack of BRCA risk factors (~5–70% depending on country), patient refusal (~5%), and reimbursement/cost (~15%). In all markets, both germline and somatic BRCA testing were common. Testing was generally performed in remote laboratories for efficiency. In US, most testing was conducted by Myriad; in EU several different tests, including 5% that were developed locally (by individual laboratories), were used. Conclusions: While there is broad knowledge and use of BRCA testing, the survey has highlighted significant barriers which may prevent ovarian cancer patients from being offered the test. Ongoing research aims to demonstrate the value of testing a broader cohort of patients, to identify individuals who may benefit from more personalized treatment approaches. Citation Format: Tyczynski JE, Moss S, De Richter P. Profile of BRCA testing in ovarian cancer patients in the US and EU [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1216.
Making Every Mobile Heart Count!
Authors: Adrian F. Hernandez
Journal: JAMA Cardiology (2016)

Michael V. McConnell, MD, MSEE; Anna Shcherbina, MEng; Aleksandra Pavlovic, BS; Julian R. Homburger, BS; Rachel L. Goldfeder, MS; Daryl Waggot, MSc; Mildred K. Cho, PhD; Mary E. Rosenberger, PhD; William L. Haskell, PhD; Jonathan Myers, PhD; Mary Ann Champagne, RN, MS; Emmanuel Mignot, MD, PhD; Martin Landray, MB, ChB, PhD; Lionel Tarassenko, MA, DPhil; Robert A. Harrington, MD; Alan C. Yeung, MD; Euan A. Ashley, MB, ChB, DPhil
Abstract 4122: C-Met inhibition sensitivity in vitro: Autocrine vs. paracrine activation of the c-Met pathway
Authors: Veronica Hughes, Dietmar W. Siemann
Journal: Cancer Research (2015)

Abstract Tumor cells frequently harbor abnormalities in signaling pathways, leading to increased migration, invasion, survival, angiogenesis, and proliferation. C-Met is one such commonly aberrant pathway. C-Met is a receptor tyrosine kinase critical for embryogenesis and liver repair, and protein levels are often elevated in a large variety of tumors. C-Met is activated by the endogenous ligand Hepatocyte Growth Factor (HGF). HGF is produced by mesenchymal cells and stimulates the c-Met protein, leading to a variety of downstream signaling pathways that result in increased migration, proliferation, survival, and angiogenesis. While many tumor cells express the c-Met receptor, a number of tumor types, including glioblastoma and osteosarcoma, have been observed to co-express both HGF and c-Met, and activate the pathway in an autocrine manner. The purpose of the current study was to determine whether tumor cells utilizing autocrine c-Met signaling would more sensitive to c-Met inhibition than those relying on the paracrine pathway. Experimental procedures include ELISA, western, migration, invasion, and clonogenic cell survival. Cell lines investigated include: two glioblastoma cell lines (U87 and U118), two osteosarcoma cell lines (OS156 and OS521), two fibrosarcoma cell lines (KHT and RIF), a breast (MDA-MB-231) and a prostate cancer cell line (PC-3). The small molecule c-Met inhibitor BMS-777607 and an HGF-neutralizing antibody were used to compare the effects interrupting the c-Met axis in these tumor cell lines. Data obtained using ELISA of conditioned media show that the glioblastoma (U87 and U118) and fibrosarcoma (KHT) cells secrete HGF, while the breast and prostate cells (MDA-MB-231; PC-3) do not. Furthermore western blot analysis showed higher basal levels of phospho-c-Met among the HGF-secreting cell lines in comparison to the non-HGF secreting cell lines, indicating that the KHT, U87, and U118 models activate c-Met in an autocrine manner, while the MDA-MB-231 and PC-3 lines activate c-Met in a paracrine manner. Importantly preliminary assessments indicate the autocrine glioblastoma and fibrosarcoma cell lines to be more sensitive to small molecule c-Met inhibition than the paracrine breast and prostate cancer cell lines. Investigations of additional cancer models are ongoing but our findings to date support the notion that cancer cells that autocrine activate the c-Met pathway may more susceptible to c-Met inhibition than those utilizing primarily paracrine activation of this pathway. Citation Format: Veronica Hughes, Dietmar W. Siemann. C-Met inhibition sensitivity in vitro: Autocrine vs. paracrine activation of the c-Met pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4122. doi:10.1158/1538-7445.AM2015-4122
TET enzymes: double agents in the transposable element–host genome conflict
Authors: Patricia Gerdes, Sandra R. Richardson, Geoffrey J. Faulkner
Journal: Genome biology (2016)

The mouse genome is replete with retrotransposon sequences, from evolutionarily young elements with mutagenic potential that must be controlled, to inactive molecular fossils whose sequences can be domesticated over evolutionary time to benefit the host genome. In an exciting new study, de la Rica and colleagues have uncovered a complex relationship between ten-eleven translocation (TET) proteins and retrotransposons in mouse embryonic stem cells (ESCs), implicating TETs as enhancers in the exaptation and function of retroelement sequences. Furthermore, they have demonstrated that active demethylation of retrotransposons does not correlate with their increased expression in ESCs, calling into question long-held assumptions regarding the importance of DNA demethylation for retrotransposon expression, and revealing novel epigenetic players in retrotransposon control. Please see related Research article: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1096-8
Comparative Analysis of Autologous Hematopoietic Cell Transplantation with Radioimmunotherapy (RIT) Based Conditioning Versus Total Body Irradiation (TBI) for High-Risk Diffuse Large Cell Lymphoma (DLCL): Toxicity and Efficacy
Authors: Amrita Krishnan, Joycelynne Palmer, Auayporn Nademanee, Andrew Raubitschek, Dave Yamauchi, Neil Martin Kogut, Laura Federico, Nicole Tsai, Stephen Forman
Journal: Blood (2010)
306. Production of Safe and Efficient AAV Vectors Using Minicircle DNA
Authors: Marco Schmeer, Tatjana Buchholz, Martin Schleef, Maria Schnödt, Anja Grünert, Ram Shankar, Thomas Fuchsluger, Hildegard Büning
Journal: Molecular Therapy (2016)

Especially in gene therapy applications, certain sequence motifs contained in plasmid DNA have to be avoided wherever possible. Such sequences are e.g. the bacterial ori or selection markers, only used for controlling the bacterial replication of the plasmid or to select for the plasmid during cloning or during production. Such sequence motifs are redundant in the intended therapeutic application and are completely removed in minicircles, i.e. circular and ccc-supercoiled expression cassettes. Since Adeno-Associated viral (AAV) vectors are produced by co-transfection of HEK293 producer cells, such bacterial sequence motifs may be an issue of an AAV vector-mediated gene transfer as well. Here, as a result of so-called reverse packaging events, an AAV vector-mediated transfer of not only the therapeutic gene but also of the antibiotic resistance gene into the target cells has been reported. Hence, this appears to be a potential risk of plasmid derived AAV vectors which can be overcome by using minicircle DNA for AAV production. Here we present first results showing that both constructs, the Helper & Packaging plasmid as well as the Transfer plasmid can be produced as minicircles although certain sequence motifs such as the ITRs have been identified to be an issue in minicircle production which has been overcome. These minicircles have been used for efficient AAV vector productions. However, only by replacing both, the Helper & Packaging plasmid as well as the transfer plasmid, encapsidation of the antibiotics resistance gene can be avoided.
Abstract 3402: Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer
Authors: Yosuke Togashi, Akihiro Kogita, Hiroki Sakamoto, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Masayuki Kitano, Masatoshi Kudo, Kazuto Nishio
Journal: Cancer Research (2015)

Abstract Purpose: We previously reported that activin produces a signal with a tumor suppressive role in pancreatic cancer (PC). Here, the association between plasma activin A and survival in patients with advanced PC was investigated. Experimental Design: The plasma activin A concentrations of patients with advanced PC were determined using an ELISA. The influence of ligands on PC cell lines was evaluated using an MTT assay and western blot analyses. The INHBA gene (beta subunit of inhibin) was overexpressed in PC cell lines, and this phenotype was investigated. Results: Contrary to our expectations, patients with high plasma activin A levels had a significantly shorter survival period than those with low levels (median survival, 314 days vs. 482 days, P = 0.034). The cellular growth of the MIA PaCa-2 cell line was greatly enhanced by activin A via non-SMAD pathways. The cellular growth and colony formation of an INHBA-overexpressed cell line were also enhanced. In a xenograft study, INHBA-overexpressed cells tended to result in a larger tumor volume, compared with a control. The bodyweights of mice inoculated with INHBA-overexpressed cells decreased dramatically, and these mice all died at an early stage, suggesting the occurrence of activin-induced cachexia. Conclusions: Our findings indicated that the activin signal can promote cancer progression in a subset of PC and might be involved in cachexia and that plasma activin A can be a novel prognostic factor in patients with advanced PC. The activin signal might be a novel target for the treatment of PC. Citation Format: Yosuke Togashi, Akihiro Kogita, Hiroki Sakamoto, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Masayuki Kitano, Masatoshi Kudo, Kazuto Nishio. Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3402. doi:10.1158/1538-7445.AM2015-3402
476. Clonal Tracking of Engineered Hematopoiesis In Vivo in Humans By Insertional Barcoding
Authors: Luca Biasco, Francesca Dionisio, Danilo Pellin, Serena Scala, Luca Basso Ricci, Samantha Scaramuzza, Cristina Baricordi, Andrea Calabria, Stefania Giannelli, Victor Neduva, David J. Dow, Eugenio Montini, Clelia Di Serio, Luigi Naldini, Alessandro Aiuti
Journal: Molecular Therapy (2015)

Upon gene therapy (GT) for adenosine deaminase (ADA) deficient-SCID and Wiskott-Aldrich Syndrome (WAS), gene-corrected hematopoietic stem/progenitor cells (HSPC) generated a stable genetically engineered hematopoietic system where each vector-marked cell is univocally barcoded by a vector integration site (IS). To study the dynamics of human hematopoietic system, we collected by LAM-PCR+Illumina sequencing 28.539.414 sequence reads corresponding to 89.373 IS tagging clones belonging to 13 different cell types purified from the bone marrow and the peripheral blood of 4 WAS patients up to 48 months after GT. We firstly identified identical IS shared among CD34+ progenitors, and mature Myeloid/Lymphoid cells as markers of the real-time clonal output of vector-marked HSPC clones in vivo. We unraveled the nature and timing of short, intermediate and long term HSPC output showing that CD34+ clones active at 3-6 months after GT are not detectable at later follow up. Distinct waves of HSPC diversity were observed during the first 6-9 months after GT reaching a homeostatic equilibrium only by 12 months. By unsupervised clustering of IS similarities among lineages we unveiled diverse HSPC output towards lymphoid, myeloid and megakaryo-erythroid cells showing hints of a NK cells origin distinct from T and B cells. We exploited IS similarities to infere and test hematopoietic hierarchies by combining conditional probability distributions and static/dynamic graphical models of dependencies. We also estimated by mark-recapture approaches that just few thousands clones (1185-2884) are responsible for the long-term maintenance of the whole genetically engineered hematopoietic system. The ongoing analyses on IS collected from 7 distinct CD34+ subtypes isolated from GT patients will further increase HSPC tracking resolution. To evaluate the preservation of activity by transplanted HSPC we exploited data derived from the IS-based tracking of 4.845 clones in ADA-SCID patients performed for up to 6 years after GT. We showed that identical IS are consistently detected at multiple lineages level even several years after GT. Strikingly, by semi-quantitative PCRs on specific vector-genome junctions we tracked a fluctuating but consistent output of marked HSPC over a period of 5 years without the manifestation of clonal quiescence phases. Since gamma-retroviral vector used in this GT trial actively transduce only replicating cells, this provide the first evidence that HSPC, awaken from dormancy in vitro, can still retain in vivo long-term activity. Overall our work constitute the first molecular tracking of hematopoietic system in humans. The information gathered are crucial for the design of therapeutic approaches for a broad spectrum of hematological diseases and tumors.
Mortalin-2 (mthsp70/PBP74/Grp75) Mediates the Erythropoietin Signal To Stimulate Growth of Purified Human Erythroid Progenitor Cells.
Authors: Rie Ohtsuka, Yasunobu Abe, Tomomi Fujii, Junji Nishimura, Koichiro Muta
Journal: Blood (2006)
Safety and Efficacy of the Terminal Complement Inhibitor Eculizumab in Japanese Patients with Paroxysmal Nocturnal Hemoglobinuria: AEGIS Phase II Clinical Study Results.
Authors: Yuzuru Kanakura, Kazuma Ohyashiki, Tsutomu Shichishima, Shinichiro Okamoto, Kiyoshi Ando, Haruhiko Ninomiya, Tatsuya Kawaguchi, Shinji Nakao, Hideki Nakakuma, Jun-Ichi Nishimura, Taroh Kinoshita, Camille Bedrosian, Marye Ellen Valentine, Keiya Ozawa, Mitsuhiro Omine
Journal: Blood (2008)
Allogeneic Stem Cell Transplantation (allo-SCT) for Secondary Acute Myeloid Leukemia (AML) Following Breast Carcinoma.
Authors: Sameh Ayari, Mohamad Mohty, Karin Bilger, Gaelle Guillerm, Denis Guyotat, Mauricette Michallet, Norbert Ifrah, Patrice Chevallier
Journal: Blood (2009)
Collegiate Sports: Professionals All But in Name Raise Unique Bioethics Concerns in the Collection of Biometric Data
Authors: Ariela Lazan, Dov Greenbaum
Journal: The American Journal of Bioethics (2016)

Karkazis and Fishman (2017) present an interesting analysis of the bioethical dilemmas facing professional sports organizations seeking to incorporate biometric data in the analysis and optimizatio...
Abstract 1217: Determining the impact of CRPC-specific p53 mutation on therapeutic response and prostate tumor progression
Authors: Jeffry L. Dean, Jennifer K. Jones, Jonathan F. Goodwin, Karen E. Knudsen
Journal: Cancer Research (2015)

Abstract Prostatic adenocarcinoma (PCa) is the most frequently diagnosed non-cutaneous malignancy and second leading cause of cancer death in men in the US. Although organ-confined disease is manageable, treatment options for disseminated PCa are limited. First-line therapy for metastatic PCa targets the androgen receptor (AR) via androgen deprivation therapy (ADT); however, tumors often recur, displaying reactivation of AR signaling despite continued therapeutic targeting. There is currently no durable treatment for this advanced disease stage, termed castrate-resistant PCa (CRPC). While most localized PCa express wild-type p53, recent high-profile, genome-wide studies identified increased TP53 gene mutation rates in advanced disease (specifically CRPC). Using these data, we noted that the patient-derived, CRPC-specific p53 mutations observed are relatively unique to prostate cancer. These mutations occur in “hotspot” clusters altered in other tumor types, but represent distinct amino acid changes seemingly unique to prostate cancer. While the underlying consequences of these CRPC-specific p53 mutations are unknown, it was hypothesized that their presence in the DNA-binding domain of p53 protein may represent “gain-of-function” (GOF) alterations that direct the transcription factor to alternative, pro-tumorigenic gene targets. Our preliminary findings strongly support this contention and reveal that these p53 mutations are major drivers of CRPC phenotypes. Specifically, our findings demonstrate that mutant p53: 1. Selectively alter p53 activity, based on analyses of PCa-relevant p53 target genes; 2. Compromise DNA damage response; 3. Alter AR signaling and response to AR-directed therapeutics; and 4. Promote transition to castration-resistance. These data are further supported by recent longitudinal studies of patient progression, wherein the R248Q mutation was found to be a key genetic alteration identifying lethal disease. While future investigation will be directed to better understand the specific contribution of individual DDR mutations, it is clear that deregulation of DNA damage repair and response pathways is likely to underlie increased genomic instability that is observed among advanced prostate cancers. Citation Format: Jeffry L. Dean, Jennifer K. Jones, Jonathan F. Goodwin, Karen E. Knudsen. Determining the impact of CRPC-specific p53 mutation on therapeutic response and prostate tumor progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1217. doi:10.1158/1538-7445.AM2015-1217
Exportin 7 (RanBP16) Plays An Essential Role in Terminal Erythroid Chromatin Condensation and Enucleation
Authors: Shilpa Hattangadi, Karly Burke, Jennifer Eng, Jeffrey D. Cooney, Junxia Wang, Maki Murata-Hori, Barry H. Paw, Harvey F. Lodish
Journal: Blood (2011)
90. Vector Biodistribution After Recombinant AAVrh10 Intrathecal Delivery in Non-Human Primates
Authors: Gwladys Gernoux, Florie Borel, Guangping Gao, Robert H. Brown, Christian Mueller
Journal: Molecular Therapy (2016)

Intrathecal (IT) delivery of adeno-associated viral (AAV) vector is currently used for the treatment of neurodegenerative disorders. To date, there is no standardized method to deliver the vector into the cerebrospinal fluid (CSF). Several parameters could impact the transduction efficacy among them the dose, the AAV serotype or the volume of injection. In this study, we analyzed the impact of large vector volume administered in the lumbar CSF on the vector biodistribution. Cynomolgus monkeys were injected with a serotype 10 AAV vector (AAVrh10) a serotype known to transduce efficiently the CNS via a pre-implanted catheter. The catheter was inserted after a hemilaminectomy at approximately the L5 vertebra, and advanced intrathecally with the tip located near the thoracolumbar junction. The rAAVrh10 (5.0 ml) was administered as two 2.5 ml infusions (the second infusion was approximately six hours after initiation of the first infusion). The infusion rate was 7.5 ml/hr over approximately 20 minutes. For the duration of both infusion, the NHPs were restrained in a prone position with the restraint table tilted approximately 30 degrees head-down. The vector biodistribution was analyzed by digital PCR and the results demonstrate that viral genomes are detected along the entire length of the spinal cord but also in substantial levels in peripheral organs. Due to viral genomes detected in lymphoid organs, we are currently analyzing the immune response to AAV capsid. These results are important for assessing the safety of IT delivery in large animal models before translation to human clinical trials.
482. Editing of the CD40L Gene Restores Regulated CD40L Expression in X-HIGM Patient T Cells
Authors: Nick Hubbard, Yumei Song, David Hagin, Karen Sommer, Andrew Scharenberg, Troy Torgerson, David Rawlings
Journal: Molecular Therapy (2015)

X-linked hyper-IgM syndrome (X-HIGM) is a primary immunodeficiency syndrome characterized by insufficient CD40 Ligand (CD40L) expression, resulting in defective T-cell help, impaired immunoglobulin class-switching and recurrent opportunistic infections. Previously, constitutive CD40L expression in murine bone marrow cells and thymocytes was achieved by retroviral gene transfer and successfully corrected immune function. However, treated animals developed severe lymphoproliferative disease, likely due to constitutive CD40L surface expression. This demonstrated the importance of preserving endogenous gene regulation in this and other gene therapy endeavors. Here, we report efficient, on-target Homology Directed Repair (HDR) editing of the CD40L locus in primary human T cells using a combination of TALEN gene targeting and a donor template delivered transiently by recombinant Adeno-Associated Virus (rAAV). Our TALEN and donor template reagents were designed to insert a coding sequence (GFP or CD40L) upstream of the endogenous translation start site within Exon 1, thus allowing transgene expression to be regulated by the endogenous CD40L promoter, and included the CD40L 3'UTR to preserve known post-transcriptional regulation features. The kinetics of GFP and edited CD40L surface expression after PMA-Ionomycin stimulation paralleled that of endogenous CD40L in unedited T-cells. Additionally, activated T-cells expressing edited CD40L were able to bind CD40-Ig similar to unedited cells. When T-cells from X-HIGM patients were edited in this fashion, CD40L expression and CD40-Ig binding was restored, and repaired activated X-HIGM T-cells induced the expression of early activation markers and class switching of naïve B-cells in vitro. Finally, we found no differences in TCR repertoire or engraftment and stability in NSG mice between T cells that underwent gene editing vs. unedited cells. These results demonstrate the feasibility of site-directed gene repair to restore normally regulated CD40L protein expression and functional T-cell help.
Increase in Proportion of Th-17 Lymphocytes in Blood Heralds Overt Acute Graft Versus Host Disease in HSCT Patients.
Authors: Andrzej Lange, Dorota Dlubek, Emilia Jaskula, Daria Drabczak-Skrzypek, Mariola Sedzimirska, Janusz Lange
Journal: Blood (2008)