tbuckley/cabot-search huggingface dataset:
Hematopoietic Stem Cell Gene Therapy for Brain Metastases Using Myeloid Cell–Specific Gene Promoters
Authors: Tereza Andreou, Nora Rippaus, Krzysztof Wronski, Jennifer Williams, David Taggart, Stephanie Cherqui, Ashley Sunderland, Yolanda D Kartika, Teklu Egnuni, Rebecca J Brownlie, Ryan K Mathew, Sheri L Holmen, Christopher Fife, Alastair Droop, Mihaela Lorger
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Background Brain metastases (BrM) develop in 20–40% of cancer patients and represent an unmet clinical need. Limited access of drugs into the brain because of the blood-brain barrier is at least partially responsible for therapeutic failure, necessitating improved drug delivery systems. Methods Green fluorescent protein (GFP)-transduced murine and nontransduced human hematopoietic stem cells (HSCs) were administered into mice (n = 10 and 3). The HSC progeny in mouse BrM and in patient-derived BrM tissue (n = 6) was characterized by flow cytometry and immunofluorescence. Promoters driving gene expression, specifically within the BrM-infiltrating HSC progeny, were identified through differential gene-expression analysis and subsequent validation of a series of promoter-green fluorescent protein-reporter constructs in mice (n = 5). One of the promoters was used to deliver tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) to BrM in mice (n = 17/21 for TRAIL vs control group). Results HSC progeny (consisting mostly of macrophages) efficiently homed to macrometastases (mean [SD] = 37.6% [7.2%] of all infiltrating cells for murine HSC progeny; 27.9% mean [SD] = 27.9% [4.9%] of infiltrating CD45+ hematopoietic cells for human HSC progeny) and micrometastases in mice (19.3–53.3% of all macrophages for murine HSCs). Macrophages were also abundant in patient-derived BrM tissue (mean [SD] = 8.8% [7.8%]). Collectively, this provided a rationale to optimize the delivery of gene therapy to BrM within myeloid cells. MMP14 promoter emerged as the strongest promoter construct capable of limiting gene expression to BrM-infiltrating myeloid cells in mice. TRAIL delivered under MMP14 promoter statistically significantly prolonged survival in mice (mean [SD] = 19.0 [3.4] vs mean [SD] = 15.0 [2.0] days for TRAIL vs control group; two-sided P = .006), demonstrating therapeutic and translational potential of our approach. Conclusions Our study establishes HSC gene therapy using a myeloid cell–specific promoter as a new strategy to target BrM. This approach, with strong translational value, has potential to overcome the blood-brain barrier, target micrometastases, and control multifocal lesions.
Moral reasoning is the process of asking moral questions and answering them
Authors: Mark Alfano
Journal: Behavioral and Brain Sciences (2019)

Reasoning is the iterative, path-dependent process of asking questions and answering them. Moral reasoning is a species of such reasoning, so it is a matter of asking and answering moral questions, which requires both creativity and curiosity. As such, interventions and practices that help people ask more and better moral questions promise to improve moral reasoning.
The recent emergence of a highly related virulent Clostridium difficile clade with unique characteristics
Authors: H.A. Shaw, M.D. Preston, K.E.W. Vendrik, M.D. Cairns, H.P. Browne, R.A. Stabler, M.J.T. Crobach, J. Corver, H. Pituch, A. Ingebretsen, M. Pirmohamed, A. Faulds-Pain, E. Valiente, T.D. Lawley, N.F. Fairweather, E.J. Kuijper, B.W. Wren
Journal: Clinical Microbiology and Infection (2019)

ObjectivesClostridium difficile is a major global human pathogen divided into five clades, of which clade 3 is the least characterized and consists predominantly of PCR ribotype (RT) 023 strains. Our aim was to analyse and characterize this clade.MethodsIn this cohort study the clinical presentation of C. difficile RT023 infections was analysed in comparison with known 'hypervirulent' and non-hypervirulent strains, using data from the Netherlands national C. difficile surveillance programme. European RT023 strains of diverse origin were collected and whole-genome sequenced to determine the genetic similarity between isolates. Distinctive features were investigated and characterized.ResultsClinical presentation of C. difficile RT023 infections show severe infections akin to those seen with 'hypervirulent' strains from clades 2 (RT027) and 5 (RT078) (35%, 29% and 27% severe CDI, respectively), particularly with significantly more bloody diarrhoea than RT078 and non-hypervirulent strains (RT023 8%, other RTs 4%, p 0.036). The full genome sequence of strain CD305 is presented as a robust reference. Phylogenetic comparison of CD305 and a further 79 previously uncharacterized European RT023 strains of diverse origin revealed minor genetic divergence with >99.8% pairwise identity between strains. Analyses revealed distinctive features among clade 3 strains, including conserved pathogenicity locus, binary toxin and phage insertion toxin genotypes, glycosylation of S-layer proteins, presence of the RT078 four-gene trehalose cluster and an esculinase-negative genotype.ConclusionsGiven their recent emergence, virulence and genomic characteristics, the surveillance of clade 3 strains should be more highly prioritized.
A KLF4-DYRK2–mediated pathway regulating self-renewal in CML stem cells
Authors: Chun Shik Park, Andrew H. Lewis, Taylor J. Chen, Cory S. Bridges, Ye Shen, Koramit Suppipat, Monica Puppi, Julie A. Tomolonis, Paul D. Pang, Toni-Ann Mistretta, Leyuan Ma, Michael R. Green, Rachel Rau, H. Daniel Lacorazza
Journal: Blood (2019)
The Absolute Lymphocyte Count Is Associated with the Prognosis in Patients with Peripheral T-Cell Lymphoma, Not Otherwise Specified
Authors: Byeong Seok Sohn, Jeongseok Kim, Dok Hyun Yoon, Shin Kim, Jooryung Huh, Sung-En Park, Young Jin Yuh, Cheolwon Suh
Journal: Blood (2017)
Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study
Authors: R Sharon Chinthrajah, Natasha Purington, Sandra Andorf, Andrew Long, Katherine L O'Laughlin, Shu Chen Lyu, Monali Manohar, Scott D Boyd, Robert Tibshirani, Holden Maecker, Marshall Plaut, Kaori Mukai, Mindy Tsai, Manisha Desai, Stephen J Galli, Kari C Nadeau
Journal: The Lancet (2019)
Abstract 19185: Do Aldosterone Antagonists Have Beneficial Effects in Patients With STEMI Without Heart Failure?
Authors: Khagendra B Dahal, Sharan Sharma, Sampath Singireddy, Paari Dominic, Pratap C Reddy, Kalgi Modi
Journal: Circulation (2017)

Introduction: Aldosterone antagonists (AA) are recommended and have been shown to have beneficial effects in patients with ST elevation myocardial infarction (STEMI) and left ventricular ejection f...
Long-Term Outcome of CML Patients Treated with Second-Generation Tyrosine Kinase Inhibitors in the Second Line: A Single Center Experience
Authors: Kamal Chamoun, Hagop M. Kantarjian, Mary Abisola Akosile, Rita Assi, Farhad Ravandi, Gautam Borthakur, Guillermo Garcia-Manero, Tapan Kadia, Marina Konopleva, Zeev Estrov, Courtney D. DiNardo, Naval Daver, Naveen Pemmaraju, Alessandra Ferrajoli, Jan A. Burger, William Wierda, Elias J. Jabbour, Jorge E. Cortes
Journal: Blood (2017)
Recombining Your Way Out of Trouble: The Genetic Architecture of Hybrid Fitness under Environmental Stress
Authors: Zebin Zhang, Devin P Bendixsen, Thijs Janzen, Arne W Nolte, Duncan Greig, Rike Stelkens
Journal: Molecular Biology and Evolution (2019)

Abstract Hybridization between species can either promote or impede adaptation. But we know very little about the genetic basis of hybrid fitness, especially in nondomesticated organisms, and when populations are facing environmental stress. We made genetically variable F2 hybrid populations from two divergent Saccharomyces yeast species. We exposed populations to ten toxins and sequenced the most resilient hybrids on low coverage using ddRADseq to investigate four aspects of their genomes: 1) hybridity, 2) interspecific heterozygosity, 3) epistasis (positive or negative associations between nonhomologous chromosomes), and 4) ploidy. We used linear mixed-effect models and simulations to measure to which extent hybrid genome composition was contingent on the environment. Genomes grown in different environments varied in every aspect of hybridness measured, revealing strong genotype–environment interactions. We also found selection against heterozygosity or directional selection for one of the parental alleles, with larger fitness of genomes carrying more homozygous allelic combinations in an otherwise hybrid genomic background. In addition, individual chromosomes and chromosomal interactions showed significant species biases and pervasive aneuploidies. Against our expectations, we observed multiple beneficial, opposite-species chromosome associations, confirmed by epistasis- and selection-free computer simulations, which is surprising given the large divergence of parental genomes (∼15%). Together, these results suggest that successful, stress-resilient hybrid genomes can be assembled from the best features of both parents without paying high costs of negative epistasis. This illustrates the importance of measuring genetic trait architecture in an environmental context when determining the evolutionary potential of genetically diverse hybrid populations.
Emerging Use of CRISPR Technology — Chasing the Elusive HIV Cure
Authors: Carl H. June
Journal: New England Journal of Medicine (2019)

A new form of gene therapy termed genetic editing or gene targeting has become possible owing to advances in genetic engineering technology.1 The intent of genetic editing is to alter the DNA code in cells with single base-pair specificity, and thus it can be considered to be an ultimate form of precision therapy. For the past two decades, genome editing has been a powerful tool for basic science research. The importance of genome editing as a research tool was recognized in 2007 by the award of the Nobel Prize in Physiology or Medicine to Smithies, Capecchi, and Evans. Until recently, . . .
CRISPR-based Activation of Endogenous Neurotrophic Genes in Adipose Stem Cell Sheets to Stimulate Peripheral Nerve Regeneration
Authors: Mu-Nung Hsu, Han-Tsung Liao, Vu Anh Truong, Kai-Lun Huang, Fu-Jen Yu, Hwei-Hsien Chen, Thi Kieu Nuong Nguyen, Pavel Makarevich, Yelena Parfyonova, Yu-Chen Hu
Journal: Theranostics (2019)

Background: Peripheral nerve regeneration requires coordinated functions of neurotrophic factors and neuronal cells.CRISPR activation (CRISPRa) is a powerful tool that exploits inactive Cas9 (dCas9), single guide RNA (sgRNA) and transcription activator for gene activation, but has yet to be harnessed for tissue regeneration.Methods: We developed a hybrid baculovirus (BV) vector to harbor and deliver the CRISPRa system for multiplexed activation of 3 neurotrophic factor genes (BDNF, GDNF and NGF).The hybrid BV was used to transduce rat adipose-derived stem cells (ASC) and functionalize the ASC sheets.We further implanted the ASC sheets into sciatic nerve injury sites in rats.Results: Transduction of rat ASC with the hybrid BV vector enabled robust, simultaneous and prolonged activation of the 3 neurotrophic factors for at least 21 days.The CRISPRa-engineered ASC sheets were able to promote Schwann cell (SC) migration, neuron proliferation and neurite outgrowth in vitro.The CRISPRa-engineered ASC sheets further enhanced in vivo functional recovery, nerve reinnervation, axon regeneration and remyelination.Conclusion: These data collectively implicated the potentials of the hybrid BV-delivered CRISPRa system for multiplexed activation of endogenous neurotrophic factor genes in ASC sheets to promote peripheral nerve regeneration.
Long noncoding RNA GSTM3TV2 upregulates LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance in pancreatic cancer
Authors: Guangbing Xiong, Chang Liu, Gang Yang, Mengyu Feng, Jianwei Xu, Fangyu Zhao, Lei You, Li Zhou, Lianfang Zheng, Ya Hu, Xiaowo Wang, Taiping Zhang, Yupei Zhao
Journal: Journal of Hematology & Oncology (2019)

Chemoresistance is one of the main causes of poor prognosis in pancreatic cancer patients. Understanding the mechanisms implicated in chemoresistance of pancreatic cancer is critical to improving patient outcomes. Recent evidences indicate that the long noncoding RNAs (lncRNAs) are involving in chemoresistance of pancreatic cancer. However, the mechanisms of lncRNAs contribute to resistance in pancreatic cancer and remain largely unknown. The objective of this study is to construct a chemoresistance-related lncRNA-associated competing endogenous RNA (ceRNA) network of pancreatic cancer and identify the key lncRNAs in regulating chemoresistance of the network.Firstly, lncRNA expression profiling of gemcitabine-resistant pancreatic cancer cells was performed to identify lncRNAs related to chemoresistance by microarray analysis. Secondly, with insights into the mechanism of ceRNA, we used a bioinformatics approach to construct a chemoresistance-related lncRNAs-associated ceRNA network. We then identified the topological key lncRNAs in the ceRNA network and demonstrated its function or mechanism in chemoresistance of pancreatic cancer using molecular biological methods. Further studies evaluated its expression to assess its potential association with survival in patients with pancreatic cancer.Firstly, we demonstrated that lncRNAs were dysregulated in gemcitabine-resistant pancreatic cancer cells. We then constructed a chemoresistance-related lncRNA-associated ceRNA network and proposed that lncRNA Homo sapiens glutathione S-transferase mu 3, transcript variant 2 and noncoding RNA (GSTM3TV2; NCBI Reference Sequence: NR_024537.1) might act as a key ceRNA to enhance chemoresistance by upregulating L-type amino acid transporter 2 (LAT2) and oxidized low-density lipoprotein receptor 1(OLR1) in pancreatic cancer. Further studies demonstrated that GSTM3TV2, overexpressed in gemcitabine-resistant cells, enhanced the gemcitabine resistance of pancreatic cancer cells in vitro and in vivo. Mechanistically, we identified that GSTM3TV2 upregulated LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance. In addition, we revealed that the expression levels of GSTM3TV2 were significantly increased in pancreatic cancer tissues and were associated with poor prognosis.Our results suggest that GSTM3TV2 is a crucial oncogenic regulator involved in chemoresistance and could be a new therapeutic target or prognostic marker in pancreatic cancer.
Abstract 802: Dynamic FRET-Based Ca-Calmodulin Measurements in Intact Ventricular Myocytes Uncover Differential Signal Integration Due to Ca-Calmodulin Affinity
Authors: Qiujing Song, Julie Bossuyt, Jeffrey Saucerman, Donald Bers
Journal: Circulation (2007)

Background: Myocyte [Ca] i varies beat-to-beat and calmodulin (CaM) transduces Ca signals to regulate many cardiac functions (e.g. via CaM-dependent kinase, CaMKII, and calcineurin, CaN). We hypothesize that the different Ca-CaM affinities of CaMKII (Kd ∼45 nM) and CaN (Kd ∼2 nM) will dictate their dynamic and tonic binding to Ca-CaM. Methods: Two adenoviral vectors encoding FRET (fluorescence resonance energy transfer) based biosensors with affinities similar to CaMKII and CaN (BsCaM-45 vs. BsCaM-2) were generated to monitor Ca-CaM dynamics in adult rabbit ventricular myocytes (with extra CaM expression via adenovirus). Results: Ca-CaM binding reduces FRET and increases the fluorescence emission ratio (F 480 /F 530 ). Figure shows the lower affinity sensor BsCaM-45 (like CaMKII) turns on and off completely with only slight diastolic increase at 1.0 Hz (5% ± 2.5%, vs. 0.1 Hz, n = 5). In contrast, the higher affinity sensor BsCaM-2 (like CaN) showed significant diastolic signal integration at 1.0 Hz (20% ± 3%, n = 5, p &lt; 0.05). BsCaM-2 (n = 5) has slower kinetics vs. BsCaM-45 (n = 5): at 1.0 Hz, time to peak: 218 ± 11 vs. 244 ± 15 ms, ns; τ-decay: 647 ± 17 vs. 321 ± 25 ms, p &lt; 0.05). Conclusion: CaM target proteins with different affinities (like CaMKII and CaN) respond very differently to the same Ca signal, (integrating vs. phasic), presumably tuned appropriately for their signaling pathway. This dynamic response shapes subsequent cellular processes in the heart. Indeed, altered diastolic [Ca] i or heart rate (as in pathophysiological states) can differentially influence downstream CaM-dependent pathways. Beat-to-beat FRET signal changes in Rabbit Ventricular Myocytes
MELD‐GRAIL‐Na: Glomerular Filtration Rate and Mortality on Liver‐Transplant Waiting List
Authors: Sumeet K. Asrani, Linda W. Jennings, W.R. Kim, Patrick S. Kamath, Josh Levitsky, Mitra K. Nadim, Giuliano Testa, Michael D. Leise, James F. Trotter, Goran Klintmalm
Journal: Hepatology (2019)

Background and Aims Among patients with cirrhosis awaiting liver transplantation, prediction of wait‐list (WL) mortality is adjudicated by the Model for End Stage Liver Disease–Sodium (MELD‐Na) score. Replacing serum creatinine (SCr) with estimated glomerular filtration rate (eGFR) in the MELD‐Na score may improve prediction of WL mortality, especially for women and highest disease severity. Approach and Results We developed (2014) and validated (2015) a model incorporating eGFR using national data (n = 17,095) to predict WL mortality. Glomerular filtration rate (GFR) was estimated using the GFR assessment in liver disease (GRAIL) developed among patients with cirrhosis. Multivariate Cox proportional hazard analysis models were used to compare the predicted 90‐day WL mortality between MELD‐GRAIL‐Na (re‐estimated bilirubin, international normalized ratio [INR], sodium, and GRAIL) versus MELD‐Na. Within 3 months, 27.8% were transplanted, 4.3% died on the WL, and 4.7% were delisted for other reasons. GFR as estimated by GRAIL (hazard ratio [HR] 0.382, 95% confidence interval [CI] 0.344‐0.424) and the re‐estimated model MELD‐GRAIL‐Na (HR 1.212, 95% CI 1.199‐1.224) were significant predictors of mortality or being delisted on the WL within 3 months. MELD‐GRAIL‐Na was a better predictor of observed mortality at highest deciles of disease severity (≥ 27‐40). For a score of 32 or higher (observed mortality 0.68), predicted mortality was 0.67 (MELD‐GRAIL‐Na) and 0.51 (MELD‐Na). For women, a score of 32 or higher (observed mortality 0.67), the predicted mortality was 0.69 (MELD‐GRAIL‐Na) and 0.55 (MELD‐Na). In 2015, use of MELD‐GRAIL‐Na as compared with MELD‐Na resulted in reclassification of 16.7% (n = 672) of patients on the WL. Conclusion Incorporation of eGFR likely captures true GFR better than SCr, especially among women. Incorporation of MELD‐GRAIL‐Na instead of MELD‐Na may affect outcomes for 12%‐17% awaiting transplant and affect organ allocation.
Cohesin-dependent regulation of gene expression during differentiation is lost in cohesin-mutated myeloid malignancies
Authors: Daniel Sasca, Haiyang Yun, George Giotopoulos, Jakub Szybinski, Theo Evan, Nicola K. Wilson, Moritz Gerstung, Paolo Gallipoli, Anthony R. Green, Robert Hills, Nigel Russell, Cameron S. Osborne, Elli Papaemmanuil, Berthold Göttgens, Peter Campbell, Brian J. P. Huntly
Journal: Blood (2019)
HSCT Engraftment Kinetics: Differences in Chimerism between Haploidentical (HI) and Matched Related (MR) Transplant Recipients (HSCT) after the 2 Step Approach
Authors: Dolores Grosso, Onder Alpdogan, Matthew Carabasi, Joanne Filicko-O'Hara, Sameh Gaballa, Margaret Kasner, Thomas R. Klumpp, Ubaldo Martinez-Outschoorn, Neil Palmisiano, Pierluigi Porcu, William O'Hara, John L Wagner, Neal Flomenberg
Journal: Blood (2018)
Defining severe obstructive lung disease in the biologic era: an endotype-based approach
Authors: Richard J. Martin, Elisabeth H. Bel, Ian D. Pavord, David Price, Helen K. Reddel
Journal: European Respiratory Journal (2019)

Severe obstructive lung disease, which encompasses asthma, chronic obstructive pulmonary disease (COPD) or features of both, remains a considerable global health problem and burden on healthcare resources. However, the clinical definitions of severe asthma and COPD do not reflect the heterogeneity within these diagnoses or the potential for overlap between them, which may lead to inappropriate treatment decisions. Furthermore, most studies exclude patients with diagnoses of both asthma and COPD. Clinical definitions can influence clinical trial design and are both influenced by, and influence, regulatory indications and treatment recommendations. Therefore, to ensure its relevance in the era of targeted biologic therapies, the definition of severe obstructive lung disease must be updated so that it includes all patients who could benefit from novel treatments and for whom associated costs are justified. Here, we review evolving clinical definitions of severe obstructive lung disease and evaluate how these have influenced trial design by summarising eligibility criteria and primary outcomes of phase III randomised controlled trials of biologic therapies. Based on our findings, we discuss the advantages of a phenotype- and endotype-based approach to select appropriate populations for future trials that may influence regulatory approvals and clinical practice, allowing targeted biologic therapies to benefit a greater proportion and range of patients. This calls for co-ordinated efforts between investigators, pharmaceutical developers and regulators to ensure biologic therapies reach their full potential in the management of severe obstructive lung disease.
Development of a novel Ara h 2 hypoallergen with no IgE binding or anaphylactogenic activity
Authors: Angelika Tscheppe, Dieter Palmberger, Leonie van Rijt, Tanja Kalic, Vanessa Mayr, Chiara Palladino, Claudia Kitzmüller, Wolfgang Hemmer, Christine Hafner, Merima Bublin, Ronald van Ree, Reingard Grabherr, Christian Radauer, Heimo Breiteneder
Journal: Journal of Allergy and Clinical Immunology (2019)

BackgroundTo date, no safe allergen-specific immunotherapy for patients with peanut allergy is available. Previous trials were associated with severe side effects.ObjectiveWe sought to determine the relative importance of conformational and linear IgE-binding epitopes of the major peanut allergen Ara h 2 and to produce a hypoallergenic variant with abolished anaphylactogenic activity.MethodsWild-type Ara h 2 and a mutant lacking the loops containing linear IgE epitopes were produced in insect cells. Conformational IgE epitopes were removed by unfolding these proteins through reduction and alkylation. IgE binding was tested by means of ELISA with sera from 48 Ara h 2–sensitized patients with peanut allergy. Basophil activation and T-cell proliferation were tested with blood samples from selected patients. Anaphylactogenic potency was tested by using intraperitoneal challenge of mice sensitized intragastrically to peanut extract.ResultsPatients' IgE recognized conformational and linear epitopes in a patient-specific manner. The unfolded mutant lacking both types of epitopes displayed significantly lower IgE binding (median ELISA OD, 0.03; interquartile range, 0.01-0.06) than natural Ara h 2 (median ELISA OD, 0.99; interquartile range, 0.90-1.03; P < .01). Basophil activation by unfolded mutant Ara h 2 was low (median area under the curve, 72 vs 138 for native wild-type Ara h 2; P < .05), but its ability to induce T-cell proliferation was retained. Unfolded mutants without conformational epitopes did not induce anaphylaxis in peanut-sensitized mice.ConclusionsBy removing conformational and linear IgE epitopes, a hypoallergenic Ara h 2 mutant with abolished IgE binding and anaphylactogenic potency but retained T-cell activation was generated.Graphical abstract