Improved syntheses of D-ribo- and 2-deoxy-D-ribofuranose phospho sugars from methyl β-D-ribopyranoside

Methyl 4-deoxy-4-dimethoxyphosphinoyl-2,3-O-isopropylidene-beta-D-ribopyranoside (12a) and methyl 2,4-dideoxy-4-dimethoxyphosphinoyl-beta-D-erythro-pentopyranoside (20) were efficiently prepared respectively from methyl 2,3-O-isopropylidene-beta-D-ribopyranoside (7a) and its 3,4-O-isopropylidene isomer (7b) in appreciably improved total yields compared with those via previously reported routes. Compounds (12a, 20) were led to D-ribofuranose and 2-deoxy-D-ribofuranose phospho sugars (4, 5)

Prevention of Pemetrexed-Induced Rash Using Low-Dose Corticosteroids : A Phase II Study

Background: Rash eruptions are a common side-effect of pemetrexed, for which the administration of 8 mg/day of dexamethasone for 3 days from the day preceding pemetrexed administration is recommended. This study aimed to prospectively assess the effectiveness of prophylactic administration of low-dose dexamethasone for pemetrexed-induced rashes. Methods: This single-arm, phase II study recruited patients with non-squamous non–small cell lung cancer and malignant pleural mesothelioma scheduled to receive chemotherapy including pemetrexed. Patients received 2 mg of dexamethasone daily from days 2 to 6 after chemotherapy with pemetrexed. The primary endpoint was the 3-week incidence of rash eruptions. Results: Twenty-five patients were enrolled between September 2017 and May 2019. The incidence of rash after 3 weeks was 16.7%. Rashes erupted mainly on the upper half of the body, such as the chest and neck, and were of grades 1 and 2 in 2 patients each. No rashes of grade 3 or higher were observed, and there were no adverse events associated with additional corticosteroids. Conclusion: Prophylactic administration of low-dose dexamethasone for 5 days from the day after pemetrexed administration resulted in a milder incidence and severity of rash. These findings may provide a standard preventative strategy for pemetrexed-induced rashes. (Trial identifier: UMIN000025666)

Switching and Emergence of CTL Epitopes in HIV-1 Infection

Background Human Leukocyte Antigen (HLA) class I restricted Cytotoxic T Lymphocytes (CTLs) exert substantial evolutionary pressure on HIV-1, as evidenced by the reproducible selection of HLA-restricted immune escape mutations in the viral genome. An escape mutation from tyrosine to phenylalanine at the 135th amino acid (Y135F) of the HIV-1 nef gene is frequently observed in patients with HLA-A*24:02, an HLA Class I allele expressed in ~70% of Japanese persons. The selection of CTL escape mutations could theoretically result in the de novo creation of novel epitopes, however, the extent to which such dynamic “CTL epitope switching” occurs in HIV-1 remains incompletely known. Results Two overlapping epitopes in HIV-1 nef, Nef126-10 and Nef134-10, elicit the most frequent CTL responses restricted by HLA-A*24:02. Thirty-five of 46 (76%) HLA-A*24:02-positive patients harbored the Y135F mutation in their plasma HIV-1 RNA. Nef codon 135 plays a crucial role in both epitopes, as it represents the C-terminal anchor for Nef126-10 and the N-terminal anchor for Nef134-10. While the majority of patients with 135F exhibited CTL responses to Nef126-10, none harboring the “wild-type” (global HIV-1 subtype B consensus) Y135 did so, suggesting that Nef126-10 is not efficiently presented in persons harboring Y135. Consistent with this, peptide binding and limiting dilution experiments confirmed F, but not Y, as a suitable C-terminal anchor for HLA-A*24:02. Moreover, experiments utilizing antigen specific CTL clones to recognize endogenously-expressed peptides with or without Y135F indicated that this mutation disrupted the antigen expression of Nef134-10. Critically, the selection of Y135F also launched the expression of Nef126-10, indicating that the latter epitope is created as a result of escape within the former. Conclusions Our data represent the first example of the de novo creation of a novel overlapping CTL epitope as a direct result of HLA-driven immune escape in a neighboring epitope. The robust targeting of Nef126-10 following transmission (or in vivo selection) of HIV-1 containing Y135F may explain in part the previously reported stable plasma viral loads over time in the Japanese population, despite the high prevalence of both HLA-A*24:02 and Nef-Y135F in circulating HIV-1 sequences

Ultrafast Control of Crystal Structure in a Topological Charge-Density-Wave Material

Optical control of crystal structures is a promising route to change physical properties including topological nature of a targeting material. Time-resolved X-ray diffraction measurements using the X-ray free-electron laser are performed to study the ultrafast lattice dynamics of VTe$_2$, which shows a unique charge-density-wave (CDW) ordering coupled to the topological surface states as a first-order phase transition. A significant oscillation of the CDW amplitude mode is observed at a superlattice reflection as well as Bragg reflections. The frequency of the oscillation is independent of the fluence of the pumping laser, which is prominent to the CDW ordering of the first-order phase transition. Furthermore, the timescale of the photoinduced 1$T^{\prime\prime}$ to 1$T$ phase transition is independent of the period of the CDW amplitude mode

Factors Affecting the Absorption of Midazolam to the Extracorporeal Membrane Oxygenation Circuit

Sedatives are administered during extracorporeal membrane oxygenation (ECMO) therapy to ensure patient safety, reduce the metabolic rate and correct the oxygen supply-demand balance. However, the concentrations of sedatives can be decreased due to absorption into the circuit. This study examined factors affecting the absorption of a commonly used sedative, midazolam (MDZ). Using multiple ex vivo simulation models, three factors that may influence MDZ levels in the ECMO circuit were examined: polyvinyl chloride (PVC) tubing in the circuit, use of a membrane oxygenator in the circuit, and heparin coating of the circuit. We also assessed changes in drug concentration when MDZ was re-injected in a circuit. The MDZ level decreased to approximately 60% of the initial concentration in simulated circuits within the first 30 minutes. The strongest factor in this phenomenon was contact with the PVC tubing. Membrane oxygenator use tended to increase MDZ loss, whereas heparin circuit coating had no influence on MDZ absorption. Similar results were obtained when a second dose of MDZ was injected to the second-use circuits

Effects of HLA-DRB1 alleles on susceptibility and clinical manifestations in Japanese patients with adult onset Still’s disease

BackgroundHLA-DRB1 alleles are major determinants of genetic predisposition to rheumatic diseases. We assessed whether DRB1 alleles are associated with susceptibility to particular clinical features of adult onset Still’s disease (AOSD) in a Japanese population by determining the DRB1 allele distributions.MethodsDRB1 genotyping of 96 patients with AOSD and 1,026 healthy controls was performed. Genomic DNA samples from the AOSD patients were also genotyped for MEFV exons 1, 2, 3, and 10 by direct sequencing.ResultsIn Japanese patients with AOSD, we observed a predisposing association of DRB1*15:01 (p = 8.60 × 10−6, corrected p (Pc) = 0.0002, odds ratio (OR) = 3.04, 95% confidence interval (95% CI) = 1.91–4.84) and DR5 serological group (p = 0.0006, OR = 2.39, 95% CI = 1.49–3.83) and a protective association of DRB1*09:01 (p = 0.0004, Pc = 0.0110, OR = 0.34, 95% CI = 0.18–0.66) with AOSD, and amino acid residues 86 and 98 of the DRβ chain were protectively associated with AOSD. MEFV variants were identified in 49 patients with AOSD (56.3%). The predisposing effect of DR5 was confirmed only in patients with AOSD who had MEFV variants and not in those without MEFV variants. Additionally, DR5 in patients with AOSD are associated with macrophage activation syndrome (MAS) and steroid pulse therapy.ConclusionThe DRB1*15:01 and DR5 are both associated with AOSD susceptibility in Japanese subjects. A protective association between the DRB1*09:01 allele and AOSD was also observed in these patients. Our data also highlight the effects of DRB1 alleles in susceptibility to AOSD

Meta-analysis of the efficacies of amiodarone and nifekalant in shock-resistant ventricular fibrillation and pulseless ventricular tachycardia

Amiodarone (AMD) and nifekalant (NIF) are used in the treatment of ventricular fibrillation or tachycardia; however, only few studies have been conducted on their efficacies. Therefore, a meta-analysis was conducted. Relevant sources were identified from PubMed, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi. The outcomes were short-term and long-term survival in patients with shock-resistant ventricular fibrillation /pulseless ventricular tachycardia. Thirty-three studies were analysed. The results showed that, compared to the control treatment, AMD did not improve short-term survival (odds ratio (OR): 1.25, 95% confidence interval (CI): 0.91–1.71) or long-term survival (OR: 1.00, 95% CI: 0.63–1.57). However, compared to the control treatment, NIF significantly improved short-term survival (OR: 3.23, 95% CI: 2.21–4.72) and long-term survival (OR: 1.88, 95% CI: 1.36–2.59). No significant difference was observed in short-term survival (OR: 0.85, 95% CI: 0.63–1.15) or long-term survival (OR: 1.25, 95% CI: 0.67–2.31) between AMD- and NIF-treated patients. The results suggest that NIF is beneficial for short-term and long-term survival in shock-resistant ventricular fibrillation/pulseless ventricular tachycardia; however, the efficacy of AMD in either outcome is not clear

Meta-analysis of the efficacies of amiodarone and nifekalant in shock-resistant ventricular fibrillation and pulseless ventricular tachycardia

Amiodarone (AMD) and nifekalant (NIF) are used in the treatment of ventricular fibrillation or tachycardia; however, only few studies have been conducted on their efficacies. Therefore, a meta-analysis was conducted. Relevant sources were identified from PubMed, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi. The outcomes were short-term and long-term survival in patients with shock-resistant ventricular fibrillation /pulseless ventricular tachycardia. Thirty-three studies were analysed. The results showed that, compared to the control treatment, AMD did not improve short-term survival (odds ratio (OR): 1.25, 95% confidence interval (CI): 0.91–1.71) or long-term survival (OR: 1.00, 95% CI: 0.63–1.57). However, compared to the control treatment, NIF significantly improved short-term survival (OR: 3.23, 95% CI: 2.21–4.72) and long-term survival (OR: 1.88, 95% CI: 1.36–2.59). No significant difference was observed in short-term survival (OR: 0.85, 95% CI: 0.63–1.15) or long-term survival (OR: 1.25, 95% CI: 0.67–2.31) between AMD- and NIF-treated patients. The results suggest that NIF is beneficial for short-term and long-term survival in shock-resistant ventricular fibrillation/pulseless ventricular tachycardia; however, the efficacy of AMD in either outcome is not clear