Molecular Epidemiology of Carbapenem-Resistant Klebsiella aerogenes in Japan.

Information regarding Klebsiella aerogenes haboring carbapenemase in Japan is limited. A comprehensive nationwide survey was conducted from September 2014 to December 2022, and 67 non-duplicate strains of carbapenem-resistant K. aerogenes were isolated from 57 healthcare facilities in Japan. Through genetic testing and whole-genome sequencing, six strains were found to possess carbapenemases, including imipenemase (IMP)-1, IMP-6, New Delhi metallo-ß-lactamase (NDM)-1, and NDM-5. The strain harboring blaNDM-5 was the novel strain ST709, which belongs to the clonal complex of the predominant ST4 in China. The novel integron containing blaIMP-1 featured the oxacillinase-101 gene, which is a previously unreported structure, with an IncN4 plasmid type. However, integrons found in the strains possessing blaIMP-6, which were the most commonly identified, matched those reported domestically in Klebsiella pneumoniae, suggesting the prevalence of identical integrons. Transposons containing blaNDM are similar or identical to the transposon structure of K. aerogenes harboring blaNDM-5 previously reported in Japan, suggesting that the same type of transposon could have been transmitted to K. aerogenes in Japan. This investigation analyzed mobile genetic elements, such as integrons and transposons, to understand the spread of carbapenemases, highlighting the growing challenge of carbapenem-resistant Enterobacterales in Japan and underscoring the critical need for ongoing surveillance to control these pathogens.

Clinical and prognostic features of Langerhans cell histiocytosis in adults.

Langerhans cell histiocytosis (LCH) is a rare disease characterized by clonal expansion of CD1a+ CD207+ myeloid dendritic cells. The features of LCH are mainly described in children and remain poorly defined in adults; therefore, we conducted a nationwide survey to collect clinical data from 148 adult patients with LCH. The median age at diagnosis was 46.5 (range: 20-87) years with male predominance (60.8%). Among the 86 patients with detailed treatment information, 40 (46.5%) had single system LCH, whereas 46 (53.5%) had multisystem LCH. Moreover, 19 patients (22.1%) had an additional malignancy. BRAF V600E in plasma cell-free DNA was associated with a low overall survival (OS) rate and the risk of the pituitary gland and central nervous system involvement. At a median follow-up of 55 months from diagnosis, six patients (7.0%) had died, and the four patients with LCH-related death did not respond to initial chemotherapy. The OS probability at 5 years post-diagnosis was 90.6% (95% confidence interval: 79.8-95.8). Multivariate analysis showed that patients aged ≥60 years at diagnosis had a relatively poor prognosis. The probability of event-free survival at 5 years was 52.1% (95% confidence interval: 36.6-65.5), with 57 patients requiring chemotherapy. In this study, we first revealed the high rate of relapse after chemotherapy and mortality of poor responders in adults as well as children. Therefore, prospective therapeutic studies of adults with LCH using targeted therapies are needed to improve outcomes in adults with LCH.

Prognostic impact of circulating tumor DNA status post-allogeneic hematopoietic stem cell transplantation in AML and MDS.

This study was performed to assess the utility of tumor-derived fragmentary DNA, or circulating tumor DNA (ctDNA), for identifying high-risk patients for relapse of acute myeloid leukemia and myelodysplastic syndrome (AML/MDS) after undergoing myeloablative allogeneic hematopoietic stem cell transplantation (alloSCT). We retrospectively collected tumor and available matched serum samples at diagnosis and 1 and 3 months post-alloSCT from 53 patients with AML/MDS. After identifying driver mutations in 51 patients using next-generation sequencing, we designed at least 1 personalized digital polymerase chain reaction assay per case. Diagnostic ctDNA and matched tumor DNA exhibited excellent correlations with variant allele frequencies. Sixteen patients relapsed after a median of 7 months post-alloSCT. Both mutation persistence (MP) in bone marrow (BM) at 1 and 3 months post-alloSCT and corresponding ctDNA persistence (CP) in the matched serum (MP1 and MP3; CP1 and CP3, respectively) were comparably associated with higher 3-year cumulative incidence of relapse (CIR) rates (MP1 vs non-MP1, 72.9% vs 13.8% [P = .0012]; CP1 vs non-CP1, 65.6% vs 9.0% [P = .0002]; MP3 vs non-MP3, 80% vs 11.6% [P = .0002]; CP3 vs non-CP3, 71.4% vs 8.4% [P < .0001]). We subsequently evaluated whether subset analysis of patients with 3 genes associated with clonal hematopoiesis, DNMT3A, TET2, and ASXL1 (DTA), could also be helpful in relapse prediction. As a result, CP based on DTA gene mutations also had the prognostic effect on CIR. These results, for the first time, support the utility of ctDNA as a noninvasive prognostic biomarker in patients with AML/MDS undergoing alloSCT.

Three novel species of the Bacillus cereus group isolated from clinical samples in Japan.

Three Gram-positive bacterial strains, BML-BC004, BML-BC017 and BML-BC059, isolated from blood samples from three inpatients in Japan, were identified as members of Bacillus cereus using matrix-assisted laser desorption ionization time-of-flight MS. The 16S rRNA gene sequences of these three strains were more than 97.1 % similar to 18 type strains belonging to the B. cereus group. Whole-genome comparisons, using average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH), confirmed that the three strains represented three individual distinct species belonging to the B. cereus group. A phylogenetic tree showed that BML-BC004, BML-BC017 and BML-BC059 were located close to B. luti, B. mobilis and B. paramycoides, respectively. Based on these phylogenetic and phenotypic data, including values below the threshold for ANI and dDDH, the three strains should be classified as representing three different novel species of the B. cereus group: Bacillus sanguinis sp. nov., with type strain BML-BC004T (=DSM 111102T=JCM 34122T), Bacillus paramobilis sp. nov., with type strain BML-BC017T (=DSM 111100T=JCM 34124T) and Bacillus hominis sp. nov., with type strain BML-BC059T (=DSM 111101T=JCM 34125T).

Emergence of Carbapenem-Resistant Providencia rettgeri and Providencia stuartii Producing IMP-Type Metallo-ß-Lactamase in Japan.

Four Providencia rettgeri isolates and one Providencia stuartii isolate were obtained from urine samples of five patients in 2018 in Japan. All of the isolates were resistant to imipenem and meropenem, and three were highly resistant to both carbapenems, with MICs of 512 µg/ml. The three highly carbapenem-resistant isolates harbored blaIMP-70, encoding a variant of IMP-1 metallo-ß-lactamase with two amino acid substitutions (Val67Phe and Phe87Val), and the other two harbored blaIMP-1 and blaIMP-11, respectively. Whole-genome sequencing revealed that an isolate harbored two copies of blaIMP-1 on the chromosome and that the other four harbored a copy of blaIMP-11 or blaIMP-70 in a plasmid. Expression of blaIMP-70 conferred carbapenem resistance in Escherichia coli Recombinant IMP-70 and an IMP-1 variant with Val67Phe but without Phe87Val had significant higher hydrolytic activities against meropenem than recombinant IMP-1, indicating that an amino acid substitution of Val67Phe affects increased activities against meropenem in IMP-70. These results suggest that Providencia spp. become more highly resistant to carbapenems by acquisition of two copies of blaIMP-1 or by mutation of blaIMP genes with amino acid substitutions, such as blaIMP-70.

Emergence of carbapenem-resistant and colistin-susceptible Enterobacter cloacae complex co-harboring blaIMP-1 and mcr-9 in Japan.

BACKGROUND: The spread of Enterobacteriaceae producing both carbapenemases and Mcr, encoded by plasmid-mediated colistin resistance genes, has become a serious public health problem worldwide. This study describes three clinical isolates of Enterobacter cloacae complex co-harboring blaIMP-1 and mcr-9 that were resistant to carbapenem but susceptible to colistin. METHODS: Thirty-two clinical isolates of E. cloacae complex non-susceptible to carbapenems were obtained from patients at 14 hospitals in Japan. Their minimum inhibitory concentrations (MICs) were determined by broth microdilution methods and E-tests. Their entire genomes were sequenced by MiSeq and MinION methods. Multilocus sequence types were determined and a phylogenetic tree constructed by single nucleotide polymorphism (SNP) alignment of whole genome sequencing data. RESULTS: All 32 isolates showed MICs of ≥2 µg/ml for imipenem and/or meropenem. Whole-genome analysis revealed that all these isolates harbored blaIMP-1, with three also harboring mcr-9. These three isolates showed low MICs of 0.125 µg/ml for colistin. In two of these isolates, blaIMP-1 and mcr-9 were present on two separate plasmids, of sizes 62 kb and 280/290 kb, respectively. These two isolates did not possess a qseBC gene encoding a two-component system, which is thought to regulate the expression of mcr-9. In the third isolate, however, both blaIMP-1 and mcr-9 were present on the chromosome. CONCLUSION: The mcr-9 is silently distributed among carbapenem-resistant E. cloacae complex isolates, of which are emerging in hospitals in Japan. To our knowledge, this is the first report of isolates of E. cloacae complex harboring both blaIMP-1 and mcr-9 in Japan.

Accuracy of cone beam computed tomography in evaluation of palatal mucosa thickness.

AIM: The purpose of this study was to investigate the accuracy of the measurement of palatal mucosa thickness using cone beam computed tomography (CBCT) and to create a conversion formula to evaluate palatal mucosa thickness more accurately. We then evaluated the palatal mucosa thickness in a Japanese population using CBCT and the conversion formula. MATERIALS AND METHODS: We evaluated palatal mucosa thickness in 10 healthy subjects at 15 sites using CBCT, digital impression, and K file. Multiple regression analysis was performed to create a conversion formula to measure thickness accurately. We then obtained CBCT data from 174 patients retrospectively, applied the conversion formula, and evaluated palatal mucosa thickness. RESULTS: Sites of measurement affected measurement error. Measurement using CBCT was 0.34 ± 0.04 mm smaller than actual measurement; therefore, a conversion formula was created. Male, age ≥60 years, and probing pocket depth ≥4 mm had significant and positive associations with palatal mucosa thickness; however, no association was observed between bleeding on probing and palatal mucosa thickness. CONCLUSION: CBCT is useful for the noninvasive and accurate measurement of palatal mucosa thickness.

Cryopreserved CD34+ Cell Dose, but Not Total Nucleated Cell Dose, Influences Hematopoietic Recovery and Extensive Chronic Graft-versus-Host Disease after Single-Unit Cord Blood Transplantation in Adult Patients.

Low cryopreserved total nucleated cell (TNC) dose in a cord blood (CB) unit has been shown to be associated with engraftment failure and mortality after single-unit cord blood transplantation (CBT) in adults. Although CB banks offer specific characteristics of cryopreserved cell dose, such as TNC, CD34+ cells, and colony-forming unit for granulocyte/macrophage (CFU-GM), the impact of each cell dose on engraftment and outcomes after single-unit CBT in adults remains unclear. We retrospectively analyzed the results of 306 CBTs for 261 adult patients in our institution between 1998 and 2016. The median age was 43 years (range, 16 to 68), the median actual body weight (ABW) was 56.2 kg (range, 36.2 to 104.0), the median ideal body weight (IBW) was 62.3 kg (range, 39.7 to 81.3), the median TNC dose was 2.46 × 107/ABW kg (range, 1.07 to 5.69), the median CD34+ cell dose was .91 × 105/ABW kg (range, .15 to 7.75), and the median CFU-GM dose was 24.46 × 103/ABW kg (range, .04 to 121.81). Among patients who achieved engraftment, the speed of neutrophil, platelet, and red blood cell engraftment significantly correlated with CD34+ cell dose, but not with TNC and CFU-GM dose, based on both ABW and IBW. In multivariate analysis, the incidence of extensive chronic graft-versus-host disease (GVHD) was significantly higher in patients receiving the highest CD34+ cell dose, based on both ABW and IBW. Nevertheless, no cell dose was associated with survival, transplantation-related mortality, and relapse. In conclusion, cryopreserved CD34+ cell dose was the best predictor for hematopoietic recovery and extensive chronic GVHD after CBT. The cryopreserved CD34+ cell dose should be used for unit selection criteria in single-unit CBT for adults.

[Autologous peripheral blood stem cell transplantation for double-refractory myeloma with K-RAS and N-RAS mutations].

The prognosis of multiple myeloma (MM) has been improved due to the introduction of novel agents like proteasome inhibitors and immunomodulatory drugs (IMiDs). However, some cases are refractory to the use of novel agents, and the prognosis of such cases is poor. A 53-year-old male was diagnosed with MM and categorized as follows: Bence-Jones protein lambda type MM, Durie-Salmon IIIA, international staging system (ISS) stage II, and revised ISS stage II. Mutations in K-RAS and IGH/FGFR3 translocation were detected at diagnosis. His tumor was refractory to seven therapeutic regimens including bortezomib, IMiDs (lenalidomide, thalidomide, pomalidomide), conventional chemotherapy, and radiation therapy. N-RAS mutations, CKS1B gains, and C-MYC split signals were detected after treatment. We performed high-dose melphalan/autologous stem cell transplantation (HD-MEL/ASCT) as a salvage therapy and achieved very good partial response. The correlation between K-RAS mutations and poor prognosis or between N-RAS mutations and reduced sensitivity to bortezomib is reported. However, RAS mutations are reported as a favorable factor for HD-MEL/ASCT. In general, mutations of both the K-RAS and N-RAS are known to be mutually exclusive. This rare MM case has mutations in both K-RAS and N-RAS, and the possible relevance of these mutations to both the refractoriness to novel therapies and sensitivity to HD-MEL/ASCT is suggested.

Enhanced natural killer cell activation by exopolysaccharides derived from yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1.

Yogurt is generally recognized as a beneficial food for our health, but research into its physiological effects has focused mainly on intestinal dysfunctions such as constipation and diarrhea. We previously found yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 (hereafter OLL1073R-1) could reduce risks of catching the common cold and flu in human trials. It was assumed that immunostimulatory exopolysaccharide (EPS) produced from OLL1073R-1 play an important role in this context. However, few studies have examined the immunostimulatory effects of traditional Bulgarian yogurts fermented with different strains of lactobacilli and their metabolites. Therefore, we screened 139 L. delbrueckii ssp. bulgaricus strains and identified OLL1073R-1 as the most robust producer of EPS. This strain was also the only strain that induced the production of IFN-γ in vitro. Oral administration of the EPS or yogurt fermented with OLL1073R-1 and Streptococcus thermophilus OLS3059 (OLL1073R-1 yogurt) augmented natural killer (NK) cell activity and induced IFN-γ production in spleen cells in mice, whereas 2 other yogurts fermented with other strains had no effect on NK cell activity. Cellular preparations of the OLL1073R-1 strain also slightly augmented NK cell activity, but were less effective than EPS itself. The EPS-dependent stimulation of NK cell activity was abrogated in IFN-γ knockout mice and in myeloid differentiation factor 88 knockout mice. Furthermore, IFN-γ production from spleen cells stimulated with EPS was completely blocked with both anti-IL-12 and anti-IL-18 antibodies in vitro. These findings suggest that NK cell activation by OLL1073R-1 yogurt is EPS-dependent, occurs via IL-12- and IL-18-mediated IFN-γ production, and requires myeloid differentiation factor 88. We showed that traditional Bulgarian yogurt could exert immunostimulatory effects by selecting starter strains and part of the mechanisms depend on IFN-γ inducible EPS produced from L. delbrueckii ssp. bulgaricus. Further investigations on processes of fermentation to increase of the EPS may lead to the development of new functional foods that keep our immune functions stable.

Microbiological and molecular epidemiological analyses of community-associated methicillin-resistant Staphylococcus aureus at a tertiary care hospital in Japan.

Molecular characterization of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is generally conducted referred to staphylococcal cassette chromosome mec (SCCmec) type IV or V. CA-MRSA is now a cause of concern since such strains have been isolated not only from individuals in a community but also from patients in healthcare settings. The aim of this study was to analyze microbiological and molecular epidemiological features of CA-MRSA strains at a Japanese tertiary care hospital using PCR based-open reading frame typing (POT). This technique allows for molecular classification into CA-MRSA (POT-CA) and hospital-associated (HA-) MRSA (POT-HA) with clonal discrimination. Clinical MRSA isolates obtained from consecutive patients between October 1, 2012 and September 30, 2013 at the hospital were analyzed in combination with the clinical definition for CA-MRSA by the Centers for Disease Control and Prevention and POT. Of 219 isolates (76 clonal groups), 64 (29.3%) were clinical-HA/POT-CA isolates (22 clonal groups). Some clones of them accumulated in this hospital and might be involved in nosocomial transmission. Virulent factors of the isolates were analyzed, and only one (1.6%) Panton-Valentine leukocidin gene positive isolate but no arginine catabolic mobile element genes positive isolate were found in clinical-HA/POT-CA. Additionally, clinical-HA/POT-CA isolates showed higher antimicrobial susceptibility than clinical-HA/POT-HA, especially to minocycline, doxycycline, and amikacin. The most frequent genotype of molecular CA-MRSA was multi-locus sequence type 5-SCCmecIV, previously not detected in Japan. Although CA-MRSA at this hospital showed low virulence and higher antimicrobial susceptibility, the risk of nosocomial infection from them should be recognized, requiring stricter infection control measures.

Functional salivary gland regeneration as the next generation of organ replacement regenerative therapy.

Oral health is maintained by the coordinated function of many organs including the teeth and salivary glands. Dysfunction of these organs causes many problems, such as dental caries, swallowing dysfunction and periodontal disease. Regenerative therapy for salivary gland tissue repair and whole-salivary gland replacement is currently considered a novel therapeutic concept that may have potential for the full recovery of salivary gland function. Salivary gland tissue stem cells are thought to be candidate cell sources for salivary gland tissue repair therapies. In addition, whole-salivary gland replacement therapy may become a novel next-generation organ regenerative therapy. Almost all organs arise from reciprocal epithelial and mesenchymal interactions of the germ layers. We developed a novel bioengineering method, an organ germ method that can reproduce organogenesis through the epithelial-mesenchymal interaction. A bioengineered salivary gland germ can regenerate a structurally correct salivary gland in vitro, and bioengineered salivary glands successfully secrete saliva into the oral cavity from ducts in the recipient through the reestablishment of the afferent-efferent neural network. The bioengineered salivary gland can also improve the symptoms of xerostomia, such as bacterial infection and swallowing dysfunction. In this review, we describe recent findings and technological developments of salivary gland regenerative therapy.

Gadd45g regulates dental epithelial cell proliferation through p38 MAPK-mediated p21 expression.

Ectodermal organs, such as teeth, hair follicles, and mammary glands, arise from their respective germs through epithelial-mesenchymal interactions during organogenesis. Growth arrest and DNA damage-inducible gene gamma (Gadd45g) have been shown to play important roles in various biological processes, such as stress responses, cell differentiation, and tumor suppression, through the regulation of cell proliferation and gene expression. We found that Gadd45g was expressed in enamel knots, which orchestrate tooth germ development as epithelial signaling centers. Gadd45g induced the expression of p21 and inhibited the proliferation of dental epithelial cells. The up-regulation of p21 expression was regulated by Gadd45g-mediated activation of the p38 MAPK pathway. Thus, our results suggest that Gadd45g is involved in the regulation of p21-mediated epithelial cell proliferation through the p38 MAPK pathway during tooth organ development.

Pathogenicity Prediction of Gene Fusion in Structural Variations: A Knowledge Graph-Infused Explainable Artificial Intelligence (XAI) Framework.

When analyzing cancer sample genomes in clinical practice, many structural variants (SVs), other than single nucleotide variants (SNVs), have been identified. To identify driver variants, the leading candidates must be narrowed down. When fusion genes are involved, selection is particularly difficult, and highly accurate predictions from AI is important. Furthermore, we also wanted to determine how the prediction can make more reliable diagnoses. Here, we developed an explainable AI (XAI) suitable for SVs with gene fusions, based on the XAI technology we previously developed for the prediction of SNV pathogenicity. To cope with gene fusion variants, we added new data to the previous knowledge graph for SVs and we improved the algorithm. Its prediction accuracy was as high as that of existing tools. Moreover, our XAI could explain the reasons for these predictions. We used some variant examples to demonstrate that the reasons are plausible in terms of pathogenic basic mechanisms. These results can be seen as a hopeful step toward the future of genomic medicine, where efficient and correct decisions can be made with the support of AI.

Comparative studies of hair shaft components between healthy and diseased donors.

Globally, the rapid aging of the population is predicted to become even more severe in the second half of the 21st century. Thus, it is expected to establish a growing expectation for innovative, non-invasive health indicators and diagnostic methods to support disease prevention, care, and health promotion efforts. In this study, we aimed to establish a new health index and disease diagnosis method by analyzing the minerals and free amino acid components contained in hair shaft. We first evaluated the range of these components in healthy humans and then conducted a comparative analysis of these components in subjects with diabetes, hypertension, androgenetic alopecia, major depressive disorder, Alzheimer's disease, and stroke. In the statistical analysis, we first used a student's t test to compare the hair components of healthy people and those of patients with various diseases. However, many minerals and free amino acids showed significant differences in all diseases, because the sample size of the healthy group was very large compared to the sample size of the disease group. Therefore, we attempted a comparative analysis based on effect size, which is not affected by differences in sample size. As a result, we were able to narrow down the minerals and free amino acids for all diseases compared to t test analysis. For diabetes, the t test narrowed down the minerals to 15, whereas the effect size measurement narrowed it down to 3 (Cr, Mn, and Hg). For free amino acids, the t test narrowed it down to 15 minerals. By measuring the effect size, we were able to narrow it down to 7 (Gly, His, Lys, Pro, Ser, Thr, and Val). It is also possible to narrow down the minerals and free amino acids in other diseases, and to identify potential health indicators and disease-related components by using effect size.

Epidemiological Characteristics of Carbapenem-Resistant Enterobacterales in Japan: A Nationwide Analysis of Data from a Clinical Laboratory Center (2016-2022).

In Japan, nationwide epidemiological surveys on carbapenem-resistant Enterobacterales (CREs), including comprehensive information, are scarce, with most data available only through public reports. This study analyzed data on the Enterobacterales family collected from nationwide testing centers between January 2016 and December 2022, focusing on isolates that met the criteria for CRE in Japan based on drug susceptibility. We investigated 5,323,875 Enterobacterales isolates of 12 different species; among 4696 (0.09%) CRE strains, the proportion of major CRE isolates was as follows: Escherichia coli, 31.3%; Klebsiella pneumoniae, 28.0%; Enterobacter cloacae, 18.5%; and Klebsiella aerogenes, 6.7%. Moreover, over a 7-year period, Providencia rettgeri, E. cloacae, K. aerogenes, and K. pneumoniae demonstrated relatively high CRE percentages of 0.6% (156/26,185), 0.47% (869/184,221), 0.28% (313/110,371), and 0.17% (1314/780,958), respectively. The number of CRE strains isolated from different samples was as follows: urine, 2390; respiratory specimens, 1254; stool, 425; blood, 252; others, 375. In the broader context, including colonization, the predominant isolates of CREs collected at nationwide testing centers are E. coli and K. pneumoniae. Furthermore, recently, attention has been directed toward less common CRE species, such as Klebsiella oxytoca and Providencia rettgeri, and thus, it might be necessary to continue monitoring these less common species.

Explainable AI for Estimating Pathogenicity of Genetic Variants Using Large-Scale Knowledge Graphs.

BACKGROUND: To treat diseases caused by genetic variants, it is necessary to identify disease-causing variants in patients. However, since there are a large number of disease-causing variants, the application of AI is required. We propose AI to solve this problem and report the results of its application in identifying disease-causing variants. METHODS: To assist physicians in their task of identifying disease-causing variants, we propose an explainable AI (XAI) that combines high estimation accuracy with explainability using a knowledge graph. We integrated databases for genomic medicine and constructed a large knowledge graph that was used to achieve the XAI. RESULTS: We compared our XAI with random forests and decision trees. CONCLUSION: We propose an XAI that uses knowledge graphs for explanation. The proposed method achieves high estimation performance and explainability. This will support the promotion of genomic medicine.

Cyclical dermal micro-niche switching governs the morphological infradian rhythm of mouse zigzag hair.

Biological rhythms are involved in almost all types of biological processes, not only physiological processes but also morphogenesis. Currently, how periodic morphological patterns of tissues/organs in multicellular organisms form is not fully understood. Here, using mouse zigzag hair, which has 3 bends, we found that a change in the combination of hair progenitors and their micro-niche and subsequent bend formation occur every three days. Chimeric loss-of-function and gain-of-function of Ptn and Aff3, which are upregulated immediately before bend formation, resulted in defects in the downward movement of the micro-niche and the rhythm of bend formation in an in vivo hair reconstitution assay. Our study demonstrates the periodic change in the combination between progenitors and micro-niche, which is vital for the unique infradian rhythm.

Genomic Landscape of Endometrial, Ovarian, and Cervical Cancers in Japan from the Database in the Center for Cancer Genomics and Advanced Therapeutics.

This study aimed to comprehensively clarify the genomic landscape and its association with tumor mutational burden-high (TMB-H, ≥10 mut/Mb) and microsatellite instability-high (MSI-H) in endometrial, cervical, and ovarian cancers. We obtained genomic datasets of a comprehensive genomic profiling test, FoundationOne® CDx, with clinical information using the "Center for Cancer Genomics and Advanced Therapeutics" (C-CAT) database in Japan. Patients can undergo the tests only after standardized treatments under universal health insurance coverage. Endometrial cancers were characterized by a high frequency of TMB-H and MSI-H, especially in endometrioid carcinomas. The lower ratio of POLE exonuclease mutations and the higher ratio of TP53 mutations compared to previous reports suggested the prognostic effects of the molecular subtypes. Among the 839 cervical cancer samples, frequent mutations of KRAS, TP53, PIK3CA, STK11, CDKN2A, and ERBB2 were observed in adenocarcinomas, whereas the ratio of TMB-H was significantly higher in squamous cell carcinomas. Among the 1606 ovarian cancer samples, genomic profiling of serous, clear cell, endometrioid, and mucinous carcinomas was characterized. Pathogenic mutations in the POLE exonuclease domain were associated with high TMB, and the mutation ratio was low in both cervical and ovarian cancers. The C-CAT database is useful for determining the mutational landscape of each cancer type and histological subtype. As the dataset is exclusively collected from patients after the standardized treatments, the information on "druggable" alterations highlights the unmet needs for drug development in major gynecological cancers.