Evaluation of Haplotype Inference Using Definitive Haplotype Data Obtained from Complete Hydatidiform Moles, and Its Significance for the Analyses of Positively Selected Regions

The haplotype map constructed by the HapMap Project is a valuable resource in the genetic studies of disease genes, population structure, and evolution. In the Project, Caucasian and African haplotypes are fairly accurately inferred, based mainly on the rules of Mendelian inheritance using the genotypes of trios. However, the Asian haplotypes are inferred from the genotypes of unrelated individuals based on population genetics, and are less accurate. Thus, the effects of this inaccuracy on downstream analyses needs to be assessed. We determined true Japanese haplotypes by genotyping 100 complete hydatidiform moles (CHM), each carrying a genome derived from a single sperm, using Affymetrix 500 K Arrays. We then assessed how inferred haplotypes can differ from true haplotypes, by phasing pseudo-individualized true haplotypes using the programs PHASE, fastPHASE, and Beagle. We found that, at various genomic regions, especially the MHC locus, the expansion of extended haplotype homozygosity (EHH), which is a measure of positive selection, is obscured when inferred Asian haplotype data is used to detect the expansion. We then mapped the genome using a new statistic, XDiHH, which directly detects the difference between the true and inferred haplotypes, in the determination of EHH expansion. We also show that the true haplotype data presented here is useful to assess and improve the accuracy of phasing of Asian genotypes

Recent developments and future directions of first-line systemic therapy combined with immunotherapy for advanced or metastatic urothelial carcinoma: a historical perspective on treatment evolution

The version of record of this article, first published in International Journal of Clinical Oncology, is available online at Publisher’s website: https://doi.org/10.1007/s10147-024-02526-y.Urothelial carcinoma presents significant treatment challenges, especially in advanced stages. Traditionally managed with platinum-based chemotherapy, the advent of immunotherapies, particularly immune checkpoint inhibitors, has revolutionized urothelial carcinoma treatment. This review explores the evolution of urothelial carcinoma management, focusing on the transition from immune checkpoint inhibitors monotherapy to innovative combination therapies. Pembrolizumab, following the KEYNOTE-045 trial, emerged as a pivotal ICI in pretreated metastatic urothelial carcinoma, outperforming traditional chemotherapy. However, limitations surfaced in untreated metastatic urothelial carcinoma patients, particularly in those with low PD-L1 expression, as evidenced by trials like IMvigor130 and KEYNOTE-361. These challenges led to the exploration of combination therapies, including immune checkpoint inhibitors with platinum-based chemotherapy, tyrosine kinase inhibitors, and antibody–drug conjugates. Notably, the CheckMate 901 trial demonstrated improved outcomes with a nivolumab–chemotherapy combination. A significant breakthrough was achieved with the combination of enfortumab vedotin, an antibody–drug conjugates, and pembrolizumab, setting a new standard in first-line treatment for locally advanced or metastatic urothelial carcinoma. Future directions involve further exploration of antibody–drug conjugates and immune checkpoint inhibitors, as seen in the TROPHY-U-01 and TROPiCS-4 trials. The review concludes that the locally advanced or metastatic urothelial carcinoma treatment landscape is rapidly evolving, with combination therapies offering promising avenues for improved patient outcomes, signaling a new era in urothelial carcinoma management

Free fatty acid receptors, G protein-coupled receptor 120 and G protein-coupled receptor 40, are essential for oil-induced gastric inhibitory polypeptide secretion

Aims/Introduction: Incretin hormone glucose‐dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) plays a key role in high‐fat diet‐induced obesity and insulin resistance. GIP is strongly secreted from enteroendocrine K cells by oil ingestion. G protein‐coupled receptor (GPR)120 and GPR40 are two major receptors for long chain fatty acids, and are expressed in enteroendocrine K cells. In the present study, we investigated the effect of the two receptors on oil‐induced GIP secretion using GPR120‐ and GPR40‐double knockout (DKO) mice. Materials and Methods: Global knockout mice of GPR120 and GPR40 were crossbred to generate DKO mice. Oral glucose tolerance test and oral corn oil tolerance test were carried out. For analysis of the number of K cells and gene expression in K cells, DKO mice were crossbred with GIP‐green fluorescent protein knock‐in mice in which visualization and isolation of K cells can be achieved. Results: Double knockout mice showed normal glucose‐induced GIP secretion, but no GIP secretion by oil. We then investigated the number of K cells and gene characteristics in K cells isolated from GIP‐green fluorescent protein knock‐in mice. Deficiency of both receptors did not affect the number of K cells in the small intestine or expression of GIP messenger ribonucleic acid in K cells. Furthermore, there was no significant difference in the expression of the genes associated with lipid absorption or GIP secretion in K cells between wild‐type and DKO mice. Conclusions: Oil‐induced GIP secretion is triggered by the two major fatty acid receptors, GPR120 and GPR40, without changing K‐cell number or K‐cell characteristics

Lymphocyte Responses to Chymotrypsin- or Trypsin V-Digested β-Lactoglobulin in Patients with Cow's Milk Allergy

<p/> <p>Chymotrypsin- or trypsin V- (a mixture of trypsin and chymotrypsin) digested β-lactoglobulin (BLG) peptides were prepared and were confirmed to have much less immunoglobulin (lg)G and lgE reactivity compared with intact BLG by IgG inhibition enzymelinked immunosorbent assay and IgE dot blotting. The lymphocyte responses to intact BLG and these peptides were examined using peripheral blood mononuclear cells (PBMCs) from 10 patients with cow's milk allergy. The PBMCs from most patients had lower lymphocyte responses to chymotrypsin- and trypsin V-digested BLG peptides than those to intact BLG. However, PBMCs from one and two patients retained significant proliferative responses to both peptides and to only the former peptide, respectively. Interferon-c production stimulated by chymotrypsin-digested peptides was still detectable in all five patients tested. Chymotrypsindigested BLG reduced lgE reactivity but still induced some lymphocyte responses.</p

Seed Germination Response to Storage Conditions of Eriocaulon heleocharioides (Eriocaulaceae), an Extinct Species in the Wild

Abstract Seed germination experiments with Eriocaulon heleocharioides Satake (Eriocaulaceae) were performed to investigate the effect of air exposure on seeds during the storage period. Although the seeds germinated both above and under water, the response and durability of germination differed from each other. Moreover, the seeds that were dried for 1 month and sown in water showed the highest germination rate (84.4%) among all combinations of conditions. This result shows that treatment by drying prior to sowing promotes the germination of this species