Nitric Oxide-Scavenging Nanogel for Treating Rheumatoid Arthritis.

Nitric oxide (NO), a radical gas molecule produced by nitric oxide synthase, plays a key role in the human body. However, when endogenous NO is overproduced by physiological disorders, severe inflammatory diseases such as rheumatoid arthritis (RA) can occur. Therefore, scavenging NO may be an alternative strategy for treating inflammatory disorders. In our previous study, we developed a NO-responsive macrosized hydrogel by incorporating a NO-cleavable cross-linker (NOCCL); here, we further evaluate the effectiveness of the NO-scavenging nanosized hydrogel (NO-Scv gel) for treating RA. NO-Scv gel is simply prepared by solution polymerization between acrylamide and NOCCL. When the NO-Scv gel is exposed to NO, NOCCL is readily cleaved by consuming the NO molecule, as demonstrated in a Griess assay. As expected, the NO-Scv gel reduces inflammation levels by scavenging NO in vitro and shows excellent biocompatibility. Furthermore, the more promising therapeutic effect of the NO-Scv gel in suppressing the onset of RA is observed in vivo in a mouse RA model when compared to the effects of dexamethasone, a commercial drug. Therefore, our findings suggest the potential of the NO-Scv gel for biomedical applications and further clinical translation.

Correction to: Loktanella aquimaris sp. nov., Isolated from Seawater.

The original version of this article unfortunately contained a mistake in the species name description. Also the accession number was published incorrectly.

Correction to: a risk stratification model for nodal peripheral T-cell lymphomas based on the NCCN-IPI and posttreatment Deauville score.

Unfortunately, the original version of this article contained several errors made during final step of article production. In the results section (fourth sentence) of the Abstract, the incomplete sentence,", 31.4% in high-risk group and 4.7% in treatment failure group.

A risk stratification model for nodal peripheral T-cell lymphomas based on the NCCN-IPI and posttreatment Deauville score.

PURPOSE: The aim of this study was to establish a risk-stratification model integrating posttreatment metabolic response using the Deauville score and the pretreatment National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) in nodal PTCLs. METHODS: We retrospectively analysed 326 patients with newly diagnosed nodal PTCLs between January 2005 and June 2016 and both baseline and posttreatment PET/CT data. The final model was validated using an independent prospective cohort of 79 patients. RESULTS: Posttreatment Deauville score (1/2, 3, and 4/5) and the NCCN-IPI (low, low-intermediate, high-intermediate, and high) were independently associated with progression-free survival: for the Deauville score, the hazard ratios (HRs) were 1.00 vs. 2.16 (95% CI 1.47-3.18) vs. 7.86 (5.66-10.92), P < 0.001; and for the NCCN-IPI, the HRs were 1.00 vs. 2.31 (95% CI 1.20-4.41) vs. 4.42 (2.36-8.26) vs. 7.09 (3.57-14.06), P < 0.001. Based on these results, we developed a simplified three-group risk model comprising a low-risk group (low or low-intermediate NCCN-IPI with a posttreatment Deauville score of 1 or 2, or low NCCN-IPI with a Deauville score of 3), a high-risk group (high or high-intermediate NCCN-IPI with a Deauville score of 1/2 or 3, or low-intermediate NCCN-IPI with a Deauville score of 3), and a treatment failure group (Deauville score 4 or 5). This model was significantly associated with progression-free survival (5-year, 70.3%, 31.4%, and 4.7%; P < 0.001) and overall survival (5-year, 82.1%, 45.5%, and 14.7%; P < 0.001). Similar associations were also observed in the independent validation cohort. CONCLUSION: The risk-stratification model integrating posttreatment Deauville score and pretreatment NCCN-IPI is a powerful tool for predicting treatment failure in patients with nodal PTCLs.

Loktanella aquimaris sp. nov., Isolated from Seawater.

Two novel bacterial strains, designated C5(T) and C9 were isolated from a fish cage at Tongyeong, South Korea and were characterized to determine their taxonomic position. The strains were Gram-negative, non-motile, strictly aerobic and short rod shaped. Growth occurred between 20 and 32 °C (optimum 30 °C) and at pH 6.0-9.0 (optimum pH 8.0) and at 0-10 % NaCl (optimum at 2 % NaCl). Based on the 16S rRNA gene sequence analysis, they were identified as a member of the genus Loktanella that belongs to the phylum Proteobacteria. Strains C5(T) and C9 were analyzed by a polyphasic approach, revealing variations in their phenotypic characters but reciprocal DNA-DNA hybridization values confirmed that they belong to the same species. Phylogenetic analysis of the 16S rRNA gene sequences of closely related species indicated their similarities were below 97 %. The predominant isoprenoid quinone is ubiquinone-10 (Q-10). The major cellular fatty acids were C16:0, and C18:1 ω7c. Major polar lipid contained phosphatidylglycerol (PG), phosphatidycholine (PC), diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE), unidentified amino lipid (AL) and unidentified lipids (L1-3). Based on phylogenetic and phenotypic data, the isolated strains represent a novel species of the genus Loktanella, for which the name Loktanella aquimaris sp. nov. is proposed. The type strains were C5(T) (=KEMB 3-892(T) = JCM 30382(T)), and a second strain is C9 (=KEMB 3-893 = JCM 30383).

Paracoccus aquimaris sp. nov., isolated from seawater.

A Gram-stain negative, motile and short rod-shaped bacterial strain, designated KF89(T), was isolated from seawater of Tong-Yeong, South of Korea. Growth occurred between 10 and 35 °C (optimum 32 °C) and at pH 6.0-9.0 (optimum pH 7.0) and at 0-7 % NaCl (optimum at 2 % NaCl). The 16S rRNA gene sequence identified it as a member of the genus Paracoccus that belongs to the phylum Proteobacteria. Based on the 16S rRNA gene sequence, the highest degree of gene sequence similarities were shared with Paracoccus homiensis DD-R11(T) (97.3 %), P. zeaxanthinifaciens ATCC21588(T) (97.1 %), P. rhizosphaerae CC-CCM15-8(T) (96.9 %), P. beibuensis JLT1284 (96.9 %) and P. aestuarii B7(T) (96.6 %). Strain KF89(T) contained Ubiquinone-10 as the major respiratory quinone, and the polar lipid profile included phosphatidylglycerol, phosphatidylcholine, diphosphatidylglycerol and an unidentified aminolipid. The major fatty acid of strain KF89(T) is C18:1 ω7c and the DNA G+C content is 57 mol%. Strain KF89(T) showed a DNA-DNA relatedness with P. homiensis KACC 11518(T) of 49 %. Based on phylogenetic and phenotypic analyses, strain KF89(T) is clearly shown to be a novel member of the genus Paracoccus. The type strain is Paracoccus aquimaris KF89(T) (=KEMB 3-508(T) = JCM 19892(T)).

Primary Cilia Mediate TSH-Regulated Thyroglobulin Endocytic Pathways.

Primary cilia are sensory organelles with a variety of receptors and channels on their membranes. Recently, primary cilia were proposed to be crucial sites for exocytosis and endocytosis of vesicles associated with endocytic control of various ciliary signaling pathways. Thyroglobulin (Tg) synthesis and Tg exocytosis/endocytosis are critical for the functions of thyroid follicular cells, where primary cilia are relatively well preserved. LRP2/megalin has been detected on the apical surface of absorptive epithelial cells, including thyrocytes. LRP2/megalin on thyrocytes serves as a Tg receptor and can mediate Tg endocytosis. In this study, we investigated the role of primary cilia in LRP2/megalin expression in thyroid gland stimulated with endogenous TSH using MMI-treated and Tg-Cre;Ift88flox/flox mice. LRP2/megalin expression in thyroid follicles was higher in MMI-treated mice than in untreated control mice. MMI-treated mice exhibited a significant increase in ciliogenesis in thyroid follicular cells relative to untreated controls. Furthermore, MMI-induced ciliogenesis accompanied increases in LRP2/megalin expression in thyroid follicular cells, in which LRP2/megalin was localized to the primary cilium. By contrast, in Tg-Cre;Ift88flox/flox mice, thyroid with defective primary cilia expressed markedly lower levels of LRP2/megalin. Serum Tg levels were elevated in MMI-treated mice and reduced in Tg-Cre;Ift88flox/flox mice. Taken together, these results indicate that defective ciliogenesis in murine thyroid follicular cells is associated with impaired LRP2/megalin expression and reduced serum Tg levels. Our results strongly suggest that primary cilia harbors LRP2/megalin, and are involved in TSH-mediated endocytosis of Tg in murine thyroid follicles.

Loss of primary cilia promotes mitochondria-dependent apoptosis in thyroid cancer.

The primary cilium is well-preserved in human differentiated thyroid cancers such as papillary and follicular carcinoma. Specific thyroid cancers such as Hürthle cell carcinoma, oncocytic variant of papillary thyroid carcinoma (PTC), and PTC with Hashimoto's thyroiditis show reduced biogenesis of primary cilia; these cancers are often associated the abnormalities in mitochondrial function. Here, we examined the association between primary cilia and the mitochondria-dependent apoptosis pathway. Tg-Cre;Ift88flox/flox mice (in which thyroid follicles lacked primary cilia) showed irregularly dilated follicles and increased apoptosis of thyrocytes. Defective ciliogenesis caused by deleting the IFT88 and KIF3A genes from thyroid cancer cell lines increased VDAC1 oligomerization following VDAC1 overexpression, thereby facilitating upregulation of mitochondria-dependent apoptosis. Furthermore, VDAC1 localized with the basal bodies of primary cilia in thyroid cancer cells. These results demonstrate that loss-of-function of primary cilia results in apoptogenic stimuli, which are responsible for mitochondrial-dependent apoptotic cell death in differentiated thyroid cancers. Therefore, regulating primary ciliogenesis might be a therapeutic approach to targeting differentiated thyroid cancers.

A cyotosol-selective nitric oxide bomb as a new paradigm of an anticancer drug.

We have reported rational design of a polymeric NO delivery micelle as a cytosol-selective NO bomb. Protected NO-donors are released from the micelle under endolysosomal conditions, and then deprotected by cytosolic glutathione. Cytosol-selective NO delivery facilitates significant tumor regression without the aid of other therapeutic modalities even in intravenous administrations.