Mechanisms of action and resistance in histone methylation-targeted therapy.

Epigenomes enable the rectification of disordered cancer gene expression, thereby providing new targets for pharmacological interventions. The clinical utility of targeting histone H3 lysine trimethylation (H3K27me3) as an epigenetic hallmark has been demonstrated1-7. However, in actual therapeutic settings, the mechanism by which H3K27me3-targeting therapies exert their effects and the response of tumour cells remain unclear. Here we show the potency and mechanisms of action and resistance of the EZH1-EZH2 dual inhibitor valemetostat in clinical trials of patients with adult T cell leukaemia/lymphoma. Administration of valemetostat reduced tumour size and demonstrated durable clinical response in aggressive lymphomas with multiple genetic mutations. Integrative single-cell analyses showed that valemetostat abolishes the highly condensed chromatin structure formed by the plastic H3K27me3 and neutralizes multiple gene loci, including tumour suppressor genes. Nevertheless, subsequent long-term treatment encounters the emergence of resistant clones with reconstructed aggregate chromatin that closely resemble the pre-dose state. Acquired mutations at the PRC2-compound interface result in the propagation of clones with increased H3K27me3 expression. In patients free of PRC2 mutations, TET2 mutation or elevated DNMT3A expression causes similar chromatin recondensation through de novo DNA methylation in the H3K27me3-associated regions. We identified subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. Targeting epigenetic drivers and chromatin homeostasis may provide opportunities for further sustained epigenetic cancer therapies.

Associations Between Lifestyle Factors and Constipation Among Survivors After the Great East Japan Earthquake: A 9-year Follow-up Study.

BACKGROUND: Disaster survivors experience deterioration in lifestyles and an increase in constipation. After the Great East Japan Earthquake in 2011, some survivors were evacuated for a long term, even after moving to temporary housing and public reconstruction housing. However, annual changes in constipation and the association between lifestyles and constipation among the survivors are still unknown. METHODS: Overall, 9,234 survivors aged 18 years or older participated in this 9-year follow-up survey after the disaster. Information about the prevalence of constipation and lifestyle factors (diet, physical activity, and mental health) was collected using a self-reported questionnaire. Their dietary intake was categorized into the following two dietary patterns: prudent (fish and shellfish, soybean products, vegetables, fruits, and dairy products) and meat (meat and eggs). Odds ratios for constipation according to lifestyle factors were calculated using a generalized linear mixed model. RESULTS: In women, the prevalence of constipation was the highest at baseline (8.7%) and remained around 5% afterward. In both men and women, older age, poor mental health, and poor physical activity were significantly associated with higher odds ratios of constipation. Moreover, a lower frequency of meals and a lower prudent dietary score were significantly associated with women's constipation. CONCLUSION: The prevalence of constipation was the highest at baseline and remained around 5% in women. Lifestyle factors, such as poor mental health, physical inactivity, and low frequency of meals were associated with constipation. Our findings suggest continuous support for the survivors with constipation for medium- to long-term after disasters.

Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1-associated myelopathy/tropical spastic paraparesis.

Human T cell leukemia virus 1 (HTLV-1) causes the functionally debilitating disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) as well as adult T cell leukemia lymphoma (ATLL). Although there were concerns that the mortality of HAM/TSP could be affected by the development of ATLL, prospective evidence was lacking in this area. In this 5-y prospective cohort study, we determined the mortality, prevalence, and incidence of ATLL in 527 HAM/TSP patients. The standard mortality ratio of HAM/TSP patients was 2.25, and ATLL was one of the major causes of death (5/33 deaths). ATLL prevalence and incidence in these patients were 3.0% and 3.81 per 1,000 person-y, respectively. To identify patients at a high risk of developing ATLL, flow cytometry, Southern blotting, and targeted sequencing data were analyzed in a separate cohort of 218 HAM/TSP patients. In 17% of the HAM/TSP patients, we identified an increase in T cells positive for cell adhesion molecule 1 (CADM1), a marker for ATLL and HTLV-1-infected cells. Genomic analysis revealed that somatic mutations of HTLV-1-infected cells were seen in 90% of these cases and 11% of them had dominant clone and developed ATLL in the longitudinal observation. In this study, we were able to demonstrate the increased mortality in patients with HAM/TSP and a significant effect of ATLL on their prognosis. Having dominant clonal expansion of HTLV-1-infected cells with ATLL-associated somatic mutations may be important characteristics of patients with HAM/TSP who are at an increased risk of developing ATLL.

Psychological Distress in Responders and Nonresponders in a 5-year Follow-up Health Survey: The RIAS Study.

BACKGROUND: People with poor health or mental conditions are generally unwilling to participate in the health examinations, and no studies have directly examined the relationship of psychological distress among disaster survivors with participation status to date. The present study thus examined psychosocial differences according to the respondent status in a 5-year follow-up survey among participants in the prospective health surveys on survivors of the Great East Japan Earthquake and Tsunami Disaster study in Iwate Prefecture, Japan. METHODS: We analyzed data from 10,203 Japanese survivors aged ≥18 years (mean age, 65.6 years; 38.0% men) and who underwent health examinations at baseline in 2011. Participants were classified into responders and nonresponders according to their 2015 health examination participation status. Psychological distress was evaluated using the Kessler 6 scale and categorized as none, mild, and severe. Multinominal logistic regression was used to examine the risk of psychological distress in relation to participation status. RESULTS: In the 2015 survey, 6,334 of 6,492 responders and 1,686 of 3,356 nonresponders were analyzed. The most common reasons for nonparticipation in the survey were participated in other health examinations, examined at a hospital, and did not have time to participate. Nonresponse in males was associated only with mild psychological stress, whereas nonresponse in females was associated with mild and severe psychological distress. CONCLUSION: Nonresponders in the follow-up survey had a higher risk of psychological distress than responders. Continuous monitoring of the health of nonresponders and responders may help to prevent future health deterioration.

Psychological distress in children and adolescent disaster survivors.

BACKGROUND: This study aimed to clarify the association between mental and behavioral changes and subsequent psychological distress among children and adolescents living in areas affected by the 2011 Great East Japan Earthquake. METHODS: We conducted a two-wave study, with waves 1 and 2 occurring in 2011 and 2014, respectively. Data of 462 respondents aged 9-14 years during wave 1 and who participated in both surveys were used in the present analysis. A factor analysis was performed using the mental and behavioral changes reported by respondents in wave 1. Psychological distress was defined as a score of ≥5 on the six-item Kessler Psychological Distress Scale, as measured in wave 2. With the factors generated in this analysis set as independent variables, the odds ratios (OR) (95% confidence intervals, 95% CIs) for psychological distress were calculated using logistic regression, adjusting for age, sex, house damage, living environment, and loss of family or friends. RESULTS: Psychological distress was present in 108 (23.4%) of the respondents. The factor analysis yielded three factors describing mental and behavioral changes: interpersonal issues, brain fog, and anxiety and panic. Of these, interpersonal issues were significantly associated with subsequent psychological distress, with an OR of 2.59 (95% CI 1.58-4.25). This association did not change even when stratified by age and sex. CONCLUSIONS: This study suggests that interpersonal issues are a significant predictor of psychological distress in children and adolescents living in areas affected by a large-scale disaster.

[Acquired thrombotic thrombocytopenic purpura following COVID-19].

COVID-19 often contributes to thrombus formation in microvessels, resulting in damaged vital organs. In this study, we report a case of COVID-19 associated with acquired thrombotic thrombocytopenic purpura (TTP). A 44-year-old man with a history of systemic lupus erythematosus presented with COVID-19 and concomitant hemolytic anemia and a marked thrombocytopenia. The patient was diagnosed with acquired TTP because ADAMTS13 inhibitor was detected and ADAMTS13 activity below the sensitivity level. The patient developed agitated neuropsychiatric symptoms, such as aphasia, disorientation, and delirium, which improved after a plasma exchange, prednisolone, and rituximab administration. Only a few reports have revealed COVID-19 with TTP, and this is the first case in Japan. Although acquired TTP rarely develops, it is an important complication of COVID-19, and thus, it should be promptly diagnosed and treated as soon as possible.

[Listeria meningitis during daratumumab/bortezomib/dexamethasone therapy in a patient with multiple myeloma].

An 88-year-old woman was diagnosed with multiple myeloma received third-line chemotherapy, including DBd (daratumumab [DARA], bortezomib, and dexamethasone [Dex]), and the myeloma was in remission. Sulfamethoxazole/trimethoprim (ST) prophylaxis was discontinued because the dose of Dex was reduced to 20 mg every 4 weeks after 21 cycles of DBd. After 28 cycles of DBd, altered consciousness with fever ensued, and she was referred to the emergency department where Listeria monocytogenes (LM) meningitis was diagnosed. CD38 inactivation is associated with increased LM susceptibility. In patients on Dara-based chemotherapy, antibiotic prophylaxis should be considered using ST, which has activity against Listeria.

[Extranodal NK/T cell lymphoma, nasal type with local recurrence in the contralateral nasal cavity 15 years after initial sequential chemoradiotherapy].

A 72-year-old woman was diagnosed with extranodal NK/T cell lymphoma of the right nasal cavity and received sequential radiochemotherapy comprising focal radiotherapy and THP-COP chemotherapy. Showed a complete tumor response to the treatment; however, the tumor recurred in the contralateral right nasal cavity 15 years after the initial treatment. This was judged to be a marginal recurrence in the radiation field. After four cycles of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy, a second complete response was achieved. It is possible that another recurrence occurs in the future, and if the lesion is localized at the time of recurrence, it may be possible to control the disease again. Careful follow-up is considered necessary.

Increase in Body Weight Following Residential Displacement: 5-year Follow-up After the 2011 Great East Japan Earthquake and Tsunami.

BACKGROUND: Previous studies have linked residential displacement as a result of the 2011 East Japan Earthquake to increases in body weight. However, no study has examined longer-term trajectories of body weight among displaced survivors. We compared body weight change between survivors relocated to temporary housing (TH) group versus other types of accommodation for up to 5 years after the Great East Japan Earthquake. METHODS: Longitudinal follow-up was conducted from 2011 to 2015 in a cohort of 9,909 residents of 42,831. We compared trends in body weight in the TH group (n = 3,169) and the non-TH group (n = 6,740) using a mixed linear regression model stratified by sex (mean age, 61.0 years old; male, 38.9%). RESULTS: In age-adjusted analysis, the body weight in the 2011 survey was not significantly different between two groups for either sex. In men, the TH group significantly increased body weight compared to the non-TH group since 2012. In women, body weight sharply increased in the TH group while body weight did not change in the non-TH group during survey time points. The interaction of living conditions and survey years was statistically significant in both sexes (men; F-value, 6.958; P < 0.001: women; F-value, 19.127; P < 0.001). CONCLUSION: Survivors relocated to temporary housing had an increased risk of weight gain. The weight gain in this group is a potential risk factor for metabolic syndrome in the post-disaster period.

[Falls and associated risk factors among elderly survivors of the Great East Japan Earthquake: RIAS Study].

Objective　An increasing incidence of disuse syndrome is commonly observed in areas affected by large-scale natural disasters. Consequently, the fall risk is high in such populations, necessitating adequate attention to fall prevention measures. It is important to identify factors associated with falls to prevent deterioration in functional ability. We investigated the risk factors associated with falls among elderly survivors in disaster-stricken areas using longitudinal data from the Research project for the prospective Investigation of health problems Among Survivors of the Great East Japan Earthquake (RIAS) Study.Methods　Of all data obtained from the RIAS Study, we used the data of 1,380 survivors who were aged ≥65 years, were not diagnosed with cancer or cardiovascular disease, did not need supportive care, and could participate in the annual survey between 2011 and 2016. Self-administered questionnaires were distributed, and anthropometric and grip tests were performed during the 2011 survey to obtain information regarding housing damage, the fear of falls, arthralgia, cognitive function psychological distress, insomnia, frequency of leaving the house, a history of hypertension, dyslipidemia, diabetes, alcohol consumption status, smoking status, and/or body mass index, and grip strength. Based on the responses obtained from each annual survey, a fall was defined as an event during which an individual had fallen at least once. Multivariate-adjusted odds ratio(OR) and 95% confidence interval(CI) for all variables related to falls were calculated using logistic regression with adjustment for sex and residential area. Similar analyses were performed based on age groups (65-74 years and ≥75 years).Results　The 5-year fall incidence rate was 35.5% (31.9% [men], 37.9% [women]). In men, cognitive dysfunction was significantly associated with falls (OR 1.50, 95%CI 1.01-2.22). In women, cognitive dysfunction (OR 1.82, 95%CI 1.34-2.47), insomnia (OR 1.41, 95%CI 1.02-1.94), dyslipidemia (OR 1.58, 95% 95% CI 1.11-2.25), and a history of smoking (OR 4.30, 95%CI 1.08-17.14) were significantly associated with falls. In women aged ≥75 years, partial housing damage (OR 7.93, 95%CI 1.85-33.91) and psychological distress (OR 2.83, 95%CI 1.09-.7.37) were also significantly associated with falls.Conclusion　This study suggests that cognitive dysfunction in both sexes and insomnia, dyslipidemia, and a history of smoking in women were significantly associated with falls, and partial housing damage and psychological distress were risk factors for falls in women aged ≥75 years. Fall prevention after large-scale natural disasters warrants close attention to known risk factors and environmental and mental health changes.

[Successful treatment with imatinib for a patient with myeloid neoplasms with eosinophilia and abnormalities of PDGFRB due to t (5;14)(q33;q22)].

A 50-year old man with a 1-year history of eosinophilia presented with an eosinophil count exceeding 13,800/mm3 in the peripheral blood at the first visit. Bone marrow examination revealed that eosinophils accounted for 30% of the nucleated cell count, and G-band karyotyping analysis detected t (5;14)(q33;q22). Using peripheral blood FISH test, he was found to have platelet-derived growth factor receptor ß (PDGFRB) locus rearrangement at 5q32-33. The level of eosinophils in the peripheral blood reduced markedly 3 days after the initiation of Imatinib mesylate, 400 mg daily. This treatment was administered for 2 years, after which the peripheral blood FISH test was negative for PDGFRB. In this disease, although most cases are with t (5;12), those with t (5;14) are relatively rare, and the long-term course of this translocation is unknown.

Development of a Unique T Cell Receptor Gene-Transferred Tax-Redirected T Cell Immunotherapy for Adult T Cell Leukemia.

Adult T cell leukemia/lymphoma (ATL) is an aggressive peripheral T cell neoplasm caused by infection with human T cell lymphotropic virus type-1 (HTLV-1). Its prognosis remains extremely poor. Tax, the most important regulatory protein for HTLV-1, is associated with the aggressive proliferation of host cells and is also a major target antigen for CD8+ cytotoxic T cells (CTLs). Based on our previous findings that Tax-specific CTLs with a T cell receptor (TCR) containing a unique amino-acid sequence motif exhibit strong HLA-A*24:02-restricted, Tax301-309-specific activity against HTLV-1, we aimed to develop a Tax-redirected T cell immunotherapy for ATL. TCR-ɑ/ß genes were cloned from a previously established CTL clone and transduced into peripheral blood mononuclear cells (PBMCs) of healthy volunteers using a retroviral siTCR vector. Then the cytotoxic efficacy against HTLV-1-infected T cells or primary ATL cells was assessed both in vitro and in vivo. The redirected CTLs (Tax-siCTLs) produced a large amount of cytokines and showed strong killing activity against ATL/HTLV-1-infected T cells in vitro, although they did not have universal activity against ATL cells. Next, in a xenograft mouse model using an HTLV-1-infected T cell line (MT-2), in all mice treated with Tax-siCTLs, the tumor rapidly diminished and finally disappeared without normal tissue damage, although all mice that were untreated or treated with non-gene-modified PBMCs died because of tumor progression. Our findings confirm that Tax-siCTLs can exert strong anti-ATL/HTLV-1 effects without a significant reaction against normal cells and have the potential to be a novel immunotherapy for ATL patients.

A pilot study to establish human T-cell leukemia virus type 1 (HTLV-1) carrier model using common marmoset (Callithrix jacchus).

BACKGROUND: For the diagnosis and treatment of adult T-cell leukemia/lymphoma (ATLL) caused by human T-lymphotropic virus type 1 (HTLV-1) are required therapeutic modalities urgently. Non-human primate models for ATLL would provide a valuable information for clinical studies. We did a pilot study to establish an ATLL non-human primate model using common marmosets (Callithrix jacchus). METHODS: We inoculated HTLV-1-producing MT-2 cells into 9-month-old marmosets, either intraperitoneally or intravenously. We next administrated MT-2 cells into 13-month-old marmosets under cyclosporine A (CsA) treatment to promote infection. HTLV-1 infection was determined by measuring HTLV-1 antibody titer in the common marmosets. RESULTS: The HTLV-1 antibody titer increased in the intraperitoneally inoculated marmoset with or without CsA treatment, and it kept over five 5 years though proviral copy number (proviral load, PVL) remained low throughout the study. CONCLUSION: We obtained HTLV-1 asymptomatic carriers of common marmosets by inoculating MT-2 cells.

[Case of Primary Mediastinal Non-Seminomatous Germ Cell Tumor with Pathological Complete Response after Induction Chemotherapy and Residual Tumor Resection Accompanied by Late-Onset Bilateral Pneumothorax].

A man in his late teens presented to our hospital with left-sided chest pain. CT showed a 12 cm sized anterior mediastinal tumor and tiny nodules in the bilateral lower lobe of the lungs. The patient also had elevated serum AFP and hCG levels. Pathological findings of the CT-guided biopsy specimen suggested a yolk sac tumor, and no testicular abnormality was seen on ultrasound. Following whole body examination, he was diagnosed with primary mediastinal non-seminomatous germ cell tumor. After sperm cryopreservation, 4 courses of BEP(bleomycin[BLM]plus etoposide[ETP]plus cisplatin[CDDP]) chemotherapy were administered to normalize the tumor markers. The mediastinal tumor shrank but was still widely in contact with the left pulmonary artery. He underwent mediastinal tumor resection and segmentectomy of the left upper lobe via a median sternotomy. The maximum tumor size was 9 cm in diameter, and pathological examination of the specimen revealed only an immature teratoma with no malignant findings. At the same time, both the lower lung nodules were resected and pathologically identified as intrapulmonary lymph nodes. No recurrence was observed, but 6 months after surgery, he made an emergency visit to our department due to dyspnea. Bilateral pneumothorax was detected, and chest tube insertion was rapidly performed that improved with only right chest drainage. Cytology of the right hemorrhagic pleural effusion showed no evidence of malignancy. It was possible that a postoperative right-to-left shunt of the anterior mediastinum was present, leading to bilateral pneumothorax.

[A Case of Philadelphia Chromosome-Positive Acute Myeloid Leukemia Extramedullary Recurrence in a Patient Undergoing Thoracoscopy for Massive Pleural Effusion].

A man in his early 70s visited a previous hospital because of pancytopenia and was diagnosed with acute myeloid leukemia based on a bone marrowexamination. The karyotype was 46,XY, t(9;22)(q34;q11.2)[2/20], and real-time polymerase chain reaction(PCR)revealed minor bcr-abl chimeric mRNA. Finally, the patient was judged as having Philadelphia chromosome- positive acute myeloid leukemia, and remission induction chemotherapy with the JALSG AML 201 protocol was initiated in combination with dasatinib to achieve complete remission. After 3 courses of consolidation chemotherapy, the anticancer drugs were discontinued because of deterioration of his general condition and renal insufficiency. Six months after the initial treatment, he was referred to our department, and no evidence of recurrence was confirmed on bone marrow examination. However, 2 months later, right massive pleural effusion was detected, and he was admitted to the department of pneumology at our hospital. Thoracoscopic pleural biopsy was performed at the time of chest tube insertion, and he was diagnosed with acute myeloid leukemia extramedullary recurrence. Peripheral myeloblasts appeared and increased rapidly, accompanied by further exacerbation of renal function; thus, he received palliative care at the department of hematology and oncology.

CD4+ CADM1+ cell percentage predicts disease progression in HTLV-1 carriers and indolent adult T-cell leukemia/lymphoma.

We recently took advantage of the universal expression of cell adhesion molecule 1 (CADM1) by CD4+ cells infected with HTLV-1 and the downregulation of CD7 expression that corresponds with the oncogenic stage of HTLV-1-infected cells to develop a flow cytometric system using CADM1 versus CD7 plotting of CD4+ cells. We risk-stratified HTLV-1 asymptomatic carriers (AC) and indolent adult T-cell leukemia/lymphoma (ATL) cases based on the CADM1+ percentage, in which HTLV-1-infected clones are efficiently enriched. AC and indolent ATL cases were initially classified according to their CADM1+ cell percentage. Follow-up clinical and flow cytometric data were obtained for 71 cases. In G1 (CADM1+ ≤ 10%) and G2 (10% < CADM1+ ≤ 25%) cases, no apparent clinical disease progression was observed. In G3 (25% < CADM1+ ≤ 50%) cases, five out of nine (55.5%) cases progressed from AC to smoldering-type ATL. In G4 (50% < CADM1+ ) cases, the cumulative incidence of receiving systemic chemotherapy at 3 years was 28.4%. Our results indicate that the percentage of the CD4+ CADM1+ population predicts clinical disease progression: G1 and G2 cases, including AC cases, are stable and considered to be at low risk; G3 cases, including advanced AC cases and smoldering-type ATL cases based on the Shimoyama criteria, are considered to have intermediate risk; and G4 cases, which are mainly indolent ATL cases, are unstable and at high risk of acute transformation.

Social Capital and Dietary Intakes Following the 2011 Great East Japan Earthquake and Tsunami.

BACKGROUND: Previous studies have identified poor dietary intake as a health risk affecting survivors of the 2011 Great East Japan Earthquake and Tsunami. We examined the association between different social factors (eg, living conditions and perceptions of community social capital) and dietary intakes among disaster-affected survivors. METHODS: We studied 6,724 survivors in four municipalities of Iwate Prefecture 3 years after the disaster. Social capital was assessed via four items inquiring about respondents' perceptions of social cohesion in their communities. Good dietary intake was defined according to the following criteria: intake of staple food ≥three times a day; intake of meat, fish and shellfish eggs, or soybean products ≥twice a day; vegetable intake ≥twice a day; and intake of fruit or dairy products ≥once a day. An individual who did not meet any of these criteria was defined as having poor dietary intake. We adjusted for covariates, including socioeconomic status, marital status, and residential area. RESULTS: Poor dietary intake was reported by 31.6% of respondents. Poisson regression analyses revealed that the following factors were related to poor dietary intake: age <65 years (men: prevalence ratio [PR] 1.48; 95% confidence interval [CI], 1.29-1.71 and women: PR 1.55; 95% CI, 1.36-1.77), difficulties in living conditions (men: PR 1.18; 95% CI, 1.00-1.39 and women: PR 1.19; 95% CI, 1.01-1.40), and low perceptions of community social capital (women: PR 1.20; 95% CI, 1.04-1.38). CONCLUSIONS: Our findings suggest that social capital plays a role in promoting healthy dietary intake among women in disaster-affected areas.

Circulating microRNAs (miR-126, miR-197, and miR-223) are associated with chronic kidney disease among elderly survivors of the Great East Japan Earthquake.

BACKGROUND: A recent study has reported that incidence of chronic kidney disease (CKD) is higher in evacuees, but the molecular mechanism still remains unclear. One plausible hypothesis is a change in vascular function following to psychological distress. In order to assess molecular mechanisms underlying this association, we examined whether cardiovascular disease (CVD)-associated miRNAs (miR-126, miR-197, and miR-223) were associated with CKD among Japanese elderly survivors after an earthquake. METHODS: We analyzed 1385 individuals (670 men and 715 women) who participated in a post-disaster health check-up after the Great East Japan Earthquake, which occurred in 2011. The check-up involved collection of information about lifestyle, clinical history, the degree of housing damage, and baseline measurement of the estimated glomerular filtration rate. Expression levels of miRNAs were determined using real-time polymerase chain reaction. Estimated glomerular filtration rate (eGFR) was calculated using sex, age, and serum creatinine. CKD was defined as eGFR < 60 ml/min/1.73m2. The multivariable regression analyses were performed to examine the associations between CVD-associated miRNAs and CKD after adjusting potential confounders. RESULTS: Mean age (standard deviation) of participants with normal kidney function and CKD was 62.7 (10.6) and 71.9 (8.1) years, respectively. Expression levels of these miRNAs in participants with CKD were significantly lower than normal kidney function (all p < 0.001). Even after adjusting for lifestyle, clinical profiles, and psychological distress, significant associations between three miRNAs and CKD still remained. A significant linear association between the cumulative score of these miRNAs and CKD was found (p = 0.04). CONCLUSIONS: This cross-sectional study suggested that CVD-associated miRNAs were an important factor of CKD in an elderly Japanese population after earthquake. Future studies need to examine this association in longitudinal dataset.

A Unique T-Cell Receptor Amino Acid Sequence Selected by Human T-Cell Lymphotropic Virus Type 1 Tax301-309-Specific Cytotoxic T Cells in HLA-A24:02-Positive Asymptomatic Carriers and Adult T-Cell Leukemia/Lymphoma Patients.

We previously reported that the T-cell receptor (TCR) repertoire of human T-cell lymphotropic virus type 1 (HTLV-1) Tax301-309-specific CD8+ cytotoxic T cells (Tax301-309-CTLs) was highly restricted and a particular amino acid sequence motif, the PDR motif, was conserved among HLA-A*24:02-positive (HLA-A*24:02+) adult T-cell leukemia/lymphoma (ATL) patients who had undergone allogeneic hematopoietic cell transplantation (allo-HSCT). Furthermore, we found that donor-derived PDR+ CTLs selectively expanded in ATL long-term HSCT survivors with strong CTL activity against HTLV-1. On the other hand, the TCR repertoires in Tax301-309-CTLs of asymptomatic HTLV-1 carriers (ACs) remain unclear. In this study, we directly identified the DNA sequence of complementarity-determining region 3 (CDR3) of the TCR-ß chain of Tax301-309-CTLs at the single-cell level and compared not only the TCR repertoires but also the frequencies and phenotypes of Tax301-309-CTLs between ACs and ATL patients. We did not observe any essential difference in the frequencies of Tax301-309-CTLs between ACs and ATL patients. In the single-cell TCR repertoire analysis of Tax301-309-CTLs, 1,458 Tax301-309-CTLs and 140 clones were identified in this cohort. Tax301-309-CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-ß CDR3, was exclusively observed in all ACs and ATL patients. However, there was no correlation between PDR+ CTL frequencies and HTLV-1 proviral load (PVL). In conclusion, we have identified, for the first time, a unique amino acid sequence, PDR, as a public TCR-CDR3 motif against Tax in HLA-A*24:02+ HTLV-1-infected individuals. Further investigations are warranted to elucidate the role of the PDR+ CTL response in the progression from carrier state to ATL.IMPORTANCE ATL is an aggressive T-cell malignancy caused by HTLV-1 infection. The HTLV-1 regulatory protein Tax aggressively promotes the proliferation of HTLV-1-infected lymphocytes and is also a major target antigen for CD8+ CTLs. In our previous evaluation of Tax301-309-CTLs, we found that a unique amino acid sequence motif, PDR, in CDR3 of the TCR-ß chain of Tax301-309-CTLs was conserved among ATL patients after allo-HSCT. Furthermore, the PDR+ Tax301-309-CTL clones selectively expanded and showed strong cytotoxic activities against HTLV-1. On the other hand, it remains unclear how Tax301-309-CTL repertoire exists in ACs. In this study, we comprehensively compared Tax-specific TCR repertoires at the single-cell level between ACs and ATL patients. Tax301-309-CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-ß CDR3, was conserved in all ACs and ATL patients, regardless of clinical subtype in HTLV-1 infection.

Polycomb-dependent epigenetic landscape in adult T-cell leukemia.

Adult T-cell leukemia-lymphoma (ATL) shows global gene expression alterations that confer cellular characteristics and unfavorable prognosis. However, molecular mechanisms of the sustained expression changes are largely unknown, because there is no study addressing the relationship between landscapes of the gene expression and epigenetic modifications. Here, we analyzed ATL epigenome and integrated it with transcriptome from primary ATL cells and those from corresponding normal CD4(+)T cells to decipher ATL-specific "epigenetic code" that was critical for cell identity. We found that polycomb-repressive complex 2 (PRC2)-mediated trimethylation at histone H3Lys27 (H3K27me3) was significantly and frequently reprogrammed at half of genes in ATL cells. A large proportion of the abnormal gene downregulation was detected at the early stage of disease progression and was explained by H3K27me3 accumulation. The global H3K27me3 alterations involved ATL-specific gene expression changes that included several tumor suppressors, transcription factors, epigenetic modifiers, miRNAs, and developmental genes, suggesting diverse outcomes by the PRC2-dependent hierarchical regulation. Interestingly, a key enzyme, EZH2, was sensitive to promiscuous signaling network including the NF-κB pathway and was functionally affected by human T-cell leukemia virus type I (HTLV-1) Tax. The Tax-dependent immortalized cells showed H3K27me3 reprogramming that was significantly similar to that of ATL cells. Of note, a majority of the epigenetic silencing has occurred in leukemic cells from indolent ATL and also in HTLV-1-infected T cells from asymptomatic HTLV-1 carriers. Because pharmacologic inhibition of EZH2 reversed epigenetic disruption and selectively eliminated leukemic and HTLV-1-infected cells, targeting the epigenetic elements will hold great promise in treatment and prevention of the onset of ATL and HTLV-1-related diseases.