tbuckley/cabot-search huggingface dataset:
Viral Vector Reprogramming of Adult Resident Striatal Oligodendrocytes into Functional Neurons
Authors: Marc S. Weinberg, Hugh E. Criswell, Sara K. Powell, Aadra P. Bhatt, Thomas J. McCown
Journal: Molecular Therapy (2017)

Recent advances suggest that in vivo reprogramming of endogenous cell populations provides a viable alternative for neuron replacement. Astrocytes and oligodendrocyte precursor cells can be induced to transdifferentiate into neurons in the CNS, but, in these instances, reprogramming requires either transgenic mice or retroviral-mediated gene expression. We developed a microRNA (miRNA)-GFP construct that in vitro significantly reduced the expression of polypyrimidine tract-binding protein, and, subsequently, we packaged this construct in a novel oligodendrocyte preferring adeno-associated virus vector. Ten days after rat striatal transduction, the vast majority of the GFP-positive cells were oligodendrocytes, but 6 weeks to 6 months later, the majority of GFP-positive cells exhibited neuronal morphology and co-localized with the neuronal marker NeuN. Patch-clamp studies on striatal slices established that the GFP-positive cells exhibited electrophysiological properties indicative of mature neurons, such as spontaneous action potentials and spontaneous inhibitory postsynaptic currents. Also, 3 months after striatal vector administration, GFP-positive terminals in the ipsilateral globus pallidus or substantia nigra retrogradely transported fluorescent beads back to GFP-positive striatal cell bodies, indicating the presence of functional presynaptic terminals. Thus, this viral vector approach provides a potential means to harness resident oligodendrocytes as an endogenous source for in vivo neuronal replacement.
Evidence for Cytogenetic and Fluorescence in Situ Hybridization (FISH) Risk Stratification of Newly Diagnosed Multiple Myeloma in the Era of Novel Therapies.
Authors: Prashant Kapoor, Rafael Fonseca, S. Vincent Rajkumar, Shirshendu Sinha, Morie A. Gertz, A. Keith Stewart, P. Leif Bergsagel, Martha Q. Lacy, David Dingli, Rhett P. Ketterling, Robert Kyle, Philip R. Greipp, Angela Dispenzieri, Shaji Kumar
Journal: Blood (2009)
Genome-wide mapping of 5-hydroxymethyluracil in the eukaryote parasite Leishmania
Authors: Fumiko Kawasaki, Dario Beraldi, Robyn E. Hardisty, Gordon R. McInroy, Pieter van Delft, Shankar Balasubramanian
Journal: Genome biology (2017)

5-Hydroxymethyluracil (5hmU) is a thymine base modification found in the genomes of a diverse range of organisms. To explore the functional importance of 5hmU, we develop a method for the genome-wide mapping of 5hmU-modified loci based on a chemical tagging strategy for the hydroxymethyl group. We apply the method to generate genome-wide maps of 5hmU in the parasitic protozoan Leishmania sp. In this genus, another thymine modification, 5-(β-glucopyranosyl) hydroxymethyluracil (base J), plays a key role during transcription. To elucidate the relationship between 5hmU and base J, we also map base J loci by introducing a chemical tagging strategy for the glucopyranoside residue. Observed 5hmU peaks are highly consistent among technical replicates, confirming the robustness of the method. 5hmU is enriched in strand switch regions, telomeric regions, and intergenic regions. Over 90% of 5hmU-enriched loci overlapped with base J-enriched loci, which occurs mostly within strand switch regions. We also identify loci comprising 5hmU but not base J, which are enriched with motifs consisting of a stretch of thymine bases. By chemically detecting 5hmU we present a method to provide a genome-wide map of this modification, which will help address the emerging interest in the role of 5hmU. This method will also be applicable to other organisms bearing 5hmU.
High-dimensional assessment of B-cell responses to quadrivalent meningococcal conjugate and plain polysaccharide vaccine
Authors: Daniel O’Connor, Elizabeth A. Clutterbuck, Amber J. Thompson, Matthew D. Snape, Maheshi N. Ramasamy, Dominic F. Kelly, Andrew J. Pollard
Journal: Genome Medicine (2017)

Neisseria meningitidis is a globally important cause of meningitis and septicaemia. Twelve capsular groups of meningococci are known, and quadrivalent vaccines against four of these (A, C, W and Y) are available as plain-polysaccharide and protein-polysaccharide conjugate vaccines. Here we apply contemporary methods to describe B-cell responses to meningococcal polysaccharide and conjugate vaccines. Twenty adults were randomly assigned to receive either a meningococcal plain-polysaccharide or conjugate vaccine; one month later all received the conjugate vaccine. Blood samples were taken pre-vaccination and 7, 21 and 28 days after vaccination; B-cell responses were assessed by ELISpot, serum bactericidal assay, flow cytometry and gene expression microarray. Seven days after an initial dose of either vaccine, a gene expression signature characteristic of plasmablasts was detectable. The frequency of newly generated plasma cells (CXCR3+HLA-DR+) and the expression of transcripts derived from IGKC and IGHG2 correlated with immunogenicity. Notably, using an independent dataset, the expression of glucosamine (N-acetyl)-6-sulfatase was found to reproducibly correlate with the magnitude of immune response. Transcriptomic and flow cytometric data revealed depletion of switched memory B cells following plain-polysaccharide vaccine. These data describe distinct gene signatures associated with the production of high-avidity antibody and a plain-polysaccharide-specific signature, possibly linked to polysaccharide-induced hyporesponsiveness.
Modulation of Interaction of Human Osteoprogenitor Cells with Hematopoietic Stem and Progenitor Cells
Authors: Frank Akwaa, Rakhil Rubinova, Benjamin J Frisch, Mark W LaMere, Kristen Marie O'Dwyer, Jane L. Liesveld, Michael W. Becker, Laura M. Calvi
Journal: Blood (2014)
Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma
Authors: Joseph P. Antonios, Horacio Soto, Richard G. Everson, Diana Moughon, Joey R. Orpilla, Namjo P. Shin, Shaina Sedighim, Janet Treger, Sylvia Odesa, Alexander Tucker, William H. Yong, Gang Li, Timothy F. Cloughesy, Linda M. Liau, Robert M. Prins
Journal: Neuro-Oncology (2016)

Adaptive immune resistance in the tumor microenvironment appears to attenuate the immunotherapeutic targeting of glioblastoma (GBM). In this study, we identified a tumor-infiltrating myeloid cell (TIM) population that expands in response to dendritic cell (DC) vaccine treatment. The aim of this study was to understand how this programmed death ligand 1 (PD-L1)–expressing population restricts activation and tumor-cytolytic function of vaccine-induced tumor-infiltrating lymphocytes (TILs). To test this hypothesis in our in vivo preclinical model, we treated mice bearing intracranial gliomas with DC vaccination ± murine anti–PD-1 monoclonal antibody (mAb) blockade or a colony stimulating factor 1 receptor inhibitor (CSF-1Ri) (PLX3397) and measured overall survival. We then harvested and characterized the PD-L1+ TIM population and its role in TIL activation and tumor cytolysis in vitro. Our data indicated that the majority of PD-L1 expression in the GBM environment is contributed by TIMs rather than by tumor cells themselves. While PD-1 blockade partially reversed the TIL dysfunction, targeting TIMs directly with CSF-1Ri altered TIM expression of key chemotactic factors associated with promoting increased TIL infiltration after vaccination. Neither PD-1 mAb nor CSF-1Ri had a demonstrable therapeutic benefit alone, but when combined with DC vaccination, a significant survival benefit was observed. When the tripartite regimen was given (DC vaccine, PD-1 mAb, PLX3397), long-term survival was noted together with an increase in the number of TILs and TIL activation. Together, these studies elucidate the role that TIMs play in mediating adaptive immune resistance in the GBM microenvironment and provide evidence that they can be manipulated pharmacologically with agents that are clinically available. Development of immune resistance in response to active vaccination in GBM can be reversed with dual administration of CSF-1Ri and PD-1 mAb.
Gene expression analysis of Manumycin, a natural farnesyltransferase (FTase) inhibitor, in drug-resistant IL-6-producing myeloma cells.
Authors: Sergio Marchini, Eleonora Marrazzo, Riccardo Bonomi, Luigi Mastromauro, Anna Maria Frassanito, Pietro Mariani, T. Fusaro, Massimo Broggini, Franco Dammacco
Journal: Cancer Research (2005)

60  Background: Multiple myeloma (MM) is a severe plasma cell malignancy which is frequently characterised, at molecular level, by constitutive Ras activation. FTase has emerged in the past as a potential target for the development of new anti-cancer agents. Based on our previous demonstration that IL-6-producing myeloma cells are refractory to Fas-drug-induced apoptosis, we have analyzed the effect of manumycin, a natural FTase inhibitor, on these IL-6-positive myeloma cells. Methods: Myeloma cells, freshly purified from bone marrow aspirates of 7 myeloma patients using CD138-microbeads, were incubated with manumycin (10 μM) for 6 to 24 hours. Drug activity and tumor cell apoptosis was evaluated by MTT assay and BrdU/PI staining, respectively. Caspase activation, Flip and Apo 2.7 Ag expression were evaluated by flow cytometry. Post-translational Ras processing was evaluated by Western blotting. Changes in gene expression after manumycin treatment were evaluated by microarray technique . Results: Manumycin prevented proliferation and induced apoptosis of myeloma cells. The effect was related to inhibition of the post-translational Ras processing. Further analysis showed that apoptosis induced by manumycin involved activation of caspase-3 and -8 and was prevented by specific caspase inhibitors. Furthermore, manumycin-induced apoptosis was associated with inhibition of constitutively active NF-kB and FLIP expression. In order to better characterise, at the molecular level, the effects of manumycin, changes in gene expression profile induced by manumycin treatment were compared to that of control untreated cells in a panel of 7600 genes (Atlass Glass Array, Beckton Dickinson, Milan Italy). Data mining revealed that at least 40 genes with a z score > or
FLT3 Internal Tandem Duplication and Kinase Domain Mutations Remain Poor Prognostic Markers in Intermediate Cytogenetic AML After Treatment with Transplant in First Remission
Authors: Mahmoud Aljurf, Hala Abalkhail, Fahed Almhareb, Naeem A. Chaudhri, Claudia Ulrike Walter, Mohammed Toulimat, Hazzaa Al Zahrani, Salem Khalil, Said Mohamed, Walid Rasheed, Fahad Alsharif, Maher Albitar
Journal: Blood (2011)
Roshini M Alles
Authors: Deirdre Lucas
Journal: BMJ (2017)

Roshini Alles trained in Sri Lanka. On completing a programme of postgraduate training in ear, nose, and throat medicine in Sri Lanka, she expanded her experience by training at St Thomas’ Hospital, London, and at the Royal National Throat, Nose and Ear Hospital (RNTNEH). She was the first doctor in Sri Lanka to obtain the MS in otorhinolaryngology. She returned to Sri Lanka in 1986, to take up the post of consultant ENT surgeon …
Analysis of Antigen-Specific T-Cell Responses and Regulatory T Cells Following Sibling Donor Immunization with Patient-Derived Idiotype Vaccine Prior to Non-Myeloablative Allogeneic Stem Cell Transplantation for Multiple Myeloma.
Authors: Myriam Foglietta, Sattva Neelapu, Daniel H. Fowler, Seth M. Steinberg, Larry W. Kwak, Michael R. Bishop
Journal: Blood (2009)
Updated Results of Combination Cytokine Immunotherapy In the Treatment of Aplastic Anemia and Myelodysplastic Syndrome (MDS)
Authors: Tapan Kadia, Farhad Ravandi, Guillermo Garcia-Manero, Elias Jabbour, Gautam Borthakur, Zeev Estrov, Sherry A. Pierce, Sergernne York, Hagop M. Kantarjian
Journal: Blood (2010)
Matched Unrelated Donor Hematopoietic Cell Transplantation Following Reduced-Intensity Conditioning for Treatment of Myelofibrosis.
Authors: David S. Snyder, Anthony S. Stein, Vinod Pullarkat, Firoozeh Sahebi, Sandra Cohen, Joycelynne Palmer, Nayan Vora, Ryotora Nakamura, Stephen J. Forman
Journal: Blood (2004)
Selective Disruption of PU.1 in Mature Dendritic Cells Affects Their Tissue Distribution and T Cell Homeostasis
Authors: Tadafumi Iino, Hiromi Iwasaki, Kentaro Kohno, Shin-ichi Mizuno, Yojiro Arinobu, Daniel G. Tenen, Boris Reizis, Koichi Akashi
Journal: Blood (2011)
It’s good to talk, actually talk
Authors: Brendan McCann
Journal: BMJ (2017)

It’s never good to start your day on the wrong end of a doctor’s finger, especially when your GP then informs you that you have an enlarged prostate gland. As a 30 year old oncologist with obstructive urinary symptoms, I had relegated prostatic hypertrophy far down my list of differential diagnoses.

A quick referral to urology, and a barrage of …
Gemtuzumab Ozogamicin with FLAG-IDA Is Effective for Children in Relapsed/Refractory Acute Myeloid Leukemia.
Authors: Bin Cho, Sun Young Kim, Dae Hyoung Lee, Young Joo Kwon, Young Shil Park, Hui Sung Hwang, Ji Kyoung Park, Pil Sang Jang, Nak Gyun Chung, Dae-Chul Jeong, Hack Ki Kim
Journal: Blood (2006)
Molecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy
Authors: Natalia Baran, Marina Konopleva
Journal: Clinical Cancer Research (2017)

Hypoxia is a known feature of aggressive solid tumors as well as a critical hallmark of the niche in aggressive hematologic malignances. Hypoxia is associated with insufficient response to standard therapy, resulting in disease progression and curtailed patients' survival through maintenance of noncycling cancer stem-like cells. A better understanding of the mechanisms and signaling pathways induced by hypoxia is essential to overcoming these effects. Recent findings demonstrate that bone marrow in the setting of hematologic malignancies is highly hypoxic, and that progression of the disease is associated with expansion of hypoxic niches and stabilization of the oncogenic hypoxia-inducible factor-1alpha (HIF1α). Solid tumors have also been shown to harbor hypoxic areas, maintaining survival of cancer cells via the HIF1α pathway. Developing new strategies for targeting hypoxia has become a crucial approach in modern cancer therapy. The number of preclinical and clinical trials targeting low-oxygen tumor compartments or the hypoxic bone marrow niche via hypoxia-activated prodrugs is increasing. This review discusses the development of the hypoxia-activated prodrugs and their applicability in treating both hematologic malignancies and solid tumors. Clin Cancer Res; 23(10); 2382-90. ©2017 AACR.
CAL-101, An Oral p110δ Selective Phosphatidylinositol-3-Kinase (PI3K) Inhibitor for the Treatment of B Cell Malignancies Inhibits PI3K Signaling, Cellular Viability and Protective Signals of the Microenvironment.
Authors: Brian J Lannutti, Sarah A Meadows, Adam Kashishian, Bart Steiner, Galina Pogosov, Olga Sala-Torra, Amy J Johnson, John C. Byrd, Jerald Radich, Neill A. Giese
Journal: Blood (2009)
Abnormal Expression and Function of the Lnk Adaptor Protein in Myeloproliferative Neoplasms (MPN).
Authors: Jean-Jacques Kiladjian, Fanny Baran-Marszak, Christophe Desterke, Bruno Cassinat, Hajer Magdoud, Elisabeth Mazoyer, Pierre Fenaux, Claude Gardin, Florence Cymbalista, Marie-Caroline Le Bousse-Kerdiles, Nadine Varin-Blank, Laura Velazquez
Journal: Blood (2009)
Abstract 10286: Myocardial Nitroso Redox Balance and Postoperative Atrial Electrical Remodelling Following Elective Cardiac Surgery on Cardiopulmonary Bypass: Molecular Mechanisms and Translational Implications of Perioperative Statin Therapy
Authors: Raja Jayaram, Nicky Goodfellow, Mei Hua Zhang, Svetlana Reilly, Michael Jones, Nikhil Pal, Rana Sayeed, Ravi DeSilva, Barbara Casadei
Journal: Circulation (2015)

Background: Systemic inflammation and increased myocardial production of reactive oxygen species (ROS) are associated with the development of postoperative atrial fibrillation (AF) and low cardiac output syndrome in patients undergoing cardiac surgery. Statins have been shown to exert rapid anti-inflammatory and antioxidant effects by inhibiting myocardial NOX2 oxidases and by increasing the bioavailability of nitric oxide (NO). Methods and Results: We first assessed the impact of cardiac surgery and cardiopulmonary bypass (CPB) on the atrial nitroso-redox balance in 116 patients and then investigated the effect of perioperative treatment with atorvastatin (80 mg once daily, for up to 6 days before surgery and 5 days thereafter) on nitric oxide synthase (NOS) activity, biopterin content, and the sources of ROS production (all by HPLC) in samples of the right atrial appendage obtained before and after CPB and reperfusion and on the postoperative atrial effective refractory period (AERP; by programmed electrical stimulation delivered using right atrial epicardial leads) in a placebo-controlled double-blind trial (ClinicalTrials.gov Identifier: NCT01780740) in 80 patients undergoing first-time elective cardiac surgery. Our findings show that increased ROS production by NOX2 and mitochondrial oxidases and uncoupling of the endothelial NOS isoform (eNOS), secondary to enzyme’s S-glutathionylation, are the main mechanism underlying the atrial nitroso-redox imbalance after CPB and reperfusion. Compared with placebo, atorvastatin prevented the rise in atrial NOX2 activity and maintained the functionally coupled status of eNOS. The AERP lengthened progressively over first four postoperative days and did not differ between the treatment groups (n= 29). Conclusions: Short-term statin therapy, at the dose conventionally used to lower LDL-cholesterol, prevents NOS uncoupling and nitroso-redox imbalance in the atrial myocardium of patients undergoing on-pump cardiac surgery. However, these changes have no significant impact on atrial refractoriness.
Perturbation of Genomic Instability by Wortmannin in Myeloma.
Authors: Jagannath Pal, Dheeraj Pelluru, Mariateresa Fulciniti, Samir B Amin, Leutz Buon, Rao Prabhala, Kenneth C. Anderson, Masood A Shammas, Nikhil C. Munshi
Journal: Blood (2009)
ATPS-87DEVELOPMENT AND IN VIVO VALIDATION OF BLOOD-BRAIN BARRIER TARGETING PEPTIDES
Authors: Kadri Toome, Pille Säälik, Anne-Mari Anton Willmore, Tarmo Mölder, Aleksander Sudakov, Kuldar Kõiv, Andrei Nikonov, Tambet Teesalu
Journal: Neuro-Oncology (2015)

Blood-brain barrier (BBB) is a major barrier to delivering drugs to the brain parenchyma. Affinity carriers able to cross BBB would allow delivery drugs for the treatment of neurological diseases such as multiple sclerosis, Huntington's, Parkinson's and Alzheimer's. In the presence of brain tumors the BBB is locally disrupted, however, the infiltrative  glioma cells distant from the tumor core hide behind intact BBB beyond the reach of anticancer therapies. Thus, the activity of brain cancer drugs would be potentiated by carriers that facilitate BBB penetration. Here, we used in vivo T7 phage display of cyclic CX7C peptide libraries on healthy Balb/C mice to identify peptides that home to brain upon systemic administration. In vivo biopanning in combination with deep sequencing of peptide-encoding phage genomic DNA and bioinformatics analyses led to identification of a peptide-phage clone that selectively homes to normal brain. Tested as an individual phage clone, the phage displaying the brain-homing peptide, KT1, showed about 50 times higher brain tropism compared to insertless control phage. In vivo alanine scan was used to map the residues that are critical for KT1 brain homing. Our ongoing work deals with elucidating the mechanism of KT1 recruitment to brain microvessels and evaluation of its potential as a BBB penetrating agent. We are also evaluating KT1 as a ligand for targeting drugs and imaging agents to glioblastomas, especially to the infiltrative guerilla glioma cells.
Prognostic Accuracy of Sepsis-3 Criteria for In-Hospital Mortality Among Patients With Suspected Infection Presenting to the Emergency Department
Authors: Yonathan Freund, Najla Lemachatti, Evguenia Krastinova, Mar van Laer, Yann-Erick Claessens, Aurélie Avondo, Céline Occelli, Anne-Laure Feral-Pierssens, Jennifer Truchot, Mar Ortega, Bruno Carneiro, Julie Pernet, Pierre-Géraud Claret, Fabrice Dami, Ben Bloom, Bruno Riou, Sébastien Beaune
Journal: JAMA (2017)

<h3>Importance</h3> An international task force recently redefined the concept of sepsis. This task force recommended the use of the quick Sequential Organ Failure Assessment (qSOFA) score instead of systemic inflammatory response syndrome (SIRS) criteria to identify patients at high risk of mortality. However, these new criteria have not been prospectively validated in some settings, and their added value in the emergency department remains unknown. <h3>Objective</h3> To prospectively validate qSOFA as a mortality predictor and compare the performances of the new sepsis criteria to the previous ones. <h3>Design, Settings, and Participants</h3> International prospective cohort study, conducted in France, Spain, Belgium, and Switzerland between May and June 2016. In the 30 participating emergency departments, for a 4-week period, consecutive patients who visited the emergency departments with suspected infection were included. All variables from previous and new definitions of sepsis were collected. Patients were followed up until hospital discharge or death. <h3>Exposures</h3> Measurement of qSOFA, SOFA, and SIRS. <h3>Main Outcomes and Measures</h3> In-hospital mortality. <h3>Results</h3> Of 1088 patients screened, 879 were included in the analysis. Median age was 67 years (interquartile range, 47-81 years), 414 (47%) were women, and 379 (43%) had respiratory tract infection. Overall in-hospital mortality was 8%: 3% for patients with a qSOFA score lower than 2 vs 24% for those with qSOFA score of 2 or higher (absolute difference, 21%; 95% CI, 15%-26%). The qSOFA performed better than both SIRS and severe sepsis in predicting in-hospital mortality, with an area under the receiver operating curve (AUROC) of 0.80 (95% CI, 0.74-0.85) vs 0.65 (95% CI, 0.59-0.70) for both SIRS and severe sepsis (<i>P</i> &lt; .001; incremental AUROC, 0.15; 95% CI, 0.09-0.22). The hazard ratio of qSOFA score for death was 6.2 (95% CI, 3.8-10.3) vs 3.5 (95% CI, 2.2-5.5) for severe sepsis. <h3>Conclusions and Relevance</h3> Among patients presenting to the emergency department with suspected infection, the use of qSOFA resulted in greater prognostic accuracy for in-hospital mortality than did either SIRS or severe sepsis. These findings provide support for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria in the emergency department setting. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT02738164