JR‐131, a Biosimilar of Darbepoetin Alfa,for the Treatment of Hemodialysis Patients With Renal Anemia: A Randomized,Double‐Blinded,Parallel‐Group Phase 3 Study

The aim of this study was to compare the efficacy and safety of intravenous JR‐131, a darbepoetin alfa biosimilar, to darbepoetin alfa in hemodialysis patients with renal anemia. In this 24‐week, multicenter, randomized, double‐blinded, parallel‐group phase 3 study, 334 hemodialysis patients with renal anemia who had been receiving darbepoetin alfa were randomized to either JR‐131 or darbepoetin alfa group. The initial dose was set based on the darbepoetin alfa dose during the observation period. The primary endpoint was change in hemoglobin level from baseline to end of treatment. The 95% confidence interval of the difference in the change in hemoglobin level between the groups was ?0.19 to ?0.20 g/dL, within the equivalent margin of ?0.5 to 0.5 g/dL. No notable treatment‐emergent adverse events were observed in either group. JR‐131 was therapeutically equivalent to darbepoetin alfa, and the safety profile of JR‐131 was similar to that of darbepoetin alfa.     

Effects of risedronate alone or combined with vitamin K2 on serum undercarboxylated osteocalcin and osteocalcin levels in postmenopausal osteoporosis

Risedronate decreases osteoporotic fracture incidence; however, its effects remain unclear in elderly osteoporotic patients. Vitamin K mediates carboxylation of osteocalcin (OC), and high undercarboxylated osteocalcin (ucOC) levels indicate vitamin K deficiency and increased osteoporotic fracture risk. We aimed to evaluate the effects of risedronate alone or combined with vitamin K₂ on serum ucOC, OC, and incidence of vertebral fractures in elderly osteoporotic patients. A total of 101 women with postmenopausal osteoporosis aged >60 years were randomly stratified into two groups—R group (n = 51), treated with risedronate alone; and R + K group (n = 50), treated with risedronate and vitamin K₂. Serum ucOC, OC and incidence of vertebral fractures were evaluated before treatment and at 6 and 12 months post-treatment. Decreased ucOC rates at 6 and 12 months were not significant between groups. However, at 6 and 12 months, decreased OC rates in the R group (p < 0.01 and 0.05, respectively) were significantly higher than in the R + K group, and ucOC/OC change rates in the R group (p < 0.05 and 0.001, respectively) were significantly lower than in the R + K group. Vertebral fracture incidence was not significantly different between the groups at 6 and 12 months. ucOC levels in patients with incident vertebral fractures were significantly higher than in patients without incident vertebral fractures in the R group at 6 months (p < 0.05). Although no significant difference was observed for ucOC decrease rate and incidence of vertebral fractures between treatments, ucOC levels in patients with incident vertebral fractures were significantly greater than in patients without when using risedronate alone.     

Preoperative biliary drainage for hilar cholangiocarcinoma

Hilar cholangiocarcinomas grow slowly, and metastases occur late in the natural history. Surgical cure and long-term survival have been demonstrated, when resection margins are clear. Preoperative biliary drainage has been proposed as a way to improve liver function before surgery, and to reduce post-surgical complications. Percutaneous transhepatic biliary drainage (PTBD) with multiple drains was previously the preferred method for the preoperative relief of obstructive jaundice. However, the introduction of percutaneous transhepatic portal vein embolization (PTPE) and wider resection has changed preoperative drainage strategies. Drainage is currently performed only for liver lobes that will remain after resection, and for areas of segmental cholangitis. Endoscopic biliary drainage (EBD) is less invasive than PTBD. Among EBD techniques, endoscopic nasobiliary drainage (ENBD) is preferable to endoscopic biliary stenting (EBS), because secondary cholangitis (due to the retrograde flow of duodenal fluid into the biliary tree) does not occur. ENBD needs to be converted to PTBD in patients with segmental cholangitis, those with a prolonged need for drainage, or when the extent of longitudinal tumor extension is not sufficiently well characterized.     

FDG-PET performed concurrently with initial I-131 ablation for differentiated thyroid cancer

Objective  

Differentiated thyroid cancers (DTCs) are commonly treated by total thyroidectomy followed by I-131 radioiodine ablation to eradicate any residual thyroid tissue and to detect any metastatic lesions on post-treatment whole body scans (TxWBS). However, some DTCs do not trap iodine, resulting in negative whole body scanning. Fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) has proven to be a valuable diagnostic technique for detecting many types of malignant tumors and metastases. The purpose of this study was to evaluate FDG-PET performed concurrently with initial I-131 ablation for its ability to detect lymph node metastasis and for its role in the management of DTC patients.     

Clinical features of uveitis in elderly patients in central Tokyo (2013–2018)

International Ophthalmology - To clarify the clinical features of uveitis in elderly patients in central Tokyo. We retrospectively identified 1424 patients with uveitis who visited the Uveitis...     

Novel Virulent Bacteriophage ΦSG005, Which Infects Streptococcus gordonii,Forms a Distinct Clade among Streptococcus Viruses

Bacteriophages are viruses that specifically infect bacteria and are classified as either virulent phages or temperate phages. Despite virulent phages being promising antimicrobial agents due to their bactericidal effects, the implementation of phage therapy depends on the availability of virulent phages against target bacteria. Notably, virulent phages of Streptococcus gordonii, which resides in the oral cavity and is an opportunistic pathogen that can cause periodontitis and endocarditis have previously never been found. We thus attempted to isolate virulent phages against S. gordonii. In the present study, we report for the first time a virulent bacteriophage against S. gordonii, ΦSG005, discovered from drainage water. ΦSG005 is composed of a short, non-contractile tail and a long head, revealing Podoviridae characteristics via electron microscopic analysis. In turbidity reduction assays, ΦSG005 showed efficient bactericidal effects on S. gordonii. Whole-genome sequencing showed that the virus has a DNA genome of 16,127 bp with 21 coding sequences. We identified no prophage-related elements such as integrase in the ΦSG005 genome, demonstrating that the virus is a virulent phage. Phylogenetic analysis indicated that ΦSG005 forms a distinct clade among the streptococcus viruses and is positioned next to streptococcus virus C1. Molecular characterization revealed the presence of an anti-CRISPR (Acr) IIA5-like protein in the ΦSG005 genome. These findings facilitate our understanding of streptococcus viruses and advance the development of phage therapy against S. gordonii infection.     

Levels of MCP-1 and GM-CSF mRNA Correlated with Inflammatory Cytokines mRNA Levels in Experimental Autoimmune Myocarditis in Rats

Infiltration of monocytes and T cells is known to be an essential trigger for the progression of experimental autoimmune myocarditis (EAM) in rats. Monocyte chemotactic protein-1 (MCP-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were shown to mediate the migration of monocytes and T cells into inflammatory sites and to proliferate monocytes. Thus, we evaluated levels of MCP-1 and GM-CSF mRNA in the myocardium of EAM in rats using a real time quantitative PCR method. We also examined the correlation of MCP-1 or GM-CSF mRNA levels with those of inflammatory cytokines such as tumor necrosis factor- &#102 (TNF- &#102 ), interleukin-1 &#103 (IL-1 &#103 ) and interleukin-6 (IL-6) in the same lesion. Levels of MCP-1, GM-CSF, TNF- &#102, IL-1 &#103 and IL-6 mRNA increased with the progression of myocarditis which was accompanied by the accumulation of ED-1 positive cells. The MCP-1 and GM-CSF mRNA levels were positively correlated with TNF- &#102, IL-1 &#103 and IL-6 mRNA levels in the same lesion of EAM. We also demonstrated that serum MCP-1 concentrations were increased during the active stage of EAM, and were correlated with MCP-1 mRNA levels in the myocardium of each rat. These findings suggest that elevated MCP-1 and GM-CSF may associate with the migration and proliferation of monocytes/macrophages in EAM. Thus, MCP-1 and GM-CSF may play an important role in the progression of EAM.     

Stereoselective hydroxylation by CYP2C19 and oxidation by ADH4 in the in vitro metabolism of tivantinib

1.?In prior studies, it has been shown that tivantinib is extensively metabolized in humans to many oxidative metabolites and glucuronides. In order to identify the responsible enzymes, we investigated the in vitro metabolism of tivantinib and its four major circulating metabolites.

2.?The primary isoforms involved in the elimination of tivantinib were CYP2C19 and CYP3A4/5. CYP2C19 showed catalytic activity for the formation of M5 (hydroxylated metabolite), but not for M4 (a stereoisomer of M5), whereas CYP3A4/5 catalyzed the formation of both metabolites. For the elimination of M4, M5 and M8 (keto-metabolite), CYP3A4/5 was the major cytochrome P450 isoform and UGT1A9 was mainly involved in the glucuronidation of M4 and M5.

3.?ADH4 was identified as one of the major alcohol dehydrogenase isoforms contributing to the formation of M6 (sequential keto-metabolite of M4 and M5) and M8. The substrate preference of ADH for M4, and not M5, was observed in the formation of M6.

4.?In conclusion, CYP2C19, CYP3A4/5, UGT1A9 and ADH4 were the primary drug metabolizing enzymes involved in the in vitro metabolism of tivantinib and its metabolites. The stereoselective hydroxylation by CYP2C19 and substrate stereoselectivity of ADH4-catalyzed oxidation in the in vitro metabolism of tivantinib was discovered.     

Aryl hydrocarbon hydroxylase represents CYP1B1, and not CYP1A1, in human freshly isolated white cells: trimodal distribution of Japanese population according to induction of CYP1B1 mRNA by environmental dioxins.

The expression level of mRNAs for cytochrome P450 (CYP) 1A1 and 1B1 in freshly prepared white cells from 72 subjects exposed to dioxins at waste incinerators was investigated. The amounts of CYP1B1 mRNA ranged from 0.16 to 671 molecules/10(7) molecules of 18S rRNA, whereas the amounts of CYP1A1 mRNA were <6 molecules/10 ng total RNA, indicating that CYP1A1 was not induced to a detectable level by environmentally exposed dioxins. The inducibility of CYP1B1 mRNA in leukocytes, defined as the ratio of CYP1B1 mRNA to the plasma concentration of dioxins, varied among the subjects. It was found that the subjects showed trimodal distribution according to inducibility: 39 (54.2%), 25 (34.7%), and 8 (11.1%) of 72 subjects were judged as poor, intermediate, and high responders to environmental dioxins, respectively. The amounts of CYP1B1 mRNA in leukocytes of the intermediate and high responders were highly correlated with the plasma concentrations of dioxins (P < 0.05 and <0.01). These results suggest that CYP1B1 with polymorphic inducibility by dioxins is involved in aromatic hydrocarbon hydroxylase activities in human lymphocytes.