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The development of vaccines against infectious diseases requires a different approach from that of therapeutics, because vaccines are inoculated into healthy individuals and have a preventive effect by activating the immunity of the inoculated human. In Japan, "The Guideline for Clinical Trials of Vaccines for the Prevention of Infectious Diseases" was published in 2010 before changes occurred in the vaccine development environment in Japan, such as the introductions of foreign vaccines and simultaneous global development. This study aimed to identify current challenges in vaccine development through a questionnaire-based survey of pharmaceutical companies in Japan and by comparing the domestic and international guidelines and surveying review reports of 35 vaccines approved in Japan between April 2010 and December 2020. Identified challenges included the requirement for protective efficacy trials, efficacy evaluation of combination vaccines, development of multiregional and foreign clinical trials, and immunization of older adults and immunocompromised patients. We propose that new vaccines against infectious diseases should be evaluated for the protective efficacy, preferably through multiregional clinical trials. Additionally, differences in the incidence of infectious diseases or in epidemic virus strains between regions may affect the trials, when multiregional clinical trials are conducted, but immunogenicity-based studies can be conducted if a correlation between protective efficacy and immunogenicity has been established. We suggest that licensed combination vaccines can be used as comparators when an antigen is added to a licensed combination vaccine. We also proposed that the efficacy of a vaccine in non-major subjects, such as older adults or immunocompromised patients could be evaluated by comparing immunogenicity in major subjects with the confirmed protective effects of the vaccine. It is expected that these revisions will lead to the rapid advancement of vaccine development, which should contribute to the improvement of public health.

The efficacy and safety of vaccines for the prevention of infectious diseases are mostly evaluated based on the induction of an immune response against antigens, and do not necessarily depend on the dose administered. Therefore, there are some specific aspects that need to be considered in the development of vaccines and have been described in "The Guidelines for the non-clinical studies of vaccines for the prevention of infectious disease" in Japan. Recent changes in the vaccine development field, such as the introduction of vaccines developed overseas in Japan and vaccine development on a global scale have increased the need for revision of these guidelines. In this study, we identified the current challenges in the development of vaccines through comparison of Japanese and international guidelines. We conducted a questionnaire-based survey of pharmaceutical industries in Japan, and found issues related to non-clinical studies, such as the necessity of safety pharmacology studies and repeated-dose toxicity studies for each route of administration. We examined international guidelines on these issues as well as review reports by regulatory authorities, and determined that the results of repeated-dose toxicity studies can be used to decide whether safety pharmacology studies are required, and that studies to evaluate toxicity due to systemic effects may not be necessary for both intramuscular and subcutaneous administration. We propose revision of the guidelines for the non-clinical studies of vaccines in Japan taking international harmonizaion into account. We expected that the revised guidelines will promote smooth and rational vaccine development.

Background In Japan, lung cancer screening by annual chest radiography has been performed for the past 30 years. However, changes in risk factor status may have influenced the efficiency of current organized lung cancer screening program. The purpose of this study was to clarify whether the reduced smoking rate in younger Japanese affects the efficiency and effectiveness of lung cancer screening. Methods We investigated chronological changes in epidemiological indicators, which support lung cancer screening programs offered by the Japan Cancer Society, such as gender- and age-specific numbers of participants and lung cancers detected by the screening by clinical stage, in relation to smoking rates from 1991 to 2016. Results Participant age at the time of screening and age at the time of cancer detection have both increased over time. The lung cancer detection rate (LCDR) in younger age cohorts tended to decrease from 1991 to 2016 in both genders, particularly men aged Conclusions These results suggest that organized lung cancer screening in Japan should be limited to higher-risk populations.

BackgroundMyelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy (MIRAGE) syndrome is a recently described congenital disorder caused by heterozygous SAMD9 mutations. The phenotypic spectrum of the syndrome remains to be elucidated.Methods and resultsWe describe two unrelated patients who showed manifestations compatible with MIRAGE syndrome, with the exception of haematological features. Leucocyte genomic DNA samples were analysed with next-generation sequencing and Sanger sequencing, revealing the patients to have two de novoSAMD9 mutations on the same allele (patient 1 p.[Gln695*; Ala722Glu] and patient 2 p.[Gln39*; Asp769Gly]). In patient 1, p.Gln695* was absent in genomic DNA extracted from hair follicles, implying that the non-sense mutation was acquired somatically. In patient 2, with the 46,XX karyotype, skewed X chromosome inactivation pattern was found in leucocyte DNA, suggesting monoclonality of cells in the haematopoietic system. In vitro expression experiments confirmed the growth-restricting capacity of the two missense mutant SAMD9 proteins that is a characteristic of MIRAGE-associated SAMD9 mutations.ConclusionsAcquisition of a somatic nonsense SAMD9 mutation in the cells of the haematopoietic system might revert the cellular growth repression caused by the germline SAMD9 mutations (ie, second-site reversion mutations). Unexpected lack of haematological features in the two patients would be explained by the reversion mutations.

Copper (Cu) is an indispensable metal for normal development and function of humans, especially in central nervous system (CNS). However, its redox activity requires accurate Cu transport system. ATP7A, a main Cu2+ transporting-ATPase, is necessary to efflux Cu across the plasma membrane and synthesize cuproenzymes. Menkes disease (MD) is caused by mutations in ATP7A gene. Clinically, MD is Cu deficiency syndrome and is treated with Cu-histidine injections soon after definite diagnosis. But outcome of the most remains poor. To estimate the standard therapy, Cu distribution in the treated classic MD patients is analyzed by synchrotron-generated X-ray fluorescence technique (SR-XRF), which identifies and quantifies an individual atom up to at subcellular level of resolution with wide detection area. SR-XRF analysis newly reveals that Cu exists in spinal cord parenchyma and flows out via venous and lymph systems. By systemic analysis, excess Cu is detected in the proximal tubular cells of the kidney, the mucosal epithelial cells of the intestine, and the lymph and venous systems. The current study suggests that the standard therapy supply almost enough Cu for patient tissues. But given Cu passes through the tissues to venous and lymph systems, or accumulate in the cells responsible for Cu absorption.

Arylnitroso compounds 1–3 easily reacted with dimethyl bromomalonate to give the corresponding N-aryl-C,C-dimethoxycarbonylnitrones (4–6). Treatment of C,C-dimethoxycarbonyl-N-( 1-naphthyl)nitrone (4) with acetylene compounds (dimethyl acetylenedicarboxylate, methyl 2-butynoate or ethyl phenylpropiolate) caused 1,3-dipolar cycloaddition to furnish the corresponding 1H-benz[g]indolines (7a-c). In a similar manner, the reactions of nitrones 5 and 6 with acetylene compounds afforded the corresponding indolines 9a-c and 11a-c together with 4-oxazolines 13a-c and 14a-c.

Arylnitroso compounds 1–3 easily reacted with dimethyl bromomalonate to give the corresponding N-aryl-C,C-dimethoxycarbonylnitrones (4–6). Treatment of C,C-dimethoxycarbonyl-N-( 1-naphthyl)nitrone (4) with acetylene compounds (dimethyl acetylenedicarboxylate, methyl 2-butynoate or ethyl phenylpropiolate) caused 1,3-dipolar cycloaddition to furnish the corresponding 1H-benz[g]indolines (7a-c). In a similar manner, the reactions of nitrones 5 and 6 with acetylene compounds afforded the corresponding indolines 9a-c and 11a-c together with 4-oxazolines 13a-c and 14a-c.

The asymmetric reaction of a lithium enolate generated from a BHA (2, 6-di-tert-buty-4-methoxyphenyl) propanoate was allowed to react with benzaldehyde in the presence of a diether-type chiral ligand affording the corresponding anti-aldol product in a moderate enantioselectivity. A tetradentate ligand induced better enantioselectivity albeit relative loss of anti-selectivity. A variation of lithiating amide agent affected the selectivity, indicating involvement of an amine as a component of the mixed aggregate. Absolute configuration of some of the aldol products was determined by standard transformations.

An external chiral tridentate amino diether ligand 7 catalyzed the condensation reaction of a lithium ester enolate 2 with an imine 3 to give the enantiomerically enriched β-lactam 4 in high yield.

2022