A quantitatively-modeled homozygosity mapping algorithm, qHomozygosityMapping, utilizing whole genome single nucleotide polymorphism genotyping data

Homozygosity mapping is a powerful procedure that is capable of detecting recessive disease-causing genes in a few patients from families with a history of inbreeding. We report here a homozygosity mapping algorithm for high-density single nucleotide polymorphism arrays that is able to (i) correct genotyping errors, (ii) search for autozygous segments genome-wide through regions with runs of homozygous SNPs, (iii) check the validity of the inbreeding history, and (iv) calculate the probability of the disease-causing gene being located in the regions identified. The genotyping error correction restored an average of 94.2% of the total length of all regions with run of homozygous SNPs, and 99.9% of the total length of them that were longer than 2 cM. At the end of the analysis, we would know the probability that regions identified contain a disease-causing gene, and we would be able to determine how much effort should be devoted to scrutinizing the regions. We confirmed the power of this algorithm using 6 patients with Siiyama-type α1-antitrypsin deficiency, a rare autosomal recessive disease in Japan. Our procedure will accelerate the identification of disease-causing genes using high-density SNP array data

Homozygosity Mapping on Homozygosity Haplotype Analysis to Detect Recessive Disease-Causing Genes from a Small Number of Unrelated, Outbred Patients

Genes involved in disease that are not common are often difficult to identify; a method that pinpoints them from a small number of unrelated patients will be of great help. In order to establish such a method that detects recessive genes identical-by-descent, we modified homozygosity mapping (HM) so that it is constructed on the basis of homozygosity haplotype (HM on HH) analysis. An analysis using 6 unrelated patients with Siiyama-type α1-antitrypsin deficiency, a disease caused by a founder gene, the correct gene locus was pinpointed from data of any 2 patients (length: 1.2–21.8 centimorgans, median: 1.6 centimorgans). For a test population in which these 6 patients and 54 healthy subjects were scrambled, the approach accurately identified these 6 patients and pinpointed the locus to a 1.4-centimorgan fragment. Analyses using synthetic data revealed that the analysis works well for IBD fragment derived from a most recent common ancestor (MRCA) who existed less than 60 generations ago. The analysis is unsuitable for the genes with a frequency in general population more than 0.1. Thus, HM on HH analysis is a powerful technique, applicable to a small number of patients not known to be related, and will accelerate the identification of disease-causing genes for recessive conditions

Hochuekkito (TJ-41), a Kampo Formula, Ameliorates Cachexia Induced by Colon 26 Adenocarcinoma in Mice

Cachexia, a major cause of cancer-related death, is characterized by depletion of muscle and fat tissues, anorexia, asthenia, and hypoglycemia. Recent studies indicate that secretions of proinflammatory cytokines such as interleukin-6 (IL-6) play a crucial role in cachexia development, and that these cytokines are secreted from not only cancer cells but also host cells such as macrophages. In this study, we investigated the therapeutic effects of hochuekkito, a Kampo formula, on cachexia induced by colon 26 adenocarcinoma in mice. Hochuekkito treatment did not inhibit tumor growth, but significantly attenuated the reduction in carcass weight, food and water intake, weight of the gastrocnemius muscle and fat tissue around the testes, and decrease of serum triglyceride level compared with controls. Furthermore, hochuekkito treatment significantly reduced serum IL-6 level and IL-6 expression level in macrophages in tissues surrounding the tumor. In vitro studies showed that hochuekkito suppressed the production of IL-6 by THP-1 or RAW264.7 macrophage cells, although it did not affect IL-6 production by colon 26 carcinoma cells. These results suggest that hochuekkito inhibits the production of proinflammatory cytokines, particularly IL-6, by host cells such as macrophages. Therefore, hochuekkito may be a promising anticachectic agent for the treatment of patients with cancer

Real-world evidence for the effectiveness and breakthrough of BNT162b2 mRNA COVID-19 vaccine at a medical center in Japan

Evidence of BNT126b2 vaccine effectiveness and breakthrough has been primarily demonstrated in populations outside of Asia; studies in the Western Pacific region are limited. Our retrospective cohort study assessed SARS-CoV-2 cases after vaccine rollout starting from mid-March 2021 at a tertiary hospital in Tokyo. Of 8,749 staff members, no fully vaccinated staff demonstrated confirmed infection, versus 19 cases in unvaccinated or partially vaccinated staff, by the end of June. Three breakthrough cases were identified in July, correlating with spread of delta variant in Tokyo. While our findings confirm the effectiveness of BNT162b2 vaccine in Asian populations, the presence of breakthrough cases despite strict infection control regulations suggest that ongoing public hygiene measures are required even after vaccination

Reversed Halo Sign in Tuberous Sclerosis Complex

We describe a reversed halo sign in a teenage girl with tuberous sclerosis complex (TSC). Lung manifestations of TSC include lung cysts corresponding to lymphangioleiomyomatosis and small nodules indicating multifocal micronodular pneumocyte hyperplasia (MMPH). However, a reversed halo sign in TSC has never been reported. The lesion was microscopically consistent with MMPH. Immunohistological findings also supported the notion that the lesion is associated with TSC