Publications by authors named "Alejandro Gutierrez"

105 Publications

METTL1-mediated mG modification of Arg-TCT tRNA drives oncogenic transformation.

Mol Cell 2021 08 4;81(16):3323-3338.e14. Epub 2021 Aug 4.

Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Harvard Initiative for RNA Medicine, Boston, MA 02115, USA. Electronic address:

The emerging "epitranscriptomics" field is providing insights into the biological and pathological roles of different RNA modifications. The RNA methyltransferase METTL1 catalyzes N7-methylguanosine (mG) modification of tRNAs. Here we find METTL1 is frequently amplified and overexpressed in cancers and is associated with poor patient survival. METTL1 depletion causes decreased abundance of mG-modified tRNAs and altered cell cycle and inhibits oncogenicity. Conversely, METTL1 overexpression induces oncogenic cell transformation and cancer. Mechanistically, we find increased abundance of mG-modified tRNAs, in particular Arg-TCT-4-1, and increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon. Accordingly, Arg-TCT expression is elevated in many tumor types and is associated with patient survival, and strikingly, overexpression of this individual tRNA induces oncogenic transformation. Thus, METTL1-mediated tRNA modification drives oncogenic transformation through a remodeling of the mRNA "translatome" to increase expression of growth-promoting proteins and represents a promising anti-cancer target.
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http://dx.doi.org/10.1016/j.molcel.2021.06.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380730PMC
August 2021

Cancer LncRNA Census 2 (CLC2): an enhanced resource reveals clinical features of cancer lncRNAs.

NAR Cancer 2021 Jun 14;3(2):zcab013. Epub 2021 Apr 14.

Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland.

Long non-coding RNAs (lncRNAs) play key roles in cancer and are at the vanguard of precision therapeutic development. These efforts depend on large and high-confidence collections of cancer lncRNAs. Here, we present the Cancer LncRNA Census 2 (CLC2). With 492 cancer lncRNAs, CLC2 is 4-fold greater in size than its predecessor, without compromising on strict criteria of confident functional/genetic roles and inclusion in the GENCODE annotation scheme. This increase was enabled by leveraging high-throughput transposon insertional mutagenesis screening data, yielding 92 novel cancer lncRNAs. CLC2 makes a valuable addition to existing collections: it is amongst the largest, contains numerous unique genes (not found in other databases) and carries functional labels (oncogene/tumour suppressor). Analysis of this dataset reveals that cancer lncRNAs are impacted by germline variants, somatic mutations and changes in expression consistent with inferred disease functions. Furthermore, we show how clinical/genomic features can be used to vet prospective gene sets from high-throughput sources. The combination of size and quality makes CLC2 a foundation for precision medicine, demonstrating cancer lncRNAs' evolutionary and clinical significance.
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http://dx.doi.org/10.1093/narcan/zcab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210278PMC
June 2021

Potential of genomic technologies to improve disease resistance in molluscan aquaculture.

Philos Trans R Soc Lond B Biol Sci 2021 05 5;376(1825):20200168. Epub 2021 Apr 5.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH25 9RG, UK.

Molluscan aquaculture is a major contributor to global seafood production, but is hampered by infectious disease outbreaks that can cause serious economic losses. Selective breeding has been widely used to improve disease resistance in major agricultural and aquaculture species, and has clear potential in molluscs, albeit its commercial application remains at a formative stage. Advances in genomic technologies, especially the development of cost-efficient genomic selection, have the potential to accelerate genetic improvement. However, tailored approaches are required owing to the distinctive reproductive and life cycle characteristics of molluscan species. Transgenesis and genome editing, in particular CRISPR/Cas systems, have been successfully trialled in molluscs and may further understanding and improvement of genetic resistance to disease through targeted changes to the host genome. Whole-organism genome editing is achievable on a much greater scale compared to other farmed species, making genome-wide CRISPR screening approaches plausible. This review discusses the current state and future potential of selective breeding, genomic tools and genome editing approaches to understand and improve host resistance to infectious disease in molluscs. This article is part of the Theo Murphy meeting issue 'Molluscan genomics: broad insights and future directions for a neglected phylum'.
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http://dx.doi.org/10.1098/rstb.2020.0168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059958PMC
May 2021

Choice of CTO scores to predict procedural success in clinical practice. A comparison of 4 different CTO PCI scores in a comprehensive national registry including expert and learning CTO operators.

PLoS One 2021 2;16(4):e0245898. Epub 2021 Apr 2.

Servicio de Cardiología, H. Clínico de Valencia. Universidad de Valencia, CIBERCV, Valencia, Spain.

Background: We aimed to compare the performance of the recent CASTLE score to J-CTO, CL and PROGRESS CTO scores in a comprehensive database of percutaneous coronary intervention of chronic total occlusion procedures.

Methods: Scores were calculated using raw data from 1,342 chronic total occlusion procedures included in REBECO Registry that includes learning and expert operators. Calibration, discrimination and reclassification were evaluated and compared.

Results: Mean score values were: CASTLE 1.60±1.10, J-CTO 2.15±1.24, PROGRESS 1.68±0.94 and CL 2.52±1.52 points. The overall percutaneous coronary intervention success rate was 77.8%. Calibration was good for CASTLE and CL, but not for J-CTO or PROGRESS scores. Discrimination: the area under the curve (AUC) of CASTLE (0.633) was significantly higher than PROGRESS (0.557) and similar to J-CTO (0.628) and CL (0.652). Reclassification: CASTLE, as assessed by integrated discrimination improvement, was superior to PROGRESS (integrated discrimination improvement +0.036, p<0.001), similar to J-CTO and slightly inferior to CL score (- 0.011, p = 0.004). Regarding net reclassification improvement, CASTLE reclassified better than PROGRESS (overall continuous net reclassification improvement 0.379, p<0.001) in roughly 20% of cases.

Conclusion: Procedural percutaneous coronary intervention difficulty is not consistently depicted by available chronic total occlusion scores and is influenced by the characteristics of each chronic total occlusion cohort. In our study population, including expert and learning operators, the CASTLE score had slightly better overall performance along with CL score. However, we found only intermediate performance in the c-statistic predicting chronic total occlusion success among all scores.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245898PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018648PMC
September 2021

A chromosome-level genome assembly for the Pacific oyster Crassostrea gigas.

Gigascience 2021 Mar;10(3)

The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UK.

Background: The Pacific oyster (Crassostrea gigas) is a bivalve mollusc with vital roles in coastal ecosystems and aquaculture globally. While extensive genomic tools are available for C. gigas, highly contiguous reference genomes are required to support both fundamental and applied research. Herein we report the creation and annotation of a chromosome-level assembly for C. gigas.

Findings: High-coverage long- and short-read sequence data generated on Pacific Biosciences and Illumina platforms were used to generate an initial assembly, which was then scaffolded into 10 pseudo-chromosomes using both Hi-C sequencing and a high-density linkage map. The assembly has a scaffold N50 of 58.4 Mb and a contig N50 of 1.8 Mb, representing a step advance on the previously published C. gigas assembly. Annotation based on Pacific Biosciences Iso-Seq and Illumina RNA-Seq resulted in identification of ∼30,000 putative protein-coding genes. Annotation of putative repeat elements highlighted an enrichment of Helitron rolling-circle transposable elements, suggesting their potential role in shaping the evolution of the C. gigas genome.

Conclusions: This new chromosome-level assembly will be an enabling resource for genetics and genomics studies to support fundamental insight into bivalve biology, as well as for selective breeding of C. gigas in aquaculture.
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http://dx.doi.org/10.1093/gigascience/giab020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992393PMC
March 2021

Investigating mechanisms underlying genetic resistance to Salmon Rickettsial Syndrome in Atlantic salmon using RNA sequencing.

BMC Genomics 2021 Mar 6;22(1):156. Epub 2021 Mar 6.

The Roslin Institute and Royal (Dick) School of Veterinary Sciences, The University of Edinburgh, Edinburgh, UK.

Background: Salmon Rickettsial Syndrome (SRS), caused by Piscirickettsia salmonis, is one of the primary causes of morbidity and mortality in Atlantic salmon aquaculture, particularly in Chile. Host resistance is a heritable trait, and functional genomic studies have highlighted genes and pathways important in the response of salmon to the bacteria. However, the functional mechanisms underpinning genetic resistance are not yet well understood. In the current study, a large population of salmon pre-smolts were challenged with P. salmonis, with mortality levels recorded and samples taken for genotyping. In parallel, head kidney and liver samples were taken from animals of the same population with high and low genomic breeding values for resistance, and used for RNA-Sequencing to compare their transcriptome profile both pre and post infection.

Results: A significant and moderate heritability (h = 0.43) was shown for the trait of binary survival. Genome-wide association analyses using 38 K imputed SNP genotypes across 2265 animals highlighted that resistance is a polygenic trait. Several thousand genes were identified as differentially expressed between controls and infected samples, and enriched pathways related to the host immune response were highlighted. In addition, several networks with significant correlation with SRS resistance breeding values were identified, suggesting their involvement in mediating genetic resistance. These included apoptosis, cytoskeletal organisation, and the inflammasome.

Conclusions: While resistance to SRS is a polygenic trait, this study has highlighted several relevant networks and genes that are likely to play a role in mediating genetic resistance. These genes may be future targets for functional studies, including genome editing, to further elucidate their role underpinning genetic variation in host resistance.
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http://dx.doi.org/10.1186/s12864-021-07443-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936450PMC
March 2021

Supervised machine learning tools: a tutorial for clinicians.

J Neural Eng 2020 Oct 9. Epub 2020 Oct 9.

Radiology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 1N4, CANADA.

In an increasingly data-driven world, artificial intelligence is expected to be a key tool for converting big data into tangible benefits and the healthcare domain is no exception to this. Machine learning aims to identify complex patterns in multi-dimensional data and use these uncovered patterns to classify new unseen cases or make data-driven predictions. In recent years, deep neural networks have shown to be capable of producing results that considerably exceed those of conventional machine learning methods for various classification and regression tasks. In this paper, we provide an accessible tutorial of the most important supervised machine learning concepts and methods, including deep learning, which are potentially the most relevant for the medical domain. We aim to take some of the mystery out of machine learning and depict how machine learning models can be useful for medical applications. Finally, this tutorial provides a few practical suggestions for how to properly design a machine learning model for a generic medical problem.
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http://dx.doi.org/10.1088/1741-2552/abbff2DOI Listing
October 2020

Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001.

Pediatr Blood Cancer 2021 01 7;68(1):e28719. Epub 2020 Oct 7.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Background/objectives: While outcomes for pediatric T-cell acute lymphoblastic leukemia (T-ALL) are favorable, there are few widely accepted prognostic factors, limiting the ability to risk stratify therapy.

Design/methods: Dana-Farber Cancer Institute (DFCI) Protocols 05-001 and 11-001 enrolled pediatric patients with newly diagnosed B- or T-ALL from 2005 to 2011 and from 2012 to 2015, respectively. Protocol therapy was nearly identical for patients with T-ALL (N = 123), who were all initially assigned to the high-risk arm. End-induction minimal residual disease (MRD) was assessed by reverse transcription polymerase chain reaction (RT-PCR) or next-generation sequencing (NGS), but was not used to modify postinduction therapy. Early T-cell precursor (ETP) status was determined by flow cytometry. Cases with sufficient diagnostic DNA were retrospectively evaluated by targeted NGS of known genetic drivers of T-ALL, including Notch, PI3K, and Ras pathway genes.

Results: The 5-year event-free survival (EFS) and overall survival (OS) for patients with T-ALL was 81% (95% CI, 73-87%) and 90% (95% CI, 83-94%), respectively. ETP phenotype was associated with failure to achieve complete remission, but not with inferior OS. Low end-induction MRD (<10 ) was associated with superior disease-free survival (DFS). Pathogenic mutations of the PI3K pathway were mutually exclusive of ETP phenotype and were associated with inferior 5-year DFS and OS.

Conclusions: Together, our findings demonstrate that ETP phenotype, end-induction MRD, and PI3K pathway mutation status are prognostically relevant in pediatric T-ALL and should be considered for risk classification in future trials. DFCI Protocols 05-001 and 11-001 are registered at www.clinicaltrials.gov as NCT00165087 and NCT01574274, respectively.
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http://dx.doi.org/10.1002/pbc.28719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369809PMC
January 2021

Development of a SNP linkage map and genome-wide association study for resistance to Aeromonas hydrophila in pacu (Piaractus mesopotamicus).

BMC Genomics 2020 Sep 29;21(1):672. Epub 2020 Sep 29.

São Paulo State University (Unesp), Aquaculture Center of Unesp, Via de Acesso Prof. Paulo Donato Castellane, s/n, Jaboticabal, SP, 14884-900, Brazil.

Background: Pacu (Piaractus mesopotamicus) is one of the most important Neotropical aquaculture species from South America. Disease outbreaks caused by Aeromonas hydrophila infection have been considered significant contributors to the declining levels of pacu production. The current implementation of genomic selection for disease resistance has been adopted as a powerful strategy for improvement in fish species. This study aimed to investigate the genetic architecture of resistance to A. hydrophila in pacu via Genome-Wide Association Study (GWAS), the identification of suggestive Quantitative Trait Loci (QTLs) and putative genes associated with this trait. The genetic data were obtained from 381 juvenile individuals belonging to 14 full-sibling families. An experimental challenge was performed to gain access to the levels of genetic variation for resistance against the bacteria using the following trait definitions: binary test survival (TS) and time of death (TD).

Results: The analyses of genetic parameters estimated moderate heritability (h) for both resistance traits: 0.20 (± 0.09) for TS and 0.35 (± 0.15) for TD. A linkage map for pacu was developed to enable the GWAS, resulting in 27 linkage groups (LGs) with 17,453 mapped Single Nucleotide Polymorphisms (SNPs). The length of the LGs varied from 79.95 (LG14) to 137.01 (LG1) cM, with a total map length of 2755.60 cM. GWAS identified 22 putative QTLs associated to A. hydrophila resistance. They were distributed into 17 LGs, and were considered suggestive genomic regions explaining > 1% of the additive genetic variance (AGV) for the trait. Several candidate genes related to immune response were located close to the suggestive QTLs, such as tbk1, trim16, Il12rb2 and lyz2.

Conclusion: This study describes the development of the first medium density linkage map for pacu, which will be used as a framework to study relevant traits to the production of this species. In addition, the resistance to A. hydrophila was found to be moderately heritable but with a polygenic architecture suggesting that genomic selection, instead of marker assisted selection, might be useful for efficiently improving resistance to one of the most problematic diseases that affects the South American aquaculture.
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http://dx.doi.org/10.1186/s12864-020-07090-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526211PMC
September 2020

Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors.

J Exp Med 2020 10;217(10)

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Peripheral sympathetic nervous system tumors are the most common extracranial solid tumors of childhood and include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Surgery is the only effective therapy for ganglioneuroma, which may be challenging due to the location of the tumor and involvement of surrounding structures. Thus, there is a need for well-tolerated presurgical therapies that could reduce the size and extent of ganglioneuroma and therefore limit surgical morbidity. Here, we found that an AKT-mTOR-S6 pathway was active in human ganglioneuroma but not neuroblastoma samples. Zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma. Inhibition of the downstream AKT target, mTOR, in zebrafish with ganglioneuroma effectively reduced the tumor burden. Our results implicate activated AKT as a tumorigenic driver in ganglioneuroma. We propose a clinical trial of mTOR inhibitors as a means to shrink large ganglioneuromas before resection in order to reduce surgical morbidity.
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http://dx.doi.org/10.1084/jem.20191871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537400PMC
October 2020

Exploiting the Therapeutic Interaction of WNT Pathway Activation and Asparaginase for Colorectal Cancer Therapy.

Cancer Discov 2020 11 23;10(11):1690-1705. Epub 2020 Jul 23.

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Colorectal cancer is driven by mutations that activate canonical WNT/β-catenin signaling, but inhibiting WNT has significant on-target toxicity, and there are no approved therapies targeting dominant oncogenic drivers. We recently found that activating a β-catenin-independent branch of WNT signaling that inhibits GSK3-dependent protein degradation induces asparaginase sensitivity in drug-resistant leukemias. To test predictions from our model, we turned to colorectal cancer because these cancers can have WNT-activating mutations that function either upstream (i.e., R-spondin fusions) or downstream ( or β-catenin mutations) of GSK3, thus allowing WNT/β-catenin and WNT-induced asparaginase sensitivity to be unlinked genetically. We found that asparaginase had little efficacy in or β-catenin-mutant colorectal cancer, but was profoundly toxic in the setting of R-spondin fusions. Pharmacologic GSK3α inhibition was sufficient for asparaginase sensitization in or β-catenin-mutant colorectal cancer, but not in normal intestinal progenitors. Our findings demonstrate that WNT-induced therapeutic vulnerabilities can be exploited for colorectal cancer therapy. SIGNIFICANCE: Solid tumors are thought to be asparaginase-resistant via asparagine synthesis. In leukemia, GSK3α-dependent protein degradation, a catabolic amino acid source, mediates asparaginase resistance. We found that asparaginase is profoundly toxic to colorectal cancers with WNT-activating mutations that inhibit GSK3. Aberrant WNT activation can provide a therapeutic vulnerability in colorectal cancer...
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http://dx.doi.org/10.1158/2159-8290.CD-19-1472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642035PMC
November 2020

Can TAVR Be Effectively and Safely Performed Without Intraprocedural TEE?

Curr Cardiol Rep 2020 07 9;22(9):80. Epub 2020 Jul 9.

Department of Cardiology, St. Antonius Hospital, Koekoekslaan 1, 3435 Cm, Nieuwegein, The Netherlands.

Purpose Of Review: The TAVR procedure is a well-established therapy for patients with severe aortic stenosis at intermediate/high risk for surgery and a potential treatment for low-risk patients. It is much less invasive with short hospital stays and presents similar results compared with SAVR. Different "minimalist approach strategies" were proposed in order to obtain this performance. In these settings, transesophageal echocardiography (TEE) became less relevant for the TAVR procedure. The present review provides an update regarding the safety of TAVR without intraprocedural TEE.

Recent Findings: Transthoracic echocardiography and fluoroscopy are the primary imaging tools during TAVR. Several studies proved that TAVR under local anesthesia without TEE is as safe as that performed under TEE guidance. However, not all patients have a proper window for TTE, and particular cases with complex anatomy can benefit from TEE support during the intervention. Intraprocedural TEE no longer plays a crucial role in the TAVR procedure, but in some instances, it remains of great help to detect and avoid complications.
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http://dx.doi.org/10.1007/s11886-020-01344-8DOI Listing
July 2020

Developments in marine invertebrate primary culture reveal novel cell morphologies in the model bivalve .

PeerJ 2020 1;8:e9180. Epub 2020 Jun 1.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom.

Cell culture provides useful model systems used in a wide range of biological applications, but its utility in marine invertebrates is limited due to the lack of immortalised cell lines. Primary cell and tissue cultures are typically used but remain poorly characterised for oysters, which can cause issues with experimental consistency and reproducibility. Improvements to methods of repeatable isolation, culture, and characterisation of oyster cells and tissues are required to help address these issues. In the current study, systematic improvements have been developed to facilitate the culture of primary cells from adult Pacific oyster tissues and identify novel cell morphologies that have not been reported previously. Cultures analysed by light microscopy, qPCR, and live cell imaging demonstrated maintenance of live, metabolically active Pacific oyster cells for several weeks post-explant. Interestingly, whole hearts dissected from adult oysters were found to continue contracting rhythmically up to 8 weeks after being transferred to a tissue culture system. Mantle tissue explants were also actively moving in the culture system. These improvements in primary cell culture of bivalves may be beneficial for research in ecotoxicology, virology, immunology, and genetic resistance to disease.
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http://dx.doi.org/10.7717/peerj.9180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271890PMC
June 2020

Characterising the mechanisms underlying genetic resistance to amoebic gill disease in Atlantic salmon using RNA sequencing.

BMC Genomics 2020 Mar 30;21(1):271. Epub 2020 Mar 30.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, EH25 9RG, UK.

Background: Gill health is one of the main concerns for Atlantic salmon aquaculture, and Amoebic Gill Disease (AGD), attributable to infection by the amoeba Neoparamoeba perurans, is a frequent cause of morbidity. In the absence of preventive measures, increasing genetic resistance of salmon to AGD via selective breeding can reduce the incidence of the disease and mitigate gill damage. Understanding the mechanisms leading to AGD resistance and the underlying causative genomic features can aid in this effort, while also providing critical information for the development of other control strategies. AGD resistance is considered to be moderately heritable, and several putative QTL have been identified. The aim of the current study was to improve understanding of the mechanisms underlying AGD resistance, and to identify putative causative genomic factors underlying the QTL. To achieve this, RNA was extracted from the gill and head kidney of AGD resistant and susceptible animals following a challenge with N. perurans, and sequenced.

Results: Comparison between resistant and susceptible animals primarily highlighted differences mainly in the local immune response in the gill, involving red blood cell genes and genes related to immune function and cell adhesion. Differentially expressed immune genes pointed to a contrast in Th2 and Th17 responses, which is consistent with the increased heritability observed after successive challenges with the amoeba. Five QTL-region candidate genes showed differential expression, including a gene connected to interferon responses (GVINP1), a gene involved in systemic inflammation (MAP4K4), and a positive regulator of apoptosis (TRIM39). Analyses of allele-specific expression highlighted a gene in the QTL region on chromosome 17, cellular repressor of E1A-stimulated genes 1 (CREG1), showing allelic differential expression suggestive of a cis-acting regulatory variant.

Conclusions: In summary, this study provides new insights into the mechanisms of resistance to AGD in Atlantic salmon, and highlights candidate genes for further functional studies that can further elucidate the genomic mechanisms leading to resistance and contribute to enhancing salmon health via improved genomic selection.
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http://dx.doi.org/10.1186/s12864-020-6694-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106639PMC
March 2020

Thermally Activated Processes for Ferromagnet Intercalation in Graphene-Heavy Metal Interfaces.

ACS Appl Mater Interfaces 2020 Jan 8;12(3):4088-4096. Epub 2020 Jan 8.

IMDEA Nanociencia , c/ Faraday 9, Campus de Cantoblanco , 28049 Madrid , Spain.

The development of graphene (Gr) spintronics requires the ability to engineer epitaxial Gr heterostructures with interfaces of high quality, in which the intrinsic properties of Gr are modified through proximity with a ferromagnet to allow for efficient room temperature spin manipulation or the stabilization of new magnetic textures. These heterostructures can be prepared in a controlled way by intercalation through graphene of different metals. Using photoelectron spectroscopy (XPS) and scanning tunneling microscopy (STM), we achieve a nanoscale control of thermally activated intercalation of a homogeneous ferromagnetic (FM) layer underneath epitaxial Gr grown onto (111)-oriented heavy metal (HM) buffers deposited, in turn, onto insulating oxide surfaces. XPS and STM demonstrate that Co atoms evaporated on top of Gr arrange in 3D clusters and, upon thermal annealing, penetrate through and diffuse below Gr in a 2D fashion. The complete intercalation of the metal occurs at specific temperatures, depending on the type of metallic buffer. The activation energy and the optimum temperature for the intercalation processes are determined. We describe a reliable method to fabricate and characterize in situ high-quality Gr-FM/HM heterostructures, enabling the realization of novel spin-orbitronic devices that exploit the extraordinary properties of Gr.
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http://dx.doi.org/10.1021/acsami.9b19159DOI Listing
January 2020

Fanconi-BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia.

PLoS One 2019 13;14(11):e0221288. Epub 2019 Nov 13.

Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, United States of America.

BRCA2 (also known as FANCD1) is a core component of the Fanconi pathway and suppresses transformation of immature T-cells in mice. However, the contribution of Fanconi-BRCA pathway deficiency to human T-cell acute lymphoblastic leukemia (T-ALL) remains undefined. We identified point mutations in 9 (23%) of 40 human T-ALL cases analyzed, with variant allele fractions consistent with heterozygous mutations early in tumor evolution. Two of these mutations were present in remission bone marrow specimens, suggesting germline alterations. BRCA2 was the most commonly mutated gene. The identified Fanconi-BRCA mutations encode hypomorphic or null alleles, as evidenced by their inability to fully rescue Fanconi-deficient cells from chromosome breakage, cytotoxicity and/or G2/M arrest upon treatment with DNA cross-linking agents. Disabling the tumor suppressor activity of the Fanconi-BRCA pathway is generally thought to require biallelic gene mutations. However, all mutations identified were monoallelic, and most cases appeared to retain expression of the wild-type allele. Using isogenic T-ALL cells, we found that BRCA2 haploinsufficiency induces selective hypersensitivity to ATR inhibition, in vitro and in vivo. These findings implicate Fanconi-BRCA pathway haploinsufficiency in the molecular pathogenesis of T-ALL, and provide a therapeutic rationale for inhibition of ATR or other druggable effectors of homologous recombination.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221288PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853288PMC
March 2020

Signatures of selection for bonamiosis resistance in European flat oyster (): New genomic tools for breeding programs and management of natural resources.

Evol Appl 2019 Oct 5;12(9):1781-1796. Epub 2019 Jul 5.

Department of Zoology, Genetics and Physical Anthropology, ACUIGEN group, Faculty of Veterinary Universidade de Santiago de Compostela Lugo Spain.

The European flat oyster () is a highly appreciated mollusk with an important aquaculture production throughout the 20th century, in addition to playing an important role on coastal ecosystems. Overexploitation of natural beds, habitat degradation, introduction of non-native species, and epidemic outbreaks have severely affected this important resource, particularly, the protozoan parasite which is the main concern affecting its production and conservation. In order to identify genomic regions and markers potentially associated with bonamiosis resistance, six oyster beds distributed throughout the European Atlantic coast were sampled. Three of them have been exposed to this parasite since the early 1980s and showed some degree of innate resistance (long-term affected group, LTA), while the other three were free of .  at least until sampling date (naïve group, NV). A total of 14,065 SNPs were analyzed, including 37 markers from candidate genes and 14,028 from a medium-density SNP array. Gene diversity was similar between LTA and NV groups suggesting no genetic erosion due to long-term exposure to the parasite, and three population clusters were detected using the whole dataset. Tests for divergent selection between NV and LTA groups detected the presence of a very consistent set of 22 markers, located within a putative single genomic region, which suggests the presence of a major quantitative trait locus associated with resistance. Moreover, 324 outlier loci associated with factors other than bonamiosis were identified allowing fully discrimination of all the oyster beds. A practical tool which included the 84 highest discriminative markers for tracing populations was developed and tested with empirical data. Results reported herein could assist the production of stocks with improved resistance to bonamiosis and facilitate the management of oyster beds for recovery production and ecosystem services provided by this species.
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http://dx.doi.org/10.1111/eva.12832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752124PMC
October 2019

Bioassay for Determining the Concentrations of Caffeine and Individual Methylxanthines in Complex Samples.

Appl Environ Microbiol 2019 12 14;85(23). Epub 2019 Nov 14.

The Freshman Research Initiative, College of Natural Sciences, The University of Texas at Austin, Austin, Texas, USA

Caffeine and other methylxanthines are stimulant molecules found in formulated beverages, including sodas and energy drinks, and in brewed beverages, such as coffee and teas. Previously, we developed a bioassay for caffeine that involves monitoring the growth of a mutant of defective in guanine biosynthesis. When supplemented with a plasmid expressing the genes for an -demethylation pathway from CBB5, these bacteria demethylate caffeine (1,3,7-trimethylxanthine) and other methylxanthines into xanthine, which is then converted into guanine to support cell growth. A major limitation of this bioassay was that it could only measure the total concentration of all methylxanthines in a mixture. Therefore, it could not be used to measure the caffeine content of beverages like teas, which contain substantial quantities of multiple methylxanthines. To overcome this limitation, we created seven new plasmids containing all subsets of the three demethylase genes (, , and ). We show that strains of containing each plasmid are able to demethylate specific subsets of methylxanthines and that they can be used to determine the concentrations of individual methylxanthines in complex mixtures containing multiple methylxanthines, including coffee doped with an additional methylxanthine. While validating this assay, we also discovered an unexpected demethylation event at the 1-methyl position when NdmB and NdmC were expressed in the absence of NdmA. The improved cell-based bioassay is inexpensive, is easy to use, and gives results comparable to standard high-performance liquid chromatography methods for measuring methylxanthine concentrations. Caffeine (1,3,7-trimethylxanthine) is the dominant neurostimulant found in coffee, teas, sodas, and energy drinks. Measuring the amount of caffeine and other methylxanthines in these beverages is important for quality assurance and safety in food science. Methylxanthines are also used in medicine and as performance-enhancing drugs, two contexts in which accurately determining their concentrations in bodily fluids is important. Liquid chromatography is the standard method for measuring methylxanthine concentrations in a sample, but it requires specialized equipment and expertise. We improved a previous bioassay that links growth to methylxanthine demethylation so that it can now be used to determine the amounts of individual methylxanthines in complex mixtures or beverages, such as coffee.
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http://dx.doi.org/10.1128/AEM.01965-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856332PMC
December 2019

Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias.

Cancer Cell 2019 04;35(4):664-676.e7

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02445, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address:

Resistance to asparaginase, an antileukemic enzyme that depletes asparagine, is a common clinical problem. Using a genome-wide CRISPR/Cas9 screen, we found a synthetic lethal interaction between Wnt pathway activation and asparaginase in acute leukemias resistant to this enzyme. Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant subtypes of acute leukemia, but not in normal hematopoietic progenitors. Sensitization to asparaginase was mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits glycogen synthase kinase 3 (GSK3)-dependent protein ubiquitination and proteasomal degradation, a catabolic source of asparagine. Inhibiting the alpha isoform of GSK3 phenocopied this effect, and pharmacologic GSK3α inhibition profoundly sensitized drug-resistant leukemias to asparaginase. Our findings provide a molecular rationale for activation of Wnt/STOP signaling to improve the therapeutic index of asparaginase.
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http://dx.doi.org/10.1016/j.ccell.2019.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541931PMC
April 2019

Detailed insights into pan-European population structure and inbreeding in wild and hatchery Pacific oysters () revealed by genome-wide SNP data.

Evol Appl 2019 Mar 31;12(3):519-534. Epub 2018 Dec 31.

Department of Animal Behavior Bielefeld University Bielefeld Germany.

Cultivated bivalves are important not only because of their economic value, but also due to their impacts on natural ecosystems. The Pacific oyster () is the world's most heavily cultivated shellfish species and has been introduced to all continents except Antarctica for aquaculture. We therefore used a medium-density single nucleotide polymorphism (SNP) array to investigate the genetic structure of this species in Europe, where it was introduced during the 1960s and has since become a prolific invader of coastal ecosystems across the continent. We analyzed 21,499 polymorphic SNPs in 232 individuals from 23 localities spanning a latitudinal cline from Portugal to Norway and including the source populations of Japan and Canada. We confirmed the results of previous studies by finding clear support for a southern and a northern group, with the former being indistinguishable from the source populations indicating the absence of a pronounced founder effect. We furthermore conducted a large-scale comparison of oysters sampled from the wild and from hatcheries to reveal substantial genetic differences including significantly higher levels of inbreeding in some but not all of the sampled hatchery cohorts. These findings were confirmed by a smaller but representative SNP dataset generated using restriction site-associated DNA sequencing. We therefore conclude that genomic approaches can generate increasingly detailed insights into the genetics of wild and hatchery produced Pacific oysters.
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http://dx.doi.org/10.1111/eva.12736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383735PMC
March 2019

Discovery and Functional Annotation of Quantitative Trait Loci Affecting Resistance to Sea Lice in Atlantic Salmon.

Front Genet 2019 8;10:56. Epub 2019 Feb 8.

Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Santiago, Chile.

Sea lice () are ectoparasitic copepods which have a large negative economic and welfare impact in Atlantic salmon () aquaculture, particularly in Chile. A multi-faceted prevention and control strategy is required to tackle lice, and selective breeding contributes via cumulative improvement of host resistance to the parasite. While host resistance has been shown to be heritable, little is yet known about the individual loci that contribute to this resistance, the potential underlying genes, and their mechanisms of action. In this study we took a multifaceted approach to identify and characterize quantitative trait loci (QTL) affecting host resistance in a population of 2,688 Caligus-challenged Atlantic salmon post-smolts from a commercial breeding program. We used low and medium density genotyping with imputation to collect genome-wide SNP marker data for all animals. Moderate heritability estimates of 0.28 and 0.24 were obtained for lice density (as a measure of host resistance) and growth during infestation, respectively. Three QTL explaining between 7 and 13% of the genetic variation in resistance to sea lice (as represented by the traits of lice density) were detected on chromosomes 3, 18, and 21. Characterisation of these QTL regions was undertaken using RNA sequencing and pooled whole genome sequencing data. This resulted in the identification of a shortlist of potential underlying causative genes, and candidate functional mutations for further study. For example, candidates within the chromosome 3 QTL include a putative premature stop mutation in TOB1 (an anti-proliferative transcription factor involved in T cell regulation) and an uncharacterized protein which showed significant differential allelic expression (implying the existence of a cis-acting regulatory mutation). While host resistance to sea lice is polygenic in nature, the results of this study highlight significant QTL regions together explaining between 7 and 13 % of the heritability of the trait. Future investigation of these QTL may enable improved knowledge of the functional mechanisms of host resistance to sea lice, and incorporation of functional variants to improve genomic selection accuracy.
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http://dx.doi.org/10.3389/fgene.2019.00056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375901PMC
February 2019

Role of Phosphatidylinositol 3-Kinase (PI3K), Mitogen-Activated Protein Kinase (MAPK), and Protein Kinase C (PKC) in Calcium Signaling Pathways Linked to the α-Adrenoceptor in Resistance Arteries.

Front Physiol 2019 6;10:55. Epub 2019 Feb 6.

Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.

Insulin resistance plays a key role in the pathogenesis of type 2 diabetes and is also related to other health problems like obesity, hypertension, and metabolic syndrome. Imbalance between insulin vascular actions via the phosphatidylinositol 3-Kinase (PI3K) and the mitogen activated protein kinase (MAPK) signaling pathways during insulin resistant states results in impaired endothelial PI3K/eNOS- and augmented MAPK/endothelin 1 pathways leading to endothelial dysfunction and abnormal vasoconstriction. The role of PI3K, MAPK, and protein kinase C (PKC) in Ca handling of resistance arteries involved in blood pressure regulation is poorly understood. Therefore, we assessed here whether PI3K, MAPK, and PKC play a role in the Ca signaling pathways linked to adrenergic vasoconstriction in resistance arteries. Simultaneous measurements of intracellular calcium concentration ([Ca]) in vascular smooth muscle (VSM) and tension were performed in endothelium-denuded branches of mesenteric arteries from Wistar rats mounted in a microvascular myographs. Responses to CaCl were assessed in arteries activated with phenylephrine (PE) and kept in Ca-free solution, in the absence and presence of the selective antagonist of L-type Ca channels nifedipine, cyclopiazonic acid (CPA) to block sarcoplasmic reticulum (SR) intracellular Ca release or specific inhibitors of PI3K, ERK-MAPK, or PKC. Activation of α-adrenoceptors with PE stimulated both intracellular Ca mobilization and Ca entry along with contraction in resistance arteries. Both [Ca] and contractile responses were inhibited by nifedipine while CPA abolished intracellular Ca mobilization and modestly reduced Ca entry suggesting that α-adrenergic vasoconstriction is largely dependent Ca influx through L-type Ca channel and to a lesser extent through store-operated Ca channels. Inhibition of ERK-MAPK did not alter intracellular Ca mobilization but largely reduced L-type Ca entry elicited by PE without altering vasoconstriction. The PI3K blocker LY-294002 moderately reduced intracellular Ca release, Ca entry and contraction induced by the α-adrenoceptor agonist, while PKC inhibition decreased PE-elicited Ca entry and to a lesser extent contraction without affecting intracellular Ca mobilization. Under conditions of ryanodine receptor (RyR) blockade to inhibit Ca-induced Ca-release (CICR), inhibitors of PI3K, ERK-MAPK, or PKC significantly reduced [Ca] increases but not contraction elicited by high K depolarization suggesting an activation of L-type Ca entry in VSM independent of RyR. In summary, our results demonstrate that PI3K, ERK-MAPK, and PKC regulate Ca handling coupled to the α-adrenoceptor in VSM of resistance arteries and related to both contractile and non-contractile functions. These kinases represent potential pharmacological targets in pathologies associated to vascular dysfunction and abnormal Ca handling such as obesity, hypertension and diabetes mellitus, in which these signaling pathways are profoundly impaired.
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http://dx.doi.org/10.3389/fphys.2019.00055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372516PMC
February 2019

PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia.

J Exp Med 2018 12 7;215(12):3094-3114. Epub 2018 Nov 7.

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondrial apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (, , or ) were associated with mitochondrial apoptosis resistance. In T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action. PRC2 loss induced apoptosis resistance via transcriptional up-regulation of the LIM domain transcription factor and downstream up-regulation of the mitochondrial chaperone These findings demonstrate the importance of mitochondrial apoptotic priming as a prognostic factor in T-ALL and implicate mitochondrial chaperone function as a molecular determinant of chemotherapy response.
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http://dx.doi.org/10.1084/jem.20180570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279404PMC
December 2018

Different mechanisms involved in liraglutide and glucagon-like peptide-1 vasodilatation in rat mesenteric small arteries.

Br J Pharmacol 2019 02 9;176(3):386-399. Epub 2018 Dec 9.

Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark.

Background And Purpose: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates insulin biosynthesis and secretion in a glucose-dependent manner and has been reported to induce vasodilatation. Here, we examined the possible vasorelaxant effect of GLP-1 and its underlying mechanisms.

Experimental Approach: Rat mesenteric arteries (diameter ≈ 200-400 μm) and human s.c. arteries were mounted in microvascular myographs for isometric tension recordings. The effect of GLP-1 on vascular responses was examined under normoglycaemic conditions and at high glucose concentrations.

Key Results: In rat mesenteric arteries and human s.c. arteries without branches, physiological concentrations (1-100 nM) of GLP-1(7-36) and liraglutide failed to cause relaxation or affect contractions evoked by electrical field stimulation. In contrast to GLP-1(7-36), liraglutide induced relaxations antagonized by the GLP-1 receptor antagonist, exendin-(9-39), in branched mesenteric arteries. In contrast to liraglutide, GLP-1 leftward shifted the concentration relaxation curves for bradykinin in s.c. arteries from patients with peripheral arterial disease, an effect resistant to exendin-(9-39). Under normoglycaemic conditions, neither GLP-1 nor liraglutide affected ACh relaxation in rat mesenteric arteries. In arteries exposed to 40 mM glucose, GLP-1, in contrast to liraglutide, potentiated ACh-induced relaxation by a mechanism that was not antagonized by exendin-(9-39). GLP-1 decreased superoxide levels measured with dihydroethidium in rat mesenteric arteries exposed to 40 mM glucose.

Conclusions And Implications: GLP-1 receptors are involved in the liraglutide-induced relaxation of branched arteries, under normoglycaemic conditions, while GLP-1 inhibition of vascular superoxide levels contributes to GLP-1 receptor-independent potentiation of endothelium-dependent vasodilatation in hyperglycaemia.
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http://dx.doi.org/10.1111/bph.14534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329621PMC
February 2019

Genomic Selection for Growth Traits in Pacific Oyster (): Potential of Low-Density Marker Panels for Breeding Value Prediction.

Front Genet 2018 19;9:391. Epub 2018 Sep 19.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Edinburgh, United Kingdom.

Pacific oysters are a key aquaculture species globally, and genetic improvement via selective breeding is a major target. Genomic selection has the potential to expedite genetic gain for key target traits of a breeding program, but has not yet been evaluated in oyster. The recent development of SNP arrays for Pacific oyster () raises the opportunity to test genomic selection strategies for polygenic traits. In this study, a population of 820 oysters (comprising 23 full-sibling families) were genotyped using a medium density SNP array (23 K informative SNPs), and the genetic architecture of growth-related traits [shell height (SH), shell length (SL), and wet weight (WW)] was evaluated. Heritability was estimated to be moderate for the three traits (0.26 ± 0.06 for SH, 0.23 ± 0.06 for SL and 0.35 ± 0.05 for WW), and results of a GWAS indicated that the underlying genetic architecture was polygenic. Genomic prediction approaches were used to estimate breeding values for growth, and compared to pedigree based approaches. The accuracy of the genomic prediction models (GBLUP) outperformed the traditional pedigree approach (PBLUP) by ∼25% for SL and WW, and ∼30% for SH. Further, reduction in SNP marker density had little impact on prediction accuracy, even when density was reduced to a few hundred SNPs. These results suggest that the use of genomic selection in oyster breeding could offer benefits for the selection of breeding candidates to improve complex economic traits at relatively modest cost.
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http://dx.doi.org/10.3389/fgene.2018.00391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156352PMC
September 2018

Gene Expression Response to Sea Lice in Atlantic Salmon Skin: RNA Sequencing Comparison Between Resistant and Susceptible Animals.

Front Genet 2018 3;9:287. Epub 2018 Aug 3.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Edinburgh, United Kingdom.

Sea lice are parasitic copepods that cause large economic losses to salmon aquaculture worldwide. Frequent chemotherapeutic treatments are typically required to control this parasite, and alternative measures such as breeding for improved host resistance are desirable. Insight into the host-parasite interaction and mechanisms of host resistance can lead to improvements in selective breeding, and potentially novel treatment targets. In this study, RNA sequencing was used to study the skin transcriptome of Atlantic salmon () parasitized with sea lice (). The overall aims were to compare the transcriptomic profile of skin at louse attachment sites and "healthy" skin, and to assess differences in gene expression response between animals with varying levels of resistance to the parasite. Atlantic salmon pre-smolts were challenged with , growth and lice count measurements were taken for each fish. 21 animals were selected and RNA-Seq was performed on skin from a louse attachment site, and skin distal to attachment sites for each animal. These animals were classified into family-balanced groups according to the traits of resistance (high vs. low lice count), and growth during infestation. Overall comparison of skin from louse attachment sites vs. healthy skin showed that 4,355 genes were differentially expressed, indicating local up-regulation of several immune pathways and activation of tissue repair mechanisms. Comparison between resistant and susceptible animals highlighted expression differences in several immune response and pattern recognition genes, and also myogenic and iron availability factors. Components of the pathways involved in differential response to sea lice may be targets for studies aimed at improved or novel treatment strategies, or to prioritize candidate functional polymorphisms to enhance genomic selection for host resistance in commercial salmon breeding programs.
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http://dx.doi.org/10.3389/fgene.2018.00287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086009PMC
August 2018

Procedural, Functional and Prognostic Outcomes Following Recanalization of Coronary Chronic Total Occlusions. Results of the Iberian Registry.

Rev Esp Cardiol (Engl Ed) 2019 May 25;72(5):373-382. Epub 2018 Jun 25.

Servicio de Cardiología, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Hospital Clínic Universitari, INCLIVA, Universitat de València, Valencia, Spain.

Introduction And Objectives: There is current controversy regarding the benefits of percutaneous recanalization (PCI) of chronic total coronary occlusions (CTO). Our aim was to determine acute and follow-up outcomes in our setting.

Methods: Two-year prospective registry of consecutive patients undergoing PCI of CTO in 24 centers.

Results: A total of 1000 PCIs of CTO were performed in 952 patients. Most were symptomatic (81.5%), with chronic ischemic heart disease (59.2%). Previous recanalization attempts had been made in 15%. The mean SYNTAX score was 19.5 ± 10.6 and J-score was > 2 in 17.3%. A retrograde procedure was performed in 92 patients (9.2%). The success rate was 74.9% and was higher in patients without previous attempts (82.2% vs 75.2%; P = .001), those with a J-score ≤ 2 (80.5% vs 69.5%; P = .002), and in intravascular ultrasound-guided PCI (89.9% vs 76.2%, P = .001), which was an independent predictor of success. In contrast, severe calcification, length > 20mm, and blunt proximal cap were independent predictors of failed recanalization. The rate of procedural complications was 7.1%, including perforation (3%), myocardial infarction (1.3%), and death (0.5%). At 1-year of follow-up, 88.2% of successfully revascularized patients showed clinical improvement (vs 34.8%, P < .001), which was associated with lower mortality. At 1-year of follow-up, the mortality rate was 1.5%.

Conclusions: Compared with other national registries, patients in the Iberian registry undergoing PCI of a CTO showed similar complexity, success rate, and complications. Successful recanalization was strongly associated with functional improvement, which was related to lower mortality.
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http://dx.doi.org/10.1016/j.rec.2018.05.020DOI Listing
May 2019

JDP2: An oncogenic bZIP transcription factor in T cell acute lymphoblastic leukemia.

J Exp Med 2018 07 25;215(7):1929-1945. Epub 2018 Jun 25.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

A substantial subset of patients with T cell acute lymphoblastic leukemia (T-ALL) develops resistance to steroids and succumbs to their disease. encodes a bZIP protein that has been implicated as a T-ALL oncogene from insertional mutagenesis studies in mice, but its role in human T-ALL pathogenesis has remained obscure. Here we show that is aberrantly expressed in a subset of T-ALL patients and is associated with poor survival. JDP2 is required for T-ALL cell survival, as its depletion by short hairpin RNA knockdown leads to apoptosis. Mechanistically, JDP2 regulates prosurvival signaling through direct transcriptional regulation of Furthermore, is one of few oncogenes capable of initiating T-ALL in transgenic zebrafish. Notably, thymocytes from transgenic zebrafish express high levels of and demonstrate resistance to steroids in vivo. These studies establish as a novel oncogene in high-risk T-ALL and implicate overexpression of as a mechanism of steroid resistance in -overexpressing cells.
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http://dx.doi.org/10.1084/jem.20170484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028512PMC
July 2018

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

Leukemia 2018 10 20;32(10):2126-2137. Epub 2018 Mar 20.

Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease.
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http://dx.doi.org/10.1038/s41375-018-0097-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148437PMC
October 2018
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