Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior.

T cells reorganize their metabolic profiles after being activated, but the systemic metabolic effect of sustained activation of the immune system has remained unexplored. Here we report that augmented T cell responses in Pdcd1-/- mice, which lack the inhibitory receptor PD-1, induced a metabolic serum signature characterized by depletion of amino acids. We found that the depletion of amino acids in serum was due to the accumulation of amino acids in activated Pdcd1-/- T cells in the lymph nodes. A systemic decrease in tryptophan and tyrosine led to substantial deficiency in the neurotransmitters serotonin and dopamine in the brain, which resulted in behavioral changes dominated by anxiety-like behavior and exacerbated fear responses. Together these data indicate that excessive activation of T cells causes a systemic metabolomic shift with consequences that extend beyond the immune system.

Genomic targets, and histone acetylation and gene expression profiling of neural HDAC inhibition.

Histone deacetylase inhibitors (HDACis) have been shown to potentiate hippocampal-dependent memory and synaptic plasticity and to ameliorate cognitive deficits and degeneration in animal models for different neuropsychiatric conditions. However, the impact of these drugs on hippocampal histone acetylation and gene expression profiles at the genomic level, and the molecular mechanisms that underlie their specificity and beneficial effects in neural tissue, remains obscure. Here, we mapped four relevant histone marks (H3K4me3, AcH3K9,14, AcH4K12 and pan-AcH2B) in hippocampal chromatin and investigated at the whole-genome level the impact of HDAC inhibition on acetylation profiles and basal and activity-driven gene expression. HDAC inhibition caused a dramatic histone hyperacetylation that was largely restricted to active loci pre-marked with H3K4me3 and AcH3K9,14. In addition, the comparison of Chromatin immunoprecipitation sequencing and gene expression profiles indicated that Trichostatin A-induced histone hyperacetylation, like histone hypoacetylation induced by histone acetyltransferase deficiency, had a modest impact on hippocampal gene expression and did not affect the transient transcriptional response to novelty exposure. However, HDAC inhibition caused the rapid induction of a homeostatic gene program related to chromatin deacetylation. These results illuminate both the relationship between hippocampal gene expression and histone acetylation and the mechanism of action of these important neuropsychiatric drugs.

The C-terminal region of activation-induced cytidine deaminase is responsible for a recombination function other than DNA cleavage in class switch recombination.

Activation-induced cytidine deaminase (AID) is an essential factor for the class switch recombination (CSR) and somatic hypermutation (SHM) of Ig genes. CSR and SHM are initiated by AID-induced DNA breaks in the S and V regions, respectively. Because truncation or frame-shift mutations at the carboxyl (C)-terminus of AID abolishes CSR but not SHM, the C-terminal region of AID likely is required for the targeting of DNA breaks in the S region. To test this hypothesis, we determined the precise location and relative amounts of AID-induced DNA cleavage using an in situ DNA end-labeling method. We established CH12F3-2 cell transfectants expressing the estrogen receptor (ER) fused with wild-type (WT) AID or a deletion mutant lacking the C-terminal 16 aa, JP8Bdel. We found that AID-ER, but not JP8Bdel-ER, caused a CSR to IgA from the addition of 4-hydroxy tamoxifen. In contrast, both WT AID and JP8Bdel induced DNA breaks in both the V and S regions. In addition, JP8Bdel enhanced c-myc/IgH translocations. Our findings indicate that the C-terminal domain of AID is not required for S-region DNA breaks but is required for S-region recombination after DNA cleavage. Therefore, AID does not distinguish between the V and S regions for cleavage, but carries another function specific to CSR.

[Usefulness of serum plasminogen activator inhibitor-1 for diagnosis and monitoring of late-onset sinusoidal obstruction syndrome after allogeneic stem cell transplantation].

Sinusoidal obstruction syndrome (SOS) was originally defined as a clinical syndrome occurring by three weeks after transplantation; however, it occurs even after three or more weeks, and such cases are called late-onset SOS. We report here a case of late-onset SOS. The patient was a 17-year-old male with acute myeloid leukemia in second complete remission. He received a preparative regimen including busulfan followed by allo-peripheral blood stem cell transplantation from an HLA-matched sibling donor. On day 28 after transplantation, he developed hepatomegaly with pain. On day 33 PAI-1 level was increased. Two days later ascites developed, leading to a diagnosis of late-onset SOS. The symptoms improved with conservative therapy and the level of PAI-1 was normalized. When hepatic impairment appears three or more weeks after transplantation, late-onset SOS should be considered. PAI-1 is a useful marker for the diagnosis and follow up of late-onset SOS.

[ABVD chemotherapy for Hodgkin lymphoma at a single institute].

Fifty-eight newly diagnosed patients with Hodgkin lymphoma were treated with ABVD chemotherapy at Yokohama City University Hematology group from October 1996 to June 2005. The median age of patients age was 41 years old and ranged from 15 to 75. Thirty-eight patients were in the early stage and 20 patients were in the advanced stage. Patients in the early stage received 3 cycles of ABVD chemotherapy and involved-field radiation therapy, while those in the advanced stage received 6 cycles of ABVD chemotherapy. The overall response rate in patients was 100% (CR 87%, PR 13%) in the early stage and 95% in the advanced stage. With a median follow-up of 44 months, the 3-year progression-free survival and overall survival were 89% and 95% in the early stage, and 70% and 81% in the advanced stage, respectively. The results of this study were similar to those previously reported in Western countries.

[Successful treatment with reduced-intensity stem cell transplantation for primary myelofibrosis].

A 60-year-old man was found to have anemia and leukocytosis from a health examination, and diagnosed with primary myelofibrosis (PMF). He was treated with low-dose melphalan but required frequent transfusions of red blood cells, and his splenomegaly enlarged. He received reduced-intensity stem cell transplantation (RIST)from an HLA-identical unrelated donor. The recovery of hematopoiesis was delayed due to the small number of transplanted cells (0.4 x 10(8)/kg). Splenomegaly and myelofibrosis gradually improved, and transfusion was not necessary 6 months later. He died of pneumonia about 1 year after transplantation. However, this case suggests that RIST is an effective treatment for PMF with giant splenomegaly.

Response to Drea et al.

We greatly appreciate the critical comments on our paper made by Drea et al. [1]. We would like to emphasize that we are not claiming or giving concrete evidence that the identified compounds are pheromones in our paper. We agree that before we can reasonably conclude that the identified compounds are indeed pheromones, we would at least need to examine whether the responses to the identified compounds are stereotypical and reproducible and exclude the effects of signature differences, such as health, relatedness and genetic quality. To this end, it will be necessary to investigate a broader range of behaviors in the future using a larger number of animals.

Response to Kappeler.

We sincerely appreciate the constructive comments made by Peter Kappeler [1] regarding our paper, "Key male glandular odorants attracting female ring-tailed lemurs" [2]. We largely agree with the points raised in these comments, and believe these should be considered as critical discussion that would enable a more reasonable assessment of our findings.

Key Male Glandular Odorants Attracting Female Ring-Tailed Lemurs.

Among rodents, information about the external world is mainly acquired via the olfactory system, which is one of five sensory modalities. Several semiochemical signals are used for inter- and intraspecies communication [1]. In contrast, primates are generally regarded as vision-oriented mammals, and have been thought to trade their olfactory sensitivity for good sight. However, strepsirrhines have a well-developed olfactory system [2] and a larger repertoire of functional olfactory and vomeronasal receptor genes than haplorhines [3, 4]. Moreover, strepsirrhines are well known for their use of olfactory communication in social behavior. Ring-tailed lemurs are a species of Malagasy strepsirrhines, and use olfactory cues for conspecific communication. Male lemurs mark their scent by spreading volatiles from the antebrachial gland on their wrists. This study combined ethological and chemical approaches to identify a key odorant(s) in antebrachial secretions involved in the sexual communication of lemurs. The results of a behavioral assay indicated that females sniff the males' antebrachial secretions longer during the breeding season than during the nonbreeding season. By examining seasonal changes in volatiles using gas chromatography-mass spectrometry, we found that the secretion of three C12 and C14 aldehydes with a fruity and floral scent significantly increased during the breeding season in a testosterone-dependent manner. Females sniffed for longer at biologically relevant concentrations of two of the aldehydes (12-methyltridecanal and tetradecanal) and were attracted to a mixture of these plus the third aldehyde, dodecanal. Our results suggest that these aldehydes are putative lemur pheromones involved in the attractiveness of males to females during the breeding season.

[Air-leak syndrome in patients with non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation].

We reported 5 patients who developed air-leak syndrome (ALS) including pneumothorax, pneumomediastinum and subcutaneous emphysema after allogeneic stem cell transplantation (SCT). The underlying diseases were AML (n=2), ALL (n=1), MDS (n=1), and CML (n=1). All patients received allogeneic SCT from related donors including 2 donors with HLA mismatch. Total body irradiation was performed as a conditioning regimen in all patients. Late-onset noninfectious pulmonary complications (LONIPC) were detected in all patients before the development of ALS. The interval from diagnosis of LONIPC to onset of ALS was 10-360 days (median, 20 days). Four of 5 patients were treated with corticosteroid for chronic graft-versus-host disease and/or LONIPC. To date, three patients have died of respiratory failure. The others are currently alive and one of these surviving patients is receiving home oxygen treatment. Physicians should be aware of this rare complication following LONIPC, because treatment of ALS is difficult in some patients.

Allogeneic hematopoietic stem cell transplantation after surgical resection of pulmonary aspergillosis in 5 patients with acute leukemia.

We report five patients with acute leukemia who underwent allogeneic hematopoietic stem cell transplantation (HSCT) following surgical resection of pulmonary aspergillosis. The patients were three men and two women with a median age of 40 (range, 32 approximately 60). The diagnosis, based on CT imaging, Aspergillus antigen, culture, and histopathology of resected lung specimens, included two proven and three possible pulmonary aspergillosis. Median duration from surgery to HSCT was 2.5 months (range, 1.0 approximately 20). Pre-transplant restrictive-type lung dysfunction was observed in four patients. Antifungal prophylaxis after HSCT was attempted with voriconazole in three patients, amphotericin-B in one patient, and micafungin in one patient. No patients experienced a relapse of pulmonary aspergillosis, although three patients died after HSCT. The causes of death included leukemia relapse in two and hemophagocytic syndrome in one. These results suggest that pre-transplant surgical resection with post-transplant prophylactic antifungal agents seems to be an effective strategy to prevent the relapse of pulmonary aspergillosis in patients with residual disease in the lung before allogeneic HSCT.

[Myocardial infiltration and formation of multiple granulocytic sarcoma of acute myeloid leukemia after cord blood transplantation].

A 57-year-old woman was diagnosed with acute myeloid leukemia (AML, M5a) with MLL rearrangement in August 2006. Cord blood transplantation (CBT) conditioned with a reduced-intensity regimen was carried out during second complete remission in March 2007. Marrow study on day 28 confirmed complete chimera and disappearance of minimal residual disease by RT-PCR. She complained of left chest pain around day 120. CT scan on day 127 showed left pleural effusion, tumors of the upper mediastinum and spleen, and pericardial effusion. She suddenly died of cardiogenic shock on day 129. Postmortem examination revealed systemic granulocytic sarcomas and infiltration of leukemic cells into the right atrium and epicardium without recurrence of leukemia in blood and marrow.

Identification of a methioninase inhibitor, myrsinoic acid B, from Myrsine seguinii Lév., and its inhibitory activities.

A methioninase inhibitor from Myrsine seguinii was purified and identified as myrsinoic acid B. Its inhibitory activities as to crude methioninase from periodontal bacteria such as Fusobacterium nucleatum, Porphyromonas gingivalis, and Treponema denticola were determined. The IC50 values were 10.5, 82.4, and 30.3 microM respectively.

Clinical Significance of Serum Ferritin at Diagnosis in Patients With Acute Myeloid Leukemia: A YACHT Multicenter Retrospective Study.

PURPOSE: A multicenter retrospective analysis was performed to evaluate the clinical significance of serum ferritin at diagnosis in patients with acute myeloid leukemia (AML). METHODS: The study cohort included 305 patients who were newly diagnosed with AML from 2000 to 2015 and received standard induction chemotherapy. Transplantation was performed in 168 patients. RESULTS: The median ferritin value was 512 ng/mL (range, 8-9475 ng/mL). Ferritin correlated with lactate dehydrogenase, C-reactive protein, white blood cell count, and blast count, and elevation of ferritin was associated with poor performance status. The median follow-up period was 58 months (range, 4-187 months) among survivors. The high ferritin group (≥ 400 ng/mL) demonstrated inferior event-free survival (EFS) at the 5-year interval (30% vs. 40%; P = .033) compared to the low ferritin group. Multivariate analysis in the high-risk karyotype revealed that high ferritin levels predicted worse EFS (hazard ratio = 2.07; 95% confidence interval, 1.28-3.33; P = .003). CONCLUSION: Elevated ferritin at diagnosis may indicate tumor burden in patients with AML and predict worse EFS in the high-risk group.

Hyper-recovery of platelets after induction therapy is a predictor of relapse-free survival in acute myeloid leukemia.

We verified the association between standard clinical and laboratory variables and the risk of relapse in acute myeloid leukemia (AML), which led us to retrospectively examine the effect of regeneration of hematopoiesis in patients with newly diagnosed AML. We used data from 230 patients who obtained remission after cytarabine-based induction chemotherapy. Platelet counts ≥500 × 109/L and hemoglobin levels ≥9 g/dL on day 28 after treatment initiation were significantly associated with relapse-free survival (RFS) rate, conferring respective multivariate risk ratios of 0.38 (95% CI: 0.18-0.79) and 0.60 (95% CI: 0.40-0.89) for the occurrence of relapse or death. No disease relapse occurred in core binding factor leukemia patients whose platelet counts recovered ≥500 × 109/L at 28 days after therapy initiation. We conclude that regeneration of hematopoiesis, especially platelet hyper-recovery, after induction chemotherapy is a significant predictor of RFS in patients with AML.

Enhanced resistance to oxidative decomposition of aqueous electrolytes for aqueous lithium-ion batteries.

An efficient electrolyte solution containing organic sulfonates for use in aqueous rechargeable lithium-ion batteries (ARLBs) is shown to provide a wide potential window and enable a high operating voltage for ARLBs.

R-CHOP therapy alone for limited-stage follicular lymphoma.

Irradiation therapy alone is a standard strategy for limited-stage FL, leading to a 10-year progression-free survival (PFS) rate of 30-50%. However, we have been administering R-CHOP therapy alone to patients with limited-stage FL. A total of 35 patients with newly diagnosed FL received R-CHOP therapy with curative intent between 2002 and 2009. The median age of the 35 patients was 61 years; 7 patients had in CS 1 FL, and 28 patients, CS 2 FL. The median number of R-CHOP cycles was 6. On completion of the R-CHOP therapy, 33 patients achieved complete response and 1 showed partial response (PR). The patient showing PR after the completion of R-CHOP was administered additional irradiation. The remaining 1 patient was not evaluated because of discontinuation of hospital visit. In all the 35 patients, the 5-year PFS rate was 70%, and the 5-year overall survival rate was 92%. In the 15 patients with a PFS>5 years, only 1 patient showed disease progression. The outcome of R-CHOP therapy alone in patients with limited-stage FL was at least equivalent to the reported outcome of irradiation therapy alone. R-CHOP therapy could be an alternative to irradiation therapy in limited-stage FL patients.

Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction.

The interior of the neuronal cell nucleus is a highly organized three-dimensional (3D) structure where regions of the genome that are linearly millions of bases apart establish sub-structures with specialized functions. To investigate neuronal chromatin organization and dynamics in vivo, we generated bitransgenic mice expressing GFP-tagged histone H2B in principal neurons of the forebrain. Surprisingly, the expression of this chimeric histone in mature neurons caused chromocenter declustering and disrupted the association of heterochromatin with the nuclear lamina. The loss of these structures did not affect neuronal viability but was associated with specific transcriptional and behavioural deficits related to serotonergic dysfunction. Overall, our results demonstrate that the 3D organization of chromatin within neuronal cells provides an additional level of epigenetic regulation of gene expression that critically impacts neuronal function. This in turn suggests that some loci associated with neuropsychiatric disorders may be particularly sensitive to changes in chromatin architecture.

Histone H3 lysine 9 methyltransferases, G9a and GLP are essential for cardiac morphogenesis.

Lysine methylation of the histone tail is involved in a variety of biological events. G9a and GLP are known as major H3-K9 methyltransferases and contribute to transcriptional silencing. The functions of these genes in organogenesis remain largely unknown. Here, we analyzed the phenotypes of cardiomyocyte specific GLP knockout and G9a knockdown (GLP-KO/G9a-KD) mice. The H3-K9 di-methylation level decreased markedly in the nuclei of the cardiomyocytes of GLP-KO/G9a-KD mice, but not single G9a or GLP knockout mice. In addition, GLP-KO/G9a-KD mice showed neonatal lethality and severe cardiac defects (atrioventricular septal defects, AVSD). We also showed that hypoplasia in the atrioventricular cushion, which is a main part of the atrioventricular septum, caused AVSD. Expression analysis revealed downregulation of 2 AVSD related genes and upregulation of several non-cardiac specific genes in the hearts of GLP-KO/G9a-KD mice. These data indicate that G9a and GLP are required for sufficient H3-K9 di-methylation in cardiomyocytes and regulation of expression levels in multiple genes. Moreover, our findings show that G9a and GLP have an essential role in normal morphogenesis of the atrioventricular septum through regulation of the size of the atrioventricular cushion.