Myeloid/Lymphoid neoplasms with abnormalities of PDGFRA

This insert represents a review of myeloid and lymphoid neoplasms with abnormalities of PDGFRA including clinical presentation, morphologic review, and cytogenetic findings

Myeloid/Lymphoid neoplasms with abnormalities of PDGFRB

This insert represents a review of myeloid and lymphoid neoplasms with abnormalities of PDGFRB including clinical presentation, morphologic review, and cytogenetic findings

Multi-ethnic genome-wide association study for atrial fibrillation

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec

Persistent indolent pancolonic marginal zone lymphoma of MALT-type with plasmacytic differentiation – A rare post-transplant lymphoma?

Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is associated with chronic inflammatory disorders. We present an indolent pancolonic MALT lymphoma occurring in a 39-year-old female with history of autoimmune hepatitis requiring liver transplant in 1997 and ulcerative colitis diagnosed in 2004. Random biopsies from a grossly unremarkable surveillance colonoscopy in 2015 revealed a dense monomorphic plasmacytoid infiltrate causing expansion of lamina propria without significant crypt infiltration or destruction. These cells were positive for CD79a and CD138 and showed lambda restriction; however, CD20, CD43, CD56, HHV8, and EBER were negative. A similar pancolonic infiltrate was identified in all prior colorectal biopsies from 2010 and 2012 upon retrospective review. Subsequent computed tomography of the abdomen revealed no bowel wall thickening nor enlarged lymph nodes. Bone marrow revealed involvement consistent with stage IV disease. Biopsies from 2010 and 2015 demonstrated clonal immunoglobulin gene rearrangement. MYD88 mutation was not detected. The overall features were indicative of MALT lymphoma. Although low-grade B-cell lymphomas are not considered part of the post-transplant lymphoproliferative disorder spectrum, such cases have been reported, and are typically EBV-negative. Patient underwent treatment with pentostatin for her MALT lymphoma reaching a sustained remission despite additional immunosuppression for resurgent hepatic dysfunction. To our knowledge, this is the first reported case of EBV-negative pancolonic MALT lymphoma with plasmacytic differentiation post liver transplant presenting in an indolent, asymptomatic fashion with persistence for greater than five years successfully managed without compromising the patient's liver transplant

Transgenic hepatitis B virus large envelope polypeptide (HBsAg) expression in hepatocytes with nuclear inclusions.

<p>(A, B) A high level of HBsAg expression in the cytoplasm of hepatocytes in nine-month-old transgenic mice. Antibody specificity was confirmed by lack of immuno-reactivity in wild-type control mice shown in the inset of (<b>B</b>). (<b>C</b>) Quantification of the relative number of hepatocytes from HBsAg transgenic mice that express the HBsAg in inclusion-bearing and normal hepatocytes (n = 5). p<0.01; ***,p<0.001; ****, p<0.0001, scale bar 50 µm.</p

Oxidative stress may play a role in nuclear inclusion formation.

<p>(<b>A</b>) HBsAg-Tg mice liver show clear 4-HNE staining in hepatocytes including within nuclear inclusions of 9-month-old mice and 4-HNE levels are decreased with NAC treatment. (<b>B</b>) Quantification revealed a significant difference in 4-HNE levels in HBsAg-Tg mice treated with (n = 5) and without NAC (n = 5). (<b>C</b>) Decreased Chop protein levels in NAC-treated HBsAg-Tg mice (n = 3) versus HBsAg-Tg (n = 3) was confirmed by Western blot. (E) Nuclear inclusions were significantly reduced in NAC treated mice (n = 7) compare to HBsAg-Tg mice (n = 5). *,p<0.05; **,p<0.01, scale bar 20 µm.</p

Nuclear inclusions are enriched with endoplasmic reticulum material.

<p>The origin of material within these inclusions was examined by Histone H3 and Calnexin staining. (<b>A</b>) None of the nuclear inclusions expressed histone H3 (n = 5). (<b>B</b>) However, almost all inclusions were clearly positive for calnexin staining (n = 5). Negative controls for Histone H3 and calnexin (no primary antibody) are shown in the insets. scale bar 20 µm.</p

Nuclear inclusions are enriched in glycogen.

<p>(<b>A</b>) HBsAg-Tg liver nuclear inclusions were enriched for Periodic acid-Schiff (PAS) staining. (B) Hepatocytes bearing nuclear inclusions were typically PAS positive (n = 5). (<b>C, D</b>) The material was confirmed to be glycogen by amylase digestion assay. scale bar 20 µm.</p