The bone marrow constitutes a favorable environment for long-lived antibody-secreting plasma cells, providing blood-circulating antibody. Plasma cells are also present in mucosa-associated lymphoid tissue (MALT) to mediate local frontline immunity, but how plasma cell survival there is regulated is not known. Here we report that a proliferation-inducing ligand (APRIL) promoted survival of human upper and lower MALT plasma cells by upregulating expression of the antiapoptotic proteins bcl-2, bcl-x_L, and mcl-1. The in situ localization of APRIL was consistent with such a prosurvival role in MALT. In upper MALT, tonsillar epithelium produced APRIL. Upon infection, APRIL production increased considerably when APRIL-secreting neutrophils recruited from the blood infiltrated the crypt epithelium. Heparan sulfate proteoglycans (HSPGs) retained secreted APRIL in the subepithelium of the infected zone to create APRIL-rich niches, wherein IgG-producing plasma cells accumulated. In lower MALT, neutrophils were the unique source of APRIL, giving rise to similar niches for IgA-producing plasmocytes in villi of lamina propria. Furthermore, we found that mucosal humoral immunity in APRIL-deficient mice is less persistent than in WT mice. Hence, production of APRIL by inflammation-recruited neutrophils may create plasma cell niches in MALT to sustain a local antibody production.

This study compared the biocompatibility, mechanical properties, and surface roughness of a pre-polymerized polymethyl methacrylate (PMMA) resin for CAD/CAM complete removable dental prostheses (CRDPs) and a traditional heat-polymerized PMMA resin. Two groups of resin substrates [Control (RC): conventional PMMA; Test (RA): CAD/CAM PMMA] were fabricated. Human primary osteoblasts and mouse embryonic-fibroblasts were cultured for biocompatibility assays. Mechanical properties and surface roughness were compared. ANOVA revealed no difference between the resin groups in the biocompatibility assays. RA demonstrated a higher elastic modulus (p=0.002), young’s modulus (p=0.002), plastic energy (p=0.002), ultimate strength (p=0.0004), yield point (p=0.016), strain at yield point (p=0.037), and toughness (p<0.0001); while RC displayed a higher elastic energy (p<0.0001). Laser profilometry concluded a rougher surface profile (p<0.0001) for RA. This study concluded that the tested CAD/CAM resin was equally biocompatible and presented with improved mechanical properties than the traditional heat-polymerized PMMA resin used in the fabrication of CRDPs.

This study evaluated the biocompatibility, mechanical properties, and surface roughness of CAD-CAM milled and rapidly-prototyped/3D-printed resins used for manufacturing complete dentures. Six groups of resin specimens were prepared, milled-base (MB), milled-tooth shade (MT), printed-tooth shade (PT), printed-base with manufacturer-recommended 3D-printer (PB1), printed-base with third-party 3D-printer (PB2), printed-base in a vertical orientation (PB2V). Human epithelial (A-431) and gingival (HGF-1) cells were cultured and tested for biocompatibility using Resazurin assays. Three-point bending and nanoindentation tests measured the mechanical properties of the resin groups. Surface roughness was evaluated using a high-resolution laser profilometer. ANOVA and post-hoc tests were used for statistical analyses (α = 0.05). There were no significant differences in biocompatibility between any of the investigated groups. MB revealed a higher ultimate strength (p = 0.008), elastic modulus (p = 0.002), and toughness (p = 0.014) than PB1. MT had significantly higher elastic modulus than PT (p < 0.001). Rapidly-prototyped resin samples with a manufacturer-recommended 3D-printer (PB1) demonstrated higher ultimate strength (p = 0.008), elastic modulus (p < 0.001), hardness (p < 0.001) and a reduced surface roughness (p < 0.05) when compared with rapidly-prototyped groups using a third-party 3D-printer (PB2). Rapidly-prototyped samples manufactured with a vertical printing orientation (PB2V) revealed a significantly lower elastic modulus than samples groups manufactured using horizontal printing orientation (PB2) (p = 0.011). Within the limits of this present study, CAD-CAM milled and rapidly-prototyped complete denture resins performed similarly in terms of biocompatibility and surface roughness. However, the milled denture resins were superior to the rapidly-prototyped denture resins with regard to their mechanical properties. Printing orientation and type of 3D-printer can affect the resin strength and surface roughness.

Summary: The disturbed erythropoiesis in patients with refractory anaemia with ring‐sideroblasts (RARS) is characterized by intramedullary apoptosis of erythroid precursors and increased iron accumulation in mitochondria. To gain insight into these pathophysiological mechanisms we compared the gene expression profile (GEP) of erythroid precursors from RARS patients to the GEP of normal erythroid precursors. Three hundred sixty four probe sets were up‐, and 253 probe sets downregulated in RARS cells. Interestingly, Growth Differentiation factor 15 (GDF15), a cytokine from the TGFβ family, was dramatically upregulated in all RARS patients. Measurement of GDF15 in the sera from twenty RARS patients confirmed this finding by showing significantly, 7·2‐fold, increased protein levels (3254 ± 1400 ng/ml vs. 451 ± 87 ng/ml in normals). In vitro studies demonstrated erythroid‐specific production of GDF15 and dependence on erythropoietin. Induction of apoptosis by arsenic trioxide, a drug which acts via reduction of the mitochondrial membrane potential, also stimulated GDF15 production. Downregulation of endogenous GDF15 production in erythoblasts by specific siRNA led to diminished erythroid differentiation. Taken together, our findings demonstrate a new role for GDF15 in normal erythropoiesis as well as in the ineffective erythropoiesis of RARS patients.