Rebound of relapses after discontinuation of rituximab in a patient with MOG-IgG1 positive highly relapsing optic neuritis: a case report

Background

Myelin oligodendrocyte glycoprotein immunoglobulin G1 (MOG-IgG1)-associated disease is suggested as a separate disease entity distinct from multiple sclerosis and neuromyelitis optica spectrum disorder. Nonetheless, the optimal treatment regimen for preventing relapses in MOG-IgG1-associated disease remains unclear.

Case presentation

We describe the case of a 45-year-old man with MOG-IgG1-positive highly relapsing optic neuritis who had experienced 5 attacks over 21?months and had monocular blindness despite prednisolone and azathioprine therapy. He began treatment with rituximab, which reduced the rate of relapse markedly. Following discontinuation of rituximab, however, the patient experienced two successive optic neuritis attacks 2 and 4?months after B-lymphocyte restoration.

Conclusions

Highly relapsing MOG-IgG1-associated disease can be prevented with rituximab even when the MOG-IgG1 titers are relatively stationary. Discontinuation of rituximab and restoration of B-lymphocytes may be associated with the rebound of disease activity.

     

Regulation of mouse oocyte microtubule and organelle dynamics by PADI6 and the cytoplasmic lattices

Organelle positioning and movement in oocytes is largely mediated by microtubules (MTs) and their associated motor proteins. While yet to be studied in germ cells, cargo trafficking in somatic cells is also facilitated by specific recognition of acetylated MTs by motor proteins. We have previously shown that oocyte-restricted PADI6 is essential for formation of a novel oocyte-restricted fibrous structure, the cytoplasmic lattices (CPLs). Here, we show that α-tubulin appears to be associated with the PADI6/CPL complex. Next, we demonstrate that organelle positioning and redistribution is defective in PADI6-null oocytes and that alteration of MT polymerization or MT motor activity does not induce organelle redistribution in these oocytes. Finally, we report that levels of acetylated microtubules are dramatically suppressed in the cytoplasm of PADI6-null oocytes, suggesting that the observed organelle redistribution failure is due to defects in stable cytoplasmic MTs. These results demonstrate that the PADI6/CPL superstructure plays a key role in regulating MT-mediated organelle positioning and movement.     

Identification of RUNX3 as a component of the MST/Hpo signaling pathway

Recent genetic screens of fly mutants and molecular analysis have revealed that the Hippo (Hpo) pathway controls both cell proliferation and cell death. Deregulation of its human counterpart (the MST pathway) has been implicated in human cancers. However, how this pathway is linked with the known tumor suppressor network remains to be established. RUNX3 functions as a tumor suppressor of gastric cancer, lung cancer, bladder cancer, and colon cancer. Here, we show that RUNX3 is a principal and evolutionarily conserved component of the MST pathway. SAV1/WW45 facilitates the close association between MST2 and RUNX3. MST2, in turn, stimulates the SAV1-RUNX3 interaction. In addition, we show that siRNA-mediated RUNX3 knockdown abolishes MST/Hpo-mediated cell death. By establishing that RUNX3 is an endpoint effector of the MST pathway and that RUNX3 is capable of inducing cell death in cooperation with MST and SAV1, we define an evolutionarily conserved novel regulatory mechanism loop for tumor suppression in human cancers.     

Agonist-induced Internalization of the Caenorhabditis elegans Muscarinic Acetylcholine Receptor GAR-3 in Chinese Hamster Ovary Cells

Many membrane-bound neurotransmitter receptors are known to be internalized by exposure to agonist. This agonist-induced receptor internalization is considered to play important roles in receptor-mediated signaling. Here we investigated the internalization of GAR-3, a Caenorhabditis elegans muscarinic acetylcholine receptor, using cultured mammalian cells. When Chinese hamster ovary cells stably expressing GAR-3 were treated with carbachol, GAR-3 was internalized in a dose- and time-dependent manner. Approximately 60% of the cell surface receptor was internalized by exposure to 1 mM carbachol for 1 h. Carbachol-induced GAR-3 internalization was suppressed by treatment with hypertonic sucrose, which blocks the formation of clathrin-coated pits. Overexpression of a dominant-negative dynamin mutant (DynK44A), but not of a dominant-negative β-arrestin mutant (Arr319–418), substantially inhibited carbachol-induced internalization of GAR-3. Thus, these data suggest that GAR-3 undergoes agonist-induced internalization via a clathrin- and dynamin-dependent but β-arrestin-independent pathway. Depletion of Ca²⁺ by simultaneous treatment of the cells with BAPTA/AM (Ca²⁺ mobilization blocker) and EGTA (Ca²⁺ influx blocker) almost completely blocked agonist-induced GAR-3 internalization. Moreover, treatment of the cells with the Ca²⁺ ionophore A23187 led to GAR-3 internalization in the absence of agonist. These results indicate that Ca²⁺ plays a critical role in GAR-3 internalization. We tested whether the third intracellular (i3) loop of GAR-3 is involved in agonist-stimulated receptor internalization. A GAR-3 deletion mutant lacking a large central portion of the i3 loop exhibited an internalization pattern comparable to that of the wild type, suggesting that the central i3 loop is not required for the internalization of GAR-3.     

ASK1 Negatively Regulates the 26 S Proteasome

The 26 S proteasome, composed of the 20 S core and 19 S regulatory particle, plays a central role in ubiquitin-dependent proteolysis. Disruption of this process contributes to the pathogenesis of the various diseases; however, the mechanisms underlying the regulation of 26 S proteasome activity remain elusive. Here, cell culture experiments and in vitro assays demonstrated that apoptosis signal-regulating kinase 1 (ASK1), a member of the MAPK kinase kinase family, negatively regulated 26 S proteasome activity. Immunoprecipitation/Western blot analyses revealed that ASK1 did not interact with 20 S catalytic core but did interact with ATPases making up the 19 S particle, which is responsible for recognizing polyubiquitinated proteins, unfolding them, and translocating them into the 20 S catalytic core in an ATP-dependent process. Importantly, ASK1 phosphorylated Rpt5, an AAA ATPase of the 19 S proteasome, and inhibited its ATPase activity, an effect that may underlie the ability of ASK1 to inhibit 26 S proteasome activity. The current findings point to a novel role for ASK1 in the regulation of 26 S proteasome and offer new strategies for treating human diseases caused by proteasome malfunction.     

Cannabis, cannabinoids and reproduction

In most countries Cannabis is the most widely used illegal drug. Its use during pregnancy in developed nations is estimated to be approximately 10%. Recent evidence suggests that the endogenous cannabinoid system, now consisting of two receptors and multiple endocannabinoid ligands, may also play an important role in the maintenance and regulation of early pregnancy and fertility. The purpose of this review is therefore twofold, to examine the impact that cannabis use may have on fertility and reproduction, and to review the potential role of the endocannabinoid system in hormonal regulation, embryo implantation and maintenance of pregnancy.     

Preparation of stabilized magnetic nanoparticles with polymerizable lipid and anchor compounds

Although the lipid-based method for coating of magnetic nanoparticles (MNPs) is rapid and simple, the unstable state of the lipid layer is a major limitation for the practical application of this method. We devised a method to prepare stabilized MNPs by covalent modifications such as lipid polymerization and anchoring of the lipid layer. The stability of the modified lipid layer was demonstrated by the stable status of enzymes immobilized on the MNPs and the resistance of the MNPs to aggregation. We also determined the maximum ratio of nonpolymerizable lipophilic compounds that can be included in the layer without significantly reducing stability.     

A possible role for FRM-1, a C. elegans FERM family protein, in embryonic development

FRM-1 is a member of the FERM protein superfamily containing a FERM domain, which is a highly conserved protein-protein interaction module found in most eukaryotes. Although FRM-1 is thought to be involved in linking intracellular proteins to membrane proteins, the specific role for FRM-1 remains to be elucidated. In an effort to explore the biological function of FRM-1, we examined the phenotype of frm-1(tm4168) mutant worms. We observed that frm-1(tm4168) worms have a delayed hatching phenotype. Twelve hours after being laid, when virtually all wild-type eggs had hatched, only 64% of frm-1(tm4168) eggs had hatched. About 3% of frm-1(tm4168) eggs failed to hatch, even 3 days after they had been laid. We also found that frm-1(tm4168) mutants displayed a temperature-sensitive sterility phenotype. About 13% of frm-1(tm4168) worms were unable to produce eggs or produced nonviable eggs at 25°C. In contrast, less than 1% of wild-type animals were sterile at this temperature. At 20°C, neither the mutant nor wild type appeared to be sterile. Western blot analysis indicates that FRM-1 is expressed throughout the developmental stages with the strongest expression at the egg stage. Immunostaining experiments revealed that FRM-1 is mainly localized to the plasma membrane of most if not all cells at an early embryonic stage and to the plasma membrane of P cells during the late embryonic stages. GFP fusion experiments showed that FRM-1 can be expressed in the pharynx and intestine at the larval and adult stages. Our data suggest that FRM-1 may participate in diverse biological processes, including embryonic development.