We previously identified a rearrangement of mixed-lineage leukemia (MLL) gene (also known as ALL-1, HRX, and HTRX1), consisting of an in-frame partial tandem duplication (PTD) of exons 5 through 11 in the absence of a partner gene, occurring in approximately 4%-7% of patients with acute myeloid leukemia (AML) and normal cytogenetics, and associated with a poor prognosis. The mechanism by which the MLL PTD contributes to aberrant hematopoiesis and/or leukemia is unknown. To examine this, we generated a mouse knockin model in which exons 5 through 11 of the murine Mll gene were targeted to intron 4 of the endogenous Mll locus. Mll PTD/WT mice exhibit an alteration in the boundaries of normal homeobox (Hox) gene expression during embryogenesis, resulting in axial skeletal defects and increased numbers of hematopoietic progenitor cells. Mll PTD/WT mice overexpress Hoxa7, Hoxa9, and Hoxa10 in spleen, BM, and blood. An increase in histone H3/H4 acetylation and histone H3 lysine 4 (Lys4) methylation within the Hoxa7 and Hoxa9 promoters provides an epigenetic mechanism by which this overexpression occurs in vivo and an etiologic role for MLL PTD gain of function in the genesis of AML.
Patients with severe chronic obstructive pulmonary disease (COPD) are at higher risk of developing invasive pulmonary aspergillosis (IPA). However, there are limited data for this disease. To evaluate risk factors and the clinical characteristics of IPA in COPD patients, we conducted a hospital-based, retrospective case-control study of 30 COPD patients with IPA and 60 COPD control patients without IPA. Patients in the case group were significantly more likely to have concurrent co-morbidities than controls. Of the IPA patients, 65.4% had worsening radiological findings vs. 11.4% in the control group (p<0.001). IPA in COPD was associated with a higher proportion of mechanical ventilation (43.3% vs. 5%; p<0.001), a longer hospital stay duration (45.8±39.1 days vs. 18.4±11.8 days; p<0.001), and higher mortality (43.3% vs. 11.4%; p<0.001). Systemic use of steroids in the stable phase, treatment with three or more antibiotics during hospitalization and antibiotic treatment longer than 10 days were independent risk factors associated with IPA. COPD patients with obvious dyspnoea, antibiotic-resistant lower respiratory tract infection and repeated detection of Aspergillus in sputum should be considered for the possibility of IPA.
BackgroundIn China, large-scale outbreaks of severe diarrhea caused by viruses have occurred in pigs since late 2010. To investigate the prevalence and genetic evolution of diarrhea-associated viruses responsible for the outbreaks, a total of 2987 field diarrheal samples collected from 168 pig farms in five provinces in Southern China during 2012–2018 were tested.ResultsPorcine epidemic diarrhea virus (PEDV) was most frequently detected virus with prevalence rates between 50.21 and 62.10% in samples, and 96.43% (162/168) in premises, respectively. Porcine deltacoronavirus (PDCoV) was the second prevalent virus with prevalence rates ranging from 19.62 to 29.19% in samples, and 70.24% (118/168) in premises, respectively. Both transmissible gastroenteritis virus (TGEV) and porcine rotavirus (PoRV) were detected at low prevalence rates of < 3% in samples and 10.12% in premises. In this study, we identified a newly emerged swine acute diarrhea syndrome coronavirus (SADS-CoV) in diarrheal samples of piglets from Fujian province in Southern China, and the prevalence rate of SADS-CoV was 10.29% (7/68). Co-infections of these diarrhea-associated viruses were common. The most frequent co-infection was PEDV with PDCoV, with an average detection rate of 12.72% (380/2987, ranging from 8.26–17.33%). Phylogenetic analysis revealed that PEDVs circulating in Southern China during the last 7 years were clustered with the variant strains of PEDV in genotype IIa. The most frequent mutations were present in the collagenase equivalent (COE) and epitope regions of the spike gene of the PEDVs currently circulating in the field. Genetic relationships of PDCoVs were closely related with Chinese strains, other than those present in the USA, South Korea, Thailand and Lao’s public.ConclusionsThe findings of this study indicated that variant PEDV, PDCoV, and SADS-CoV were leading etiologic agents of porcine diarrhea, and either mono-infections or co-infections of pathogenic enteric CoVs were common in pigs in Southern China during 2012–2018. Thus, significant attention should be paid in order to effectively prevent and control porcine viral diarrhea.
Interleukin-15 (IL-15) is a pleiotropic proinflammatory cytokine with inefficient posttranscriptional processing. We hypothesized that endogenous IL-15 could affect disease progression in the well-described C57Bl/6 (B6) 3 (C57Bl/6 ؋ DBA/2) F1 hybrid ( IntroductionBone marrow transplantation (BMT) is a potentially curative therapy for patients with heritable immunodeficiencies and malignant diseases including leukemia, lymphoma, and myeloma. 1 While the conditioning regimen for BMT leads to direct tumor destruction, donor-derived allogeneic T cells can exert an important graft-versus-tumor (GVT) effect: recipients of allogeneic transplants have a decreased probability of relapse compared with recipients of autologous, syngeneic, or T-cell-depleted bone marrow transplants. 2,3 However, allogeneic BMT also carries a significant risk for graft-versus-host disease (GVHD), an immunologic attack of allogeneic donor T lymphocytes against normal recipient tissues, the magnitude of which depends in large part on the degree of HLA incompatibility between donor and recipient. Even with appropriate prophylaxis, the incidence of acute GVHD ranges from 30% in HLA-identical donor-recipient pairs to 70% for donorrecipient pairs HLA-incompatible at 2 loci. 1,4 Thus, GVHD remains the most significant obstacle to the wider application of BMT for the treatment of malignancy.GVHD is characterized by a cycle of tissue destruction and inflammation initiated by the preparative regimen for transplantation and propagated by alloreactive donor T cells. 5 Transplant recipients are prepared for BMT with a regimen that obliterates their current bone marrow stores and potentially their residual leukemia. However, this regimen is also highly toxic to the gastrointestinal system and allows release of gram-negative bacterial lipopolysaccharide (LPS) across the intestinal mucosa. 6 LPS is a potent stimulator for the production of tumor necrosis factor ␣ (TNF-␣), interleukin-1 (IL-1), and IL-12. 6,7 IL-12 polarizes donorderived T cells toward a proinflammatory Th1/Tc1 phenotype, producing interferon ␥ (IFN-␥) and TNF-␣; 8,9 IFN-␥ and TNF-␣ induce major histocompatibility complex (MHC) expression by host-derived antigen-presenting cells (APCs), which results in efficient presentation of alloantigen to donor-derived T cells. 10,11 These donor-derived Th1/Tc1-polarized T cells in turn produce IL-2, expand, and infiltrate host epithelial tissues. Thus, the inflammation of acute GVHD is influenced in large part by the cytokine cascade within the host after transplantation.The role of IL-15, a T-and natural killer (NK) cell growth factor, in allogeneic GVHD has not been addressed. Originally isolated because of its ability to restore T-cell growth in the presence of IL-2-neutralizing antibodies, 12,13 IL-15 mRNA is widely and abundantly expressed in multiple tissues. However, IL-15 is inefficiently translated and secreted with multiple posttranscriptional checkpoints. [14][15][16] 36,37 We therefore hypothesized that alteration of endogenous IL-15 produ...
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