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Heterozygous Chd8 mutant mice display autistic-like behaviours and small but global changes in brain gene expression, which are associated with delays in neuronal development. Autistic-like behaviour in Chd8 mutant mice Mutations in CHD8 , a gene encoding a chromatin remodeller, are strongly linked to autism spectrum disorders (ASDs). Keiichi Nakayama and colleagues show that mice heterozygous for Chd8 mutations display ASD-like behaviour and small but global changes in gene expression in the brain. Gene set enrichment analysis revealed that neurodevelopment was delayed in Chd8 mutant mouse embryos. Expression of RE-1 silencing transcription factor (REST) target genes was reduced in embryonic brains of Chd8 mutant mice as well as in the brains of humans with ASD, and CHD8 was found to physically interact with REST in mouse brain tissue. These data suggest that CHD8 haploinsufficiency may affect gene expression in the brain through abnormal REST activity. Autism spectrum disorder (ASD) comprises a range of neurodevelopmental disorders characterized by deficits in social interaction and communication as well as by restricted and repetitive behaviours 1 . ASD has a strong genetic component with high heritability. Exome sequencing analysis has recently identified many de novo mutations in a variety of genes in individuals with ASD 2 , 3 , with CHD8 , a gene encoding a chromatin remodeller, being most frequently affected 4 , 5 , 6 , 7 , 8 . Whether CHD8 mutations are causative for ASD and how they might establish ASD traits have remained unknown. Here we show that mice heterozygous for Chd8 mutations manifest ASD-like behavioural characteristics including increased anxiety, repetitive behaviour, and altered social behaviour. CHD8 haploinsufficiency did not result in prominent changes in the expression of a few specific genes but instead gave rise to small but global changes in gene expression in the mouse brain, reminiscent of those in the brains of patients with ASD. Gene set enrichment analysis revealed that neurodevelopment was delayed in the mutant mouse embryos. Furthermore, reduced expression of CHD8 was associated with abnormal activation of RE-1 silencing transcription factor (REST), which suppresses the transcription of many neuronal genes. REST activation was also observed in the brains of humans with ASD, and CHD8 was found to interact physically with REST in the mouse brain. Our results are thus consistent with the notion that CHD8 haploinsufficiency is a highly penetrant risk factor for ASD, with disease pathogenesis probably resulting from a delay in neurodevelopment.

Posttransplant relapse represents the greatest obstacle to the success of allogeneic hematopoietic cell transplantation (HCT) for patients with acute myeloid leukemia (AML). This study investigated clinical features and outcomes of posttransplant relapse of AML based on data for 1265 patients with AML suffering relapse after allogeneic HCT conducted during complete remission (CR). Relapse occurred at a median of 6.1 months. The incidence rate of relapse peaked at 29.0 per 100 patient-years during the first 3–6 months period post transplant, after which the rate declined over time, and after 3 years remained consistently at less than 1 per 100 patient-years. The probability of overall survival (OS) after posttransplant relapse was 19% at 2 years, with 68% of deaths being attributed to leukemia. The interval from transplantation to relapse was identified as the strongest indicator for OS. Donor lymphocyte infusion (DLI) and second allogeneic HCT (HCT2) were administered to 152 (12%) and 481 (38%) patients, respectively. Landmark analyses showed some signs of survival benefit when these procedures were performed during CR, but no benefit was gained when performed during non-CR. Our findings clarify clinical features of posttransplant relapse of AML, and indicate the urgent need for developing effective bridging to cellular therapies.

CHD8 is an ATP-dependent chromatin-remodeling factor encoded by the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Although many studies have examined the consequences of CHD8 haploinsufficiency in cells and mice, few have focused on missense mutations, the most common type of CHD8 alteration in ASD patients. We here characterized CHD8 missense mutations in ASD patients according to six prediction scores and experimentally examined the effects of such mutations on the biochemical activities of CHD8, neural differentiation of embryonic stem cells, and mouse behavior. Only mutations with high prediction scores gave rise to ASD-like phenotypes in mice, suggesting that not all CHD8 missense mutations detected in ASD patients are directly responsible for the development of ASD. Furthermore, we found that mutations with high scores cause ASD by mechanisms either dependent on or independent of loss of chromatin-remodeling function. Our results thus provide insight into the molecular underpinnings of ASD pathogenesis caused by missense mutations of CHD8 .

Estrogen receptor α (ERα) is a transcription factor that induces cell proliferation and exhibits increased expression in a large subset of breast cancers. The molecular mechanisms underlying the up-regulation of ERα activity, however, remain poorly understood. We identified FK506-binding protein 52 (FKBP52) as a factor associated with poor prognosis of individuals with ERα-positive breast cancer. We found that FKBP52 interacts with breast cancer susceptibility gene 1 and stabilizes ERα, and is essential for breast cancer cell proliferation. FKBP52 depletion resulted in decreased ERα expression and proliferation in breast cancer cell lines, including MCF7-derived fulvestrant resistance (MFR) cells, suggesting that inhibiting FKBP52 may provide a therapeutic effect for endocrine therapy–resistant breast cancer. In contrast, FKBP51, a closely related molecule to FKBP52, reduced the stability of ERα. Consistent with these findings, FKBP51 was more abundantly expressed in normal tissues than in cancer cells, suggesting that these FKBPs may function in the opposite direction. Collectively, our study shows that FKBP52 and FKBP51 regulate ERα stability in a reciprocal manner and reveals a regulatory mechanism by which the expression of ERα is controlled.

In the randomized, double-blind, phase 3 GRAPHITE study (NCT03657160), anti-α 4 β 7 integrin antibody vedolizumab showed greater efficacy than placebo for prevention of lower-gastrointestinal (GI) acute graft-versus-host disease (aGVHD) after unrelated allogenic hematopoietic stem cell transplantation (allo-HSCT). This post hoc analysis assessed the efficacy and safety of vedolizumab versus placebo for lower-GI aGVHD prevention in Japanese and non-Japanese patients, when added to standard GVHD prophylaxis (calcineurin inhibitor + methotrexate/mycophenolate mofetil + / − anti-thymocyte globulin [ATG]). The analysis included 35 (18 vedolizumab-treated, 17 placebo-treated) Japanese and 298 (150 vedolizumab-treated, 148 placebo-treated) non-Japanese patients. Lower-GI aGVHD-free survival by day + 180 after allo-HSCT (primary endpoint) was 94% in vedolizumab-treated versus 81% in placebo-treated Japanese patients (HR 0.36; 95% CI 0.03–4.01; P = 0.2) and 84% in vedolizumab-treated versus 70% in placebo-treated non-Japanese patients (HR 0.47; 95% CI 0.28–0.78; P = 0.002). The number of events for the 5 key secondary endpoints (lower-GI aGVHD-free and relapse-free survival, Grade C–D aGVHD-free survival, non-relapse mortality, overall survival, and Grade B–D aGVHD-free survival) by day + 180 was lower in vedolizumab- versus placebo-treated Japanese patients. No safety concerns were identified for vedolizumab use as lower-GI aGVHD prophylaxis in Japanese patients.

The disease-specific impact of anti-thymocyte globulin (ATG) in allogeneic hematopoietic cell transplantation (allo-HCT) has not been determined. We retrospectively assessed the impact of ATG in allo-HCT using nationwide registry data from the Japan Society for Transplantation and Cellular Therapy. We included patients who received their first allo-HCT between 2007 and 2018 for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or malignant lymphoma (ML). In total, 8747 patients were included: 7635 patients did not receive ATG and 1112 patients received ATG as GVHD prophylaxis. The median follow-up period of surviving patients was 1457 days. There was no significant impact of pretransplant ATG on the OS or NRM rates in patients with ALL, AML, or ML. In patients with MDS, the probability of 3-year OS was 53.3% in the non-ATG group and 64.2% in the ATG group (P = 0.001). The cumulative incidence rates of relapse and NRM at 3 years were 14.2% and 30.3% (95% CI 27.2–33.3%), respectively, in the non-ATG group and 17.1% and 18.1% in the ATG group (P = 0.15 and P < 0.001). The same finding was observed in a propensity-score matched cohort. Our study suggests that the clinical benefit of ATG could vary among hematological diseases.

Relapsed acute leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with poor prognosis. In a subset of patients, durable remissions can be achieved with a second allo-HSCT (allo-HSCT2). However, many patients experience relapse after allo-HSCT2 and they may be considered for a third allo-HSCT (allo-HSCT3). Nevertheless, the benefit of allo-HSCT3 remains unconfirmed. Thus, herein a retrospective analysis of 253 allo-HSCT3s in patients with relapsed/refractory acute leukemia was carried out. In total, 29 (11.5%) survived at a median follow-up of 794 days (range: 87–4 619). The 3-year leukemia-free survival and overall survival (OS) rates were 9.7% and 10.9%, respectively. Patients who maintained remission for ≥2 years after allo-HSCT2 had a significantly better 3-year OS (35.8%) than those who experienced early relapse (<1 year, 7.8%; 1–2 years, 14.0%; P = 0.004). Complete remission at allo-HSCT3, performance status score of 0–1 at allo-HSCT3, grade I acute graft-versus-host disease after allo-HSCT2, and relapse ≥2 years after allo-HSCT2 were associated with better survival in patients who received allo-HSCT3. The prognosis after allo-HSCT3 in patients with relapsed/refractory acute leukemia is generally unfavorable. However, given the lack of alternative treatment options, allo-HSCT3 may be considered in a group of patients.

The SARS-CoV-2 pandemic disrupted healthcare systems worldwide, particularly affecting hematopoietic stem cell transplantation (HSCT) activities. Understanding the impact of the SARS-CoV-2 pandemic on transplant practices, especially in Japan, where cord blood transplantation (CBT) is prevalent, is crucial. A total of 40,444 allogeneic HSCT cases in Japan between 2011 and 2021 were examined using an interrupted time series analysis to assess the impact of COVID-19 on CBT utilization. Following the SARS-CoV-2 pandemic, CBT cases demonstrated a significant increase (11.06 [95% confidence interval (CI): 1.87 to 20.25] cases per month), whereas bone marrow transplantation cases decreased, by 10.74 cases per month (95% CI, −19.84 to −1.63 cases per month). Total HSCT cases remained stable with a level change of 5.47 cases per month (95% CI, −10.07 to 21.01 cases per month) and a trend change of −1.11 cases per month (95% CI, −2.22 to 0.004 cases per month). The interrupted time series analysis showed significantly increased CBT cases in Japan, highlighting its crucial role as an alternative transplant source during the pandemic. CBT offset the impact of the decrease in bone marrow transplantation and contributed to the maintenance of HSCT activity in Japan during the unprecedented crisis.

Eight-barbel loaches belonging to the genus Lefua have diverged into seven species in freshwaters of East Asia. Recent studies have discovered a new population in the Kuzuryu River drainage system of Fukui Prefecture, central Japan. Based on the results of the genetic analyses and morphological comparisons, we describe this population as a new species, Lefua nishimurai sp. nov. Body width, interorbital width, orbit diameter, preanal length, snout length, and the newly examined head width greatly contributed to the discrimination between L. torrentis , L. tokaiensis and L. nishimurai sp. nov. The new species can be distinguished from other congeners by combining the following characteristics: 1) eyes positioned dorsally on the head; 2) a narrow conspicuous longitudinal mark between the base of the outer rostral barbel and the eye; 3) small dark spots on the body, dorsal, and caudal fins; 4) a small dorsal fin and eye diameter; and 5) black spots above and below the base of the caudal fin. Based on the phylogenetic relationships of the genus, L. nishimurai sp. nov. is estimated to have diverged early from its common ancestor in central Japan. Understanding the natural history of this new species and implementing conservation measures are crucial because of its narrow, fragmented distribution and presence in vulnerable habitats.

Prognosis for patients undergoing hematopoietic cell transplantation (HCT) has been improving. Short-term survival information, such as crude survival rates that consider deaths immediately after the transplantation, may not be sufficiently useful for assessing long-term survival. Using the data of the Japanese HCT registry, the net survival rate of patients who survived for a given period was determined according to age, disease, and type of transplant. We included a total of 41,716 patients who received their first allogeneic hematopoietic cell transplantation between 1991 and 2015. For each disease, age group, graft source subcategory, net survival was calculated using the Pohar-Perme method, and 5-year conditional net survival (CS) was calculated. Ten-year net survivals of total patient cohort were 41.5% and 47.4% for males and females, respectively. Except for myelodysplastic syndrome, multiple myeloma, and adult T-cell leukemia/lymphoma, 5-year CS for 5-year transplant survivors exceeded 90%. CS was especially high for aplastic anemia, of which was over 100% for children and younger adults receiving cord blood, suggesting that these patients have similar longevity to an equivalent group from the general population. These findings provide useful information for long-term survival, and can serve as benchmark for comparisons among registries, including other cancers.