Clinical outcomes of hypomethylating agents and venetoclax in newly diagnosed unfit and relapsed/refractory paediatric, adolescent and young adult acute myeloid leukaemia patients.

Venetoclax (VEN) combined with hypomethylating agents (HMA) decitabine or azacitidine is used for adult acute myeloid leukaemia (AML), but its application in paediatric, adolescent and young adult (AYA) AML lacks prospective studies. We performed a retrospective chart review of paediatric and AYA AML patients treated with HMA + VEN at Cincinnati Children's Hospital Medical Centre. Twenty-seven patients received 30 HMA + VEN treatment courses for relapsed/refractory (R/R, n = 21) or newly diagnosed (n = 9) AML due to ineligibility for intensive chemotherapy.

Major cell-types in multiomic single-nucleus datasets impact statistical modeling of links between regulatory sequences and target genes.

Epigenomic profiling, including ATACseq, is one of the main tools used to define enhancers. Because enhancers are overwhelmingly cell-type specific, inference of their activity is greatly limited in complex tissues. Multiomic assays that probe in the same nucleus both the open chromatin landscape and gene expression levels enable the study of correlations (links) between these two modalities.

Combined epigenetic and immunotherapy for blastic and classical mantle cell lymphoma.

Classical MCL (cMCL) constitutes 6-8% of all B cell NHL. Despite recent advances, MCL is incurable except with allogeneic stem cell transplant. Blastic mantle cell lymphoma (bMCL) is a rarer subtype of cMCL associated with an aggressive clinical course and poor treatment response, frequent relapse and poor outcomes.

Distribution and Pathogenicity of Two Cutthroat Trout Virus (CTV) Genotypes in Canada.

The sole member of the genus (family ) is cutthroat trout virus (CTV) but recent metatranscriptomic studies have identified numerous fish hepevirus sequences including CTV-2. In the current study, viruses with sequences resembling both CTV and CTV-2 were isolated from salmonids in eastern and western Canada. Phylogenetic analysis of eight full genomes delineated the Canadian CTV isolates into two genotypes (CTV-1 and CTV-2) within the genus.

Transcriptomic Profiling of Canine Atrial Fibrillation Models After One Week of Sustained Arrhythmia.

[Figure: see text].

Pediatric Patient With Ulcerative Colitis-Associated Bronchiectasis.

We report a unique case of ulcerative colitis-associated bronchiectasis in a pediatric patient 6 years after colectomy. The patient presented with a chronic cough and had a computed tomography demonstrating bronchiectasis. She was treated with sputum expectoration (airway clearance) via chest physiotherapy and pulse-dose steroids with a prolonged oral taper.

Sphingosine kinase-2 is overexpressed in large granular lymphocyte leukaemia and promotes survival through Mcl-1.

Sphingolipid metabolism is increasingly recognised as a therapeutic target in cancer due to its regulation of cell proliferation and apoptosis. The sphingolipid rheostat is proposed to control cell fate through maintaining balance between pro-apoptotic and pro-survival sphingolipids. This balance is regulated by metabolising enzymes involved in sphingolipid production.

Integrative analysis of vascular endothelial cell genomic features identifies AIDA as a coronary artery disease candidate gene.

Background: Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD) and blood pressure (BP) or hypertension. Many of these loci are not linked to traditional risk factors, nor do they include obvious candidate genes, complicating their functional characterization. We hypothesize that many GWAS loci associated with vascular diseases modulate endothelial functions.

Phase 1-2 study of vorinostat (SAHA), cladribine and rituximab (SCR) in relapsed B-cell non-Hodgkin lymphoma and previously untreated mantle cell lymphoma.

Altered DNA methylation and histone acetylation in lymphoma provided the rationale for using vorinostat (SAHA), cladribine and rituximab (SCR) in non-Hodgkin lymphomas (NHL) in this phase 1-2 study (NCT00764517). Treatment included cladribine 5 mg/m intravenously (IV) (days 1-5), rituximab 375 mg/m IV (weekly 4× for cycle 1 and 1×/month) and vorinostat orally once daily (days 1-14) every 28 days for up to six cycles. Phase 1 included relapsed patients (n = 10) in a standard 3 + 3 dose escalation design (vorinostat: 200, 300 and 400 mg).

In vivo virulence and genomic comparison of infectious Salmon Anaemia Virus isolates from Atlantic Canada.

The infectious salmon anaemia virus (ISAV) is capable of causing a significant disease in Atlantic salmon, which has resulted in considerable financial losses for salmon farmers around the world. Since the first detection of ISAV in Canada in 1996, it has been a high priority for aquatic animal health management and surveillance programmes have led to the identification of many genetically distinct ISAV isolates of variable virulence. In this study, we evaluated the virulence of three ISAV isolates detected in Atlantic Canada in 2012 by doing in vivo-controlled disease challenges with two sources of Atlantic salmon.

TRAIL mediates and sustains constitutive NF-κB activation in LGL leukemia.

Large granular lymphocyte (LGL) leukemia results from clonal expansion of CD3 cytotoxic T lymphocytes or CD3 natural killer (NK) cells. Chronic antigen stimulation is postulated to promote long-term survival of LGL leukemia cells through constitutive activation of multiple survival pathways, resulting in global dysregulation of apoptosis and resistance to activation-induced cell death. We reported previously that nuclear factor κB (NF-κB) is a central regulator of the survival network for leukemic LGL.

Synthesis, Characterization, and Properties of Weakly Coordinating Anions Based on tris-Perfluoro-tert-Butoxyborane.

A convenient method for the preparation of strongly Lewis acidic tris-perfluoro-tert-butoxyborane B(OR) (1), (OR = OC(CF)) was developed, and its X-ray structure was determined. 1 was used as a precursor, guided by density functional theory (DFT) calculations and volume-based thermodynamics, for the synthesis of [NEt][NCB(OR)] (3) and [NMe][FB(OR)] (5) and the novel large and weakly coordinating anion salts [Li 15-Crown-5][B(OR)] (2) and [NEt][CN{B(OR)}] (4). The stability of [B(OR)] was compared with that of some related known weakly coordinating anions by appropriate DFT calculations.

Manipulation and mobilisation for neck pain contrasted against an inactive control or another active treatment.

Background: Manipulation and mobilisation are commonly used to treat neck pain. This is an update of a Cochrane review first published in 2003, and previously updated in 2010.

Objectives: To assess the effects of manipulation or mobilisation alone compared wiith those of an inactive control or another active treatment on pain, function, disability, patient satisfaction, quality of life and global perceived effect in adults experiencing neck pain with or without radicular symptoms and cervicogenic headache (CGH) at immediate- to long-term follow-up.

Sphingosine kinase inhibitors decrease viability and induce cell death in natural killer-large granular lymphocyte leukemia.

Sphingolipid metabolism has been identified as a potential therapeutic target in cancer. Sphingosine-1-phosphate (S1P) is a potent bioactive sphingolipid metabolite produced by sphingosine kinases-1 and -2 (SPHK1 and SPHK2). Elevated SPHK1 has been found in numerous cancer types and been shown to contribute to survival, chemotherapeutic resistance and malignancy.

The pathogenesis and treatment of large granular lymphocyte leukemia.

Large granular lymphocyte (LGL) leukemia is a spectrum of rare lymphoproliferative diseases of T lymphocytes and natural killer cells. These diseases frequently present with splenomegaly, neutropenia, and autoimmune diseases like rheumatoid arthritis. LGL leukemia is more commonly of a chronic, indolent nature; however, rarely, they have an aggressive course.

Selective hydrosilation of CO2 to a bis(silylacetal) using an anilido bipyridyl-ligated organoscandium catalyst.

A rigid anilido bipyridyl ligand has been designed for use in an organoscandium-based carbon dioxide hydrosilation catalyst. Ligand attachment by alkane elimination results in metalation of an aryl C-H bond in a 3,5-di-tert-butylphenyl group installed on the pyridyl unit, thus rendering the ligand tetradentate. Insertion of CO2 into the newly formed Sc-C bond leads to a κ(1) carboxylate which, when treated with the borane B(C6F5)3, becomes hemilabile.

STAT3 mutations indicate the presence of subclinical T-cell clones in a subset of aplastic anemia and myelodysplastic syndrome patients.

Large granular lymphocyte leukemia (LGL) is often associated with immune cytopenias and can cooccur in the context of aplastic anemia (AA) and myelodysplastic syndromes (MDS). We took advantage of the recent description of signal transducer and activator of transcription 3 (STAT3) mutations in LGL clonal expansions to test, using sensitive methods, for the presence of these mutations in a large cohort of 367 MDS and 140 AA cases. STAT3 clones can be found not only in known LGL concomitant cases, but in a small proportion of unsuspected ones (7% AA and 2.

Does IL-15 have a causative role in large granular lymphocyte leukemia?

Evaluation of: Mishra A, Liu S, Sams GH et al. Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation. Cancer Cell 22(5), 645-655 (2012).

STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia.

Chronic lymphoproliferative disorders of natural killer cells (CLPD-NKs) and T-cell large granular lymphocytic leukemias (T-LGLs) are clonal lymphoproliferations arising from either natural killer cells or cytotoxic T lymphocytes (CTLs). We have investigated for distribution and functional significance of mutations in 50 CLPD-NKs and 120 T-LGL patients by direct sequencing, allele-specific PCR, and microarray analysis. STAT3 gene mutations are present in both T and NK diseases: approximately one-third of patients with each type of disorder convey these mutations.

Large granular lymphocyte leukemia: from dysregulated pathways to therapeutic targets.

Large granular lymphocyte (LGL) leukemia is a clonal lymphoproliferative disorder of cytotoxic lymphocytes characterized by an expansion of CD3(+) cytotoxic T lymphocytes or CD3(-) natural killer cells. Patients present with various cytopenias including neutropenia, anemia and thrombocytopenia. In addition, there is an association of T-cell large granular lymphocytic leukemia with rheumatoid arthritis.