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BACKGROUND: Adolescents and young adults (AYAs) represent a small proportion of patients with cancer. The genomic profiles of AYA patients with cancer are not well-studied, and outcomes of genome-matched therapies remain largely unknown. PATIENTS AND METHODS: We investigated differences between Japanese AYA and older adult (OA) patients in genomic alterations, therapeutic evidence levels, and genome-matched therapy usage by cancer type. We also assessed treatment outcomes. RESULTS: AYA patients accounted for 8.3% of 876 cases. Microsatellite instability-high and/or tumor mutation burden was less common in AYA patients (1.4% versus 7.7% in OA; P = 0.05). However, BRCA1 alterations were more common in AYA patients with breast cancer (27.3% versus 1.7% in OA; P = 0.01), as were MYC alterations in AYA patients with colorectal cancer (23.5% versus 5.8% in OA; P = 0.02) and sarcoma (31.3% versus 3.4% in OA; P = 0.01). Genome-matched therapy use was similar between groups, with overall survival tending to improve in both. However, in AYA patients, the small number of patients prevented statistical significance. Comprehensive genomic profiling-guided genome-matched therapy yielded encouraging results, with progression-free survival of 9.0 months in AYA versus 3.7 months in OA patients (P = 0.59). CONCLUSION: Our study suggests that tailored therapeutic approaches can benefit cancer patients regardless of age.
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INTRODUCTION: Oral frailty leads to poor nutritional status, which, in turn, leads to frailty. This cross-sectional study aimed to determine regional differences in the prevalence of oral frailty and to identify factors associated with oral frailty using 3-level multilevel models. METHODS: This study comprised 165,164 participants aged ≥65 y without long-term care requirements in the Japan Gerontological Evaluation Study. The dependent variable was oral frailty, which was calculated based on age, number of teeth, difficulty in eating tough foods, and choking. The individual-level independent variables included sociodemographics, present illness, social participation, frequency of meeting friends, and social capital. The local district-level independent variable was social capital (n = 1,008) derived from exploratory factor analyses. The municipality-level independent variable was population density (n = 62). Three-level multilevel Poisson regression analysis was performed to calculate the prevalence ratios (PRs). RESULTS: The prevalence of oral frailty in municipalities ranged from 39.9% to 77.6%. Regarding district-level factors, higher civic participation was significantly associated with a lower probability of oral frailty. At the municipality level, the PR of the rural-agricultural area was 1.17 (95% confidence interval, 1.11-1.23) (reference: metropolitan). CONCLUSION: These results highlight the usefulness of oral frailty prevention measures in encouraging social participation in rural areas. KNOWLEDGE TRANSFER STATEMENT: The results of the present study showed regional differences in oral frailty. In particular, rural-agricultural areas show higher prevalence rates of oral frailty than those in metropolitan cities. Promoting measures of social participation among older adults may help prevent oral frailty in rural areas.
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Prior to the manufacture of new chemicals, regulations mandate a thorough review of the chemicals under risk management. This review involves evaluating their effects on the environment and human health. To assess these effects, a review report that conforms to the OECD Test Guidelines must be submitted to the regulatory body. One of the essential components of the report is an assessment of the biodegradability of chemicals in the environment. In addition to conventional methods, quantitative structure-activity relationship (QSAR) models have been developed to predict the properties of chemicals based on their structural features. Although a greater number of chemicals in the learning set may enhance the prediction accuracy, it may also lead to a decrease in accuracy due to the mixing of different structural features and properties of the chemicals. To improve the prediction performance, it is recommended to use only the appropriate data for biodegradability prediction as a training set. In this study, we propose a novel approach for the optimal selection of training set that enables a highly accurate prediction of the biodegradability of chemicals by QSAR. Our findings indicate that the proposed method effectively reduces the root mean squared error and improves the prediction accuracy.
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Aprendizado de Máquina , Relação Quantitativa Estrutura-Atividade , Humanos , Medição de RiscoRESUMO
Social participation prevents social isolation and loneliness among older adults while having numerous positive effects on their health and well-being in rapidly aging societies. We aimed to estimate the effect of retaining more natural teeth on social participation among older adults in Japan. The analysis used longitudinal data from 24,872 participants in the Japan Gerontological Evaluation Study (2010, 2013, and 2016). We employed a longitudinal modified treatment policy approach to determine the effect of several hypothetical scenarios (preventive scenarios and tooth loss scenarios) on frequent social participation (1 = at least once a week/0 = less than once a week) after a 6-y follow-up. The corresponding statistical parameters were estimated using targeted minimum loss-based estimation (TMLE) method. Number of teeth category (edentate/1-9/10-19/≥20) was treated as a time-varying exposure, and the outcome estimates were adjusted for time-varying (income, self-rated health, marital status, instrumental activities of daily living, vision loss, hearing loss, major comorbidities, and number of household members) and time-invariant covariates (age, sex, education, baseline social participation). Less frequent social participation was associated with older age, male sex, lower income, low educational attainment, and poor self-rated health at the baseline. Social participation improved when tooth loss prevention scenarios were emulated. The best preventive scenario (i.e., maintaining ≥20 teeth among each participant) improved social participation by 8% (risk ratio [RR] = 1.08; 95% confidence interval [CI], 1.05-1.11). Emulated tooth loss scenarios gradually decreased social participation. A hypothetical scenario in which all the participants were edentate throughout the follow-up period resulted in a 11% (RR = 0.89; 95% CI, 0.84-0.94) reduction in social participation. Subsequent tooth loss scenarios showed 8% (RR = 0.92; 95% CI, 0.88-0.95), 6% (RR = 0.94; 95% CI, 0.91-0.97), and 4% (RR = 0.96; 95% CI, 0.93-0.98) reductions, respectively. Thus, among Japanese older adults, retaining a higher number of teeth positively affects their social participation, whereas being edentate or having a relatively lower number of teeth negatively affects their social participation.
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Perda de Dente , Humanos , Masculino , Idoso , Perda de Dente/epidemiologia , Atividades Cotidianas , Saúde Bucal , Renda , Envelhecimento , JapãoRESUMO
Tooth loss is a risk factor for increased mortality; however, the underlying mechanism remains unclear. This study aimed to evaluate the mediating effect of weight change on the relationship between tooth loss and mortality risk. This was a 10-y follow-up prospective cohort study using the data from the Japan Gerontological Evaluation Study (JAGES). The participants were independent older adults aged ≥65 y at baseline and were followed up from 2010 to 2020. The incidence of death in 2013 and 2020, incidence of >5% weight loss/gain in 2010 and 2013, and the number of remaining teeth in 2010 were used as the outcome, mediator, and explanatory variables, respectively. We conducted causal mediation analysis by fitting the Cox proportional hazard model, including possible confounders. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) of the total effect (TE), natural indirect effect (NIE), and proportion mediated (PM) were estimated. Among the 34,510 participants, the mean age was 72.6 (SD = 5.4) y, and 47.6% were men. From 2013 to 2020, 14.0% of the participants (n = 4,825) died, 60.5% (n = 20,871) had 0 to 19 remaining teeth, and 17.2% (n = 5,927) and 8.4% (n = 2,907) experienced >5% weight loss and gain, respectively. The mortality rate was 0.016 per person-year among those with ≥20 remaining teeth and 0.027 per person-year among those with 0 to 19 remaining teeth. Weight loss of >5% significantly mediated the association between tooth loss and higher mortality risk (TE: HR, 1.28 [95% CI, 1.16 to 1.40]; NIE: HR, 1.03 [95% CI, 1.02 to 1.04]; PM, 13.1%); however, we observed a slight mediating effect for >5% weight gain (NIE: HR, 1.003 [95%CI, 1.0001 to 1.01]; PM, 1.3%). The present study suggests that a clinically meaningful level of weight loss mediated the association between tooth loss and increased risk of mortality among independent older adults.
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Perda de Dente , Masculino , Humanos , Idoso , Feminino , Perda de Dente/epidemiologia , Estudos Prospectivos , Fatores de Risco , Japão/epidemiologia , MortalidadeRESUMO
Merkel cell carcinoma (MCC) is a rare malignant cutaneous neuroendocrine tumour affecting mainly elderly patients and is more common in the West than in Asia. It is associated with Merkel cell polyomavirus (MCPyV), immunosuppression, and ultraviolet light. In this study, we retrospectively investigated the first series of MCC from Taiwan and identified 19 cases from three tertiary centres. All patients were males with a median age of 67.5. Twelve (63%) cases occurred in the extremities, with one unique case presenting initially as nodal metastasis of unknown primary. Immunohistochemically, the great majority of tumours expressed CK20 (89%), synaptophysin (89%), and INSM1 (84%), with none positive for TTF1. Eleven (58%) cases were positive for MCPyV by immunohistochemistry (clone CM2B4). All patients were treated with excision, including four with additional radiotherapy and one with radiotherapy and chemotherapy. Nodal status and treatment modalities significantly affected survival. The median survival time of MCPyV-positive cases was much longer than the negative cases (median 40 vs. 10 months). In summary, we presented the first report on the clinicopathological features of MCC in Taiwan, with 58% cases associated with MCPyV. The prognosis of patients with MCPyV-positive tumours was better than those negative for MCPyV.
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Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Neoplasias Cutâneas , Idoso , Carcinoma de Célula de Merkel/patologia , Feminino , Humanos , Masculino , Infecções por Polyomavirus/complicações , Infecções por Polyomavirus/patologia , Prognóstico , Proteínas Repressoras , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , TaiwanRESUMO
OBJECTIVE: Low molecular weight compounds that reduce the expression of MMP13 at the mRNA level might serve as disease-modifying osteoarthritis (OA) drugs (DMOADs). The objective of this study was to identify a candidate DMOAD that targets MMP13 expression. DESIGN: High-throughput screening was performed to identify compounds that suppress inflammatory cytokine-induced MMP13 expression. Ingenuity pathway analysis (IPA) using isobaric tags for relative and absolute quantification (iTRAQ)-based proteomic analysis was conducted to identify signaling pathways related to cytokines. MMP13 expression in chondrocytes was evaluated through RT-qPCR and western blotting analyses. Additionally, 10-week-old mice were subjected to destabilization of the medial meniscus (DMM) surgery to induce OA and were sacrificed 12 weeks post-surgery for pathological examination. OA was evaluated using the OARSI scoring system. RESULTS: Colchicine was identified as a DMOAD candidate as it inhibited inflammatory cytokine-induced MMP13 expression in vitro, and the colchicine-administered mice with DMM presented significantly lower OARSI scores (adjusted P: 0.0242, mean difference: 1.6, 95% confidence interval (CI) of difference: 0.1651-3.035) and significantly lower synovial membrane inflammation scores (adjusted P: 0.0243, mean difference: 0.6, 95% CI of difference: 0.06158-1.138) than mice with DMM. IPA further revealed that components of the Rho signaling pathways are regulated by cytokines and colchicine. IL-1ß and TNF-α activate RAC1 and SRC signals, respectively, leading to the phosphorylation of PLC-γ1 and synergistic induction of MMP13 expression. Most notably, colchicine abrogates inflammatory cytokine-induced phosphorylation of PLC-γ1, leading to the induction of MMP13 expression. CONCLUSIONS: Colchicine is a potential DMOAD candidate that inhibits MMP13 expression and consequent cartilage degradation by disrupting the SRC/RAC1-phospho-PLCγ1-Ca2+ signaling pathway.
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Condrócitos/metabolismo , Colchicina/farmacologia , Metaloproteinase 13 da Matriz/efeitos dos fármacos , Fosfolipase C gama/metabolismo , Animais , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Osteoartrite , Fosforilação , RNA Mensageiro/metabolismo , Transdução de Sinais , Membrana Sinovial/patologiaRESUMO
The coronavirus disease 2019 (COVID-19) pandemic has led to economic contraction and significant restrictions on society. The shock to the economy could lead to a deterioration of physical health outcomes, including dental health. The present study investigated the association between worsened socioeconomic conditions due to the COVID-19 pandemic and dental pain in Japan. The mediating effects of psychological distress and oral health-related behaviors were also evaluated. Cross-sectional data from the Japan COVID-19 and Society Internet Survey conducted from August to September 2020 (n = 25,482; age range, 15-79 y) were analyzed. Multivariable logistic regression models were fitted to evaluate the independent associations of household income reduction, work reduction, and job loss due to the COVID-19 pandemic with dental pain within a month. Dental pain was reported by 9.8%. Household income reduction, work reduction, and job loss were independently associated with dental pain after adjusting for confounders (odds ratios: 1.42 [95% confidence interval (CI), 1.28-1.57], 1.58 [95% CI, 1.41-1.76], 2.17 [95% CI, 1.64-2.88], respectively). The association related to household income reduction was mediated by psychological distress, postponing dental visits, toothbrushing behavior, and between-meals eating behavior by 21.3% (95% CI, 14.0-31.6), 12.4% (95% CI, 7.2-19.6), 1.5% (95% CI, -0.01 to 4.5), and 9.3% (95% CI, 5.4-15.2), respectively. Our findings showed that worsened socioeconomic conditions due to the COVID-19 pandemic deteriorated dental health. Policies that protect income and job loss may reduce dental health problems after the pandemic.
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COVID-19 , Pandemias , Adolescente , Adulto , Idoso , Estudos Transversais , Humanos , Japão/epidemiologia , Pessoa de Meia-Idade , Dor , SARS-CoV-2 , Adulto JovemRESUMO
STUDY QUESTION: Is oocyte cryopreservation an applicable option for fertility preservation in unmarried patients with haematological malignancies? SUMMARY ANSWER: Oocyte cryopreservation via the vitrification method is accessible and may be considered an option for fertility preservation in unmarried patients with haematological malignancies. WHAT IS KNOWN ALREADY: Haematological malignancies are most commonly observed amongst adolescent and young adult women. Although the survival rate and life expectancy of those with haematological malignancies have improved, chemotherapy and radiotherapy may impair their reproductive potential. Oocyte cryopreservation is thus an ideal option to preserve their fertility. STUDY DESIGN SIZE DURATION: This study retrospectively evaluated 193 unmarried patients (age: 26.2 ± 0.4 years) with haematological malignancies, who consulted for oocyte cryopreservation across 20 different fertility centres in Japan between February 2007 and January 2015. The primary outcome measures were the oocyte retrievals and oocyte cryopreservation outcomes. The secondary outcome measures were the outcomes following oocyte warming for IVF. PARTICIPANTS/MATERIALS SETTING METHODS: The patients had commenced ovarian stimulation cycles via antagonist, agonist, natural and minimal methods for oocyte retrievals, defined according to the treatment strategy of each respective fertility centre. A vitrification method using the Cryotop safety kit was used for oocyte cryopreservation. ICSIs were used for insemination of warmed oocytes. The endometrial preparation method for embryo transfer was hormonal replacement therapy, except in the case of a patient who underwent a spontaneous ovulatory cycle. MAIN RESULTS AND THE ROLE OF CHANCE: Among 193 patients, acute myeloid leukaemia (n = 45, 23.3%) was most common, followed by acute lymphoid leukaemia (n = 38, 19.7%) and Hodgkin's lymphoma (n = 30, 15.5%). In total, 162 patients (83.9%) underwent oocyte retrieval, and oocytes were successfully cryopreserved for 155 patients (80.3%). The mean number of oocyte retrieval cycles and cryopreserved oocytes were 1.7 ± 0.2 and 6.3 ± 0.4, respectively. As of December 2019, 14 patients (9.2%) had requested oocyte warming for IVF. The survival rate of oocytes after vitrification-warming was 85.2% (75/88). The rates of fertilisation and embryo development were 80.0% (60/75) and 46.7% (28/60), respectively. Ten patients (71.4%) had successful embryo transfers, and seven live births (50.0%) were achieved. LIMITATIONS REASONS FOR CAUTION: This study was limited by its retrospective nature. Additionally, there remains an insufficient number of cases regarding the warming of vitrified oocytes to reliably conclude whether oocyte cryopreservation is effective for patients with haematological malignancies. Further long-term follow-up study is required. WIDER IMPLICATIONS OF THE FINDINGS: Oocyte retrieval and oocyte cryopreservation were accessible for patients with haematological malignancies; however, the number of oocyte retrievals may have been limited due to the initiation of cancer treatments. Acceptable embryonic and pregnancy outcomes could be achieved following oocyte warming; therefore, our results suggest that oocyte cryopreservation can be considered an option for fertility preservation in patients with haematological malignancies. STUDY FUNDING/COMPETING INTERESTS: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.
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Although they are known to share pathophysiological processes, the relationship between periodontitis and chronic obstructive pulmonary disease (COPD) is not fully understood. The aim of the present study was to test the hypothesis that periodontitis is associated with a greater risk of development of COPD, when smoking is taken into account. The analysis in a 5-y follow-up population-based cohort study was based on 900 community-dwelling Japanese adults (age: 68.8 ± 6.3 [mean ± SD], 46.0% male) without COPD aged 60 or older with at least 1 tooth. Participants were classified into 3 categories according to baseline periodontitis severity (no/mild, moderate, and severe). COPD was spirometrically determined by a fixed ratio of <0.7 for forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and by FEV1/FVC below the lower limit of normal. Poisson regression was used to calculate the relative risk (RR) of developing COPD according to the severity of periodontitis. The population attributable fraction (PAF) was also calculated. During follow-up, 22 (2.4%) subjects developed COPD. Compared with no/mild periodontitis subjects, a significantly increased risk of COPD occurred among severe periodontitis subjects (RR = 3.55; 95% confidence interval [CI], 1.18 to 10.67), but no significant differences were observed between the no/mild and moderate categories (RR = 1.48; 95% CI, 0.56 to 3.90). After adjustment for potential confounders, including smoking intensity, the relationship between severe periodontitis and risk of COPD remained significant (RR = 3.51; 95% CI, 1.15 to 10.74). Likewise, there was a positive association of periodontitis severity with risk of COPD ( P for trend = 0.043). The PAF for COPD due to periodontitis was 22.6%. These data highlight the potential importance of periodontitis as a risk factor for COPD.
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Periodontite , Doença Pulmonar Obstrutiva Crônica , Idoso , Estudos de Coortes , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , EspirometriaRESUMO
Chlorine resistant reverse osmosis (RO) membranes were fabricated using a multi-walled carbon nanotube-polyamide (MWCNT-PA) nanocomposite. The separation performance of these membranes after chlorine exposure (4800 ppm·h) remained unchanged (99.9%) but was drastically reduced to 82% in the absence of MWCNT. It was observed that the surface roughness of the membranes changed significantly by adding MWCNT. Moreover, membranes containing MWCNT fractions above 12.5 wt.% clearly improved degradation resistance against chlorine exposure, with an increase in water flux while maintaining salt rejection performance. Molecular dynamics and quantum chemical calculations were performed in order to understand the high chemical stability of the MWCNT-PA nanocomposite membranes, and revealed that high activation energies are required for the chlorination of PA. The results presented here confirm the unique potential of carbon nanomaterials embedded in polymeric composite membranes for efficient RO water desalination technologies.
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Somatic G17V RHOA mutations were found in 50-70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1-STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1-STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1-STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA-VAV1 axis may provide a new therapeutic target in AITL.
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Linfadenopatia Imunoblástica/metabolismo , Linfoma de Células T/metabolismo , Proteínas Proto-Oncogênicas c-vav/metabolismo , Transdução de Sinais , Proteína rhoA de Ligação ao GTP/metabolismo , Biomarcadores Tumorais , Linhagem Celular Tumoral , Citocinas/metabolismo , Análise Mutacional de DNA , Humanos , Linfadenopatia Imunoblástica/genética , Linfoma de Células T/genética , Mutação , Fatores de Transcrição NFATC/metabolismo , Fosforilação , Ligação Proteica , Proteínas Proto-Oncogênicas c-vav/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Proteína rhoA de Ligação ao GTP/genéticaRESUMO
The purpose of this study was to clarify the effect of swallowing disorders on functional decline in community-dwelling older adults receiving home care. This was a 1-year follow-up survey of 176 individuals ≥60 years living at home and receiving homecare services, without total dependence in basic daily living activities, in two mid-sized municipalities in Fukuoka, Japan. Functional decline was measured using the Barthel index (BI), and the primary outcome was total dependence in basic daily living activities (BI ≤ 20 points). Swallowing function was assessed using cervical auscultation, and the primary predictor was swallowing disorders. Logistic regression models were used to assess univariate and multivariate associations between baseline swallowing function and functional decline during follow-up. During follow-up 16 (9.1%), the participants became totally dependent in basic daily living activities. The participants with swallowing disorders had 6.41 times higher odds of total dependence in basic daily living activities compared to participants with normal swallowing function. After adjusting for potential confounders, swallowing disorders were significantly associated with higher odds of total dependence in basic daily living activities (odds ratio = 5.21, 95% confidence interval = 1.33-20.44). Regarding swallowing disorders, the corresponding population attributable fraction (%) of the incidence of total dependence in basic daily living activities was 50.4%. The current findings demonstrated that swallowing disorders were associated with greater risk of functional decline in basic daily living activities among older adults living at home and receiving home nursing care. Maintenance and improvement of swallowing function may prevent late-life functional decline.
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Transtornos de Deglutição/epidemiologia , Avaliação Geriátrica , Serviços de Assistência Domiciliar , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Transtornos de Deglutição/fisiopatologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Vida Independente , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Folicular , Proteínas de Neoplasias/sangue , Receptores de Interleucina-2/sangue , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Humanos , Linfoma Folicular/sangue , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Rituximab , Taxa de Sobrevida , Vincristina/administração & dosagemRESUMO
The absolute peripheral blood lymphocyte count at diagnosis is known to be a strong prognostic factor in patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), but it remains unclear as to which peripheral blood lymphocyte population is reflective of DLBCL prognosis. In this cohort, 355 patients with DLBCL treated with R-CHOP from 2006 to 2013 were analyzed. The low absolute CD4+ T-cell count (ACD4C) at diagnosis negatively correlated with the overall response rate and the complete response rate significantly (P<0.00001). An ACD4C<343 × 106/l had a significant negative impact on the 5-year progression-free survival and the overall survival as compared with an ACD4C⩾343 × 106/l (73.7% (95% confidence interval (CI)=66.7-79.5) versus 50.3% (95% CI=39.0-60.6), P<0.00001 and 83.3% (95% CI=77.1-88.0) versus 59.0% (95% CI=47.9-68.5), P<0.00000001, respectively). Multivariate analysis revealed that the ACD4C was an independent prognostic marker (hazard ratio=2.2 (95% CI=1.3-3.7), P<0.01). In conclusion, a low ACD4C at diagnosis served as an independent poor prognostic marker in patients with DLBCL.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prognóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/patologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Rituximab , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
Recent genetic analysis has identified frequent mutations in ten-eleven translocation 2 (TET2), DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 2 (IDH2) and ras homolog family member A (RHOA) in nodal T-cell lymphomas, including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified. We examined the distribution of mutations in these subtypes of mature T-/natural killer cell neoplasms to determine their clonal architecture. Targeted sequencing was performed for 71 genes in tumor-derived DNA of 87 cases. The mutations were then analyzed in a programmed death-1 (PD1)-positive population enriched with tumor cells and CD20-positive B cells purified by laser microdissection from 19 cases. TET2 and DNMT3A mutations were identified in both the PD1+ cells and the CD20+ cells in 15/16 and 4/7 cases, respectively. All the RHOA and IDH2 mutations were confined to the PD1+ cells, indicating that some, including RHOA and IDH2 mutations, being specific events in tumor cells. Notably, we found that all NOTCH1 mutations were detected only in the CD20+ cells. In conclusion, we identified both B- as well as T-cell-specific mutations, and mutations common to both T and B cells. These findings indicate the expansion of a clone after multistep and multilineal acquisition of gene mutations.
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Biomarcadores Tumorais , Linfoma Extranodal de Células T-NK/genética , Mutação , Alelos , Substituição de Aminoácidos , Linfócitos B/metabolismo , Linfócitos B/patologia , DNA Metiltransferase 3A , Rearranjo Gênico do Linfócito T , Predisposição Genética para Doença , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imuno-Histoquímica , Imunofenotipagem , Linfoma Extranodal de Células T-NK/metabolismo , Linfoma Extranodal de Células T-NK/patologia , Especificidade de Órgãos/genética , Fenótipo , Análise de Sequência de DNA , Recombinação V(D)J , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
The total number of natural teeth was related to swallowing function among older adults; however, limited information is available regarding the impact of occluding pairs of teeth on swallowing function. This study aimed to examine the association between posterior teeth occlusion and dysphagia risk in older nursing home residents. This cross-sectional study included 238 residents aged ≥60 years from eight nursing homes in Aso City, Japan. Swallowing function was evaluated using the modified water swallowing test (MWST); the primary outcome was dysphagia risk (MWST score ≤3). Posterior teeth occlusion was assessed using number of functional tooth units (FTUs), determined based on number and location of the remaining natural and artificial teeth on implant-supported, fixed or removable prostheses. Univariate and multivariate logistic regression analyses were performed to examine the association between posterior teeth occlusion and dysphagia risk, adjusted for the covariates of number of natural teeth, demographic characteristics, comorbidities, physical function, body mass index and cognitive function. Of the 238 subjects, 44 (18·5%) were determined to be at risk of dysphagia based on the MWST scores. The odds ratio (OR) of dysphagia risk decreased in subjects with higher total FTUs [OR = 0·92, 95% confidence interval (CI) 0·87-0·98]. After adjusting for covariates, this association remained significant (OR = 0·90, 95% CI 0·84-0·97). Loss of posterior teeth occlusion was independently associated with dysphagia risk in older nursing home residents. Maintaining and restoring posterior teeth occlusion may be an effective measure to prevent dysphagia.
Assuntos
Transtornos de Deglutição/fisiopatologia , Comportamento Alimentar/fisiologia , Casas de Saúde , Perda de Dente/fisiopatologia , Idoso de 80 Anos ou mais , Estudos Transversais , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/prevenção & controle , Diagnóstico Precoce , Feminino , Avaliação Geriátrica , Humanos , Japão/epidemiologia , Masculino , Higiene Bucal , Medição de Risco , Perda de Dente/complicaçõesRESUMO
We herein investigated, using a corticotropin-releasing factor (CRF) agonist and antagonists, whether CRF plays a role in the pathogenesis of ischemia/reperfusion-induced small intestinal lesions in rats. Under pentobarbital anesthesia, the superior mesenteric artery was clamped (ischemia) for 75 min, followed by reperfusion with removal of the clamp. After a 24-h reperfusion, the area of hemorrhagic lesions that developed in the small intestine was measured. Urocortin I (CRF receptor 1/2 agonist), astressin (CRF receptor 1/2 antagonist), NBI27914 (CRF receptor 1 antagonist), or astressin 2B (CRF receptor 2 antagonist) was administered i.v. twice: 5 min before ischemia and 6 hours after reperfusion. Ischemia/reperfusion caused hemorrhagic lesions in the small intestine in ampicillin- and aminoguanidine-inhibitable manners, accompanied by enterobacterial invasion and the up-regulation of inducible nitric oxide synthase expression and myeloperoxidase activity. The severity of ischemia/reperfusion-induced lesions was significantly reduced by astressin and astressin 2B, but not by NBI27914, with the suppression of bacterial invasion, myeloperoxidase activity, and inducible nitric oxide synthase expression. In contrast, urocortin I markedly aggravated these lesions, and this response was completely abrogated by the co-administration of astressin 2B, but not NBI27914. The gene expression of CRF, CRF receptor 1, and CRF receptor 2 was observed in the small intestine, and remained unchanged following ischemia/reperfusion. These results suggest that ischemia/reperfusion caused hemorrhagic lesions in the small intestine, the pathogenesis of which involved enterobacteria and inducible nitric oxide synthase/nitric oxide. These lesions were aggravated by urocortin I in an astressin 2B-inhibitable manner, but suppressed by astressin in a CRF receptor 2-dependent manner. Endogenous CRF may be involved in the pathogenesis of ischemia/reperfusion-induced enteritis, possibly via the activation of peripheral CRF receptor 2.